CA1271199A - Protected cyclopentanols - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Protected Cyclopentanols Compounds of formula (C) (C) where either RD represents a hydroxymethyl group and RE represents a hydroxyl group or RD represents a protected hydroxymethyl group and RE represents a protected hydroxyl group or RE represents a hydroxyl group and RD represents an ethenyl group and R
represents a hydroxyl or protected hydroxyl group or a leaving group with the proviso that either RD represents a protected hydroxymethyl group and RE represents a protected hydroxyl group or RF represents a protected hydroxyl group.

Description

7~

Protected Cyclopentanols This invention relates to new protected cyclopentanols of use as intermediates in preparing uracil derivatives having antiviral activity.
Deoxyuridine derivatives such as 2'-deoxy-5-iodouridine (Prussoff and Goz: Handbook of Experimental Pharmacvlogy, Part II of Antineoplastic and Immuno-suppressive Agents, Springer-Verlag, New York 1975, 10 pages 27~-347) and 2'-deoxy-5-vinyluridine (Cheng et al, Antimicrobial Agents and Chemotherapy 10, 1, 119-122 (1976) have been found tolpossess antiviral activity~ The activity of these compounds, however, is not very specific. British Patent Specification 15 No. 1,601,020 discloses E-5-(2-bromo and iodo-vinyl)-

2'-deoxyuridine which are described as having selective antiviral activity against herpes simplex viruses.
There is a need, however, for compounds with better and more selective antiviral activity.
We have now found a small group of uracil derivatives which have improved selective activity against viruses, especially Herpetoviridae which compounds have the general formula (I):
o ~N I
O N (I~
HO

~`
~0 wherein R is a chlorine, bromine or iodine atom and physiologically acceptable salts thereof with bases~
In the compounds of formula ~I) the halovinyl group is in the E-configuration and the pyrimidine ring is in the ~-configurat:ion relati.ve to the cyclopentane ring.
The compounds of formula (I) as well as processes for their preparation and compositions containing them are described and claimed in our co-pending Canadian applicati.on Serial No. 436,838. In the present application we claim intermediates of use in preparing the compounds of formula (I).
As described in Canadian application Serial No. 436,838 the compounds of formula (I) may be prepared by trea-tment of a compound of -formula tII):
ORl ~ C02H

O
_ ~ (II) or a salt thereof (where Rl, R and R , which may be the same or different, represent hydrogen atoms or protecting groups) with a halogenating agent followed where necessary by removal of any protecting groups.
The compounds of formula (II) may be prepared by depro-tection of the carboxyl group of a compound of formula (III):

~71~

3 .

ORl ~1"~ ,_ Co2R4 ~ ~ (III~
R'o R~O

(where Rl, R2 and R3 are as previously defined and R4 represents a carboxyl protecting group).
S The compounds o formula (III) may he prepared hy reaction of a compound of formula ~IV):

N ~
~ ~ ~ (IV) -R'O

R~O
(where Rl, R2 and R3 are as previously defined and X is an anion e.g. chloride ion) with an ester of acrylic acid:

CH~=CHC02R

(where R4 is as previously defined).
The compounds of formula (IV) may be prepared by reaction of a compound of formula (V):

~ 7~3 C3

- 4 - 20208-1211D
ORl ~, O ~ N ~
R30 ~ (V) ~20~

(where Rl, R2 and R3 are as previously defined) with a mercury salt HgX2 (where X is as previously defined).
Ac~ording to one embodimant descrlbed in Canadian application Serial No. 436,838, the compounds of formula (V~
wherein R2 and R3 each ,represents a protec~ing group may alter-natively be prepared by reacting compounds of formula (XIX), R3ao~CH2 ~ "~ (XIX) R2 aO ' (where R2a and R3a represent protecting groups as previously defined in relation to R2 and R3 and Z represents a leaving group~
with a compound of formula (XX):
' 1 fR
. N ~ (XX) O ~ N ~
~: :

' ~'''~'~ .
' .

