GB2089787A - N-substituted azetidinones - Google Patents

Abstract

The present invention relates to new compounds of the formula: <IMAGE> wherein R<1> is amino or substituted amino, R<2> is carboxy or protected carboxy, R is hydroxymethyl, protected hydroxymethyl or formyl, R<1> is hydrogen and R'' is hydroxy, halogen or a group of the formula <IMAGE> in which R<4> is lower alkyl, or R<1> and R'' are linked together to form a group of the formula: = O or = P(R<5>)3 in which R<5> is; lower alkyl, aryl or di(lower) alkylamino, and Y is hydrogen or lower alkoxy, or a salt thereof. The compounds of the present invention are useful as intermediates in the preparation of 1-oxade- thia-3-cephem antimicrobials.

Description

1

GB2 089 787A 1

SPECIFICATION N-substituted azetidinones

The present invention relates to new compounds of the formula:

V ,0—Ch2R

>1-

10

/-y

15

20

25

30

R2 'R'

wherein R1 is amino or substituted amino,

R2 is carboxy or protected carboxy,

R is hydroxymethyl, protected hydroxymethyl or formyl,

R1 is hydrogen and R" is hydroxy, halogen or a group of the formula a

0

II

-P(OR4)2

in which R4 is lower alkyl, or R1 and R" are linked together to form a group of the formula: = 0 or = P(R5)3 in which R5 is; lower alkyl, aryl or di(lower) alkylamino, and Y is hydrogen or lower alkoxy, or a salt thereof.

The compounds of the present invention are useful as intermediates in the preparation of 1-oxadethia-3-cephem compounds of the formula:

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45

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55

or a salt thereof in which R\ R2 and Y are as designated above, and which 1-oxadethia-3-cephem compounds form are disclosed and claimed in published British Patent Application No. 2014562 A.

The novel compounds can be prepared by the processes as illustrated by the following scheme.

(1) Y Hz N

r

H0CHz-R7

0

H?N-

R2

or its derivafcfves at 0 the formyl group

/—

ch2R'

R

(m)

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45

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55

or a salt thereof or its derivative at the formyl group or a salt thereof

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GB2089 787A 2

Introduction of Y subsfcituents (s) R*

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45

Rz or its derivatives at the formyl group or a salt thereof -N^

t$* .

CHoR70 Oxidative rU.—r^^cHoR^1 cleavage I 1

or its derivatives at the formyl group or a salt thereof

(20

or its derivatives at the formyl group or a salt thereof

Y

CH2 R halogenation R

■CH2R7q or its derivatives at the formyl group or a salt thereof Y

R1

0

R2 (IT)

or its derivatives at the Formyl group or a salt thereof

CH2-R7a

R3a

R2

M

or its derivatives at the formyl group or a salt thereof

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45

3

GB2089 787A 3

Y

f

10

15

20

■tk^-K3a

T

C&)

or a salt thereof v

1

CH2— R71> P1

Removal cf

R

jtcvuuru i u> i on protective J—NwR , 0' |^R3b group 0 |^R3^

^ch2CH2OH

R2 (lb)

or a salt thereof

/^C^CHO

R

0yidal:""'> J-i .R3«

(T p- R3b R2

(la)

or a salt thereof

25

10

15

20

25

wherein R1, R2 and Y are each as defined above; R3a is hydrogen and R3b is a group of the formula:

30 ||

P(OR4)2

in which R4 is a lower alkyl, or R3a and R3b are linked together to form a group of the formula: = P(R5)3 in which Rs is lower alkyl, aryl or di(lower) alkylamino.

35 R6 is lower alkyl;

R7 is hydroxymethyl, a protected hydroxymethyl or formyl;

R7a is a protected hydroxymethyl or formyl

R7b is a protected hydroxymethyl, and

X is halogen

40 The term "lower" is intended to mean 1 to 6 carbon atom(s).

Substituted amino may include an amino group substituted with suitable substituent(s) conventionally used in cephalosporin and penicillin chemistry as the substituent of amino group at their 7th or 6th position.

Suitable "substituted amino" may include acylamino, hydrazino, and an amino group 45 substituted with other groups than the acyl groups such as ar(lower)alkyl (e.g. benzyl, phenethyl or trityl), ar(lower)alkylidene (e.g. benzylidene or 3,5-di(tert-butyl)-4-hydroxybenzylidene).

Suitable "protected carboxy" may include esterified carboxy in which said ester may be one such as the lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester or 1 -cyclopropylethyl 50 ester);

lower alkynyl ester (e.g. ethynyl ester or propynyl ester);

mono (or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester or 2,2,2-trichloroethyl ester); lower alkanoyloxy(lower)alkyl ester (e.g. acetoxy-methyl ester, propionyloxymethyl ester, butyry-loxy-methyl ester, valeryloxymethyl ester, pivaloyloxy-methyl ester, hexanoyloxymethyl ester, 2-55 acetoxy-ethyl ester or 2-propionyloxyethyl ester);

lower alkanesulfonyl(lower)alkyl ester (e.g. 2-mesylethyl ester); ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, diphenylmethyl ester, bis(me-thoxy-phenyl)methyl ester, 3,4-dimethoxybenzyl ester or 4-hydroxy-3,5-ditertiarybutylbenzyl 60 ester); and aryl ester which may have one or more suitable substituent(s) (e.g. phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl ester or cumenyl ester).

Suitable "lower alkoxy" may include one which may be branched, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy or hexyloxy.

Suitable "lower alkyl" which includes branched chain alkyl is for example, methyl, ethyl, 65 propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

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55

60

65

4

GB2 089 787A 4

Suitabie "aryl" may include phenyl, tolyol, ::ylyl, mesityl, cumsnyl and naphthyi and the like. Suitable "di(lower)alkylamino" may include dimthylamino, diethylamino, dipropylamino and methylethylamino.

Suitable "protected hydroxy" moiety in the term "protected hydroxymethyl" may include 5 acyloxy and hydroxy group substituted with other conventional protective group than the acyl 5 groups such as ar(lower)alkyl as aforementioned or the like.

Suitable "halogen" includes chlorine, bromine, fluorine and iodine.

Suitable "acyl moiety" in the terms "acylamino" and "acyloxy" as mentioned above may include carbamoyl, aliphatic acy! group and acyl group containing an aromatic ring, which is 10 referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl. 10

Suitable example of said acyl may be illustrated as follows:—-

Aliphatic acyl such as lower or higher alkamoyl (e.g. formyl, acetyl, succinyl, hexanoyl and heptanoyl, stearoyl);

lower or higher alkoxycarhonyl (e.g. methoxy csrbonyI, ethoxycarbonyl, t-butoxycarbonyl, t-15 pentyloxycarbonyl and heptyloxycarbonyl); or 15

lower or higher alkanesulfonyl (e.g. methanesulfonyl and ethanesulfonyl); aromatic acyl such as aroyl (e.g. benzoyl, toluoyl and naphthoyl);

ar(lower)alkanoyl (e.g. phenylacetyl and phenylpropionyl,);

20 aryloxycarbonyl (e.g. phenoxycarborivl and naphthyloxycarbonyl); 20

aryloxy(lower)alkanoyl (e.g. phenoxyacetyl and phenoxypropionyl);

arylglyoxyloyl (e.g. phenylglyoxyloyi and naphthylglyoxyloyl); or arenesulfonyl (e.g. benzenesulfonyl and p-toluenesulfonyl,);heterocyclic acyl such as heterocycliccarbonyl (e.g. thenoyl, furoyl and nieotinoyl);

25 heterocyc!ic(!ower)a!lcanoyi (e.g. thienylaeety!, thiazolylacetyl and tetrazolylacetyl); or 25

heterocyclicglyoxyloyl (e.g. thiazolylglyoxyloyl and thienylglyoxyloyl); in which suitable heterocyclic moiety in the terms "heterocycliccarbonyl", "heterocyclic(lower)alkanoyl" and "heterocyclicglyoxyloyl" as mentioned above means, in more detail, saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur 30 and nitrogen atom. And, especially preferable heterocyclic group may be heterocyclic group 30 such as unsaturated 3 to 8-membered more preferably 5 or 6-membered)heteromonocyclic group containing from 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyi, pyrazolyl,

pyridyl and its N-oxide, dihydropyridyl pyrimidinyi, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-35 1,2,4-triazolyl, 1H-1,2,3-triazolyl and 2H-1,2,3-iriazolyl), tetrazolyl (e.g. 1 H-tetrazolyl and 2H- 35 tetrazolyl),

saturated 3 to 8-membered (more preferably 5 or-6-msmbered)heteromonocyclic group containing from 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyi, piperidino and piperazinyl; unsaturated condensed heterocyclic group containing from 1 to 4 nitrogen atom(s), 40 for example, indolyl, isoindolyl, benzimedazolyl, quinolyl, isoquinolyl, indazolyl and benzotriazo- 40 lyl; unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and from 1 to 3 nitrogen atom(s), for example, oxazolyl,

isoxazolyl and oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazoIyl and 1,2,5-oxadiazolyl);

saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group 45 containing 1 or 2 oxygen atom(s) and from 1 to 3 nitrogen aiom(s), for example, morpholinyl 45 and sydnonyl;

unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s) and from 1 to 3 nitrogen atom(s), for example, benzoxazolyl and henzoxadiazolyl; unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteronnonocycIic group containing 1 or 2 sulfur atom(s) and 50 from 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl, (e.g. 1,2,3- 50

thiadiazolyl, 1,2,4-thiadiazolyI, 1,3,4-thiadiazolyl and 1,2,5-thiadiazolyl), and dihydrothiazinyl;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing from 1 or 2 sulfur atom(s) and from 1 to 3 nitrogen atom(s), for example,

thiazolidinyl;

55 unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group 55 containing from 1 or 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl and dihydrodithiolyl;

unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and from 1 to 3 nitrogen atom(s), for example, benzothiazolyl and henzofhiadiazolyl; unsaturated 3 to 8-membered (more preferably 5 to 6-membered) heteromonocyclic group containing an oxygen 60 atom, for example, fury I; 60

unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 or 2 sulfur atom(s), for example, dihydrooxathiinyl;

unsaturated condensed heterocylic group containing 1 or 2 sulfur atom(s), for example, benzothienyl and benzodithiinyl; and 65 unsaturated condensed heterocyclic group containing an oxygen atom and 1 or 2 sulfur 65

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GB2 089 787A 5

10

atorn(s), for example, benzoxathiinyl.

