CS226027B2 - Method of preparing new penemcarboxylic acid derivatives - Google Patents

Description

The present invention relates to a process for the preparation of novel penemarboxylic acid derivatives and their salts.

The present invention provides a process for the preparation of the novel penemarboxylic acid derivatives of formula (I)

where β is 0 or 1,

R is hydrogen, C 1 -C 4 alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl, phthalidyl, -CHtCHp-O-COOCgHj, or -CHgNHCOR 'wherein R is C 1 -C 5 alkyl, aryl moiety selected from phenyl and benzyl, or cycloalkyl a (C 3 -C 6) group,

Z represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a carbamoyl226027 oxy group, a mercapto group, a pyridinium group or a radical of the formula OR *, OCOR *, NHCOR * or SR * '; 1-4 carbon atoms, an aryl radical selected from the group consisting of phenyl and benzyl, 5-methyl-1,3,4-thiadiazol-2-yl, 1-methyl-5-tetrazolyl, 1,2,3-triazole -5-yl or pyrazinyl; and

R *** represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 3 -C 6 cycloalkyl group or a C 1 -C 4 hydroxyalkyl group, the alcoholic function of which may be either free or protected with a p-nitrobenzyloxycarbonyl or dimethyl-tert-butylsilyl radical.

The substituent at position 6 may be of the α or β configuration. A configuration is preferred.

The compounds produced have a broad spectrum of antibacterial activity and further have the ability to inhibit beta-lactamase. It should be noted that the stereochemistry at the 5-carbon atom of the compounds obtained by the process of the invention, as well as the stereochemistry of all intermediates formed in the preparation of the compounds of the invention, are the same as those of natural penicillins and cephalosporins.

According to the invention, the compounds of the above formula (I) are prepared by producing a compound of the formula (II)

in which

R is C 1 -C 4 alkyl and

R *** is as defined above, reacted with an acetylene derivative of the general formula

X -CSCY in which

X * is a radical of the formula CH 2 Z *, wherein Z * is a hydrogen or halogen atom, a hydroxyl group, an amino group or a radical of the formula OR *, OCOR * or NHCOR *, wherein R * is as defined above, and

Y represents a hydrogen atom, a C 1 -C 4 alkyl group, a cyano group or a radical of the formula COOR or CH 2 Z *, wherein R and Z * are as defined above, to give a compound of formula III wherein:

R, R *, X * and Y are as defined above and isomerized to a compound of formula IV under basic conditions

(III)

in which

R, r ', X * and Y are as defined above, wherein X, if different from X, is optionally converted by substitution reaction to X, representing CH 2 Z, where Z, as defined above, is converted to compound of formula XI (IV)

COOR 'in which

X, and R '' are as defined above and

Ph represents a phenyl group, namely

(a) ozonolysis of a substituent at the 1-position corresponding to the formula

COOR where

R is as defined above, carried out in solution at reduced temperature,

b) cleavage of the 1-position substituent corresponding to the formula

COOR where

R is as defined above in step (a) by mild alkaline hydrolysis or silica gel treatment,

c) condensing the 1-unsubstituted azetidinone obtained in step b) with a glyoxylate of the formula

CHOCOOR wherein R is as defined above, by refluxing in a solvent,

(d) chlorine of the 1-position substituent corresponding to the formula in which:

H is as defined above in step c) by the action of a chlorinating agent,

e) a conversion substituent at the i-position corresponding to the formula

COOR '' where

R is as defined above in step d) to a substituent of the formula

'3

PPh.

COOR in which

R. is as defined above and Ph represents a phenyl group, by reaction with triphenylphosphine,

f) reduction of the 4-beta-sulfoxide moiety with a reducing agent; and

(g) ozonolysis of a double bond in a grouping where:

X and Y are as defined above, in solution at reduced temperature, wherein the individual reaction steps may be carried out in the order a), b), c), d), e), f), g) or a), f), (b), (c), (d), (e), (g), and reaction step (f), if subsequent to reaction step (e), is carried out under acidic conditions, the compound of formula XI is cyclized by heating in an inert solvent to 50 to 140 ° C to give a compound of formula I wherein n is 0, which is then optionally oxidized to the corresponding compound of formula I wherein q is 1.

Pharmaceutically usable salts of the penemarboxylic acids of formula I, such as sodium, potassium, benzathine or procaine salts and the like, which are typically formed with penicillins and cephalosporins, may also be prepared in accordance with the invention.

The compounds obtained by the process of the invention are used for the manufacture of pharmaceutical compositions comprising a compound of formula I or a salt thereof in admixture with a conventional carrier suitable for oral and parenteral administration.

The following scheme shows the process steps for the preparation of the compounds of formula I according to the invention.

In OH <

Y (vii) Co j (d)

COOR (I; η -1)

If B. ' is hydrogen, compounds of formula II are prepared from (5R) -6-aminopenicillanic acid, i.e. 6-APA, according to the known general procedure of Cignarella et al., Journal of Organic Chemistry, 27, 2668 and Evrarda et al., Nature 201. 1 124.

When R is an alkyl, cycloalkyl or hydroxyalkyl group as defined above, R 'may be introduced as described by Di Ninno et al., Journal of Organic Chemistry 42, 2960 (1977).

When R 'is an alkoxy group as defined above, it can be introduced into the 6-position by the method of Hauser et al., Helv. Chem. Acta 50, 1327 (1967) and Giddings et al., Tetrahedron Letters 11, 995 (1978), using 6-APA as starting material.

In contrast, compounds of formula II wherein r 'is hydrogen can be converted to compounds of formula II wherein b' is alkyl, cycloalkyl or hydroxyl as defined above, wherein the substituent is introduced at the 6-position using a strong base, This is illustrated in the following examples.

Compounds of formula II wherein B is alkyl, cycloalkyl or hydroxyalkyl as defined above may also be prepared from a suitable S-oxide penicillanic acid ester as illustrated in the following examples. The substitution of position 6 is stereospecifically controlled to position 6a.

The penicillanic acid S-oxide ester of formula II (R is C 1 -C 4 alkyl and R 'is as defined above) can be heated in an inert solvent such as benzene or toluene, usually at 70 to 140 ° C, with suitable an acetylene derivative of the general formula

X'C5CY in which

X 'is CH 2 Z *, wherein z' is hydrogen, halogen, hydroxy, amino, carbamoyloxy or OR *, OCOR * or NHCOR * and

Y is hydrogen, C 1 -C 4 alkyl, cyano or COOR or CH 2 Z ', wherein:

R and Z * are as defined above.

If X 'has a meaning other than X, it can be converted by known substitution reactions to a group X, wherein X is represented by the group CH 2 Z, wherein Z is as defined above.

The compound of formula III can be isomerized by treatment with a base to form a compound of formula IV, which can be converted to the final compound of formula I by the following procedure. The compound of formula IV can be selectively ozonized at the double bond of an isopropenyl group to give a compound of formula V (a = ¹ ) »which can be reduced by treatment with a suitable reducing agent such as phosphorus tribromide or sodium iodide in acetyl chloride to the compound of formula V (a = which is then hydrolyzed to a compound of formula VI (a ⁼ zero) under mild basic conditions or by treatment with silica gel. Condensation with a suitable glyoxylic acid ester yields a compound of formula VII (a = zero) which, by treatment with a chlorinating agent such as thionyl chloride and pyridine, can be converted to a chloro compound of formula VIII (a = zero) ).