3~ _~

- 5 - 20208-121LD
(where Rl i5 as previously defined) or a base salt thereof. Such compounds may then, if desired, he deprotected as described in Canadian application Serial No. 436,83~
The reaction may be effected in an organic solvent such as for example a sulphoxide e.q. dimethylsulphoxide, an amide such as dimethylformamide, an ether e.g. tetrahydrofuran or water. The reaction is generally carried out at a temperature in the range 0 to 120C e.g. 30-100C and in the presence of an organic or in-organic base such as sodium or potassium hydride, carbonate or bicarbonate or triethylamine. The leaving group represented by Z
may, for example be a halogen atom e.g. Cl, Br or an acyloxy group such as a hydrocarbylsulphonyloxy group e.g. methanesulphonyloxy or p-toluenesulphonyloxy.
Compounds o-f,ormula (XIX) may be prepared by treatment o compounds of formula (XXI):

R3aO-CH ~, \ - (~1) ~ 0 R2 aO -(where ~2a and R~a are as previously defined) with a rea~ent serving to introduce the desired group Z. Thus, for example, a haloyen atom may be introduced by halide ion displacement or using an oxyhalide reagent such a~ thionyl chloride. Alternatively an acyloxy group Z may be introduced by reaction with an appropriate acyl halide such as e.g. tos~l chloride. The reaction may, if desired, be carried out in the presence of a base e.g. pyridine or triethylamine and is conveniently efected in a medium such as water; an alcohol e.g. methanol or ethanol; a halogenated hydro-carbon e.g. chl~roform, or carbon tetrachloride7 or a substit~ted amide e.g. N,N-dimethylfo~mamide, ~3 or a ketone e.g. ace~one. ~emperatures ar~ generally ;n the range -20C to ~70~C e.g. OC to ~50C.
Alternatively, the base itselE may be the solvent.
Compounds of eormula (XXI) may be prepared by deprotecting compounds o formula (XXII):

R O-CH2 ~

~ OR (XXII) R2a~

( here R2a and R3a are as p~eviously defined and R represents a protecting group such as those described in relation to R2 and R3). It will be appreciated that the group Rll should be one which can be selectively cemoved, for example a trialkylsilyl group such as a dimethyltertiarybutylsilyl group.
Such a group may be removed by rea~tion with tetraalkyl-ammonium halides e.g. tetra-n-butylammonium fluoride or with hydrogen 1uoeide in aqueous acetonltrile.
~he reaction may conveniently be carried ou~ in solven~s such as ethers, e.g~ tetrahydrofuran and at a temperature in the range -50C ~o +50C e.g.
-20C to ~20C.
Compounds of formula (XXII) may be prepared by ~he introduction of hydroxyl protectin~ groups R2a and R3a into a compound of formula (XXIII~:

HO-CH
~0 ~
~ -- ORll (XXIII) ~7~

(where RlL is as previously defined).
Introd~ction of the hydroxyl protecting groups R2a and ~3a may be carried out according to any appropriate conventional method. Suitable reagents for the introduction of protecting groups include alkyl and aralkyl halides such as methoxymethyl chloride and benzyl bromide. The reaction is optionally carried out in the presence of a base such as diiso-propylethylamine and in organic solvents such as ethers e.g. tetrahydrofuran, hydrocarbons e.g.
benzene, haloqenated hydrocarbons e.g. dichloromethane.
The reaction may be carried out in the temperature range -50C to +50C e.g. -20C to ~20C.
Compounds of formula (XXIII) may be prepared by ozonolysis of compounds of formulai(XXIV) OR (XXIV) HO

(where Rll is as previously defined) followed by the reduction of the products formed therefrom with an alkali met21 borohydride such as sodium borohydride. The r~action may be carried out in organic solvents such as an alcohol e.g. methanol F
halogenated hydrocarbons e.g. dichloromethane;
ethers e.~. tetrahydrofuran or mixtures thereof and at a tempera~ure in the range -70C to ~50C.
~5 Compounds of formula (XXIV) may be prepared from compounds of formula (XXV):

3~3 ORl 1 ( XXV ) (where Rll is as previously defined) using a Grignard reagent capable of introducing a vinyl group, for example vinyl magnesium bromide. The reaction may conveniently be carried out in the presence of a catalyst such as cuprous iodide and in an organic solvent such as a halogenated hydrocarbon e.g. dichloromethane; an ether e.g. tetrahydrofuran or mixtures thereof and a-t a tempera-ture in the range -70C to +50 DC .
Compounds of formula (XXV) may be prepared from the known compound of formula (XXVI):

~ D /OH (XXVI) by reaction with a reagent serving to introduce the protecting group Rll.
The reaction may be carried out in the presence of a coupling agent such as an imidazole and in an crganic solven-t such as an amide for example dimethylformamide and at a temperature in the range -50C to ~50C for example -20C to ~20DC.
According to an alternative embodiment described in Canadian application Serial No. 436,838 the compounds of formula (I) may be obtained by reacting compounds of formula (XXVII):
.

..
.
.

