CS207655B2 - Method of preparation of the halogenated 7-oxo-4-thia-2,6-diazabicyclo/3,2,8/hept-2-ens - Google Patents

Description

(54) A process for the preparation of halogenated 7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-enes

The present invention relates to a process for the preparation of halogenated 7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-enes of formula Ib

where

R "is benzyl or phenoxymethyl,

Y is 1-morpholinyl and 1-piperidyl,

X is 2,2,2-trichloroethoxy, benzyloxy, p-nitrobenzyloxy, methoxy and

Hal is a halogen atom, characterized in that the compound of formula IIb is diphenyl-

wherein R ', X and Y are as defined above, by reacting with at least one molar equivalent of a molecular halogen, an N-halide or an N-halimide as halogenating agents in a halogenated hydrocarbon such as dichloromethane, chloroform or carbon tetrachloride in an ether such as tetrahydrofuran, or in a di-lower alkyl-lower alkanamide, such as dimethylformamide, or mixtures thereof at -50 ° C to +50 ° C.

Compounds of formula (Ib) are novel compounds which are valuable intermediates for the preparation of the β-cephem (IV) according to the following reaction scheme.

removal of protecting groups

_x CH ₂ Hal cyclization

wherein R ', Hal, X and Y are as defined above and Y' is a hydroxyl group and A and B are hydrogen atoms or an amino protecting group.

In the above formulas, the ABN group is amino or substituted amino. Said substituted amino may be acylamino, hydrocarbylamino, hydrocarbylideneamino, silylamino, sulfenylamino, or the like, conventional protecting groups containing up to 20 carbon atoms, used in the chemistry of cephalosporins or penicillins.

Examples of acyls in these acylamino groups are inorganic acyls such as carbon acyls (e.g., alkoxycarbonyl, arylalkoxycarbonyl, or aryloxycarbonyl), sulfuric acyl, phosphoric acyl (e.g., dialkoxyphosphinyl, dialkoxythiophosphonyl, or alkoxyaminophosforoyl, and arylalkyanlyl, such as aalkanalkylo, alkylsulfonyl, arylsulfonyl or alkylphosphonyl. These groups may, where possible, be interrupted by a heteroatom in the chain or may be unsaturated or substituted, for example with a halogen atom (for example fluorine, chlorine or bromine), nitrogen-functional groups (for example amino, hydrazino, azido, alkylamino, alkylideneamino, acylimino) , imino, or nitro), oxygen functionalities (e.g., hydroxy, alkoxy, arylalkoxy, aryloxy, acyloxy, or oxo), sulfur functions (e.g., mercapto, alkylthio, arylalkylthio, arylalkylthio, aryloxythio, aryloxythio, aryloxythio, aryloxythio, aryloxythio, aryloxythio aryloxy-sulfinyl), carbon-functional groups (e.g., alkyl, alkenyl, arylalkyl, aryl, carboxy, carbonyl, carbamoyl, alkanoyl, aroyl, aminoalkyl, arylalkanoyl , or cyano) or phosphorus functional groups (e.g., phosphono or phosphoroyl). A and B can also together tyyrate the diacyl group of a polybasic acid (e.g. phthaloyl, pyridine-2,3-dicarbonyl, maleinoyl or succinoyl).

More preferred groups of this acyl may be penicillin side chain acyls (e.g., phenylacetyl, phenoxyacetyl, heptanoyl) or acyls that are convertible into groups useful for the antibacterial effect of the end products (e.g., hydrogen, N-tert-butoxy-2-phenylglycinamino, alpha- ( 1-carbomethoxy-1-isopropen-2-yl) amino-alpha-phenylglycyl, 4-phenyl-2,2-dimethyl-5-exo-1,3-dimidazolidin-1-yl, alpha-diphenylmethoxycarbonyl-alpha-phenylacetamido ).

The hydrocarbon groups which may be represented by A and / or B may be easily cleavable aliphatic hydrocarbon groups containing from 1 to 20 carbon atoms (for example alkyl, alkenyl, arylalkyl or other aliphatic hydrocarbon groups) or easily cleavable monocyclic aromatic hydrocarbon groups (for example phenyl or pyrimidyl). These groups may, where possible, be interrupted by a heteroatom in the chain or may be unsaturated or substituted with a substituent (for example, a halogen atom or a nitrogen function, an oxygen function, a sulfur function, a carbon function or a phosphorus function). Λ and B may also form together a divalent hydrocarbon group (for example alkylene, arylalkylene, alkylidene, arylalkylidene, alpha-halo- or alkoxyarylalkylidene, diarylmethylidene or eycloalkylidene), which may, where possible, be interrupted by a heteroatom in the chain or substituted with the substituent mentioned above or which may be unsaturated.

When group A is acyl and group B is a hydrocarbon, they may be joined together with the nitrogen atom bonded to the 7-position of the cephem ring to form a cyclic group (for example, a 4-oxo-3-imidazolidinyl ring).

Silyl (e.g., trialkylsilyl) and sulfenyl (e.g., phenylsulfenyl or o-nitrophenylsulfenyl), which may be represented by A and / or B, are conventional amino protecting groups.