The compound of formula IX (a = zero) can be selectively ozonized as a phosphonium salt under acidic conditions to give a compound of formula XI which is cyclized at from 50 to 140 ° C to a compound of formula I in a simple manner by heating in an inert solvent such as toluene. in which a is 0.

In the case of compounds of formula IX (a = '), this compound must first be reduced to a compound of formula X and then selectively ozonized to a compound of formula XI which provides a compound of formula I.

Alternatively, the reduction of the sulfoxide moiety can already be carried out for the intermediate of formula (V). Compounds of formula (I) wherein a is 1 are readily prepared from compounds of formula (I) wherein a is 0 by a known oxidation process. Preferably, percyelines can be used as oxidizing agents, with m-chloroperbenzoic acid and peracetic acid being particularly preferred.

When R @ 1 ^{, x} is a hydroxyalkyl group as defined above, the reaction process is preferably carried out while protecting the alcohol function.

Compounds of formula I in which R is hydrogen may be obtained by hydrolysis or hydrogenolysis of the respective esterified compounds.

A number of in vitro experiments were performed to demonstrate the efficacy of (5R) -acetoxymethyl-2-acetoxymethyl-2-penem-3-carboxylate (laboratory designation FCE / 20077 / B40 / 341) to demonstrate superior antibacterial activity of the compounds of the present invention. (5R) -Acetoxymethyl-2 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -2-penem-3-carboxylate (Compound A) and two comparative compounds. The following Table I summarizes the results of the above experiments with respect to the minimum inhibitory concentration (MIC).

Table I

Minimum inhibitory concentration < g / ml

Strain FCE / 20077 / B40 / 341 Compound A Ampicillin Cefoxitin Staphylococcus aureus 209P 0,39 ' 0.39 50.19 0.78 Staphylococcus aureus 1.56 0.78 1.56 0.78 Staphylococcus aureus PV2 0.39 0.78 50.19 0.78 Staphylococcus aureus Smith ATCC 13709 50.19 0.39 50.19 0.78 Streptococcus pyogenes ATCC 12384 3.12 0.78 3.12 1.56 Escherichia coli B. 1.56 0.78 0.39 1, 56 Escherichia coli VI4 1.56 0.78 1.56 3.12 Escherlchia coli V23 3.12 0.78 3.12 12.5 Enterobacter sp. VI9 12.5 »100 > 100 12.5 Klebsiella pneumoniae ATCC 10031 3.12 50 0.78 Klebsiella sp. R2 25 - 50 2.5 Proteus vulgaris V1 5 3.12 6.25 1, 56 0.78 Proteus mirabilis VI5 0.39 0.78 50.19 0.78 Proteus mirabilis 525 3.12 0.78 0.39 1, 56 Shigella flexneri 0.39 0.39 50.19 0.78 Pseudomonas aeruginosa 3.12 0.39 25 6.25 Salmonella typhimurium 1.56 0.78 0.78 3.12 Salmonella panamae F15 1.56 0.78 0.78 1, 56 Salmonella Saint 1.56 0.78 0.78 3.12 Paul F20 Salmonella Derby F14 3.12 0.78 0.78 3.12 Salmonella montevideo F16 3.12 U, 78 0.78 3.12

The following examples serve to illustrate the invention in greater detail without limiting its scope in any way.

In the following examples, the abbreviations in the NMR spectra data have the following meanings:

s = singlet d = doublet dd = double doublet t = triplet m '= multiplet

The signal positions are given in p values

He did

4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S-oxide

COCOCH3 OCOCH3

OCOCH3

0C0CH3

A solution of 2.0 g of methylpenicilate-S-oxide and 2.8 g of butindiol diacetate in 40 ml of toluene was refluxed for 24 hours. The title compound was purified by silica gel column chromatography using a dichloromethane / ethyl acetate (96: 4) mixture as eluent. 1.4 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S-oxide are obtained.

NMR Spectrum (CDCl3):

2.03 (with, ch ₃ -c-) 1, 2.15 and 2.20 (two s, 2 CH ₃ CO), 2.88 (dd, J _gem = 14 Hz, ^J vic cis = 4 Hz, C-3-Ho. 3.38 (dd . ^J gem ^{= 14Hz} > ^J vic ^trans = ^2Hz > C-3-β), 3.83 (with, ch ₃ o), 4.88 (J _yic = 6 Hz, CH ₂ -C široký), 4.92 (broad s, CH ₂ -C =), 4.93 to 1 li (and) 5.33 (m, = CH ₂ a -NC1, 5.32 (dd, J _vic = 4 Hz and 2 Hz, C-4-H),

CH

I coo

6.47 It, J = 6 Hz _VLC = CC (H _2); .

H

Example 2

4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one-S-oxide

COOCH3

OCOCH3 eyes ₃

Dissolve 1.7 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S-oxide in 80 ml of dichloromethane, add 0 0.5 ml of triethylamine and the solution was allowed to stand at room temperature for several hours. Evaporation of the solvent affords the title compound, in pure form and in quantitative yield.

226027 10

NMR spectrum (CDCl3): \

2.13 (9H) and 2.32 (3H) (two s, 2 CHjCO 2 and CH ₃ - <I =), 2.92 (dd, J _gem = 15 Hz, ^J Vio ^OIS = 5 Hz, C- 3-HI), 3.38 (dd, J _gem = 15 Hz, <J _vlc trans = 2.5 Hz, C-3-β),

3.82 (s, CH ₃ O), 4.88 (d, J _vic = 6.5 Hz, CH ₂ -C =), 4.92 (s, CH ₂ -C =), (H)

5.15 (dd, J _yic = 5 and 2.5 Hz, C-4-H), 6.50 (t, J _vic = 6.5 Hz, = C- (H ₂ )).

H

Example 3

4-beta-vinylthio- (1,2-diacetoxymethyl) -1-methoxyoxaloylazetidin-2-one-S-oxide

2.0 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one-S-oxide are dissolved in 150 ml of dichloromethane and, after cooling to A stream of ozone in oxygen is bubbled through the solution at -78 ° C until a faint blue color develops. The solution was allowed to spontaneously warm to room temperature, then shaken with an aqueous solution of Na ₂ S ₂ Oj and dried over sodium sulphate. The organic phases gave 1.4 g of the title compound after evaporation of the solvent in vacuo.

NMR Spectrum (CDCl3):

2.05 and 2.08 (two seconds, 2 CH ₃ CO), 3.03 (dd, J _gem = 17) ^H z. ^J l ₀ cis = 5.5 Hz, C-3-Ησ), 3.50 ^<dd - ^J gem = ¹⁷ Hz, J _yic trans = 3 Hz, C-3-β), , 3.90 (with, ch ₃ o), 4.82 < ^d · ^d knows = ⁶ · 5 Hz, CH ₂ -C =), 4.90 (s, CH ₂ -C =), . 5.32 (dd, ^{1 J} vio 5.5 and 3 Hz, (H) C-4-H), 6.47 (t, J _vio = 6.5 Hz, = 0-0 (¾)).

H

IR (dichloromethane): 1,830 cm ^- ' 0 = 0 (beta-lactam) 1,750 cm ^- ' 0 = 0 (ester) 1,715 cm ^-1 c = o (amide).