As to the heterocyclic group as mentioned above, the following points are to be noted. That is, in case that the heterocyclic group is specifically thizolyl group having amino or protected amino as a substituent in its molecule, said thiazolyl group include tautomeric isomers, = which are caused by the specific behaviour of the thiazole ring. That is, for example, said amino-or 5

protected aminothiazolyl group is represented by the formula:

(wherein R8 is amino or protected amino), and in case that the group of the formula (A) takes the formula:

15 15

N—n

A J M

R8

20 .20

(wherein R8 is amino or protected amino), said group of the formula (A') can also be alternatively represented by its tautomeric formula:

"

(wherein R8' is imino or protected imino). That is, both of the said groups of the formulae (A')

30 and (A") are in the state of tautomeric equilibrium which can be represented by the following 30 equilibrium:

- -/&-■

(A') (A11)

40 40

(wherein R8 and R8' are each as defined above).

These types of tautomerism between 2-amino-thiazole compounds and 2-iminothiazoline compounds as stated above have been well known in the arts, and it is obvious to a person skilled in arts that both of the tautomeric isomers are equilibrated and lie in the reciprocally

45 convertible state, and accordingly it is to be understood that such isomers are included within 45 the same category of the compound per se. Accordingly, the both of the tautomeric forms are clearly included within the scope of the present invention. In the present specification, the object and starting compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor, i.e. 2-amino (or protected amino)thiazolyi and the formula:

50 50

R8' -

55 55

only for the convenient sake.

The acyl moiety as stated above may have from one to ten, same or different, suitable substituent(s) such as lower alkyl (e.g. methyl, ethyl, etc.); lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc); lower alkylthio (e.g. methylthio, ethylthio, etc.); lower alkylamino (e.g. methylam-

60 ino, etc.); cyclo-(lower)alkyl (e.g. cyclopentyl, cyclohexyl, etc.); cyclo 60

(lower)alkenyl (e.g. cyclohexenyl; cyclohexadienyl, etc.); halogen; amino; protected amino;

hydroxy; protected hydroxy; cycano; nitro; carboxy; protected carboxy; sulfo; sulfamoyl; imino; oxo; amino(lower)-alkyl (e.g. aminomethyl, aminoethyl, etc.); carbamoyloxy; protected carbamoy-loxy; a group of the formula: = N-OR9 wherein R9 is hydrogen, lower alkyl, lower alkenyl (e.g.

65 vinyl, allyl, 2-butenyl, etc.), lower alkynyl (e.g. ethynyl, 2-propynyl, etc.), cyclo(lower)alkyl (e.g. 65

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GB2 089 787A 6

lower alkynyl (e.g. ethynyl, 2-propynyl, etc.), cyclo(lower)alkyl (e.g.cyclopropyl, cyclohexyl, etc.) or ar(lower)alkyl such as phenyl(lower)alkyl (e.g. benzyl, phenethyl, etc.).

In this connection, when the acyl moiety has a group of the formula: = N-OR9, wherein R9 is as defined above, as substituent(s), there are geometrical isomers (syn and anti isomers) due to 5 the presence of double bond. And, for example, the syn isomer means one geometrical isomer 5 having the group of the formula:

-C-CO-

II

10 N-O- 10

and the corresponding anti isomer means the other geometrical isomer having the group of the formula:

15 -C-CO- 15

i

-O-N

Suitable ' ar(lower)alkanoyl which may have a sulfo group" may include phenyl(lower)alkanoyl 20 (e.g. phenylacetyl and phenylpropionyl) and lower alkanoyi substituted with a sulfo and a phenyl 20 group (e.g. 2-sulfo-2-phenylacetyl).

Suitable "aryloxy(iower)alkanoyl in the term "aryloxy(lower)alkanoyl which may have suitable substituent(s)" may include phenoxy(lower)aikanoyl (e.g. phenoxyacetyl and phenoxypropionyl.

Suitable "unsaturated 3 to 8-membered heteromonocyclic group containing from 1 to 4 25 nitrogen atom(s)" in the term "lower alkanoyi substituted with an unsaturated 3 to 8-membered 25 heteromonocyclic group containing from 1 to 4 nitrogen atom(s) which may have suitable substituent(s)" may include the ones as aforementioned.

Suitable "unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and from 1 to 3 nitrogen atom(s)" in the terms "lower alkanoyi substituted with an 30 unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and from 30 1 to 3 nitrogen atom(s) which have a protected amino group" and "lower alkanoyi substituted with an unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and from 1 to 3 nitrogen atom(s) which have an amino group" may include the ones as aforementioned.

35 Suitable "heterocyclic groups" in the terms "a heterocyclic group which may have suitable 35 substituent(s)", "a heterocyclic group having a protected amino group" and "a heterocyclic group having an amino group" may include the ones as aforementioned as "heterocyclic moiety".

Suitable "lower alkanoyi moieties" in the terms "lower alkanoyi substituted with an 40 unsaturated 3 to 8-membered heteromonocyclic group containing from 1 to 4 nitrogen atoms 40 which may have suitable substituent(s)", "lower alkanoyi substituted with an unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and from 1 to 3 nitrogen atom(s) which may have suitable substituent(s)", "lower alkanoyi substituted with an unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and from 1 to 45 3 nitrogen atom(s) which have a protected amino group" and "lower alkanoyi substituted with 45 an unsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and from 1 to 3 nitrogen atom(s) which have an amino group" may include acetyl, propionyl and butyryl.

Suitable "substituents" in the terms "aryloxy(lower) alkanoyi which may have suitable 50 substituent(s)", "lower alkaonyl substituted with an unsaturated 3 to 8-membered heteromono- 50 cyclic group containing 1 or 2 sulfur atom(s) and from 1 to 3 nitrogen atom(s) which may have suitable substituent(s)", "lower alkanoyi substituted with an unsaturated 3 to 8-membered heteromonocyclic group containing from 1 to 4 nitrogen atom(s) which may have suitable substituent(s)" and "a heterocyclic group which may have suitable substituent(s)" may include 55 lower alkyl (e.g. methyl and ethyl), lower alkoxy (e.g. methoxy, ethoxy and propoxy), lower 55

alkylthio (e.g. methylthio and ethylthio), lower alkylamino (e.g. methylamino); cycIo(lower)-alkyl (e.g. cyclopentyl and cyclohexyl), cyclo(lower) alkenyl (e.g. cyclohexenyl and cyclohexadienyl), halogen, amino, protected amino, hydroxy, cyano; nitro, carboxy, protected carboxy, sulfo,

sulfamoyl, imino, oxo and amino(lower)alkyl (e.g. aminomethyl and aminoethyl).

60 Suitable "lower alkylene moieties" in the terms "hydroxyimino(lower)alkylene", "lower 60

alkoxyimino(lower)alkylene", "lower alkenyloxyimino(lower)alkylene", "lower alkynyloxyimino-(lower)alkylene", cyclo(lower)aikoxyimino(lower)alkylene" and "ar(lower)alkoxyimino(lower)alky-lene" may include methylene, ethylene, trimethylene and propylene.

Suitable "lower alkoxy moiety" in the term "lower alkoxyimino(lower)alkylene" may include 65 methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy and hexyloxy. 65

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GB2 089 787A 7

Suitable "lower alkenyloxy moiety" in the term "lower alkenyloxyimino(lower)alkylene" may include vinyloxy, allyloxy and butenyloxy.

Suitable "lower alkynyloxy moiety" in the term "lower alkynyloxyimino(lower)alkylene" may include ethynyloxy, propynyloxy and butynyloxy.

5 Suitable "cyclo(lower)alkoxy moiety" in the term "cyclo(lower)alkoxyimino(lower)alkylene" may include cyclopentyloxy and cyclohexyloxy.

Suitable "ar(lower)alkoxy moiety" in the term "ar(lower)alkoxyimino(lower)alkylene" may include phenyl-(lower)alkoxy (e.g. benzyloxy and phenethyloxy).