Examples of acyl groups -A and B in the above formula are the following groups:

1. alkanoyl containing from 1 to 5 carbon atoms

2. haloalkanoyl containing from 2 to 5 carbon atoms;

3. azidoacetyl,

4. Cyanoacetyl

5. acyl groups of formula λγ-CQQ * -CO- wherein Q and Q 'are hydrogen or methyl and Ar is phenyl, dihydrophenyl or a monocyclic heterocyclic aromatic group containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur and which may be substituted by an inert group, for example alkyl or alkoxy containing from 1 to 3 carbon atoms, chlorine, bromine, iodine, fluorine, trifluoromethyl, hydroxyl, cyano, aminomethyl, amino or nitro,

6. acyl groups of the formula * Ar-G-CQQ'-CO where G is an oxygen or sulfur atom and Ar, Q, Q 'are as defined above,

7. acyl groups of the formula

Ar-CHT-COwhere Ar is as defined above and

T is (i) amino, ammonium, amino substituted with conventional amino protecting groups such as benzyloxycarbonyl, alkoxycarbonyl of 1 to 4 carbon atoms, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexyloxycarbonyl, methoxymethyl,

-trichloroethoxycarbonyl, guanidylcaramoyl, optionally substituted ureidocarbonyl, alkanoyl of 1 to 5 carbon atoms, pyrocarbonyl, thiopyroncarbonyl, pyridonylcarbonyl, homocyclic heterocyclyl, hydroxy-substituted, monocyclic aromatic, monocyclic aromatic, or an alkyl of 1 to 3 carbon atoms, an aminoalkyl of 1 to 3 carbon atoms, a halogen atom, a trifluoromethyl or an alkyl of 1 to 3 carbon atoms or a hydroxyalkyl of 1 to 3 carbon atoms or an amino group protected in the form of phthalimido or enamines; . (ii) a hydroxy or acyloxy group containing from 1 to 7 carbon atoms; (iii) a carboxy or alkoxycarbonyl group containing from 2 to 7 carbon atoms, an indanyloxycarbonyl group, a phenoxycarbonyl group or *;

iv) azido, cyano, carbamoyl, alkoxy sulfonyl, sulfo, or alkoxy sulfonyl.

8. 2-sydnon-3-alkanoyl containing from 3 to 5 carbon atoms;

9. (2- or 4-pyridon-1-yl) acetyl

10. amino-protected 5-aminoadipoyl, 5-aminoadipoyl aroyl or alkanoyl of 1 to 10 carbon atoms, chloroalkanoyl of 1 to 5 carbon atoms or alkoxycarbonyl of 2 to carbon atoms or 5-aminoadipoyl of protected carboxy benzhydryl, 2,2,2 -trichloroethyl, trialkylsilyl, C1-C6 alkyl, nitrobenzyl or methoxybenzyl, and

11. Aoyls of the formula

LO-GO where L is an easily cleavable, optionally substituted hydrocarbon group containing from 1 to 8 carbon atoms (for example 2,2,2-trichloroethyl), isobornyl, tert-butyl, 1-methylcyclohexyl, 2-alkoxy tert-butyl, benzyl, p (nitrobenzyl or p-methoxybenzyl).

Alternatively, A and B may be taken together to form a diaoyl group derived from a C 4 -C 12 polyhydric acid, C 1 -C 6 alkylidene or C 7 -C 9 arylmethylidene.

In the above, examples of Ar groups are furyl, thienyl, pyrryl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thiatriazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidyl, pyrimidyl, pyrimidyl, pyrimidyl, pyrimidinyl, pyrimidyl , triazinyl and dihydrophenyl, each of which is optionally substituted with halogen, C 1 -C 3 alkyl, hydroxyl, aminomethyl or C 1 -C 3 alkoxy.

The process of the present invention can be carried out by reacting a compound of formula IIb with a molecular halogen, an N-halide or an N-halide as a halogenating agent. Representative halogenating agents fall into the categories below.

x ', BrCl, IBr, CgHjI.Xj, Ο ^ Ν.ΗΧ'.χ', Ο ^ ΝίΟΗ ^ Χ'.Χ ^,

2. = NX '(alkyl) ₄ NX'.X', (acyl) NHX ', (acyDgNX' wherein alkyl or acyl contains up to 7 carbon atoms and x 'is chlorine, bromine or iodine.

When these halogenating agents are used as such which act through a halogen radical, the reaction is carried out by the action of heat, light, peroxide (peracids, peroxide, hydroperoxide and the like), azo compound (azobisisobutyronitrile, etc.) or other free radical initiator.

When these halogenating agents are used as such which act through halogen cations, the reaction is optionally carried out in the presence of an acid scavenger (organic or inorganic bases, for example sodium carbonate, pyridine, quinoline, lutidine, diethylamine, triethylamine and the like). The onion ion of the starting compound is easier to halogenate to give the desired compound in higher yield under mild conditions.

If these halogenating agents are used over the carbanions of the starting compound, the starting compounds are reacted with an anionic reagent (alkali metal hydrides, alkali metal amides, alkali metal alkoxides, lithium dialkylamine, lithium hexaalkyldisilazane, trialkylamine, Grignard reagents, etc.) to form the anionic reagent. % of a carbanion, followed by reaction with a halogenating agent. The reaction is carried out in a halogenated hydrocarbon, ether or amide as solvents at a temperature of from -50 ° C to + 50 ° C, preferably from -25 ° C to 0 ° C, so as to avoid side reactions.