Example 4

4-beta-vinylthio- (1,2-diacetoxymethyl) -1-methoxyoxaloylazetidin-2-one

COOCH

OCOCH ₃ eyes ₃

A solution of 1.4 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -1-methoxyoxaloylazetidin-2-one-S-oxide in 10 ml of anhydrous dimethylformamide was cooled to -25 ° C and 0.9 ml of bromide was added thereto. phosphorus. After 10 minutes, the mixture was diluted with ethyl acetate and washed twice with saturated sodium bicarbonate solution. After drying over sodium sulfate and evaporation of the solvent, 0.9 g of the title compound is obtained.

NMR Spectrum (CDCl3):

2.07 (s, 2 CH 3 CO 2), 3.17 (dd, J _gem = 19 Hz, J _vic trans = 3.5) Hz, C- -3-Hp), 3.65 ^J gem = ' ⁹ Hz, J _vic cis = 5 Hz, C-3-Η), 3.90 (s, CH-10), , 4.73 < ^d > ^J vic = = 6.5 Hz, CH ₂ -C =), 4.88 (br s, CH ₂ -C =), 5.52 (dd, J _v . _c = 5 a 3,5 Hz, C-4-H), (H) 6.25 ^(t > ^J vic = ⁶ > ⁵⁾ Hz = CC (H _2)).

H

IR (chloroform):

815 cm ^-1 C = 0 (beta-lactam)

745 cm ^- C = 0 (ester)

710 cm ^-1 C = O (amide).

Example 5

4-beta-vinylthio- (1,2-diacetoxymethyl) azetidin-2-one

Y °

COOCH3

OCOCH3

OCOCH3

OCOCH

OCOCH

1.5 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -1-methoxyoxaloylazetidin-2-one are dissolved in 100 ml of methanol and a few grams of silica gel are added with stirring. After one hour, the silica gel was filtered off and the methanolic solution was evaporated, yielding 0.8 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) azetidin-2-one.

226027 12

NMR Spectrum (CDCl3):

2.25 (s, 2 _CH3 CO), 2.98 (dd, J _gem = 15 Hz, J trans = _YIC 2 Hz, C-3-Hp),

3.48 (dd, J _gem = 15 Hz, J _vic = 4.5 Hz cis C-3 Ηα), 4.78 (d, J = 7 Hz _YIC, CH ₂ -C =), (H)

4.87 (a, CH ₂ -C =), 5.03 (dd, J = 4.5 _YIC and 2 Hz, C-4-H), 6.02 (t, J = 7 Hz _YIC = CC _(H?)), 7.13 (br s, NH).

»O

H

IR (chloroform):

770 cm ^-1 C = O (beta-lactam)

740 cm ^- 'C = O (ester).

Example 6

4-beta-vinylthio- (1,2-ciacetoxymethyl) azetidin-2-one-S-oxide

Dissolve 0,800 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -1-methoxyoxaloylazetidin-2-one-S-oxide in 80 ml of methanol and add a few grams of silica gel while stirring. After one hour the silica gel was filtered off and after evaporation of the solvent 0.5 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) azetidin-2-one-S-oxide was obtained.

NI / IR spectrum (deuterochloroform):

2.13 (s, 2 CH-JCO), 3.0-3.3 (m, 2 protons per C-3), 4.70 (m, C-4-H),

4.88 (C, J, _YIC = 6Hz, CH ₂ -C =), 4.93 (s, _CH2 -C =), 6.53 (t, J = 6Hz _YIC = CC (H ₂₎ ), (Η) H

7.23 (s, NH).

spectrum (chloroform):

790 cm ^- 'C = O (beta-lactam)

745 cm ^- 'C = 0 (ester).

226027 '

Example 7

4beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one ococh ₃ ococh ₃ rOCOCH. ^Ococh 3 cooch ₂ ococh ₃

0.7 g of acetoxymethylglyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate) was dissolved in 30 ml of benzene and the solution was refluxed for 20 minutes using a Dean-Stark water trap.

After cooling to 50-60 ° C, 0.7 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) azetidin-2-one dissolved in 10 ml of benzene is added and the solution is heated under reflux for 2 hours. The title compound results in an almost quantitative yield and can be used as a crude mixture for the next reaction step. For analytical purposes, a pure sample is obtained by preparative thin layer chromatography.

NMR Spectrum (CDCl3):

2.07 (with. 3 ch ₃ co), 2.97 (aa, j _gem = 18 Hz, J _{in c} trans = 2 Hz, C- 3-Ηβ), 3.40 (aa, - ^J gem = ^{18 Hz, J} vic ^cis = ^{4 Hz} < , c-3-η »), 4.70 (a, J _vic = 6 Hz, CH-C =) (H) 4.77 (with, CH ₂ -C)), -5.0 to 5.4 (m, C-4-H) and -N-CH-COO-), 5.77 (s, -COO-CH ₂ -OCO-) 0 (H) 6.12 (t, ^J vic * ^6Hz >

and

H

Example 8

4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) azetidin-2-one

O

ococh ₃ ococh ₃ ococh ₃

-OCOCH3 Cooch ₂ Ococh ₃ Cooch ₂ Ococh ₃

A solution of 0.6 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one in 15 ml of tetrahydrofuran is cooled to 0 ° C, 0.115 grams of pyridine are added and 0.104 ml of thionyl chloride and the mixture was stirred for 10 minutes. The insoluble material was filtered off and the solution was evaporated in vacuo at room temperature to give the title compound in high yield. For analytical purposes, the sample is purified by preparative thin layer chromatography, but the crude mixture can be used for the next reaction step without purification.

226027 14

NUR spectrum (deutero-chloroform):

2.14 (s, 3 CH ₃ CO), 3.10 (dd, J _gem = 15.5 Hz, J _vic trans = 2 Hz, C-3-Hp),

3.55 (dd, J _gene = 15.5 Hz, J _vic cis = 5 Hz, C-3-H 2), 4.77 (d, J _vic = 6.5 Hz, CH ₂ C =), ( H)

4.83 (s, _CH2 -C =), 5.4 to 5.9 (m, C-4-H and -N-CHC1-), 5.68 (s, -COO-CH-OCO-) ,

6.13 (t, J _vic = 6.5 Hz, = CC (H _2)).

H

Example 9

4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxycarbonyl) -1-triphenylphosphoranylidenemethyl) azetidin-2-one

Xococh ₃ ^Ococh 3 Cooch ₂ Ococh ₃

If Y ^X ₀ OCOCH _3> - Y _P ^N <^ ₂ ^OCOCH 3 OCOCH ₃ Cooch fioztok 0.430 g 4beta-vinylthio- (1,2-čiacetoxymetyl) -1- (1-acetoxymetyloxykarbonyl 1-chloromethyl) azetidin-2-one in 5 ml of tetrahydrofuran and 5 ml of dioxane containing 0.520 g of triphenylphosphine and 0.08 ml of pyridine was stirred overnight at 50 ° C. The obtained phosphorane was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (70:30). 0.400 g of the title compound is obtained.