Suitable "protected amino group" in the terms "lower alkanoyi substituted with an unsatu-10 rated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and from 1 to 3 nitrogen atom(s) which have a protected amino group" and "a heterocyclic group having a protected amino group" may include acyl as aforementioned and amino group substituted with other conventional protective groups such as ar(lower)alkyl as aforementioned, and the like. Preferable examples of acyl for R1a are ar(lower)alkanoyl having a sulfo group, more preferably 15 lower alkanoyi substituted with a sulfo and a phenyl groups (e.g. 2-sulfo-2-phenylacetyl);

aryloxy(lower)alkanoyl, more preferably phenoxy(lower)-alkanoyl (e.g. phenoxyacetyl, phenoxy-propionyl);

tetrazolyl(lower)alkanoyl (e.g. 2-(1 H-tetrazol-1-yl)-acetyl-3-(1 H-tetrazol-1-yl)propionyl); aminothiazolyl(lower)alkanoyl (e.g. 2-(2-amino-thiazol-4-yl)acetyl);

20 protected aminothiazolyl(lower)alkanoyl, preferably acylaminothiazolyl(lower)alkanoyl, more preferably lower alkanoylaminothiazolyl(lower)alkanoyl (e.g. 2-(2-formamidothiazol-4-yl)acetyl); aminothiazolylglyoxyloyl (e.g. 2-(2-aminothiazol-4-yl)-glyoxyloyl);

protected aminothiazolylglyoxyloyl, preferably acylaminothiazolylglyoxyloyl, more preferably lower alkanoylaminothiazolyglyoxyloyl (e.g. 2-(2-formamidothiazol-4-yl)glyoxyloyl); 25 ar(lower)alkanoyl having a lower alkoximino group, more preferably 2-lower alkoxyimino-2-phenylacetyl (e.g. 2-methoxyimino-2-phenylacetyl, 2-ethoxyimino-2-phenylacetyl, and 2-propoxy-imino-2-phenylacetyl);

aminothiazolyl(lower)alkanoyl having a hydroxyimino group, more preferably 2-hydroxyimino-2-aminothiazolacetyl [e.g. 2-hydroxyimino-2-(2-aminothiazol-4-yl)acetyl);

30 protected aminothiazolyl(lower)alkanoyl having a hydroxyimino group, preferably acylaminothi-azolyl(lower)-alkanoyl having a hydroxyimino group, more preferably 2-hydroxyimino-2-lower alkanoylaminothiazolylacetyl [e.g. 2-hydroxyimino-2-(2-formamidothiazol-4-yl)acetyl,);

aminothiazolyl(lower)alkanoyl having a lower alkoxyimino group, more preferably 2-lower alkoxyimino-2-amino-thiazolylacetyl [e.g. 2-methoxyimino-2-(2-aminothiazol-4-yl)acetyl, 2-ethoxy-35 imino-2-(2-aminothiazol-4-yl)acetyl, 2-propoxyimino-2-(2-aminothiazol-4-yl)acetyl, 2-isopropoxy-imino-2-(2-aminothiazol-4-yl)acetyl, 2-butoxyimino-2-(2-aminothiazol-4-yl)acetyl, 2-pentyloxyim-ino-2-(2-aminothiazol-4-yl)acetyl, 2-hexyloxyimino-2-(2-aminothiazol-4-yl)acetyl);

protected aminothiazolyl (lower)alkanoyl having a lower alkoxyimino group, preferably acylam-inothiazolyl-(lower)alkanoyl having a lower alkoxyimino group, more preferably 2-lower alkoxyim-40 ino-2-lower alkanoylaminothiazolylacetyl [e.g. 2-methoxyimino-2-(2-formamidothiazol-4-yl)acetyl, 2-ethoxyimino-2-(2-formamidothiazol-4-yl)-acetyl, 2-propoxyimino-2-(2-formamidothiazol-4-yl)ace-tyl, 2-isopropoxyimino-2-(2-formamidothiazol-4-yl)acetyl, 2-butoxyimino-2-(2-formamidothiazol-4-yl)acetyl, 2-pentyloxyimino-2-(2-formamidothiazol-4-yl)acetyl, 2-hexyloxyimino-2-(2-formamidoth-iazol-4-yl)acetyl,);

45 aminothiazolyl(lower)alkanoyl having a lower alkenyloxyimino group, more preferably 2-lower alkenyloxyimino-2-(2-aminothiazolylacetyl [e.g. 2-vinyloxyimino-2-(aminothiazol-4-yl)acetyl, 2-al-lyloxyimino-2-(2-aminothiazol-4-yl)acetyl,);

protected aminothiazolyl(lower)alkanoyl having a lower alkenyloxyimino group, preferably acylaminothiazolyl-(lower)alkanoyl having a lower alkenyloxyimino group, more preferably 2-50 lower alkenyloxyimino-2-lower alkanoylaminothiazolylacetyl [e.g. 2-allyloxyimino-2-(2-formami-dothiazol-4-yl)acetyl, etc.];

aminothiazolyl(lower)alkanoyl having a lower alkynyloxymino group, more preferably 2-lower alkynyloxyimino-2-aminothiazolylacetyl [e.g. 2-ethynyloxyimino-2-(2-aminothiazol-4-yl)acetyl, 2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetyl, etc.];

55 protected aminothiazolyl(lower)alkanoyl having a lower alkynyloxyimino group, preferably acylaminothiazolyl(lower)-alkanoyl having a lower alkynyloxyimino group, more preferably 2-lower alkynyloxyimino-2-lower alkanoylaminothiazolylacetyl [e.g. 2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetyl, etc.];

aminothiazolyl(lower)alkanoyl having an ar(lower)-alkoxyimino group, more preferably 2-60 phenyl(lower) alkoxyimino-2-aminothiazolylacetyl [e.g. 2-benzyloxyimino-2-(2-aminothiazol-4-yl)-acetyl, etc.];

protected aminothiazolyl(lower)alkanoyl having an ar(lower)alkoxyimino group, preferably acylaminothiazolyl-(lower)alkanoyl having a phenyl(lower)alkoxyimino group, more preferably 2-phenyl(lower)alkoxyimino-2-lower alkanoylaminothiazolylacetyl [e.g. 2-benzyloxyimino-2-(2-for-65 mamidothiazol-4-yl)acetyl, etc.];

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GB2089 787A 8

aminothiadiazolyl(lower)alkanoyl having a lower alkoxyimino group, more preferably 2-lower alkoxyimino-2-aminothiadiazolylacetyl [e.g. 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)ace-tyl, 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl, 2-propoxyimino-2-(5-amino-1,2,4-thia-diazol-3-yl)acetyl, 2-hexyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl, etc.];

5 protected aminothiadiazolyl(lower)alkanoyl having a lower alkoxyimino group, preferably 5

acylaminothiadiazolyl(lower)alkanoyl having a lower alkoxyimino group, more preferably 2-lower alkoxyimino-2-lower alkanoylaminothiadiazolylacetyl (e.g. 2-methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetyl, etc);

aminopyridyl(lower)alkanoyl having a lower alkoxyimino group, more preferably 2-lower 10 alkoxy-imino-2-amino-pyridylacetyl (e.g. 2-methoxyimino-2-(6-aminopyridin-2-yl)acetyl, 2-ethoxy- 10 imino-2-(6-aminopyridin-2-yl)acetyl, 2-propoxyimino-2-(6-aminopyridin-2-yl)acetyl, etc);

protected aminopyridyl(lower)alkanoyl having a lower alkoxyimino group, preferably acylami-nopyridyl(lower)alkanoyl having a lower alkoxyimino group, more preferably 2-lower alkoxyim-ino-2-lower alkanoylaminopyridylacetyl (e.g. 2-methoxyimino-2-(6-formamidopyridin-2-yl)acetyl, 15 etc.); 15

aminopyrimidinyl(lower)alkanoyl having a lower alkoxyimino group, more preferably 2-lower alkoxyimino-2-aminopyrimidinylacetyl (e.g. 2-methoxyimir»o-2-(4-aminopyrimidin-2-yl)acetyl, 2-ethoxyimino-2-(4-aminopyrimidin-2-yl)acetyl, 2-propoxyimino-2-(4-aminopyrimidin-2-yl)acetyl,

etc.);

20 protected aminopyrimidinyl(lower)alkanoyl having a lower alkoxyimino group, preferably 20

acylaminopryimidinyl (lower)alkanoyl having a lower alkoxyimino group, more preferably 2-lower alkoxyimino-2-lower alkanoylaminopyrimidinylacetyl (e.g. 2-methoxyimino-2-(4-formamidopyrimi-din-2-yl)acetyl, etc.);

dihydrooxathiinyl(lower)alkanoyl having a lower alkoxyimino group, more preferably 2-lower 25 alkoxyimino-2-dihydrooxathiinylacetyl (e.g. 2-methoxyimino-2-(5,6-dihydro-1,4-oxathiin-2-yl)ace- 25 tyl, 2-ethoxyimino-2-(5,6-dihydro-1,4-oxathiin-2-yl)-acetyl, 2-propoxyimino-2-(5,6-dihydro-1,4-oxathiin-2-yl)acetyl, etc.); and furyl(lower)alkanoyl having a lower alkoxyimino group, more preferably 2-lower alkoxyimino-2-furylacetyl (e.g. 2-methoxyimino-2-(2-furyl)acetyl, 2-ethoxyimino-2-(2-furyl)acetyl, 2-propoxyim-30 ino-2-(2-furyl)acetyl, etc.). 30

The processes for preparing the object compounds of the present invention are explained in detail in the following.

Compounds of the present invention having the formula:

35 Y 35

40 c\r -,/\o3b 40

in which R is -CH2CHO,-CH2CH20H or a reactive derivative of either of these groups and R1, R2, R3a, R3b and Y are as hereinbefore defined are useful in the preparation of 1-oxadethia-3-45 cephems. Two processes are as follows:— 45

Process 1

50

55

Y

1_l /

0—CH2 CHO Cvclizatrion i ————•

R3a

R2

(la)

60 or its reactive derivatives at the formyl group or a salt thereof

R2 .

(n)

or a salt thereof

50

55

60

9

GB2 089 787A 9

Process Z Y

10

R

—-S CH2CH2OH Oxidation R

f IS** 0'

R2 (lb)

/"Y

(n)

10

15 or its reactive derivatives at the hydroxymethyl group or a salt thereof or a salt thereof

Process 1

The object compound (XI) or a salt thereof can be prepared by subjecting the compound (la) 20 or its reactive derivatives at the formyl group or a salt thereof to cyclization.

Suitable salt of the compound (la) may include an acid addition salt such as an organic acid salt (e.g. acetate, maleate, tartrate, benzenesulfonate and toluenesulfonate) or an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate and phosphate); a metal salt (e.g. sodium salt, potassium salt, calcium salt and magensium salt); ammonium salt; and an organic amine salt 25 (e.g. triethylamine salt and dicyclohexylamine salt).

Suitable reactive derivatives at the formyl group of the compound (la) may include all conventional reactive derivatives at the formyl group and reactive derivatives having equivalent workability to the compound (II) in this reaction. Suitable example of such reactive derivatives may include acetal (e.g. dimethyl acetal and diethyl acetal), hemiacetal, hydrate(diol), thioacetal, 30 hemithioacetal and mono (or di)acy!ated diol.

