CA1331379C - Pregnane derivatives - Google Patents

Abstract

Abstract The present invention provides novel pregnane derivatives of the formula:

Description

TITLE OF THE INVENTION

Pregnane derivatives BACKGROUND OF THE INVENTION
Field of the Invention The pr.esent invention relates to novel pregnane .

derivatives. .
The pregnane derivatives according to the inven-:~ tion are of value as synthetic intermediates for the production of vitamin D3 derivatives having a hydroxy .
group in the la-position, such as la-hydroxy-vitamin ~
.........
D3, which are known to be effective in the treatment of disorders of calcium metabolism such as chronic renal failure, dysparathyroidism, osteomalacia, osteoporosis and so on. ~ ~
Description of the Related Art ; ~.
The hitherto-known processes for producing vitamin D3;derivatives having a hydroxy group in the la-position ~ -include, for example, the process for producing la-hydroxy-vitamin D3 ~lsing~cholesterol 2s a starting material (U.S. Patents Nos. 3,741,996 and 3,901,928), the pxocess f~r produc.ing la,25-.dihydro- , ;~
xy- vitamin D3 using cholesta-1,5,7-trien-3-on-25-ol .;.
derived:from cholesta- 1,4,6-trien-3-on-25-ol as a synthetic intermediate (Japanese Patent Applicatior. .:~
La1d-open No. 5I-1000563,. and the process for produc~

,,,

- 2 - 133~379 ing (24R)-1,24,25-trihydroxy-vitamin D3 by subjecting (24R)-la,3~,24,25-tetrahydroxycholesta-5,7-diene to ultraviolet irradiation in an inert organic solvent and, then, isomerizing the resulting (24R)-la, 24, i:
25-tr~hydroxy-previtamin D3 (Japanese Patent Applica-tion Laid-open No. 51-108046). It is also known that certain pregnane derivatives, such as (20S)-lar3B-diacetoxypregn-s-ene-2o-carbaldehyde~ etc., which are ~;
derived fxom (20S)-21-hydroxy-20-methyl-6~-methoxy-3a,5-cyclo-Sa-pregnane, (20S)-21-hydroxy-20-methyl-pregna-1,4-dien-3-one, etc. by the processes shown ;" ~ ~
~3i~; ~ below can be converted to la,25-dihydroxy-vitamin D3 and other compounds (U.S. Patent No. 4,193,921). ~-;-...
,, " , , , , ! ~ . ! ' ~' `
~','~ .
~, ~:, ~c~

Z Z ~ E

O =~ Q~ ~-1 .~1 . .~

Q ~' ~

n O O ¦ a ¦ # ~ ~ I ~ ;

~,:
.

- 4 - 1~3~3~9 `
, .. .. . .

~OH

~22 0 H20, CH30H

~':

OH - I~ OJ

0 ~ p-Toluenesulfonic acid, benzene :~

0~

",~o--THP

Li, NH3 NaBH4 (C2HS)2 CH30H ~

O ~:
f o TH~

~ I !' '' (Ac)2o E~O~ ~ N~}N(CH3)2 'i'2~' . ~ Pyridine :

,.: :
~: .

,~: . , .
~ -;':
~r - - - .. ., .. , .. ,,: . .. . ..

_ 5_ 13~.37 ,-.. -` . :.

:, f ` ' AcO ~\, ~i H20 AcO . AcOH

~OH
~ AcO ~ Dimethyl sulfoxide :~
.~ ~ I ~ N = C = N

AcO ~ ~3ridi2ne Benzene "~CHO

AcO
HOOC-COOH
~ , r T
Ether AcO

: In~tbe above formulas, Tnp is a 2-tetrahydropyranyl ~: group; Ac is an acetyl group: the dotted line (~
indicates that thé su~stituent is in the i~-configuration:
the solid line I - ) indi~cates that the substituent is in the B-configurati~n: the wavy line ( ~ 3 indi~ates ~' .

133~.3~

that the substituent is either in the a-configuration or in the ~-configuration There is also known a process by which la,25,26-trihydroxy-vitamin D3 is synthesized from the afore-mentioned (20s)-la,3B-diacetoxypregn-5-ene-20-carb-~ aldehyde (U.S. Patent No. 4,407,754) ;~ While a variety of processes are thus known for the production of vitamin D3 derivatives having a hydroxy group in the la-position, it is obviously preferable that, in the production of such vitamin D3 dexivatives having a hydroxy group in the l~-position, one have as many compounds as possible to choose from as synthetic intermediates, for one would then enjoy the utmost flexibility in selecting the optimum process sequence according to the availability of starting compounds.
It is, therefore, an object of the invention to ;~
provide novel compounds which can be converted to various vitamin D3 derivatives having a hydroxy group in the l~-position. ~;
~ ~ It i5 another object of the invention to provide -~ processes for producing such novel compounds.
SUMMARY OF THE INVENTION
The aforementioned objects of the present "j, ~
. ~"

,-':

133~.37~ :

invention are accomplished by providing pregnane derivatives of the following general formula x l ~:~ , ~X2 ';
~ ~ D ~
A ~ (I) ~ ~
D3D'D5 ' ~:

wherein Al is in the a-configuration and represents a ;~
hydrogen atom or a hydroxyl group, and A2 i9 such that where Al is in the a-configuration and represents a ;hyd:rogen atOm,~A2 is in the ~-configuration and repre-sents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy gr~oup, an N-arylcarbamoyloxy group, an N,N-di(lower alkylicarbamoyloxy~group, a tri-substituted silyloxy ~:
group or an alkoxymethoxy group which may optionally be substituted and ~that where Al is in the ~-configuration and represents a hydroxyl group, A2 is in the ~-configura--i~ tion and represents a hydrogen atom, or Al and A2 :~
jointly represent an oxo group (=O); Dl is in the a-conflgurat1on~and~represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower a~lkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a ~, ~, .
";
- : :

13~ 37~ :

tri-substituted silyloxy group or an alkoxymethoxy group which may optionally be substituted, and D2 is in the a-configuration and represents a hydrogen atom, or Dl and D2 jointly represent an epoxy group (-O-) which is in the a-configuration or a single bond; D3 is in the ~-configuration and represents a hydroqen atom, D4 is in the a-configuration and re~resents a hydroxyl group, D is in the ~-configuration and represents a hydrogen atom, D6 is in the a-configuration and repre-sents a hydroxyl group, a lower alkoxycarbonyloxy group, an acyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarb~moyloxy group or an N,N-di(lower alkyl)- :

carbamoyloxy group, D7 is in the ~-configuration and repre~ents a hydrogen atom; provided that D3 and D4 may jointly represent an epoxy group ~-0-) which is in-the -configuration or a single bond, D4 and D5 may jointly represent a single bond, D5 and D6 may jointly represent an epoxy group (-O-) which is in the ~-configuration or a single bond, and D6 and D7 may jointly represent a single bond; and Xl and x2 each ! ':
is a lower alkoxyl group or jointly represent a lower :
alkylenedioxy group or an oxo group (=O); and the production processes described hereinafter under (1) through (5).
(1) A process for producing a 7~-hydroxypregna-1,4-133~ 379 g . .
.

dien-3-one-20-carbaldehyde characterized by cultivating a microbe of the genus Alcaligenes which is capable of producing 7a-hydroxypregna-1,4-dien-3-one-20-carbaldehyde by utilizing 3a~7~-dihydroxy-5B-cholanic acid and/or a salt thereof as a substrate, in a medium containing 3a,7~-dihydroxy-5~-cholanic acid and/or a salt thereof. -(2) A process for producing a pregnane derivative.. of ~:
the general formula X3 :~

HO

HO' ~
OH
wherein X3 and X4 have the meanings defined hereinafter, characterized by reducing a pregnane derivative of the , ;~ general formula :~: 3 ~ X
:~ ~X4 .
O

A~
" Al2 ~o ~. wherein All is in the ~-configuration and represents a ::

~.. ' ' 1333 37~

,~
..

hydrogen atom, and A12 is in the B-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group or an N,N-di(lower alkyl)carbamoyloxy group, or All and A12 jointly represent an oxo group (=O); and X3 and X4 each is a , lower alkoxyl group or jointly represent a lower i alkylenedioxy gxoup. ;
¦~ (3) A process for producing a pregnane derivative of the general formula , ~ A ~H

wherein A13, X3 and X4 have the meanings defined y~ : hereinafter, characterized by reducing a pregnane derivative of the general formula 4 .

A~

i~, . , ~ :

5,~ ' '''`' ` '"' ' ~' ', :: :` . ' .' " ` , ' ` .' ' 133~ 37~

...., . ,~

wherein A13 is in the ~-configuration and represents a tri-substituted silyloxy group or an alkoxymethoxy group which may optionally be substituted; X3 and X4 have the meanings defined he~einbefore.
(4) A process for producing a pregnane derivative of the general formula ~ Xl ' ~
~ ~X7 A~
.,;
wherein A14, D1~6, Xl and x2 have the meanings defined hereinafter, characterized in that a pregnane derivative of the general formula .
Xl l6r ~

3 ~ ~ : A~H ~

:~ wherein A14 is in the ~-configuration and represents a ,-~ hydroxyl group, an acyloxy group, a lower alkoxycarbonyl-~ oxy group, an N-lower alkylcarbamoyloxy group, an ~s, ,~ - .
~ - ~ N-arylcarbamoyloxy group, an N,N-di (lower alkyl)carbamoyl~
~f'~

5~C ~
, .. . .

:~ :

` 13~ 3~

'';'`' ' :' oxy group, a tri-substituted silyloxy group or an alkoxymethoxy group which may optionally be substituted;
D16 is in the a-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-aryl-carbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy ; group, a tri-substituted silyloxy group or an alkoxy-methoxy group which may optionally Be substituted; X
and X have the meanings defined hereinbefore, is subjected to dehydration reaction.
l5) A process for producing a pregnane derivative of the general formula ~ ~1 y~x 2 A

wherein Al5, A17, Xl and x2 have the meanings defined - hereinafter, characterized in that a pregnane derivative of the general formula :~
,~ 1 ` i - I ' ' ' ' " ' :
.^;: ~X2 ' ~,:
,.. ,,, D l7 1~
,~;^ ~,IJ

AI~J~Dl8 :
,~ , ;" ~33~ 37~

;
wherein Al5 is in the B-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyl-oxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carba-moyloxy group, a tri-substituted silyloxy group or an alkoxymethoxy group which may optionally be substituted;
Dl7 is in the a-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-aryl-carbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-substituted silyloxy group or a lower alkoxymethoxy group; D18 is in the a-configuration and ,. .
represents an acyloxy group, a lower alkoxycarbonyloxy ::
group, an N-lower alkylcarbamoyloxy group, an N-aryl-carbamoyloxy group or an N,N-di(lower alkyl)carbamoyloxy group; X and X~ have the meanings defined hereinbefore, is caused to react in the presence of a palladium compound.
DETAILED DESCRIPTION OF THE INVENTION -~
The pregnane derivatives of general formula (I) ; which are provided by the present invention can be roughly groupediinto a class of pregnane derivatives of the general formula .~.
~, ` X l ::
~X2 f ~- :

j, : ' ' ' ~ ~ ~ ., " ~ . . .. ~ : . .

- 14 - 133~37~

wherein Xl and x2 have the meanings defined hereinbefore (which compounds will hereinafter be referred to sometimes as pregnane derivative (I-l)); a class of pregnane derivatives of the general formula X' ~x2 8 ~ (I-2) D",~,LJ

wherein D8 and b9 jointly represent an epoxy group O-) which is in the ~-configuration or a single bond, :
and Xl and XZ have ~le meanings defined .:
hereinbefore (which compounds will hereinafter be referred to sometimes as pregnane derivative (I-2)J; a ~:
alass of pregnane derivatives of the general formula ~;

~ ~ X2 (I-3) - wherein A3 is in the a-configuration and represents a i.~, }i~ hydrogen atom, A4 is in the ~-configuration and represents ~ a hydroxyl group or a lower alkanoyloxy group, or A3 ~-~

.. ,, ~ , " ,:
:, .

133~ 3~

and A4 jointly represent an oxo group (=0); and Xl and X have the meanings defined hereinbefore (which --compounds will hereinafter be referred to sometimes as pregnane derivative (1-3)); a class of pregnane deri-vatives of the general formula Xl ~ ~ ~2 (;I-4) ~' DI

wherein A5 is in the ~-configuration and represents a hydroxyl group or a lower alkanoyloxy group; D10 is in the ~-configuration and represents a hydroxyl group, a lower alkoxycarbonyloxy group, a lower alkanoyloxy . ~ group, an N-lower alkylcarbamoyloxy group, an N-aryl-: carbamoyloxy group or an N,N-di(lower alkyl)carbamoyl- :~
~ ~ oxy group, and Dll is in the ~-configuration and repre-r`~ sents a hydrogen atom,--or DlO and Dll jointly represent .,~.
a single bond; and Xl and x2 have the meanings defined hereinbefore (which compounds will hereinafter be referred to sometimes as pregnane derivative ~I-4)); a class of pregnane derivatives of the general formula : ~ :

, :
..~

~. ,, . ~ : . :: :. . . . .

133~ 379 ~1 ~x2 Dl2 ~ (I-5) A6~ :

wherein A6 is in the ~-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyl-oxy group, an N-lower alkylcarbamoyloxy group, an :~:
N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carba- ;.~.
moyloxy group, a tri-substituted silyloxy group or an alkoxymethoxy group which may optionally be substituted;
12 ~ : ~
D is in the.~-configuration and represents a.hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoy70xy group, an N-aryl-:carbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group,~:a tri-substituted silyloxy group or an alkoxy- ~:
methoxy~group which may optionally be substituted and X and~X2 have:the meanings defined hereinbefore~ (which compounds will hereinafter be referred to sometimes as pregnane derivative:(I-5)); a class of pregnane deriva-tives of the~general formula `~

- ~ 0 ~ ~ (I-6) . :

HO~

.. :-.

~ :

17 ~33~ 37~

wherein Xl and X have the meanings defined hereinbefore (which compounds will hereinafter be referred to sometimes as pregnane derivative tI-6? ); a class of pregnane derivatives of the general formula O." ~, 7~
~8 wherein A7 is in the -configuration and represents a :~
hydrogen atom or a hydroxyl group, and A8 is such that where A7 is a hydrogen atom in the ~-configuration, A8 ~ i ~
is in the ~-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxyca_bonyloxy group, an N-lower alkylcarbamoyloxy group, an N-aryl-: carbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy : :group, a tri-substituted silyloxy group or an alkoxy-methoxy group which may optionally be substituted and ~;
where A is a hydroxyl group in the ~-configuration, 5~ ~ A8 is in the B-configuration and represents a hydrogen ~:
` atom, or A7 and~A8 jointly represent an oxo:group ~=0);

and Xl and x2 have the meanings defined hereinbefore (which compounds will hereinafter be referred to sometimes as pregnane derivative (I-7)); a class of ~, ~' ~''` . ' ~.
5`,'~ ~
~;

- 18 - 133~37~
:

pregnane derivatives of the general :

formula xl ~2 D 13 ~ :`
~ (I-8 :: A9 ~

`~ OH

;~ wherein A9 is in the ~-configuration and represents a ~ hydroxyl group, an acyloxy group, a lower alkoxycarbonyl-~ oxy group, an N-lower alkylcarbamoyloxy group, an , N-arylcarbamoyloxy group, an N,N-di~lower alkyl)-carbamoyloxy group, a tri-substituted silyloxy group or an alkoxymethoxy group which may optionally be sub- .
stituted; Dl3 is in the ~-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxy-carbonyloxy group, an N-lower alkylcarbamoyloxy group, an~N-aryl~arbamoyloxy group,: an N,N-di(lower alkyl)-carbamoyloxy group, a tri-substituted silyloxy group or an alkoxymethoxy g~roup which may optionally be substituted;
and X and X have the meanings defined hereinbefore (which compounds will hereinafteribe referred to sometimes as pregnane derivative (I-8)); and a class of `;

pregnane derivatives~of the~general formula ~33~

~X?
Dl4 ~ ~ (I-9 ~JAq D 1S

wherein A10 is in the ~-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyl-oxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyl-oxy group, a tri-substituted silyloxy group or an alkoxymethoxy group which may optionally be substituted; ::~
D14 is in the ~-conflguration and represents a hydroxyl -::
~group, an acyloxy group, a lower alkoxycarbonyloxy ~
group, an N-lower alkylcarbamoyloxy group, an N-aryl- :~:
carbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy .
group, a tri-substituted silyloxy group or an alkoxy-methoxy group which may optionally be substituted; ~-D15 is in the -configuration and represents a hydroxyl group, an acyloxy group, a lower aIkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-aryl- ~: :
carbamoyloxy group or an N,N-di(lower alkyl)carbamoyloxy group; and Xl and X2 have the meanings defined herein-~:~
before twhLch compounds will hereinafter be referred to sometimes as pregnane derivative (I-9)).

~331 3~

.~ .
Referring to the above general formulas, A2, A , A , A , A , A9, A10, A12, A13 A14 AlS Dl D6 D10 D12 D13 D14, D15, D16, D17, D18, Xl, X2, X3 and X4 are explained in detail below.

The acyloxy group repxesented by A2, A6, A8, A ~ A ~ A ~ A14, AlS, Dl D6 D12 D13 D14 lS

D16, D17 or D18 is exemplified by lower alkanoyloxy groups such as acetoxy, propionyloxy, butyryloxy, valeryloXy, etc. and aroyloxy groups such as benzoyloxy, methylbenzoyloxy, naphthoyloxy and so on. The lower alkanoyloxy group represeted by A4, A5 or D10 is exemplified by acetoxy, propionyloxy, butyryloxy, valeryloxy and so on. The lower alkoxycarbonyloxy , ~ .
group represented by A ~ A ~ A , A9, A10, A12, A14 A15 Dl D6 D10 12 D13 D14 D15 D16 D17 or Dl8 is exemplified by methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyl-oxy, butoxycarbonyloxy and so on. The N-lower alkylcar-bamolyloxy group represented by A2 t A6, A8, A9, AlO, ~-~
A , A14, AlS, Dl, D6, Dl, D12 D13 D14 D15 D
D17 or D18 is exemplified by N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N-propylcarbamoyloxy, N-butylcar-bamoyloxy and so on. The N-arylcarbamoyloxy group represented by A2, A~6! A8, A9, A10, A12, A14, AlS, Dl, ~
D6 D10 D12 D13 D14, D15, D16, D17 or D18 is exemplified ~`

,, .
~" . :~
.,......................................................................... ~ .

.,, ,~

133~.37~

`' by N-phenylcarbamoyloxy, N-tolylcarbamoyloxy, N-naphthyl-ci~rbamoyloxy and so on. The N,N-di(lower alkyl)carba-~ moyloxy group represented by A2, A6, A8, A9, AlO, A12, 1 A , A , D , D , D12, D13, D14 DlS D16 D17 D18 exemplified by N,N-di(methyl)carbamoyloxy, N,N-di(ethyl)-carbamoyloxy, N,N-di(propyl)carbamoyloxy, N-ethyl-N-methylcarbamoyloxy and so on. The tri-substituted j~ silyloxy group represented by A2, A6, A8, A9, A10, A13, l~ A14 A15 Dl Dl2, D13, D14, Dl6 or Dl7 is exemp- -~

lified by trimethylsilyloxy, t-butyldimethylsilyloxy, ~-~ t-butyldiphenylsilyloxy, tripropylsilyloxy and so on.
The alkoxymethoxy group which may optionally be substituted, which is represented by A2, A6, A8, A9, A13 A14 A15 Dl D12, Dl3, D14, D16 or D , is exemplified by methoxymethoxy, ethoxymethoxy, propo-xymethoxy, butoxymethoxy, methoxyethoxymethoxy, tetra-,,~
ydropyranyloxy, tetrahydrofuranyloxy, methoxyisopropyl-oxy and so on. The lower alkoxy group represented by X , X2, X3 or X4 is exemplified by methoxy, ethoxy, pro-poxy, butoxy and so on. The lower alkylenedioxy group ~-- represented jointly by X and X and the lower aIkyl-- enedioxy group represented jointly by X3 and X4 are ;
-~ exemplified by ethylenedioxy, methylethylenedioxy, dimethylethylenedioxy, 1,2-dimethylethylenedioxy, trimethylenedioxy, 1-methyltrimethylenedioxy, .~

133~ 37~ ::

2-methyltrimethylenedioxy, 2,2-dimethyltrimethylenedioxy and so on.
The pregnane derivative of general formula (I) according to the invention can be produced by the following processes. The compounds of formula (I-l-l) :
and the compounds of general formula (I-1-2) [which will hereinafter be referred to sometimes as compound l-l) and compound (I-1-2), respectively] fall within the category of pregnane derivative (I-1). The compounds ~:
of general formula (I-2-1) and the compounds of general formula (I-2-2) [which will hereinafter be referred to ~:
. .
~:~ sometimes as compound (I-2-1) and compound (I-2-2), ~
, . , respectivelyl are subsumed in the category of pregnane ~` derivative (I-2). The compounds of general formula (I-3-1), compounds of general formula (I-3-2) and . . ~ ..
compounds of general formula II-3-3) [which will hereinafter be referred to sometimes as compound (I-3-lj, compound (I-3-2) and compound (I-3-3), respect- ~
ively] are subsumed in the category of pregnane deri- ~ .
vative (I-3). The compounds of general formula II-4-l), compounds of general formula (I-4-2), compounds of general formulla ~I-4-3) and compounds of general formula (I-4-4) [which will hereinafter be referred to -~
sometimes as compound (I-4-1), compound (I-4-2), compound (I-4-3) and compound (I-4-4), respectively] ~
: ' ,,, , ~ ~
. . .

133~.3~

. .
are subsumed in the category of pregnane derivative (I-4). The compounds of general formula (I-5-1), compound of formula (I-5-2), compounds of general formula (I-5-3), compounds of general formula (I-5-4a), compounds of general formula (I-5-4b) and compounds of general formula (I-5-4c) [which will hereinafter be referred to sometimes as compound (I-S-l), compound (I-5-2), ~`
compound (I-5-3), compound (I-5-4a), compound (I-5-4b) an~ compound (I-5-4c), respectively] are subsumed in the category of pregnane derivative (I-5). The com-pounds of general formula (I-6-1) [which will herein-after be referred to sometimes as compound (I-6-1)] are subsumed in the category of pregnane derivative (I-6).
The compounds of general formula (I-7-1), compounds of general formula (I-7-2) and compounds of general formula (I-7-3) Lwhich will hereinafter be referred to sometimes as compound (I-7-1), compound (I-7-2) and compound (I-7-3), respectivelyl ~are subsumed in the category of pregnane derivative (I-7). The compounds of general formula (I-8-1), compounds of general formula (I-8-2) and compounds of general formula (I-8-3) [which will hereinafter bè~referréd to sometimes as compound 8-1), compound (I-8-2) and compound (I-8-3), respectively] are subsumed in the category of pregnane derivative (I-8). The compounds of general formula ~? '`, ~

- 24 - 13 3~ 3q~

(I-9-la), compounds of general formula (I-9-lb) and .
compounds of general formula (I-9-lc) [which will hereinafter be referred to sometimes as compound (I 9-la), compound (I-9-lb) and compo~lnd (I-9-lc), respectively] are subsumed in the category of pregnane derivative (I-9).
::

~ ~ !

,~

,, -," , ; ~ ! ` , '~`'~' ' ' , , " ~.

~: ' ' "~ ~ .

- 25 _ 1 33`~379~

- ~COORl ,, ' ; ~', ~ Biotransformation HO"~"OH -:~ ~ CHO

~ ' o~ OH

.~,.-.
~ ~ , ) Acetalization, dehydration Y
y2 -~

. ~ , ~ , i ! , . ~ ~ .

. yl ;' ~: = ~ y~ Dehydration OH
1-2) ~ , ~ - 26 -3 ~ 3 ~ ~
i .... . - .
yl . .
y~ y2 :: .

la,2a-Epoxidation ~- . (I-2-1) > (1-2-2) ,.,:~ Y' ~' y~y2 ~

6a,7a-EpoxidAtion ~
> ~ ~ ~-~"~ 3-1 ) ~ ,--~ ~ ~Redu~:tlon ~y2 ~;~

~ ,0 (1-3-2) ~ I ! y l ~y2 cylation Io~
'O (1-3-3) L ` 3 .:
j,-', :
" -! /

~ - 27 - 1 3 3 ~ 3 ~9 , -y Reduction O

'OH ( 1 - 4 -1 ~ y y2 ~ ~terification '' Zl ~ (1-4-2) ' I ,? y 1 ~
~ Conjugated diene formation ~ ~ y2 ,~JJ ( I-4-3 ) ,-Alcoholysis ~ ~2 ~ ~ HO~ ( ~_4_4~ ~

....
- ~-i,, - 28 - 133137~ ~
, " ; . ~ ,, , yl ,, ' Reduction HO ~ Y

~: HO' ~ ( I-S-l ) ~ i;
~, CEO
Deprotection HO ~ `

:HO~ ( I-5-2) ..., ~,~.
V l ~y 2 Reductlon 2-2~ HC~`'~ (l-6-l) ~ 4,5a-Epoxidation ~ y2 ~

~ ~ ~ HO` ~ ( I -7-1 ) ~ ~ `
~ , ,i`

,.,: :
"-~, ~Z,,: :
, , , .

~ 133~.379 ..

~; yl Oxidat~on O
(I-7-1) ~ ~ ~ ' ; ~ (1-7-2) .' O

:~- Reduction .. j , yl ~ ' Inversion , ~ y2 ;~ ~ Reduction ~ 1 ~ ~

~ Z30~ ~ ~
~ :~ . 'c5 ( I - 7- 3 ) ::
Reduc-~ : .-tion ~ . Reduction ~ -, ' ~ yl ~' ~ ~ y2 ~:
; ~ ~ l ~:
~ ( 1-8~

Pro- y .~ -, :~ tec-:; ~ tion ~ y2 ~.. . : , ~ Z30~
OH ( 1 - 8- 2 ) . -~ - 30 - ~33~37~ ~
....
y l y2 Protection Z -(I-8-1) , Protection ~ 8-2) > z30 ~ )H ( I-8-3 ) :
yl - ~ y2 ~
~: Z40 ~ :
I 8 ~njugated diene formation ~ ;~.
~: . yl z3 ~ ( !-5-3 ) ~i~ Rearrangement, ~ y2 1~ carbonic z40 ~ Conjugat -11 esterification - I I diene l ~: ~ ~ formation ¦ :
Z3~~~ Z; tl-9-1a) . ~:

Depro-tection r~ y l Z7 ~Y7 1 'onjugated diene Z60 OH (~-9-lb) Esterifi-.* cation~

240 ~y2 . ~' z a~oZ8 (l-9-lc) ¢- ~ -133~ 379 :
31- :
~i :` ~,CHO ~,~CHO ~:
I Z40 ~ ~ HO ~
~I-5-3) Deprotection ~ IDeprotection ~ ~

,. Z30 Z30 :

( I-S-4a) ( 1--5--4b ) ¦ DeprotectionZ40 f ~ Depro-~ t41C)on :
t : ~
Depro- :
tection- .

Deprotection Deprotection . . > (I-5-1) - > (I-5-2) ~ ~ :~

In~the above formulas, Rl is a hydrogen atom, an alkali metal atom or one-half of an alkaline earth : metal~atom;:Y and~Y each is a lower aIkoxyl group ::
or~j~ointly represent a lower alkylenedioxy group; zl ::
LS~ a lower alkanoyl group; z2 is a lower alkoxycarbonyl group, a lower alkanoyl group, an N-lower alkylcarbamo- ~:
yl: group,~an N-ar~ylcarbamoyl group or an N,N-di(lower alkyllcarbamoyl~group; Z3 and Z4 each is an acyl~
group, a lower alkoxycarbonyl group, an N-lower alkyl-:I carbamoyl group, anlN_airylcarbamoyl group, an N,N- ! ' ~i , : di~(lower alkyl)carbamoyl group, a tri-substituted silyl ~-.
: group:or~an~:alkoxymethyl group which may optionally be~

substitutéd Z5 is~a lower alkoxycarbonyl group; z6 ~ -' ~,, ~
~',. , ~':''-1 3 3 ~ 3 ~ ~

' '''`''' and Z7 each is a hydrogen atom, an acyl group, a lower alkoxycarbonyl group, an N-lower alkylcarbamoyl group, 1 an N-arylcarbamoyl group, an N,N-di(lower alkyl)carbamoyl ~ group, a tri-substituted silyl group or an alkoxymethyl ii o ~ group which may optionally be substituted; and Z~ is an s~ acyl group, an N-lower alkylcarbamoyl group, an N-aryl-Y~ carbamoyl group or an N,N-di(lower alkyl)carbamoyl i~ group.
The biotransformation (microbial transformation) i~ of 3,7~-dihydroxy-5~-cholanic acid (which will herein-after be referred to as chenodeoxycholic acid) and/or a salt thereof, which is represented by the general :
formula (II), into 7~-hydroxypregna-1,4-dien-3-one-20-carbaldehyde of formula (I-l-l) is accomplished by :~:
cultivating a microbe of the genus Alcaliqenes which is capable of producing 7~-hydroxypregna-1,4-dien-3-~ ~,. ~ ..
one-20-carbaldehyde by utilizing chenodeoxycholic acid -~:
and/or a salt thereof as a substrate, in a medium ~.
containing chenodeoxycholic acid and~or a salt thereof.
As an example of said microbe of the genus Alcaligenes being capable of producing 7~-hydroxypregna-1,4-dien- :~
3-one-20-carbaldehyde by utilizing chenodeoxycholic acid and/or a salt thereof as the substrate, there may be mentioned the strain Alcaliqenes faecalis D4020-R15 [deposited at Fermentation Research Institute, the Agency of Industrial Science and Technology, the ~, ~

~, .

," ~,," , s', .-. '" ' ' ", ',, ,- ' ,'. . . ,; ,- ' ...;:

i3~ 37~

Ministry of International Trade and Industry at 1-3, Higashi l chome, Tsukuba-shi, Ibaraki Prefecture, Japan (postal zone code 305) as of November 1, 1982 (transferred from FERM P-6300 dated January 4, 1982); deposit number FERM BP-204]. This strain is a mutant of the strain Alcaliqenes faecalis D4020 [deposited at Fermentation Research Institute, the Agency of Industrial Science and Technology, the Ministry of International Trade and Industry at 1-3, Higashi l chome, Tsukuba-shi, Ibaraki Prefecture, Japan (postal zone code 305) as of September 11, 1982 (trans-ferred from FE~M P-6298 dated January 4, 1982); deposit ,~, .. ~
number FERM BP-182] as derived by subjecting the parent strain to mutagenic treatment. The bacteriological characteristics of these strains are described in 5~
European Patent Publication No. o,oa7,787.

The aforesaid salt of chenodeoxy-cholic acid includes salts of chenodeoxycholic acid with alkali metals such as sodium, potassium, etc. or -with alkaline earth metals such as calcium, magnesium and so on. The concentration of chenodeoxycholic acid and/or a salt thereof in the medium may generally range from about 1 to about 200 g/l. However, in view of the production yield of 7-hydroxypregna-1,4-dien-3 5 '- : ~:
~ one-20-carbaldehyde, conditions for cultivation and ~ ~

, ~, ,:

~ - 34 - 133~7~
.. ..
economic efficiency such as operability, workability and so on, the concentration range of about 10 to 100 g/l is preferred. While the cultural methods that can j be employed are generally the same as those used fox aerobic culture of ordinary microorganisms, shake culture or submerged culture with aeration and agitation, using a liquid medium is usually adopted. Incorporated ~-in the medium are those nutrient sources which can be utilized by the microbe of the genus Alcaliqenes being capable of producing 7~-hydroxypregna-1,4-dien-3-one-20-carbaldehyde by utilizing chenodeoxycholic acid and/or a salt thereof as a substrate. In regard to ^~ carbon sources, chenodeoxycholic acid and/or a salt thereof may be used as a sole carban source or it may be used in combination with glucose, glycerin, peptone, meat extract, yeast extract and so on. As nitrogen sources, there may be employed various inorganic nitrogen sources such as ammonium sulfate, ammonium chloride, ammonium phosphate, ammonium nitrate, sodium nitrate, potassium nitrate, etc. and organic nitrogen sources such as polypeptone, peptone, meat extract and so on.~!In addition, inorganic salts such as potassium monohydrogen phosphate, potassium dihydrogen phosphate, magnesium sulfate, etc. are ~ incorporated in the medium. No specific cultural 1 ,~": ,.
1,,.

,-,", :
,~"~ ~

'' ~.

133~ 37~

conditions are required but generally shake culture orsubmerged culture with aeration and agitation is carried out at a temperature of about 25 to 30C for a period ranging from about 10 hours to about 7 ~ays.
The 7a-hydroxypregna-1,4-dien-3-one-20-carbaldehyde accumulated in the culture broth is markedly less soluble in water than is the substrate chenodeoxycholic acid or salt thereof and, therefore, generally separates out as a precipitate in the broth. The ~ -~
harvest of the accumulated 7a-hydroxypregna-1,4-dien-3-one-20-carbaldehyde can be accomplished, for example, by the following procedures. The insoluble fraction separated by centrifugation or filtration of the culture broth is rinsed with water, if necessary, to remove the residual chenodeoxycholic acid and/or salt thereof and, ,~
~ ~ then, extracted with an organic solvent capable of ;j" ~
dissolving 7a-hydroxypregna-1,4-dien-3-one-20-carbalde-hyde, such as a single solvent, e.g. ethyl acetate, !,,: ~
~-~ chloroform, methanol, etc., or a mixed solvent, e.g. a ,~. . ~
mixture of ethyl acetate and methanol, whereby an extract containin~ 7a-hydroxypregna-1,4-dien-3-one-20-carbaldehyde i;s obtained~ An alternative procedure comprises extracting the culture broth containing the precipitate and cells with an organic solvent which is capable of dissolving 7a-hydroxypregna-1,4-dien-3-one ~,.,`,C ~ ~

~` :
, - ., .-.

- 36 ~3~
.

20-carbaldehyde and is immiscible with water, such as a single solvent such as ethyl acetate, chloroform, etc.
or a mixed solvent such as a mixture of ethyl acetate and methanol to give an extract containing 7a-hydroxy-pregna-1,4-dien-3-one-20-carbaldehyde. From the extract obtained in any of the above manners, the microbial cells and other insoluble impurity are removed by centrifugation or filtration as required and, then, the organic solvent is distilled off to recover the desired 7-hydroxypregna-1,4-dien-3-one-20-carbaldehyde. The 7a-hydroxypregna-1,4-dien-3-one-20-carbaldehyde thus recovered contains substantially no residual substrate chenodeoxycholic acid or salt thereof or any byproduct, and, therefore, by subjecting it to recrystallization, for example from aqueous methanol, the object compound 7a-hydroxypregna-1,4-dien-3-one-20-carbaldehyde can be easily obtained in high purity.
; The conversion of 7a-hydroxypregna-1,4-dien-3-one-20-carbaldehyde (I-l-l) to compound (I-2-1) can be ~
accomplished by subjecting the 7~-hydroxypregna-1,4-dien- ~-3-one-20-carbaldehydeito dehydrative acetalization reaction or by the steps of acetalizing the 7a-hydroxy-pregna-1,4-dien-3-one-20-carbaldehyde to give the ~;
corresponding compound (I-1-2) and subjecting this compound (I-1-2) to dehydration reaction. The first-~, :
J', ',",' ' ~

.~ .

I - 37 - 1~3 ~ 37~
" -mentioned dehydrative acetalization reaction is accompli-shed by reacting 7~-hydroxypregna-l~4-dien-3-one~2o-carb-aldehyde and an acetalizing agent under reflux in an aromatic hydrocarbon solvent such as benzene, toluene, etc. in the presence of an acid catalyst such as p-toluenesul-fonic acid, pyridinium p-toluenesulfonate, camphorsulfonic acid, phosphorus tribromide, etc. under azeotropic dehydration conditions. The acetalizing agent is exemplified by lower alcohols such as methanol, ethanol, propanol, butanol, etc.; lower alkylene glycols includ-ing various ethylene glycols, e.g. ethylene glycol, 1,2-propanediol, 2-methyl-1,2-propanediol, 2,3-butanediol, etc. and trimethylene glycols, e.g. 1,3-propanediol, 1,3-butanediol, 2-methyl-1,3-propanediol, 3-methyl-1,3-butanediol, 2-methyl-1,3-butanediol, 2,2-dimethyl-1,3-propanediol, etc.; and lower alkylene acetals of ketones, such as 2-butanone ethylene acetal, 3-pentanone , ethylene acetal, 2-butanone(2,2-dimethyltrimethylene) acetal and so on. The second-mentioned procedure of conducting acetalization and dehydration reactions independently is carried out in the following manner.
Thl1s, 7-hydroxyp~egna-1,4-dien-3-one-20~carbaldehyde and a lower alcohol, a trimethylene glycol or the li~e, which is ~ ~.
among said acetalizing agents, are first reacted in a ~-halogenated hydrocarbon solvent, such as methylene ',',~

' ~ ' . ;' - 38 - ~33~37~

chloride, chloroform etc., in the presence of a dehyd-rating agent, such as molecular sieves, copper sulfate, etc., and an acid catalyst, such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, camphorsulfonic acid, etc., at a temperature of about 0 to 50C. The dehydrating agent is then removed from the resulting reaction mixture and the solvent is distilled off.
Then, the residue is subjected to a separation-purifica-~i tion procedure such as chromatography, recrystallization, etc. to recover compound (I-1-2). Then, this compound (I-1-2) is reacted under reflux in the same aromatic hydrocarbon solvent as mentioned above in the presence of an acid catalyst such as p-toluenesulfonic acid, camphorsulfonic acid, etc. under azeotropic dehydration conditions. In the dehydrative acetalization reaction and the acetalization reaction preceding the dehydration ^~
reaction, the~acetalizing agent is generally used in a ~;
proportion of about 2 to 10 moles, preferably about 2.5 ...,. ~ .
to 5 moles, per mole of 7~-hydroxypregna- 1,4-dien-3-one-20-carbaldehyde. The proportion of the solvent is generally about 10 to 200-fold by weight based on - ;~7~-hydroxypregna- 1,4_dien_3_one-20-carbaldehyde and ~ ~ the proportion of the acid catalyst is generally about fJ.-~; O ~ 001 to 0.3 mole, preferably about 0.005 to 0.1 mole, ~ per mole of 7~-hydroxypregna- 1,4-dien-3-one-20-carbal-., :
Jjz' ~

.~" ~
" ~ "~ "~

_ 39 _ 13.~
. .
.... .
dehyde. In the acetalization reaction preceding the dehydration reaction, the dehydrating agent is generally used in an amount capable of removing at least one mole, preferably about 2 to 10 moles, of water from the reaction system based on each mole of 7~-hydroxypregna-1,4-dien-3-one-20-carbaldehyde. In the dehydration reaction of compound (I-1-2), the solvent is generally used in an amount ranging from about 10 to 200-fold by weight based on compound (I-1-2) and the acid catalyst is generally used in a proportion of about 0.001 to 0.3 :-mole, preLerably about 0.005 to 0.1 mole, per mole of compound ~I-1-2).
The separation and purification of compound (I-2-1) from the reaction mixture obtained by the dehydrative ~

acetalization or the sequential acetalization and ~
dehydration reactions can be performed by the same - procedures as those used commonly for the recovery of products of organic synthetic reactions from reaction ~,.. ~ -mixtures. For example, the compound (I-2-1) can be isolated by mixing the reaction mixture with an aqueous solution of sodium hydrogen carbonate, extracting thè
resulting mixture with a solvent such as hexane, ~;
diethyl ether, benzene, ethyl acetate, methylene chloride, etc., then removing the solvent from the extract by distillation and subjecting the residue to a "

/: ~ !