NMR Spectrum (CDCl3):

2.05 (s, 3 CH ₃ CO), 4.70 (d, J _yic = 6.5 Hz, CH ₂ -C =), 4.73 (s, CH ₂ -C =), (H)

5.77 (s, (-CH ₂ -C00 -0C0-), 5.90 (t, J _vic = 6.5 Hz, = CC (H _2)), 7.1 to 8, (m, 3 CgHj)

H

He did

4beta-Acetylglycolylthio-1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one

PPh,

OCOCH ₃

OCOCH, cooch ₂ eyes ₃

cooch ₃ ococh ₃

0.7 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-aetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one is dissolved in 40 ml of dichloromethane and after cooling to -20 ° C 50 ml is added. 10% trifluoroacetic acid in dichloromethane. After a few minutes the reaction solution at temperature -20 ° F · begins to indicate a stream of ozone in oxygen and the placing is continued _picking: when there is a weakly coloring blueing. At this point, the reaction was stopped and a few drops of trimethyl phosphite were added. The organic solution was washed with saturated sodium bicarbonate solution and dried over sodium sulfate to give 0.550 g of the title compound.

NMR Spectrum (CDCl3):

2.10 and 2.15 (two d, 2 CH2O), 4.72 (s, -CO-CH2-OCO-), 5.64 (s, -COO-CH2-OCO),

7.1 to 8.0 (m, 3 CgH4),

Example 11 (5R) -Acetoxymethyl-2-acetoxymethyl-2-penem-3-carboxylate

cooch ₃ ococh ₃ ococh ₃

COOCH ₂ OCOCH ₃

0.7 g of 4-beta-acetylglycolylthio-1- (1-acetomethyloxycarbborboryl-1-triphenylphosphoranylidenemethyl) azetidin-2-one is dissolved in 30 ml of absolute toluene and the solution is heated under reflux for 2 hours. The reaction mixture, consisting of the title compound and triphenylphosphine oxide, was purified by column chromatography over a short column of silica gel, eluting with dichloromethane / ethyl acetate (97: 3). 0.250 g of acetoxymethyl-2-acetoxymethyl-2-penem-3-carboxylate is obtained.

NMR Spectrum (CDCl3):

2.11 and 2.13 (two s, 2 CH 2 CO), 3.49 (dd, J _gem = 16.5 Hz, J _{v q} trans = 2 Hz, C-6-β),

3.86 (dd, J _gem = 16.5 Hz ', J _vic cis = 3.8 Hz, C-6-6α), 5.12 and 5.45 (two d, J _geffl = = 15.5 Hz , = _C-CH2), 5.68 (dd, J = 3.8 _YIC and 2 Hz, C-5 H), 5.87 (s, -COO-CH-OCO-).

IR (chloroform):

800 cm ^-1 C = O (beta-lactam) .1,750-1,725 cm ^-1 C = 0 (ester).

UV spectrum (ethanol): λ325 nm.

Q1SX

Mass spectrum: m / e 315.04108 (1H ⁺ ); For Ο ^ Η ^ ΜΟγδ calculated 315.04127.

Example 12

4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-p-nitrobenzyloxycarbonyl-1-hydroxymethyl) azetidin-2-one

OAc

OAc

The title compound was obtained as described in Example 7, starting with p-nitrobenzyl glyoxylate, which was freshly prepared by ozonolysis of p-nitrobenzyl fumarate.

NMR Spectrum (CDCl3):

2.1 (s, 6H), 2.8-3.7 (m, 2H), 4.7-4.9 (m, 5H), 5.1-5.6 (m, 2H), 5.2 ( m, 1 Η)

6.1 (m, 1H); 7.5-8.3 (m, 4H).

Example 13

4-beta-vinylthio- (1,2-diacetoxymethyl) - (1-p-nitrobenzyloxycarbonyl-1-chloromethyl) azetin-2-one

The title compound was prepared as described in Example 8.

NtlR spectrum (deuterochloroform):

2.1 (s, 6H), 2.8-3.7 (m, 2H), 4.7-4.9 (m, 4H), 5.2-5.4 (m, 1H),

5.4 (m, 2H), 6.1-6.3 (m, 2H), 7.5-8.4 (m, 4H).

Example 14

4-beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one

no ₂

The title compound was prepared as described in Example 9

Example 15 ♦ beta-Ethylglycolylthio-1- (1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one

The title compound was prepared as described in Example 10.

Example, 6 (5R) -p-Nitrobenzyl-2-acetoxymethyl-2-penem-3-carboxylate

The title compound was prepared as described in Example 11.

NMR Spectrum (CDCl3):

3.75 (1H, dd, J = 2.3Hz, 16.8Hz, H-6a), 3.87 (1H, dd, J = 3.6Hz, 16.8Hz, H-6p),

5.14 (1H, d, J = 15.8 Hz, = C-H ₂ O-), 5.05 (1H, d, J = 15.8 Hz, = C-CH ₂ O),

5.71 (1H, dd, J = 2.3Hz, 3.6Hz, H-5).

1 "] d ⁺⁸ ° ° ¹ · ^{2 in} chloroform), spectrum (chloroform):

800 (beta-lactam), 1750 and 1720 cm ^-1 .

UV spectrum (ethanol):

265 (t 11,000) and 322 (c 7,000) nm.

Mass spectrum: m / e 378 (M ^& lt ^{; +} & gt ^; ).

Melting point: 122-123 ° C.

226027 18

Example 17 (5R) -2-Acetoxymethyl-2-penem-3-carboxylic acid

OAc cooch ₂

oyno ₂

OAc

COOH

200 mg of (5R) -p-nitrobenzyl-2-acetoxymethyl-2-penem-3-carboxylate, prepared as described in the preceding example, was dissolved in 12 ml of ethyl acetate. 0.211 sodium bicarbonate solution and 400 mg of 10% palladium on carbon are then added, and the resulting biphasic mixture is shaken under a hydrogen atmosphere for 60 minutes. After filtering off the catalyst, the aqueous phase is acidified with 20 ml of 5% aqueous citric acid and extracted three times with methylene chloride. The organic layers were dried over sodium sulfate and evaporated to give 60 mg of the title compound.

IR (chloroform):

790 (beta-lactam), 1735 and 1700 cm ^-1 .

UV spectrum (ethanol): 300 nm.

Example 18 (5R) -2- (1-Methyl-1H-tetrazol-5-yl) thiomethyl-2-penem-3-carboxylic acid

The title compound is obtained as described in the preceding Example. (5R) -p-Nitrobenzoyl-2- (1-methyl-1H-tetrazol-5-yl) thiomethyl-2-penem-3-carboxylate was obtained in a similar manner as described in the above examples.

spectrum (chloroform):

800 (beta-lactam), 1750 and 1720 cm ^-1 .

Example 19

Methyl-6alpha- (1'-hydroxyethyl) penicilane-S-oxide

O

OH

H * COOCH

A solution of 2.3 g of methylpenicilate S-oxide in 50 ml of anhydrous tetrahydrofuran was cooled to -78 ° C, lithium diisopropylamide (freshly prepared from 5 ml of diisopropylamine and ml of a 1.6M solution of butyllithium in hexane) dissolved in anhydrous tetrahydrofuran was added, and the mixture was allowed to stand for 10 minutes at -78 ° C. 5 ml of acetaldehyde are then added in portions, the reaction mixture is stirred for 15 minutes, then treated with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the ethyl acetate extract is washed twice with water and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on a short column of silica gel using a 1: 1 mixture of dichloromethane and ethyl acetate as eluent. The yield is 1.5 g. The title compound consists of a mixture of (2: 3) epimers on a hydroxyl-bearing carbon atom (according to NMR spectrum), with the new carbon-to-carbon bond being carried out under the stereospecificity of the reaction. conditions only in alpha-position.