ORl N ~ R

~ ~ (XXVII) (where R and Rl are as previously defined) or a base salt thereof with a compound of formula (XIX~ as defined above. The reaction is analogous to that described above to obtain compounds of for-mula ~V) by reaction of compounds of formula (XIX) with compounds o-E formula (XX). The preferred conditions are as described for that reaction. The reaction is followed, where necessary by removal of any protecting groups as described in Canadian applica-tion Serial ~o. ~36,838.
Alternatively the compounds of -formula (XIX) may be prepared ln situ by treatment of a compound of formula (XXI) with a dialkylazodicarboxylate, e.g. diethylazodicarboxylate, and a tertiary phosphine e.g. triphenylphosphine in a solvent such as tetrahydrofuran or acetonitrile.
Mixtures of isomers may be separated at any convenient stage of the synthesis, for example, either before or after removal of protecting groups. Thus the desired epimer may, where necessary, be separated from the corresponding epimer by conven-tional means, for example, by fractional crystallisation and/or chromatography. Optically active isomers of the compounds may be obtained by resolution of the racemic mixtures using conventional means7 see for example 'Stereochemistry of Carbon Compounds' by E.L. Eliel (McGraw Hill, 1962) and 'Tables of Resolving A~ents' by S.H. Wilen.
The intermediates of formulae (XIX), (XXI), (XXII), (XXIII~ and (XXIV) are closely related .

,~ , . , .. , . - .

.

, : ' : `

~L~71:1L9~

chemically and may be expressed as having the formula (C):

RD ~ ~I~R~
/ (C) RE~

~here either R~ represents a hydroxymethyl group and RE represents a hydroxyl group or RD represents a protected hydroxymethyl group and RE represents a protected hydroxyl group or RE represents a hydroxyl group and RD represents an ethenyl gr~up and R
represents a hydroxyl or protected hy~roxyl group or a group Z as defined above with the proviso that either RD represents a protected hydroxymethyl group and RE represents a protected hydroxyl group or R represents a protected hydroxyl group. These intermediates of formula (C) are novel and constitute features of the present invention.
The following examples illustrate the invention~
Temperatures are in C. The nomenclature used is in accordance with the Chemical Abstracts system.
Solutions were dried by use of magnesium sulphate. Flash column chromatography was carried out over silica using the method described by W.E.
Still et al, J. Org. Chem. 1978, 14, 2923.

' .~

: . :

~7~

Intermediate A
~ 7~L~iL~(+)-3-[[(l,l~Dimethylethyl)dimethylsilyl~o_y~-

6~oxabicy~clo[3,1,01hexane A solution of (1~,3~,5~)-(+)-3-hydroxy-6-oxabicyclo[3,1,0]tlexane (2.5 g) in dry DMF (25 ml) was treated with imidazole ~3.40 g), the solution cooled to 0 under N2 and t-butyldimethylsilyl chloride (4.15 g) added. The solution was stirred at 0 for 10 minutes, allowed to warm up to room temperature and stirring continued for a further 18 hours. The mixture was poured into water (150 ml) and extracted with pentane (2 x 150 ml). The organic phase was washed with water (2 x 150 ml), dried and concentrated to afford the crude ~roduct as a colourless oil. The latter was purified by flash chromatography, elution with 7% EtOAc/hexane affording the title com~ound as a colourless mobile oil (309 g);
~ ~CDC13) 5.56 (lH, ABX, CHOSi), 6.52 (2H,s, CH -CH),

7.86-8.08 (4H, ABX, CH2), 9.1 (9H,s, CMe3~, 9.96 (6H,s,Me) ~L~7~

Example 1 (1~,2~,4~ (+)-4-[~ Dimethylethyl)dimethy-ls-ilyl]
oxy]-2-ethenylcYciopentanol A stirred suspension of cuprous iodide (190 mg) in dry THF (10 ml) at -30 under N2 was treated dropwise with a solution of vinylmagnesium bcomide(lM
in THF, 10 ml) causing a greyish coloured suspension to form. The latter was stirred at -30 for 15 minutes and then a solution of Intermediate A (1.50 g) in dry THF (5 ml) added dropwise. The resulting dark coloured sol~tion was stirred at -30 ~or 15 minutes, the mixture allowed to slowly warm to 0 (_. 0.5h) and then stirred for a further 2 hours. The reaction was quenched ~y pouring into saturated NH4Cl solution (100 ml) and extracted with ether (2 x 100 ml). The combined organic extracts were washed with further saturated NH4C1 solution (100 ml), dried and concentrated to afford the crude product as a pale yellow oil. The latter was purified by flash chromatography, elution ~ith