The present reaction, in the case where the compound la, in which R3a and R3b are linked together to form a group of the formula:— = P(RS)3 wherein R5 is as defined above, is used as the starting compound, is usually carried out in around neutral condition or in the presence of a base as mentioned hereinafter. The reaction is usually carried out in a solvent such as benzene, 35 methylene chloride, dimethylsulfoxide, ethyl acetate, tetrahydrofuran or any other solvent which does not adversely affect the reaction. The reaction temperature is not critical, and the reaction is preferably carried out at ambient temperature or under warming.

In case where the compound la, in which R3a is hydrogen and R3b is a group of the formula:

40 0

15

20

25

30

35

40

-P(OR4)2

wherein R4 is as defined above, is used as the starting compound, the present reaction is 45 preferably carried out in the presence of a strong base such as alkali metal hydride (e.g. sodium 45 hydride or lithium hydride), alkaline earth metal hydride (e.g. calcium hydride), alkali metal t-alkoxide (e.g. sodium t-butoxide or potassium t-butoxide), ar(lower)alkyl alkali metal (e.g. trityl sodium or trityl lithium or aryl alkali metal (e.g. phenyl lithium). The reaction is usually carried out in a solvent such as benzene, tetrahydrofuran, dioxane or any other solvent which does not 50 adversely affect the reaction. The reaction temperature is not critical, and the reaction is usually 50 carried out at ambient temperature, under warming or heating.

Process 2

The object compound (XI) or a salt thereof can be prepared by subjecting the compound (lb) 55 or its reactive derivatives at the hydroxymethyl group or a salt thereof to oxidation. 55

Suitable salt of the compound (lb) can be referred to the ones exemplified as the salt of the compound (la).

Suitable reactive derivatives at the hydroxymethyl group of the compound (lb) may include the compound wherein the hydroxymethyl group of the compound (lb) is transformed into methyl 60 group having an acid residue such as halogen (e.g. chlorine or bromine), arenesulfonyloxy (e.g. 60 p-toluenesulfonyloxy or p-nitrobenzenesulfonyloxy) or haloformyloxy (e.g. chloroformyloxy).

Suitable oxidizing agent to be used in this oxidation reaction may include conventional ones which can oxidize hydroxymethyl or reactive derivatives of the hydroxymethyl group to formyl.

In case that the starting compound has 2-hydroxyethoxy group at the 4th position of the 65 azetidinone ring, said oxidizing agent may include (1) an activated dimethylsulfoxide formed by 65

10

GB2089787A 10

a reaction of dimethylsulfoxide and dicyclohexylcarbodiimide, dimethylsulfoxide and acetic anhydride, dimethylsulfoxide and phosphorus pentoxide, dimethylsulfoxide and sulfur trioxide-pyridine, dimethylsulfoxide and keteneimine, dimethulsulfoxide and chlorine, dimethylsulfoxide and mercuric acetate, dimethylsulfide and N-chlorosuccinimide, dimethylsulfide (or 5 methylphenylsulfide) and chorine, etc.; (2) chrome compound such as chromium trioxide- 5

pyridine, chromium trioxide-sulfuric acid, alkali metal dichromate (e.g. sodium dichromate,

potassium dichromate, etc.), lower alkyl chromate (e.g. t-butyl chromate, etc.) and the like.

The oxidation using dimethylsulfoxide and dicyclohexylcarbodiimide is preferably carried out in the presence of proton-donor such as an acid (e.g. phosphoric acid, trifluoroacetic acid, 10 dichloroacetic acid, etc.), a mixture of acid and base (e.g. trifluoroacetic acid-pyridine, 10

phosphoric acid-pyridine, etc.) or the like.

The present oxidation reaction is carried out without or in the presence of an acid or a base and it is optionally selected according to a kind of oxidizing agent to be used.

The present oxidation is carried out without or with solvent such as benzene, toluene, 1 5 chloroform, methylene chloride, carbon tetrachloride, diethyl ether, dimethylformamide or any 15 other solvent which does not adversely affect the reaction, and the solvent is optionally selected according to a kind of oxidizing agent to be used.

In case that the starting compound of the present oxidation reaction is in a form of reactive derivatives at the hydroxymethyl group, suitable oxidizing agent may include dimethylsulfoxide 20 and the like. The present oxidation is preferably carried out in the presence of a base (e.g. 20

sodium bicarbonate, triethylamine, etc.).

The reaction temperature of the oxidation reaction of this process is not critical, and the reaction is carried out under cooling, at ambient temperature, under warming or under heating. The reaction temperature is optionally selected according to a kind of oxidizing agent to be used. 25 By the present oxidation reaction, there is produced the compound of the formula (la) and 25 said compound (la), without isolation, is immediately cyclized to give the object compound (XI).

Preparation 1

The compound 111 or its derivatives at the formyl group or a salt thereof can be prepared by 30 reacting the compound II or a salt thereof with a compound having the formula H0CH2-R7, or a 30 derivative at the formyl group.

The present reaction is preferably carried out in the presence of inorganic metal salt such as a silver salt (e.g. silver tetrafluoroborate, silver oxide or silver perchlorate), stannic chloride or zinc chloride.

35 The reaction is usually carried out in a solvent such as methylene chloride, toluene, 35

chloroform or any other solvents which do not adversely affect the reaction.

The reaction temperature is not critical, and the reaction is preferably carried out under cooling or at ambient temperature.

40 Preparation 2 40

The compound IV or its derivatives at the formyl group or a salt thereof can be prepared by reacting the compound 111 or its derivatives at the formyl group or a salt thereof with an acylating agent.

The acylating agent to be used for the present reaction may include one of the formula: 45 R1a-OH wherein R1a is defined above, or its reactive derivatives at the carboxy group or a salt 45 thereof.

Suitable reactive derivatives at the carboxy group of the compound (XI) may include an acid halide, an acid anhydride, an activated amide and an activated ester. The suitable example may be an acid chloride; an acid azide;

50 a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. 50

dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.) or aromatic carboxylic acid 55 (e.g. benzoic acid, etc.); 55

a symmetrical acid anhydride;

an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; and activated ester (e.g. cyanomethyl ester, methoxy-methyl ester,

dimethyliminomethyl ((CH3)2£ = CH-) ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 60 2,4-dinotrophenyl ester, trichlorophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, 60 mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, piperidyl ester, 8-quinolyl thioester, or an ester with N,N-dimethylhydroxylamine, 1-hydroxy-2-(1 H)pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxy-6-chloro-1 H-benzotriazole, and the like. These reactive 65 derivatives at the carboxy group can optionally be selected from them according to the kind of 65

11

GB2089787A 11

the compound (XIV) to be used.

The salts of the compound (XI) may be salts with an inorganic base such as an alkali metal salts (e.g. sodium or potassium salt) or an alkaline earth metal salt (e.g. calcium or magnesium salt), a salt with an organic base such as trimethylamine, triethylamine, dicyclohexylamine or the 5 like.

The reaction of the compound III with the compound XII is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene cloride, ethylene chlcoride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other solvent which does not adversely influence: the reaction.

10 Among these solvent, hydrophilic sovents may be used in a mixture with water.

When the compound (XI) is used in a free acid form or its salt form in the reaction, the reaction is preferably carried out in the prescence of a conventional condensing agent such as carboniimide compound (e.g. N,N1-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholonoethyl-carbodiimide, N-cyclohexyl-N'-)4-diethylaminocyclohexyl)carbodiimide, N,N'-15 diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N,N'-(3-dimethylaminopropyl) carbodiimide, etc.), N,N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxy-chloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, N-20 ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3'-sulfonate, 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1 H-benzotriazole, Vimlseier reagent (e.g. (chloromethylene)dimethyl- ammonium chloride, a compound formed by the reaction of dimethylformamide with phosphorus oxychloride, etc.) or the like.

The reaction may also be carried out in the presence of an inorganic or an organic base such 25 as an alkali metal bicarbonate, alkali metal carbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline, or the like. When the base or the condensing agent is in liquid, it can be used also as a solvent. The reaction temperature is not critical, and the reaction is usually carried out under cooling or at ambient temperature.

30 The present acylating reaction includes, within its scope, the cases that the amino group and the hydroxy group in the compound III are transformed into the corresponding acylated group according to the reaction conditions and kinds of the introduced group in the course of the reaction and/or in post-treatment of the reaction.

35 Preparation 3

The compound V or its derivatives at the formyl group or a salt compound thereof can be prepared by ozonolysis of the compound IV or its derivatives at the formyl group or a salt thereof, and if necessary, reducing the resulting compound.

The present reaction is usually carried out in a solvent such as ethyl acetate, methyl acetate or 40 any other solvents which do not adversely affect the reaction.

The reaction temperature is not critical and the reaction is preferably carried out under cooling or at ambient temperature.

In case that the corresponding ozonide compound is produced in the present reaction, the compound V or its derivatives at the formyl group or a salt thereof can be obtained by further 45 reducing the ozonide compound with a conventional reducing agent such as acid sodium sulfite, dimethyl sulfide or trimethylphosphite.

The present reaction is usually carried out in a solvent such as ethyl acetate or any other solvents which do not adversely affect the reaction.

The reaction temperature is not critical and the reaction is preferably carried out under cooling 50 or at ambient temperature.

Preparation 4

The compound VI or its derivatives at the formyl group or a salt thereof can be prepared by subjecting the compound IV or its derivative at the formyl group or a salt thereof to oxidative 55 cleavage reaction.

Suitable oxidizing agent used in the present oxidative cleavage reaction may include ozone, sodium dichromate and potassium permanganate.

The present reaction is usually carried out in a solvent such as ethyl acetate, methyl acetate or any other solvents which do not adversely affect the reaction.

60 The reaction temperature is not critical and the reaction is preferably carried out under cooling or at ambient temperature.