NMR Spectrum (CDCl3):

1.27 (s, α-CH ₃ ), 1.40 (d, 3H, J = 5.7 Hz, ε g ₃ -CHOH) major isomer, 1.48 (d, 3H,

J = 5.7 Hz, CH 2 -CHOH) minor isomer, 1.70 (s, 3H, p-CH 3), 3.4 to

3.8 (m, 1H, H-6), 3.80 (s, 3H, COOCH3), 4.1-4.7 (m, 1H, [ _beta ] HOH), 4.50 (s, 1H, H) -3), 4.98 (d, J = 1.9 Hz, 1H, H-5) minor isomer, 5.05 (d, J = 1.9 Hz,

1H, H-5) major isomer.

Example 20

Methyl 6- (1-hydroxyethyl) -3-penicillanate

To a solution of 2.2 g of methylpenicilate in 30 ml of anhydrous tetrahydrofuran was added under a nitrogen atmosphere in a slight excess of lithium diisopropylamide at -78 ° C, then excess acetaldehyde was added dropwise and the mixture was stirred for 5 minutes. The mixture was poured into water and extracted with methylene chloride. The organic layers were dried over sodium sulfate and evaporated in vacuo. 0.8 g of the title compound is obtained.

Example 21

Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate

1.2 g of methyl 6- (1-hydroxyethyl) -3-penicillanate was dissolved in 40 ml of tetrahydrofuran, cooled to -78 ° C and treated with 1 equivalent of butyllithium. Then, 1.2 equivalents of p-nitrobenzyloxycarbonyl chloride was added to the reaction mixture obtained. After standing at -78 ° C for 30 minutes, the reaction mixture was allowed to stand at room temperature for 60 minutes, then poured into water and extracted with methylene chloride. After drying over sodium sulfate and evaporation, 1.4 g of the title compound is obtained.

Example 22

Methyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate-S-oxide

1.8 g of methyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate are dissolved in 50 ml of methylene chloride and 1.5 equivalents of m-chloroperbenzoic acid are added at 0 ° C. The organic phase is shaken with saturated sodium bicarbonate solution, extracted, dried over sodium sulphate and evaporated. 1.4 g of the desired sulfoxide are obtained.

The product has the following physicochemical constants.

Ervthro-configuration:

NMR Spectrum (CDCl3):

1.20 (s, 3H, and _revere-3), 1.55 (d, J = 6.5 Hz, 3H, CH-JCH), 1.70 (s, 3Η, β-CH-j)

3.82 (s, 3H, COOCH ₃ ), 3.88 (dd, J = 2.0, 4.0 Hz, 1H, J-6), 4.50 (s, 1H, S-3), 4 85 (d, J = 2.0 Hz, 1 H, H-5), 5.19 (m, 1 H, CHO), 5.31 (s, 2H, CH 2 Ph),

7.4 to 8.4 (a, 4H, Q1 O3);

. Threo-configuration:

NMR Spectrum (CDCl3):

1.23 (s, 3H, α-β 2 ₃ ), 1.51 (d, J = 6.5 Hz, 3H, C ^CH), 1.70 (s, 3Η, β- £ β ₃ ),

3.77 (dd, J = 2.0, 7.0 Hz, 1H, H-6), 3.81 (s, 3H, S £ ₃ COO), 4.51 (s, 1H, β-3) ,

4.96 (d, J = 2.0 Hz, 1H, H-5), 5.28 (m, 1H, .delta.), 5.32 (s, 2H, 1H, Ph), 7.4-7.

8.4 (m, 4H, ₂ PfcNO).

Example 23

4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxy-

OCOCH ₃

OCOCH3

A solution of 2.0 g of methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate-S-oxide and 2.4 g of butindiol diacetate in 50 ml of toluene was heated under reflux for 24 hours. The reaction product was purified by column chromatography using a 9: 1 mixture of dichloromethane and ethyl acetate as eluent. This gave 1.1 g of the title compound.

The product has the following physicochemical constants.

Ervthro-Conflguration:

NUR spectrum (deuterochloroform):

1.46 <d, J = 6.0 Hz, 3H, £ & jCH) , CHg, 2.06 (s, 9H, ococh ₃ , ococh ₃ , —IL 11 3.72 (with, 3H, Cooch ₃ ), 3 73 m 1H, 2-6), 4.80 (d, J = 6.0 Hz, 2 H, Η \ 2B ₂ ), 4.87 (with, 2H, ch ₂ qcoch ₃ ) 5.00 (s, 2H, = _CH2); 5.26 (s, 2H, C0C £ ₂ Ph) 4 , 9 to 5.2

(m, 3H, SiOH, H-5, C 8 COOCH 4), 6.42 (t, J = 6.0 Hz, 1H, = /), 7.4 to 6.4 (m, 4H,

- £ H-NC ₂₎ and L6 Spectrum (chloroform):

750 cm ^- 'C = 0 (esters)

780 cm "’ C = O (beta-lactam).

Ihreo-Conflguration:

CH,

NUR spectrum (deuterochloroform):

1.40 (d, J = 6.0 Hz, 3H, CH-jCH), 1.97, 2.05, 2.10 (β, 9H, OCO ₃ S _3> OCO ₃ g ₃ ,. Δ 64 (m, 1H, fl-6), 3.75 (β, 3H, COOCH ₃ ), 4.75 (d, J = 7.0-Hz, 2H, β-flOOCO),

4.8 to 5.2 (m, 3H, £ -5, CHO, _CH-COOCH3), 6.43 (t, J «7.0 Hz, 1H, H),

7.4 to 8.4 (m, 4H, P &NOg);

ifi spectrum (chloroform):

». Á SHJ

745 cm "’,> C = O (esters)

760 em ^{-1 J}

785 cm ^-1 C = O (beta-lactam)

Example 24

4beta-vinylthlo- (1,2-diacetoxymethyl) -3 - ('- p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one-S-oxide oco ₂ pnb

OCOCHj

OCOCHj

COOCHj

OCO.PNB 9

OCOCH

OCOCH

COOCHj

1.3 g of 4-beta-vinylthio- (1,2-diaethoxymethyl) -3- (1-p-nitrobenzyloxymethyl ^, bonyloxyethyl) -1- (methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S-oxide Dissolve in 80 ml of dichloromethane, add 0.3 ml of triethylamine and leave the mixture to stand at room temperature for 2 hours. Evaporation of the solvent afforded the pure title compound in quantitative yield.

The product has the following physicochemical constants:

NMR Spectrum (CDCl3):

CHoch ₃ , OCOCH ₃ ),

1.50 (d, J = 6.5 Hz, 3H, (JH 3 CH)), 2.05, 2.07 (s, 9H, 2.27 (s, 3H, J = Z), 3.73 (β, 3H, COO (H ₃ ), 3.80 (m, 1H, H-6), 4.78 (d, J = 6.0 Hz, H), 4, t

2H, 83 (s, 2H, _CH2 OCU), 4.9 to 5.3 (m, 2H, H-5, OH), 5.25 (s, 2H,

CjlgPh), 6.42 (t, J = 6.0 Hz, 1H, H), 7.4 to 8.4 (m, 4H, P & - NO ₂₎ j

XC spectrum (chloroform):

710 cm ”C = O (unsaturated ester)

755 cm '' C = O (esters)

775 cm @ -1 C = O (beta-lactam).