~ "", "" , ,, " ,, ,, ",, '. ".,: ~ ,V~ , "~

; ~ 40 - `~ 7~
-, .
purification procedure such as chromatography, recrys-tallization and so on.
I The conversion of compound ~I-2-1) to compound j (I-2-2) is accomplished by reacting compound (I-2-1) with hydrogen peroxide in a solvent mixture of a lower alcohol such as methanol, ethanol, etc. with water in the presence of a base such as an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide, etc., at a temperature within the range of about 0 to 30C. The proportion of the base is generally about 0.2 to 0.5 `-mole per mole of compound (I-2-1). The proportion of I hydrogen peroxide is generally about 2 to 20 moles, i~ preferably about 3 to 10 moles, per mole of compound ~ (I-2-1). This 1,2a-epo~idation reaction can be i ~
~ expediently carried out by adding an about 30~ aqueous ::
~- solution of hydrogen peroxide, which is commercially ;~ available, and said base to a solution of compound -~- (I-2-1) in about 10 to 100-fold by weight, relative to -~ (I-2-1), of a lower alcohol and stirring the mixture at ~-~ room temperature for about 12 to 24 hours.

From the reaction mixture thus ~*ained by the above 1,2a-epoxidation, compound (I-2-2) can be I separated and purified by the following and other ~ proc~dur~s. Thus, th~ reaction~lnixture is first ,...

:

,~: :
, 1~3~ 37~

diluted with water and a portion of the solvent lower alcohol is distilled off under reduced pressure. The residue is extracted with a solvent such as diethyl ether, ethyl acetate, chloroform, methylene chloride and so on. The extract is then washed successively with aqueous potassium iodide solution and aqueous sodium chloride solution and the solvent is distilled off under reduced pressure. The residue is subjected to a separation-purification procedure such as chromato-graphy, recrystallization, etc. to recover the desired .~ compound (I-2-2). :~:
.- The compound ~I-2-l) and compound (I-2-2) can be :~
respectively subjected to deprotection reaction to give -.
the corresponding aldehydes. :~
yCHO :~
: Deprotection ~~

CHO :
eprotection ~"
(I-2-2) 2-4) ~;
G~

,',~, :.'.
.,',~',' ~' `
~:.". ' .
~: .

,':

, - 42 - 133~7~
: `
.
j The conversion of compound tI-2-1) to pregna-1,4,6-trien~3-one-20-carbaldehyde of formula (I-~-3) [which will hereinafter be referred to sometimes as compound i (I-2-3)] and the conversion of compound (I-2-2) to 1~,2~-epoxypregna-4,6-dien-3-one-20-carbaldehyde of !:~ formula (I-2-4) ~which will hereinafter referred to sometimes as compound (I-2-4)] are accomplished by reacting compound (I-2-1) or compound (I-2-2) with a ~` lower alkanone such as acetone, 2-butanone, 3-pentanone, . etc. in the presence of about 0.001 to 0.1 mole, per mole of compound (I-2-1) or (I-2-2), of an acid such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, etc.
`~ at a temperature of about 20 to 80C or by reacting compound (I-2-1) or compound (I-2-2) with water or a lower alcohol, such as methanol, ethanol, etc., in the presence of about 0.01 to 1 mole, per mole of compound 2-1) or (I-2-2), of an acid, such as hydrochloric acid, p-toluenesulfonic acid, etc., at a temperature within the range of about -10C~to about 60~C. The lower alkanone is generally used in a proportion o~ about 100 to 1000-fold by weight based on compound (I-2-1) or ~G ~ ~ , compound (I-2-2?.l The iproportion of s~aid water or lower alcohol is generally about 10 to 200-fold by weight based on compound (I-2-1) or compound (I-2-2).
Where water is used, a water-miscible organic ,~

- 43 - 133~7~

solvent such as tetrahydrofuran, 1,2-dimethoxyethane, etc. is preferably present in the reaction system. The preferred proportion of such organic solvent is about 20 to 100-fold by weight based on compound (I-2-1) or compound (I-2-2).
The separation and purification of compound (I-2-3) or compound (I-2-4) from the reaction mixture obtained by the above deprotection reaction can be carried out by the following and other procedures.
After removal, if necessary, of the lower alkanone, lower alcohol or/and organic solvent from the reaction mixture by distillation, the residue is diluted with water and extracted with methylene chloride. The extract is washed successively with water, a~ueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and the solvent is distilled off ~-~5'~
under reduced pressure. Finally the residue is ~-purified by chromatography, recrystallization, etc. to ~-give compound (I-2-3) or compound (I-2-4).
The compound (I-2-3) or compound (I-2-4) can be ~ .
converted to a pregnane derivative of general formula 2~ wherein Xl!and X2 jointly represenlt a lower alkyl-~ enedioxy group, for example by reacting compound (I-2-3) or ~i-~~ (I-2-4) with a lower alkylene acetal of a ketone such ;~

as 2-butanone~2,2-dimethyltrimethylene)acetal in the , ,~.:~' , ' ~ , ' ;, ~' ' '~' ' " ' ', ' "". '' ': " ' '' " ' ' ' `: ' ' '. ' .: ' ' "- ' ~ 33~.37~

; - 44 -. . . ,;
presence of an acid catalyst such as pyridinium p-toluene~
sulfonate, etc., in an aromatic hydrocarbon solvent such as ~enzene, toluene, etc. under refluxing.
The conversion of compound ~I-2-2) to compound (I-3-1) is carried out by reacting compound (I-2-2) with an organic peracid such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and so on. The organic peracid is generally used in a proportion of about 1 to 10 moles, preferably about 2 to 8 moles, per mole of compound (I-2-2). This reaction is generally conducted in a halogenated hydrocarbon solvent such as ~ ~ .
chloroform, methylene chloride, etc. at a temperature of about 0 to 30C. This 6a,7a-epoxidation reaction can be expediently carried out by adding said organic ,,,,~,,, ~ ~
peracid or a solution thereof in about 50 to 200-fold by welght, based on said organic peracid, of a halogenated hydrocarbon to a solution of compound (I-2-2) in about 10 to 100-fold by weight, based on ~--compound (I-2-2), of a halogenated hydrocarbon solvent and stirring the resulting mixture at room temperature for about 6 hours to about 3 days. For the purpose of ~-neutralizing the organic acid liberated from said ~ ~
organic peracid, about 1 to 5 moles, based on each mole ~ -of compound ~ 2-2), of a basic compound, such as sodium carbonate, potasslum carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc., is --, ~ " - .

133~ 37~ ` ~

.- ~
preferably present in the reaction system.
The separation and purification of compound (I-3-l) from the 6~,7a-epoxidation reaction mixture can -~
be carried out by the following and other procedures.
The reaction mixture is washed successively with aqueous potassium iodide solution and aqueous sodium chloride solution, the solvent is then distilled off ~- under reduced pressure and the residue is subjected to ~
a purification procedure such as chromatogrpahy, recrystallization, etc. to give compound (I-3-1).
- ; The reduction reaction of compound (I-3-1) to compound (I-3-2) is carried out by contacting the compound (I-3-1) with a reducing agent such as sodium borohydride. The reducing agent is generally used in a proportion of about 0.5 to 2.0 moles, pre~erably about 0.8 to 1.2 moles, per mole of compound II-3-1). This reaction is generally conducted in an alcohol solvent, such as methanol, ethanol, etc., or an ether solvent, s~uch~as tetrahydrofuran, 1,2-dimethoxyethane, etc., at -~
a temperature within the range of about 0 to 25C. The amount of the solvent is generally about 20 to 100-fold by weight based~on compound (I-3-1). This reaction càn , ,.
- ~be advantageously conducted by dissolving compound (I-3-1) in said solvent`, adding the reducing agent ~ .
- ~

'-/ :
i ,~ .
i" ~

i~"
' - 46 - 1~3~

~ . , gradually under stirring and cooling at about 0C and finally stirring the mixture at about 0C for a period ranging from about 10 minutes to about an hour.
The separation and purification of compound (I-3-2) from the reaction mixture obtained by the above reduction reaction can be carried out by the follcwing and other procedures. The reaction mixture is diluted with water and, after addition of a small amount of cold hydrochloric acid, extracted with methylene chloride. The extract is washed with cold aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution in that order and the solvent is distilled off under reduced pressure. Finally, the residue is subjected to a purification procedure such as chromatography, recrystallization, etc. to give compound ~I-3-2).
The conversion of compound (I-3-2) to compound (I-3-3) is accomplished by reacting the compound (I-3-2) with a lower alkanoic acid anhydride, such as acetic anhydride, proplonic anhydride, butyric anhydride, valeric anhydride, etc., or a lower alkanoic acid halide, such as acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, etc., in the presence of a basic compound, such as pyridine, triethylamine, etc., at a temperature within the range s~
~i ,:

9 ~ 133~ 37~
! ' - 47 ~
¦ of about 0 to 25C. The lower alkanoic acid anhydride or lower alkanoic acid halide is generally used in a proportion of about 1 to 10 moles per mole of compound (I-3-2). The amount of said basic compound may generally range from about 2 to 20 moles per mole of compound ¦ (I-3-2) but is preferably not less than about 2 moles per mole of said lower alkanoic acid anhydride or lower alkanoic acid halide. This acylation reaction may be conducted in an organic solvent such as methylene chloride, diethyl ether and so on. The amount of such organic solvent is generally not more than about 200-fold by weight based on compound (I-3-2). This reaction can be advantageously carried out by adding said lower alkanoic acid anhydride or lower alkanoic acid halide gradually to a mixture of said compound (I-3-2) a~d basic compound or a solution thereof in an organic solvent under cooling at about 0C and, then, stirring the mixture at room temperature for about 2 to 12 hours. This acylation reaction may be hastened by permitting an esterification catalyst such as 4-(di-methylamino)pyridine to be present in the reaction system in a proportion of`about 0.01 to 0.1 mole per mole of compound (I-3-2).

-~- From the reaction mixture thus obtained by the -r, above acylation reaction, the product compound (I-3-3) "' , ,, ~, ' 133~ 37~
sj - 48 ~

can be separated and purified by the following and other procedures. To the reaction mixture is added a solvent such as diethyl ether or methylene chloride and the solution is washed with water. Where pyridine was used as said basic compound, this washing is preferably performed with an a~ueous solution of copper sulfate.
After washing, the organic layer is distilled under reduced pressure to remove the solvent and the residue is subjected to a purification procedure such as chromatography, recrystallization etc. to recover the s~ desired compound ~I-3-3).
- The compounds (I-3-l), (I-3-2) and (I-3-3) can be respectively subjected to deprotection reaction to give the corresponding aldehydes.
~CHO
Deprotection ..
(I-3-l) --J~ ~

3-4) - '~:
, ~;
,,, ~, CHO

_2) DeProtèc~iOn ~ ~

(1-3-5) , t-~

~ ~ .
~.'.j : .
t ~ -!~

- 49 - 133~.3~ ~

CH() Deprotecti '5'~ , ' ~
3-2) - zlo ~ ~

(1-3-6) ~:
~: wherein zl has the meaning defined hereinbefore. ~::
,2;6~,7~-Diepoxy-3-oxopregn-4-ene-20-carbaldehyde of formula (I-3-4) [which will hereinafter be referred to sometimes as compound tI-3-4)], 1~,2~;6~,7~-diepoxy-3 : .:
hydroxypregn-4-ene-20-carbaldehyde of formula (I-3-5) ~t [which will hereinafter be referred to sometimes as ,.-:: :
compound (I-3-5)], and compounds of general formula (I-3-6) [which will hereinafter be referred to sometimes as compound (I-3-6)] can be produced by the same reaction and workup procedures as those described for the ;converslon o' compound (I-2-1) or compound (I-2-2) to compound~(I-2-3) or compound (I-2-4) except that, in - :

lieu~of compound (I-2-1;~ or (I-2-2), compound (I-3~
compound (I-3-2j or compound (I-3-3) is subjected ::

to deprotection.
The compound (I-3-4), compound (I-3-5) or compound (I~3-~) can be converted to the :corresponding compound:
(I-3-1), compound~(I-3-2) or compound (I-3-3), for example by reactiAg compound ~I-3-4), (I-3-5) or (I-3-6) with a ~`: ``,.`
5~

1 ~ 3 ~ ~ 7~

lower alkoxytrimethylsilane such as methoxytrimethyl-j silane, ethoxytrimethylsilane, etc. or a bisttrimethyl-silyloxy) lower alkane such as 1,2-bis(trimethylsilyl-oxy)ethane, 2,2-dimethyl-1,3-bis~trimethylsilyloxy)pro-pane, etc., in the presence of trimethylsilyl trifluoro-methanesulfonate at a temperature within the range of about -lOO~C to about -60C. This conversion may be performed in a solvent such as methylene chloride, chloroform, and so on.

~ The reduction reaction of compound (I-3-3) to } compound (I-4-1) is carried out by treating compound (I-3-3) with a reducing agent in the presence of a palladium compound and a tertiary phosphine. As the pa~lladium compound, tris(dibenzylideneacetone)di-palladium(chloroform), palladium acetate, palladium nitrate, palladium chloride, bis(acetylacetonato)-palladium, tetrakis(triphenylphosphine)palladium, etc.
can be used. The proportion of the palladium compound is generally about 0.01 to 0.5 mole per mole of compound ~: .
(I-3-3). As examples of said tertiary phosphine, there ~ ~-may be mentioned tributylphosphine, triethylphosphine, ~- triphenylphosphine, tritolylphosphine, 1,2-bis(diphenylphos-phino)ethane, and so on. The proportion of such tertlary phosphine is generally about 1 to 20 moles per mole of ;
,, the palladium compound. As examples of the reducing;~
agent that can be employed, there may be mentioned ~- salts of formic acid such as ammonium formate, ~' ~' :- 133~.37~

, . . .
triethylammonium formate, trimethylammonium formate, etc.
and metal hydride compounds such as sodium borohydride, lithium aluminum hydride, lithium triethylborohydride, diisobutylaluminum hydride, sodium cyanoborohydride, tributyltin hydride, polymethylhydrosiloxane and so on.
The proportion of the reducing agent is generally about 2 to lO moles per mole of compound (I-3-3). This reaction is preferably conducted in an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc. at a temperature within the range of about 0 to 120C. The proportion of said solvent is preferably about 30 to 100-fold by weight based on compound (I-3-3). This reaction is preferably conducted by adding said palladium compound and tertiary phosphine to an ether solvent in an inert atmosphere such as ~-argon gas or nitrogen gas at room temperature, stirring ~, the mixture for about 5 to 60 minutes, then adding said reducing agent to the resulting solution, stirring the mixture further for about 10 to 60 minutes, adding a solution of compound (I-3-3) in an ether solvent, and stirring the mixture under reflux for about 10 minutes to about 24 hours t ' .i ~
From the reaction mixture thus obtained by the i :.
~- above reduction reaction, the product compound (I-4-1) can be separated and purified by the following and :,...

.
, ~ .

r ~

- 52 - ~ 3 3 ~ 3 7 ~

other procedures. The reaction mixture is diluted with methylene chloride and washed successively with cold hydrochloric acid, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution. From the organic layer separated, the solvent is distilled off under reduced pressure and the residue is subjected to a purification procedure such as chromatograpy, recrystallization and so on to recover the desired compound (I-4-1).
In the above reduction reaction, there are cases in which an 33-alkanoyloxy-1~,2~-epoxypregn-4-en-7a-ol of the general formula yl 2 ~ ~:
:C:

OH ( III) i~

wherein yl/ y2 and zl have the meanings defined hereinbefore, [which will hereinafter be referred to sometimes as compound (III)3 is by-produced but this compound (III) can be converted to compound (I-2-2), for example by the following process.

..~, .-~'' " ' ; 133~ 3~
.' -- 5 3 :, yl trlI) ~ Ho~

~ -~
1~ Y' ~ .

~ Oxidation ~ yl ~
Dehydration ~ "~" ~

2-2) ~ ~;

In~ the~ above~formulas, yl and Y~ have the meanings defined hereinbefore.
T~hus, .a~lcoholysis !~ compound (II~I),with a lower alcohol, such~as methanol, ethanol, etc., in the:~
presence of a~basic compound, such~as anhydrous~
potassium carbonate, anhydrous sodium carbonate, etc., .s~

- 54 - 133~7~

.
at a temperature of about 0 to 30C yields an la,2a-epoxypregn-4-ene-3~,7a-diol derivative of general formula (IV). This 1~,2a-epoxypregn-4-ene- 3~,7a-diol derivative (IV) is oxidized with manganese dioxide in a solvent, such as hexane, diethyl ether, methylene chloride, chloroform, etc., at room temperature to give an la,2~-epoxy-7~-hydroxypregn-4-en-3-one derivative of general formula (V) and finally this 1~,2a-epoxy-7a-hydroxypregn-4-en-3-one derivative is subjected to dehydration reaction in t-butyl alcohol in the presence of potassium t-butoxide at room temperature to give the compound (I-2-2). The compound (I-2-2) thus obtained can be subjected to said 6~,7~-epoxidation to compound 2-3) and to the reduction to compound (I-6-1) which will be described hereinafter.
The conversion of compound (I-4-1) to compound (I-4-2) is accomplished by reacting the compound

4-1) with an esterifying agent in the presence of a : ; :
~ basic compound such as pyridine, triethylamine, etc. at ., , ~
,'G, a temperature within the range of about 0 to 100CC.
~ The esteriying agent is exemplified by lower alkyl - halocarbonates;such as methyl chlorocarbonate, - ethyl chlorocarbonate, propyl chlorocarbonate, iso-propyl chlorooarbonate, butyl chlorocarbonate, methyl ;~
bromocarbonate, ethyl bromocarbonate, etc.; lower , ~ ~

,, .
, .~ ....

1~3~.~7~

alkanoic acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, etc.; lower alkanoic acid halides such as acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, etc~; N,N-di~lower alkyl)carbamoyl halides such as N,N-dimethylcarbamoyl chloride, N,N-diethylcarbamoyl chloride, N,N-dipropylcarbamoyl chloride, etc.; lower alkyl isocyanates such as methyl isocyanate, ethyl isocyanate, propyl isocyanate, etc.; and aryl isocyanates such as phenyl isocyanate, tolyl isocyanate and so on. Where a lower alkyl halocarbonate is used as the ,~
esterifying agent, there is produced a pregnane deriva-tive of general formula II-4-2) wherein Z is a lower alkoxvcarbonyl group, and where a lower alkanoic acid anhydride or a lower alkanoic acid halide is used, there is produced a pregnane derivative of general formula (I-4-2) wherein z2 is a lower alkanoyl group.
Where an N,N-di(lower alkyl)carbamoyl halide is used as the esterifying agent, there is produced a pregnane derivative of general formula (I-4-2) wherein z2 is an N,N-di(lower alkyl)carbamoyl group, while the use of a lower al~yl i'socyànte gives rise to a pregnane derivative of general formula (1-4-2) wherein z2 is .. . .
-~ an N-lower alkylcarbamoyl group. Where an N-aryl iso- t:`

~ cyanate is used, a pregnane derivative of general ~

:, :

~ - 56 - 13~ ~ 3~

formula (I-4-2) wherein z2 is an N-arylcarbamoyl group is produced. The proportion of the esterifying ¦ agent is generally about 1.2 to 20 moles per mole of compound (I-4-1). When the esterifying agent is a ! lower alkyl halocarbonate, a lower alkanoic acid anhydride, a lower alkanoic acid halide or an N,N-di(lower alkyl)carbamoyl halide, said basic compound is preferably used in a proportion of about 2 to 40 moles per mole of compound (I-4-11 and in a proportion not lesc than about 2 moles per mole of the esterifying agent. Where a lower alkyl isocyanate or r ' ~ an aryl isocyanate is used as said esterifying agent, the basic compound is generally used in a proportion of about 0.0001 to 10 moles per mole of compound (I-4-l).
This esterification reaction may be conducted in a ,,. ~
solvent such as methylene chloride, diethyl ether, ~;
benzene, toluene, etc. and the proportion of such solvent is generally not more than about 200-foLd by weight based on compound (I-4-1). This reaction can be advantageously carried out by adding the esterifying . ~ .
~ agent gradually to a mixture of said compound (I-4~
-` and basic compound or a solution thereof in a solvent -7'~ under cooling at about 0C and then stirring the ,.,.,. ~
mixture at a temperature within the range of about 0 to 0~ for about 10 minutes to about 12 hours. Wh~re ~;

'; ' ~' ' ~ 57 ~ 13~7~ ~;
,~::
the reaction is conducted using a lower alkyl halocarbonate, a lower alkanoic acid anhydride, a lower alkanolic acid halide or an N,N-di(lower alkyl)carbamoyl halide as the esterifying agent, the esterification reaction can be hastened by permitting :
an esterification catalyst such as 4-(dimethylamino)-pyridine or the like to be present in the reaction system in a proportion of about 0.01 to 0.1 mole per mole of compound (I~4-1). ~;
From the reaction mixture thus obtained from the :-above esterification reaction, the product compound (I-4-2) can be separated and purified by the following and other procedures. After addition of water, if necessary, the reaction mixture is added to methylene chloride and the solution is washed with water. From the organic layer separated, the solvent is distilled ~: :
off under reduced pressure and the residue is subjected to a purification procedure such as chromatography, re- --crystallization and so on to recover the desired compound (I-4-2). ~;
The oonversion of compound (I-4-2) to compound (I-4-3;) is accomplishedi~by reacting the compound (I-4-2) in the presence of a palladium compound. The palladium compound is exemplified by tris(dibenzyl- -~
ideneacetone)dipalladium(chloroform), palladium acetate, ~-.

-,. .

t - 58 - 133~37~

palladium nitrate, palladium chloride, bis(acetyl-acetonato)palladium, tetrakis(triphenylphosphine)palladium and so on. The proportion of the palladium compound is generally about 0.01 to O.S mole per mole of compound (I-4-2). The palladium atom derived from such palladium compound is preferably available as coordinated by a tertiary phosphine in the reaction system and, therefore, il such a tertiary phosphine may be added to the reaction system as necessary. As examples of such tertiary phosphine, there may be mentioned tributylphosphine, triethylphosphine, triphenylphosphine, tritolylphosphine, 1,2-bis(diphenylphosphino)ethane and so on. The . ~
-~ proportion of the tertiary phosphine is generally about ~` 1 to 20 moles per mole of the palladium compound. The reaction temperature is generally in the range of about 20 to 150C. This conjugated diene-forming reaction is preferably conducted in an ether solvent such as 1,4-dioxane, tetrahydrofuran, etc. and the proportion of such solvent is preferably about 5 to 500-fold by weight based on compound (I-4-2). This reaction can be ~-~ advantageously carried out by adding the palladium ;~
compound, as well as the tertiary phosphine if desired, to said ether solvent in an inert atmosphere such as argon gas or nitrogen gas at room temperature, stirring the mixture for about S to 60 minutes, then adding a ~'' '`'' ~.

,-"
,,, , ~ ~

- 59 - i33~.37~

solution of compound (I-4-2) in the same ether solvent as mentioned above, and stirring the mixture under reflux for about 1 to 15 hours.
From the reaction mixtuxe thus obtained by the above conjugated diene-forming reaction, the product compound (I-4-3) can be separated and purified by the following and other procedures. The reaction mixture is filtered through a glass filter with the aid of Florisil and the filtrate is concentrated under reduc~d pressure. The concentrate is then subjected to a purification procedure such as chromatography, re-crystallization and so on to recover the compound (I-4-3).
The conversion of compound ~I-4-3) to compound -4-4) is carried out by reacting the compound (I-4-3) with a lower alcohol, such as methanol, ethanol, etc., in the presence of a basic compound, such as anhydrous potassium carbonate, anhydrous sodium carbonate and so on. Th~ proportion of the basic compound is generally about 2 to 10 moles~per mole of compound (I-4-3). The lower alcohol is generally used in a proportion of about 100 to l,~000-fold by weight based on compound ! ' ': ;
(I-4-3). The reaction temperature is generally in the range of about O to 30C. This alcoholysis reaction is preferably carried out by adding said basic compound to :'': '' .
~ ,.

~ - 60 ~ 3 3 ~ 3 7 ~

g :~:~
a solution of compound (I-4-3) in a lower alcohol and ~-stirring the mixture at room temperature for about 0.5 to 12 hours.
From the reaction mixture thus obtained by the :~
above alcoholysis reaction, the product compound (I-4-4) can be separated and purified by the following : and other procedures. The reaction mixture is filtered through a glass filter with the aid of Celite* and the filtrate is concentrated under reduced pressure. The ~:~
concentrate is diluted with water and extracted with :~
methylene chloride. From the resulting extract, the ~ :
solvent is distilled off and the residue is subjected ::
-.:
to a purification procedure such a- chromatography, ~-, ~ recrystallization and so on to recover the compound (I-4-4).
Among compounds of formula (I-4), compounds of the ;-~
general formula ~:
-~.. ,; , wherein yl and Y2lhave the meanings defined ! ' i, ' , hereinbefore, twhich compounds will hereinafter be ~ ~~
~'~ ?.: - ' . .

;~ ~ * Trade-Mark , :

- 61 - 13~

~, referred to ~ometimes as compound (I-4-5)] and compounds 1, of the general formula 1 yl ~;~ HO ",oz2 II-4-6) ~;~ ~ wherein yl~ y2 and z2 have the meanings defined hereinbefore, [which compounds will hereinafter be j referred to sometimes as compound (I-4-6)] can be obtained by the same xeaction and workup procedures as -.~ those described hereinbefore for the conversion of ~ ;
i~ compound (I-4-3) to compound (I-4-4) except that, in lieu of compound (I-4-3), compound (I-4-1) or (I-4-2) ::
is subjected to alcoholysis. ~ `
Among compounds ~I-4), aldehydes of the general ~
formula ~:
CHO

As ~10 (I 4-7) wherein A5, D10 and~Dll have the meanings defined hereinbefore, [which aldehydes will hereinafter be referred to sometimes as compound (I-4-7)1 are derived - 62 - 13~379 from acetals of the yeneral formula yl y2 ~ (I-4') ¦ A ~Dl i A5 DI Dll yl and y2 have the meaningS
defined hereinbefore, [which acetals will hereinaf~er be referred to sometimes as compound (I-4')] RUch as compound (I-4-1), compound (I-4-2), compound (I-4-3)~
compound (I-4-4), compound (I-4-5) and compound -- .
(I-4~6). The compound (I-4-7) can be obtained by the same reactlon and workup~procedures as those described hereinbefore for the:conversion of compound (I-2-1) or compound (I-2-2) to compound (I-2-3) or compound (I-2-4) except that, ln lleu of compound (I-2-1) or (I-2-2), compound (I-4') are subjected to deprotection. ~-~
The compound (I-4-5) or compound (I-4-6) can be acylated in the same manner as for the conversion of compound (I-3-2)~ to compound (I-3-3) to thereby give a compound (I-4-I) or compound (I-4-2). Moreover, ~3,';.i;~'~compound (I-4-7) can be acetallzed, for example in the :~-same manner as for the conversion :of compound (I-2-3) ~ -: or~(I-2-4) to a pregnane derivative of general formula I-2j wherein Xl and x2 jointly represent a lower ~':"' ;

l - 63 - 133~37~ ~
, . -alkylenedioxy group, to give a compound of general formula (I-4') wherein yl and y2 jointly represent a lower alkylenedioxy group.
The conversion of compound (I-4-4) to compound

5-l) is accomplished by reacting the compound 4-4) with a reducing agent such as lithium aluminum hydride, zinc borohydride or the like. The amount of the reducing agent is generally about 0.5 to 20 moles per mole of compound (I-4-4). This reduction reaction is preferably conducted in an ether solvent, such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether, etc., at a temperature of about 25 to 120C, and ~-the preferred proportion of such ether solvent is about 20 to 2,000-fold by weight based on compound (I-4-4).
This reaction can be advantageously conducted by adding a solution of compound (I-4-4) in an ether solvent , ,~,. .: ~
gradually to a mixture of said reducing agent and ether -solvent at room temperature and refluxing the mixture for a period ranging from about lO minutes to about 2 hours.
From the reaction mixture thus obtained by the ~`
above reduction reaction, the prod~ct compoundi(I-5-1) i can be separated and purified by the following and other procedures. Thus, water is gradually added to ~- :
the reaction mixture to decompose the excess reducing ~ -".. , ~

,, ~ , ~,,.
~' .,~ ~ ', I - 64 - ~ 3 ~ ~ 3 ~ e~
.
agent and, then, the ether solvent is distilled off under reduced pressure. To the residue is added cold hydrochloric acid, follo~ed by extraction with methylene chloride or chloroform. The extract is washed with a~ueous sodium chloride solution and the solvent is distilled off under reduced pressure. Finally the ;~
residue is subjected to a purification procedure such as chromatDgraphy, recrystallization, etc. to recover :-the compound (I-~-l). -la,3~-Dihydroxypregna-5,7-diene-20-carbaldehyde of formula (I-5-2) can be produced by the same reaction and workup procedures as those described hereinbefore ~ for the conversion of compound (I-2-1) or compound ;~
II-2-2) to compound (I-2-3) or compound (I-2-4) except ~;~ that, in lieu of compound (I-2-1), compound (I-5-1) is ~ subjected to deprotection reaction.
¦ The conversion of compound (I-2-2) to compound (I-6-1) can be achieved by contacting the compound (I-2-2) with a reducing agent such as sodium borohydride, zinc borohydride or the like. The amount of the reducing agent is generally about 0.25 to 2.0 moles and preferably about 0.8 to 1.2 moles per mole of ~- compound (I-2-2). This reduction reaction is generally ~- conducted in an alcohol solvent, such as methanol, ethanol, etc., an ether solvent, such as tetrahydrofuran, ". :

~:, - 65 - 133~ 3 1,2-dimethoxyethane, etc., or a mixture of such solvents at a temperature within the range of about 0 to 40C.
The proportion of the solvent is generally ahout 10 to 100-fold by weight based on compound (I-2-2). This reaction can be advantageously conducted by dissolving -~
compound (I-2-2) in a solvent, adding the reducing agent gradually to the solution with stirring and cooling at about 0C, and stirring the mixture further at a temperature of about 0C for a period ranging from about 10 minutes to about 5 hours.
-~ From the reaction mixture thus obtained by the above reduction reaction, the product compound (I-6-1) can be separated and purified by the following and other procedures. To the reaction mixture are added water and a small amount of cold diluted hydrochloric acid in succession, followed by extraction with methylene chloride. The extract is washed successively with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and the solvent is distllled off under reduced pressure. The residue is finally purified, for example by chromatography, recrystalliza-tion, etc., to'recover the compound (I-6~
The conversion of compound (I-6-1) to compound (I-7-1) can be accomplished by reacting the compound -,,~. ~.: .
~- (I-6-1) with a peracid-such as m-chloroperbenzoic acid, :` :
~ - 66 - 133~7~

perbenzoic acid or the like. The proportion of the peracid is generally about 1 to 2 moles per mole of compound (I-6-1). This 4~,5~-epoxidation reaction is generally conducted in an inert solvent, such as methylene chloride, chloroform, etc., in the presence ~ .
or absence of a saturated aqueous solution of sodium hydrogen carbonate. The proportion of the solvent is generally about lQ to 200-fold by weight based on ; compound (I-6-l) and the proportion of the aqueous sodium hydrogen carbonate is generally not more than about 200-fold by weight based on compound (I-6-l). This reaction is preferably carried out by dissolving or suspending compound (I-6-1) in an organic solvent, adding said peracid gradually at a temperature ranging from 0 to 40C, preferably from 15 to 30C, preferably in the presence of a saturated aqueous solution of sodium hydrogen carbonate, the proportion of which is about 10 ~- to 20-fold by weight based on compound (I-6-1), and then stirring the mixture at room temperature for a period ranging from about l to 12 hours.
From the reaction mixture thus obtained by the J, above epoxidationlreaction, the product compound ~I-7-1) can be separated and purified by the following ~; and other procedures. The reaction mixture is sub-jected to phase separation and the aqueous layer is ~, ~,',~': ' .
~- :
,,, ", .

.',, .
~:
,. ~
, .

" , , . , . , , - ~ : : - , ~ . . . : . . .

~ - 67 - ~3~37~ ~

extracted with an organic solvent such as diethyl ether, ethyl acetate, methylene chloride, and so on.
The organic layer is combined with this extract and the mixture is washed successively with water, a~ueous potassium iodide solution, aqueous sodium thiosulfate solution, water ! aqueous sodium hydrogen carbonate solution, and aqueous sodium chloride solution to remove the excess peracid and byproduct acid such as m-chlorobenzoic acid, benzoic acid and so on. Then, the solvent is distilled off under reduced pressure to recover the compound (I-7-1) as a crude product. This crude product is recrystallized to give a pure product of compound ~I-7-1). The crude product of compound 7-1) can be directly submitted, without purification, to the conversion reaction for the synthesis of compound 7-2) or compound (I-7-3).
The conversion of compound (I-7-1) to compound 8-1) can be accomplished by reaoting the compound 7-1) with Collins reagent. The Collins~reagent can be prepared by dissolving about I to 20-fold by weight, based on chromium oxide, of pyridine in not more than about 20-fold ~y weight, based on chromi~m oxide, of an inert solvent~such~as methylene chloride, chloroform or the like, and~Ddding chromium oxide gradually thereto under ice-cooling and stirring. The proportion of `,';~ :' - 68 - 1 33~ ~ 7~ ;
... .
Collins reagent is about 1 to 50 moles, preferably 2 to 20 moles, per mole of compound (I-7-1). This oxidation reaction is generally conducted in an inert solvent such as methylene chloride, chloroform, etc. and the proportion of such solvent is about 10 to 200-fold by weight based on compound (I-7-1). This reaction is preferably conducted by dissolving the compound (I-7-1~ ;-in a solvent, adding the resulting solution to a sus-pension of Collins reagent with stirring a~ a temperature within the range of -20C to 40C, preferably -10C to 20C, and then stirring the mixture for about 0.5 to 12 hours, preferably for 0.5 to 3 hours. It is expedient, for all practical purposes, to prepare Collins reagent in the solvent and subsequently carry out the reaction with compound (I-7-l) in the resulting solution.
Prom the reaction mixture ~thus obtained by the above oxidation reaction, the product compound (I-7-2) can be separated and purified by the following and other procedures. The reaction mixture is diluted with ethyl acetate and filtered with the aid of Celite. The filtrate is then washed with water, aqueous copper sulfate solution,'water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution in that order. The resulting solution is concentrated and the concentrate is purified by recrystallization to ~ :
, .......................................................................... .

~.,'' .

~ - 69 - ~ 3~3 3~ ~
~::
recover compound (I-7-2). The crude product of compound (I-7-2) may be directly subjected, without purifica-tion, to the reaction for conversion to compound (I-7-3) or (I-8-1).
~ he conversion of compound (I-7-2) to compound (I-8-1) can be accomplished by contacting the compound (I-7-2) with a reducing agent such as lithium aluminum hydride, sodium bis(methoxyethoxy)aluminum hydride, lithium borohydride and so on. The proportion of the reducing agent is generally about 0.75 to 5 moles and ~ preferably about 0.8 to 2.5 moles per mole of compound (I-7-2). This reduction reaction is generally conducted . in an inert solvent which may be an ether solvent such as tetrahydrofuran, diethyl ether and so on. The proportion of this solvent is about 10 to 200-fold by weight based on compound (I-7-2). This reaction is preferably carried out by dissolving compound (I-7-2) `' in a solvent, adding the resulting solution gradually to :~ a solution of the reducing agent under stirring at a temp-erature within the range of -20 to 80C, preferably -10 to ~:
40C, and stirring the mixture at a temperature within the range of 10 to 40C for 0.5 to 12 hours. :~
-~ From the reaction mixture thus obtained by the - above reduction reaction, the product compound (I-8-1) can be separated and purified by the following and `~
~--, :
..:
:
v, :

- 70 133:~79 ~
.`.- ``, , .
.,~
other procedures. The reaction mixture is diluted with ether and the excess reducing agent is decomposed with a saturated aqueous solution of sodium sulfate, followed by filtration with the aid of Celite. The filtrate ! thus obtained is concentrated and the concentrate is ~ , recrystallized from ethyl acetate to give the desired compound (I-8-1).
The compound (I-7-3) can be produced by subjecting compound (I-7-1) to Mitsunobu reaction to cause a ; steric inversion of the 3-hydroxyl group and, if .; ~
, necessary, further to hydrolysis and protective group exchange reaction.
The conversion of compound (I-7-1) to a compound of general formula ~I-7-3) wherein Z3 is an acyl group rwhich will hereinafter be referred to sometimes as compound (I-7-3a)] is accomplished by reacting -~ , .
;~-~ compound (I-7-1) with a carboxylic acid having the corresponding acyl group in the presence of a tertiary -phosphine, such as triphenylphosphine etc., and an azodicarboxylic acid lower alkyl ester, such as diethyl azodicarboxylate or the like. The proportion of said tertiary phosphlne is about 1 to 3 moles, preferably about 1.5 to 2 moles, per mole of compound (I-7-1).
The proportion of said carboxylic acid is about 1 to 3 ~ moles, preferably about 0.9 to 1.2 moles, per mole of ;~
-~ -i,;~ :
~:~

L - ~ i~ ~ ' i i- :, ' ;. :,: .
~,- . .. . . ... ...............

~ - 71 - 133~7~

~ ~.
compound (I-7-1). The proportion of said azodicarboxylic acid lower alkyl ester is about 1 to 3 moles, preferably about 1.5 to 2 moles, per mole of compound (I-7-1).
This reaction is generally conducted in an inert solvent which may be an aromatic hydrocarbon such as toluene, benzene, etc. or an ether solvent such as tetrahydrofuran, diethyl ether and so on. The pro-portion of such solvent is about 10 to 200-fold by weight based on compound (I-7-1). The reaction can be advantageously carried out by adding said azodicarboxylic :
acid lower alkyI ester gradually to a solution or ;~
suspension of compound (I-7-lj, tertiary phosphine and carboxylic acid at a temperature of -10 to 80C, preferably 0 to 30C, and stirring the mixture for 0.5 i~ ; to 12 hours.
From the reaction mixture thus obtained, the product compound (I-7-3a) can be separated and puriied by the following and other procedures. The reaction mixture is diluted with water and extracted with a solvent such as diethyl ether, ethyl acetate, etc. and the extract is washed with aqueous sodium chloride solution and so-~on. ~The~siolvent is then distilled off from the solution under reduced pressure and the residue~is purified~, for~example by chromatography, recrystallization,~etc., to recover the compound ~ -7-3a).

~,~ ..