8% EtOAc~hexane yielding the title compound as ~ a colourless oil (1.25 g).
Analysis Found : C, 64.54; H, 11.07~
C13H26O2Si requires: C, 64.40; H, 10-81%
Example 2 (1~,2~,4~)-(+)-[t(l,l-DimethylethYl)dimethyl~ilYl~oxy~-2-hydroxy]cyclopenta~emethanol Oxygenated ozone was bubbled through a solution of the product of Example 1 (6~68 g) in dry methanol ~100 ml) and dichloromethane (50 ml) cooled to -70 until a deep blue colouration appeared. Sodium borohydride (1.05 gl was then quickly added in one portion and stirring at -70 continued for 30 minutes. Further sodium borohydride (1.05 g) was then added, the mixture allowed to slowly warm to room temperature tca. ]hr.) and then stirred '-,"' '' ' : ' ~.27~

for a further 30 minutes. The solvents were evaporated and the residue partitioned between dichloromethane (250 ml) and saturated ammonium chloride solution (250 ml)~ The aqueous layer was further extracted S with dichloromethane (1 x 250 ml)~ the combined organics dried and concentrated to afford the crude product as an opaque viscous oil. The latter was purified by flash chromatography, elution with 5~ MeOH/C~2C12 yielding the title compound as a viscous colourless oil (5.34 g.) Analysis Found: C, 52.94; H, 10.89~
C12H26O3SiØ1 H2O requires: C, 58.06; H, 10.64%

Example 3 I

(1~;3~,4a)-(+)-(1,1-D_met~ethvl)dimethyl ~
methoxy)-3-[(methoxymethoxy)methyllcyc-lopentyl~oxy]silane To a solution of the product of Example 2 (5.0 g), and N,N-diisopropylethylamine (7.87 g, 10.6 ml) in dry dichloromethane (100 ml), cooled to 0 under nitrogen, was added chloromethylmethyl ether (90%: 5.44 g, 5.19 ml,) dropwise over 10 minutes. The mixture was stirred at 0 for 5 minutes, allowed to warm up to room temperature and stirring continued o~ernight. The solution was washed with water (100 ml), the aqueous layer extracted with further dichloromethane (1 x 50 ml) and the combined orga;.ic layers dried. Concentration afforded the crud~ product as an orange oil which was purif;ed by ~lash chromatography, elution with 10% EtOAc/hexane yielding the title comPound as a colourless mobile oil (S.l g) Analysis Found: C, 57.51; H, 10.75~
C16H34O5Si requires: C, 57~44, H, 10055%

7~9'3 Exam~
(1~,3~,4~ 3-(Methoxymethoxy)-4-[(methoxymethoxy)-methyl]cyclopentanol.
~ solution of the product of Example 3 (5O0 g~
in THF (150 ml), stirred and cooled to 0, was treated with tetra-n-butylammonium fluoride (lM
in THF, 16 ml~. The solution was allowed to warm up to room temperature and stirred for a further 4 hours. The mixture was concentrated to ca. 30 ml and sub]ected to flash chromatography. Elution with EtOAc/hexane (9:1) afforded the title compound as a pale yellow oil (3.2 g).
(CDC13)5.24-5.4 (4H,2XAB, OCH2O), 5.67 (lH,m,CHOCH2), 5.9 (lH,m~CHOH), 6.4-6.7(8H,m~2s, OMe, Cl 2)~ 7.45(1H,m,CHCH2O) 15 7.6 (lH,d,OH), 7.9-8.4(4H,m~2xCH2) Example 5 (1~,3~,4~)-(+)-3-(Methoxymethoxy)-4-~(methoxymethoxy)-methyllcycl_pentanol~ 4-met~ylbenzenesulphonate A mixture o~ the product of Example 4 (1 g), para-toluenesulphonyl chloride (0.96 g) and dry pyridine (20 ml) was stirred at room temperature overnight.
The pyridine was removed in vacuo at 35, the residue taken up in dichloromethane (50 ml) and the solution washed with copper (II) sulphate solution (3 x 50ml).
The organ;c phase was dried and concentrated to afford the crude product as a yellow oil~ The latter was purified by flash chromatographyO Elution with EtOAc/hexane ~1:1) afforded the title compound as a colourless oil (1.18 g) Analysis Found: Cl 54.68; H, 6.57%
C17H~6O7S requires : C, 54.52; H, 6.99%