^T hrc9-K <? Nflfflrag9 =

NMR Spectrum (CDCl3):

_x ch ₃ ), 2.28 (s, 3H,

1.45 (d, J = 6.0 Hz, 3H, CH ₃ FIB), 2.10 (s, 9H, 0C0CH ₃ / ^ 3

- = /), 3.70 (dd, J = 2.0, 6.0 Hz, 1H, g-6), 3.77 (s, 3H, COOCH3),

4.82 (d, J = 7.0 Hz, 2H, CH ₂ OCO), 4.82 (s, 2H, CH ₂ OCO), 5.10 (d, J = 2.0 Hz, 1H, ϋ-5 5.0 to 5.3 (m, 1H, CHO), 5.23 (s, 2H, .beta.H ₂ Ph), 6.52 (t, J = 7.0 Hz, 1H,

H, 7.4-8.4 (m, 4H, PfcNOp;

IR (chloroform):

710 cm ”C = O (unsaturated ester)

755 cm ”C = 0 (esters)

780 cm -1 C-O (beta-lactam).

Example 25

4-beta-Wentylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloylaseidin-2-one-S-oxide

OCO.PNB 9

COOCH3

OCOCH3

OCOCH3

/ »

A solution of 1.1 g of 4beta-vinylthio- (1,2-diacetoxymethyl) -3- (p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one-S-oxide in Cool 100 ml of dichloromethane to -78 ° C and allow ozone to pass through oxygen until a blue color develops. The resulting solution was shaken with an aqueous solution of Na ₂ SO ₂ ^and dried over sodium sulfate. Evaporation gave 0.5 g of the title compound.

Example 26

4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloylazetidin-2-one

OCOlPNB

-'Η-7 ^x > f ^x 0C0CH _{3 0 <} Λ — N o ^ OCOCH ₃ cooch ₃

A solution of 0.8 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloylazetidin-2-one in 15 ml of anhydrous dimethylformaraid was cooled to -20 ° C and added to with 0.6 ml of phosphorus tribromide. After 10 minutes, the reaction solution was diluted with ethyl acetate and washed twice with sodium bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated to give 0.4 g of the reduced compound.

Example 27

4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) azetidin-2-one

1.2 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxyoxaloyl-azetidin-2-one are dissolved in methanol and 2 g of silica gel are added after 60 minutes. the insoluble matter is filtered off and the organic phase is evaporated. Silica gel short column chromatography gave 0.4 g of the title compound.

Example 28

4-beta-vinylthio- (1,2-diaethoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one

COOCH ₂ OCOCH ₃

0.6 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) azetidin-2-one, which is dissolved in 30 ml of benzene and 0.6 g of acetoxymethylglyoxalate (freshly prepared by ozonolysis of diacetoxymethyl fumarate) is heated to reflux. The reaction is complete after 2 hours. The condensation product can be used without further purification for the next reaction step.

Example 29

4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) azetidin-2-one

OCOCH ₃

OCOCH3

OCOCH3

OCOCH3

COOCH ₂ OCOCH ₃

COOCH ₂ OCOCH ₃

0.5 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxyaethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one is dissolved in 12 ml of anhydrous tetrahydrofuran and the solution was cooled to 0 ° C. To the reaction solution was added 1.1 equivalents of pyridine and 1.1 equivalents of thionyl chloride, stirred for 10 minutes, then the insoluble portion was filtered off and the solution was evaporated at room temperature to give the title compound in almost quantitative yield. The product obtained can be used for the next reaction step without further purification.

Example 30

4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one oco ₂ pnb

-N Cl

- y

OCOCH3

OCOCH3

COOCH ₂ OCOCH _{3 PPh} JT ^OCOCH 3 N @ ^KF 7 </ OCOCH ₃ OCOCH ₂ COOCH ₃

A solution of 0.760 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one in 10 ml of tetrahydrofuran and 10 ml of dioxane is treated with with two equivalents of triphenylphosphine and 1.1 equivalents of pyridine are stirred overnight at 50 ° C. The phosphorane was purified by column chromatography on silica gel using dichloromethane / ethyl acetate (70:30) as eluent. 0.480 g of the title compound is obtained.

Example 31

4beta-Ethylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one

OCO-.PNB

\ Eye ₃ hK / OCOCH ₃

COOCH ₂ OCOCH ₃

OCOjPNB <* ^S 'y ^ OCOCHj γΡΡΚ ₃ cooch ₂ eyes ₃

0.45 g of 4-beta-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one is dissolved in 50 ml of dichloromethane and the solution is cooled. at -20 ° C. To the solution was added 30 ml of a solution of trifluoroacetic acid in dichloromethane and after a few minutes ozone was bubbled through the reaction solution until oxygen became slightly blue. The reaction was stopped and a few drops of trimethyl phosphite were added. The organic phases are washed with saturated sodium bicarbonate solution and dried over sodium sulfate. 0.260 g of the title compound is obtained.

Example 32 (5R) -Acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate

ococh ₃

COOCH ₂ OCOCH ₃ OCOCH ₃ Cooch ₂

0.210 g of 4-beta-acetylglycolthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one is dissolved in 7 ml of toluene and the solution is heated under reflux for 2 hours. . Chromatographic purification on a short column of silica gel using dichloromethane / ethyl acetate (95: 5) as eluent gave 0.050 g of the title compound.

Example 33 (5R) -Acetoxymethyl-6- (1-hydroxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate

OCO.PNB

₃ OCOCH ₃ OCOCH ₂ Cooch

OH

OCOCH cooch ₂ ococh ₃

0.060 g of 5R-aetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate is poured into a mixture of water, ethanol and potassium monohydrogen phosphate and hydrogenolysis is carried out in the presence of 10% palladium on carbon. Flash purification by silica gel column chromatography affords 0.015 g of the title compound.

Example 34

(a) 6alpha-Methoxy-penicillanic acid methyl ester

800 mg of 6alpha-methoxypenicillanic acid methyl ester (prepared as described by Giddings et al. In Tetrahedron Letters, 11, 995 (1978)) is dissolved in 20 ml of dichloromethane and 570 mg of m-chloroperbenzoic acid is added portionwise at room temperature. The organic phases are washed with saturated sodium bicarbonate solution and evaporated. The title compound crystallized from ethyl ether in a yield of 150 mg.

b) 3.alpha.-methoxy-4beta-vinylthio- (1,2-diacetoxymetyl) -1- (methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S-oxide, CH ₃ for

COOCH-.

CH ₃ O,

In - / - Y - OCOCH ₃ - / OCOCH ₃ - cooch ₃

550 mg of 6α-methoxypenicillanic acid S-oxide ester are dissolved in 25 ml of toluene, 1.2 g of butindiol diacetate are added and the resulting solution is refluxed for 10 hours. The reaction mixture was purified by silica gel column chromatography using 10% ethyl acetate in dichloromethane as eluent. 450 mg of the title compound are obtained.

c) 3α-Methoxy-4beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one-S-oxide

400 mg of 3alpha-methoxy-4beta-vinylthio- (1,2-diacetoxymethyl) -1- (methoxycarbonyl-2-methyl-2-propenyl) azetidin-2-one-S-oxide are dissolved in 10 ml of dichloromethane and the solution is taken together with a few drops of triethylamine was stirred at room temperature for 2 hours. Evaporation of the solvent gave the pure title compound.