'I , ~ - 72 - 133~37~ ~:

The compound (I-7-3a) can be reacted with a basic substance, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, etc., in an alcohol solvent, such as ethanol, methanol, etc., to give a compound of general formula (I-7-3) wherein Z3 2 is a hydrogen atom [which compound will hereinafter be referred to sometimes as compound (I-7-3b)]. The amount of said basi~ compound is generally 0.05 to 3 moles and preferably 0.1 to 1.5 moles per mole of compound (I-7-3a). This deprotection reaction is generally carried out at a temperature within the ,~ . ~
~s- ~ range of 0 to 40C.
j,~:
From the reaction mixture thus obtalned, the compound (I-7-3b) can be recovered by the following and ; other procedures. The reaction mixture is diluted with water and extracted with a solvent such as diethyl ether, ethyl acetate, etc. and the extract is washed successively witb water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution.
The solvent is then distilled off under reduced `
` pressure and the residue is purified, for example by -~
recrystallization', tb~recover the compound (I-7-3b).
The oompound (I-7-3b) can also be produced by reducing the compound (I-7-2). For example, this reduction can be carried out by contacting compound .,, :
,~
. ~

~ - 73 - ~33~

7-2) with a reducing agent such as sodium borohydride.
r The proportion of the reducing agent is generally about 0.25 to 2.0 moles, preferably about 0.8 to 1.2 moles, per mole of compound (I-7-2). This reduction reaction is generally conducted in an alcohol solvent such as ethanol, methanol, etc., and the proportion of such solvent is generally about 10 to 100-fold by weight based on compound (I-7-2). The reaction temperature is generally in the range of about 0 to 40C. This reaction can be advantageously carried out by dissolv-ing compound (I 7-2) in a solvent, adding said reducing :~
agent gradually thereto under stirring and cooling at about 0C, and stirring the mixture at a temperature of about 0C for a period ranging from about 10 minutes to about 5 hours.
From the reaction mixture thus obtained by the above reduction reaction, the compound (I-7-3b) can be separated and purified by the following and other procedures. To the reaction mixture is added diluted hydrochloric acid under ice-cooling to decompose the excess reducing agent, followed by dilution with water.
The re$ulting dilution is then extracted with an organic solvent such as ether, ethyl acetate, methylene chloride, etc. and the extract is washed with cold aqueous sodium hydrogen carbonate solution and aqueous , .
, ~
~' ~, ~ 74 ~ 1 3 ~ 3 7r~

sodium chloride solution in that order. The solvent is then distilled off under reduced pressure and the -residue is purified by recrystallization to recover the compound (I-7-3b). The crude compound (I-7-3b) may be directly subjected, without prior purification, to the next reaction.
.
The 3~-hydroxyl group of compound (I-7-3b) can be protected to give a compound of general formula (I-7-3) wherein Z3 is a lower alkoxycarbonyl group, an N-lower alkylcarbamoyl group, an N-arylcarbamoyl group ; or an N,N-di(lower alkyl)carbamoyl group [which compound will hereinafter be referred to sometimes as compound (I-7-3c)] and a compound of general formula (I-7-3) wherein Z3 is a tri-substituted silyl group or an alkoxymethoxy group which may optionally substituted IwhLch compound will hereinafter be referred to some-times as compound (I-7-3d)]. Protection of the 3B-hydro-xyl group can be accomplished by the conventional ~`~
procedure known for protection of hydroxyl groups.
The conversion of each of compound (I-7-3a), ~ compound (I-7-3b) and compound (I-7-3c) lwhich will -~ hereinafter be collectively referred to sometimes as compound (I-7-3a - c)] to compound (I-8-1) can be accomplished by contacting compound (I-7-3a - c) with a reducing agent such as lithium aluminum hydrLde, sodium :

~, ;; , ~,.

i,~; :

I - 75 - ~3~.37.~
~ , bis(methoxyethoxy)aluminum hydride, lithium tri-sec-butylborohydride, lithium borohydride and so on. The proportion of the reducing agent is generally about 0.75 t~ 5 moles and preferably about 0.8 to 2.5 moles per mole of compound (I-7-3a - c~. This reduction reaction is generally conducted in an inert solvent which may be an ether solvent such as tetrahydrofuran, diethyl ether and so on. The proportion of this solvent is about lO to 200-fold by weight based on compound (I-7-3a - c1. This reaction can be advan$age-;~ ously carried out by dissolving compound ~I-7-3a - c) -in a solvent, adding the resulting solution gradually to a solution or suspension of the reducing agent with stirring at a temperature of -20 to 80C, preferably lO to 90C, and stirring the resulting mixture further ~; at a temperature in the range of lO to 40C for O.S to 12 hours.
Prom the reaction mixture thus obtained by the ~,, , above reduction reaction, the compound (I-8-l) can be separated and purified by the following and other -~
procedures. The reaction mixture is diluted with ether and the excess reducing~agent is decomposed with a ! :i ~;
saturated aqueous solution of sodium sulfate, followed by filtration with the aid of Celite. The filtrate is concentrated~and the concentrate is recrystallized from ~ : `"'""' 3'~,:
' ~' ~ ~ , , - 76 - 133~3~

ethyl acetate to recover the desired compound (I-8-1).
The conversion of compound (I-8-1) to a compound of general formula (I-8-2) wherein Z3 is an acyl group, a lower alkoxycarbonyl group, an N-lower alkyl-carbamoyl group, an N-arylcarbamoyl group or an N,N-di(lower alkyl)carbamoyl group [which compound will hereinafter be referred to sometimes as compound (I-8-2a?] can be accomplished by reacting compound (I-8-1) with an esterifying agent in the presence of a basic compound such as pyridine, triethylamine a~d so on. The esterifying agent is exemplified by lower al~yl halocarbonates such as methyl chlorocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate, butyl chlorocarbonate, methyl bromocarbonate, ethyl bromo-carbonate, etc.; carboxylic acid anhydrides including lower alkanoic acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, valeric anhyd~
ride, etc. and aromatic carboxylic acid anhydrides such as benzoic anhydride etc.; carboxylic acid halides ~, including lower alkanoic acid halides such as acetyl chloride, propionyl chloride, butyryl chloride, valeryl -chloride, etc. andlaromatic carboxylic acid halides such as benzoyl chloride, p-methylbenzoyl chloride, naphthoyl chloride, etc.; N,N-di(lower alkylJcarbamoyl halides such as N,N-dimethylcarbamoyl chloride, N,N-',:.
, :

,, , " ~
'~
~,~

~ _ 77 _ ~ 33~
.; ~

diethylcarbamoyl chloride, N,N-dipropylcarbamoyl ¦ chloride, etc.; lower alkyl isocyanates such as methyl isocyanate, ethyl isocyanate, propyl isocyanate, etc.;
and aryl isocyanates such as phenyl isocyanate, tolyl isocyanate and so on. Where an alkyl halocarbonate is used as the esterifying agen,t, there is produced a compound of general formula (I-8-2) wherein ,~ Z3 is a lowex alkoxycarbonyl group. Where a carboxylic acid anhydride or a carboxylic acid halide is used as the esterifying agent, there is produced a compound of general formula (I-8-2) wherein Z is an acyl group.
~,- Where the esterifying agent is an N,N-di(lower alkyl)-carbamoyl halide, there is produced a compound of general formula (I-8-2) in which Z3 is an N,N-di(lower ,j~:
~; alkyl)carbamoyl group. Where a lower alkyl isocyanate "~
is used as the esterifying agent, there is produced a ` compound of general formula (I-8-2) wherein Z3 is an i- -~ .
~- N-lower alkylcarbamoyl group. The use of an aryl isocyanate as the esterifyinq agent gives rise to a compound of general formula (I-8-2) wherein Z3 is an N-arylcarbamoyl group. The amount of the esterifying ;~
agent is gene~ally a~bout 1.0 to 5 moles per mole of compound (I-8-1). Where the esterifying agent is an alkyl halocarbonate, a carboxylic acid ~- anhydride, a carboxylic acid halide or an N,N-di(lower ,., " : :' ` - 78 - ~ 333 3 7~
alkyl)carbamoyl halide, the basic compound is generally used in a proportion of about 2 to 40 moles per mole of -compound (I-8-1) and preferably in a proportion of not less than about 2 moles per mole of the .esterifying agent. It is preferable that a catalyst such as 4-(N,N-dimethylamino)pyridine, 4-pyrrolidinopyridine or the like be present in the reaction system in an amount ranging from about 0.001 to 0.1 mole per mole of compound ~I-8-1). Where the esterifying agent is a lower alkyl isocyanate or an aryl isocyanate, the basic compound is generally used in a proportion of about .
0.0001 to 10 moles per mole of compound (I-8-1). These ~ -~
esterification reactions are generally conducted at a -temperature of about 0 to 100C. This esterification ., .~ ~
reaction may be conducted in a solvent such as methylene chloride, chloroform, diethyl ether, benzene, toluene and so on, and the amount of such solvent is generally not more than about 200-fold by weight based on com-pound (I-8-1). The reaction can be advantageously carried out by adding said esterifying agent gradually to a mixture of said compound (I-8-1) and basic com-pound,, if d:esired'plus said catalyst, or'a solution thereof in said solvent, under cooling at about 0C
and, then,~stirring the mixture at a temperature of ~:
about 0 to 100C for a period of about 10 minutes to about 12 hours. :~

~,r ~

33~ 37~
:. - 79 -From the reaction mixture thus obtained by the above esterification reaction, the product compound (I-8-2a) can be separated and purified by the following and other procedures. The reaction mixture is poured ~ in cold diluted hydrochloric acid, followed by extrac-.~: tion with methylene chloride. The extract is washed ~: with aqueous sodium hydrogen carbonate solution and aqueous sodilm chloride solution in that order and the solvent is then distilled off. If necessary, the residue is further purified by recrystallization or column chromatography to recover the desired compound (I-8-2aJ.
. The conversion of compound II-8-l) to a compound of general formula (I-8-2) wherein Z3 i5 a tri-sub-;~
stituted silyl group or an alkoxymethyl group which may optionally be substituted lwhich compound will hereinafter be referred to sometimes as compound (I-8-2b)3 is accomplished by reacting:compound (I-8-1) with a tri-substituted silyl halide, such as trimethylsilyl .
chloride, t-buty.ldimethylsilyl chloride, t-butyldiphenylsilyl : chloride, tribenzylsilyl chloride, triisopropylsilyl : chloride, etc., or an alkoxymethyl chloride, such as r ~ methoxymethyl chloride, methoxyethoxymethyl chLoride, .~.
etc., in thé presence of a basic substance or alterna-tively with a vinyl ether compound, such as ethyl vinyl ;~
"~ ~

~ - 80 - 1331~ 7~ :

.
~ ether, 3,4-dihydropyran, methyl isopropenyl ether, :' etc., in the presence of an acid catalyst.
In the above protection reaction using a tri-substituted silyl halide or an alkoxymethyl chloride, the proportion of the tri-substituted silyl halide is 0.9 to lO moles and preferably l.0 to 2.5 moles per mole of compound (I-8-l), and the proportion of the -alkoxymethyl chloride is also in the range of 0.9 to lO
moles and preferably l.0 to 2.5 moles per mole of compound (I-8-l). As examples of said basic substance, there may be mentioned various organic bases such as p~rridine, triethylamine, etc., metal hydrides such as sodium hydrlde, potassium hydride, etc., and organometallic compounds such as methyllithium, butyllithium, phenyl-lithium and so on. The proportion of said basic aubstance is generally 0.9 to 50 moles and preferably l.0 to 20 moles per mole of compound (I-8-l). This protection reaction may be conducted in the presence of ;~
a~solvent.~ The solvent mentioned just above is a solvent which does not interfere with the reaction and includes tetrahydrofuran, diethyl ether, N,N-dimethylfor-mamider dimethyl sulfoxide, methylene chlbride and so -~
on. The amount of the solvent is about lO to 200-fold by weiqht based on compound (1-8-l). This reaction can be advantageously carried out by adding a tri-substi-tuted silyl halide or an alkoxymethyl chloride to a mixture of said compound (I-8-1), basic substance and solvent and, then, stirring the resulting mixture at 0 to 80C for 1 to 12 hours. However, it is preferable that said mixture of compound (I-8-1), basic substance and solvent be stirred at -20C to 80C, where a metal hydride is used as the basic substance, or at -100 to oC, where an organometallic compound is used, for 0.5 to

6 hours before proceeding with the reaction with the tri-substituted silyl halide or alkoxymethyl chloride.
From the reaction mixture thus obtained, the product compound (I-8-2b) can be separated and purified by the following and other procedures. The reaction mixture is first poured in water, followed by extraction with ether or the like. The resulting extract is washed successively with cold diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and the solvent is distilled off. If necessary, the residue is purified, ' for example by recrystallization, column chromatography, etc., to recover the desired compound (I-8-2b).
In the pr~teçtion reaction of compound (I-8-1) with a vinyl ether compound , the proportion of the vinyl ether compound is generally 0.8 to 50 moles and preferably 1.1 to 20 moles per mole of compound (I-8-1).

'' ' .' : .

1, - 82 - 133~.37~

3 The aforementioned acid catalyst is exemplified by :
sulfonic acids such as p~toluenesulfonic acid, etc.; salts of sulfonic acids such as pyridinium p-toluenesulfonate, etc.; inorganic acids such as hydrochloric acid, etc.; phosphorus oxychloride; and so on. The propor-tion of said acid catalyst is generally 0.01 to 2 moles and preferably 0.05 to 0.2 mole per mole of compound 8-1). This reaction may be conducted in a solvent, which should be a solvent that does not interfere with the reaction and may for example be methylene chlorlde, chloroform or benzene. The proportion of the solvent is generally 10 to l,000-fold by weight based on compound (I-8-1). This reaction is carried out by mixing the compound (I-8-1) with the vinyl ether compound, adding the solvent if desired, further adding ~ ;
the acid catalyst at a temperature within the range of -10 to 30C, and finally stirring the mixture at -10 to 60C for 5 minutes to 24 hours. From the reaction ,, . ~,, . ~ :
mixture thus obtained, the product compound (I-8-2b) can be separated and purified by the following and other procedures. The reaction mixture is diluted with ~
ether and washed with aqueous sodium hydrogen carbonate -solution and aqueous sodium chloride solution. The solvent is then distilled off and, if necessary, the residue is ~ purified, for example by recrystallization, chromato-~ - 83 - 1~3.~7~ :
. - `

graphy, etc. to recover the desired compound (I-8-2b)~
The compound (1-8-2b) can also be obtained by reduction of compound (I-7-3d). The conversion of compound (I-7-3d) to compound (I-8-2b) can be accomp-lished by the same reaction and workup procedures as those described for the conversion of compound (I-7-3a - c) to compound (I-8-l) except that compound (I-7-3d) ;-~
in lieu of compound (I-7-3a - c) is subjected to ~- reduction.
The conversion of compound (I-8-2) to a compound of general formula (I-8-3) wherein Z4 is an acyl group, a lower alkoxycarbonyl group, an N-lower alkyl-carbamoyi group, an N-arylcarbamoyl group or an N,N-di(lower alkyl)carbamoyl group lwhich compound will hereinafter be referred to sometimes as compound 8-3a)] can be accomplished by the same reaction and workup procedures as those described for the conversion - of compound (I-8-l) to compound (I-8-2a) except that compound (I-8-2) in lieu of compound (I-8-l) ls sub-jected to esteriflcation.
The conversion of compound (I-8-2) to a compound of general form'ula' (I-8-3) wherein Z4 is a tri-sub-stituted silyl group or an alkoxymethyl group which may optionally be~substituted twhich compound will hereinafter ~-~
-~ be referred to sometimes as compound (I-8-3b)] can be ~

~, ~ ',, , ~,:

Z
accomplished by the same reaction and workup procedures as those described for the conversion of compound 8-1) to compound (I-8-2b) except that compound (I-8-2) in lieu of compound ~I-8-1) is protected.
The compound (I-8-3) can be produced from compound (I-8-1) without isolation of the intermediate compound (I-8-2). -~
The conversion of compound (I-8-3) to compound 5-3) is accomplished by subjecting compound ~I-8-3) to dehydration reaction in the presence of an acid catalyst. This dehydration reaction can be carried out, for example by contacting compound (I-8-3) with an acid such as an inorganic acid, e.g. sulfuric ac~id, hydrochloric acid, etc., an organic acid, e.g.
ormic acid, acetic acid, propionic acid, monochloroacetic acid, dlchloroacetic acid, etc., a sulfonic acid, e.g.
p-toluenesulfonic acid, camphorsulfonic acid, etc. or a sulfonic acid salt, e.g. ~yridinium p-toluenesulfonate, etc., in an organic solvent such as dimethyl carbonate, l diethyl carbonate, tetrahydrofuran, dioxane, toluene, 1 benzene, ethyl acetate, butyl acetate, etc. at a temperàture~whichlmay range from about O to 150C. ~he amount of such acid~is dependent on its species but is generally about 0.01 to 50 moles per mole-of compound ~I-8-3).~ The amount of the solvent is i,': : ::
~ .
,' ' ... - i j - 85 - 133~.379 generally about 10 to 100-fold by weight based on compound (I-8-3). This reaction can be carried out by dissolving compound (I-8-3) in said solvent, adding said acid and stirring the mixture at a temperature of about 0 to 150C for 5 minutes to 24 hours.
.
From the reaction mixture thus obtained by the above dehydration reaction, the product compound . -(I-5-3) can be separated and purified by the following and other procedures. The reaction mixture is poured in ice-water and extracted with ether. The extract is ~-~
neutralized with aqueous sodium hydroxide solution, aqueous sodium hydrogen carbonate solution or the like and washed with aqueous sodium chloride solution. The solvent is ~-then distilled off and, if necessary, the residue is purified by recrystallization, column chromatography, etc., to recover the desired compound (I-5-3).
The conversion of compound (I-8-3) to compound 9-la~ is accomplished by reacting compound (I-8-3) with a carbonic acid di-lower alkyl ester in the presence of an organic acid such as formic acid, acetic ;~
acid, propionic acid, monochloroacetic acid and so on. ~;
The carbonic acididi-lower alkyl ester may for example be dimethyl carbonate, diethyl carbonate, dipropyl carbonate or the like and its proportion is generally about 10-to 200-foId by weight based on compound -~

:

i~: ' . , .
''.
.~ .

~33~3 ! - 86-J
8-3). The proportion of said organic acid is generally about 0.1 to 10-fold by weight based on compound (I-8-3). The reaction temperature is preferably in the range of about 50 to 150C. This rearrangement-carbonic esterification reaction can be carried out by dissolving compound (I-8-3) in said carbonic acid di-lower alkyl ester, adding said organic acid thereto, and heating the mixture at about 50 to 150C for 1 to 48 hours.
From the reaction mixture thus obtained, the product compound (I-9-la) can be separated and purified by the following and other procedures. The reaction mixture is poured in cold water and extracted with diethyl ether. The extract is washed successively with cold aqueous sodium hydroxide solution, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, and the solvent is distilled off. The residue is purified by recrystallization or column chromatography to recover the desired compound (I-9-la).
The conversion of compound (I-9-la) to compound 9-lb) can be accomplished by the same reaction and workup procedures as those described for the conversion of compound (I-7-3a) to compound (I-7-3b) except that ~ -:
compound (I-9-la) in lieu of compound (I-7-3a) is subjected to deprotection.
,, - ~

,~, i ~.:
, ' 1 ~ 3 ~

i, ~ :
The conversion of compound (I-9-lb) to compound (I-9-lc) can be accomplished by the same reaction and workup procedures as those described for the conversion of compound (I-8-1~ to compound (I-8-2a) except that compound (I-9-lb) in lieu of compound (I-8-1) is subjected to esterification.
The compound (I-5-3) can be produced by reacting compound (I-9-la) or compound (I-9-lc) in the presence ~-of a palladium compound. Examples of the palladium compound include tris(dibenzylideneacetone)dipalla- -dïum(chloroform), palladium acetate, palladium nitrate, ;~ palladium chloride, bis(acetylacetonato)palladium., '5'~ , tetrakis(triphenylphosphine)palladium, and so on. The j~
proportion of the palladium compound is generally about 0.01 to 0.5 mole per mole of compound (I-9-la) or (I-9-lc). The palladium atom derived from this palladium compound is preferably present as coordinated by a tertiary phosphine in the reaction system and, there-fore, a tertiary phosphine may be added to the reaction system as necessary. The tertiary phosphine may for example be tributylphosphine, triethylphosphine, j~ triphehylphosphine, tritolylphosphine, 1,2-bis(diphényl-phosphino)ethane or the like and its proportion is generally about 1 to 20 moles per mole of the palladium compound. The reaction temperature is generally in the ~, ~'', , "~ ""i"",,, ,,,,,, ",-", ," ~ "~

i ` - 88 - 133~37~
1,~
range of about 20 to 150C. Preferred examples of the solvent are ether solvents such as 1,4-dioxane, tetra-hydrofuran and so on. The amount of the solvent is preferably about 5 to 500-fold by weight based on compound (I-9-la) or (I-9-lc). The reaction can be advantageously conducted by stirring a solution of the palladium compound and, if used, the tertiary phosphine -in said ether solvent for about 5 to 60 minutes at room temperature in an inert atmosphere such as argon gas or nitrogen gas, then adding a solution of compound ~ i ~^ (I-9-la) or (I-9-lc) in the same ether solvent as above, and stirring the mixture under reflux for about -;~ 1 to 24 hours.
From the reaction mixture thus obtained, the ;~ lS product compound (I-5-3) can be separated and purified ,.~: ~
~ by the following and other procedures. The reaction ,~ *
mixture is filtered with the aid of Florisil, the filtrate is concentrated under reduced pressure, and ;~
the concentrate is puriLied by chromatography, recrystal-lization or the like to recover the desired compound (I-5-3)-~: :
~ . The conversion of compound (I-5-3) to compound ~ , ~ " ~
(I-5-4a) can be accomplished by reacting compound ;~
5-3) with a lower alkanone, such as acetone, 2-butanone, 3-pentanone, etc., in the presence of about 0.001 to * Trade-Mark s .,, :~ :
c - 89 - 1~:3~3~ ~

O.l mole, based on mole of compound (I-5-3), of an acid, such as p-toluenesulfonic zcid, pyridinium p-toluene-sulfonate, sulfuric acid, hydrochloric acid, copper sulfate, etc., at a temperature of about 20 to 80C or by subjecting compound (I-5-3) to hydrolysis in the presence of about O.Ol to 5 moles, based on each mole of compound (I-5-3), of an acid, such as hydrochlo-ric acid, acetic acid, p-toluenesulfonic acid, copper sulfate, etc., at a temperature of about -10 to 60C.
The amount of said lower alkanone is generally about lO to l,000-fold by weight based on compound 5-3). In~the case of hydrolysis reaction, water is generally used in a proportion of about lO to 200-fold by weight based on compound (1-5-3). In the latter case, it is preferable that a water-miscible organic ~-solvent such as tetrahydrofuran, l,2-dimethoxyethane, metbanol, ethanol, etc. be concomitantly present in the reaction~system. The preferred~amount of such~organic solvent 1S about 20 to l00-fold by weight based on compound (I-5-3).
From the deprotection reaction mixture thus obtained, the product compound (I-5-4a) can be separat-ed and purified by the following and other procedures.
The lower~alkanone, organic solvent, etc. used for the reaction are~first d~stilled off and the residue l5 ~.~
,,, , ~ - .
,,~, ~ .

, .~

- 90 - 133337~ ~

diluted with water and extracted with an organic solvent such as methylene chloride, diethyl ether or the like. The extract is washed successively with ~3 water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and the solvent is distilled off under reduced pressure. The residue is then purified by chromatography, recrystallization or the like to recover the desired compound (I-5-4a).
~ The compound (I-5-4a) can be subjected to depro- ;
i tection reaction to give a pregnane derivative of ,~
general formula (I-5-4b), general formula (1-5-4c) or formula (I-5-2). Moreover, compound (I-5-3) can be subjected to deprotection reaction to give compound I-5-1). These deprotection reactions can be carried out by the conventional procedure for converting an organic compound having a protected hydroxyl grol~p to an organic compound havlng a free hydroxy group.
The pregnane derivative (I-5) having a free ` hydroxyl group in the l~-position and/or in the 3~
posltion~ such as compound (I-S-l), compound (I-5-2), ~- compound (I-5-4a), compound (I-5-4b) and compound ^ (I-5-4c),~can be,sub~e;cted to protection reaction, fdr 5-~ - example in the same manner as for the conversion of compound (I-8-l) to compound (I-8-2) or (I-8-3), to thereby protect the free hydroxy group or groups.

- 91 13~37~

The pregnane derivative of general formula (I-6), (I-7), (I-8) or (I-9) wherein Xl and x2 each is a lower alkoxyl group or ~ointly represent a lower alkyl-enedioxy group, such as compound (I-6-1), compound (I-7-1), compound (I-7-2), compound (I-7-3), compound ~I-8-1), compound (I-8-2), compound (I-8-3), compound (I-9-la), compound (I-9-lb) and compound (I-9-lc), can be subje~ted to deprotection reaction to give a pregnane derivative of general formula (I-6), ~I-7), 8) or tI-9) wherein Xl and x2 jointly represent an oxo group. For example, a pregnane derivative of general formula (I-6), (I-7), (I-8) or (I-9) wherein xl and x2 each is a lower alkoxyl group or jointly ~.
represent a lower alkylenedioxy group can be converted : to the corresponding aldehyde by the same reaction and workup procedures described for.the conversion of compound (I-5-3) to compound (I-5-4a) except that said derivative in . ~- ~
lieu of compound (I-5-3) is subjected to deprotection.
The pregnane derivative of general formula (I-6),

7), (I-8) or ~I-9) wherein Xl and x2 jointly ~
represent an oxo group can be converted to a pregnane :
derivative of general formula (I-6j, 1I-7~ 8) or (I-9) wherein Xl and x2 jointly represent a lower ~:- alkylenedioxy group by reacting the starting pregnane ~:~
~:~ derivative with a lower alkylene acetal of a ketone, :~
E;~

,.;, -.,~, . .

,'''~ .
,,.~
, , ~

1~3~ 37~ ;

such as 2-butanone (2,2-dimethyltrimethylene) acetal, in an organic solvent, such as benzene, toluene, etc., in the presence of an acid catalyst, such as pyridinium p-toluenesulfonate, etc., under reflux conditions.
The pregnane derivative of general formula (I-5) wherein A is in the ~-configuration and represents an acyloxy group, a lower alkoxycarbonyloxy group, an -N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-substituted silyloxy group or an alkoxymethoxy group which may optionally be substituted; D12 is in the ~-configuration and represents an acyloxy group, a -~
lower alkoxycarbonyloxy group, an N-lower alkylcarba-moyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-substituted ~ ~-silyloxy group or an alkoxymethoxy group which may optionally be subs~tituted; and Xl and x2 jointly ;~
represent an oxo group ~which derivative will herein- ~
after be referred to sometimes as compound (I-5')] can also ~ ' be~derived from a pregnane derivative of general formula ~;;
tI-8j wherein A9 means the same group as A6 in general formula (I-5) representing the compound (I-5'); D13 means the same group as D12 in general formula (I-5) representing the compound (I-5') and X1 and x2 jointly represent an oxo group [which derivative will ~ :~,'`
ç~ ~
~ ~ :
ç,~

33~ 3 ~
~ `

hereinafter be referred to sometimes as compound (I-8')]
or a pregnane derivative of general formula (I-9) wherein AlO means the same group as A6 in the general formula (1-5) representing compound (I-5');
Dl4 means the same group as Dl2 in general formula 5) representing compound (I-S'), DlS is in the ~-configuration and represents an acyloxy group, a lower al~oxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group or an N,N-di(lower alkyl)caxbamoyloxy group; and Xl and x2 jointly . ~: represent an oxo group [which derivative will hereinafter , ~
. ~;~ be referred to sometimes as compound (I-9')]. Thus, . ~ the compound (I-S') can be produced by the same reaction . ~ and workup procedures as described for the conversion :~ of compound (I-8-3) to compound (I-S-3) except that : compound (I-8') in lieu of compound (I-8-3) is subjected to dehydration reaction, or by the same reaction and workup procedures described for the conversion of :
compound tI-9-la) or (I-9-lc) to compound (I-5-3) except that compound (I-9') in lieu of compound II-9-la) ~-or (I-9-lc) is subjected to conjugated diene- forming i~ reaction. ~ ; i laj3~-Dihydroxypregna-5~7-diene-2o-carbaldehyde of formula (I-5-2) can be converted to la-hydroxy-- vitamin D3 by the following and other processes.

, 1, ~ :
, ':

~;-:~
; 133~ 37,~

,. ..
.., ~CHO ~,CHO

HOcatalyst T~P~
( 1 - 5 - 2 ) , ~
OH

~MgBr THP_o ~X
~ =p~ lU) ; ' 02Cl OS02CH
Basic compoun3 ~~

" ' " ' i ~ . '; ! . , ~ 5', ' ~ : :
:",`. ~, ::
i'}~
~' i, :
,, ~ ,, ~ - 95 - ~3~3~

,.

j~
'` THP-O
LiAlH

`~1 THP-O~ (~) ~3: Water or HO 1 lower alcohol : ~ , 1 Acid catalyst HO ( X ) t~ eri HO"` OH (~

In the above formulas, ~HP, dotted line ( ), solid line~ and~wavy line (~ ) have the meanings :defined hereinbefore.
:la,3B-Dihydroxypregna-5,7-diene-20-carbaldehyde of ;:~

~: ': ~': ' '.

~'5 :.
~', ~ - 96 - ~3~37~

formula (I-5-2) can be converted to the compound of formula (VI) by reacting the aldehyde with 3,4-dihydro-2H-pyran in a solvent such as methylene chloride or the like in the presence of an acid catalyst such as pyridinium p-toluenesulfonate or the like at a temperature ranging from about 0 to 20C. The compound of formula ~VI) is then reacted with isoamylmagnesium bromide in an ether solvent such as diethyl ether, tetrahydrofuran or the like at a temperature of about -10C to 70C to give a :
compound of formula (VII). This compound of formula (VII) is reacted with methanesulfonyl chloride in the ' presence of a basic compound such as pyridine, triethyl-amine or the like at a temperature of about 0 to 20C ~'~
to give a compound of formula (VIII). This reaction ;~:~
may be conducted in a solvent such as methylene chloride. :
The compound of formula (VIII) is then reacted with lithium aluminum hydride in an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane or the like at a temperature ranging from about 20 to 70C to give a ~:~
compound of formula (IX). The compound of formula (IX)~:~
is reacted with water or a lower alcohol such as ~;~
methanol, ethan'ol'or '~he like in the pre~ence of an acid catalyst such as hydrochloric acid, pyridinium ~`
p-toluenesulfonate or the like at a temperature of about 10 to 60C to give a compound of formula (X).

3~ ~
~ - 97 -~}
Then, this compound of formula ~X) may for example be irradiated with ultraviolet light in the known manner described in Japanese Patent Application Laid-open J No. 52-108964 (1977) and ~he resulting compound ,: may be isomerized to give la-hydroxy-Vitamin D3 of formula {XI).

~ . :
,': , ~

~" ~

. ~:

r~ , ~''' ':
' ~' .

~' , ~ f~
I '',~,' - 98 - ~ b~

The examples given hereinafter are further illust-rative of the invention. It should be understood that ;~ the invention is by no means limited to these specific ~ :
examples.
Example 1 The strain Alcaligenes faecalis D4020-K15 (F~RM BP-204) was cultivated in the following manner. Thus, 2.0 g of chenodeoxycholic acid, 0.05 g of glucose, 0.2 g of ammonium nitrate, 0.1 g of potassium dihydrogen phosphate, 0.6 g of potassium monohydrogen phosphate, 0.05 g of magne-sium sul ate heptahydrate, 0.05 g of yeast extract, 0.05 g of peptone and 0.2 g of sodium hydroxide were mixed and made up with tap water to make 100 ml (pH 7.5) for use as a ~
culture medium. This medium was put in a 500-ml shaking ;~-flask and sterilized by autoclaving at 120C for 15 ~-~ minutes. A seed culture (5 ml) of the above strain as prepared by overnight cultivation in the same medium as above on a test tube shaker was added into the above 500 m~ Sakaguchi flask and shake culture was carried out at 30C for 2 days. The resulting culture broth ~ .
was adjusted to pH 9.0 with lN-aqueous sodium hydroxide solution and centrifuged to separate the precipitate and microbial cells from the supernatant. The ~s;~;
recovered precipitate and cells are mixed with 500 ~

.. . .

'~

~ ~ .

`~
-" :

:~ 133~.37~
ml of ethyl acetate, followed by centrifugation to separate the ethyl acetate layer from the cells. The ethyl acetate layer was dried over anhydrous sodium sulfate and the ethyl acetate was distilled off under reduced pressure. The procedure gave 1.4 g of 7a-hydroxypregna-1,4-dien-3-one-20-carbaldehyde.
A portion of this 7~-hydroxypregna-1,4-dien-3-one-20-carbaldehyde was taken and dissolved in methanol to give a 1~ solution and 25 ~1 of this solution was injected into a high performance liquid chromatograph equipped with a ~-Bondapak C-18 column (Waters Associates, -~
Inc., U.S., HLC-GPC-244). As the mobile phase, a 25/75 (v/v) mixture of water and methanol preadjusted to pH 4.0 was passed at a flow rate of 1 ml/min. Differential refractometry was used as the detection method. The . ~
HPLC peak area was calculated with an integrator (Shimadzu Corporation, Shimadzu Chromatopak C-R3A). The purity of the above 7a-hydroxypregna-1,4-dien-3-one-20-carbaldehyde based on the area ratio was 96.6%.
The identification of 7~-hydroxypregna-1,4-dien-3-~`x~ one-20-carbaldehyde was made as follows.
Mass spectrum (m/e): 342 ~M] , 324 [M-H2O] -H-NMR spe'ctrum ;(90 MHz) ~CMscl3 * Trade-Mark , ,,. ,:

I ~

133~3~ :

- 1 0 0 - ; :

0.74 (s, 3 H), 1.06 (d, 3 H), 1.18 (s, 3 H), 3.97 (br, 1 H), 6.08 (d, 1 H), 6.17 (d, 1 H), 7.00 (d, 1 H), 9.55 (d, 1 H) Example 2 The cultivation procedure of Example 1 was repeated except that chenodeoxycholic acid was used in an amount of l.0 g instead of 2.0 g, that sodium hydroxide was used in an amount of 0.1 g instead of 0~2 g and that the cultivation time was l day ins~ead of 2 days. The resulting culture broth was adjusted to pH 9.0 with lN-aqueous sodium hydroxide solution and centrifuged to separate the cells and the precipitate formed in the course of culture from the supernatant. The precipitate ;- `-and cells were mixed with 50 ml of water and the mixture was centrifuged to separate the aqueous layer from the insoluble fraction. The insoluble fraction j~
was mixed with 200 ml of methanol and the mixture was céntrifuged to separate the cells from the methanol ~ ~-layer. The methanol~layer was diIuted with 10 ml of water~and the methanol~was distilled off under reduced pressure. The resulting precipitate was recovered by filtration andl~dried toigiive 0.77 g of 7~-hydroxypregna-1,4-dien-3-one-20-carbaldehyde. Determined by high performance~liquld~chromatography, this product;had a purity of 95.1%. ~

,.,:
,:~,: ,:
,. ..
,~ ~, .. . '~
,, ~ .
. ~ ,:

133~ 37~

To the 7a-hydroxypregna-1,4-dien-3-one-20-carbalde-hyde obtained as above was added 10 m of methanol and the mixture was warmed to obtain a homogenous solution. ~ -This solution was diluted with 7 ml of warm water and, then, allowed to cool to room temperature. This procedure yielded 0.62 g pure crystals showing a purity of 98%.
Example 3 In 200 ml of benzene were dissolved 5.00 g (14.6 mmoles) of 7~-hydroxypregna-1,4-dien-3-one-20-carbalde-hyde and 4.56 g (43.8 mmoles) of 2,2-dimethyl-1,3-pro-panediol, followed by addition of lO0 mg of p-toluene-sulfonic acid. The mixture was ref:luxed for S hours, with the byproduct wzter being con~tantly r~moved from ,.,~
the reaction system by means of a Dean-Stark trap. The reaction mixture was cooled to room temperature and -~
washed with aqueous sodium hydrogen carbonate solution. ~-The aqueous layer was extracted with ether-hexane (70:30, v/v) and the extract was combined with the organic layer. This mixture was washed with aqueous sodium chloride solution and dried over magnesium sulfateiand thé'sdlvent was distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eleuent: ethyl acetate-hexane =
10, v/v) to recover 5.53 g of 20-(5,5-dimethyl-1,3-~:

" . ~

s.,,:

, ' , , -.

- 102 - ~333~

dioxan-2-yl)pregna-1,4,6-trien-3-one (yield: 92%).
H-NMR spectrum (90 MHz) ~TMCl3:
0.70 (s, 3 H), 0.78 Is, 3 H), 1.07 (d, J=6 Hz, 3 H), 1.17 (s, 3 H), 1.19 (s, 3 H), 3 2~3.7 (m, 4 H), 4.38 (d, J=1.5 Hz , 1 H), 5.9-6.2 (m, 3 H), 6.24 (dd, J=10, 1.5 Hz, 1 H), 7.06 (d, J=10 Hz, 1 H) ;~
IR spectrum (XBr):
2940, 2860, 1655, 1605, 1100 cm 1 Example 4 In 200 ml of methylene chloride were dissolved ;
S.00 g (14.6 mmoles) of 7a-hydroxypregna~1,4~dien-3~ ;j ,, , -one~20~carbaldehyde and 4.56 g (43.8 mmoles) of 2,2-~imethyl~1,3~propanediol, followed by addition of 100 mg of p-toluenesulfonic acid and 20 g of molecular , ~
sieve 4A 1/16. The mixture was stirred gently at room ~ ;
temp rature for 12 hours. From the reaction mixtrue thus obtained! the molecular sieve was filtered off and ~-~
the~solvent in the filtrate was distilled off under ;
reduced pressure. PinalIy the residue was purified by silica gel chromatography (eluent: ethyl acetate~hexane ~;~
= 1:10l, v~v) *o give f3.14 g of 20-~(5,5-dimethyl~1,3 dLoxan~2~yl)~7a~hydroxypregna~1,4-dien-3-one lyield:
50t).

..

'.'-~ .

~ . .

13~3.37~
:

. . .
H-NMR spectrum (90 MHz) ~TDCl3:
0.80 (s, 3 H), 0.83 (s, 3 H), 1.~7 (d, J=6 Hæ, 3 H3, 1.17 (s, 3 H), 1.22 (s, 3 H), 3.2-3.7 (m, 5 H), 4.53 (d, J=1.5 Hz, 1 H), 6.10 (m, 1 H), 6.22 (dd, J=10, 1.5 Hz, 1 H), 7.21 (d, J=10 Hz, 1 H) Example 5 To a solution of 3.00 g (6.98 mmoles) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-7~-hydroxypregna-1,4-dien-3-one in 200 ml of benzene was added 50 mg of p-toluene-sulfonic acid and the mixture was refluxed for 5 hours, with the byproduct water being constantly removed from the~reaction system by means of a Dean-Stark trap. The reaction mixture thus obtained was cooled to room t~emperature and wa~shed with aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ether~and the extract was combined with the organic layer. This mixture was washed with aqueous sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Finally the residue was purified by ~
silica gel chr~matography (eluent: ethyl ,acetate-he~ane -~
10, v/v) to recover 2.58 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one (yield:~90%). The H-NMR spectrum of this product was in agreement with : 1 ' ' , ~ I
~. .