Solvents include halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, di-chlorobenzene and the like), ethers (diethyl ether, ethylene glycol, dimethyl ether, tetrehydrofuran, tetrahydropyran, dioxane, morpholine, anisole, etc.), amides (dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide). mixtures.

During the reaction, the cis-trans isomerization can take place at the substituent in the alpha-position of the geometric isomer, which reaction is included within the scope of the present invention.

The cyclization can be carried out by reacting compounds of formula III with

i) acid ii) base or iii) solvent, optionally in the presence of a catalyst. The starting compounds tend to cyclize almost automatically and under various mild conditions, whereby the cephem compounds can be isolated in good yield.

The acids used include mineral acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, sulfuric acid), sulfonic acids (e.g. alkanesulfonic acid, arylsulfonic acid), phosphonic acid, carboxylic acids (e.g. formic acid, acetic acid, haloalkanoic acid, oxalic acid, phthalic acid) and other organic or inorganic acids or their salts with a weak base (such as aromatic or aliphatic bases, ammonia, alkaline earth metals, aluminum, silver) or salts of these acids with common bases including alkali metal salts. Lewis acids may also be used, preferably in an aprotic solvent.

Bases used for the basic medium preferably include these weak bases. Strong bases (e.g. alkali metal hydroxide, alkali metal carbonate, tertiary ammonium hydroxide) may be used under certain mild conditions as they degrade starting or final compounds, especially beta-lactams. Lewis bases may also be used.

The cyclization catalyst may be neutral or alkaline silica gel, alumina, diatomaceous earth, florisil and other catalysts.

In some cases, the cyclization may be by treatment with a solvent (for example, a high polarity solvent including amides such as hexamethylphosphoric triamide, dimethylformamide, formamide and the like, alcohols and water). In some cases, polar solvents accelerate the reaction. The reaction is believed to be the result of catalysis of the hydrogen halide produced by the initial reaction.

The reaction is preferably carried out in a solvent with heating or cooling or at room temperature. If necessary, the reaction medium is stirred under inert gas.

Preferred solvents are polar solvents such as alcohols, carboxylic acids, amides, nitriles, nitrocarbons, sulfoxides, aqueous solvents, and solvents capable of highly dissolving the starting materials, such as esters, ethers, halogenated hydrocarbon solvents, which sometimes facilitate the reaction. The reactions generally proceed rapidly at room temperature and the desired cephem or cepham compounds are obtained in high yields.

The end product is 3-hydroxy-3-cephem-4-carboxylic acid or 3-oxocepham-4-carboxylic acid of general formula 17. 7 some of the substituents at the 3 or 7 position of the cephem ring vary during the reaction or processing and as a result the corresponding substituents in the starting and resulting substances are different. Optionally, these substituents can be converted back or converted to others by known methods.

Halogenation, deprotection and cyclization can be carried out in one step, namely without isolation of intermediates and without removal of reaction solvents.

Some starting materials are prepared by the following procedures.

Preparation 1

To a solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylideh) acetate (504 mg) in tetrahydrofuran (8 mL) was added dropwise with ice-cooling methanesulfonyl chloride (0.13 mL) and triethylamine (0.23 mL). After three hours the mixture was evaporated to leave a residue which was dissolved in methylene chloride, washed with water, dried (MgSO 4) and evaporated. Purification of the residue by chromatography on silica gel containing 10% water (15 g) using benzene / ethyl acetate (5: 1) afforded p-nitrobenzyl-alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3,2,0] Hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate (353 mg). Colorless foam.

The product does not contain a geometric isomer in alpha position. IR: ^ _j-1 HCl 7gq _(<730 cm ^'1. NMR: 5CDC1 ₃ 2.60, s, 3H, 3.18, s, 3H, 4.58 + 4.88, ABq, (14 Hz) 2H 5.24, s, 2H, 5.92 @ + 6.08, ABq, (5 Hz), 2H, 6.73-8.20, m, 9H.

5

To a solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) of acetate (940 mg) in dimethylformamide containing 10% tetrahydrofuran (5 mL) was added p-toluenesulfonyl chloride (456 mg). After cooling to -70 ° C, the solution was treated with triethylamine (0.3 mL). The reaction mixture was allowed to warm slowly to room temperature, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The product obtained is chromatographed on silica gel with 10% water using benzene with 5% ethyl acetate. There was thus obtained p-nitrobenzyl .alpha .- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo D, 2,0] hept-2-en-6-yl; (sulfonyloxyethylidene) acetate (644 mg). l5: ^{l3 max 1785> 1735 NMR! 8 CDG1} 3 ² ' ⁴⁵ ' ^s ' ^3H ' ^{4.75 + 4} · ²⁰ » ^{AB <1} ' ^(14Hz) ' ^2H '

5.15, s, 2H, 8.30-6.6, m, 13 H.

2076 55

Preparation 3

To a solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] alpha- (1-methanesulfonylethylidene) acetate (298 mg) in benzene (3 mL) was added morpholine (0.095 mL) at 7-10 ° C. After 130 minutes, the reaction mixture was filtered and the filtrate was poured into ice water and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and evaporated to give p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6 -yl] - alpha - (1-morpholinoethylidene) acetate (284 mg). Foam. Yield 97 ', 1%.

The product is a mixture (about 1: 1) of the geometric isomers of the substituent at the elf position.