226027 28

d) 3alpha-methoxy-4beta-vinylthio- (1,2-diacetoxymethyl) -1-methoxyoxaloylazetidin-2-one-S-oxide

g Dissolve 3alpha-methoxy-4beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) azetidin-2-one-S-oxide in 200 ml of dichloromethane, solution The mixture was cooled to -70 ° C and ozone in oxygen was introduced until blue. After addition of a few drops of trimethylphosphite, the solvent was evaporated to give the pure title compound.

(e) 3α-Methoxy-4beta-vinylthio- (1,2-diacetoxymethyl) -1-methoxyoxaloylazetidin-2-one

800 mg of 3alpha-methoxy-4beta-vinylthio- (1,2-diacetoxymethyl) -t-methoxyoxaloylazetidin-2-one-S-oxide are dissolved in 30 ml of anhydrous dimethylformamide, cooled to -20 ° C and added to the solution. 0.5 ml of phosphorus tribromide and stirred for 10 minutes. The reaction mixture is poured into ethyl acetate, washed several times with water, the organic phase 3e is dried over sodium sulphate and evaporated. The residue consists essentially of the title compound only and is used in the next step without further purification.

(f) 3α-Methoxy-4-beta-vinylthio- (1,2-di-acetoxymethyl) azetidin-2-one

COOCH,

OCOCH ₃

OCOCH3

The crude residue obtained in the previous paragraph was dissolved in 100 ml of methanol and 3 g of silica gel were added with stirring. The mixture was stirred for 2 hours, then the silica gel was filtered off and the residue was purified by silica gel column chromatography using 20% ethyl acetate in dichloromethane as eluent. 400 mg of the title compound are obtained.

NMR spectrum (CDCl3):

2.08-2.11 (two singlets, 6H, OCO 3 H 3), 3.55 (s, 3H, OCH 3), 4.68 (d, J = 6.5 Hz,

2H, H 'CH _2), 4.81 (br s, 3H, S _X ^ _/ ß £ ₂ \ ^{»H" 4) »4» 86 (d' J} ~ ^{2> Hz} °>

1H, 2-3), 6.04 (t, J = 6.5 Hz, 1H, H- (S)), 6.50 (broad ainglet, 1H, NSJ).

(g) 3α-Methoxy-4beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-aethoxymethyloxycarbonyl-1-hydroxymethyl) azetidin-2-one

CH, O _{Z. Λ}

OCOCH ₃ _. Λ-f- Y Y O OCOCH ₃

OCOCH3 * - ⁿ x ^ oh'L ^ ococh ₃ cooch ₂ ococh ₃

250 mg of 3alpha-methoxy-4beta-vinylthio- (1,2-diacetoxymethyl) azetidin-2-one are dissolved in 20 ml of benzene and the solution is refluxed for 3 hours with 300 mg of acetoxymethylglyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate). . The crude reaction mixture was purified by silica gel column chromatography using 40% ethyl acetate in dichloromethane as eluent. 150 mg of pure title compound are obtained as a mixture of diastereoisomers.

h) 3.alpha.-methoxy-4beta-vinylthio- (1,2-diacetoxymetyl) -1- (1-acetoxymetyloxykarbonyl 1-chloromethyl) azetidin-2-one 3% ^CM j__jX ^S \ / \% ^CH3 OCOCH 3, - * ^S ^ \ ^X J \ 0C0CH3 _0> - ^N - ^ ° ^H L / OCOCH ₃ * _o ^ -n ^ cL / ₂ COOCH ₃ OCOCH ₃ OCOCH ₃ OCOCH ₂ Cooch

150 mg methoxy-3.alpha.-4beta-vinylthio- _(1> 2-diacetoxymetyl) -1- (1-acetoxymetyloxykarbonyl -1-hydroxymethyl) azetidin-2-one was dissolved in Γ0 ml of anhydrous tetrahydrofuran, cooled to -20 ° C stoichiometric amounts of pyridine and thionyl chloride were added thereto, and the mixture was stirred for 10 minutes. The reaction mixture was freed from insoluble materials by filtration through Celite, and the filtrate was evaporated at room temperature to give a residue which was used in the next step without further purification.

(i) 3α-Methoxy-4-beta-vinylthio- (1,2-di-acetoxymethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azidin-2-one ^CH3 °% Ο € ΟΟΗ _{3 0} > - ^N -yClL / ° COCH ₃

COOCH ₂ OCOCH ₃ ^CH 3

Ph rPh,

OCOCH

OCOCH cooch ₂ eyes ₃

The crude residue obtained in the previous example, consisting of almost pure 3α-methoxy-4beta-vinylthio- (1,2-diacetoxymethyl) -1-O-acetoxymethyloxycarbonyl-1-chloromethyl) azetidin-2-one, is dissolved in 10 ml of toluene, added. with 200 mg of triphenylphosphine and the resulting solution was refluxed under nitrogen for 2 hours. Purification of the phosphate by chromatography over a short silica gel column eluting with 40% ethyl acetate in dichloromethane gave 180 mg of the title compound.

1) 3alpha-Methoxy-4beta-acetylglycolylthio-1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one ^CH 3%

OCOCH3 with XOCOCH3 ^PPh3

ČOOCH ₂ OCOCH _{30 0c0CH3}

O

COOCH ₂ OCOCH ₃

230 mg of 3alpha-methoxy-4beta-vinylthio- (1,2-diacetoxymethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one are dissolved in 50 ml of di-chloromethane and the solution is cooled to -20 ° C. 0.5 ml of trifluoroacetic acid is added. Ozone in oxygen was then added to the resulting solution until blue, followed by a few drops of trimethylphosphite, the reaction mixture was diluted with dichloromethane and washed several times with saturated sodium bicarbonate solution. Drying over sodium sulfate and evaporation of the solvent gave 180 mg of a pure title compound.

m) (5 R) -acetoxymethyl-6a-methoxy-2-acetoxymethyl-2-penem-3-carboxylate _of the _CH3.

^S ^ ^z ^ 'OCOCH ₃ ' η = ρ _Γ ' ₃ cooch ₂ eyes ₃ ch ₃ o,

OCOCH cooch ₂ ococh ₃

180 mg of 3alpha-methoxy-4beta-acetylglycolylthio-1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one are dissolved in 20 ml of toluene and the solution is heated under reflux for 2 hours under nitrogen. The title compound was purified by silica gel column chromatography using 5% ethyl acetate in dichloromethane as eluent. 50 mg of the expected product are obtained.

NMR spectrum (deuterochloroform, δ values):

2.11 (s, 6H, OCOCH ₃₎

3.56 (s, 3H, OCH-1), 4.94 (d, J = .7 Hz, 1H, H-4),

5.26 (double doublet center, 2H,

5.55 (d, J = 1.7 Hz, 1H, H-3),

5.86 (s, 2H, COO CH ₂ OCOCH ₃₎ j

IR (chloroform):

795 cm ^-1 (beta-lactam), 1,745 to 1,720 cm ^-1 (esters).