;,: :

133~ ~7~ ~

that of the 20~(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one obtained in Example 3.
Example 6 A 10 weigh~ ~ solution of sodium hydroxide in methanol (1.16 ml) and 6.36 m of a 30 weight ~ solution of hydrogen peroxide in water (containing 62.3 mmoles of hydrogen peroxide) were added to a solution of 4.66 g (11.3 mmoles) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pre-gna-1,4,6-trien-3-one in 150 mt of methanol and the ;~
mixture was stirred at room temperature for 16 hours.
The reaction mixture thus obtained was diluted with water and after the methanol was partially distilled off under reduced pressure at room temperature, the residue was extracted with ether. The extract was washed successively with a~ueous potassium iodide solution and aqueous sodium chloride solution and the organic layer was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromato- ~-graphy (eluent: ethyl acetate~hexane -1:10, v/v) to :..
recover 3.72 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1,2~-epoxypregna~4,6-dien-~3-one (yield: j77 H-NMR spectrum (90 MHz) ~CDlsl3:

0.71 (s, 3 H), 0.77 (s, 3 H), 1.08 (d, J=6 Hz, 3 H), 1.18 (s, 6 H), 3.2-3.7 (m, 6 H), ' ~

.

~ 3 ~

4.40 (d, J=1.5 ~z, 1 H), 5.65 (s, 1 H), 6.07 (s, 2 H) IR spectrum (KBr):
2940, 2860, 1670, 1615, 1105 cm~
Example 7 A solution of 0.664 g (3.85 mmoles) of m-chloroper-benzoic acid in 50 m~ of chloroform was mixed with a solution of 0.328 g (0.769 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl) -la, 2a-epoxypregna-4,6-dien-3-one in 10 m~ of chloroform and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and the precipitate was washed with chloroform. The filtrate and the washings were com-~-~ bined, diluted with chloroform and washed successively with aqueous potassium iodide solution and aqueous -~ sodium chloride solution. Finally the organic layer - ~ was dried over magnesium sulfate and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent:
ethyl acetate-hexane: l:10, v~v) to recover 0.258 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;6a,7a-diepoxy-pregn-4-en-3-one (yield. 76%). ~ ! "
H-NMR spectrum (90 MHz) ~C C13 ~ 0.71 (s, 3 H), 0.75 (s, 3 H), 1.07 (d, J=6 ;

: ' ~,.:

:~

- 106 - ~33~3~

Hz, 3 H), 1.13 (s, 3 H), 1.17 (s, 3 H), `
3.2-3.7 (m, 8 H), 4.40 (d, J=1.5 Hz, 1 H), 6.10 (d, J=1.5 Hz, 1 ~) IR spectrum (KBr):
2900, 1680, 1150, 1105, 870 cm~
Example 8 To a solution of 0.43 g (1.0 mmole) of 20-~5,5~
dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-4~6-dien-3-one in 10 ml of methylene chloride was added 3 ml of 0.5 M-a~ueous sodium hydrogen carbonate solution ;~ under stirring and cooling in an ice-water bath, followed by gradual addition of 0.34 g (2.0 mmoles) of .:
m-chloroperbenzoic acid. The mixture was stirred at ~
- ~ room tempera~ture for 2 days. The reaction mixture thus ~-obtained was subjected to phase separation and the a~ueous layer was extracted twice with 10 ml portions ~`
~ of~methylene chloride. The extract was combined with -~; the organic layer obtained above and the mixture was washed successively with aqueous potassium iodide : : .
solution and aqueous sodium chloride solution, and dried over magnesium sulfate. ~he solvent was then distilled off unde,r reduced pressure and the residue was purifled by silica gel chromatography (eluent:
ethyl acetate-hexane = 1:10, v/v) to recover 0.35 g of 2O-(~5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;6a,7a-diepoxy- ~;

:~

- 107 - ~33~37t~ :

pregn-4-en-3-one (yield:79%). The H-MNR and IR
spectra of this product were in agreement with those of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;6~,7~-di-epoxypregn-4-en-3-one obtained in Example 7.
Example 9 To a solution of 0.105 g (0.237 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2~;6~,7~-diepoxypregn-4-en-3-one and 6 m of ethanol was added 9 mg (0.237 mmole) of sodium borohydride at a temperature of 0C and the mixture was stirred at 0C for 30 minutes. To the reaction mixture were added water and lN-hydrochloric acid in the order mentioned and the mixture was extract-ed with methylene chloride. The aqueous layer was further extracted with methylene chloride and the extract was pooled with the previous methylene chloride extract. The mixture was washed successively with cold saturated sodium hydrogen carbonate solution and aqueous sodium chloride solution and the organic layer was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:
ethyl acetate-hexane =~1:10, v/v) to recouer 0.084 g!of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2~;6~,7a-diepoxy-p.egn-4-en-3B-ol (yield: 80%).
1H-NMR spectrum (90 MHz) ~CMsl3:

- 108 - ~33~37~

0.70 (s, 3 H), 0.73 (s, 3 H), 0.95 (s, 3 H), 1.06 (d, J=6 Hz, 3 H), 1.17 (s, 3 H), 3.2-3.7 ~
(m, B H), 4.40 (d, J=1.5 Hz, 1 H), 4.3-4.5 ~ -~br, 1 H), 5.70 (dd, J=2.2, 1.9 Hz, 1 H) IR spectrum (CHC13)~
3400, 2940, 1105 cm 1 ; ~
Example 10 ~;
To a mixture of 0.084 g (0.189 mmole) of 20-(S,5-dimethyl-1,3-dioxan-2-yl)-la,2~;6a,7a-diepoxypregn-4-en-3~-ol, 0.5 m~ (6.18 mmoles) of dry pyridine and 5~ ml of methylene chloride was gradually added 0.1 m~ (1.06 mmoles) of acetic anhydride dropwise at a temperature of 0C and the solution was stirred at room remperature ~-for 8 hours. The reaction mixture thus obtained was diluted with methylene chloride and washed with saturated aqueous copper (II) sulfate solution. The aqueous layer (washings) was extracted with methylene chloride and the extract was combined with the organic layer.
The resulting mixture was washed with water and aqueous sodium chloride solution in that order and dired over ~ , ~
magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane:
1:10, v/v) to recover 0.083 g of 20-(5,5-dimethyl-1,3- ;~
dioxan-2-yl)-la,2a;6~,7a-diepoxypregn-4-en-3~-yl :
-:

1~3~ 3~
, 109 acetate (yield: 90%).
~-NMR spectrum (90 MHz) f~ T~M~ 3:
0.70 (s, 3 H), 0.73 (s, 3 ~), 0.98 (s, 3 H), 1.06 (d, J-~6 Hz, 3 H), 1.17 (s, 3 H), 2.15 ~ ~-ls, 3 H), 3.1-3.7 Im, 8 H), 4.40 (d, J=1.5 Hz, 1 H), 5.5-5.7 (m, 2 H) Example 11 A mixture of 11.6 mg (0.0112 m~mole) of tris(dibenzyl-id,eneacetone)dipalladium(chloroform), 22.4 ~' (0.0898 mmole) of tributylphosphine and 2 ml of dry tetrahydro-furan was stirred in an atmosphere of argon gas at room , - , temperature for 10 minutes. To this mixture was added 14.2 mg (0.224 mmole) of ammonium formate, followed ~,y stirring for 30 minutes. To the resulting mixture was further added a solution of 27.3 mg (0.0561 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;6a,7a-diepoxy- ;
pregn-4-en-3~-yl acetate in 2 ml of dry tetrahydrofuran and~the mixture was refluxed for 10 minutes. The reacticn mixture wac cooled to room teperature, diluted wi~th methylene chloride and washed with cold lN-hydrochloric acid. The aqueous layer (washings) was extracted with methyle,ne chloride and the extràct was comkined with the organic layer. The resulting mixture was washed successively with;~cold saturated aqueous sodlum hydrogen llo- ~3~7~
... .
, . , carbonate solution and aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled o~f under reduced pressure. Purification of the residue by silica gel chromatography (eluent: ethyl acetate-hexane = 1:5, v/~) gave 11.0 mg of 20-(5,5-di-methyl-1,3-dioxan-2-yl)-la,2a-epoxy-7a-hydroxypregn-5-en-3~-yl acetate (yield: 40%). In addition, 11.8 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2a-epoxy-7a-hydxo-xypregn-4-en-3~-yl-acetate was recovered as a byproduct (yield: 43%).
Analytical data on 20-(5~5-dimethY~ 3-dioxan-2-yl) la,2a-ePoxv-7a-hYdroxypreqn-s-en-3B-yl- acetate H-NMR spectrum (90 MHz) 6CMS13:
0.70 (s, 6 H), 1.04 ~s, 3 H), 1.17 (s, 3 H), 1.18 (d, J=6 Hz, 3 H), 2.09 (s, 3 H), 3.1-3.7 (m, 6 H), 3.7-3.9 (m, 1 H), 4.37 lbr. s, 1 H), 5.1-5.3 (m, 1 H), 5.71 (d, J=5.5 Hz, 1 H) Analytical data on 20-(5,5-dimethyl-1,3-dioxan-2-vl?-la,2a-epoxy-7a-hvdroxypregn-4-en-3~-vl acetate H-NMR spectrum (90 MHz) ~CDsl3:
; 0.70 (s, !6 H), 1.06 (d, J=5.5 Hz, 3 H~ 9 (s, 3 H), 1.17 (s, 3 H), 2.14 (s, 3 H), 3.2-3.8 (m, 7 H), 4.37 (br. s, 1 H), 5.14 (d, J=2 Hz, 1 H), 5.57 (dd, J=3, 5.5 Hz, 1 H) 3 :~ 3 7 ~ ~ ~
,.. ~ .

IR spectrum (CHCl3):
2940, 1730, 1240, 1105 cm~
Example 12 To a mixture of 49.0 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2~-epoxy-7~-hydroxypregn-5-en-3~-yl acetate, 0.24 m~ (3 mmoles) of pyridine and lO
ml of dry methylene chloride was added 0.1 ml (1.3 mmoles) of methyl chlorocarbonate dropwise at a tempe-rature of 0C and the mixture was stirred at room temperature for 8 hours. The reaction mixture was ; -~
washed with cold lN-hydrochloric acid and the aqueous layer (washings) was extracted with methylene chloride.
The extract W45 combined with the organic layer and the resulting mixture was washed successively with water, aqueous sodium hydrogen carbonate solution and aqueous ~;
sodium chloride solution and dried over magnesium ~
sulfate. The solvent was then distilled off under ~-reduced pressure and the residue was purified ~y silica , . .
-~ gel chromatograpky (eluent: ethyl acetate-hexane = -~
. . ..
10, viv) to recover 43.7 mg of 20-(5,5-dimethyl- ~-~
1,3-dioxan-2-yl)-la,2~-epoxy-7~-methoxycarbonyl-oxypregn-5-en-3~-yl acetate (yield: 80%).
H-NMR spectrum (90 MHz) CCMS13: ;~
0.70 (s,~6 H), 1.04 (s, 3 H), 1.17 (s, 3 H), 1.18 (d, J=6 Hz, 3 H), 2.09 (s, 3 H), 3.1-:

.~33~ 37~ ::

3.7 (m, 6 H), 3.75 (s, 3 H), 4~37 (br. s, 1 H), 4.7-4.9 (m, 1 H), 5.1-5.3 (m, 1 H), 5.71 (d, J=5.5 Hz, 1 H) Example 13 To a mixture of 49.0 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1,2a-epoxy-7a-hydroxypregn-5-en-3~-yl acetate, 0.24 ml (3 mmoles) of pyridine, 0.5 ' mg (o.no4 mmole) of 4-(dimethylamino)pyridine and 10 m~
of dry methylene chloride was added 0.12 ml (1.3 mmoles) of acetic anhydride dropwise at a temperature of~0C~and the solution was stirred at room temperature ~' for 10 hours. The reaction mixture was diluted with 20 ml of~methylene chloride and washed with cold lN-hydro- '-ohlorlc acid~. The aqueous layer~ (washings) was extracted ''~
with~me~hylene chloride and the extract was combined with;~the~organic }ayer. The resulting mixture was ' '-~
washed successlvely~wlth wa~ter, aqueous sodium hydrogen ''' carbonate~solution and aqueous sodLum chloride solution ~ ~' and dried over magnesium~sulfate. The solvent -was distilled off under reduced pressure and the ";i~
resid~e was~pùrified'by'silica gel chrom~atogràphy ' " -'-(eluent: e~thyl aoetate-hexane = l:10, v/v) to recover 4~5 mg of 7a-aoetoxy-20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregn-5-en-3B-yl acetate (yield: 85%).
H-NMR spectrum (90 MHz) ~TMsl3~
?, ~
. -: . .. .

f'~

1~3~ 3~

. , 0.70 (s, 6 H), 1.04 (s, 3 H), 1.17 (s, 3 ~), 1.18 (d, J=6 Hz, 3 H), 2.05 (s, 3 H), 2.09 (s, 3 H), 3.1-3.7 (m, 6 H), 4.36 (br. s, 1 H), 4.8-5.0 (m, 1 H), 5.1-5.3 (m, 1 H), 5.64 (d, J=5.5 Hz, 1 ~) Example 14 A mixture of 49.0 mg (0.1 mmole) of 20-(5,5-dime-thyl-1,3-dioxan-2-yl)-la,2a-epoxyo7~-hydroxypregn-5-en-3~-yl acetate, 0.24 ml (3 mmoles) of pyridine, 0.5 mg (0.004 mmole) of 4-(dimethylamino)pyridine, 0.12 m -(1.3 mmoles) of N,N-dimethylcarbamoyl chloride and 10 m~ of dry toluene was~ stirred at a temperature of 60C
for~l0 hours. The reaction mixture thus obtained was cooled to room temperature, diluted with 50 m~ of methylene chloride, washed with water 3 times and fLnally washed with aqueous sodium chloride solution.
The~organic layer wa~s dried over magnesium sulfate and~ ~`
the~solvent was distilled off under reduced pressure. ~;~
Finally the residue was~purified by silica gel chromato-qraphy (eluent: ethyl acetate-hexane = 1:10, v/v) to recover 37 mg of 7~-(N,N-dimethylcarbamoyloxy)-20-(5,5-dimethyl-L,3-dioxan-2 yl) la,2a-epoxypreg~n-5-en-3 acetate (yield: 70%).
IH-NMR spectrum (90 MNz) ~TDs 3: ~ ~;

.. . . . .

''~,: ` ~
:, :f~ ~ :

- 114 - 1~3137~

0.70 (s, 6 H), 1.05 (s, 3 H), 1.17 (s, 3 H), 1.18 (d, J=6 Hz, 3 H), 2.09 (s, 3 H), 2.79 (s, 3 H), 2.82 (s, 3 H), 3.2-3.8 !m, 6 H), 4.38 (br. s, 1 H), 4.7-4.9 (m, 1 H), 5.1-5.3 (m, 1 H), 5.72 (d, J=S Hz, 1 H) Example 15 In 5 ml of toluene was dissolved 49.0 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2~-epoxy-7~-hydroxypregn-5-en-3~-yl acetate, followed by addition of one drop of pyridine. Then, 0.1 ml (1.7 mmoles) of methyl isocyanate was added at a temperature of 0C and the mixture was stirred at a temperature of 60C for 30 minutes. The reaction mixture thus obtained was cooled to room temperature, poured in ice-water, and extracted 3 times with 20 ml portions of methylene chloride. The extrats are pooled, washed successively with water and ~- -aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was then distilled off -:
under reduced pressure. Finally the residue was purified by silica gel chromatography (eluent: ethyl ,~.
~; acetate-hexane = 1:10, v/v) to recover 35 mg of 20-(5,5-dimethyl-1,,3~dioxan-2-yl)-1~,2~-epoxy-7~-(N-methyl-~
carbamoyloxy)pregn-5-en-3~-yl acetate (yield: 65%). `;
.. ~
~ 1H-NMR spectrum (90 MHz) CCMS13: ~

~ , ;

13~.37~

0.70 (s, 6 H), 1.05 (s, 3 H~, 1.17 (s, 3 H), 1.20 (d, J=6 Hz, 3 H), 2.09 (s, 3 H), 2.8 (d, J=6 Hz, 3 H), 3.2-3.8 (m, 6 H), 4.40 (br. s, 1 H), 4.7-4.9 (m, 1 H), 5.1-5.3 (m, 2 H~
5.70 (d, J=5 Hz, l H) Example 16 The procedure of Example 15 was repeated except that 0.14 m~ (1.3 mmoles~ of phenyl isocyanate was used ;
in lieu of 0.1 m~ of methyl isocyanate to give 43 mg of ~ ;
20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7~-(N-phenylcarbamoyloxy)pregn-5-en-3~-yl acetate (yield~
71%). ;;
~ .
H-NMR spectrum (90 MHzj ~TMCl3:
~ 0.71 (s, 6 H), 1.06 (s, 3 H), l.l$ (s, 3 H),;~
;~ 1.20 (d, J=6 Hz, 3 H), 2.10 (s, 3 H), 3.2-3.8 ; (m, 6 H), 4.39 (br. s, l H), 4.7-4.9 Im, l H), 5.1-5.3 (m, l H), 5.70 (d, J=5 Hz, l H), 6.92 ~; ~ (br. s, 1 H), 7.1-7.7 (m, 5 H) Example 17 - ~ A mixture of 10.3 mg (0.00997 mmole) of tris(di- ~-benzylideneacetone)dipalladium(chloroform), l9.9 ` (0.0798 mmole~) 'ofltributylphosphine and 5 ml of dry;~
1,4-dioxane was stirred in an atmosphere of argon gas ~;~ at room temperature for lO minutes. ~o this m~xture was added a solution of 43.6 mg (0.0798 mmole) of "

- 116 - ~3~371~ ~

....
20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2~-epoxy-7~-methoxy-carbonyloxypregn-S-en-3~-yl acetate in 2 m~ of dry 1,4-dioxane, and the mixture was refluxed for 8 hours.
The reaction mixture was cooled to room temperature and filtered through a glass filter with the aid of Florisil.
The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel chromatogra-phy teluent: ether-hexane = 1:10, v/v) to give 17.4 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a--epoxypregna-5,7-dien-3~-yl acetate. In addition, 15.3 mg of the starting compound 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2a-epoxy-7~-methoxycarbonyloxypregn-5-en-3~-yl acetate was recovered. The yield of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-yl acetate was 71% based on consumed 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2a-epoxy-7a-methoxycarbonyloxypregn-5-en-3~-yl acetate.
H-NMR spectrum l90 MHz) ~CMsl3:
0.62 (s, 3 H), 0.71 (s, 3 H), 1.00 (s, 3 H), 1.10 (d, J=6 Hz, 3 H), 1.17 (s, 3 H), 2.10 (s, 3 H), 2.3-2.6 (m, 2 H), 3.16 (d, J=4 Hz, 1 H), 3.2-3.7 (m, 5 H), 4.40 (br. s, 1 H), 5.0-5.7 (m, 3 H) Example 18 The proceduxe of Example 17 was repeated except that 42.3 mg (0.0798 mmole) of 7~-acetoxy-20-(5,5-di-~" , - , , , " ~ , . ~, - . , :

3 ~ ~ ~

,' :
methyl-1,3-dioxan-2-yl)-la,2a-epoxypregn-5-en-3B-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7a-methoxycarbonyloxy-pregn-S-en-3~-yl acetate to give 17.6 mg of 20-15,5-dimethyl-1,3-dioxan-2-yl)-la,2-epoxypregna-5,7-dien-3~-yl acetate. In addition, 14.0 mg of 7a-acetoxy-20-(5,5-dimethyl-1,3-dioxan-2-yll-la,2a-epoxypregn-5-en 3~-yl acetate was recovered. The yield of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2~-epoxypregna-5,7-dien- -~
3~-yl acetate was 70% based on consumed 7a-acetoxy-20- -~
(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregn-5-en-3~-yl acetate. The lH-NMR spectrum of the product -20-(5,5-dimethyl-1,3-dioxan-2-ylj-la,2a-epoxypregna-..
5,7-dien-3~-yl acetate was in agreement with that of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-yl acetate obtained in Example 17.
Example 19 The procedure of Example 17 was repeated except that 44.6 mg (0.0798 mmole) of 7a-(N,N-dimethylcarba- ; ~;
moyloxy)-20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy~
pregn-5-en-3~-yl acetate was used in lieu of 43.~ mg of 20-(5,5-dimethy~-1,3-dioxan-2-ylj-la,2a-epoxy-7a-methoxy-carbonyloxypregn-5-en-3B-yl acetate to give 16.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3B-yl acetate. In addition, 16.0 mg of '' ,,~
~ :

, - i :

., -~,: , . . ;,,:,~ ,.. ,. ::.. .: ,., ,, :, .,, , - ., .. . . ;.. -133~ 37~

7~-(N,N-dimethylcarbamolyoXy)-20-(5,5-dimethyl-1,3-dio-xan-2-yl)-la,2~-epoxypregn-5-en-3~-yl acetate was recovered. The yield of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1,2a-epoxypregna-5,7-dien-3~-yl acetate was 69%
based on consumed 7~-(N,N-dimethylcarbamoyloxy)-20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregn-5-en-3~-yl acetate. The lH-NMR spectrum of the product 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-yl acetate was in agreement with that of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-yl acetate obtained in Example 17.
Example 20 -The procedure of Example 17 was repeated except that 43.5 mg (0.0798 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl) -la, 2a-epoxy-7a-(N-methylcarbamoyloxy)-pregn-5-en-3~-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7a-methoxy-~arbonyloxypregn-5-en-3~-yl acetate to give 16.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-yl acetate. In addition, 15.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7~-(N-methylcar-bamoyloxy)pregn-5-en-38-yl acetate was recovered. The yield of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1,2a-epoxy-pregna-5,7-dien-3B-yl acetate was 68~ based on consumed :~, '~

1~3~

,`` ~, 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7a-(N-me-thylcarbamoyloxy)pregn-5-en-3~-yl acetate. The lH-NM~
spectrum of the product 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-yl acetate was in agreement with that of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a epoxypregna-5,7-dien-3~-yl acetate obtained in Example 17.
Example 21 ` The procedure of Example 17 was repeated except that 48.4 mg (0.0798 mmole) of 20-(5,5-dimethyl-1,3- -~
dioxan-2-yl~-la,2a-epoxy-7a-(N-phenylcarbamoyloxy)pregn-5-en-33-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7a-methoxy-carbonyloxypregn-S-en-3~-yl acetate to give 16.3 mg of -~
~ 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2a-epoxypregna-5, ;~ 7-dien-3B-yl acetate. In addition, 17.4 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7~-(N-phenyl-carbamoyloxy)pregn-5-en-3B-yl acetate was recovered.
T-he yield of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2~-epoxypregna-5,7-dien-3B-yl acetate was 68% based on ; ;~
consumed 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2~-epoxy- `
7a-(N-phenylcarbamoyloxy)pregn-5-en-3B-yl acetate. The lH-NMR spectrum of the product 20-(5,5-dimethyl-1,3-di- ~ ;
oxan-2-yl)-1~,2a-epoxypregna-5,7-dien-3~-yl acetate was - in agreement with that of the 20-(5,5-dimethyl-1,3-di-~ ~ ''' .

- 120 - ~33~37~
~. .
oxan-2-yl)-la,2a-epoxypregna-5,7-dien-3B-yl acetate obtained in Example 17.
Example 22 To a mixture of 49.0 mg (0.1 mmole) of 20-(5,5-di-methyl-1,3-dioxan-2-yl)-1~,2~-epoxy-7-hydroxypregn-5-en-3~-yl acetate, 0.24 m~ (3 mmoles) of pyridine, 0.5 ~;
mg (0.004 mmole) of 4-(dimethylamino)pyridine and 10 m~
of methylene chloride was added 0.10 m~ (1.3 mmoles) of ~.
methanesulfonyl chloride dropwise at a temperature of 0C and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with 20 m~
of methylene chloride, then washed successively with cold lN-hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, and dried over magnesium sulfate. The :~
solvent was then distilled off under reduced pressure.
Finally the residue was purified by silica gel chromato- :~
graphy (eluent: ethyl acetate-hexane = 1:10, v/v) to :~
give 25.5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2 -epoxypregna-5,7-dien-3~-yl acetate (yield:~54%).
The H-NMR spectrum of this product was in agreement : :
with that of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-yl acetate obtained in . . ~
~ Example 17.
~, , .
Example 23 . .

3 7 ~

To a solution of 5 mg (0.0106 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2~-epoxypregna-5,7-dien-3~-yl acetate in 2 ml of dry methanol was added 7.3 mg (0.0528 mmole) of anhydrous potassium carbonate and the mixture was stirred at room temperature for 2 hours.
The reaction mxiture was filtered through a glass filter with the aid of Celite and the filtrate was concentrated under reduced pressure. Finally the concentrate was purified by silica gel chromatography (eluent: ethyl acetate-hexane = 1:5, v/v) $o give 4 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-~ 5,7-dien-3~-ol (yield: ca. 90%).
-~ lH-NMR spectrum (90 ~Hz) ~CMsl3:
0.64 (s, 3 H), 0.71 (s, 3 H), 1.01 (s, 3 H), - ;
1.10 (d, J=6 Hz, 3 H), 1.18 (s, 3 H), 3.16 (d, J=4 Hz, 1 H), 3.2-3.7(m, 5 H), 4.0-4.3 ~ (m, 1 H), 4.41 (br. s, 1 H), 5.3-5.5 (m, 1 - H), 5.6-5.8 (m, 1 H) UV spectrum (ethanol) ~max 278 nm (~:5847) Example 24 ~-To a suspension of 4 mg (0.1 mmole) of lithium ~;~
alumin~m hydride in 4 ml of dry tetrahydrofuran was added a solution of 3.8 mg (0.00887 mmole) of 20-(5,5- ~ -dimethyl- 1,3-dioxan-2-yl) -la, 2~-epoxypregna-5,7-dien-; 3B-ol in 2 ml of dry tetrahydrofuran at a temperature ,.

, ~

~333 37~

of 60C and the mixture was stirred at 60C for 30 minutes. To the reaction mixture was added water to decompose the excess lithium aluminum hydride and the tetrahydrofuran was distilled off under reduced pressure at a temperature not exceeding 60~C. To the residue was added cold lN-hydrochloric acid and the mixture was extracted with chloroform. The extract was washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under ~
reduced pressure and the residue was purified by silica ;
gel chromatography (eluent: ethyl acetate-hexane = 1:5, v/v) to give 3 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-5,7-diene-1~,3~-diol (yield: ca. 80%).
H-NMR spectrum (90 MHz) ~CDC13 0.63 (s, 3 H), 0.71 (s, 3 H), 0.91 (s, 3 H), 1.10 (d, J=6 Hz, 3 H), 1.18 (s, 3 H~, 3.2-3.7 m, S H), 4.0-4.3 (m, 1 H), 4.41 (br. s, 1 H), 5.3-5.5 (m, 1 H), 5.6-5. 8 (m, 1 H) UV spectrum (ethanol) Amax:
-- 271, 282 (E : 5847), 293 nm Example 25 ~-In lO ml ofiacetone was dissolved 4.3 mg (0.010 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-~,7-~- diene-1~,3~-diol, followed by addition of 1 m~ of a 1 mmole~l solution of p-toluenesulfonic acid in acetone : :
:

l~f3~ 3~f .' '``' ....
(containing O.OOl mmole of p-toluenesulfonic acid).
The mixture was refluxed for 2 houxs. The reaction mixture thus obtained was cooled to room temperature and the solvent was distilled off under reduced pressure.
The residue was dissolved in 40 ml of methylene chloride and this methylene chloride solution was washed with ~-saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in that order and dried over magnesium sulfate. The solvent -~
was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane = l:5, v/v) to give 2.8 mg of lfx,3B-dihydroxypregna-5,7-diene-20-carbaldehyde (yield: 82%).
NMR spectrum (90 MHz) ~CDsl3:
;~-0.71 (s, 3 H), 0.92 (s, 3 H), 1.06 (d, J-6 Hz, 3 H), 3.2-3.8 (m, l H), 4.0-4.3 (m, l H), 5.3-5.5 (m, l H), 5.6-5.8 ~m, l H), 9.54 (d, l H) Example 26 In 100 ml of acetone was dissolved 0.410 g (1.0 mmole) of 20-(51,5-dimethyl-l,3-dioxan-2-yl)pregna-1,4,6-trien-3-one, followed by addition of lO mg (0.05 mmole) of p-toluenesulfonic acid. The mixture was stirred at room temperature for 12 hours. From the reaction mixture thus obtained, the solvent was distill-- 124 - 13~.3~2~

ed off under reduced pressure and the residue was diluted with methylene chloride. The methylene chloride solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magne-sium sulfate. The solvent was then distilled off under ;
reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane =1:5, v/v) to recover 0.243 g of 3-oxopregna-1,4,6-triene-20-carbaldehyde ~yield: 75 H-NMR spectrum (90 MHz) ~CDC13 0.76 (s, 3 H), 1.08 (d, J=6 Hz, 3 H), 1.20 (s, 3 H), 5.9-6.2 (m, 3 H), 6.19 (dd, J=10, 1.5 Hz, 1 H), 7.02 (d, J=10 Hz, 1 H), 9.57 ~ ~d, J=3 Hz, 1 H) ;~; --~ Example 27 ! ~ The procedure of Example 26 was repeated except that 0.426 g (1.0 mmole) of 20-(5,5-dimethyl-1,3-dioxan- ~ - --~ 2-yl)-la,2~-epoxypregna-4,6-dien-3-one was used in lieu ~
~: .
of 0.410 g of 20~(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one to give 0.205 g of la, 2a-epoxy-3-oxopregna-4,6-diene-20-¢arbaldehyde (yield: 60%).

H-NMR spectrum (90 MHz) ~CMcl3:

':~

- 125 _ ~33~3~ ~

0.77 (s, 3 H), 1.09 (d, J=6 Hz, 3 H), 1.20 (s, 3 H), 3.2-3.7 ~m, 2 H), 5.67 (s, 1 H), 6.09 (s, 2 H), 9.55 (d, J=3 Hz, 1 H) Example 28 In 10 m~ of acetone was dissolved 44.2 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2~;6a,7 diepoxypregn-4-en-3-one, followed by addition of 5 mg (0.02 mmole) of pyridinium p-toluenesulfonate. The -~
mixture was refluxed for 2 hours. The reaction mixture thus obtained was cooled to room temperature and the solvent was distilled off under reduced pressure. The ., ~ .
residue was diluted with methylene chloride and this methylene chloride solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution . ~
and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:
ethyl acetate-hexane =~1:5, v/v) to recover 19.6 mg of ~-~
.~ la,2~;6~,7a-diepoxy-3-oxopregn-4-ene-20-carbaldehyde (yield: 55~
H-NMR spectrum (90!MHz) ~TDCl3:
0.76 (s, 3 H), 1.08 (d, J=6 Hz, 3 H), 1.15 ~; (s, 3 H), 3.2-3.7 (m, 4 H), 6.11 (d, J=1.5 i,i ~ Hz, l H), 9.S4 (d, J=3 Hz, 1 H) ,, , " ' ., ~

~ .
''.

- 126 - ~33137.~
"

Example 29 The procedure of Example 28 was repeated except that 44.4 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;6a,7a-diepoxypregn-4-en-3~-ol was used in lieu of 44.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;6a,7a-diepoxygregn-4-en-3-one to give 19.0 mg of la,2a;6,7a-diepoxy-3~-hydroxypregn-4-ene-20-carbalde-hyde (yield: 53%).
H-NMR spectrum (90 MHz) ~TMsl3~
0.73 (s, 3 H), 0.96 (s, 3 H), 1.06 (d, J=6 ~z, 3 H), 3.2-3.7 (m, 4 H), 4.3-4.5 (br, 1 H), 5.71 (m, 1 H), 9.52 (d, J=3 Hz, 1 H) Example 30 In 5 ml of acetone was dissolved 24.3 mg (0.05 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2;6,7a-.
diepoxypregn-4-en-3~-yl acetate, followed by addition of 2.5 mg (0.01 mmole) of pyridinium p-toluenesulfonate.
The mixture was refluxed for 2 hours. The reaation mixture thus~obtained was cooled to room temperature and the solvent was distilled off under reduced pressure.
To the residue was added methylene chloride and the mixture was washedlsuccessively with saturated a~ueous I ;
sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under -~
:::
~
: .

;~' ~ ';

~ 127 - ~333 37~ ~

reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane = 1:5, ;
v/v) to recover 9.6 mg of 3~-acetoxy-la,2~;6a,7a-diepoxypregn-4-ene-20-carbaldehyde Iyield: 48~).
H-NMR spectrum (90 MHz) ~CDC13 0.74 (s, 3 H), 0.99 (s, 3 H), 1.07 (d, J=6 Hz, 3 H), 2.15 (s, 3 H), 3.1-3.7 (m, 4 H), -5.5-5.7 (m, 2 H), 9.54 (d, J=3 Hz, 1 H) Example 31 The procedure of Example 23 was repeated except that 4.9 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-di-oxan-2-yl)-la,2a-epoxy-7a-hydroxypregn-5-en-3~-yl acetate was used in lieu of S mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-yl acetate to give 3.7 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregn-5-ene-3~,7a-diol (yield: 83%).
H-NMR spectrum (90 MHz) ~TMS
0.70 (s, 6 H), 1.04 (s, 3 H), 1.18 (s, 3 H), : ~:
1.19 (d, J=6 Hz, 3 H), 3.1-3.7 (m, 6 H), 3.7-3.9 (m, 1 H), 4.1-4.3 (m, 1 H), 4.38 (br.
s, 1 H), 5.70 (d, J=5 Hz, 1 H) ~ Example 3 2 The procedure of Example 23 was repeated except that 5.5 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-.,,~. , . : . : . . : ^ .. .. , ,:

- 128 - ~3~7~
, 2-yl)-la,2~-epoxy-7a-methoxycarbonyloxypregn-5-en-3B-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-yl acetate to give 2.9 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7a-methoxycarbonyloxypregn-5-en-38-ol (yield: 58%).
H-NMR spectrum (90 MHz) ~CDsl3:
0.70 (s, 6 H), 1.04 (s, 3 H), 1.17 (s, 3 H), 1.18 (d, J=6 Hz, 3 H), 3.1-3.7 (m, 6 H), 3.76(s, 3 H), 4.1-4.3 (m, 1 H), 4.38 (br. s, 1 H), 4.7-4.9 (m, 1 H), 5.70 (d, J=5 Hz, 1 ~) Example 33 The procedure of Example 23 was repeated except that 5.6 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-7a-(N,N-dimethylcarbamolyoxy)-la,2a-epoxypregn-5-en-3~-yl acetate was used in lieu of 5 mg of 20-(5,5- ~;
dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-yl acetate to give 3.7 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-7a-(N,N-dimethylcarbamoyloxy)-la,2a-epoxypregn-5-en-3~-ol (yield: 72g).
H-NMR spectrum (90 MHz) ~CDsl3:
- 0.70 ~srl6 X~ 1.05 (s~i 3 H), 1 18 (s, 3 H), 1.18 (d, J=6 Hz, 3 H), 2.79 (s, 3 H), 2.83 ~s, 3 H), 3.2-3.8 (6 H), 4.1-4.3 (m, 1 H), , . .

' ' ~
,~ :
,.

, , - , , . . , - . , .. ,, ., .. , . , .. , . . ~ .

1333 ~7t~ -, .`` ~' ' 4.40 (br. s, 1 H), 4.7-4.9 ~m, 1 H), 5.1-5.3 -~
(m, 1 H), 5.5-5.8 ( 1 H) Example 34 ;~`
The procedure of Example 23 was repeated except -that 6.1 mg (0.01 mmole) of 20-~5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7a-(N-phenylcarbamolyoxy)pregn-5-en-.:
3B-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3B-yl acetate to give 4.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7a-(N-phenylcarbamoyloxy)pregn-5-en-3B-ol (yield: 74~

H-NMR spectrum (90 MHz) ~TMS 3:

0.~71 (s, 6 H), 1.05 (s, 3 H), 1.18 (s, 3 H), -~

1.19 (d, J=6 Hz, 3 H), 3.1-3.9 (m, 7 H), - 4.1-4.3 (m, 1 H), 4.39 (br. s, 1 H), 5.70 (d, ;~ J=5 Hz, 1 H), 6.90 (br. s, 1 H), 7.1-7.7 (m, ;~
-~ ; 5 H) ,,~, , Example 35 The procedure of Example 23 was repeated except that 5.5 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy-7a-(N-methylcarbamoyloxy)pregn-S-en- ~;-3B-~yliacetate *as~used in lieu of 5 mg o~ 20-~5,5-di-methyl-1,3-dioxan-2-yl) -la, 2a-epoxypregna-5,7-dien-3B-yl acetate to give 3.8 mg of 20-(5,5-dimethyl-1,3-dioxan-'',' ' ~' ~

" , ~
: ' - 130 ~ 133~

2-yl)-la,2a-epoxy-7~-(N-methylcarbamoyloxy)pregn-5-en-3B-ol (yield: 76%).
H-NMR spectrum (90 MHz) ~CDsl3:
0.70 (s, 6 H), 1.05 (s, 3 H), 1.17 (s, 3 H), 1.20 (d, J=6 Hz, 3 H), 2.80 (d, J=6 Hz, 3 H), 3.2-3.8 (m, 6 H), 4.1-4.3 (m, 1 H), 4.40 (br. ;~
s, 1 H), 4.7-4.9 (m, 1 H), 5.1-5.3 (m, 2 H), 5.70 (d, J=5 ~z, 1 H~
Example 36 In 2.5 m~ of acetone was dissolved 2.2 mg ~0.005 ~-mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2~-epoxy--~ pregn-5-ene-3~,7~-diol, followed by addition o 0.5 m of a l mmol/l solution of p-toluenesulfonic acid in acetone (containing 0.0005 mmole of p-toluenesulfonic acid). The mixture was stirred at room temperature for 12 hours. From the reaction mixture thus obtained, the ~;
solvent was distilled off under reduced pressure and , . . . methylene chloride was added to the residue. This methylene chloride solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution and dried over magnesiumi sùlfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate--: : ,.
~ hexane = 1:5, v/v) to recover 1.2 mg of la,2~-epoxy- 1 ~
~" , : ~
,, ,, ~, ,,-", :~' ,'' i ~ ' . :

- 131 - 1 333. 3 7~
....
3B,7a-dihydroxypregn-5-ene-20-carbaldehyde (yield:
67%).
H-NMR spectrum (90 MHz) ~CDC13 0.73 (s, 3 H), 1.06 (s, 3 H), 1.20 (d, J=6 Hz, 3 H), 3.1-3.7 (m, 2 H), 3.7-3.9 (m, 1 H), 4.1-4.3 (m, 1 H), 5.71 (d, J=5 Hz, 1 H), 9.55 (d, J=3 Hz, 1 H) Example 37 The procedure of Example 36 was repeated except that 2.5 mg (0.005 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2a-epoxy-7a-methoxycarbonyloxypregn-5-en-3B-ol was used in lieu of 2.2 mg of 20-(5,5-dimethyl-1,3-di-oxan-2-yl)-la,2a-epoxypregn-5-ene-3B,7a-diol to give .3 mg of la,2a-epoxy-3B-hydroxy-7a-methoxycarbonyloxy-- - -5 ~ pregn-5-ene-20-carbaldehyde (yield: 62%).