IR: [delta] 1768, 1685, 1612, 1623 cm ^& lt ^; -1 &gt;. NMR: δ CDCl-1.90, s, 1H, 2.42, s, 1H, 3.17-3.43, m, 4H, 3.52-3.88, m, 4H, 4.87, s, 2H, 5.21, s, 2H, 5.58-6.00, m, 2H, 6.80-8.22, m, 9H.

Preparation 4

To a solution of 2,2,2-trichloroethyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate (1.52 g) in benzene (30 mL) was added at below 10 ° C with morpholine (0.48 mL). After stirring for 1 hour, the mixture was washed with water, dried and evaporated. Purification of the residue by silica gel chromatography affords 2,2,2-trichloroethyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6- yl] - alpha - (1-morpholinoethylidene) acetate (0.76 g). Yield = 50%.

The product is a mixture of isomers of the substituent at the alpha position.

NMR δ CDC1 ₃ 1.88 + 2.42, s, 3H, 3.1 to 3.9, m, 8H, 4.73, AB q, (12 Hz), 2H, 4.95, s,

2H, 5.7-6.2, m, 2H, 6.8-7.5, m, 5H.

Preparation5

To a stirred solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1- Hydroxyethylidene acetate (500 mg) in tetrahydrofuran (20 mL) was added dropwise with methyl chloroformate (200 mg) and triethylamine (216 mg) under ice-cooling.

After one hour, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methoxycarbonyloxyethylidene) acetate (546 mg). Foam. Yield 97%.

The product is a mixture (about 2: 1) of the geometric isomers in the alpha position.

^{lC: v} max ^{13 7S3} ' ^{1 732} > ^{1 642} > ^{1 612} > ^{1 600 cm} -1 · 8CDCl ₃ 1.95, s, 1H, 2.47, s, 2H, 3.68, s, 1H, 3.80, s, 2H, 4.54 + 4.86, ABq, (14 Hz), 4 / 3H, 4.86, s, 2 / 3H, 5-25, s, 3H, 5.73-6.03, m, 2H, 6.70-8.16, m, 9H.

Preparation 6

To a solution of 2,2,2-trichloroethyl alpha- [3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo [3.2.0] hept-2-en-6-yl] -alpha- ( 1-hydroxyethylidene) acetate (450 mg) in methylene chloride (7 mL) was added at -25 ° C methanesulfonyl chloride (0.093 mL) and triethylamine (0.48 mL) and the mixture was held at this temperature for 40 minutes. To the resulting solution of 2,2,2-trichloroethyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate was added dropwise with morpholine (0.112 mL) and the mixture was stirred for 1.3 hours. The reaction mixture is washed with water, dried and the residue is purified by chromatography on silica gel with 10% water to give 2,2,2-trichloroethyl-alpha- [3-benzyl-7-oxo-4-thia-2,6- diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate (205 mg).

The product is a mixture (about 1: 1.6) of the geometric isomers in the alpha position.

NMR CDC1 ₃ 6 1.67, s, +2.35, s (3H), 2.83 to 4.00, m, 8H, 2.31, s, 2H, 4.45 + 4.88, q, (12Hz), 4.47 + 4.83, q, (12Hz), (2H), 5.60-6.12, m, 2H, 7.22, s, +7.23, s, (5H).

Preparation 7

To a stirred solution of p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) Methylsulfonyl chloride (0.18 mL) and triethylamine (0.31 mL) were added under ice-cooling with ice-cooling (680 mg) in tetrahydrofuran (15 mL) and the reaction mixture was stirred for one hour. The precipitated crystals are filtered off and the filtrate is evaporated. Purification of the residue (800 mg) by chromatography on silica gel with 10% water (25 g) afforded p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2] eluted from the fractions eluted with benzene and ethyl acetate (2: 1). 6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate (609 mg). Yield 76.6%.

The product does not contain geometric isorner in alpha position.

^{l5: in} max ^l3 ' ⁷⁸⁴ ' ^{1 728} ' ^{1 700} > ^{1 6.4 cm} ”' ·

NMR CDC1 ₃ 6 2.58, s, 3H, 3.00, s, 3H, 3.79, s, 2H, 5.18, s, 2H, 5.85 + 6.00, ABq, (5Hz) 2H, 7.22, s, +8.23, m, 9H.

Preparation 8

To a solution of p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl-alpha - (1-methanesulfonyloxyethylidene) acetate (609 mg) in methylene chloride (3 mL) was added morpholine (0.2 mol) at -15 and the mixture was stirred at this temperature for 50 min. The reaction mixture was poured into ice water and extracted with methylene chloride. The extract was washed with water, dried and evaporated, and the purified foam (569 mg) was purified by chromatography on silica gel (25 g) to obtain p-nitrobenzyl alpha- [3-benzyl-7-oxo] from the fractions eluting with 2: 1 benzene / ethyl acetate. -4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate (452 mg). Yield: 75.5%. Foam.

The product does not contain geometric isomers in alpha position. ^lcsv max ^{1; 3 1 778} >' ⁶⁹⁵ ' ^{1 6.5cm} ~ '·

NMR: δ CDCl ₃ 2.37, s, 3H, 3.00-3.73, m, 8H, 3.86, s, 2H, 5.20, s, 3H, 5.73 + 5.88, ABq, (5Hz), 2H, 7.15 - 8.28, m , 9H.