Preparation 5

The compound VIII or its derivatives at the formyl group or a salt thereof can be prepared by 65 reducing the compound V or its derivatives at the formyl group or a salt thereof.

5

10

15

20

25

30

35

40

45

50

55

60

65

12

GB2089 787A 12

The present reduction can be carried out by a conventional method which is applied to the reduction of -CO- group to the corresponding -CH(OH)- group, for example, by using a combination of a metal (e.g. zinc) and an organic or inorganic acid (e.g. acetic acid, propionic acid and hydrochloric acid), lithium borohydride, sodium borohydride, aluminium amalgam or 5 catalytic hydrogenation. 5

The present reaction is preferably carried out in a solvent such as methylene chloride, tetrahydrofuran or any other solvents which do not adversely affect the reaction.

The reaction temperature is not critical and the rection is preferably carried out under cooling at ambient temperature or under warming. 10 10

Preparation 6

The compound VIII or its derivatives at the formyl group or a salt thereof can be prepared by reacting the compound VI or its derivatives at the formyl group or a salt thereof with the compound VII.

15 The present reaction is usually carried out in a solvent under anhydrous conditions. Suitable 15 solvents are those such as benzene, toluene or any other solvents which do not adversely affect the reaction.

The reaction temperature is not critical and the reaction is preferably carried out under warming or heating.

20 20

Preparation 7

The compound IX or its derivatives at the formyl group or a salt thereof can be prepared by halogenating the compound VIII or its derivatives at the formyl group or a salt thereof.

The present halogenation can be carried out by using a conventional halogenating agent such 25 as phosphorus trihaiide, phosphorus pentahalide, phosphorus oxychloride and thionyl halide. 25

The present reaction may be carried out in the presence of a base such as lutidine or pyridine.

The reaction is usually carried out in a solvent such as methylene chloride or any other solvents which do not adversely affect the reaction.

The reaction temperature is not critical and the reaction is preferably carried out under 30 cooling, at ambient temperature or under warming. 30^

Preparation 8

The compound X or its derivatives at the formyl group or a salt thereof can be prepared by reacting the compound IX or its derivatives at the formyl group or a salt thereof with a 35 compound of the formula: 35

P(OR4)3 or

40 HP(0R4)2 40

or P(R5)3

wherein R4 and R5 are each as defined above.

45 In case that 45

O

II

HP(0R4)2

50 50

is used in the present reaction, the present reaction is preferably carried out in the presence of an base as aforementioned.

The reaction is usually carried out in a solvent such as methylene chloride, benzene or any other solvents which do not adversely affect the reaction.

55 The reaction temperature is not critical and the reaction is preferably carried out at ambient 55 temperature or under warming.

Preparation 9

The compound lb or a salt thereof can be prepared by subjecting the compound Xa or a salt 60 thereof to elimination reaction of the protective groups of the hydroxy. 60

The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis and the like.

Hydrolysis using an acid is one of the common and preferable method for eliminating the protective group. Suitable acid may include an organic or an inorganic acid, for example, formic 65 acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and hydrochloric acid. The 65

13

GB2 089 787A 13

acid suitable for the reaction can be selected according to the kind of protective group to be eliminated. When the elimination reaction is conducted with the acid, it can be carried out in the presence or absence of a solvent. Suitable solvent may include an organic solvent, water or a mixed solvent thereof. When trifluoroacetic acid is used, the elimination reaction may preferably 5 be carried out in the presence of anisole.

Hydrolysis with a base is preferably applied for eliminating acyl group, for example, haloalkanoyl (e.g. trifluoroacetyl). Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate 10 (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassium 15 hydrogen phosphate, etc.), or the like, and an organic base such as trialkylamine (e.g.

trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo (4,3,0)non-5-ene, 1,4-diazabicyclo(2,2,2)-octane, 1,5-diazabicyclo(5,4,0)undecene-5 or the like. The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

20 The reaction is usually carried out in a solvent such as methanol, ethanol, or any other solvents which do not adversely affect the reaction.

The reaction temperature is not critical and the reaction is preferably carried out under cooling, at ambient temperature or under warming.

25 Preparation 10

The compound la or a salt thereof can be prepared by oxidizing the compund lb or a salt thereof.

The present reaction can be carried out substantially in the same method as illustrated in Process 2 above.

30 The following examples are given for the purpose of illustrating the present invention:— Example 1

(a) Preparation of the starting compound:

(1) Ethylene glycol (132.0 g.) was added to a solution of a mixture of 4a and 4/? isomers of 35 benzyl 2-(2-oxo-3j8-amino-4-chloroazetidin-1-yl)-3-methyl-2-butenoate p-toluenesulfonate (118.2

g.) in methylene chloride (300 ml.). Silver oxide (68.5 g.) and silver tetrafluoroborate (57.6 g.) were in turn added thereto with stirring at — 30 to — 25°C. The resulting mixture was stirred for 30 minutes at — 35 to — 30°C and then stirred for 40 minutes by gradually elevating the reaction temperature from — 30°C to 2 or 3°C. The reaction mixture was poured into benzene 40 (2.0 I.), and a saturated aqueous solution of sodium bicarbonate (0.7 I.) and sodium chloride (80 g.) were added thereto under ice-cooling. The mixture was stirred for 30 minutes and filtered with celite. The organic layer was separated, washed twice with a saturated aqueous solution of sodium chloride (0.8 I.), dried over magnesium sulfate and concentrated under reduced pressure to give oil of a mixture of 4a and 4/3 isomers of benzyl 2-[2-oxo-3/?-amino-4-45 (2-hydroxy-ethoxy)azetidin-1-yl]-3-methyl-2-butenoate (47.4 g.).

I.R. (Film)

3350, 1770, 1730 cm"1 N.M.R. (CDCI3,5)

2.00 (3H, s), 2.25 (3H, s), 3.10 (1H, broad s),3.4-3.8 (4H, m), 5.1-5.6 (4H, m), 7.2-7.5 50 (5H, m)

(2) Pyridine (23.7 g.) was added at — 30°C to a solution of a mixture of 4a and 4/? isomers of benzyl 2-[2-oxo~3/?-amino-4-(2-hydroxy-ethoxy)azetidin-1 -yl]-3-methyl-2-butenoate (47.4 g.) in methylene chloride (0.8 I.), and then phenoxy-acetyl chloride (51.15 g.) was added dropwise thereto. The resulting mixture was stirred for 1 hour at — 30 to — 20°C and then for 30

55 minutes under ice-cooling. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate (1 I.) and 0.5 N hydrochloric acid (0.4 I) were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (0.3 I.), dried over magnesium sulfate and concentrated under reduced pressure to give oil (83.8 g.). The oil was subjected to column chromatography on silica gel (2.0 kg.) and eluted with a 60 mixture of benzene and ethyl acetate (5:1 or 3:1) to first give benzyl 2-[2-oxo-3;6-

phenoxyacetamido-4a-(2-phenoxyacetoxyethoxy)azetidin-1-yl]-3-methyl-2-butenoate (1.1 g.). I.R. (CH2CI2)

3400, 1770, 1720, 1690 cm-1 N.M.R. (CDCI3, 8)

65 2.02 (3H, s), 2.25 (3H, s), 3.65-3.95 (2H, m), 4.10-4.40 (2H, m), 4.50 (2H, s), 4.63 (2H,

5

10

15

20

25

30

35

40

45

50

55

60

65

14

GB2 089 787A 14

s), 5.00-5.45 (4H, m), 6.85-7.50 (15H or 16H, m)

And then, from the subsequent fractions, a mixture of 4a and 4/? isomers of benzyl 2-[2-oxo-3/?-phenoxyacetamide-4-(2-phenoxyacetoxyethoxy)azetidin-1-yl]-3-methyl-2-butenoate (19.4 g.) was obtained.

5 Further, from the following fractions, benzyl 2-[2-oxo-3/?-phenoxyacetamido-4/?-(2- 5

phenoxyacetoxyethoxy)-azetidin-1-yl]-3-methyl-2-butenoate (17.2 g.) was obtained.

I.R. (CH2CI2)

3400,1770,1720,1690 cm"1 N.M.R. (CDCI3, 8)

10 2.00 (3H, s), 2.25 (3H, s), 3.5-3.75 (2H, m), 4.0-4.3 (2H, m), 4.55 (4H, s), 5.15-5.52 10

(4H, m), 6.75-7.50 (15H or 16H, m)

(3) (i) Ozone gas was passed for 1 hour at — 60 to — 62°C into a solution of benzyl 2-[2-oxo-3/?-phenoxy-acetamido-4/?-(2-phenoxyacetoxyethoxy)azetidin-1-yl]-3-methyl-2-butenoate (16.3 g.) in ethyl acetate (165 ml.). The mixture was elevated to a temperature of ice-cooling, and ethyl 15 acetate (160 ml.) and a solution of sodium bisulfite (28.1 g.) and sodium sulfite (7.0 g.) in 15

water (280 ml.) were added thereto. After stirring for 5 minutes, the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml.), dried over magnesium sulfate and concentrated under reduced pressure to give oil (16.1 g.). The oil was crystallized with a mixture of diethyl ether and methanol (10:1) (120 ml.) 20 to give crystals of benzyl 2-[2-oxo-3/?-phenoxyacetamido-4/?-(2-phenoxyacetoxyethoxy)azetidin-1- 20 yl]glyoxylate (10.0 g.). From the mother liquor, the same compound (0.71 g.) was obtained, mp 102 to 103°C (dec.).