EXAMPLE 35 (5R) -acetonyl-6a-methoxy-2-acetoxymethyl-2-penem-3-carboxylates by CH _3,

^ OCOCHj

COOCH ₂ COCH ₃

The title compound is obtained in an analogous manner to Example 34g), h), i), 1) and m) except that acetonylglyoxylate is used in place of the acetoxymethylglyoxylate used in Example 34g).

IR (chloroform):

800, 1745, 1710 cm ^-1 .

Example 36 (5R) -6α-Methoxy-2-acetoxymethyl-2-penem-3-carboxylic acid

OCOCH cooch ₂ coch ₃ ch ₃ o,

OCOCH,

COOH

260 mg of (5R) -acetonyl-6α-methoxy-2-acetoxymethyl-2-penem-3-carboxylate are dissolved in 25 ml of tetrahydrofuran, the solution is diluted with 5 ml of water, cooled to 0 ° C and treated with 7, 9 ml of a 0.1K aqueous sodium hydroxide solution and the mixture was allowed to stand at 0 ° C for 10 minutes. The reaction solution was washed twice with methylene chloride, the aqueous phase was overlaid with methylene chloride, and 4 ml of a 20% aqueous citric acid solution was added thereto with stirring. The aqueous phase was extracted twice with methylene chloride, the combined organic phases were dried over sodium sulfate and evaporated to give 80 mg of the title compound.

IR (chloroform):

795, 1740, 1700 cm ^-1 .

Claims (3)

SUBJECT OF THE INVENTION 1. A process for the preparation of the novel penemarboxylic acid derivatives of the general formula I (O): R ' CH ₂ Z COOR (I) in which a is 0 or 1, R '' is hydrogen, C 1 -C 4 alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzhydryl , acetoxymethyl, pivaloyloxymethyl, phthalidyl, SKU pin -CHlCHjJ formula -O-COOCgHj or a group of formula ^,, -CH2NHCOR ^', *, where R * lower alkylene alkyl group having 1 to 5 carbon atoms, an aryl radical selected from the group including phenyl and benzyl, or C 3 -C 6 cycloalkyl, Z represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a carbamoyloxy group, a mercapto group, a pyridinium group or a radical of the formula OR ', OCOR', NHCOH or SR **, wherein each of R * and R represents a (C1-C4) alkyl group, an aryl radical selected from the group consisting of phenyl and benzyl, 5-methyl-1,3,4-thiadiazol-2-yl a 1-methyl-5-tetrazolyl group, a 1,2,3-triazol-5-yl group or a pyrzinyl group; and R 'represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 3 -C 6 cycloalkyl group or a C 1 -C 4 hydroxyalkyl group whose alcohol function may be <5 free or protected by a p-nitrobenzyloxycarbonyl or dimethyl-tert-butylsilyl radical, characterized in that the peat is of the general formula II R <' O, s .. (II) OH ^Z coon in which R is C 1 -C 4 alkyl and R is as defined above, reacted with an acetylenic derivative of the general formula X'-CSCY in which X 'represents a radical of the formula CH 2 Z', wherein Z 'represents a hydrogen or halogen atom, a hydroxyl group, an amino group or a radical of the formula OR *, OCOR * or NHCOR', wherein R * is as defined above and Y represents a hydrogen atom, a C 1 -C 4 alkyl group, a cyano group or a residue of the formula COOR or CH 2 Z ', where R and Z' are as defined above, to form a compound of formula III O (III) in which R, Η * ’*, X * and Y are as defined above and isomerized to a compound of formula IV (IV) under basic conditions COOR wherein R 1, R *, X 'and Y are as defined above, wherein X', if different from X, is optionally converted by substitution reaction to X 'representing CH 2 Z, wherein Z is as defined above, this compound is converted to a compound of formula XI COOR in which X, r 'and R are as defined above and Ph represents a phenyl group, namely (a) ozonolysis of a substituent at the 1-position corresponding to the formula CH ₃ COOR where R is as defined above, carried out in solution at reduced temperature, b) cleavage of the 1-position substituent corresponding to the formula Y ° COOR where R is as defined above in step (a) by mild alkaline hydrolysis or silica gel treatment, c) condensation of the 1-unsubstituted azetidinone obtained in step b) with a glyoxylate of the formula chocoor in which> R is as hereinbefore defined, by refluxing in a solvent, d) chlorination of the 1-position substituent corresponding to the formula COOR226027 in which R as defined above, introduced in step c) by the action of a chlorinating agent, e) a conversion substituent at the 1-position corresponding to the formula COOR · 'where R '' has the above meaning, introduced in step d), to a substituent of the formula γ ^ΡΡ 3 3 COOR— in which. * # / / R is as defined above and Ph represents a phenyl group, by reaction with triphenylphosphine, f) reduction of the 4-beta-sulfoxide moiety with a reducing agent; and (g) ozonolysis of a double bond in a grouping where: X and Ϊ are as defined above, in solution at reduced temperature, wherein the individual reaction steps may be carried out in the order a), b), c), d), e), f), g) or a), f), (b), (c), (d), (e), (g) and reaction step (f), if subsequent to reaction step (e), is carried out in an acidic medium, the compound of formula XI is cyclized by heating in an inert solvent to 50 to 140 ° C to give a compound of formula I wherein a is 0, which is then optionally oxidized to the corresponding compound of formula I wherein a is 1. 2. The process according to item 1, for the preparation of compounds of the above general formula I, in which a has a value of 0, R is hydrogen, C1-C4alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzhydryl, acetoxymethyl, a pivaloyloxymethyl group, a phthalidyl group, a radical of the formula -CH 1 CH 2 -JO-COOC 3 H 3 or -CH 3 NHCOR ... wherein R 'represents a C 1 -C 5 alkyl group or an aryl radical selected from the group consisting of phenyl and benzyl, Z is as in 1 a R ^# represents a hydrogen atom, characterized in that the compounds of the above general formula (II), acetylenic derivatives of the general formula (I) are used as starting materials X * —C = CY and glyoxylates of general formula CHOCOOR * wherein 'R, X' and Y are as defined in 1 and 'R' and R are as defined in this point, and the reaction is terminated after cyclization of the compound of formula XI. 3. The process according to item 1, for the preparation of compounds of the above general formula I, in which a has the value 0, R is hydrogen, C1-C4alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl, phthalidyl, the remainder of the formula -CH (CH ₃ ) -O-COOC ₂ H ₅ or -CH ₃ NHCOR ..... where R represents a C 1 -C 5 alkyl group or an aryl radical selected from the group consisting of phenyl and benzyl, Z is as in 1 and is C1 -C4 alkyl, C3 -C6 cycloalkyl or C1 -C4 hydroxyalkyl; up to 4 carbon atoms, the alcoholic function of which may be either free or protected by a p-nitrobenzyloxycarbonyl or dimethyl-tert-butylsilyl radical, characterized in that the compounds of the general formula (II), acetylenic derivatives of the general formula X'-CSCY and glyoxylates of the general formula CHOCOOR in which R, X 'and Y are as defined in t and R 'and R *' are as defined herein, and the reaction is complete after cyclization of the compound of formula XI.