These products are also new and follow the folks formula,

R '

AND

(Id) cox wherein R 'and X are as defined above, Y is a carbon acyloxy group containing up to 12 carbon atoms, a disubstituted amino group having 2 to 20 carbon atoms or an aromatic or aliphatic sulfonyl group having 1 to 20 carbon atoms.

Preferred groups for Y are cyclopropylmethoxycarboxy, carbobenzoxy, methoxycarboxy, C 4 -C 8 alkylene amino, morpholin-4-yl, C 2 -C 6 dialkylamino, C 1 -C 12 alkanesulfonyloxy or 4-C arylsulfonyloxy R 1 is benzyl and phenoxymethyl.

where Ϊ is a disubstituted amino group, the following methods may be prepared as set forth in the preparations above.

Compounds Xld, by whose reactions conventional

acylation with a sulfonyl acid acceptor

ch ₃

O-sulfonyl

ch ₃

N-, wherein A, B, R and X are as defined above, and the dashed line means when R and B are hydrogen atoms and n is a carboxyl acyl group that the substituents may be linked to form an azetidinothiazoline bicyclic ring at temperature from -30 ° C to 0 ° C.

The process may be carried out in a single vessel, in particular it is not necessary to isolate intermediates and remove the reaction solvents at any of the steps for preparing the enamine.

The preparation of enamines by the above process and halogenation, thiol deprotection and cyclization can also be carried out in a single vessel, namely without isolation of any intermediate or even without removal of any solvent during the reaction, yielding up to 80% or more of the cephem compound from IId, wherein i is hydroxyl. In other words, the reaction can be carried out simply as one reaction. In the case of solvents, a solvent is selected which is suitable for all reactions. Typical examples are ethereal solvents (e.g. tetrahydrofuran, tetrahydropyran and dioxane), amide solvents (e.g. dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide) and halogenated hydrocarbon solvents (e.g. chloroform, methylene chloride and dichloroethane).

As mentioned above, the present invention is a simple process starting from cheap penicillins for the preparation of key intermediates of 3-hydroxy-3-cephem compounds in high yield.

The present invention is illustrated by the following examples.

Example

Dissolve p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (i-hydroxyethylidene) acetate (939 mg) in tetrahydrofuran (14 mL), the solution was cooled to -40 ° C, triethylamine (0.67 mL) and methanesulfonyl chloride (0.187 mL) were added, and the mixture was stirred at -40 ° C and 30 min for 30 min. minutes at 0 ° C. To this solution was added morpholine (0.209 mL), the reaction mixture was stirred at 0 ° C for two hours, N-bromosuccinimide (393 mg) was added. After stirring at 0 ° C for 1.5 hours, diluted with water (100 mL) and extracted ethyl acetate. The extract was washed with water, dried over sodium sulfate and evaporated to give a foam (1.359 g) which was purified by silica gel chromatography containing 10% water to give p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-alpha-4- thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha-methanesulfonyl-alpha-acetylacetate (81.7 mg, yield 7.5%), p-nitrobenzyl alpha- [3-Phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-morpholino-2-bromoethylidene) acetate (956.8) mg, 77.5%) and p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] - alpha (1-morpholinoethylidene) acetate (120.5 mg, 11.2% yield).

Example 2

Dissolve p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) acetate (278 mg) in methylene chloride, the solution was cooled to -20 ° C, methanesulfonyl chloride (0.05 mL) and triethylamine (0.20 mL) were added with stirring, and the reaction mixture was stirred under argon for 10 minutes. To this solution was added morpholine (0.062 mL) with cooling and stirred for 15 minutes. Then N-chlorosuccinimide (97 mg) reaction was added

The mixture was stirred at -20 ° C for two hours, washed with water, dried and evaporated. Purification of the obtained residue (368 mg) by chromatography on silica gel with 10% water (18.4 g) using benzene / ethyl acetate (1: 1) afforded p-nitrobenzyl-alpha- [3-phenoxymethyl-7-oxo-4-thia] -2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-morpholino-2-chloroethylidene) acetate (106 mg,

31.2%) and 1S-Nitrobenzyl-alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha-1 (morpholinoethylidene) acetate (134 mg, 42.0%).

Example 3

Dissolve p-nitrobenzyl-alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-one-6-yl] -1-hydroxyethylidene) acetate ( 940 mg) in dichloromethane (14 mL), the solution was cooled to -25 ° C, triethylamine (0.97 mL) and methanesulfonyl chloride (0.187 mL) were added and the reaction was allowed to proceed for 1.5 hours. To this solution was added morpholine (0.209 mL), the reaction mixture was maintained at -25 ° C for one hour, and a solution of bromine in carbon tetrachloride (3.2 mmol of bromine) was added. After 30 minutes, the reaction mixture was washed with 5% aqueous sodium bicarbonate, and water, dried and evaporated, purifying the residue (1457 mg) and chromatography on silica gel containing 10% water (100 g) using a mixture of benzene and ethyl acetate (2 g). : 1), obtaining p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha-methanesulfonyl- alpha- (dibromaeetyl) acetate (132.8 mg, 8.8 and p-nitrobenzyl-alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2) -en-6-yl] -alpha- (1-morpholino-2-bromoethylidene) acetate (1033.5 mg, 83.7%).