I.R. (Nujol)

3380, 1810, 1750, 1735, 1710, 1670 cm"1 25 N.M.R. (CDCI3, 8) 25

3.92-4.40 (4H, m), 4.56 (2H, s), 4.59 (2H, s), 5.35 (2H, s), 5.50-5.77 (2H, m),

7.80-8.50 (15 H or 16H, m)

(ii) Ozone gas was passed for 80 minutes at — 60 to — 64°C into a solution of a mixture of 4a and 4/8 isomers of benzyl 2-[2-oxo-3/?-phenoxyacetamido-4-(2-

30 phenoxyacetoxyethoxy)azetidin-1-yl]-3-methyl-2-butenoate (18.0 g.) in ethyl acetate (180 ml.), 30 and then a solution of sodium bisulfite (31.2 g.) and sodium sulfite (8.0 g.) in water (300 ml.) was added thereto. The organic layer wass separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give oil (16.1 g.). The oil was crystallized with a mixture of diethyl ether and methanol (10:1) 35 (80 ml.) to give crystals, which was collected by filtration to give crystals of benzyl-2-[2-oxo-3/?- 35 phenoxyacetamido-4/?-)2-phenoxyacetoxyethoxy)-azetidin-1-yl]glyoxylate (5.96 g.), mp 103°C (dec.).

(iii) Ozone gas was passed for 15 minutes at — 55 to — 60°C into a solution of benzyl 2-[2-oxo-3/?-phenoxyacetamida-4/?-(2-phenoxyacetoxyethoxy)azetidin-1 -yl]-3-methyl-2-butenoate (3.0

40 g.) in methyl acetate (60 ml.). The reaction mixture was poured into a mixture of ethyl acetate 40 (300 ml.) and a solution of sodium bisulfite (9.0 g.) and sodium hydroxide (1.1 g.) in water (100 ml.). The ethyl acetate layer was separated, washed with warer, dried over magnesium sulfate and concentrated under reduced pressure to give oil (2.76 g.). The oil was dissolved in methanol (40 ml.) and the solution was stirred for 1 hour at ambient temperature, which was 45 concentrated under reduced pressure to give oil (3.2 g.). The oil was subjected to column 45

chromatography on silica gel (30 g.) and eluted with chloroform or a mixture of chloroform and ethyl acetate (1:1) to give oil of 2-oxo-3/?-phenoxyacetamido-4/?-(2-

phenoxyacetoxyethoxy)azetidine (970 mg.). The oil was crystallized with a mixture of diethyl ether and methanol (10:1) to give crystals of the same compound (800 mg.), mp 100 to 102°C 50 (dec.). 50

Mass (m/e) 414 (M+)

I.R. (Nujol)

3380, 3200, 1785, 1760, 1720, 1660 cm"1 N.M.R. (CDCI3, 8)

55 3.72 (2H, t, J = 5Hz), 4.31 (2H, m), 4.54 (2H, s), 4.64 (2H, s), 5.07 (1H, d, J = 4Hz), 55

5.45 (1 H, dd, J = 4, 10 Hz), 6.85-7.50 (12H, m)

(iv) Ozone gas was passed for 60 minutes at — 60 to — 62°C into a solution of a mixture of 4a and 4/? isomers of benzyl 2-[2-oxo-3/?-phenoxyacetamido-4-(2-

phenoxyacetoxyethoxy)azetidin-1-yl]-3-methyl-2-butenoate (20.88 g.) in methyl acetate (400 60 ml.). The reaction mixture was elevated to a temperature of ice-cooling and poured into a 60

mixture of ethyl acetate (2.0 I.) and a solution of sodium bisulfite (63.0 g.) and sodium hydroxide (7.8 g.) in water (600 ml.). The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride (1.0 I.), dried over magnesium sulfate and concentrated under reduced pressure to give oil (19.1 g.). The oil was dissolved in methanol 65 (400 ml.) and the solution was stirred for 1 hour at ambient temperature, which was 65

15

GB2 089 787A

15

concentrated under reduced pressure to give oil (17.0 g.). The oil was subjected to column chromatography on silica gel (350 g.) and eluted with a mixture of benzene and ethyl acetate (2:3 or 1:2) to give oil of 2-oxo-3/?-phenoxyacetamido-4/?-(2-phenoxyacetoxyethoxy)azetidine (3.65 g.). The oil was crystallized with a mixture of diethyl ether and methanol (10:1) (60 ml.)

5 to give crystals of the same compound (2.27 g.). This compound was identified with the compound obtained in Example 1 (a) (3) (iii) by melting point, I.R. and N.M.R. spectra.

(4) (i) Zinc powder (5.50 g.) was added under ice-cooling to a solution of benzyl 2-[2-oxo-3/J-phenoxyacetamido-4/?-(2-phenoxyacetoxyethoxy)azetidin-1-yl]-glyoxylate (5.50 g.) in a mixture of methylene chloride (27.5 ml.) and acetic acid (27.5 ml.). The resulting mixture was stirred for 1 10 hour at the same temperature and for 30 minutes at ambient temperature. Zinc powder was filtered off with celite and the celite layer was washed three times with ethyl acetate (10 ml.). The filtrate and the washings were combined and poured into ethyl acetate (150 ml.). The ethyl acetate layer was in turn washed with water (70 ml.), 5% aqueous solution of sodium bicarbonate (70 ml.) and water (50 ml. X 2), dried over magnesium sulfate and concentrated 15 under reduced pressure to give foamy powder of benzyl 2-[2-oxo-3/}-phenoxyacetamido-4/?-(2-phenoxyacetoxy-ethoxy)azetidin-1-yl]glycolate (a mixture of epimers at 2 position) (5.50 g.). I.R. (CH2CI2)

3410, 1780, 1740, 1690 cm"1

(ii) Benzene (40 ml.) was added to 2-oxo-3/?-phenoxyacetamido-4/?-(2-phenoxyacetoxyethoxy) 20 azetidine (414 mg.), and t-butyl glyoxylate monohydrate (1.48 g.) was added thereto. The resulting mixture was refluxed for 23 hours. The reaction mixture was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give oil of t-butyl 2-[2-oxo-3/?-phenoxyacetamido-4/?-(2-phenoxyacetoxyethoxy)-azetidin-1 -yl]glycolate (a mixture of epimers at 2 position) (680 mg.).

25 I.R. (CHCI3)

3500,3420,1780,1735,1690 cm"1 N.M.R. (CDCI3, 8)

1.45 (9H, s), 3.5-3.9 (2H, m), 4.0-4.4 (2H, m), 4.50 (2H, s), 4.58 (2H, s), 5.17 (1H, d, J = 4Hz), 5.27 (1H, s), 5.45 (1H, dd, J = 4, 9Hz), 6.75-7.45 (11H, m) 30 (5) 2,6-Lutidine (3.10 g.) was added under ice-cooling to a solution of benzyl 2-[2-oxo-3j8-phenoxyacetamido-4/?-(2-phenoxyacetoxyethoxy)azetidin-1 -yl]-glycolate (a mixture of epimers at 2 position)(5.50 g.) in methylene chloride (100 ml.), and then a solution of thionyl chloride (3.45 g.) in methylene chloride (5 ml.) was added dropwise thereto. After stirring for 45 minutes under ice-cooling, the reaction mixture was washed twice with a cold aqueous solution 35 of sodium chloride (50 ml.), dried over magnesium sulfate and concentrated under reduced pressure to give foamy power of benzyl 2-chloro-2-[2-oxo-3/?-phenoxyacetamido-4/?-(2-phenoxyacetoxyethoxy)azetidin-1-yl]acetate (a mixture of epimers at 2 position) (5.90 g.). I.R. (CH2CI2)

3400, 1790, 1760, 1690 cm"1 40 (6) Triphenylphosphine (3.80 g.) was added to a solution of benzyl 2-chloro-2-[2-oxo-3/S-phenoxyacetamido-4/?-(2-phenoxyacetoxyethoxy)azetidin-1-yl]acetate (a mixture of epimers at 2 position (5.90 g.) in methylene chloride (60 ml.), and the resulting mixture was refluxed for 2 hours in a stream of nitrogen gas. The reaction mixture was poured into ethyl acetate (300 ml.). The mixture was in turn washed with 5% aqueous solution of sodium bicarbonate (50 ml.) and 45 water (50 ml. X 2), dried over magnesium sulfate and concentrated under reduced pressure to give foamy substance (8.80 g.). This substance was subjected to column chromatography on silica gel (90 g.) and eluted with a mixture of benzene and ethyl acetate (1:1) to give foamy powder of benzyl 2-triphenylphosphoranylidene-2-[2-oxo-3/?-phenoxyacetamido-4/?-(2-phenoxyacetoxyethoxy)azetidin-1-yl]acetate (4.84 g.).

50 I.R. (CHCI3)

3400, 1760, 1680 cm"1 N.M.R. (CDCI3, 8)

3.5-3.8 (2H, m), 3.9-4.1 (2H, m), 4.44 (4H, s), 4.5-4.9 (2H, m), 5.0-5.3 (2H, m) (7) An 1N aqueous solution of sodium hydroxide (1 ml.) was added under ice-cooling to a 55 solution of benzyl 2-triphenylphosphoranylidene-2-[2-oxo-3/?-phenoxyacetamido-4/?-(2-phenoxyacetoxyethoxy)azetidin-1-yl]acetate (1.50 g.) in a mixture of methanol (40 ml.) and water (10 ml.). The resulting mixture was stirred for 15 minutes under ice-cooling and for 1.5 hours at ambient temperature. The reaction mixture was concentrated to a volume of about 20 ml., and ethyl acetate (100 ml.) was added thereto. The ethyl acetate layer was in turn washed 60 with 5% aqueous solution of sodium bicarbonate (20 ml.) and water (30 ml.), dried over magnesium sulfate and concentrated under reduced pressure to give oil (1.42 g.). The oil was subjected to column chromatography on silica gel (15.) and eluted with ethyl acetate to give foamy powder of benzyl 2-triphenylphosphoranylidene-2-(2-oxo-3/?-phenoxyacetamido-4/?-(2-hydroxyethoxy)azetidin-1-yl)acetate (960 mg.).