5~ lH-NMR spectrum (90 MHz) ~TMsl3:

0.73 (s, 3 H), 1.06 (s, 3 H), 1.18 ~d, J=6 ~ ;

Hz, 3 H), 3.1-3.7 (m, 2 H), 3.75 (s, 3 H), 4.1-4.3 (m, l H), 4.7-4.9 (m, 1 H), 5.71 (d, J=5 Hz, 1 H), 9.5~ (d, J=3 Hz, 1 H) Example 38 THe procedure of Example 36 was repeated èxcept that 2.5 mg ~0.005 mmole) of 20-(5,5-dimethyl-1,3-di-~ oxan- ?-Yl)- 7a-(N ,~N-dimethylcarbamoyloxy)-la,2a-epoxy-- pregn-5-en-3B-ol was used in lieu of 2.2 mg of 20-',;'~ , ~ ' "' ' '~
.

- 132 - 1~3~ 3 7~ ~:

(5,5-dimethyl-1,3-dioxan-2-yl)-1,2a-epoxypregn-5-ene-3~,7a-diol to give 1.5 mg of 7a-(N,N-dimethylcarbamoyl-oxy)-la,2a-epoxy-3B-hydroxypregn-5-ene-20-carbaldehyde (yield: 704).
H-NMR spectrum (90 MHz) ~CMsl3:
0.72 (s, 3 HJ, 1.05 (s, 3 H), 1.16 ~d, J=6 Hz, 3 H), 2.78 (s, 3 H), 2.82 (s, 3 H), 3.1-3.7 Im, 2 H), 4.1-4.3 (m, 1 H), 4.7-4.9 (m, 1 H), 5.71 (d, J=S Hz, 1 H), 9.55 (d, J=3 Hz, 1 H) Example 39 The procedure of Example 36 was repeated except that 2.8 mg (0.005 mmole) of 20-(5,5-dimethyl-1,3-di-;~ oxan-2-yl)-la,2a-epoxy-7a-(N-phenylcarbamoyloxy)pregn--~ S-en-3~-ol was used in lieu of 2.2 mg of 20-(5,5-di--~ methyl-1,3-dioxan-2-yl)-la,2a-epoxypregn-5-ene-3~,7a-~ diol to give 1.5 mg of 1,2a-epoxy-3~-hydroxy-7a-(N- -- ~ phenylcarbamoyloxy)pregn-5-ene-20-carbaldehyde (yield~
63%).
H-NMR spectrum (90 MHz) ~CMcl3:
0.71 (s, 3 H), 1.05 (s, 3 H), 1.17 (d, J=6 Hz, 3,H),, 3,1-3.8 (m, 2 H), 4.1-4.3 ~m, llH), 4.7-4.9 (m, 1 H), 5.70 (d, J=5 Hz, 1 H), 6~92 (br. s, 1 H), 7.1-7.7 (m, 5 H), 9.54 (d, J=3 -~ Hz, 1 H) ~33~ 37~

Example 40 The procedure of Example 36 was repeated except that 2.5 mg (0.005 mmole) of 20-(5,5-dimethyl 1,3-di-oxan-2-yl)-1~,2~-epoxy-7a-(N-methylcarbamoyloxy)pregn-5~en-3~-ol was used in lieu of 2.2 mg of 20-~5,5-di- ~ -methyl-1,3-dioxan-2-yl)- la, 2a-epoxypregn-5-ene-3~,7a-diol to give 1.3 mg of 1~,2~-epoxy-3~-hydroxy-7a-(N-methyl-carbamoyloxy)pregn-S-ene-20-carbaldehyde (yield: 62%).
H-NMR spectrum (90 MHz) ~CMsl3:
0.70 (s, 3 H), 1.05 (s, 3 H), 1.16 ~s, 3 H), 1.19 (d, J=6 Hz, 3 H), 2.82 (d, J=6 Hz, 3 H), 3.2-3.8 (m, 2 H), 4.1-4.3 (m, 1 H), 4.7-4.9 ., ~
-(m, 1 H), 5.1-5.3 (m, 1 H), 5.69 (d, J25 Hz, ` .
1 H), 9.54 (d, J=3 Rz, 1 H) Example 41 In 4 m~ of acetone was dissolved 4.9 mg (0.01 j , ~ mmole) of 20-~5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy- ~
5,' ' ~ 7a-hydroxypregn-5-en-3~-yl acetate, followed by addition ~ -~
~,. -:. .: . -of 1 ml of a 1 mmol/l solution of p-toluenesulfonic acid in acetone (containing O.OOi mmole of p-toluenesulfonic acid). The mixture was stirred at room temperature for 12 houris. From the reaction mixture thus obtained, the solvent was distilled off~under reduced pressure and the residue was diluted with methylene chloride. This methylene chloride solution was washed successively with ;~;

,, . ~ ~

':

~ 33~ 37c~

., -- ,.

saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography ~eluent: ethyl acetate-hexane = l:S, v/v) to recover 2.7 mg of 3~-acetoxy-la,2a-epoxy-7a-hydroxypregn-5-ene-20-carbaldehyde (yield~
67%).
H-NMR spectrum 190 MHz) ~TMsl3:
0.70 (s, 3 H), 1.04 (s, 3 H), 1.19 (d, J=6 Hz, 3 H), 2.10 (s, 3 H), 3.1-3.7 (m, 2 H), 3.7-3.9 (m, 1 H), 5.1-5.3 (m, 1 H), 5.72 (d, J=5 Hz, 1 H), 9.55 (d, J=3 Hz, 1 H) Example 42 The procedure of Example 41 was repeated except that 5.5 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan--yl)-la~2a-epoxy-7a-methoxyc~rbonyloxypregn-5-en-3~-yl acetate was used in lieu of 4.9 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1,2a-epoxy-7a-hydroxypregn-5-en-3~-yl acetate to give 3.4 mg of 3~-acetoxy-la,2a-epoxy-7a-methoxycarbonyloxypregn-5-ene-20-carbaldehyde (yield:
74%).
H-NMR spectrum (90 MHz) ~CMcl3 0.73 (s, 3 H), 1.06 (s, 3 H), 1.19 (d, J=6 ~
Hz, 3 H), 2.10 (s, 3 H), 3.1-3.7 (m, 2 H), ;

; ..

- 135 - ~ ~33 37~ ~ ~

3.76 (s, 3 H), 4.7-4.9 (m, 1 H), 5.1-5.3 (m, 1 H), 5.70 (d, J=5 Hz, 1 H), 9.56 (d, J=3 Hz, 1 H) Example 43 The procedure of Example 41 was repeated except that 4.7 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2~-epoxypregna-5,7-dien-3B-yl acetate was used in lieu of 4.9 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)- ;~
1~,2~-epoxy-7~-hydroxypregn-5-ën-3B-yl acetate to give 2.6 mg of 3~-acetoxy-la,2a-epoxypregna-5,7-diene-20-carbaldehyde (yield: 68%).
H-NMR spectrum (90 MHz) ~TMS 3:
0.63 (s, 3 H), 1.01 (s, 3 H), 1.11 (d, J=6 :
. . .
Hz, 3 H), 2.10 (s, 3 H), 3.1-3.7 (m, 2 H), 5.0~5.7 (m, 3 H), 9.53 (d, J=3 Hz, 1 H) Example 44 ~-~The procedure of Example 36 was repeated except that 2.2 mg (0.005 mmolel of 20-(5,5-dimethyl-1,3-di-oxan-2-yI)-1~,2~-epoxypregna-5,7-dien-3~-ol was used in lieu of 2.2 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)~
,........................................................................ .:
-1~,2a-epoxypregn-5-ene-3~,7~-diol to give 1.0 mg of 1,2~-epoxy-3~-hydroxyjpregna-5,7-diene-20-carbaldehyde ~i~

(yield: 58%).

H-NMR spectrum (90 MHz) ~CDIC13 ,: :
. ::
: ':

:

- 136 - 33~ 3 ~9 `~
, `.~ , 0.64 (s, 3 H), 1.02 (s, 3 ~), 1.12 (d, J=6 -~
Hz, 3 H), 3.1-3.7 (m, 2 H), 4.0-4.3 (m, 1 H), 5.3-5.5 (m, 1 H), 5.6-5.8 (m, 1 H), 9.55 (d, J=3 Hz, 1 H) Example 45 ~, The procedure of Example 3 was repeated except that 2.72 g (43.8 mmoles) of ethylene glycol was used in lieu of 4.56 g of 2,2-dimethyl-1,3-propanediol to give 4.56 g of 20-(1,3-dioxolan-2-yl)pregna-1,4,6-trien- ~ ;
3-one (yield: 85~).
, ~
H-NMR spectrum (90 MHz) ~CMsl3 0.79 (s, 3 H~, 1.08 (d, J=6 Hz, 3 H), 1.20 ~s,~3 H), 3.7-4.0 (br, 4 H), 4.80 (br. s, 1 H), 5.9-6.3 (m, 3 H), 6.28 (dd, J=10, 1.5 Hz, I H), 7.10 (d, J=10 Hz, 1 H) Example 46 The procedure of E~mple 6 was repeated except that 4.16 g (11.3 mmoIes)~of 20-(1,3-dioxolan-2-yl)pregna-; 1,4,~6-trien-3-one was used in lieu of 4.66 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one~to ;~
give 3.25~g of 20-(1,3-dioxolan-2-yl)-la,2a-epoxypregna-` 4,6-dien-3-one (yield' ! ts%) . : I ~ :
.
- lH-NMR spectrum~(90 MHz) ~CMsl3:

~: ' ;' ~ ,,~ , , 5:" .'''~ ' ~33~7~

0.78 (s, 3 H), 1.09 (d, J=6 Hz, 3 H), 1.19 (s, 3 H), 3.7-4.0 (br, 4 H), 4.80 (br. s, 1 H), 5.67 (s, 1 H), 6.09 (s, 2 H) Example 47 The procedure of Example 7 was repeated except that 0.295 g (0.769 mmole) of 20-(1,3-dioxolan-2-yl)-la,2a-epoxypregna-4,6-dien-3-one was used in lieu of ~ -~
0.328 g of 20-(5,5-dimethyl-1,3-dioxan-2-yli-la,2a~
epoxypregna-4,6-dien-3-one to give 0.231 g of 20-(1,3-dioxolan-2-yl)-la,2a;6a,7~-diepoxypregn-4-en-3-one (yield: 75%).
- H-NMR spectrum (90 MHz) ~CMCl3:
0.74 (s,~3 H), I.06 (d,'J=6 Hz, 3 H), 1.12 (s, 3 H), 3.2-3.7 (m, 4 H), 3.7-4.0 (br, 4 H), -~
4.79 (br. s, 1 H), 6.09 (d, 1 Hj ,,~
Example 48 The procedure of Example 9 was repeated except that 0.095 g (0.237 mmole) of 20-(1,3-dioxolan-2-yl)~
la~,2;6a,7a-diepoxypregn-4-en-3-one was used in lieu of ; -0.105 g of 20-(5,5-dimethyl-1,3-dioxan-2-yli-la,2u;6a,7a- ;~
diepoxypregn-4-en-3-one to give 0.074 g of 20-(1,3-di- ~;
oxolan-2-yl)-la,2a;6a;7a-diepoxypregn-4-en-3~-ol (yiè~d:' ~-- ~ 78%).
~ - 1H-NMR spectrum (~0 MHz) ~C S 3 ",~

,, : :~

- 138 - 13~37~
. . . .
0.72 ~s, 3 H), 0.94 (s, 3 H), 1.05 (d, J=6 ~z, 3 H), 3.2-3.7 (m, 4 H), 3.7-4.0 (br, 4 ~), 4.3-4.5 (br, 1 H), 4.79 (br. s, 1 H), 5.68 (dd, J=2.2, 1.9 Hz, 1 H) ~-Example 49 The procedure of Example 10 was repeated except that 0.076 g (0.189 mmole) of 20-~1,3~dioxolan-2-yl)-la,2a;6a,7a-diepoxypregn-4-en-3~-ol was used in lieu of 0.084 g of 20-(5,5-`dimethyl-1,3-dioxan-2-yl)-la,2a;6a,7~-diepoxypregn-4-en-3B-ol to give 0.074 g~of 20-(1,3-dioxolan-2-yl)-la,2;6,7-diepoxypregn-4-en- ~ ;
; 3~-yl acetate (yield: 88%).
- ~ lH-NMR spectrum ~90 MHz) ~TMS 3:
0.72 (s,~3 H), 0.97 (s, 3 H), 1.05 (d, J-6 Hz, 3 H), 2.13 (s, 3 H), 3.1-3.7 (m, 4 H), -~
,, 3 7-4.0 (br, 4 H), 4.80 (br. s, 1 H), 5.5-5.7 Example 50 The procedure of Example ll;was repeated except that 24.9 mg (0.0561 mmole) of 20-(1,3-dioxolan-2-yl)-1, 2a; 6a, 7a-diepoxypregn-4-en-3~-yl acetate was used in lieu of 27.3 mglof 20-(5,5-dimethyl-1,3-dioxan-l2-yl)-~
~la,2a;6a,7a-diepoxypregn-4-en-3B-yl acetate to give 9.5 ~-mg of 20-(1,3-dioxolan-~2-yl)-la,2a-epoxy-7a-hydroxypregn-~ 5-en-3~-yl acetate (yield: 38%) and, as a byproduct, :''' ~'',' ' ' ' ' "
~, . .
~' ~

13~137.~

10.3 mg of 20-(1,3-dioxolan-2-yl)-la,2a-epoxy-7~-hydroxy-pregn-4-en-3~-yl acetate (yield: 41%).
Analytical data on 20-(1,3-dioxolan-2-yl)-la,2~-epoxy-7~-hydroxypreqn-5-en-3B-vl acetate H-NMR spectrum (90 MHz) ~CMsl3:
0.71 (s, 3 H), 1.05 (s, 3 H), 1.19 (d, J=13 Hz, 3 H), 2.10 (s, 3 H), 3.1-3.7 (m, 2 H), ~-~
3.7-4.0 (5 H), 4.81 (br. s, 1 H), 5.1-5.3 (m, --~
1 H), 5.72 (d, J=5 Hz, 1 H) Analytical data on 20-(1,3-dioxolan-2-Yl)-1~,2~-ePox~
7a-hYdroxyereqn-4-en-3~-yl acetate H-NMR spectrum (90 MHz) ~CTDcl3:
0.71 (s, 3 H), 1.07 (d, J=6 Hz, 3 H), 1.10 (s,~3 H), 2.15 (s,~3 H), 3.2-4.0 (7 H), 4.81 ;
s ~ (br. s, 1 H), 5.15 (d, J=2 Hz, 1 H), 5.58 (dd, J=5.5, 3 Hz,- 1 H) ~;
Example 51 The procedure of Example 12 was repeated except ., ~-~ that 44.6 mg (O.l mmole) of 20-(1,3-dioxolan-2-yl)-la,2a-epoxy-7a-hydroxypregn-5-en-3B-yl acetate was used in lieu of 49.0 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)- ~-~
la,2a-epoxy-7~-hydroxypregn-S-en-3B-yl ac!etate to givè

37.8 mg of 20-(1,3-dioxolan-2-yl)-1~,2a-epoxy-7~-methoxy-~i- carbonyloxypregn-5-en-3~-yl acetate (yield: 75%) H-NMR spectrum (90 MHz) ~TMscl3:

"-~ .

13~137~

0.71 (s, 3 H), 1.05 (s, 3 H), 1.19 (d, J=13 Hz, 3 H), 2.10 (s, 3 H), 3.1-4.0 (9 H), 4.81 ~br. s, 1 H), 4.7-4.9 (br. s, 1 H), 5.1-5.3 (m, 1 H), 5.72 (d, J=5 Hz r 1 H) Example 52 ~
The procedure of Example 17 was repeated except ;~-that 40.2 mg (0.0798 mmole) of 20-(1,3-dioxolan-2-yl)- ~
la,2a-epoxy-7a-methoxycarbonyloxypregn-5-en-3~-yl ~ ;
acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl- i~
1,3-dioxan-~-yl)-la,2~-epoxy-7a-methoxycarbonyloxy-pregn-5-en-3~-yl acetate to give 15.5 mg of 20-(1,3-dioxolan-2-yl)-la,2~-epoxypregna-5,7-dien-33-yl acetate.
~ In addition, 14.2 mg of the starting compound 20-(1,3-5' '~ ~ dioxolan-2-yl)-1,2a-epoxy-7a-methoxycarbonyloxy-pregn-5-en-3~-yl acetate was recovered. The yield of -~
20-(1,3-dioxolan-2-yl)-la,2a-epoxypregna-5,7-dien-33-yl ^
acetate was 70~ based on consumed 20-(1,3-dioxolan-2- -yl)-la,2~-epoxy-7a-methoxycarbonyloxypregn-5-en-3~-yl -`-;
acetatê.
H-NMR spectrum (90 MHz) ~CMcl3 0.63 (s, 3 H), 1.01 (s, 3 H), 1.11 (d, J=6 `
; Hz, 3 H), 2.11 (s, 3 H), 2.3-2.6 (m, 2 H), 3.17 (d, J=4 Hz, 1 H), 3.2-4.0 (5 H), 4.81 -~ (br. s,~l N), 5.0-5.7 (m, 3 H) , ~,,: ~ .
, , ~:, -~s ' '' ':

- 141 - ~33~371~

Example 53 The procedure of Example 23 was repeated except that 4.5 mg (0.0106 mmole) of 20-(1,3-dioxolan-2-yl)-1,2a-epoxypregna-5,7-dien-3~-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2~-epoxypregna-5,7-dien-3~-yl acetate to give 3.7 mg of 20-(1,3-dioxolan-2-yl)-la,2~-epoxypregna-5,7-dien-3~-ol (yield: 90%).
H-NMR spectrum (90 MHz) ~CDC13 0.63 (s, 3 H), 1.01 (s, 3 H), 1.11 (d, J=6 Hz, 3 H), 3.15 (d, J=4 Hz, 1 H), 3.2-4.0 (5 H), 4.0-4.3 (m, 1 H), 4.80 (br. s, 1 H), 5.3-5.5 (m, 1 H), 5.6-5.8 (m, 1 H) ~ Example 54 ~ -;
-~ The procedure of Example 24 was repeated except that 3.4 mg (0.00887 mmole) of 20-(1,3-dioxolan-2-yl)-la,2a-epoxypregna-5,7-dien-3~-ol was used in lieu of 3.8 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxy--~ pregna-5,7-dien-3~-ol to give 2.7 mg of 20-(1,3-dioxolan-2-yl)pregna-5,7-diene-1,3~-diol (yield: 78%).
lH-NMR spectrum (90 MHz) ~CDC13 , ~
0.65 (s, 3 H), 0.93 (s, 3 H), 1.12 (d, J=6 Hz, 3 H), 3.2-4.0 (5 H), 4.0-4.3 (m, 1 H), ~ ,.
~ 4.82 (br. s, 1 H), 5.3-5.5 (m, 1 H), 5.6-5.8 -- (m, 1 H) ,~. ,, -, ', ~

~.

- 142 - 133~37~

~; ~
Example 55 The procedure of Example 25 was repeated except that 3.9 mg (0.010 mmole) of 20-(1,3-dioxolan-2-yl)- `
pregna-5,7-diene-la,3~-diol was used in lieu of 4.3 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-5,7-diene-la,3~-diol to give 2.7 mg of la,3B-dihydroxypregna-5,7-diene-20-carbaldehyde (yield: 78 Example 56 The procedure of Example 4 was repeated except that 3.2 g (100 mmoles) of methanol was used in lieu of -`.-4.56 g of 2,2-dimethyl-1,3-propanediol to give 2.55 g ~:~
O~ ?a-hydroxy-21,21-dimethoxy-20-methylpregna-1,4-dien- `~-~
3-one (yield: 45~j.
H-NMR spectrum (90 MHz) ~TMS 3 0.75 (s, 3 H), 1.06 (d, J=6 Hz, 3 H), 1.18 (s, 3 H), 3.38 (s, 3 H), 3.41 (s, 3 H), 3.97 (1 H), 4.40 (br. s, 1 H), 6.09 (1 H?, 6.18 (dd, J=10, 1.5 Hz, 1 H), 7.02 (d, J=10 Hz, 1 H) Example 57 The procedure of Example 5 was repeated except ~ `~
that 2.50 g (6.44 mmoles) of 7a-hydroxy-21,21-dimethoxy- , !,, 20-methylpregna-1,4-dien-3-one was used in lieu of 3.00 g of 20-(S,S-dimethyl-1,3-di~oxan-2-yl)-7a-hydroxypregna-1,4-dien-3-one ~to give 2.00 g of 21,21-dimethoxy-20~

: .

.,,, - ~, "

": :' .:.
,~ , - :

- 143 - 13~$7~
...~.
.. ~................................................................................ :
methylpregna-1,4,6-trien-3-one (yield: 84%).

H-NMR spectrum l90 MHz) ~CT~scl3:
~ 0.77 (s, 3 H), 1.07 (d, J=6 Hz, 3 H), 1.18 ¦ (s, 3 H), 3.38 (s, 3 H), 3.41 (s, 3 H), 4.39 (br. s, 1 H), 5.9-6.2 (m, 3 H), 6.22 (dd, J=10, 1.5 Hz, 1 H), 7.04 (d, J=10 Hz, 1 H) Example 58 To a solution of 2.00 g (5.4 mmoles) of 21,21-dimethoxy-20-methylpregna-1,4,6-trien-3-one in 70 ml of methanol were added a 10 wt ~ solution of sodium ~ ~ hydroxide in methanol (0.55 ml) and 3.04 ml of a 30 wt - ~ % aqueous solution of hydrogen peroxide (containing 29.8 mmoles of hydrogen peroxide) and the mixture was ;~ otirxed at room temperature~for 14 hours. The reaction mixture was worked up in the~same manner as Example 6 ~ -to recover 1.56 g of la,2~-epoxy-21,21-dimethoxy-20-methylpregna-4,6-dien-3-one (yield: 75%).
H-NMR spectrum (90 MHz)~CMsl3 0.76 (s, 3 H), 1.06 ~d, J=6 Hz, 3 H), 1.16 ts, 3 H), 3.2-3.7 (8 H), 4.38 (br. s, 1 H~
5.63 (s, 1 H), 6.05 (s, 2 H) ~ 1 E*ample 59 -~ ~ A mixture ;of 0.836 g (0.5 mmole~ of m-chloroper- ;~
;~ benzoic acid and 70~ml of chloroform was added to a ~;"~ :
.,,,, ~ ~ ~:

- 144 - ~ . 3 7 ~

mixture of 0.772 g (2.0 mmoles) of la,2~-epoxy-21,21-dimethoxy-20-methylpregna-4,6-dien-3~one and 20 m~ of chloroform and the whole mixture was stirred at room temperature for 1 day. The reaction mixture thus obtained was worked up in the same manner as Example 7 to recover 0.498 g of la,2a;6a,7a-diepoxy-21,21-dime-thoxy-20-methylpregn-4-en-3-one (yield: 62%).
H-NMR spectrum (90 MHz) ~TMS 3:
0.72 (s, 3 H), 1.04 (d, J-6 Hz, 3 H), 1.10 (s, 3 H), 3.2-3.7 (10 H), 4.39 (br.
s, 1 H), 6.08 (d, 1 H) ~- Example 60 -. :
-~ To a solution of 0.402 g (1 mmole) of 1~,2a;6a,7~-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3-one in 30 ml of tetrahydrofuran was added 38 mg (1 mmole) of ; sodium borohydride at a temperature of 0C and the .,,,.~ :
~-~ mixture was stirred at 0C for 30 minutes. The reaction mixture was diluted with water and neutralized by adding cold lN-hydrochloric acid in small portions.
,i . .
c-~ From this mixture, the tetrahydrofuran was distilled -,....................................................................... .
off under reduced pressure at a temperature not exceeding 20C and the resïdue was diluted with water and extracted with methylene chloride. The extract was washed with ~`~ aqueous sodium chloride solution and dried over magnesium sulfate. The solve~t was then distilled off under -, '~

~ J

,_ reduced pressure. Finally the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane = 1:10, v/v) to recover 0.250 g of 1~,2~;6~,7~-diepoxy-21,21-dimethoxy- 20-methylpregn-4-en-3B-ol (yield:
62%).
H-NMR spectrum (90 MHz) ~CMscl3:
0.71 (s, 3 H), 0.93 (s, 3 H), 1.04 (d, J=6 Hz, 3 H), 3.2-3.7 (10 H), 4.3-4.5 (2 H), 5.69 ~ ~-(1 H) Example 61 To a mixture of 0.202 g (0.50 mmole) of 1~,2~;6~,7 diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3~-ol, 0.5 mQ (6.18 mmoles) of dry pyridine and 10 mt of methylene ~; chloride was gradually added 0.1 m~ (1.06 mmoles) of acetic anhydride dropwise at a temperature of 0C and ~ -~
the resulting solution was stirred at room temperature for 14 hours. The reaction mixture was then worked up i~ in the same manner as Example lO to recover 0.185 g of s- 1~,2ai6~,7a-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3~-yl acetate (yield: 83%).
H-NMR spectrum (90 MHz) ~TMsl3: i 0.73 (s, 3 H), 0.97 (s, 3 H), 1.05 (d, J=6 ~ -~
Hz,~3 H), 2.13 (s, 3 H), 3.1-3.7 (10 H), 4.40 (br. s, 1 H), 5.5-5.7 (2 H) ~-~- Example 62 ::
,,', ~, , - 146 ~

The procedure of Example 11 was repeated except that 25.0 mg (0.0561 mmole) of la,2~;6a,7a-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3~-yl acetate was used in lieu of 27.3 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2~;6a,`7a-diepoxypregn-4-en-3~-yl acetate to ~ -give 9.8 mg of 1,2~-epoxy-7~-hydroxy-21,21-dimethoxy-20-methylpregn-5-en-3~-yl acetate (yield: 39%) and, as a byproduct, 10.6 mg of la,2a-epoxy-7a-hydroxy-21,21-dimethoxy-20-methylpregn-4-en-3~-yl acetate (yield:
42%).
Analytical data on la,2a-ePoxy-7a-hYdroxy-21,21-dimethoxy-20-methylpregn-5-en-3~-Yl acetate ~; lH-~MR spectrum (90 MHz) ~CMcl3: ~`~
0.70 (s, 3 H), 1.04 (s, 3 H), 1.18 (d, J=6 Hz, 3 H), 2.09 (s, 3 H), 3.1-3.7 (8 H), 3.7-3.9 (1 H), 4.39 (1 H), 5.1-5.3 (1 H), ~ , 5.70 (d, J=S Hz, 1 H) Analytical data on la,?a-epoxY-7a-hYdroxy-2l~2l-di methoxY-2o=methvlpr-e~n-4-e-n-3~-yl acetate H-NMR spectrum (90 MHz) ~CMcl3:

0.70 (s, 3 H), 1.06 (d, J=6 Hz, 3 H), 1.09 (s, 3 H);, 2.14 ls, 3 H), 3.2-3.9 l9 H), 4.39 (br. s, 1 H), 5.14 (d, J=2 Hz, 1 H), 5.56 (dd, J=5.5, 3 Hz, 1 H) Example 63 ', '~

~ .
.

1331~7~

The procedure of Example 12 was repeated except that 45~0 mg (0.1 mmole) of la,2a-epoxy-7a-hydroxy-21,21-dimethoxy-20-methylpregn-5-en-3~-yl acetate was used in lieu of 49.0 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yll-la,2a-epoxy-7~-hydroxypregn-5-en-3~-yl acetate to give 39.0 mg of la,2a-epoxy-21,21-dimethoxy-7a-methoxy-carbonyloxy-20-methylpregn-5-en-3~-yl acetate (yield:
77%).
H-NMR spectrum (90 M~z) ~TDC 3:
0.70 (s, 3 H), 1.03 (s, 3 H), 1.16 (d, J=6 ~-Hz, 3 H), 2.10 (s, 3 H), 3.1-4.0 (11 H), -~
4.40 (br. s, 1 H), 4.7-4.9 (1 H), 5.1-5.3 (1 H), 5.70 (d, J=5 Hz, 1 H) Example 64 , ~
The~procedure of Example 17 was repeated except ~-that 40.4 mg (0.0798 mmole) of la,2a-epoxy-21,21-di-methoxy-7a-methoxycarbonyloxy-20-methylpregn-5-en-3~-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl- -1,3-dioxan-2-yl)-1~,2a-epoxy-7a-methoxycarbonyloxypregn-5-en-3~-yl acetate to give 15.6 mg of la,2a-epoxy-21,21-dimethoxy-20-methylpregna-5,7-dien-3~-yl acetate. ~, In addition, 14.1~mg of the starting compound i~,2a-epoxy-21,21-dimethoxy-7a-methoxycarbonyloxy-20-methylpregn-5 en-3~-yl acetate was recovered. The yield of la,2a-epoxy-21,21-dimethoxy-20-methylpregna-5,7-dien-3~-yl acetate -, ~
,~ ~,, ::
,~" . ~;"

~' :
;, - 148 - 13~.37~

.
was 70% based on consumed la,2a-epoxy-21,21-dimethoxy-7a-methoxycarbonyloxy-20-methylpregn-5-en-3~-yl acetate.
H-NMR spectrum (90 MHz) ~TMsl3:
0.62 (s, 3 H), 0.99 (s, 3 H), 1.09 (d, J=6 ~`~
Hz, 3 H), 2.09 (s, 3 H), 2.3-2.6 (m, 2 ~), 3.16 (d, J=4 Hz, 1 H~, 3.2-3.7 (7 H), 4.40 ~
(br. s, 1 H), 5.0-5.7 13 H) ;-Example 65 The procedure of Example 23 was repeated except that 4.6 mg (0.0106 mmole~ of la,2a-epoxy-21,21-di-methoxy-20-methylpregna-5,7-dien-3~-yl acetate was used in lieu of S mg of 20-(S,S-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-5,7-dien-3B-yl acetate to give 3.5 mg of la,2a-epoxy-21,21-dimethoxy-20-methylpregna 5,7-dien-~; 3~-ol (yield: ca. 85%).
H-NMR spectrum (90 MHz) ~CMsl3:
~- 0.64 (s, 3 H), 1.01 (s, 3 H), 1.09 (d, J=6 ; ~ Hz, 3~H), 3.16 (d, J=4 Hz, 1 H), 3.2-3.7 (7 H), 4.0-4.3 (1 H), 4.39 (br. s, 1 H), 5.3-5.5 (m, 1 H), 5.6-5.8 (m, 1 H) --~
Example 66 The procedure of Example 24 was repeated except that 3.4 mg (0.00887 mmole) of la,2a-epoxy-21,21-di-methoxy-20-methylpregna-5,7-dien-3B-ol wa-~ used in lieu of 3.8 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)~la,2a- ,- -~
~' ~`,;'.

'~

,,, , `

,. - ,, , " , -,, , ,. , ,- , , , , . - . ., : .. -:: . , : "

- 149 - I3~7t~

epoxypregna-5,7-dien-3~-ol to give 2.6 mg of 21,21-dimethoxy-20-methylpregna-5,7-diene-1~,3~-diol lyield:
¦ ca. 75%) H-NMR spectrum (90 MHz) ~TMS 3:
0.64 (s, 3 H), 0.92 (s, 3 H), 1.11 ~d, J=6 Hz, 3 H), 3.2-3.7 (7 H), 4.0-4.3 (m, 1 ~
4.40 (br. s, 1 H), 5.3-5.5 (m, 1 H), 5.6-5.8 Im, 1 H) Example 67 The procedure of Example 25 was repeated except that 2.6 mg (0.00667 mmole) of 21,21-dimethoxy-20-methylpregna-5,7-diene-la,3~-diol was used in lieu of 4.3 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-5,7--~ diene-1~,3~-diol to give 1.8 mg of 1~,3B-dihydroxy-,, pregna-5,7-diene-20-carbaldehyde (yield:78%). ~-Example 68 -~ In 200 m~ of ethanol was dissolved 13.0 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-4,6-dien-3-one, followed by addition of 1.0 g of sodium borohydride under ice-cooling. The mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was néùtriallzéd with diluted hydrochloric acid under ice-cooling, diluted with water and extracted - with methylene chloride. The extract was washed with aqueous sodium chloride solution and dried over magne-.. . .
, :

.. j . :,;... . ..
. ., ~ .:
sium sulfate. The solvent was then distilled off under reduced pressure to recover 12.1 g of a crude product.
Purification of this crude product by silica gel chromatography gave 10.6 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,2~-epoxypregna-4,6-dien-3~-ol ~yield:
81~) having the following physical properties.
H-NMR spectrum (90 MHz) ~TMsl3:
0.70 (s, 3 H), 0.74 ~s, 3 H), 1.07 (d, J=6.2 Hz, 3 H), 1.17 (s, 6 H), 3.11-3.74 (6 H), 4.38 (d, J=1.8 Hz, 1 H), 4.50 (br. s, 1 H), 5.18 (br. s, 1 H), 5.66 (d, J=9.7 Hz, 1 H), 5.90 (dd, J=9.7, 2 Hz, 1 H) IR spectrum (XBr):
3480 cm~1 Example 69 In 200 ml of tetrahydrofuran was dissolved 11.7 g of 20-(1,3-dioxolan-2-yl)-1,2~-epoxypregna-4,6-dien-3-one, followed by addition of 36 ml of a 1.0 M solution of diisobutylaluminum hydride in toluene under ice-coolLng. The mixture was stirred under ice-cooling for 15 minutes. Then, the reaction mixture was worked up in the same manner as ~xa~ple 68 to recover 9.4 g of 20-(1,3-dioxolan-2-yl)-1,2~-epoxypregna-4,6-dien-3a-ol (yield: 80%) showing the following physical properties.
H-NMR spectrum (90 MHz) CCMS13:

~ ...... . , .. , ,.,,., i .... , .i ". ,.. , ,. ,.... . .. . . ", ...

- 151 - 133137~ ~

0.79 (s, 3 H), 0.95 Id, J=6.2 Hz, 3 H), 1.17 (s, 3 H), 3.10-3.36 (2 H), 3.70-4.00 (4 H), 4.50 (br. s, 1 H), 4.80 (br. s, 1 H), 5.18 (br. s, 1 H), 5.66 (d, J=9.7 Hz, 1 H), 5.90 ;
(dd, J=9.7, 2 Hz, 1 H) ~
IR spectrum (XBr): ~-3480 cm 1 Example 70 In 200 ml of tetrahydrofuran was dissolved 11.8 g of la,2~-epoxy-21,21-dimethoxy-20-methylpregna-4,6-dien-3-one, followed by addition of 36 ml of a 1.0 M solution . ~ ~
of sodium triethylborohydride in tetrahydrofuran under ice-cooling. The mixture was stirred under ice-cooling ~
for 15 minutes, after which it was worked up in the ~-same manner as Example 68 to give 10.24 g of la,2a- ~-epoxy-21,21-dlmethoxy-20-methylpregna-4,6-dien-3a-ol (yield- 85%) showing the~following physical properties.
H-NMR spectrum~(90 MHz) ~CDsl3: ;
0~.75 (s, 3 H), 0.96 (d, J=6.2 Hz, 3 H), 1.16 (s, 3~H), 3.10-3.36 (2 H), 3.38 ~s, 3 H), 3.41 (s, 3 H), 4.38 (br. s, 1 H), 4.51 (br. -s, 1 H)l, 5.i8 (br. s, 1 H), 5.66 (d, J=9.i Hz, 1 H),~ 5.gO ~dd, J=9.7, 2 Hz, 1 H) IR spectrum~(KBr):
y~ 3480~cm~~

,.
., .

~ ,.

Example 71 In 250 m~ of methylene chloride was dissolved 10.6 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-4,6-dien-3a-ol and the solution was stirred under ice-cooling. To this solution were added 200 ml of saturated aqueous sodium hydrogen carbonate solution -and 7.67 g of 80~i m-chloroperbenzoic acid, and the -~
solution was stirred at room temperature for 2 hours.
The organic layer was separated from the reaction mixture and the aqueous layer was extracted with ethyl acetate. The organ1c layer was combined with the extract and the mixture was washed successively with water, aqueous potassium iodide solution, aqueous ~;` sodium thiosulfate solution, water, aqueous sodium r ~ hydrogen carbonate solution and aqueous sodium chloride , ~ .
:~ solution and dried over potassium carbonate. The solution was then concentrated under reduced pressure to~recover 15.5 g of 20-~5,5-dimethyl-1,3-dioxan-2-yl)-la,2~;4~,5~-diepoxypregn-6-en-3~-ol as a substantially pure product showing the following physical properties.
H-NMR spectrum (90 MHz) ~TDsl3: -~
0.70 (s~ 3 Hj, 0.74 (s, 3 H), I.07 (d, J=6.2 Hz, 3 H), 1.18 (s, 6H), 3.04-3.75 (7 H), 4.24 (br. s, 1 H), 4.38 (d, J=1.8 Hz,~ 1 H), 5.14 -~ (dd, J=9.9 Hz, 2.0 Hz, 1 H), 5.88 (d, J=9.9 ~ Hz, 1 H) ,~.