Example 4

Dissolve p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] alpha- (1-hydroxyethylidene) acetate (940 mg) in dichloromethane (14 ml), the solution was cooled to -25 ° C, triethylamine (0.6 ml) and methanesulfonyl chloride (0.17 ml) were added, and the reaction mixture was stirred for 1.5 hours. To the solution was added morpholine (0.209 mL), the reaction mixture was maintained at -25 ° C for 1.5 hours, bromine (2.2 mmol) dissolved in carbon tetrachloride (2.2 mL) was added and after 30 minutes at -25 ° C. A 5% aqueous sodium bicarbonate solution was added, washed with water, dried and evaporated. Purification of the residue (1.134 g) by chromatography on silica gel with 0% water (100 g) using benzene / ethyl acetate (3: 1) was added. yielding p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] alpha- (1-morpholino-2- bromoethylidene) acetate (852.6 mg, 69%) and p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6 -yl] -alpha-met hansulfonyl-alpha-acetylacetate (1,332.2 mg, 12.2%).

Example 5

Dissolve p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) ) acetate (827 mg) in methylene chloride (10 mL), cooled to -20 ° C, and a solution of methanesulfonyl chloride (1 M in methylene chloride) was added,

2.2 mL) and a solution of triethylamine (1 M in methylene chloride, 2.2 mL), stir the reaction for minutes, cool to -25 ° C, add morpholine (0.35 mL), stir for 65 minutes, add

N-bromosuccinimide (340 mg) and the reaction mixture was stirred for one hour. The reaction mixture was washed with water, dried (MgSO4) and evaporated. Purification of the residue by silica gel chromatography containing 10% water (30 g) afforded p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2- en-6-yl] - alpha - (1-morpholino-2-bromoethylidene) acetate (710 mg). Yield 65%.

Example 6

Dissolve p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) acetate ( 940 mg) in tetrahydrofuran (14 ml), triethylamine (0.61 ml) and methanesulfonyl chloride (0.172 ml) were added and the reaction mixture was stirred at -5 to -20 ° C for one hour. To the resulting solution of p-nitrobenzyl alpha- [3-phenoxymethyl-71 L]

-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate, morpholine (0.209 mL) was added, the reaction mixture was stirred at -15 to -20 ° C for 1.5 hours, and at 0 ° C for two hours, to give a solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [b] 3,2,0] hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate, which is cooled to -15 ° C, pyridine (0.174 ml) is added, and after 5 minutes a solution of bromine in chloride The reaction mixture was stirred at the same temperature for 15 min, poured into water (50 mL), extracted with ethyl acetate (50 mL), washed with water, dried (MgSO 4) and evaporated. Purification of the residue by chromatography on silica gel with 10% water yields p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-this-2] from the eluted benzene / ethyl acetate (2: 1) fractions. 6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (2-bromo-1-morpholinoethylidene) acetate (1.109 g, m.p. 89.7%), and p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha - (2-bromo-1-morpholinoethyl) -alpha-methanesulfonyl acetate (85 mg, 7.7% yield).

A similar reaction using N, N-dimethylformamide (14 mL) instead of tetrahydrofuran gave ₉ not the same products (90 mg, 73.6% and 100 mg, 9.0%).

Example 7 * p-Nitrobenzyl alpha- [3-benzyl-7-oxo-ethylidene] -2,6-diaza-4-thiabicyclo [3.2.0] hept-2-en-6-yl] -alpha is suspended. - (1-hydroxyethylidene) acetate (2,265 g) in anhydrous tetrahydrofuran (30 ml) and treated dropwise with a solution of triethylamine (1, ¹ g) and methanesulfonyl chloride (630 mg) in tetrahydrofuran (2 ml) at 1-2 ^J C and the reaction mixture was stirred for 25 minutes.

To the resulting solution of p-nitrobenzyl alpha- [3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) ) acetate, a solution of morpholine (480 mg) in tetrahydrofuran (2 mL) was added, and the reaction mixture was stirred for 15 minutes to give a solution of p-nitrobenzyl .alpha .- [3-benzy 1-7-oxo-2,6-diaz. α-4-thiabicyclo [3.2.0] hept-2-en-6-yl] -α-α- (1-morpholinoethylidene) acetate, which was cooled to -20 ° C, pyridine (396 mg) was added and a solution of bromine in carbon tetrachloride (1 mol / liter, 5 ml), after 5 minutes poured into dilute hydrochloric acid, extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated. Purification of the obtained residue by silica gel chromatography (50 g) afforded p-nitrobenzyl .alpha .- [3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo [3.2.0] fractions eluting with benzene / 10% ethyl acetate. Hept-2-en-6-yl] - alpha - (2-bromo-5-morpholinoethylidene) acetate (2.36 g). Yield 78%.

The product can be diluted with 5% hydrochloric acid (10 mol equiv

Valent and methanol and stirring at room temperature for 3 hours gave p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate in more than 70% yield.