65 I.R. (CHCIg)

5

10

15

20

25

30

35

40

45

50

55

60

65

16

GB2089 787A

16

3400, 1760, 1740, 1680 cm-1 N.M.R. (CDCI3, 8)

3.2-3.7 (4H, m), 4.24 (2H, s), 4.76 (2H, s), 4.9-5.2 (2H, m)

"Preparation of Benzyl 7j8-phenoxyacetamido-1-oxadethia-3-cephem-4-carboxylate" 5 (1) Dicyclohexylcarbodiimide (310 mg.) and pyridine (40 mg.) were added to a mixture of dimethylsulfoxide (1.5 ml.) and benzene (3 ml.), and then benzyl 2-triphenylphosphoranyl-idene-2-(2-oxo-3/?-phenoxyacetamido-4/?-(2-hydroxyethoxy)azetidin-1-yl)acetate (344 mg.) was added thereto with stirring. To the mixture was added dropwise a solution of trifluoroacetic acid (28 mg.) in benzene (0.2 ml.), and the resuling mixture was stirred for 14 hours at ambient 10 temperature. In the course of the reaction, benzyl 2-triphenylphosphoranylidene-2-(2-oxo-3/?-phenoxyacetamido-4/?-formylmethoxyazetidin-1-yl)-acetate was produced, and immediately cyclized to give the object compound, which was purified as follows.

Benzene (30 ml.) was added to the reaction mixture, and insoluble material was filtered off. The filtrate was in turn washed with 1% hydrochloric acid (10 ml.), water (10 ml.), 5% aqueous 15 solution of sodium bicarbonate (10 ml.) and water (10 ml. X 2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give oil (380 mg.). The oil was subjected to column chromatography on silica gel (8 g.) and eluted with a mixture of benzene and ethyl acetate (1:1) to give powder of benzyl 7/?-phenoxyacetamido-1-oxadethia-3-cephem-4-carboxylate (173 mg.).

20 I.R. (CHCI3)

3420, 1795, 1725, 1690 cm"1 N.M.R. (CDCI3, 8)

4.52 (4H, broad s), 5.06 (1 H, d, J = 4Hz), 5.28 (2H, s), 5.76 (1 H, dd, J = 4, 10Hz), 6.50

(1H, t, J = 2Hz), 6.9-7.5 (11H, m),

25 (2) Benzyl 2-triphenylphosphoranylidene-2-(2-oxo-3/?-phenoxyacetamido-4/?-(2-

hydroxyethoxy)azetidin-1-yl)-acetate (180 mg.) was dissolved in a mixture of dimethylsulfoxide (1.8 ml.) and acetic anhydride (1.8 ml.), and the solution was stirred for 15 hours at ambient temperature in a stream of nitrogen gas. In the course of the reaction, benzyl 2-triphenylphosphoranylidene-2-(2-oxo-3/?-phenoxy-acetamido-4/?-formylmethoxy-azstidin-1 -30 yl)acetate was produced and then cyclized. The reaction mixture was concentrated under reduced pressure to about half volume and benzene was added to the residue. The mixture was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give oil (200 mg.), which was purified by preparative thin-layer chromatography to give benzyl 7/?-phenoxyacetamido-1-oxadethia-3-cephem-4-carboxylate.

35 (3) A solution of benzyl 2-triphenylphosphoranylidene-2-(2-oxo-3/?-phenoxyacetamido-4/?-(2-hydroxyethoxy)-azetidin-1-yl)acetate (200 mg.) in methylene chloride (4 ml.) was added under ice-cooling and stirring to a solution of chromium trioxide-pyridine complex (465 mg.) in methylene chloride (9 ml.). After stirring for 1 hour, chromium trioxide-pyridine complex (470 mg.) was added thereto and the mixture was stirred for 30 minutes. In the course of the 40 reaction, benzyl 2-triphenylphosphoranylidene-2-(2-oxo-3/?-phenoxyacetamido-4/3-

formylmethoxyazetidin-1-yl)acetate was produced and cyclized to give the object compound. The reaction mixture was in turn washed with 5% hydrochloric acid, 5% aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and concentrated under reduced pressure to give oil (150 mg.), which was purified by preparative thin-layer chromatography using a 45 mixture of benzene and ethyl acetate (2:1) as a developing solvent to give benzyl 7/?-phenoxyacetamido-1-oxadethia-3-cephem-4-carboxylate.

Example 2

The following compounds were prepared according to the similar manner to that of Example

50 1.

1)Benzyl 7/?-amino-1-oxadethia-3-cephem-4-carboxylate, oil.

I.R. (CHCI3)

3350, 1785, 1720 cm"1

2) Benzyl 7/?-amino-1-oxadetbia-3-cephem-4-carboxylate p-toluenesulfonate, mp 148 to 55 153°C (dec.).

3) 7/?-Amino-1-oxadethia-3-cephem-4-carboxylic acid.

I.R. (Nujol) 2700-2270, 2120, 1805, 1630, 1540, 1505 cm"1

4) Benzyl 7a-methoxy-7/S-amino-1-oxadethia-3-cephem-4-carboxylate, oil.

I.R. (CH2CI2)

60 1785,1725 cm"1

5) Benzyl 7/?-(2-methoxyimino-2-(2-formamidothiazol-4-yl)-acetamido)-1 -oxadethia-3-cephem-4-carboxylate (syn isomer) powder.

I.R. (Nujol)

3250, 1795, 1725, 1690, 1680 cm"1 65 6) Benzyl 7/?-(2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-

5

10

15

20

25

30

35

40

45

50

55

60

65

17

GB2 089 787A

17

carboxylate (syn isomer) mp 120°C.

7) Benzyl 7/?-(2-isopropoxyimino-2-(2-formamidothiazol-4-yl)acetamido)-1 -oxadethia-3-cephem-4-carboxylate (syn isomer), crystal, mp 162 to 166°C.

8) Benzyl 7/?-(2-methoxyimino-2-(6-formamidopyridin-2-yl)acetamido)-1 -oxadethia-3-cephem-4-5 carboxylate (syn isomer), which was decomposed up to 170°C.

9) Benzyl 7/3-{D, L-2-sulfo-2-phenylacetamido)-1-oxadethia-3-cephem-4-carboxylate,

amorphous solid.

I.R. (CH2CI2)

3280, 1790, 1720, 1670, 1635 cm"1 10 10) Benzyl 7j8-(2-methoxyimino-2-(4-aminopyrimidin-2-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylate (syn isomer), mp 120 to 137°C.

11) Benzyl 7/?-(2-methoxyimino-2-(5-amino-1,2,4,-thiadiazol-3-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylate (syn isomer)

I.R. (Nujol)

15 3450, 3360, 3240, 1790, 1735, 1675 cm

12) Benzyl 7/?-(2-n-butoxyimino-2-(2-formamidothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylate (syn isomer).

I.R. (Nujol)

1780, 1720, 1670, 1630 cm"'

20 13) Benzyl 7jS-(2-n-pentyloxyimino-2-(2-formamidothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylate (syn isomer), mp 136 to 147°C.

14) Benzyl 7/?-(2-methoxyimino-2-phenylacetamido)-1-oxadethia-3-cephem-4-carboxylate (syn isomer), mp 157 to 158.5°C.

15) Benzyl 7/?-(2-(2-formamidothiazol-4-yl)glyoxylamido)-1-oxadethia-3-cephem-4-carboxylate, 25 mp 220 to 221 °C (dec.).

16) Benzyl 7/?-(2-methoxyimino-2-(5,6-dihydro-1,4-oxathiin-2-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylate (syn isomer).

I.R. (Nujol)

3400, 1795, 1725, 1680, 1640 cm"1 30 17) Benzyl 7/?-(2-(1H-1,2,3,4-tetrazol-1-yi)acetamido)-1-oxadethia-3-cephem-4-carboxylate, mp 181 to 183°C.

18) Benzyl 7/?-(2-rnethoxyimino-2-(2-furyl)acetamido)-1-oxadethia-3-cephem-4-carboxylate (syn isomer).

I.R. (Nujol)

35 3390, 1795, 1730, 1690, 1635 cm"1

19) 7/?-(2-Ethoxyimino-2-(2-aminothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), which is gradually decomposed from 150°C.

20) 7j8-(2-lsopropoxyimino-2-(2-formamidothiazol-4-yl)-acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer) mp 171 to 210°C (dec.).

40 21) 7/?-(2-lsopropoxyimino-2-(2-aminothiazol-4-yl)-acetamido)-1-oxadethia-3-cephem-4-carboxylic acid hydrochloride (syn isomer), which is softened at 65 to 70°C and gradually decomposed up to 140°C.

22) 7(8-(2-n-Butoxyimino-2-(2-formamidothiazol-4-yl)-acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), which is decomposed up to 165°C. 45 23) 7/?-(2-n-Butoxyimino-2-(2-aminothiazol-4-yl)-acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), dp>200°C.

24) 7/?-(2-n-Pentyloxyimino-2-(2-formamidothiazol-4-yl)-acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), mp 142 to 147°C (dec.).

25) 7/8-(2-n-Pentyloxyimino-2-(2-aminothiazol-4-yl)-acetamido)-1-oxadethia-3-cephem-4-50 carboxylic acid hydrochloride (syn isomer) (powder), mp 118 to 124°C (dec.).

26) 7/?-(2-Methoxyimino-2-(6-formamidopyridin-2-yl)-acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), mp 130 to 160°C (dec.).

27) 7/?-(2-Methoxyimino-2-(6-aminopyridin-2-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (powder), mp 100 to 140°C (dec.).

55 28) 7/8-(2-Methoxyimino-2-phenylacetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), mp 80 to 95°C (dec.).

29) 7/?-2-(2-Formamidothiazol-4-yl)glyoxylamido)-1-oxadethia-3-cephem-4-carboxylic acid, mp 200 to 22Q°C (dec.).

30) 7/?-(2-(2-Aminothiazol-4-yl)glyoxylamido)- i oxadethia-3-cephem-4-carboxylic acid, 60 dp>240°C.