"'~'' '` ,, : . :
' ``' - 153 - 133~37~
. . , lR spectrum lKBr):
3400 cm 1 Example 72 The procedure of Example 71 was repeated except that the reaction was conducted using 9.56 g of 20-(1,3-dioxolan-2-yl3-la,2a-epoxypregna-4,6-dien-3a-ol in lieu of 10.6 g of 20-15,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-4,6-d~ien-3a-ol in th~ absence of an aqueous sodium hydrogen carbonate solution to give 13.3 g of 20-l1,3-dioxolan-2-yl)-la,2a;4a,5a-diepoxypregn-6-en-3a-ol. This is a substantially pure product showing the following physi¢al properties.
H-NMR spectrum (90 MHz) ~CMcl3:
. . -,; ~ , ~:
0.78 (s, 3 H1, 0.94 ~d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 3.04-3.40 (3 H), 3.72-3.98 (4 H), 4.24 (~r. s, 1 Hl, 4.79 (d, J=1.8 Hz, 1 H), 5.15 (dd, J=9.8 Hz, 2.0 Hz, 1 H), 5.90 (d, J=9.9 Hz, 1 H) lR spectrum (KBr)~

3420~cm ~Example 73 -The proced~relof Example 71 was repeated except -~ that 9.61 g of la,2a-epoxy-21,21-dimethoxy-20-methyl-pregna-4,6-dien-3~-ol was used in lieu of 10.6 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a-epoxypregna-4, ,,~ ,, ~ :

~ r ~ 154 -6-dien-3~-ol to give 14.2 g of 1,2~;4~,5~-diepoxy-21,21-dimethoxy-20-methylpregn-6-en-3~-ol as a substantially pure product showing the following physical properties.
H-NNR spectrum (90 MHz) ~CMscl3:
0.76 (s, 3 H), 0.97 (d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 3.05-3.42 (3 H), 3.38 (s, 3 H), 3.42 (s, 3 H), 4.24 (br. s, 1 H), 4.39 (br.
s, 1 H), 5.14 (dd, J=9.8 Hz, 2.0 Hz, 1 H), 5.89 (d, J=9.9 Hz, 1 H) IR spectrum (XBr):

Example 74 In 100 m~ of methylene chloride was dissolved 15.5 g of the 20-t5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxypregn-6-en-3~-ol obtained in Example 71. This solution was added dropwise, under ice-cooling, to a complex prepared from 45 m~ of pyridine and 24.8 g of chromium o~ide in 160 m~ of methylene chloride and after completion of dropwise addition, the mixture was further stirred under ice-cooling for 1 hour. The reaction mixture ~hus obtained was diluted with ethyl acetate and filtered with the aid of Celite. The ~ ;
filtrate was washed successively with water, aqueous copper sulfate solution, water, aqueous sodium hydrogen 155 - 133~.37~

carbonate solution and aqueous sodium chloride solution and dried over sodium sulfate. Finally, the solution was concentrated under reduced pressure to recofver 8.9 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2~;4a,5x-di-epoxypregn-6-en-3-one as a substantially pure product showing the following physical properties.
1H-NMR spectrum (90 MHz) fSCTMS13: -0.70 (s, 3 H), 0.74 ~s, 3 H), 1.07 (d, J=6.2 Hz, 3 H), 1.08 (s, 3H), 1.12 (s, 3 H), 3.20-3.67 (7 H), 4.38 (br. s, 1 H), 5.05 (d, J-9.8 Hz, 1 H), 5.95 (d, J=9.8 Hz, 1 H) IR spectrum (KBr): -~
1705 cm 1 Example 75 The procedure of Example 74 was repeated except that 13.3 g of the 20-(1,3-dioxolan-2~yl)-la,2f~;ga,5a-diepoxypregn-6 en-3a-ol prepared in Example 72 was used - in li~u of 15.5 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxypregn-6-en-3fa-ol to give 9.1 g of 20-(1,3-dioxolan-2-yl)-la,2a;4a,5a-diepoxypregn-6-en- ~;~
3-one as a substantially pure product showing the following physicallproperties. f f ~ -H-NMR spectrum (90 MHz) fSTMsl3:
0.79 ~s, 3 H), 0.96 (d, J=6.2 Hz, 3 H), 1.12 (s, 3 H), 3.20-3.40 (3 H), 3.69-4.00 (4 H), .,, ~-, .

''~ .

; .

- 156 - ~ 3~ ~

4.80 (br. s, 1 H), 5.05 (d, J=9.8 Hz, 1 H), 5.95 (d, J=9.8 ~z, 1 H) IR spectrum (KBr):
1705 cm 1 Example 76 The procedure of Example 74 was repeated except that 14.2 g of la,2a;4a,5a-diepoxy-21,21-dimethoxy-20-methylpregn-6-en-3a-ol prepared in Example 73 was used in lieu of 15.5 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)~
1,2;4,5~-diepoxypregn-6-en-3a-ol to give 8.5 g of la,2a;4,5~-diepoxy-21,21-dimethoxy-20-methylpregn-6-en-3-one as a substantially pure product showing the following physical properties.~
H-NMR spectrum (90 MNz) ~TMCl3:
, ~ :
-~ 0.75 (s, 3H), 0.98 (d, J=6.2 Hz, 3 H), 1.13 ~
- , ; . .
~s, 3 H), 3.20-3.40 (3 H), 3.39 (s, 3 H), 3.42 ~s, 3 H), 4.39 (br. s, 1 H), 5.05 (d, ~- J=9.8 Hz, 1 H), 5.95 (d, J=9.8 Hz, lH) IR spectrum (KBr)~

1705 cm~

Example 77 In 10 m~ of ~oluene was dissolved 1.5 g of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2;4,5a-diepoxy-- pregn-6-en-3a-ol, followed by addition of 0.62 g of , ~
~ ~enzoic acid and 1~07 g of triphenylphosphine. The ., "~

ç ~ ~ :

! y i '~

- 157 - ~3~.~7~
~" :
mixture was stirred under ice-cooling. To the mixture thus obtained, 0.71 g of diethyl azodicarboxylate was added dropwise and the mixture was stirred under ice-cooling for 30 minutes. The resulting reaction mixture was poured in water and extracted with ether.
The extracts were com~ined, washed with aqueous sodium chloride solution and dried over sodium sulfate, followed by concentration under reduced pressure. The procedure yielded 1.6 g of substantially pure 20-~5,5-dimethyl-1,3-dioxan-2-yl)-la,2~;4a,5a-diepoxy-3~-benzo-yloxypregn-6-ene having the following physical proper-ties.
. lH-NMR spectrum (90 MHz) 6CMS13:
0.65 (s, 3H), 0.70 ~s, 3 H), 1.00 (d, J=6.2 Hz, 3 H), 1.12 (s, 6 H), 2.70-3.80 (7 H), .
~ 4.38 (br. s, 1 H), 5.11 (dd, J=9.6, 2.0 Hz, 1 :~ H), 5.50 (br. s, 1 H), 5.84 ld, J=9.6 Hz, 1 ~- H), 7.2-7.7 (m, 3 H), 7.9-8.2 (m, 2 H) IR spectrum (KBr):

~- 1720 cm~
:~ :
Example 78 The procedure of Éxample 77 was repe/ated except that 1.4 g of the 20-(1,3-dioxolan-2-yl)-la,2a;4a,5a-diepoxypregn-6-en-3~-ol prepared in Example 72 and 0.27 ;
g of acetic acid were used in lieu of 1.5 g of 20-(5,5-` ~' ':, : .

dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxypregn-6-en-3a ol and 0.62 g of benzoic acid, respectively, to give 1.5 g of 20-(1,3-dioxolan-2-yl)-3~-acetoxy-la,2a;4a,5a-diepoxypregn-6-ene as a substantially pure product showing the following physical properties.
H-NMR spectrum (90 MHz) ~CMsl3:
0.75 (s, 3 H), 0.94 (d, J=6.2 Hz, 3 H), 1.12 (s, 3 H), 2.07 (s, 3 H), 3.1-3.5 (3 H), 3.7 4.0 (4 H), 4.81 (br. s, 1 H), 5.12 (d, J=9.6 Hz, 1 H), 5.38 (br. s, 1 H), 5.85 ld, J=9.5 Hz, 1 H) IR spectrum (KBr):
1735 cm ` Example 79 ~ The procedure of Example 77 was repeated except - that 1.4 g of the la,2a;4a,5a-diepoxy-21,21-dimethoxy-; 20-methylpregna-6-dien-3a-ol prepared in Example 73 was used in lieu of 1.5 g of 20-(5,5-dimethyl~1,3-dioxan-2-yl)-1~,2a;4a,5a-diepoxypregn-6-en-3a-ol to give 1.6 g ~- ~ of 3~-benzoyloxy-la,2a;4a,5a-diepoxy-21,21-dimethoxy-20-methylpregn-6-ene as a substantially pure product showing the folldwing physical properties.
H-NMR spectrum (90 MHz) ~CMsl3 ; 0.76 (s, 3 H), 0.97 (d, J=6.2 Hz, 3 H), 1.18 `~ (s, 3 H), 3.1-3.5 (3 H), 3.38 (s, 3 H1, 3.42 ' ,.,' ~

,. . .,. . :
,, - :

(s, 3 H), 4.38 (br. s, 1 H~, 5.11 (dd, J=9.6, `~
2.0 Hz, 1 H), 5.50 (br. s, 1 H), 5.84 (d, J-9.6 Hz, 1 H), 7.2-7.7 (m, 3 H), 7.9-8.2 (m, 2 H) IR spectrum (XBr)~
1720 cm 1 Example 80 In 20 mQ of methanol was dissolved 1.6 g of the , 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxy- -~
3B-benzoyloxypregn-6-ene obtained in Example 77, ,~ followed by addition of 1.0 g of potassium carbonate.
The mixture was stirred under ice-cooling for 2 hours.
The reaction mixture~thus obtained was poured in water ,., ., , ~.
and extracted with ether. The extracts were pooled, washed with aqueous sodium chloride solution ~nd dried over sodium sulfate, followed by concentration under reduced pressure. The procedure yielded 1.2 g of substantially pure 20-(5,5-dimethyl-1,3-dioxan-2-yl)~
la,2a;4~,5~-dlepoxypr~egn-6-en-3B-ol having the following physical properties.
H-NMR spectrum (90 MHz) ~CDC13 0.65 (s, 3 H), 0.70 (s, 3 Hi, i . o o (d, J-6.2 Hz, 3~H), 1.12 (s, 6 H) 2.70-3.80 (7 H), 4.33 (br. s, 1 H), 4.58 (1 H), 5.12 (d, J=9.6 Hz, 1 H), 5.85 (d, J=9.5 Hz, 1 H) ~`

" ;~

~ ~, ,, .

` ;~/ . ! .

- 160 - ~33~7~ ~

IR spectrum (XBr):
3450 cm~l Example 81 The procedure of Example 80 was repeated except that 1.5 g of the 20-(1,3-dioxolan-2-yl)-3~-acetoxy-la,2;4a,5a-diepoxypregn-6-ene prepared in Example 78 was used in lieu of 1.6 g of 20-(5,5-dimethyl-1,3-di-oxan-2-yl)-la,2a;4a,5a-diepoxy-3B-benzoyloxypregn-6-ene ~-~
to give 1.1 g of 20-(1,3-dioxolan-2-yl)-3~-acetoxy-la,2a;4a,5a-diepoxypregn-6-en-3~-ol as a substantially pure product showing the following physical properties.
;~ lH-NMR spectr~m (90 MHz) ~CDC13 `~-; 0.75 (s, 3 H), 0.94 (d, J=6.2 Hz, 3 H), 1.12 - ~ (s, 3 H), 3.1-3.5 (3 H), 3.7-4.0 (4 H), 4.57 ~-~ (1 H), 4.81 (br. s, 1 H), 5.12 (d, J=9.6 Hz, ~`
1 H), 5.8S (d, J=9.6 Hz, 1 H) IR spectrum (KBr):
3450 cm~1 ~;
Example 82 The procedure of Example 80 was repeated except ~ that 1.6 g of the 3~-benzoyloxy-la,2a;4a,5a-diepoxy--~ 21,21-dimetho*y~20-methylpregn-6-ene prepared in l -- Example 79 was used in lieu of 1.6 g of 20-(5,5-di-;~ methyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxy-3~-benzoyl-xypregn-6-ene to give 1.1 g of la,2a;4a,5a-diepoxy-~X,~'~

',: :' ~33~.3~
21,21-dimethoxy-20-methylpregn-6-en-3~-ol as a sub-stantially pure product showing the following physical properties.

1H-NMR spectrum (90 MHz) ~CTMS13:
0.76 (s, 3 H), 0.97 (d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 3.1-3.5 (3 H), 3.38 (s, 3 H), 3.42 (s, 3 H), 4.38 ~br. s, 1 H), 4.55 (br. s, 1 ~;
H), 5.11 (dd, J=9.6, 2.0 Hz, 1 H), 5.84 (d, J=9.6 Hz, 1 H~
IR spectrum (KBr):

Example 83 `
, ,~
In 20 ml of ethanol was dissolved 2.0 g of the : ~ - ". ,, 20-(S,S-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxy- -pregn-6-en-3 one obtained in Example 74, followed by ~;
.,,~ ~:::
addition of 0.2 g of sodium borohydride under ice-cool-ing. The mixture was stirred under ice-cooling for 2 hours. The reaction mixture thus obtained was poured in water and extracted with ether. The extracts were pooled, washed with aqueous sodium chloride solution and dried over sodium sulfate, followed by concentra-tion under reducedi pressuire. The procedure gave 1.$ g of substantially pure 20-(S~S-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxypregn-6-en-3~-ol showing physical properties identical with those of the compound obtained r i': ~

~ . ~

V' ' `` 1333.3~
.~ ..
in Example 80.
Example 84 The procedure of Example 83 was repeated except :
that 1.8 g of the 20-(1,3-dioxolan-2-yl)-la,2a;4a,5a-diepoxypregn-6-en-3-one prepared in Example 75 was used in lieu of 2.0 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)- ~-la,2a;4a,5a-diepoxypregn-6-en-3-one to give 1.1 g of 20-(1,3-dioxolan-2-yl)-la,2a;4a,5a-diepoxypregn-6-en-3~-ol as a substantially pure product showing the same~:
physical properties as the compound obtained in Example 81.
Example 85 The procedure of;Example 83 was repeated except that 1.8 g of la,2a;4a,5a-diepoxy-21,21-dimethoxy-20-methylpregn-6-en-3-one prepared in Example 76 was used ~
in:lieu of 2.0 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)- ::~:
la,2a;4a,5a-diepoxypregn-6-en-3-one to give 1.1 g of 1a,2a;4a,5a-diepoxy-21,21-dimethoxy-20-methylpregn-6-. - :en-3~-ol~as a~substantially pure product showing the :~
same physical properties as the compound obtained in Bxample 82.
i ! ' Example 86 In 10 ml:of methylene chloride was dissolved 0.1 g : -of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxy-. - . .....
,., ~, ..

,~,~ ' ' '' ' -: :

i` 133~37`~
~:
pregn-6-en-3~-ol, followed by addition of 1 m~ of pyridine and 0.05 g of N,N-dimethyl-4-aminopyridine.
Then, 0.1 m of methyl chlorocarbonate was added slowly dropwise under ice-cooling, and the resulting mixture ;~
was stirred at room temperature for 3 hours. The reaction mixture thus obtained was poured in cold diluted hydrochloric acid and extracted with methylene chloride. The extracts were pooled, washed with water, -aqueous copper sulfate solution, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution in that order and dried over sodium sulfate.
- The solution was concentrated under reduced pressure to recover 0.11 g of substantially pure 20-(5,5-dimethyl-1,3-dioxan-2-yl)-lQ,2a;4a,5Q-diepoxy-3~-methoxycarbonyl-oxypregn-6-ene having the following physical properties.
H-NMR spectrum (90 MHz) ~CDsl3 3.77 (s, 3 H) ~ ~-L~ IR spectrum (KBr):

1745 c~-Example 87 J~ ' ' In 10 mQ of toluene was dissolved 0.1 g of 20-(1,3-dioxolan-2-yl)~la,2Q;4Q,5Q-diepoxypregn-6l-en-3~-ol, ~ followed by addition of one drop of pyridine. Then, ~-- 0.2 m~ of methyl isocyanate was added under ice-cooling. -.
The mixture was stirred at a temperature of 60C for 30 ' ~ ~ 3 ~
minutes. The reaction mixture thus obtained was poured in ice-water and extracted with methyle~e chloride.
The extracts were pooled, washed with water and aqueous sodium chloride solution and dried over sodium sulfate, followed by concentration under reduced pressure. The procedure gave O.ll g of substantially pure 20-(1,3-dioxolan-2-yl)-la~2~;4~5a-diepoxy-3B-(N-methylcarbamoyl) oxypregn-6-ene showing the following physical properties.
H-NMR spectrum (90 MHz) ~TDCsl3 2.80 (d, J=6 Hz, 3 H) IR spectrum (KBr):
1710 cm l Example 88 In lO ml of toluene was dissolved O.l g of l,2a;4~,5a-diepoxy-2l,2l~dimethoxy-20-methylpregn-6-en-3B-ol, followed hy addition of one drop of pyridine.
Then, 0.14 m~ of phenyl isocyanate was added under ;~
ice-cooling. This solution was stirred at a tempera-ture of 60C for 30 minutes. The reaction mixture thus obtained was poured in ice-water and extracted with methylene chloride. The extracts were pooled, washed with water and aqueous sodium chloride solution and dried over sodium sulfate, followed by concentration ~-under reduced pressure. ~he procedure gave 0.12 g of sub~tantia11y pure 1,2a;4~,5~-diepoxy-21,21-dimethoxy-, . .

`:: 133~.37~
- 165 - ~
.'''~.` ,,,,:
20-methyl-3~-(N-phenylcarbamoyl)oxypregn-6-ene showing the following physical properties.
H-NMR spectrum (90 MHz) ~TDCl3 6~92 (br. s, 1 H), 7.1-7.7 (m, 5 H) IR spectrum (KBr):
1725 cm 1 Example 89 In 10 m~ of toluene was dissolved 0.1 g of 20-~5,5 dimethyl-1,3-dioxan-2-yl)-1~,2~;4a,5a-diepoxypregn-6-en-3~-ol, followed by addition of 1 ml of pyridine and O.OS g of N,N-dimethyl-4-aminopyridine. Then, 0~1 ml " ~ ~
of N,N-dimethylcarbamoyl chloride was slowly added ;~
dropwise under ice-cooling. The mixture was stirred at 60C for 10 hours, at the end of which time the mixture ~;~ was poured in cold diluted hydrochloric acid and extracted with methylene chloride. The extracts were pooled, washed successively with water, aqueous copper sulfate solution, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution ~- and dried over sodium sulfate, followed by concentration under reduced pressure. The procedure gave 0.12 g of substantially pure 20-(5,5-dimethyl-1,3-dioxan-2-yI)-la,2a;4~,5a-diepoxy-3~-(N,N-dimethylcarbamoyl)oxypregn-6-ene showing the following physical properties.
H-NMR spectrum (90 MHz) ~TMS 3:
~"
, ~ .
,; ..
,= ~ '.

- 166 - ~3~

2.79 (s, 3 H), 2.82 (s, 3 H) IR spectrum (KBr):
1690 cm~l Example 90 -In 5 ml of N,N-dimethylformamide was dissolved 0.1 g of 20-~5,5-dimethyl-1,3-dioxan-2-yl)-la,2a; 4a, 5a-diepoxypregn-6-en-3B-ol t followed by addition of 0.15 g ;~
of imidazole and 0.17 g of tert-butyldimethylsilyl chloride. The mixture was stirred at room temperature for 10 hours. The reaction mixture thus obtained was poured in water and extracted with ether. The extracts were pooled, washed with water and aqueous sodium chloride solution and dried over sodium sulfate, , ~ . ..
-~ followed by concentration under reduced pressure. The ;-procedure gave 0.12 g of substantially pure 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxy-3B-~tert-a bu~tyldimethylsilyl)oxypregn-6-ene showing the ~ollowing ~-physical-properties.

-NMR spectrum (90 MHz) ~TDCl3 0.15 (s, 6 H), 0.94 ~s, 9 H) Example 91 ` In 2 m~ of tètrahydrofuran was dissolved 0.1 g of ~

-~ ~ 20-(1,3-dioxolan-2-yl)-1,2a;4a,5a-diepoxypregn-6-en- ~^

~- 3B-ol and the solution was added to a suspension of 0.015 g of 60% sodium hydride in 5 ml of tetrahydrofuran.

The mixture was stirred at room temperature for 1 ; i, - - :

,, , ~"
,'''" ' ~ ~.'~

- 167 - ~3~3~

hour, at the end of which time 0.03 g of chloromethyl methyl ether was added. The mixture was stirred at a temperature of 40C for 4 hours. The reaction mixture thus obtained was poured in ice-water and extrac~ed with ether. The extracts were pooled, washed successi-vely with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, and dried over sodium sulfate, followed by concentration under reduced pressure. The procedure gave 0.10 g of substantially pure 20-tl,3-dioxolan-2-yl)-1~,2~;4~,5a-diepoxy-3B-(methoxymethyl)oxypregn-6-ene showing the following physical properties.
H-NMR spectrum (90 MHz) ~CMcl3 3.34 (s, 3 H), 4.65 (br. s, 2 H) - Example 92 The procedure of Example 90 was repeated except that 0.1 g of la,2a;4a,5a-diepoxy-21,21-dimethoxy-20-methylpregn-6-en-3B-ol was used in lieu of 0.1 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4~,5~-diepoxy-pregn-6-en-3~-ol to give 0.11 g of 3~-ttert-butyldi-methylsilyl)oxy-l~2~;4~s~-diepoxy-2l~2l-dimethoxy-2 methylpregn-6-~ene as a substantially pure product ! ' `
showing the following physical properties.
~-NMR spectrum (90 MHz) ~TDCl3 0.12 (s, 6 H), 0.92 (s, 9 H) : ' , ' ~3~7f~

Example 93 In 20 m~ of tetrahydrofuran was dissolved 8.9 g ofthe 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1,2a;4,5a-di-epoxypregn-6-en-3-one obtained in Example 74 and the solution was added dropwise to a suspension of 2.8 g of lithium aluminum hydride in 50 ml of tetrahydrofuran ~ -under ice-cooling. After completion of dropwise addition, the mixture was stirred at room temperature for 2 hours. The excess reducing agent was decomposed with saturated aqueous sodium sulfate solution and the mixture was filtered with the aid of Celite. The residue was washed thoroughly with ethyl acetate and the washings were combined with the filtrate. This solution was concentrated under reduced pressure and the concentrate was recrystallized from ethyl acetate. The procedure yielded 2.93 g of 20-t5~5-dimethyl-l~3-dioxan-" ~
; 2-yl)pregn-6-ene-1~,33,5-triol showing the following `~ physical properties.

~-~ 1H-NMR spectrum (90 MHz) ~TMCl3 ~ 0.70 ts, 3H), 0.71 (s, 3 H), 0.88 (s, 3 H), - 1.05 (d, J=6.2 Hz, 3 H), 1.17 (s, 3 H), 3.34 (d, J=10.6 Hz, l~H), 3.43 (d, J=10.6 Hz, 1 H), 3.58 (d, 10.6 Hz, 2 H), 3.84 (m, 1 - 4.11 (d, J=10.3 Hz, 1 H), 4.38 (d, J=2.5 Hz, ;~
, -,- ~
. ~ .
,,, - , ,, :

, -, , - 169 - i33~379 :~

1 H), 5.56 (d, J=9.7 Hz, 1 H), 5.71 (d, J=9.7 Hz, 1 H) ~R spectrum (KBr):
3500 cm~
Example 94 In 50 m~ of tetrahydrofuran was dissolved 9.1 g of ; the 20-(1,3-dioxolan-2-yl)~la,2~;4~,5a-diepoxypregn-6-en-3-one, followed by addition of 22 ml of a 3.4 M
solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene under ice-cooling. The mixtrue was stirred at room temperature for 2 hours. After the excess reducin~ agent was decomposed with saturated aqueous sodi1lm sulfate solution, the reaction mixture was filtered with the aid of Celite. The residue was thoroughly washed with ethyl acetate and the washings were combined with the filtrate. This solution was ;corlcentrated under reduced pressure and the cancentrate was ;~
recrystallized from ethyl acetate to give 2.75 g of 2~0-~(1,3-dioxolan-2-yl)preqn-6-ene-1~,3~,5~-triol showing the following physical properties.
H-NMR spectrum (90 MHzj ~TMCl3 ~;
0.75 j(s, 3 ~), 0188 (s, 3 H), 0-9? (d, J=6.2 ;`
Hz, 3 H), 3.65-4.01 (m, 4 H), 3.84 (m, 1 H), 4.11~(d, J-10.3 Hz, 1 H), 4.79 (d, J=2.5 Hz, 5~

,.-, . " -ii" : ~

- 170 - 1 3 3 3 3 7 ~

1 H), 5.56 (d, J=9.7 Hz, 1 H), 5.71 (d, J=9.7 Hz, 1 H) ¦ IR spectrum (KBr):
3450 cm~l Example 95 In 50 ml of tetrahydrofuran was dissolved 8.5 g of the la,2~;4~,5a-diepoxy-21,21-dimethoxy-20-methylpregn-6-en-3-one obtained in Example 76, followed by dropwise addition of 100 mQ of a 1.0 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran under ice-cooling. After completion of dropwise addition, the mixture was stirred at room temperature for 2 hours. The excess reducLng agent was decomposed with ~; water and the residual alkylborane was decomposed with alkaline hydrogen peroxide, followed by extraction with ethyl acetate. The extracts were pooled, washed with aqueous sodium chloride solution, and dried over sodium Xi~ sulfate, followed by concentration under reduced --~ pressure. RecrystalIization of the concentrate from ethyl acetate gave 2.90 g of 21,21-dimethoxy-20-methylpregn-6-ene-la,3~,5a-triol showing the following physical properties.
H-NMR spectrum (90 MHz) ~CDC13:
- 0.75 (s, 3 H), 0.88 (s, 3 H), 0.97 ( d, J=6.2 Hz, 3 H), 3.75 (s, 3 H), 3.81 (s, 3 H), 3.84 ! ' ' . ~
'~, ` :

''''~ ;'' - 171 - 1~ 3 ~ 3~
,.--. `, (m, 1 H), 4.11 (d, J=10.3 Hz, 1 H), 4.40 (br. s, 1 H), 5.56 Id, J=9.7 Hz, 1 H), 5.71 (d, J=9.7 Hz, 1 H) IR spectrum (KBr):
3450 cm Example 96 In 5 m~ of tetrahydrofuran was dissolved 0.1 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxy-; pregn-6-en-3~-ol and the sblution was added dropwise to a suspension of 0.05 g of lithium aluminum hydride in 5 -ml of tetrahydrofuran under ice-cooling. After comple-tion of dropwise addition, the mixture was stirred at room temperature for 2 hours. Thereafter, the reaction ;-mixture was worked up in the same manner as Example 93 to~recover 0.07 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-pregn-6-ene-1~,3~-5~-triol having~the same physical -~
-~ porperties as the compound obtained in Exmple 93.
Example 97 - In 5 m~ of tetrzhydrofuran was dissolved 0.1 g of -~
~- 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxy-3~-methoxycarbonyloxypregn-6-ene, followed by addition of 0.2 ml of al~3.4 M !so'lution of sodium bis(2-methoxy- ~;
~ ethoxy)aluminum hydride in toluene under ice-cooling.
'æ'~ ~ The mixture was stirred at room temperature for 2 - ~ hours. Thereafter, the same workup procedure as .,~ .
.. . .

- 172 - ~ ?~3~ 3~

described in Example 94 was followed to recover 0.05 g of 20-(~,5-dimethyl-1,3-dioxan-2-yl)pregn-6-ene-la,3~,5a-triol showing the same physical properties as the compound obtained in Æxample 93.
Example 98 In 5 ml of tetrahydrofuran was dissolved 0.1 g of 20-(1,3-dioxolan-2-yl)~3~-acetoxy-la,2a;4a,5~-diepoxy-pregn-6-ene, followed by dropwise addition of 1 ml of a 1.0 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran under ice-cooling. After completion~of dropwise addition, the mixture was stirred at room temperature for 2 hours. Thereafter, the same workup procedure as described in Example 95 was followed to recover 0.06 g of 20-(1,3-dioxoIan-2-yl)pregn-6-ene-la,3~,5a-triol showing the same physical properties as , ~ ~
the compound obtained in Example 94.

Example 99 ,J ~ .
~ In S m~ of tetrahydrofuran was dissolved 0.1 g of , ~ :
20-~1,3-dioxolan-2-yl)-1,2a;4a,5~-diepoxy-3~-(N-methyl-car~amoyl)oxypregn-6-ene and this solution was added -. .
dropwise to a suspension of 0.05 g of lithium aluminum ~ -hydridq in 5 mliof tetrahydrofuran under ice-cooling After completion of dropwise addition, the mixture was sti~red at room temperature for 2 hours. Thereafter, - the reaction mixture was worked up in the same manner .',' ~

- 173 - 133~37~ ~

as Example 93 to recover 0.07 g of 20-(1,3-dioxolan-2-yl)pxegn-6-ene- la,3~,5a-triol showing the same physical properties as the compound obtained in Example 94.
Example 100 In 5 m~ of tetrahydrofuran was dissolved 0.1 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5~-diepoxy- -3~-(N,N-dimethylcarbamoyl)oxypregn-6-ene and the solution was added dropwise to a suspension of 0.05 g of lithium aluminum hydride in 5 ml of tetrahydrofuran under ice-cooling. After completion of dropwise addition, the mixture was stirred at room temperature for 2 hours. Thereafter, the reaction mixture was worked up in the same manner as Example 93 to recover 0.06 g of -~;~
20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-6-ene-la,3~,5~-triol showing the same physical properties as the compound obtained in Example 93. ~--Example 101 ;.,,.~ ~
~ In 5 m~ of tetrahydrofuran was dissolved 0.1 g of . ! , - la,2a;4a, Sa-diepoxy-21j21-dimethoxy-20-methyl-3~-(N-=- phenylcarbamoyl)oxypregn-6-ene and the solution was added dropwise to a suspénsion of 0.05 g of lithium aluminum hydride in 5 m~ of tetrahydrofuran under . ~ ice-cooling. After completion of dropwise addition, ;
the mixture was stirred at room temperature for 2 -4 _ 1 ~ hours. Thereafter, the reaction mixture was worked up , :

133~ 3~

in the same manner as Example 93 to give 0.07 g of 21,21-dimethoxy-20-methylpregn-6-ene-la,3~,5~-txiol showing the same physical properties as the compound obtained in Example 95.
Example 102 In 5 ml of tetrahydrofuran was dissolved 0.1 g of 3~-benzoyloxy-la,2a;4a,5~-diepoxy-21,21-dimethoxy-20-methylpregn-6-ene and the solution was added dropwise to a suspension of 0.05 g of lithium aluminum hydride -~
in 5 ml of tetrahydrofuran under ice-cooling. After completion of dropwise addition, the mixture was stirred at room temperature for 2 hours. Thereafter, the reaction mixture was worked up in the same manner as Example 93 to recover 0.07 g of 21,21-dimethoxy-20-methylpregn-6-ene-la,3~,5a-triol showing the same physical properties as the compound obtained in Example 95. - -Example 103 In 9 mQ of methylene chloride was suspended 400 mg o 2o-(s,s-dimethy~ 3-dioxan-2-yl)preqn-6-ene-l~3~sa- ~-triol, followed by addition of 2.2 m~ of pyridine and a ~-~
catalytic amount of N~N-dimethyl-4-aminopyridine. To this mixture was slowly added 0.75 ml of methyl chloro-carbonate dropwise under ice-cooling and the mixture r~ ", ~' ~ - ''"'"'' ~' '"'', ' ~ ~'.
',~'';: ~.
:
~ .

133~ ~73 .:
was stirred at room temperature for 45 minutes. The resulting reaction mixture was poured in cold diluted hydrochloric acid and extracted with methylene chloride.
The extracts were pooled, washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution! and dried over magnesium sulfate, followed by concentration under reduced pressure. Finally the concentrate was purified by silica gel chromatography to recover 486 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(methoxycarbonyl)oxypregn-6-ene-la,5a-diol showing the following physical properties.
H-NMR spectrum (90 MHz) ~CMcl3 0.70 (s, 6 H), 0.88 (s, 3 H), 1.05 (d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 3.34 (d, J=10.5 Hz, 1 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 (d, J=10.5 Hz, 2 H), 3.77 (s, 3 H), 4.10 (1 H), 4.38 (d, J=2.4 Hz, 1 H), 5.33 (m, l H), 5.51 (d, J=9.8 Hz, 1 H), 5.91 (d, J=9.8 Hz, 1 H) IR spectrum (KBr):
3250, 1750 cm~

:

1~3~ 3~

Example 104 In 5 ml of pyridine was dissolved 400 mg of 20-tl~3-dioxolan-2-yl)pregn-6-ene~ 3~5~-triol. To this solution was added 0.11 mQ of acetic anhydride at a temperature of -10 - 0C and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture thus obtained was poured in ice-water and stirred at room temperature for 30 minutes. This mixture was then ~;
extracted with ether and the extracts were pooled, washed successively with water, cold diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over magnesium sulfate, followed by concentration under reduced pressure. Finally the concentrate was purified by silica gel chromatography to give 420 mg of 20-(1,3-dioxolan-2-yl)-3~-acetoxypregn-6-ene-1,5a-diol showing the following properties.
H-NMR spectrum (90 MHz) ~CMcl3~
0.72 (s, 3 H), 0.88 ~s, 3 H), O.9S (d, J=6.2 Hz, 3 H), 2.05 (s, 3 H), 3.70-4.05 (m, 4 H), 4.10 (l H), 4.79 (br. s, 1 H), 5.23 (m, 1 H), 5.51 (d, J=9.8 Hz, 1 H), 5.91 (d, J=9~.8 Hz, lH) -:
IR spectrum ~KBr):

-;~ 3240, 1730 cm 1 "
~ .

- 177 - 133~37~
` ;:

Example 105 ;~
In methylene chloride was suspended 400 mg of 21,21-dimethoxy-20-methylpregn-6-ene-la,3~,5a-triol, followed by addition of 2 ml of pyridine. To this suspension was added 0.14 ml of benzoyl chloride and the mixture was stirred for 2 hours. Thereafter, the reaction mixture was worked up in the same manner as Example 103 to recover 430 mg of 3B-benzoyloxy-21,21-dimethoxy-20-methylpregn-6-ene-la,5a-diol showing the following physical properties.
H-NMR spectrum (90 MHz) ~CMscl3: `
0.72 (s, 3 H), 0.88 (s, 3 H~, 0.95 (d, J=6.2 Hz, 3 H), 3.38 (s, 3 H), 3.40 (s, 3 H), 4.10 -~
- ~ (1 H), 4.38 (br. s, 1 H), 5.30 (m, 1 H), 5.51 d, J=9.8 Hz, 1 H), 5.91 (d, J=9.8 Hz, 1 H), 7.2-7.7 (m, 3 H), 7.9-8.2 (m, 2 H) ;
IR spectrum (K~r):
3240, 1720 cm 1 ,:,, .
Example 106 In 20 ml of toluene was suspended 400 mg of ' ~ 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-6-ene-la,3~,5~--~ ~ triol, followed by add~tion of one drop ~f pyridine ? l ;.
;, To this suspension was~added 0.8 ml of methyl isocyanate under ice-cooling and the~mixture was stirred at 60C
for 45 minutes. The reaction mixture thus obtained was ':; .:

~, ~

~, ' .~., - 178 - 1~3~7~

poured in ice-water and extracted with methylene chloride. The extracts were pooled, washed with water and aqueous sodium chloride solution, and dried over sodium sulfate, followed by concentration under reduced pressure. Finally the concentrate was purified by silica gel chromatography to recover 486 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(N-methylcarbamoyl)oxypregn-6-ene-la,Sa-diol showing the following physical properties.
H-NMR spectrum (90 MHz) ~TMsl3 0.70 (s, 6 H), 0.88 (s, 3 H), 1.05 (d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 2.76 (d, J=6 Hz, 3 ~-~
H), 3.34 (d, J=lO.S Hz, 1 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 (d, J=lO.S Hz, 2 H), 4.10 (1 H), 4.38 (d, J=2.4 Hz, 1 H), 5.20 (1 H), 5.33~;~
(m, 1 H), S.S1 (d, J=9.8 Hz, 1 H), S.91 (d, ~ :
J=9.8 Hz, 1 H) ~;
IR spectrum (KBr):
3250, 1710 cm 1 Example 107 In 20~m~ of toluene was suspended 400 mg of --20-(S,S-dimethyl-1,3-dioxan-2-yl)pregn-6-ene-la,3~,Sa-triol, foIlowe~ by addition of one drop of pyridine~
To this suspension was added 0.8 ml~of phenyl isocyanate under ice-cooling and the mixture was stirred at 60C
for 45 minutes.~ The reaction mixture thus obtained was ,~

- 179 - ~ ~3~ ~7 poured in ice-water and extracted with methylene chloride. The extracts were pooled, washed with water and aqueous sodium chloride solution, and dried over sodium sulfate, followed by concentration under reduced pressure. Finally the concentrate was puLified by silica gel chromatography to recover 412 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(N-phenylcarbamoyl)oxypregn-6-ene-la,5a-diol showing the following physical properties.
H-NMR spectrum (90 MHz) ~CMscl3:
0.70 (s, 6 H), 0.88 (s, 3 H), 1.05 (d, J-6.2 Hz, 3 H), 1.18 (s, 3 H), 3.34 (d, J=10.5 Hz, 1 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 ~d, J=10.5 Hz, 2 ~), 4.10 (1 H), 4.38 (d, J=2.4 Hz, 1 H), 5.30 (m, 1 H), 5.49 (d, J=9.8 Hz, 1 H), 5.90 (d, J=9.8 Hz, 1 H), 6.80 (br. s, 1 H), 7.1-7.7 (S H) ~ IR spectrum (KBr):
-~ 3350, 1720 cm Example 108 In 20 ml of toluene was suspended 400 mg of 20-(5,5-dimethyl-1,3-dioxan-~-yl)pregn-6-ene-1~,3~,5a-triol, followed by addition of S m~ of pyridine and b.1 -~ g of N,N-dimethyl-4-aminopyridine. To this suspension was added 0.8 ml of N,N-dimethylcarbamoyl chloride ` under ice-cooling and the mixture was stirred at 60C
.- :

.-., ~, :

133~ ~7~

for 10 hours. The reaction mixture thus obtained was poured in cold diluted hydrochloric acid and extracted with methylene chloride. The extracts were pooled, washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, and dried over sodium sulfate, followed by concentration under reduced pressure. Finally the concentrate was purified by silica gel chromatography to recover 435 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(N,N-dimethylcarbamoyl)oxypregn-6-ene- la,5a-diol showing the following physical pro-~ ~
perties. -~- lH-NMR spectrum (90 MHz) ~TCDsl3:
0.70 (s, 6 H), 0.88 (s, 3 H), 1.05 (d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 2.78 ~ 2.81 (each s, 6 H), 3.34 (d, J=10.5 Hz, 1 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 (d, J=10.5 Hz, 2 H), 4.10 (1 H), 4.38 (d, J=2.4 Hz, 1 H), 5.34 (m, 1 H), 5.50 (d, J=9.8 ~z, 1 H), 5.89 (d, J=9.8 H z, 1 H ) ~ ;

s~ IR spectrum (KBr): ~
1 ~ ~, 3300, 1695 cm ; -~ Example 109 `
In 20 ml of N,N-dimethylformamide was dissolved ;~ 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-6-ene- -la,3B,5a-triol, followed by addition of 0.6 g of imidazole. Then, 0.7 g of tert-butyldimethylsilyl r':' ~ ~

~"' ' I :

133~ 3~

. . ~ .
,: '' chloride was further added under ice-cooling and the mixture was stirred at room temperature for 10 hours.
The reaction mixture thus obtained was poured in water and extracted with ether. The extracts were pooled, washed with water and aqueous sodium chloride solution, and dried over sodium sulfate, followed by concentra-tion under reduced pressure. Finally the concentrate was purified by silica gel chromatography to recover 490 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(tert-butyldi-methylsilyl)oxypregn-6-ene-1~,5~-diol showing the following physical properties.
H-NMR spectrum (90 MHz) ~CMcl3:
0.13 (s, 6 H), 0.70 (s, 6 H), 0.88 (s, 3 H), 0~95 (s, 9 H), 1.05 (d, J=6.2 Hz, 3 H), 1.18 ,.:
~; (s, 3 H), 3.34 (d, J=10.5 Hz, 1 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 (d, J=10.5 Hz, 2 H), --~ 4.10-4.50 (2 H), 4.38 (d, J=2.4 Hz, 1 H), , 5.50 (d, J=9.8 Hz, 1 H), 5.89 (d, J=9.8 Hz, 1 H~

-~ IR spectrum (KBr):
, ~ ~

' Example 110 In 5 ml of tetrahydrofuran was dissolved 20-(1,3-dioxolan-2-yl)pregn-6-ene-la,3~,5~-triol. This solu- l ~

- tion was added to a suspension of 60 mg of 60% sodium ~ ~ -~ :
, "
" " " ~ "

~, , . , : ' ' ,' ;, , ' . ~' . ' . . . ' ' '.!. : , . .. .. .