Example 8 * Diphenylmethyl alpha- [3-benzyl-6-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) acetate (4.4 g) in tetrahydrofuran (60 ml), the solution was cooled to -20 ° C, triethylamine (2.84 ml) was added with stirring, and methanesulfonyl chloride (0.82 ml) was added dropwise to the yellow solution. The reaction mixture was allowed to react for 30 minutes. To the resulting solution of diphenylmethyl-alpha- [β-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) morpholine (0.96 ml) was added at -40 ° C, the reaction mixture was stirred for 3.5 hours, pyridine (0.77 ml) was added to the resulting solution of diphenylmethyl alpha-[3-benzyl-7-oxo- 4-Thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate, cooled to -40 ° C, is added bromine, (0 (49 ml), the reaction mixture was stirred for 30 minutes to give diphenylmethyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0} hept-2-en-6]. -yl] - alpha - (2-bromo-1-morpholinoethylidene) acetate in more than 70% yield. To this solution was added dropwise 5% hydrochloric acid (72 mL) and methanol (60 mL) was stirred at room temperature for three hours and allowed to stand overnight in the refrigerator. The reaction mixture was evaporated, the residue was dissolved in methyl chloride, washed with water, dried over sodium sulfate and evaporated. Purification of the obtained residue i. chromatography on silica gel with 10% water (150 g) afforded diphenylmethyl 7-phenylacetamido-3-hydroxy-3-eephem-4-carboxylate (3, 1: 1, after crystallization from n-hexane) from the fractions eluted with benzene / ethyl acetate (4: 1). 51 g), mp 93-96 ° C. Yield: 70%. IR: in CHCl _3, 410, 1782, 1674, 1610 cm ^-1 . NMR: δ CDCl ₃ 3.20, s, 2H, 3.64, s, 2H, 4.97, d, (4Hz), IH, 5.66, dd, (9: 4), 1H, 6.77, d, (9Hz), 1H,

6.90, s, 1H, 7.35. M, 15H.

Example 9

Dissolve p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate (452 mg) in methylene chloride (5 mL), N-bromosuccinimide (170 mg) was added at -20 ° C and the reaction stirred for 80 minutes, poured into ice water and extracted with methylene chloride. The extract was washed with water, dried (MgSO4) and evaporated. Purification of the residue (461 mg) by silica gel chromatography (25 g) yielded p-nitrobenzyl .alpha .- [3-benzyl-7] fraction eluting with benzene / ethyl acetate (2: 1). oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (2-bromo-1-morpholinoethylidene) acetate (289 mg).

Yield 54.5%. IR: _ν , _770j , ₆₉₀₎ , g _{10 cm -1} . _{Nmr : δ CDCl 3> 00} _ _{3-74> 8 H>}

5.52, s, 2H, 4.47, +4.71, ABq, (13Hz), 2H, 5.23, s, 2H, 5.68, d, (4Hz), 1H, 5.94, d, (4Hz), 1H, 7.20 8.25, m, 9H.

Example 10

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Purification of the obtained residue by chromatography on silica gel containing 10% water and evaporation of fractions containing the desired compound afforded the brominated azetidine acetic acid derivative (2). The reaction conditions are given in Table I and the physical constants are given in Table II.

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Diphenylmethyl alpha - [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.1] hept-2-en-6-yl] -alpha (1-hydroxyethylidene) acetate 84 g) was dissolved in tetrahydrofuran (60 ml), cooled to -20 ° C, triethylamine (2.84 ml) was added with stirring, methanesulfonyl chloride (0.82 ml) was added dropwise and allowed to react for 30 minutes . To the resulting solution of diphenylmethyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxy) ethyl] acetate morpholine (0.96 ml) was added at -40 ° C and stirred for 3.5 hours to the resulting solution of diphenylmethyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] Hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate cooled to -40 ° C was added pyridine (0.77 mL) followed by bromine (0.49 mL) and the reaction is stirred for 30 minutes. Diphenylmethyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (2-bromo-1) was obtained. (morpholinoethylidene) acetate. At room temperature, 5% hydrochloric acid (72 ml) and methanol (60 ml) were added dropwise with stirring over 3 hours, and the reaction mixture was allowed to stand overnight in the refrigerator. The residue obtained by evaporation of the reaction mixture is dissolved in methylene chloride, washed with water and dried over sulfate

J sodium and evaporated. The obtained residue (5.83 g) was purified by chromatography on silica gel containing 10% water (150 g) and from the fractions eluted with benzene / ethyl acetate (4: 1) to give diphenylmethyl 7-phenylacetamido-3-hydroxy-3-cerium-4- carboxylate (3.51 g), mp 93-96 ° C after crystallization from n-hexane. Yield 70%. IR: ^X ^ 3 3410, 1782, 1674, 1610 cm • NMR: ^δ υυυ ^± 3 3,20s2H, 3,64s2H, 4,97d (4Hz) 1H 5,66dd (9: 4Hz)! H, 6.77d (9Hz) 1H,

6.90s1H, 7.35m15H.

Example 12

To a stirred suspension of p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1- hydroxyethylidene) acetate (9.06 g) in tetrahydrofuran (120 mL) was added triethylamine (5.68 mL) at -20 ° C under nitrogen atmosphere to give a clear solution. To this solution was added methanesulfonyl chloride (1.65 mL) and the reaction mixture was stirred at the same temperature for 30 minutes, morpholine (1.92 mL) was added, the mixture was warmed to 0 ° C and stirred for 5 hours. After cooling to -30 to -35 ° C, pyridine (1.54 ml) and bromine (3.12 g) were added and the reaction mixture was stirred for 20 minutes, warmed to ice-water temperature, 5% hydrochloric acid was added. (144 mL) and methanol (120 mL). After stirring at room temperature for 3 hours, the reaction mixture was allowed to stand overnight at 0 ° C. The separated crystals were collected by filtration to give p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (6.678 g); t. t.