31) 7/?-(2-(1H-1,2,3,4-Tetrazol-1-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid, mp 164 to 167°C (dec.).

32) 7/J-(2-Methoxyimino-2-(2-furyl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), mp 197°C (dec.).

65 33) 7/?-(2-Methoxyimino-2(5,6-dihydro-1,4-oxathiin-2-yl)acetamido)-1-oxadethia-3-cephem-4-

5

10

15

20

25

30

35

40

45

50

55

60

65

18

GB2 089 787A

18

carboxylic acid (anti isomer), mp 163 to 165 to 165°C (dec.).

34) 7/?-(D,L-2-sulfo-2-phenylacetamido)-1-oxadethia-3-cephem-4-carboxylic acid (amorphous solid).

I.R. (KBr)

5 1790,1730,1680 cm-1

35) 7/?-Phenoxyacetamido-1-oxadethia-3-cephem-4-carboxylic acid, mp 174 to 176°C.

36) 7/?-(2-Methoxyimino-2-(2-formamidothiazol-4-yl)-acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol)

10 3600-2200, 1780, 1720, 1670 cm"1

37) 7/?-(2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid hydrochloride (syn isomer).

I.R. (Nujol)

3400-2400, 1780, 1730, 1680, 1640 cm"' 1 5 38) 7/?-(2-Methoxyimino-2-(2-aminothiazo!-4-y!)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), powder.

I.R. (Nujol)

3600-2400, 1785, 1720, 1660 cm"1

39) Benzyl 7/?-(2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamido)-1 -oxadethia-3-cephem-4-20 carboxylate (syn isomer), amorphous solid.

I.R. (CH2CI2)

3370, 3250-3020, 1790, 1720, 1680, 1630 cm-1

40) Benzyl 7/?-(2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido)-1 -oxadethia-3-cephem-4-carboxylate (syn isomer).

25 I.R. (CH2CI2)

3380, 3290, 1790, 1720, 1680, 1635, 1540 cm"1

41) Benzyl 7/?-(2-benzyloxyirnino-2-(2-formamidothiazol-4-yl)acetamido)-1 -oxadethia-3-cephem-4-carboxylate (syn isomer).

I.R. (CH2CI2)

30 3350, 3270-3120, 1790, 1720, 1680, 1630, 1540 cm-1

42) 7/?-(2-Methoxyimino-2-(4-aminopyrimidin-2-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), crystal.

I.R. (Nujol)

3460, 3350, 3260, 1780, 1630 cm"1 35 43) 7jS-(2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), powder.

I.R. (Nujol)

3400, 3350, 3260, 1780, 1700, 1640 cm"1

44) 7/S-(2-Allyloxyimino-2-(2-formamidothiazol-4-yl)-acetamido)-1-oxadethia-3-cephem-4-40 carboxylic acid (syn isomer).

I.R. (Nujol)

3450, 3330, 3170, 1770, 1690, 1645, 1635, 1620, 1540 cm"1

45) 7/?-(2-(2-Propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxySic acid (syn isomer)

45 I.R. (Nujol)

3250, 1780, 1720, 1680, 1660 cm"1

46) 7/?-(2-Benzyloxyimino-2-(2-formamidothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), crystalline solid.

I.R. (Nujol)

50 3250, 1780, 1670, 1540 cm"1

47) 7/8-(2-Allyloxyimino-2-(2-aminothiazol-4-yS)-acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol)

3300, 1780, 1660, 1540 cm"1 55 48) 7/?-(2-(2-Propynyloxyimino)-2-(2-aminothiazol-4-yl)-acetamido)-1 -oxadethia-3-cephem-4-carboxylic acid hydrochloride (syn isomer) which is gradually decomposed with coloration till 160°C.

49) 7/?-(2-Benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), mp 150 to 170°C (gradually decomposed with coloration). 60 50) Benzyl 7j6-(2-methoxyimino-2-(5,6-dihydro-1,4-oxathiin-2-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylate (anti isomer), mp 142 to 144°C.

51) Benzyl 7a:-methoxy-7/?-(2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido)-1 -oxadethia-3-cephem-4-carboxylate (syn isomer), amorphous solid.

I.R. (CH2CI2)

65 3350,1780,1720,1690 cm'1

5

10

15

20

25

30

35

40

45

50

55

60

65

Claims (1)

19

GB2 089 787A

19

52) Benzyl 7a-methoxy-7/?-(2-(2-formamidothiazol-4-yl)-acetamido)-1 -oxadethia-3-cephem-4-carboxylate.

I.R. (CH2CI2)

3350, 1780, 1720, 1690 cm~1 5 53) 7a-Methoxy-7/}-(2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido)-1 -oxadethia-3-cephem-4-carboxylic acid (syn isomer), amorphous solid.

N.M.R. (acetone-d6, 8)

3.58 (3H, s), 3.97 (3H, s), 4.68 (2H, m), 5.16 (1H, s), 6.40 (1H, t, J = 3Hz), 7.60 (1H, s), 8.70 (1H, s), 8.75 (1H, s). 10 54) 7a-Methoxy-7/?-(2-(2-formamidothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid, amorphous solid.

I.R. (Nujol)

3290, 3150, 1765, 1680 cm"1

55) 7a-Methoxy-7/3-(2-methoxyimino-2-(2-aminothiazol-4-yl) acetamido)-1-oxadethia-3-15 cephem-4-carboxylic acid hydrochloride (syn isomer)

I.R. (Nujol)

1780, 1720, 1680, 1630 cm"1

56) 7a-Methoxy-7/?-(2-(2-aminothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid hydrochloride, powder.

20 I.R. (KBr)

1780, 1700, 1630 cm"1

57) 7/?-(2-ethoxyimino-2-(2-formamidothiazol-4-yl)-acetamido)-1-oxadethia-3-cephem-4-carboxylic acid (syn isomer), crystal, mp 132 to 139°C.

58) 7/?-{2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic 25 acid hydrochloride (syn isomer), crystal, mp 150 to 158°C (dec.).

59) Benzyl 7/?-(2-(2-formamidothiazol-4-yl)acetamido)-1 -oxadethia-3-cephem-4-carboxylate I.R. (Nujol)

3300,3110, 1780, 1725, 1695, 1650, 1540 cm"'

60) 7/J-(2-(2-Formamidothiazol-4-yl)acetamido)-1 -oxadethia-3-cephem-4-carboxylic acid. 30 I.R. (Nujol)

3280, 3100, 1770, 1720, 1695, 1650 cm-1

61) 7/?-(2-(2-Aminothiazol-4-yl)acetamido)-1-oxadethia-3-cephem-4-carboxylic acid.

I.R. (Nujol)

3540, 3480, 3250, 3050, 1770, 1660 cm"1

35

Example 3

Benzyl 2-(2-oxo-3/?-phenyoxyacetamido-4a)-(2-phenoxy-acetoxyethoxy)azetidin-1-yl)-3-methyl-2-butenoate obtained in Example 1(a) (2) was in turn treated as described in Examples 1(a) (3) (i), 1(a) (4) (i), 1(a) (6), 1(a) (7) and 1(b) (1) to 1(b) (3) to give 4-benzyIoxycarbonyl-7/?-40 phenoxyacetamido-1-oxa-5-aza-6/?-bicyclo (4,2,0)-oct-3-ene-8-one, which has the following structural formula:

H H

mp 131 to 134 °C.

I.R. (Nujol)

55 3300, 1780, 1715, 1675 cm'1 N.M.R. (CDCI3,)

4.55 (4H, m), 4.9-5.3 (2H, m), 5.37 (2H, s), 6.43 (1H, t, J = 3Hz), 6.9-7.5 (11H, m) CLAIMS

60 1. A compound of the formula:

5

10

15

20

25

30

35

40

45

50

55

60

20

GB2 089 787A

20

10

wherein R1 is amino or a substituted amino,

R2 is carboxy or a protected carboxy,

R is hydroxymethyl, protected hydroxymethyl or formyl,

R' is hydrogen and R" is hydroxy, halogen or a group of the formula:

15

0

II

-P(OR4)2

20 in which R4 is lower alkyl, or R' and R" are linked together to form a group of the formula: = 0 or = P(R5)3

in which R5 is lower alkyl, aryl or di(lower) alkylamino, and

Y is hydrogen or lower alkoxy,

or a salt thereof.

25 2. The compound of claim 39, wherein R1 is phenoxy(lower)alkanoylamino,

R2 is carboxy or phenyl(lower)alkoxycarbonyl,

R is hydroxymethyl, phenoxy(lower)alkanoyloxymethyl or formyl,

R' is hydrogen and R" is hydroxy or halogen, or 30 R'and R" are linked together to form a group of the formula:

= 0 or = P(R5)3 in which Rs is phenyl, and

Y is hydrogen.

3. A process for preparing a compound of the formula:

35

R1 S ^

40 (1)

/^Y

0 R2

45

wherein R1 is amino or a substituted amino, R2 is carboxy or a protected carboxy, and Y is hydrogen or lower alkoxy,

or a salt thereof, which comprises: 50 1) subjecting a compound of the formula:

55

60

5

10

15

20

25

30

35

40

45

50

55

60

wherein R1, R2 and Y are each as defined above, and R3a is hydrogen and R3b is a group of the formula:

21 GB2089 787A 21

0

II

-P(OR4)2

5 in which

R4 is lower alkyl, or

R3a and R3b are linked together to form a group of the formula:

= P(R5)3 in which R5 is lower alkyl, aryl or di(lower)alkylamino,

or its reactive derivatives at the formyl group or a salt thereof, to cyclization; 10 or

2) subjecting a compound of the formula:

10

15 R

Y

r

20

CH2CH20H <T >R31>

R2

15

20

wherein R1, R2, R3a, R3b and Y are each as defined above, or its reactive derivatives at the hydroxymethyl group or a salt thereof, to oxidation.

Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd.—1982.

Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.