- 182 - 1~3~
.. .. ...
hydride in S ml of tetrahydrofuran under ice-cooling and the mixture was stirred at room temperature for 1 hour. To the resulting mixture was added 120 mg of chloromethyl methyl ether, followed by stirring at a temperature of 60C for 2 hours. The reaction mixture was poured in ice-water and extracted with ether. The extracts were pooled, washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, and dried over sodium sulfate, followed by concentration under reduced pressure. Finally the concentrate was purified by silica gel chromatography to recover 420 mg of 20-(1,3-dioxolan-2-yl)-3~-(methoxy-methyl)oxypregn-6-ene-1~,5~-diol showing the following physical properties.
~lH-NMR spectrum (90 MHz) ~TDC13:
- ~ 0.72 (s, 3 H), 0.88 (s, 3 H), 0.95 (d, J=6.2 Hz, 3 H), 3.34 (s, 3 H), 3.70-4.05 (m, 4 H), 4.10 (1 H), 4.40 (m, 1 H), 4.79 (br. s, 2 H), 5.51 (d, J=9.8 Hz, 1 H), 5.91 (d, J=9.8 Hz, 1 IR spectrum (XBr):
3?40 cm~
Example 111 The reaction and workup procedures of Example 109 ~were repeated except that 400 mg of 21,21-dimethoxy-20-:

, . , ~, :-,.

~L33~ 37~

.

methylpregn-6-ene-la,3~,5a-triol was used in lieu of 400 mq of 20-(5,5-dimethyl-1,3-dioxan-2-yl~pregn-6-ene-la,3~,5a-triol to give 500 mg of 3~-tert-butyldimethyl-silyloxy-21,21-dimethoxy-20-methylpregn-6-ene-1,5a-diol.

H-NMR spectrum (90 MHz) ~CMsl3:
0.12 (s, 6 H), 0.72 (s, 3 ~), 0.88 (s, 3 H), 0.93 (s, 9 H), 0.95 (d, J=6.2 Hz, 3 H), 3.38 (s, 3 H), 3.40 (s, 3 H), 4.10-4.50 (3-H), 5.51 (d, J=9.8 Hz, 1 H), 5.91 (d, J=9.8 Hz, 1 H) IR spectrum (XBr):

3240 cm~l Example 112 In 5 m~ of tetrahydrofuran was dissolved 100 mg of ~,,, :~ , 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxy-3~-(tert-butyldimethylsilyl)oxypregn-6-ene and the solution was added dropwise to a suspension of 50 mg of lithium aluminum hydride in 5 m~ of tetrahydrofuran under ice-cooling. This mixture was stirred at room temperature for 2 hours. Thereafter, the reaction mixture was wor~ed up in the same manner as Example 93 to recover 49!mg ~f 20~(5,5-dimethyl-1,3-dioxan-2-yl 3~-(tert-butyldimethylsilyl)oxypregn-6-ene-la,5~-diol which showed the same physical properties as the ,.i --- compound obtained in example 109. ~
.'-- :
~:

~:

~,.,~ 1, , ''' - 184 - ~t~3~37~ ~
, .
.....

Example 113 In 5 m~ of tetrahydrofuran was dissolved 100 mg of 20-(1,3-dioxolan-2-yl)-1,2a;4a,5a-diepoxy-3B-(methoxy-methyl)oxypregn-6-ene, followed by addition of 0.2 ml of a 3.4 M solution of sodium bis(2-methoxyethoxy)alumi- ~ ~
num hydride in toluene under ice-cooling. The mixture ~ :
was stirred at room temperature for 2 hours. Thereafter, the reaction mixture was worked up in the same manner ~
as Example 94 to recover 42 mg of 20-(1,3-dioxolan-2-:;
yl)-33-(methoxymethyl)oxypregn-6-ene-la,5a-diol showing ~
the same physical properties as the compound obtained `
in Example 110. -Example 114 ~ , .
~he reaction and workup procedures of Example 112 :
were repeated except that 100 mg of la,2;4a,5a-diepoxy- ~:
~,~
21,21-dimethoxy-20-methyl-3B-(tert-butyldimethylsilyl)- ~.
oxypregn-6-ene was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,2a;4a,5a-diepoxy-3~-(tert-~-~ butyldimethylsilyl)oxypregn-6-ene to give 5Q mg of 3~-tert-butyldimethylsilyloxy-21,21-dimethoxy-20-, . .
methylpregn-6-ene-la,5a-diol showing the same physical ::
properties as the compound obtained in Example 111.
Example 115 In 5 ml of methylene chloride was dissolved 262 mg of ,, :
20-(5,5-diméthyl-1,3-dioxan-2-yl)-3B-(methoxycarbonyl-, , ,, , . . : ... :.. :..... ;" , , " . .. .. .....

- 185 - ~ ~
., ~

oxy)pregn-6-ene-1~,5a-diol, followed by addition of 1.7 m of diisopropylethylamine and a catalytic amount of 4-(N,N-dimethylamino)pyridine. The mixture was stirred under ice-cooling. To this mixture was slowly added 0.19 m~ of methyl chlorocarbonate and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture thus obtained was poured in ice-water and extracted with ether. The extrac*s were pooled, washed successively with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, and dried over magnesium sulfate, followed by concentration under reduced pressure. Finally the concentrate was purified by column chromatography to ~-~ recover 243 mg of 20-(S,S-dimethyl-1,3-dioxan-2-yl)-la,3~-~is(methoxycarbonyloxy)pregn-6-en-Sa-ol showing the following physical properties.
1H-NMR spectrum (90 MHz) ~CMC13:
-~ 0.70 (s, 6 H), 0.99 (s, 3 H), 1.05 (d, J=6.2 -~ Hz, 3 H), 1.16 (s, 3 H), 3.33 (d, J=11.4 Hz, 1 H), 3.43 (d, J=11.4 Hz, 1 H), 3.59 (d, J=11.4 HZ, 2 H), 3.77 & 3.78 (each s, 6 H~
4.37 (br. s, l ~H), 4.85 (t, J=3 HZ, 1 H), 5.53 (m, 1 H), 5.58 (br. s, 2 H~
IR spectrum (KBr):
- 3320, 1750 cm~
-~ !

.
j ~:

- 186 - ~33~.37~
~, Example 116 The reaction and workup pxocedures of Example 105 were repeated except that 350 mg of 20-(1,3-dioxolan-2-yl)-3B-acetoxypregn-6-ene-la,5a-diol was used in lieu of 400 mg of 21,21-dimethoxy-20-methylpregn-6-ene-la,3B,5a-triol to give 400 mg of 20-(1,3-dioxolan-2-yl)-3~-acetoxy-la-benzoyloxypregn-6-en-Sa-ol showing the following physical properties.
H-NMR spectrum (90 MHz) ~TMCl3: ;
0.72 (s, 3 H), O.9S (d, J=6.2 Hz, 3 H), 1.00 ~ ;
(s, 3 H), 2.05 (s, 3 ~), 3.70-4.05 (m, 4 H), 4.79 (br. s, 1 H), 4.95 (1 H), 5.23 (m, 1 H), 5.60 (br. s, 2 H), 7.2-7.7 (3 H), 7.9-8.2 (2 H) IR spectrum (KBr):
3320, 1735, 1720 cm~
-~ Example 117 ~ The reaction and workup procedures of Example 106 .~
were repeated except that 350 mg of 3~-benzoyloxy-21,21-dimethoxy-20-methylpregn-6-ene-la,5a-diol was used in ::
lieu of 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-6-ene-la,3~,5a-itriol to give 380 mg of 3~-benzoyloxy-21,21-dimethoxy-20-methyl-la-(N-methylcarbamoyl)oxy-~ pregn-6-en-Sa-ol showing the following physical -~- properties.

,. , ,........................................................................... ..

, , .

H-NMR spectrum (90 MHz) ~CMcl3 0.72 (s, 3 H), 0.95 (d, J=6.2 Hz, 3 H), 1.02 ;;~
(s, 3 H), 2.80 (d, J=6 Hz, 3 H), 3.38 (s, 3 H), 3.40 (s, 3 H), 4.38 (br. s, 1 H), 4.95 (1 H), 5.15 (1 H), 5.30(m, lH), 5.61(br. s, 2H), 7.2-7.7 (m, 3 H), 7.9-8.2 (m, 2 H) IR spectrum (KBr):
3240, 1720, 1710 cm 1 Example 118 The reaction and workup procedures of Example 107 were repeated except that 350 mg of 20-(5,5-dimethyl-3-dioxan-2-yl)-3B-(N-methylcarbamoyl)oxypregna-l~sa- -;
diol was used in lieu of 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-6-ene-la,3~,5a-triol to glve 355 mg of 20~-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(N-methyl~
carbamoyl)oxy-la-~N-phenylcarbamoyl)oxypregn-6-en-5a-ol showing the following physical properties. ~-H-NMR~spectrUm /90~MNz) ~CMscl3~
0.70 (s, 6 H),; 0.99 (s, 3 H), 1.05 (d,~J-6.2 Hz, 3 H), 1.18 (s, 3 H), 2.76 (d, J=6 Hz, 3 .,., ~ - :
H), 3.34 (d, J=10~5 Hz, 1 H), 3.44 (d, J=10.5 -~

; Hz, 1' H), 3;.57 (d, J=10.5 Hz, 2 H), 4.38 td, J=2.4 Hz~, l H), 5.01 (1 H), 5.20 (1~H), 5.33 (m, 1 Hj~,~ 5.7~0~(br. s, 2~H), 6.75 (br. s, 1 N)~, 7.1-7.7 (5~H) ~'.5'`'' ~ .' ' ~
~' ~ ~ ' ` '.' .'~ " ' ` .

1 3 3 ~

IR spectrum (KBr):
3250, 1720, 1710cm 1 Example 119 The reaction and workup procedures of Ex~mple 108 were repeated except that 350 mg of 20-(5,5-dimethyl- ;~
1,3-dioxan-2-yl)-3~-(N-phenylcarbamoyl)oxypregn-6-ene-1~,5~-diol was used in lieu of 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-6-ene-1~,3~,5a-triol to give 340 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-l~-(N,N-dimethylcarbamoyl)oxy-3~-(N-phenylcarbamoyl)-oxypregn-6-en-5~-ol showing the following physical properties.
H-NM~ spectrum (90 MHz) ~TDsl3:
0.70 (s, 6 H), 0.99 (s, 3 H), 1.05 (d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 2.78 & 2.81 (each s, 6 H), 3.34 (d, J=10.5 Hz, 1 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 (d, J-10.5 Hz, 2 H), 4.38 (d, J=2.4 Hz, 1 H), 5.00 (1 H), 5.30 (m, 1 H), 5.68 (br. s, 2 H), 6.80 (br. s, 1 H), 7.1-7.7 (S H) ~" ~ . ..
IR spectrum (KBr): ! ~ `

3350,`'17!20,`1690 cm~1 ¦ ~-Example 120 ~
i ~- The reaction and workup procedures of Example 109 were repeated except that 350 mg of 20-(5,5-dimethyl- ¦
., ' , !
.r;

" 1' - 189 - ~3~37~ ::
.
1~3-dioxan~2-yl)-3B-(N,N-dimethylcarbamoyl)oxypregn-6-ene-1~,5a-diol was used in lieu of 400 mg of 20-(5tS-dimethyl-1,3-dioxan-2-yl)pregn-6-ene-la,3~,5a-triol to give 335 mg of 20-(S,S-dimethyl-1,3-dioxan-2-yl)-la-~tert-butyldimethylsilyl)oxy-3~-(N,N-dimethylcarbamoyl)-oxypregn-6-en-Sa-ol showing the following physical properties.
H-NMR spectrum (90 MHz) ~TDCl3:
0.15 (s, 6 H), 0.70 (s, 6 H), 0.93 (s, 3 H~, 0.97 (s, 9 H), 1.05 (d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 2.78 & 2.81 (each s, 6 H), 3.34 (d, ~ - ~ J=10.5 ~z, 1 H), 3.44 id, J=10.5 Hzt 1 H) -` 3.57 (dt J=10.5 Hzt 2 H)t 4.2-4.5 (2 H)t 5.34 (mt 1 H)t 5.65 (br. s, 2 H) -~ IR spectrum (KBr):
- 3320, 1695 cm 1 ;~
Example 121 The reaction and workup procedures of Example 110 were repeated except that 400 mg of 20-(S,S-dimethyl-1,3-dioxan-2-yl)-3~-(tert-butyldimethylsilyl)oxypregn-6-ene-la,5~-diol was used in lieu of 400 mg of 20-(1,3-dioxolan-2-yl~pregn-6-ene-la,3~,5a-t~iol to give ~ ~
320 mg of 20-(S,S-dimethyl-1,3-dioxan-2-yl)-3~-(tert- ~-butyldimethylsilyl)oxy-la-(methoxymethyl)oxypregn-6- ;~
en-5a-ol showing the following physical properties.

~ .

- lgo - 1 3 3 ~
i ....................................................................... . -~
H-NMR spectrum (90 MHz) ~CMcl3:
0.13 (s, 6 H), 0.70 (s, 6 H), 0.95 (s, 9 H), ~-0.99 (s, 3 H), 1.05 (d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 3.34 (d, J=10.5 Hz, 1 H), 3.36 (s, 3 H), 3.44 (d, J=10.5 Hz, l H), 3.57 (d, J=10.5 Hz, 2 H), 4.10-4.50 (2 H), 4.38 (d, J=2.4 Hz, 1 H), 4.80 (br. s, 2H), 5.65 (br.
s, 2H) IR spectrum (KBr):
3350 cm~
Example 122 The reaction and workup procedures of Example 104 were repeated except that 350 mg of 20-(1,3-dioxolan-2-yl)~-3~-(methoxymethyl)oxypregn-6-ene-la,5a-diol was ;;
used in lieu of 400 mg of 20-~1,3-dioxolan-2-yl)pregn-6-ene-la,3~,5a-triol to give 360 mg of 20-(1,3-dioxolan- :
;2~-yl)~-la-acetoxy-3B-(methoxymethyl)oxypregn-6-ene-la,Sa-diol sho~wing the followlng physical properties.
H-NMR spectrum (90 MHz) ~CMcl3:
0.72 (s, ~3 H), O.9S (d, J=6.Z Hz, 3 H), 0.98 (s, 3 H), 2.07 (s, 3 H), 3.70-4.05 (m, 4 H), ; 4.40~m,~1 H),'4!79 (br. s, l H)~, 4.99 (1 H), 5.70 (br. s, 2 H) ~.' ~- IR spectrum (~Br):
,,, , ~, ~ ,.
~ - 3240, 1735 cm 1 ~:
," ::

19~ 3~
.....
Example 123 In 5 ml of pyridine was dissolved 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-6-ene-la,3~,5a-triol, followed by addition of S0 mg of 4-(N,N-dimethyl-amino)pyridine and 1 ml of acetic anhydride. The mixture was stirred at room temperature for 2 hours.
The reaction mixture was then worked up in the same manner as Example 104 to give 420 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,3~-diacetoxypregn-6-en-Sa-ol ~;~
showing the following physical properties.
H-NMR spectrum (90 MHz) ~TMsl3:
0.70 (s, 6 H), 0.99 ~s, 3 H), 1.05 (d, J=6.2 Hz, 3 H), 1.16 (s, 3 H), 2.03 & 2.07 (each s,~;
6 H), 3.33~(d, J~11.4 Hz, 1 H), 3.43 (d, J=11.4 Hz, 1 H), 3.59 (d, J=11.4 Hz, 2 H), r~ 4.37 (br. s, 1 H), 4.85 (t, J=3 Hz, 1 H), ;~
j , ,:
5.53 (m, 1 H), 5.58 (br. s, 2 H) IR spectrum (KBr):
3320, 1735 cm~
Example 124 ;~
In 10 ml of dimethyl carbonate was dissolved 345 mg of 20-(5,5-dimethyi-i,3-dioxan-2-ylj-la,3~-bis-(methoxycar~onyloxy)pregn-6-en-Sa-ol, followed by addition of 0.2 ml of acetic acid. The mixture was refluxed in an atmosphere of~argon gas for 10 hours.

.,, ~

.

r~

- 192 - ~3~3~

The reaction mixture was poured in ice-water and extracted with ether. The extracts were pooled, neutralized with cold aqueous sodium hydroxide solution and aqueous sodium hydrogen carbonate solution, and washed with aqueous sodium chloride solution, followed ~`
by concentration under reduced pressure. Finally the concentrate was pu~ified by column chromatography to -recover 40 mg of 20-!5,5-dimethyl-1,3-dioxan-2-yl)-la,3~-bis(methoxycarbonyloxy)pregna-5,7-diene showing the following physical properties.
H-NMR spectrum (90 MHz) ~CMscl3~
0.61 (s, 3 H), 0.70 (s, 3 H), 1.00 ~s, 3 H), .~ .
.07 (d, J=6.2 Hz, 3 H), 1.17 (s, 3 H), 3.25 (d, J=10.8 Nz, 1 H), 3.42 (d, J=10.8 Hz, 1 H), 3.60 (d, J=10.8 Hz, 2 H), 3.77 & 3.79 (each s, 6 H), 4.39 (br. s, 1 H), 4.62-5.12 (2 H), 5.36 (m, 1 H), 5.68 (m, 1 H) ~-IR spectrum (KBr): ~-~
~ 1740 cm~

-~- Example 125 .,,;, ~ ~:
In 10 ml of diethyl carbonate was dissolved 350 mg of 20-~1,3-dioxolan-2-yl)-3B-acetoxy~ benzoyloxypregh~

6-en-5a-ol, followed by addition of 0.1 m~ of monochloro-~acetic acid. The mixture was stirred under heating at -100C in an atmosphere of argon gas for 10 hours. The - . . .

~:,,,: .. ,1`.
, ,:,:, , . . . , . . : , .: ~ : ; :

- 193 - 1333.37~ ~
,. ~

reaction mixture was then worked up in the same manner as Example 124 to give 120 mg of 20-(1,3-dioxolan-2-yl)-3~-acetoxy-la-benzoyloxypregna-5,7-diene showing the following physical properties. ;
H-NMR spectrum (90 MHz) ~TMsl3:
0.65 (s, 3 H), 0.95 (d, J=6.2 Hz, 3 H), 1.00 (s, 3 H), 2.05 (s, 3 H), 3.70-4.05 (m, 4 H~
4.79 (br. s, 1 H), 4.70-5.10 (2 H), 5.38 (m, 1 H), 5.70 (m, 1 H), 7.2-7.7 (3 H), 7.9-8.2 (2 H) IR spectrum (KBr):
1735, 1720 cm 1 ~, ~: , .
Example 126 In 10 ml of tetrahydrofuran was dissolved 350 mg of 3~-benzoyloxy-21,21-dimethoxy-20-methyl-la-(N-methyl-~ carbamoyl)oxypregn-6-en-5a-ol, followed by addition of 7~ 50 mg of dichloroacetic acid. The mixture was refluxed in an~atmosphere of argon gas for 12 hours. The - reaction mixture was then worked up in the same manner as~Example 124 to give 120 mg of 3~-benzoyloxy-21~,21-dimethoxy-2p-methyl-la-(N-methylcarbamoyl)oxypregna-5,7- ~-diene showing the following physical properties.
H-NMR spectrum (90 MHz) ~CMscl3~
0.64 (s, 3 H), 0.95 (d, J=6.2 Hz, 3H), 1.02 ~- ~ (s, 3 H), 2.80 (d, J=6 Hz, 3 H), 3.38 (s, ;, . :~-- - , ,", ., , ., ~ .. "- .:

, :
,, , ~
.,; ~, - 194 - ~ .37~ :`
.,- ..
3 H), 3.40 (s, 3 H), 4.38 (br. s, 1 H), 4.95 (1 H), 4.7-5.1 (2 H), 5.36 (m, 1 H), 5.68 (m, 1 H), 7.2-7.7 (m, 3 H), 7.9-8.2 (m, 2H) IR spectrum (KBr):
1720, 1710 cm Example 127 In 10 ml of dioxane was dissolved 350 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~-(N-phenylcarbamoyl)-oxy-3~-(N-methylcarbamoyl)oxypregn-5~-ol, followed by addition of 50 mg of p~toluenesulfonic acid. The mixture was stirred in an atmosphere of argon gas at room temperature for 3 hours. The reaction mixture was then~worked up in the same manner as Example 124 to give llO mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(N- ~;
methyLcarbamoyl)oxy-1~-(N-phenylcarbamoyl)oxypregna-5,7-diene showing the following physical properties.
H-NMR spectxum (90 MHz) ~CMcl3:
0.65;(s, 3 H), 0.70 (s, 3 H), 0.99 (s, 3 H), 1.05 (d, J=6.~2 Hz, 3 H), 1.18 (s, 3 H)j 2.76 (d, J=6 Hz, 3 H), 3.34 (d, J=10.5 Hz, 1 H), -~
3.44 (d, J=10.5 Hz, l H), 3.57 (d, J=10.5 Hz, -`-2 H),i4.38 (d, ~=2.4 Hz, 1 H), 4.65-5.15 (2 ;~
H), 5.~20 ~1 H), 5.36 (m, 1 H), 5.68 (m, 1 H), ~ " , ~
6.75~(br. ~s, 1 H), 7.1-7.7 (5 H) IR spectrum~/XBr): ~-~

~, ~ - : , ,.,,,, ~:

- 195 - 1~3~7~ ~
, . ..
,`~
1720, 1710 cm 1 --Example 128 In 10 ml of toluene was dissolved 350 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~-(N,N-dimethyl-carbamoyl)oxy-3~-(N-phenylcarbamoyl)oxypregn-6-en-5-ol, followed by addition of 50 mg of pyridinium p-toluene-sulfonate. The mixture was stirred in an atmosphere of argon gas at room temperature for 10 hours. The reaction mixture was then worked up in the same manner as Example 124 to give 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la-(N,N-dimethylcarbamoyl)oxy-3~-(N-phenylcarbamoyl)oxypregna-5,7-diene showing the ; following physical properties.
H-NMR spectrum (90 MHz) 6CDC13:
0.61 (s, 3 H), 0.70 (s, 3 H), 0.99 (s, 3 H), .05 (d, J=6.2~ Hz, 3 H), 1.18 (s, 3 H), 2.78 ~-~
2.81 (each o, 6 H), 3.34 (d, J=10.5 Hz, 1 N), 3.44 /d, J=10.5 Hz, 1 H), 3.57 (d~, J=10.5 Hz, 2 H), 4.38~(d, J=2.4 Hz, 1 H), 4.65-5.15 ~
(2 H)~, 5.36~(m, 1 H),~5.70 (m, 1 H), 6.80 ;~;
~- (br. s, 1 H), 7.1-7.7 (5 H) , ~ IR spectrum'(RBr) .~ -1 `
1720, 1695~cm Example 129 ~ '":,;

~, I ~

- 196 - 1~.379 -In 10 ml of benzene was dissolved 350 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la-(tert-butyldimethyl-silyl)oxy-3B-(N,N-dimethylcarbamoyl)oxypregn-6-en-5a--ol, followed by addition of one drop of concentrated sulfuric acid. The mixture was stirred in an atmosphere of argon gas under ice-cooling for 1 hour. The reaction mixture was then worked up in the same manner as Example 124 to give 135 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl~-la-(tert-butyldimethylsilyl)oxy-3B-(N~N-dimeth carbamoyl)oxypregna-5,7-diene showing the following~
properties.
H-NMR spectrum (90 MHz) ~CDsl3:
0.15 (s, 6 H), 0.61 (s, 3 H), 0.70 (s, 3 H), ;~
0.93 (s, 3 H), 0.97 (s, 9 H), 1.05 (d, J=6.2 ~, Hz, 3 H), 1.18 (s, 3 H) 2.78 & 2.81 (each s, 6 H), 3.34 (d, J=10.5 Hz, 1 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 (d, J=10.5 Hz, 2 H), 4.2-4.5 (2 H), 4.90 (m, 1 H), 5.38 (m, 1 H), S.68 (m, 1 H) `~ IR spectrum (XBr):
1695 cm `
Example 130 In 10 ml of ethyl acetate was dissolved 400 mg of ~, ~
20-(5,5-dimethyl-1,3-dioxan-2-yl)-3B-(tert-butyldi- ~;
-~ methylsilyl)oxy-la-(methoxymethyl)oxypregn-6-en-Sa-ol, ~ .
,- ~

., , , , ., , ., , , ,, , .. ., . , . . ., . . . .- .............. . .

~ "~ :. , , - . j ., - " .. .: . . . . . ; : :

1~3~.37~ :
~ - 197 -`'''`. ~:

followed by addition of 0.2 m~ of acetic acid. The mixture was refluxed in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in ~;;
the same manner as Example 124 to give 150 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(tert-butyldimeth~
ylsilyl)oxy-la-(methoxymethyl)oxypregna-5,7-diene showing the following physical properties.
H-NMR spectrum (90 MHz) ~CDC13 0.13 (s, 6 H), 0.61 (s, 3 H), 0.70 (s, 3 H), 0.95 (s, 9 H), 0.99 (s, 3 H), 1.05 (d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 3.34 (d, J=lO.S Hz, ~ ;~
1 H)~, 3.36 (s, 3 H), 3.44 (d, J=lO.S Hz, 1 H), 3.57 (d, J=lO.S Hz, 2 H\, 4.10-4.50 (2 H), 4.38 ~d, J=2.4 Hz, 1 H), 4.80 ~br. s, 2 Hj, 5.35 (m, 1~ H), 5.~70 (m, 1 H) Example 131 In lO ml of butyl acetate was dissolved 350 mg of 20~ ,3-dioxolan-2-yl)-la-acetoxy-3B-(methoxymethyl)oxy-pregn-6-en-Sa-ol,~followed by addition of 0.2 ml o~f aaetic acid. The mixture was stirred in an atmosphere -~
of argon gas under heating at 100C for 12 hours. The reaction mixture was then worked up in the same manner as Example 124~to~give 100 mg of 20-(1,3-dioxolan- ;;`~
2-y1)-la-acetoxy-3B-~(methoxymethyl)oxypregna-5,7-diene ~ `-showing the following physical properties. -~

~ ~' ' ' ',';';' '~
~r ~ :~

~:,' .

- 198 - 1~3~37~ ~

H-NMR spectrum (90 MHz) ~CDC13 0.62 (s, 3 H), 0.95 (d, J=6.2 Hz, 3 H), 0.98 (s, 3 H), 2.07 (s, 3 H), 3.35 (s, 3 H), 3.70-4.05 (m, 4 H), 4.30 (m, 1 H), 4.65 (br.
s, 2 H), 4.79 (br. s, 1 H), 4.99 (1 H), 5.35 (m, 1 H), 5.70 (m, 1 H) ~ ~
IR spectrum ~KBr): ~ -1735 cm 1 Example 132 ~-In 10 m~ of dimethyl carbonate was dissolved 345 mg of 20-(5,5-dimethyl-1~3-dioxan-2-yl)-la,3~-bis(methoxy-carbonyloxy)pregn-6-en-5a-ol, followed by addition of 0.2 ml of acetic acid. The mixture was refluxed in an atmosphere of argon gas for 10 hours. The reaction mixture was poured in ice-water and extracted with ether~. The~extracts were pooled, neutralized with cold aqueous~ sodium~hydroxide solution and aqueous sodium -hydrogen carbonate solution, and washed with aqueous sodium chloride solution. The solvent was distilled off undér reduced pressure and the residue was purified by column chromatography to recover 140 mg of 20-(5,5-dimethyi-1,3-dioxan-2-yl~-la,3~,7a-tris(methoxycarbonyl- ;
: ~ .
oxyJ~pregn-S-ene~showing~the following physical properties. : ;-~
H-NMR spéctrum (90 MHz) ~CMscl3:

;, ~,,, f . , ~;~

':` ~

-~ ~ '?~

3 ~ ~ 7 ~
0.68 (s, 6 H), 1.05 (s, J=6.2 Hz, 3 H), 1.08 (s, 3 H), 1.16 (s, 3 H), 3.25 (d, J=10.8 Hz, 1 H), 3.42 (d, J=10.8 ~z, 1 H), 3.60 (d, J=10.8 Hz, 2 H), 3.77, 3.78 & 3.80 (each s, 9 H), 4.37 (br. s, 1 H), 4.72-5.12 (3 H), 5.90 (d, J=5.7 Hz, 1 H), IR spectrum (KBr):
1745 cm l Example 133 In 10 m~ of dimethyl carbonate was dissolved 350 ;~ mg of 20-(1,3-dioxolan-2-yl)-3~-acetoxy-la-benzoyloxy-pregn-6-en-5~a-ol, f~ollowed by addition of 0.1 m~ of ~-monochloroacetic acid. The~mixture was stirred in an atmosphere of argon gas under heating at a temperature of 100C for 10 hours. T~he reaction mixture was then ~ -~
worked up ln the same manner as Example 132 to give lO0 mg~of 20-l1,3-dioxolan- 2-yl)-3~-acetoxy-l~-benzoyloxy- `~
7a-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties. ~
H-NMR spectrum ~90 MHz) ~TMS
~-~ 0.72 (s, 3 H), 0.95 (d, J=6.2 Hz, 3 H), 1.08 -~
(s, 3IH), 2.05 (s, 3 H), 3.70-4.05 (m, 4 H), 3.80 (s, 3 H), 4.79 (br. s, 1 H), 4.70-5.10 ~ :
(3 H), 5.91 ~d, J=5.8 Hz, 1 H), 7.2-7.7 (3 -~
H), 7.9-8.2 (2 H) ,: - , ~" ~
~ ~`
;,', ~ I : ' `:
, : , :-':~: l ::

- 200 - 133~3~ :

IR spectrum (KBr):
1745, 1735, 1720 cm~
Example 134 In 10 ml of dimethyl carbonate was dissolved 350 mg of 3~-benzoyloxy-21,21-dimethoxy-20-methyl-la-(N- -methylcarbamoyl)oxypregn-6-en-5a-ol, followed by addition of 50 mg of dichloroacetic acid, and the mixture was heated in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 90 mg of 3~-benzoyl-oxy-21,21-dimethoxy-20-methyl-la-(N-methylcarbamoyl)oxy-7a-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
H-NMR spectrum ~90 MHz) ~CMsl3:
0.74 (s, 3 H), 0.95 (d, J=6.2 Hz, 3 H), 1.08 (s, 3 H), 2.80 (d, J=6 Hz, 3 H), 3.38 (s, 3 ~;~
H), 3.40 (s, 3 H), 3.77 (s, 3 H), 4.38 (br.
s, 1 H), 4.95 (1 H), 4.7-5.1 (3 H), 5.88 (d, J=5.7 Hz, 1 H), 7.2-7.7 (m, 3 H), 7.9-8.2 (m, 2 H~
IR spectrum (KBr):
-- ; 1750,~17;20,'1710 cm 1 ,,: . .
Example 135 In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-(5,5-dimethy1-1,3-dioxan-2-yl)-la-(N-phenyl-i~ :
: .

k';'~_ j- ', ` ' , . ; ~

-- 201 -- ~ r~
.-.
carbamoyl)oxy-3~-(N-methylcarbamoyl)oxypregn-5~-ol, followed by addition of 50 mg of p-toluenesulfonic acid. The mixture was stixred in an atmosphere of argon gas at room temperature for 3 hours. The reac-tion mixture was then worked up in the same manner as Example 132 to give 120 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(N-methylcarbamoyl)oxy-la-(N-phenyl-carbamoyl)oxy-7a-(methoxycarbonyl~oxypregn-5-ene showing the following physical properties.
H-NMR spectrum (90 MHz) 6TMS 3: ~
0.70 (s, 6 H), 1.05 (d, J=6.2 Hz, 3 H), 1.05 (s, 3 H), 1.18 (s, 3 H), 2.76 (d, J=6 Hz, 3 H), 3.34 (d, J=10.5 Hz, 1 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 (d, J=10.5 Hz, 2 H), 3.78 (s, 3 H), 4.38 (d, J=2.4 Hz, 1 H), 4.65-5.15 (3 '~
H), 5.20 (1 H), 5.90 (d, J=5.7 Hz, 1 H), 6.75 ~;~
(br. s, 1 H), 7.1-7.7 (5 H) IR spectrum ~KBr):
1745, 1720, 1710 cm~l `~
Example 136 In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-l5,5-dimethyl 1,3-dioxan-2-yl)-1~-(N,N-di-methylcarbamoyl)oxy-3~-(N-phenylcarbamoyl)oxypregn-6-en-5a-ol, followed by addition of 50 mg of pyridinium p-toluenesulfona~e. The mixture was stirred in an `:

, - ,.:: .: :......... , .: -, .,:: .. .... :. .-: . : . - . . ~: .

- 202 - ~33~.~7~
. :.~. .
atmosphere of argon gas at room temperature for 10 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 150 mg of 20-(5,5-di-methyl- 1,3-dioxan-2-yl)-la-(N,N-dimethylcarbamoyl)oxy-3~-(N-phenylcarbamoyl)oxy-7~-(methoxycarbonyl)oxypregn-5-ene showing the following physcial properties.
H-NMR spectrum (90 MHz) ~CD5C13 0.70 (s, 6 H), 1.05 (d, J=6.2 Hz, 3 H), 1.08 -~

(s, 3 H), 1.18 (s, 3 H), 2.78 & 2.81 (each s, 6 H), 3.34 (d, J=lO.S Hz, 1 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 (d, J=10.5 Hz, 2 H), 3.76 (s, 3 H), 4.38 (d, J=2.4 Hz, 1 H), . ~ ~
4.65-5.15 (3 H), 5.90 (d, J=5.7 Hz, 1 H), 6.80 (br. s, 1 H), 7.1-7.7 (5 H) -~ IR spectrum (KBr):
1745, 1720, 1695 cm 1 Example 137 In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(tert-butyl-dimethylsilyl)oxy-3~-(N,N-dimethylcarbamoyl)oxypregn-6-en-5~-ol, followed by addition of one drop of concent-rated sulfuric acid. The mixture was stirred in an atmosphere of arqon gas under ice-cooling for 1 hour.
The reaction mixture was then worked up in the same manner as Example 132 to give 95 mg of 20-(5,5-dimethyl~

j, :
~.

,:,,". :~ ", . ,,, : ,-,:~,. :: :: . , : :: :: ;,:, ~,"",, ,, , " ," ,i"", , , , :" ",,,~:,,, ,, " - ". ",, , ," : ~,, :: :,: " ::~: :, - 203 - ~3~f~ff~3 7~f .':
1,3-dioxan-2-yl) -lf~- (tert-butyldimethylsilyl)oxy-33-(N,N-dimethylcarbamoyl) OXy-7f~- (methoxycarbonyl~oxypregn-5-ene showing the following physical properties.
H-NMR spectrum (90 MHz) ffSTDcl3 0.15 (s, 6 H), 0.70 (S, 6 H), 0.97 (s, 9 H), 1.05 (d, J=6.2 Hz, 3 H), 1.08 (s, 3 H), 1.18 (S, 3 H), 2.78 & 2.Bl (each s, 6 H), 3.34 (d, J=10.5 Hz, 1 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 (d, J=10.5 Hz, 2 H), 3.77 (S, 3 H), 4.2-4.5 (3 H), 4.7-S.1 (2 H), 5.90 (d, J=5.8 Hz, 1 H) IR spectrum lXBr):
1745~ 1695 cm 1 -~; Example 138 In 10 ml of dimethyl carbonate was dissolved 400 :~ , mg of 20- (5~ 5-dimethyl-1,3-dioxan-2-yl)-3~-(tert-butyl-dimethylsilyl)oxy-lol-(methoxymethyl)oxypregn-6-en-50l-ol, followed by addition of 0.2 ml of acetic acid. The mixture was refluxed in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 120 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(tert-butyldimeth-yl S ilyl ) OXy- 1 a- (methoxymethyl) OXy- 7a- (methoxycarbonyl)- foxypregn-5-ene showing the following physical properties.
,,, ' , , , ' ' ' " - ~ ,, f -, ' , ' .: ' ' ~ . :' :' ' ,, ' ' " " ',,' ' ' " - . ' ' ' '' ' ' . ': ' '"~ ' : :

:, '- ' , ': , :,: ', ' ' ' ' .' ,,::, ' ,:, ':: ' ' , -' ::, ',: : : ' '' ::, ' 1~33 37~

H-NMR spectrum (90 MHz) ~TMsl3:
0.13 (s, 6 H), 0.70 (s, 6 H), 0.95 (s, 9 H), 1.05 (d, J=6.2 Hz, 3 H), 1.08 (s, 3 H), 1.18 (s, 3 H), 3.34 (d, J=10.5 Hz, 1 H), 3.36 (s, 3 H), 3.44 (d, J=10.5 Hz, 1 H~, 3.57 ~d, J=10.5 Hz, 2 H), 3.78 (s, 3 H), 4.10-4.50 (2 H), 4.38 (d, J=2.4 Hz, 1 H), 4.7-5.1 (2 H), 5.90 (d, J=5.7 Hz, 1 H) IR spectrum (KBr):
1745 cm~1 Example 139 ; In 10 m9 of dimethyl carbonate was dissolved 350 mg o 2~o-(li3-dioxolan-2-y~ a-acetoxy-3B-(methoxy~
met~yl)oxypregn-6-en-5~-ol, following by addition of 0.2 m~ of acetic acid. The mixture was stirred in an -~
atmosphere of argon~gas at a temperature of~ 100C for 12 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 130 mg of 20-~1,3- ;`-~
dioxolan-2-yl)-l~-acetoxy-3~-(methoxymethyl)oxy-7- -~
(methoxycarbonyl)oxypregn-S-ene showing the following l;~
-~ physical properties.
H,NM~ spectrum (9~MHz) ~TMscl3~
0!75 (s, 3 H`~,~ 0.95 (d, J-6~.2 Hz,~3 H), 1.07 ~-(s, 3 H), 2.07 (s, 3 H), 3.35 (s, 3 H), ,,~ , .;
7`'.~` 3.70-4.05 (m, 4 H), 3.78 (s, 3 H), 4.30 (m, 1 ~-~.", ,~, : :: ::
i ' " ~ ' : :: , ::
, - ;~05 - 133~.37~

H), 4.79 (br. s, 2 H), 4.7-S.1 (2 H), 5.90 (d, J=5.7 Hz, 1 H) IR spectrum (KBr):
1745, 1735 cm~
Example 140 -~
In 5 m~ of methanol was dissolved 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,3~,7~-tris(methoxy-carbonyloxy)pregn-5-ene, followed by addition of 30 mg of sodium methoxide, and the mixture was stirred at room temperature for S hours. The reaction mixture was poured in water and extracted with methylene chloride.
The extracts were pooled, washed with aqueous sodium chloride solution and concentrated under reduced pressure. The concentxate was recrystallized from ethyl acetate to give 65 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-5-ene-la,3~,7a-triol showing the following physical properties. -~
H-NMR spectrum (90 MHz) 6~DC13:
; 0.68 (s, 6 H~, O.9S (s, 3 H), 1.05 (d, J=6.2 -- Hz, 3 H), 1.16 (s, 3 H), 3.25 (d, J=10.8 Hz, , :
~`~ 1 H), 3.42 (d, J=10.8 Hz, 1 H), 3.60 (d, J=10.,~ H,z, 2 H), 4.37 ~r. s, 1 H), 3.7-4.2 (3 H), 5.80 (d, J=5.7 Hz, 1 H) IR spectrum ~KBr):

',- , , ;:, ,": , ,,~ .