201 ° C. Yield 71%.

Example 13

To a solution of benzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) acetate ( Triethylamine (0.96 ml) and methanesulfonyl chloride (0.28 ml) were added at -30 ° C to -20 ° C in tetrahydrofuran (15 ml) and the reaction mixture was stirred for 55 minutes to give benzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabieyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate, then add morpholine ( (0.40 mL) and the reaction mixture was stirred at -10 ° C to 3 ° C for 5 hours to give benzyl alpha- [3-benzyl-7-oxoy-4-thia-2,6-diazabieyclo [3,2, O] hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate. After cooling to -35 ° C to -30 ° C, pyridine (0.27 mL) and bromine in carbon tetrachloride (1 mmd / mL;

3.2 mL), the reaction mixture was stirred for 20 minutes to give benzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -J-alpha α- (1-morpholino-2-bromoethylidene) acetate, 5% hydrochloric acid (13 ml) and methanol (50 ml) were added and hydrolysis and cyclization were carried out overnight at 0 ° C to obtain the desired cephem product. The solvent was removed under reduced pressure and the remaining solution was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and water, dried over sodium sulfate and purified by chromatography on silica gel containing 0% water. Fractions containing the desired product were combined and evaporated. Crystallization of the residue from methanol / ether / hexane gave benzyl 7-phenox. nylacetamido-3-hydroxy-3-cephem-4-carboxylate, m.p. 149-162 ° C.

NMR δ CDC1 ₃ 3,28d2H, 3,63s2H, 4,98d (5Hz) 1H, 5,30s2H, 5,60d4 (5; 8Hz) 1H, 6,37d (8Hz) 1H;

7.4s + 7.4s 10H, 11.6brs1H. IR: ®θ ^Χ 3 3420, 1785, 1680, 1615 cm ^- '.

Example 14

To a solution of benzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-aza-bicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) acetate ( 2.12 g) in tetrahydrofuran (30 mL) at -30 ° C were added triethylamine (1.42 mL) and methanesulfonyl chloride (0.41 mL), the reaction mixture was stirred for 70 minutes to give benzyl alpha- [3-phenoxymethyl] -7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (methanesulfonyloxyethylidene) acetate, then add morpholine (0.6 mL) and the reaction mixture was stirred at 0 ° C for 4 hours and 50 minutes. Benzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-morpholinoethylideneacetate) to which pyridine (0.385 mL) and bromine (0.25 mL) were added after cooling to -50 ° C, and after stirring for 30 minutes, benzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-bicyclo] was obtained. [3,2,0] hept-2-en-6-yl] -alpha- (1-morpholino-2-bromoethylidene) acetate, to which was added 5% hydrochloric acid (36 ml) methanol (42.5 ml) and tetrahydrofuran (12.5 mL) to give a clear solution.The solution was concentrated and the resulting solution was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and concentrated to give a residue (2.31 g). containing 10% water gave benzyl 7-beta-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate (1.11 g), mp 126-127 ° C.

Example 15

At -30 to -20 ° C, to a solution of benzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) acetate (2.014 g) in tetrahydrofuran (20 ml) was added triethylamine (1.36 ml) and methanesulfonyl chloride (0.40 µl) and the reaction mixture was stirred for 45 minutes. Benzyl alpha - [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate is obtained, piperidine (0.60 mL) was added, the reaction mixture was stirred at -10 ° C to 0 ° C for 4 hours to give benzyl alpha- [3-Benzyl-7-oxo-4-thia-2,6-diazabicyclo ( 3,2,0] hept-2-en-6-yl] -alpha- (1-piperidinoethylidene) acetate, after cooling to -30 to -25 ° C pyridine (0.38 ml) and a solution of bromine in chloride are added carbon dioxide (1 mmol / mL; 4.5 mL) and the reaction was stirred for 20 minutes to give benzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] - hept-2-en-6-yl] -alpha- (1-piperidino-2-bromoethylidene) acetate to which was added 5% hydrochloric acid (18 ml) and methanol (70 ml) and the reaction mixture was kept overnight at 0 ° C to effect hydrolysis and cyclization to give the cephem product, the solvent was removed under reduced pressure, and the solution was extracted with ethyl acetate. It was purified by chromatography on silica gel containing 10 (6 water). Product containing fractions were combined and evaporated. Crystallization of the residue from methanol-ether-hexane gave benzyl 7-beta-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (1.014 g), mp 149-162 ° C.

Claims (1)

SUBJECT OF THE INVENTION 17 A process for the preparation of halogenated 7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-enes of the formula (Ib) COX where R 'is benzyl or phenoxymethyl, Y is 1-morpholinyl and 1-piperidinyl, X is 2,2,2-trichloroethoxy, benzyloxy, p-nitrobenzyloxy, diphenylmethoxy, and Hal is a halogen atom, characterized in that the compound of formula IIb is halogenated N ^X S CH, c = c; (lib) cox wherein R ', X and Y are as hereinbefore defined, by reaction with at least one molar equivalent of a molecular halogen, N-halide or N-halide as halogenating agents in a halogenated hydrocarbon such as dichloromethane, chloroform or carbon tetrachloride, in an ether such as tetrahydrofuran, or in a di-lower alkyl-lower-alkenamide such as dimethylformamide or a mixture thereof at a temperature of -50 ° C to +50 ° C.