:'- , ' ~7~ 3 Example 6 (1~,3~,4~--(+)-1-L3-(Methoxymethoxy)-4-[(metho~ymethoxv)-methyllcyclopentyl]-2~4(lH~3H)-pyrimidinedione A mixture of the product of Example 5 (374 mg), finely ground anhydrous potassium carbonate (414 mg) and uracil (336 mg) in dry DMSO (5 ml) was stirred under nitrogen at 90 for 15 hours. The resulting dark coloured solution was poured into brine ~ca.
50 ml) and the mixture extracted with dichloromethane (3 x 30 ml). The organic phase was washed with brine (1 x 50 ml), dried and concentrated to afford the crude product as a yellow oil. The latter was purified by flash chromatography. Elution with 5-8% MeOH/CH2C12 afforded the titlle compound ~s a pale yel]ow oil (138 mg) ~ (CDC13) 1.13 (lH, br s, NH), 2.68 (lH, d, N-CH=CH), 4.25 (lH,d, ~-CH=CH), 4.88 (lH, quin., H-l'), 5.35 (4H, s, OCH2O), 5.88 (lH, dt, CH-O-CH2 5.3-5.46 (2H, m, CH2O), 6.62 (6H, s, OMe).
Exam~le 7 (la,3~,~4~)-(+)~ 3 Hydroxy-4-(hydroxYmethyl)cyclo-pentyl]-2,4(lH,3H~ ~yrimidinedione A mixture of the product of Example 6 and p-toluenesulphonic acid ~1.40 g) in methanol (100 ml), was heated under gentle reflux on a steam bath fc. 1 hour. The solution was cooled, stirred and t~eated with R8050 polyvinylpyridine resin (Reilly Corporation) until pH6 was attained (ca. 2 9 resin).
Filtration and concentration yielded the crude product as a pale yellow oil. The latter was purified by flash chromatography. Elution with 15~ MeOH/CH2C12 afforded the title compound as a white crystalline powder (1.1 g) m.p. lS9-162 ~7~

The product of Example 7 may be converted to a com-pound of formula (I) by a method ana:Logous to that exemplified in Intermediates 10 to 12 and Example 1 of the specification of our Canadian Patent Application Serial No. 436,838, now Patent No. 1,257,595, from which this application is divided.

~7~
17 ~ 20208-1211D
Example_8 (+)-(E)-5-~2-Bromoethenyl)~ 1~3~4~)-3-hydroxY-4-(hydroxy~et~yl~-cycloeentyl]-2,4 (lH,3~)-pyrimidinedione A mixture of the product of Example 5 (37~ mg), (E)-5-(2-bromovinyl)uracil (326 mg) and finely ground anhydrous potassium carbonate (207 mg) was stirred in dry DMSO (S ml) at 90 under nitrogen for 4h.
The dark coloured mixture was poured into water (S0 ml) and extracted with dichloromethane (3 x 25 ml).
The combined organic phases were washed with brine (50 ml), dried and concentrated to afford a yellow oil. The latter was purieied by flash chromatography eluting with 2~ methanol/dichloromethane to give crude ~ (Ej-5-(2-bromoethenyl)-1~[(1,3~,4~)-3-methoxymethoxy-4-[(methox~methoxy)methyl]-cyclopentyl3-2,4(lH,3H)-pyrimidinedione (42 mg~ which was taken up in methanol (5 ml), para-toluenesulphonic acid (50 mg) was added and the solution re~luxed for lh. The mixture was neutralised by the addition Gf R8050 polyvinylpyridine resin (Reilly Corporatio~) and subsequently evaporated onto flash silica (ca 1 9).
The latter was applied to a flash chromatography column eluting with 10% methanol/~ichloromethane to yield the title compound (11 mg). m.p. 179-183td).

,~,

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Compounds of formula (C) (C) where either RD represents a hydroxymethyl group and RE repre-sents a hydroxyl group or RD represents a protected hydroxy-methyl group and RE represents a protected hydroxyl group or RE
represents a hydroxyl group and RD represents an ethenyl group and RF represents a hydroxyl or protected hydroxyl group or a leaving group with the proviso that either RD represents a protected hydroxymethyl group and RE represents a protected hydroxyl group or RF represents a protected hydroxyl group.

2. Compounds according to claim 1 of formula (XIX) (XIX) where R2a and R3a represent protecting groups and Z represents a leaving group.

3. Compounds according to claim 1 of formula (XXI) (XXI) where R2a and R3a represent protecting groups.

4. Compounds according to claim 1 of formula (XXII) (XXII) where R2a, R3a and R11 represent protecting groups.

5. Compounds according to claim 1 of formula (XXIII) (XXIII) where R11 represents a protecting group.

6. Compounds according to claim 1 of formula XXIV

(XXIV) where R11 represents a protecting group.