- 206 ~ 3.~7~ ~

Example 141 The reaction and workup procedures of Example 140 were repeated except that 95 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(tert-butyldimethylsilyl)oxy-3~-(N,N-dimethylcarbamoyl)oxy-7a-(methoxycarbonyl)oxy-pregn-5-ene was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,3B,7a-tris(methoxycar-bonyloxy)pregn-5-ene to give 55 mg of 20-~5,5-dimethyl- -~-1,3-dioxan-2-yl)-la-(tert-butyldimethylsilyl)oxypregn-5-ene-3~,7a-diol showing the following physical properties.
H-NMR spectrum (90 MHz) ~CMsl3:
0.15 (s, 6 H), 0.70 (s, 6 H), 0.92 (s, 3 H), 0.97 (s, 9 H), 1.05 ~d, J=6.2 Hz, 3 H), 1.18 (s, 3 H), 3.34 (d, J=10.5 Hz, 1 H), 3.44 (d, ~-J=10~5 Hz, 1 H), 3.57 (d, J=10.5 Hz, 2 H), 3.8-4.5 (4 H), 5.70 (d, J=5.8 Hz, 1 H) -~ IR spectrum (KBr):
3350 cm~l ~ .~
Example 142 The reaction and workup procedures of Example 140 -~ were repeated except that 120 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)l3~-(tert-buty}dimethylsilyl)oxy-la- ! ,~ ¦ ' ; (methoxymethyl)oxy-7a-(methoxycarbonyl)oxypregn-5-ene ~- was~used in lieu of 1~00 mg of 20-(5,5-dimethyl-1,3- ~;

- 207 ~ 37~

dioxan-2-yl)-1~,3~,7a-tris(methoxycarbonyloxy)pregn-5-ene to give 65 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(tert-butyldimethylsilyl)oxy-1~-(methoxymethyl)-oxypregn-5-en-7a-ol showing the following physical properties.
H-NMR spectrum (90 MHz) ~CMsl3: -0.13 (s, 6 H), 0.70 (s, 6 H), O.95(s, 9 H), 1.05 (d, J=6.2 Hz, 3 H), 1.08 (s, 3 H), 1.18 (s, 3 H), 3~34 (d, J=10.5 Hz, 1 H), 3.36 (s, 3 H), 3.44 (d, J=10.5 Hz, 1 H), 3.57 (d, J=10.5 Hz, 2 H), 3.78 (s, 3 H~, 4.10-4.50 (3 H), 4.38 (d, J=2.4 Hz, 1 H), 4.79 (br. s, 2 H), 5.90 (d, J=5.7 Hz, 1 H) IR spectrum (KBr):
3400 cm 1 Example 143 ., .
-~ The reaction and worjkup procedures of Example 140 , - .
were repeated except that 90 mg of 20-(1,3~dioxolan-2-yl)-; l-acetoxy-3~-/methoxymethyl)oxy-7~-(methoxycarbonyl)oxy-pregn-5-ene was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,3~,7~-tris(methoxycarbonyloxy)pregn-5-ene to give 65 mg of 20-(1,3-dioxolan-2 yl)-3B-(methoxy-methyl)oxypregn-5-ene-la,7~-diol showing the following properties.
;~ 1H-NMR spectrum (90 MHz) ~CMcl3:
,, ~~ '~.
~ ' -'.
- . , ,' - 208 - ~3 f--0.75 (s, 3 H), 0.94 (s, 3 H), 0.95 (d, J-6.2 Hz, 3 H), 3.35 (s, 3 H), 3.70-4.05 (m, 4 H), ;~
3.8-4.3 (3 H), 4.79 (br. s, 2 H), 5.75 (d, J=5.7 Hz, 1 H) ~
IR spectrum (KBrj: -3400 cm Example I44 The reaction and workup procedures of Example 140 were repeated except that 85 mg of 3~-benzoyloxy-21,21-dimethoxy-20-methyl-la-(N-methylcarbamoyl)oxy-7~-(methoxycarbonyl~oxypregn-5-ene was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,3B,7~
tris(methoxycarbonyloxy)pregn-5-ene to give 45 mg of 21,21-dimethoxy-Z0-methylpregn-5-ene-la,3~,7a-triol showing the following physical properties.
H-NMR spectrum (90 MHz1 ~TMS 3 0.69 (s, 3 H), 0.94 (s, 3 H), 0.95 (d, J=6.2 Hz, 3 H), 3.38 ~ 3.40 (each s, 6 H), 3.7-4.3 ~3 H), 4.40 (br. s, 1 H), 5.75 (d, J=5.7 Hz, 1 ~-~ IR spectrum (KBr):

Examples 145 to 149 The esteriflcation~reaction of the 7a-hydroxy ~group of compound (I-9-lb) ~100 mg) and the separation ,"i', ~:
~: ~'', `` 1~33.37`~ ~
, ....

,ç~

and purification of the product compound (I-9-lc) were conducted in the same manner as described in Examples :.
104 to 108. The groups possessed by the specific compounds (I-9-lb) used in the reaction are shown in ::
Table l and the groups possessed by the product compounds (I-9-lc), and the yields and IR spectra (KBr) of the latter are shown in Table 2. ;~

~' ~
' ~ :

!
~ ' ' `':

,~',, ~

,'''''~' , ~:
, ,~, . ~
~ ~ ' :';',';: ~

~3~ 37~
- 210 - ~

w~ ;

~ : ~ ,~ ~7u,~- D^ ~a~ u~-a =~ a~;

. ~ 3 ~

~ ~: N 3: t~ O :1: 2 ~ ~-,, G) I ~ CJ . ':
::,~ ~ . ~ o ~: ,~ _~

-,. ~ ` : H ~ N . ~ , ~ U ~ ~ ! .
. U U a~ ~

~ ~ ' .~ ~ ~ ~ ZO '` ~
~ ~ r ~'~

~,',,~-- 211- ~33~37~
;, ~

,~ U~ o o o U~
_ ~ ... ~ ~ ~ o~
c~ r~ D
H ~
_ _ ~r\ It a~ s~
~ ~5 ,1 ~ o a~ o~
~ ~ . :

t~ 0~ ~ ~N ,~ o o ~ . -~ N I ..
C~ C.)--U t.
: ~ ~ ~ g O ~ O
::~; ' 1 .~.
. ~ ~ ~ î~ .
: ~ ~ O O ~ t~ ~ ~' ~ I I O _~ , O ~ ~ ~ . ~

~-~ o ~ ~ 1~ o ~ 0 Qlz I _ ~ o Z ~ ~' :: _ 'C4 1 U ~ .
O ~ ~ I O -~:

: r~ H . ` ; ~ .
~-- N O O ^ O ~
~ ~~ y ~;
_l cn jZ : ~
,- ~ u~

/ , :, ' , , , . ''..' . : ~ ' . - ' . . . , ' i . .

133~ 379 Example 150 -In 10 m~ of dioxane was dissolved 25 mg of tris-(dibenzylideneacetone)dipalladium(chloroform), followed ~y addition of 45 ~l of tri-n-butylphosphine. The mixture was stirred in an atmosphere of argon gas at room temperature for 10 minutes. To this mixture was added a solution of 270 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-~a,3~,7a-tris(methoxycarbonyloxy)pregn-5-ene in lO mD of dioxane and the mixture was refluxed for 12 hours. The resulting reaction mixture was ;-cooled to room temperature and filtered with the aid of Florisil. The filtrate was concentrated under reduced ~- -pressure and the concentrate was purified by column chroma-tography. ~he procedure yielded 118 mg of 20-(5,5-dlmethyl-1,3-dioxan-2-yl)-lcY,3~-bis(methoxycarbonyloxy)-pregna-5,7-diene showing the same physical porperties as the compound obtained in Example 124.
Examples 151 to 155 The conjugated diene-forming reaction of compound (I-9-lc) (in a given amount) in the presence of the palladium compound and tertiary phosphine (provided, however, that no tertiary phosphine was used in Example ¦
1553 and the separation and purification of the result-ing product compound (I-5-3) were carried out in the ¦
same manner as described in Example 150. The groups - ~13 - 133137~
,. :
possessed by the specific compounds (I-9-lc) used for the reaction, the amounts of said compounds and the :
species of palladium compound and tertiary phosphine used are shown in Table 3 and the yields and physical values of the product compounds (I-5-3) are shown in Table 4. The amounts of palladium compound and tertiary phosphine were 0.1 and 0.4 equivalents, respectively, based on compound (I-9-lc).

: ` :
- ~ ' . ~. , ,. :
. ~

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U-l R.J-) O Z ~ D.
C~8 Z ~ ~ ~
O ~ "5 ~ . `
C,~ C U~_ O O U) O O
u D.a~ E ~ ~ I` ~ o ~ E 8 . ,, ~ ~ N N
~_ ~0 ,, r~
O 0~ o o 0~ O~
_ (J~ U O
D ~1 ~ 1~1 U--U ~ 1 1'7 ^ V

h N U U U U U _ ~ _, ;
E r~ ~ ~ ~0 :.
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~ ~ C~ ~., N~0 0 o . ~

~1 W I o u u o o I cc h ~ N U o _ ,~ UZ lS ~

I ~ Y y ~`1 , .
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, ~:

215 - 1 3 ~ ~ ~ 7~

~ X X - ~

Ei ~ ~ E ~N V :~.
a ~ D o~ _ _ ~ ~v~ x ~ x x~ ~
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~: z ~ o è E ~ ~ ~ ~v : .
I _ O CO ~ D
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P. H U '.
. .~ ~ ~ .,,',, ~ ~

~,: ~ a~ u~(a o 1 ~:

- 216 - 13~337~ ~
::, Example 156 In 5 ml of acetone was dissolved 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~,3~-bis~methoxycar-bonyloxy)pregna-5,7-diene, followed by addition of one drop of concentrated sulfuric acid, and the mixture was refluxed in an atmosphere of argon gas for 3 hours. ~ -The reaction mixture was poured in ice-water and extracted with ether. The extracts were pooled and washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, followed by concentration under reduced pressure. Finally the ~;~
concentrate was purified by recrystallization from ether. ~
The procedure yielded 55 mg of la,3~-bis(methoxycarbonyl- ;;
; oxy)pregna-5,7-diene-20-carbaldehyde showing the ~ ;~
following physical properties.
H-NMR spectrum (90 MHz) ~CDC13 0.66 (s, 3 H), 1.02 (s,~3 H), 1.15 (d, J=6.4 Hz, 3 H), 3.77 ~ 3.79 (each s, 6 H), 4.6-5.2 (2 H), 5.40 fm, 1 H), 5.65 (m, 1 H), 9.58 (d, J=3.5 Hz,.1 H) IR spectrum (KBr):
- I740,i~17~25 cm'li ~ :
Example 157 ~ `
In 5 m~ of tetrahydrofuran was dissolved 100 mg of`~-20-(1,3-dioY.olan-2-yl)-3B-acetoxy-1~-benzoyloxypregna-", ~

: ',,: -- 217 - 1 ~3~.37~ :

5,7-diene, followed by addition of 1 ml of water and 10 mg of p-toluenesulfonic acid. The mixture was stirred in an atmosphere of argon gas at 50C for 3 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 45 mg of 3B-acetoxy-la-benzoyl-oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
~-NMR spectrum (90 MHz) ~TMsl3~
0.66 (s, 3 H), 1.01 (s, 3 H), 1.15 (d, J=6.2 Hz, 3 H), 2.05 (s, 3 ~), 4.60-5.20 (2 H), '~
5.38 (m, 1 H), 5.70 (m, 1 H), 7.2-7.7 (3 H), 7.9-8.2 (2 H), 9.58 (d, J=3.5 Hz, 1 ~) IR spectrum (KBr):
1735, 1725, 1720 cm~

Example 158 In 5 m of methanol was dissolved 100 mg of 3~-benzoyloxy-21,21-dimethoxy-20-methyl-1~-(N-methyl-carbamoyl)oxypregna-5,7-dione, followed by addition of 5~ml of water and 100 mg of copper sulfate. The mixture was stirred in an atmosphere of aroon gas at a temperature of 60C for 7 hours. The reaction mixture . .
was then worked u~ in,the same manner as,Example 156 to give 60 mg of 3~-benzoyloxy-la-lN-methylcarbamoyl)oxy-~- pregna-5,7-diene-20-carbaldehyde showing the following -, physical properties.
~,,, 5,"~' ' .

H-NMR spectrum (90 MHz) ~CDs13 -0.66 (s, 3 H), 1.02 (s, 3 H), 1.15 (d, J=6.2 Hz, 3 H), 2.80 ~d, J=6 Hz, 3 H), 4.6-5.2 (3 H), 5.36 (m, 1 H), 5.68 (m, 1 H), 7.2-7.7 (m, 3 H), 7.9-8.2 (m, 2 H), 9.58 (d, J=3.5 Hz, 1 H) IR spectrum (KBr):
1725, 1720, 1710 cm 1 Example 159 In 5 ml of ethanol was dissolved 105 mg of ::..:,,.,,,,,~
20-(5,5-dimethyl-1,3-dioxan-2-yl)-1-lN-phenylcarbamoyl)-oxy-3~-(N-methylcarbamoyl)oxypregna-5,7-diene, followed by addition of 1 m of~3N-hydrochloric acid, and the ;-;
mixture~was stirred in an atmosphere of argon gas at 40C for 3 hours. The reaction mixture was then worked Up iD the same manner as Example 156 to give 52 mg of 3~-(N-methylcarbamoyl)oxy-l~-(N-phenylcarbamoyl)oxypre~
gn~a-5,7-d~iene-20-carbaldehyde showing the following phys1cal properties. ~ ~ -H-NMR spectrum (90 MHz) ~CDC13 0.65 (s, 3 H), 1.02 (s, 3 H), l.lS(d, J=6.2 Hz, 3 H~, 2176~ (d, J=6!Hz, 3 H)i~, 4.65-5.1g ~2 H), 5.20~(1 H), 5.36 (m, 1 H), 5.68 (m, 1 H), ,- ~ " . ~,. -- 6.75 (br. s, 1 H), 7.1-7.7 (5 H), 9.58 (d, ~- J=3.5 Hz, 1 H) , .

,~ - ' - 219 ~ 13~3~ ~

IR spectrum (KBr):

1725, 1720, 1710 cm~
. i Example 160 In 10 m~ of 2-butanone was dissolved 95 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~-lN,N-dimethylcarb- -amoyl)oxy-3~-(N-phenylcarbamoyl~oxypregna-5,7-diene, followed by addition of S0 mg of pyridinium p-toluenesul-fonate, and the mixture was stirred in an atmosphere of argon gas at a temperature of 50C for 10 hours. The reaction mixture was then worked up in the same manjner as Example 156 to give 45 mg of l~-(N,N-dimethyl-carbamoyl)oxy-3B-(N-phenylcarbamoyl)oxypregna-5 diene-20-carbaldehyde showing the following physical properties.
-NMR spectrum (90 MHz) ~CMcl3 ~ .
0.66 (s, 3 H), 1.02 (s, 3 H), 1.15 (d, J=6.2 Hz, 3 H), 2.78 & 2.81 ~each s, 6 H), 4.65-5.15 (2 H), 5.36 (m, l H), 5.70 (m, 1 H), 6.80 (br.~ s, l H), 7.1-7.7 (5 H), 9.60 (d, 3=3.5 , ~ . .
-~; Hz, 1 H) IR spectrum (KBr):

1725,i 1720,'1i6~5 cm~l Example 161 In 10 m~ of acetone~was dissolved 110 mg of ; 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1~-(tert-butyldi-.;r, l ' ~ ~' :'i.'`~ ': ' ' . .

- 220 - ~ ~3~7~ ~

methylsilyl)oxy-3~-(N,N-dimethylcarbamoylloxypregna-5,7-diene, followed by addition of 10 mg of p-toluenesulfonic acid. The mixture was refluxed in an atmosphere of argon gas for 4 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 63 ;
mg of la-(tert-butyldimethylsilyl)oxy-3~-~N,N-dimethyl-carbamoyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
H-NMR spectrum (90 MHz) ~CDC~3 0.15 (s, 6 H), 0.66 (s, 3 H), 0.97 (s, 9 H), 1.02 (s, 3 H), 1.15 (d, J=6.2 Hz, 3 H), 2.78 2.81 (each s, 6 H), 4.2-4.5 (1 H), 4.90 (m, --1 H), 5.38 (m, 1 H), 5.68 (m, 1 H), 9.60 (d, J=3.4 Hz, 1 H) IR spectrum (XBr):
1725, 1695 cm 1 ~
Example 162 ~ -In 5 ml of tetrahydrofuran was dissolved 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3~-(tert-butyldimethylsil~
oxy-la-(methoxymethyl)oxypregna-5,7-diene, followed by addition of 5 ml of 80% acetic acid. The mixture was refluxed in an atmosphére ~f argon gas for 12 hours. !
The reaction mixture was then worked up in the same manner as Example 156 to give 50 mg of 3~-(tert-butyl-dimethylsilyl)oxy-l~-(methoxymethyl)oxypregna-5,7- ~;~
`' '~ ;

, , , ", , , . ., j., , ., , " " ~ . , .:,, -.

- 221 - ~ ~3~.37v~ ~

., diene-20-carbaldehyde showing the following physical properties.
H-NMR spectrum (90 MHz) ~TDsl3:
0.13 (s, 6 H), 0.66 (s, 3 H), 0.95 (s, 9 H), 1.01 (s, 3 H), 1.14 (d, J=6.2 Hz, 3 H), 3.40 (s, 3 H), 4.10-4.50 (2 H), 4.80 (br. s, 2 H), 5.35 (m, 1 H), 5.70 (m, 1 H), 9.59 (d, J=3.5 Hz, 1 H) IR spectrum (KBr)~
1725 cm Example 163 ~; In 10 mQ of acetone was dissolved 100 mg of ~ 20-(1,3-dioxolan-2-yl)-la-acetoxy-3~-~methoxymethyl)oxy-- ~ pregna-5,7-diene, followed hy addition of one drop of 70~ perchloric acid, and the mixture was refluxed in an . ~, .
atmosphere of argon gas for 2 hours. The reaction mixture was then worked up in the same manne~ as Example 156 to give 40 mg of la-acetoxy-3~-(methoxy-methyl)oxypregna-5,7-diene-20-carbaldehyde showing the ~ following physical properties.
i 1H-NMR spectrum (90 MHz) ~TMS13:
0.66 ~s,,3 H),!l~.00 (s, 3 H), 1.,16 (d, J=6.~2 ~;
Hz, 3 H), 2.07 (s, 3 H), 3.35 ~s, 3 H), 4.30 (m, 1 H), 4~.65 (br. s, 2 H), 4.99 (1 H), 5.35 - ;

- .
, ~ ' :.

~ 1 333 37~ ~:
..,. :.
.... ;. .
(m, 1 H), 5.70 (m, 1 H), 9.57 (d, J=3.5 Hz, 1 H) IR spectrum (XBr):
1735, 1725 cm 1 Example 164 In 10 me of methanol was dissolved 100 mg of 1~,3~-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbal- - i~-dehyde, followed by addition of 100 mg of potassium carbonate. The mixture was stirred at room temperature ;~
for 1 hour. The reaction mixture thus obtained was poured in water and extracted with methylene chloride.
The extracts were pooled and washed with aqueous sodium chloride solution, followed by concentration under reduced pressure. The concentrate was recrystallized from ether to recover 78 mg of 3~-hydroxy-la-(methoxycarbonyl-oxy~pregna-5,7-diene-20-car~aldehyde showing the ~-~
following physical properties.
H-NMR spectrum (90 MHz) ~CMcl3 ;, ~
~ 0.66 (s, 3 H3, 1.02 (s, 3 H), 1.15 (d, J=6.4 ~
~ - , Hz, 3 H), 3.77 (s, 3 H), 4.03 (m, 1 H), 4.90 (br. s, 1 H), 5.40 (m, 1 H), 5.65 (m, 1 H), ; 9.58 j(d,l J=3.5~Hz, 1 H) IR spectrum IKBr):

3450, 1740, 1725 cm~

Example 165 ' ~ ':

- 223 - ~3~3~.~

In 10 mt of methanol was dissolved 100 mg of la-acetoxy-3~-~methoxymethyl)oxypregna-5,7-diene-20-carbaldehyde, followed by addition of 50 mg of sodium methoxide. The mixture was stirred in an atmosphere of argon gas for 2 hours. The reaction mixture was then worked up in the same manner as Example 164 to give 80 mg of la-hydroxy-3~-(methoxymethyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical proper-ties.
H-NMR spectrum (90 MHz) ~CMcl3:
0.66 (s, 3 H), 0.94 (s, 3 H), 1.16 (d, J=6.2 Hz, 3 H), 3.35 (s, 3 H), 3.76 (br. s, 1 H), 4.20 (m, 1 H), 4.65 (br. s, 2 H), 5.35 (m, 1 H), 5.70 (m, 1 H), 9.57 (d, J=3.5 Hz, 1 H) IR spectrum (KBr): -3450, 1725 cm Example 166 The reaction and workup procedures of Example 164 were repeated except that 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,3~-bis(methoxycarbonyloxy)pregna-5,7-diene was used in lieu of 100 mg of la,3~-bis(methoxy-carbonyloxy)pregnà-5,7-diene-20-carbaldehyde to givei85 `~
mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl) -la- (methoxy-carbonyl)oxypregna-5,7-dien-3~-ol showing the following physical properties.
lH-NMR spectrum (90 MHz) ~TMsl3:

- 224 - ~ 3 3 3 3 7 ~
. -;.:,, 0.63 (s, 3 H), 0.70 (s, 3 H), 1.02 (s, 3 H), 1.09 (d, J=6.4 Hz, 3 H), 1.17 (s, 3 H), 3.2-3.7 (4 H~, 3.77 (s, 3 H), 4.05 (m, 1 H), 4.40 (br. s, 1 H), 4.90 (br. s, 1 H), 5.40 (m, 1 H), 5.65 (m, 1 H) ~;
IR spectrum (KBr)~
3450, 1740 cm~
Example 167 ;-~
The reaction and workup procedures of Example 164 were repeated except that 100 mg of 3~-benzoyloxy-21,21-dimethoxy-20-methyl-1~-(N-methy~lcarbamoyl)oxypregna-5,7-dlene was used in lieu of 100 mg of la,3B-bis(methoxy- ~;
carbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 65 mg of 21,21-dime.hoxy-20-methylpregna-5,7-diene-1~,3 diol showing the following physical properties.
H-NMR spectrum (90 MHz) CCMsl3: ~
0 75 (s, 3 H), 0.94 (s, 3 H), 0.96 (d, J=6.2 ~ -Hz, 3 H), 3.38 & 3.41 (each s, 6 H), 3.76 (br. s, 1 H), 4.03 (m, 1 H), 4.38 (br. s, 1 H3, 5.36 (m, 1 H), 5.68 (m, 1 H) IR spectrum (KBr):
; 3400 cm 1 ~
Example 168 The reaction and workup procedures of Example 164 were repeated except that 100 mg of 20-(1,3-dioxolan-2- -~

~ ~ - ' '.

- 225 - ~3.~37~ ~

yl)-la-acetoxy-3~-(methoxymethyl)oxypregna-5,7-diene was used in lieu of 100 mg of 1~,3~-bis(methoxycarbonyl-oxy)pregna-5,7-diene-20-carbaldehyde to gi~e 72 mg of 20-(1,3-dioxolan-2-yl)-3~-(methoxymethyl)oxypreqna-5,7--dien-la-ol showing the following physical properties.
H-NMR spectrum (90 MHz) ~CDsl3:
0.79 (s, 3 H), 0.95 (d, J=6.2 Hz, 3 H), 0.96 (s, 3 H), 3.35 (s, 3 H), 3.7-4.0 (5 H), 4.30 (m, 1 H), 4.65 (br. s, 2 H), 4.80 (br. s, 1 H), 5.35 (m, 1 H), 5.70 (m, lH) IR spectrum (KBr): ~
3350 cm~l ~ -Example 169 The reaction and workup procedures of Example 156 were repeated except that 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3B-(methoxycarbonyl)oxypregna-5,7- ~-dien-la-oI was used in lieu of 100 mg of 20-(5,5-di-methyl-1,3-dioxan-2-yl)-la,3~-bis(methoxycarbonyloxy)-pregna-5,7-diene to give 55 mg of 3~-hydroxy~ (metho-xycarbonyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
H-NMR spe¢trum ~90 MHz) ~CDC13 ~ ;
0.66 (s, 3 H), 1.02 (s, 3 H), 1.15 (d, J=6.4 Hz, 3 H), 3.77 (s, 3 H), 4.05 (m, 1 H~, 4.40 - 226 - 1~ 37~

(br. s, 1 H), 4.65 (br. s, 2 H), 5.40 (m, 1 H), 5.65 (m, 1 H), 9.58 (d, J=3.5 Hz, 1 H) IR spectrum (KBr) 3450, 1740, 1725 cm 1 Example 170 ~
The reaction and workup procedures of Example 156' ;-were repeated except that 100 mg of 21,21-dimethoxy-20- '-methyl-pregna-5,7-diene-1,3B-diol was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3'dioxan-2-yl)-la,3B-bis~
(methoxycarbonyloxy)pregna-5,7-diene to give 45 mg of ~ -~
1~,3~-dihydroxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
H-NMR spectrum (90 MHz~ ~CDC13 0.66 (s, 3 H), 0.94 (s, 3 H), 1.15 (d, J=6.2 Hæ, 3 H), 3.76 (br. s, 1 H), 4.03 (m, 1 H), 5.36 (m, 1 H), 5.68 (m, 1 H), 9.58 (d, J=3.5 ~ Hz, 1 H), '~ IR spectrum (KBr):
~ ~, 3400, 1725~cm 1 ~ Example 171 '' The reaction and workup procedures of Example 156' were repeat'ed except'tha't 100 mg of 20-(1,3-dioxolan`'2- "

'yl)-3~-(methoxymethyl)oxypregna-5,7-dien-1~-ol was used .
in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-la,3B-bis~methoxycarbonylQxy)pregna-5,7-diene to give -'~

, j . .
. . .

- 227 - ~33~37~
,.

53 mg of 1~-hydroxy-3~-(methoxymethyl)oxypregna-5,7~
diene-20-carbaldehyde showing the following physical properties.
H-NMR spectrum (90 MHz) ~CDsl3:
0.65 (s, 3 H), 0.95 (d, J=6.2 Hz, 3 H), 0.96 (s, 3 H), 3.35 (s, 3 H) 3.77 (br. s, 1 H), 4.30 (m, 1 H), 4.65 (br. s, 2 H), 5.35 (m, 1 H), 5.70 (m, 1 H), 9.58 (d, J=3.5 Hz, 1 H) IR spectrum ~KBr):
3350, 1725 cm 1 Example 172 In 10 ml of methylene chloride was dissolved 0.50 g of 1~,3B-dihydroxypregna-5,7-aiene-20-carbaldehyde, followed by addition of 1 m~ of 3,4-dihydropyran and 0.05 g of p-toluenesulfonic acid. The mixture was stirred at room temperature for 2 hours. The reaction mixture thus obtained was diluted with ether, washed successively with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, and ~-dried over sodium sulfate, followed by concentration under reduced pressure. Finally the concentrate was purified by columnlchromatography to give 0.48 g of la, 3B-bis(tetrahydropyran-2-yloxy)pregna-5,7-diene-20 .~ ,: .. , carbaldehyde showing the following physical properties.
IR spectrum (KBr):

:

- 228 - ~33.1.3~'~
. , ':, 1725 cm 1 Reference Examples -(1) To 20 ml of a tetrahydrofuran solution of the isoamylmagnesium bromide prepared from 2.27 g of ' isoamyl bromide and 0.48 g of magnesium was slowly added a solution of 5.12 g of la,3B-bis(tetrahydropyran-2-yloxy)pregna-5,7-diene-20-carbaldehyde in 30 ml of tetrahydrofuran under ice-cooling. After the addition, the mixture was further stirred at 0C for 1 hour. To the reaction mixture thus obtained was added 2N aqueous sodium hydroxide solution, followed by extraction with diethyl ether. The extract was washed with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled off under,reduced pressure and the residue ,~- , was purified by silica gel column chromatography. The pro~edure yielded 4.84 g of lar3B-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-ol (yield: 83%) showing the following physical property. -' FD mass spectrum:
[M]~ 584 ~ ' (2) In 20 ml of pyridine'was dissolved 0i.58 g of the la,3B-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-ol obtained as above. To this solution was added 0.12 g of methanesulfonyl chloride and the mixture was "
,:

, ,- :, . .,, : - , ,, , : - ., : : :, , , . :. , :: .-, - : , 229 - 1~3~.37~ :
.: , stirred at 0C for 2 hours. Then, at room temperature, the reaction mixture was diluted with water and extract-ed with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The procedure yielded 0.57 g of la,3~-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-yl methanesulfonate (yield: 86~).
(3) To a solution of 0.10 g of lithium aluminum hydride in 5 mQ of tetrahydrofuran was added 0.66 g of 1~,3B-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-yl methanesulfonate under heating and the mixture was refluxed for 2 hours. The resulting reaction mixture was cooled and, then, water and diluted hydrochloric acid were added in succession. The mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with water and extracted with diethyl ether.
The extract was washed with diluted hydrochloric acid and aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled~ aff and'the' residue was purified by silica gel column chromatography and recrystallized from methanol. The procedure yielded 0.18 g of cholesta~
5,7-diene-1~,3~-diol (yield: 45~) showing the following ~:

- 230 - 133~.37~

physical properties.
m.p.: 155-158C
UV spectrum ~max (ethanol):
263, 272, 282 nm FD mass spectrum:
[M] 400 ~-' : ' ~

,~

Claims (17)

Claims:

1. A pregnane derivative of the general formula wherein A1 is in the .alpha.-configuration and represents a hydrogen atom or a hydroxyl group, and A2 is such that where A1 is in the .alpha.-configuration and represents a hydrogen atom, A2 is in the .alpha.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl) carbamoyloxy group, a tri-(lower alkyl or phenyl) substituted silyloxy group, an alkoxymethoxy group or alkoxymethoxy group substituted by methoxy and that where A1 is in the .alpha.-configuration and represents a hydroxyl group, A2 is in the .beta.-configuration and represents a hydrogen atom, or A1 and A2 jointly represent an oxo group (=O); D1 is in the .alpha.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl) substituted silyloxy group or an alkoxymethoxy group, alkoxymethoxy group substituted by methoxy, and D2 is in the .alpha.-configuration and represents a hydrogen atom, or D1 and D2 jointly represent an epoxy group (-O-) which is in the .alpha.-configuration or a single bond; D3 is in the .alpha.-configuration and represents a hydrogen atom, D4 is in the .alpha.-configuration and represents a hydroxyl group, D5 is in the .alpha.-configuration and represents a hydrogen atom, D6 is in the .alpha.-configuration and represents a hydroxyl group, a lower alkoxycarbonyloxy group, an acyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group or an N,N-di(lower alkyl)-carbamoyloxy group, D7 is in the .beta.-configuration and represents a hydrogen atom; provided that D3 and D4 may jointly represent an epoxy group (-O-) which is in the .alpha.-configuration or a single bond, D4 and D5 may jointly represent a single bond, D5 and D6 may jointly represent an epoxy group (-O-) which is in the .alpha.-configuration or a single bond, and D6 and D7 may jointly represent a single bond; and X1 and X2 each is a lower alkoxy group or jointly represent a lower alkylenedioxy group or an oxo group (=O); with the proviso that, when D4 and D5 jointly represent a single bond, D6 and D7 jointly represent a single bond, D2 represents hydrogen, D3 represents hydrogen, D1 represents a hydroxyl group, a C1-4 acyloxy group or a C1-4 alkoxy carbonyl group, and A1 is hydrogen or hydroxyl, A2 is hydroxyl, a C1-4 acyloxy group or a C1-4 alkyloxy carbonyl group, X1 and X2 jointly represent an oxo group (=O).

2. The pregnane derivative of Claim 1, which has the general formula wherein X1 and X2 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group or an oxo group (=O).

3. The pregnane derivative of Claim 1, which has the general formula wherein D8 and D9 jointly represent an epoxy group (-O-) which is in the .alpha.-configuration or a single bond, and X1 and X2 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group or an oxo group (=O).

4. The pregnane derivative of Claim 1, which has the general formula wherein A3 is in the .alpha.-configuration and represents a hydrogen atom, A4 is in the .beta.-configuration and represents a hydroxyl group or a lower alkanoyloxy group, or A3 and A4 jointly represent an oxo group (=O); and X1 and X2 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group or an oxo group (=O).

5. The pregnane derivative of Claim 1, which has the general formula wherein A5 is in the .beta.-configuration and represents a hydroxyl group or a lower alkanoyloxy group; D10 is in the .alpha.-configuration and represents a hydroxyl group, a lower alkoxycarbonyloxy group, a lower alkanoyloxy group, an N-lower alkylcarbamoyloxy group, an N-aryl-carbamoyloxy group or an N,N-di(lower alkyl)carbamoyloxy group, and D11 is in the .beta.-configuration and represents a hydrogen atom, or D10 and D11 jointly represent a single bond; and X1 and X2 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group or an oxo group (=O).

6. The pregnane derivative of Claim 1, which has the general formula wherein A6 is in the .beta.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl)substituted silyloxy group, an alkoxymethoxy group or an alkoxymethoxy group substituted by methoxy; D12 is in the .alpha.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl)substituted silyloxy group, an alkoxymethoxy group or an alkoxymethoxy group substituted by methoxy; and X1 and X2 jointly represent an oxo group (=O).

7. The pregnane derivative of Claim 1, which has the general formula wherein X1 and X2 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group or an oxo group (=O).

8. The pregnane derivative of Claim 1, which has the general formula wherein A7 is in the .alpha.-configuration and represents a hydrogen atom cr a hydroxyl group, and A8 is such that where A7 is a hydrogen atom in the .alpha.-configuration, A8 is in the .beta.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl)substituted silyloxy group, an alkoxymethoxy group or an alkoxymethoxy group substituted by methoxy and where A7 is a hydroxyl group in the .alpha.-configuration atom, A8 is in the .beta.-configuration and represents the hydrogen atom, or A7 and A8 jointly represent an oxo group (=O); and X1 and X2 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group or an oxo group (=O).

9. The pregnane derivative of Claim 1, which has the general formula wherein A9 is in the .beta.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl)substituted silyloxy group, an alkoxymethoxy group or an alkoxymethoxy group substituted by methoxy; D13 is in the .alpha.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl)substituted silyloxy group, an alkoxymethoxy group or an alkoxymethoxy group substituted by methoxy; and X1 and X2 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group or an oxo group (=O).

10. The pregnane derivative of Claim 1, which has the general formula wherein A10 is in the .beta.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl)substituted silyloxy group, an alkoxymethoxy group or an alkoxymethoxy group substituted by methoxy; D14 is in the .alpha.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl)substituted silyloxy group, an alkoxymethoxy group or an alkoxymethoxy group substituted by methoxy; D15 is in the .alpha.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkyl-carbamoyloxy group, an N-arylcarbamoyloxy group or an N,N-di(lower alkyl)carbamoyloxy group; and X1 and X2 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group or an oxo group (=O).

ll. A process for producing 7.alpha.-hydroxypregna-1,4-dien-3-one-20-carbaldehyde characterized by cultivating a microbe of the genus Alcaligenes which is capable of producing 7.alpha.-hydroxypregna-1,4-dien-3-one-20-carbaldehyde by utilizing 3.alpha.,7.alpha.-dihydroxy-5.beta.-cholanic acid and/or a salt thereof as a substrate, in a medium containing 3.alpha.,7.alpha.-dihydroxy-5.beta.-cholanic acid and/or a salt thereof.

12. The process of Claim 11, wherein the microbe belongs to the species Alcaligenes faecalis.

13. The process of Claim 12, wherein the microbe is the strain Alcaligenes faecalis D4020-K15 (FERM BP-204).

14. The process for producing a pregnane derivative of the general formula wherein X3 and X4 have the meanings defined hereinafter, characterized by reducing a pregnane derivative of the general formula wherein A11 is in the .alpha.-configuration and represents a hydrogen atom, and A12 is in the .beta.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group or an N,N-di(lower alkyl)carbamoyloxy group, or A11 and A12 jointly represent an oxo group (=0); and X3 and X4 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group.

15. A process for producing a pregnane derivative of the general formula wherein A13, X3 and X4 have the meanings defined hereinafter, characterized by reducing a pregnane derivative of the general formula wherein A13 is in the .beta.-configuration and represents a tri-(lower alkyl or phenyl)substituted silyloxy group, an alkoxymethoxy group or alkoxymethoxy group substituted by methoxy; X3 and X4 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group.

16. A process for producing a pregnane derivative of the general formula wherein A14, D16, X1 and X2 have the meanings defined hereinafter, characterized in that a pregnane derivative of the general formula wherein A14 is in the .beta.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl)substituted silyloxy group, an alkoxymethoxy group or alkoxymethoxy grouplsubstituted by methoxy; D16 is in the .alpha.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-substituted silyloxy group or an alkoxymethoxy group which may optionally be substituted, X1 and X2 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group or an oxo group (=0), is subjected to dehydration reaction.

17. A process for producing a pregnane derivative of the general formula wherein A15, A17, X1 and X2 have the meanings defined hereinafter, characterized in that a pregnane derivative of the general formula wherein A15 is in the .beta.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl)substituted silyloxy group, an alkoxymethoxy group or an alkoxymethoxy group substituted by methoxy; D17 is in the .alpha.-configuration and represents a hydroxyl group, an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcar-bamoyloxy group, an N-arylcarbamoyloxy group, an N,N-di(lower alkyl)carbamoyloxy group, a tri-(lower alkyl or phenyl)-substituted silyloxy group or a lower alkoxymethoxy group;

D18 is in the .alpha.-configuration and represents an acyloxy group, a lower alkoxycarbonyloxy group, an N-lower alkylcarbamoyloxy group, an N-arylcarbamoyloxy group or an N,N-di(lower alkyl)carbamoyloxy group; and X1 and X2 each is a lower alkoxyl group or jointly represent a lower alkylenedioxy group or an oxo group (=0), is caused to react in the presence of a palladium compound.