CS207654B2 - Method of preparation of derivatives of 7-acykamino-3-hydroxy-3-cefeme-4-carboxyl acid or the oxofore thereof - Google Patents

Description

The present invention relates to a process for the preparation of 7-ocylainino-3-hydroxy-3-cephem-4-carboxylic acid derivatives of the formula Ia or the corresponding 3-oxocepham compounds of the formula Ib

cox cox (Ia) (Ib) where A

A and B are hydrogen or N- is phenylacetamido, phenoxyacetamido or phthalimido, B

X is hydroxyl, methoxy, 2,2,2-trichloroethoxy, benzyloxy, p-nitrobenzyloxy or diphenylmethoxy which is characterized by cyclizing a compound of formula II (II) wherein A, B and X are as defined above and Hal is a halogen atom, such as a chlorine or bromine atom,

in a reaction medium such as methanol, ethanol, tetrahydrofuran, dioxane, benzene, hexamethylphosphoric triamide, dichloromethane, chloroform or water by reaction with an acid such as hydrochloric acid, perchloric acid, sulfuric acid, aluminum chloride, mercuric chloride, silica, or with a base such as dimethylaniline or a solvent such as hexamethylphosphoric triamide or a mixture of dichloromethane and methanol, optionally in the presence of a catalyst.

To date, many experiments have been reported for large-scale synthesis of the 3-cephem ring, but with the exception of cephalexin, there has been no industrial production of cephalosporins to synthesize the nucleus. The present invention relates to mild cyclization to give 3-hydroxy-3-cephem compounds via 4-mercapto-azetidinone derivatives.

3-Hydroxy-3-cephem compounds (Xa) are useful intermediates for the synthesis of useful cephem compounds (e.g. 3-methoxy-7- (alpha-phenylglycinamido) -3-cephem-4-carboxylic acid, 3-chloro-7- (alpha-phenylglycinamido) 3-Cephem-4-carboxylic acid, 3-bromo-7- (2-thienylacetamido) -3-cephem-4-carboxylic acid).

The starting compounds of formula II, IV or V may be prepared from compounds of formula

_of CH ₂ Hal or

cox (IV) (V) wherein A, B, Hal and X are as defined above, R 'is part of the acyl group R'CO-, and Y is a dir substituted amino group containing 2 to 20 carbon atoms, by treatment with aqueous acid in situ or after isolation.

The starting compounds can also be prepared from compounds of formula VI

(VI) wherein A, B, Hal, X and Y are as defined above and R 'is a hydrocarbon group having 1 to 20 carbon atoms, optionally substituted with an inert group selected from halogen, alkyl, nitro, alkoxy, alkoxycarbonyl or alkoxy having from 1 to 5 carbon atoms, by reacting the compounds with a Lewis acid (e.g. boron halide, aluminum halide, titanium halide or titanium tetraalkanoate in a solvent such as a halogenated hydrocarbon, aromatic hydrocarbon, ester, amide, alcohol, nitroalkane or ether , at a temperature of -10 ° C to +80 ° C, in particular 0 ° C to +40 ° C for 15 minutes to 6 hours, in particular for 1 hour to 3 hours.

Starting compounds can also be prepared from or X compounds of formulas VII, VIII, IX

!

R

R '

cox cox (ix) (x) wherein A, B, R, X and 1 are as defined above and R is hydrogen or a thiol protecting group. The process is characterized in that in successive reactions the reaction is carried out

i) sulfonylation to prepare compounds of formula XI or XII r '

Or

CH,

....... N.

in CH,

I ^c \ oz Cox (XI), (XII), wherein A, B, R, R 'and X are as defined above and Z is a sulphonyl group by treatment with a sulfonylating agent (especially alkanesulfonyl containing 1 to 5 carbon atoms or aryl sulfonyl halide having 6 to 12 carbon carbon) in the presence of a base, in particular a C 3 -C 9 trialkylamine and a C 4 -C 9 aromatic base, at -30 ° C to 20 ° C (especially -25 ° C to 0 ° C) for 15 minutes to 5 hours (especially 30 minutes to 3 hours.

ii) forming an enamine with a disubstituted amine containing from and yielding compounds of formulas XIII or XIV of up to 20 carbon atoms

/ \

Y (XIII)

CH

COX (XIV) wherein A, B, R, R and X are as defined above and Y is a disubstituted amino group containing 2 to 20 carbon atoms by treatment with 1 molar equivalent or even more (1 to 1.5 molar equivalent) of an amine (especially C 4 -C 8 alkyleneamine, morpholine, C 2 -C 6 dialkylamine) at -30 ° C to 20 ° C (especially -25 ° C to 0 ° C) for 5 minutes to 5 hours (especially 15 minutes) and (iii) then halogenating the product obtained in step (ii), with one molar equivalent or more (especially 1 to 2 mol) of a halogenating agent (especially molecular halogen, N-halamide or N-halimide), in 10 to 200 times by weight of a solvent (especially a halogenated hydrocarbon or ether) at a temperature of -50 ° C to + 50 ° C (preferably from -25 ° C to 0 ° C for 15 minutes to 4 hours (preferably from 0.5 to 3 hours)) This reaction sequence yields the desired starting material.

The latter process and the cyclization of the present invention can be carried out in one step, i.e. without isolation of any intermediate and without removal of solvent between reactions.

The thiol substituent R may be readily cleavable without adversely affecting the other portion of the molecule before or during the cyclization reaction. It may be an acyl group, for example tert-butoxycarbonyl, carbobenzoxy, cyclopropylmethoxycarbonyl, cyclopropylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, for example -alkoxy, acetyloxy, acetyloxy, , 1-benzoyloxyethyl), a monocyclic or dicyclic aromatic thio group (e.g., thiadiazolylthio, thiazolylthio, benzothiazolylthio, phenylthio, o-nitrophenylthio, naphthylthio, and the like).

In the compounds of formula V

N S (V)

CH, Hal

W ² cox

R 'is an acyl group represented by R'CO, Hal, X and Y as defined above, which can readily be hydrolyzed with aqueous acid to give 4-mercapto-3-R -CONH-azetidinone compounds.

The amine derivatives of formulas IV, V, XIII and XIV contain a Y group which is a disubstituted amino group containing from 2 to 20 carbon atoms. Preferred amino groups include dialkylamino groups, alkylarylalkylamino groups, alkylalkenylamino groups, alkylene amino groups, diarylalkylamino groups, dialkenylamino groups, and similar amino groups optionally substituted with an inert group, wherein the core may be interrupted by a heteroatom. The groups are intermediate and cleave from the product in the final step. The type of group can be very different if the reactions are not disturbed by this diversity. Most preferred groups are morpholino, C 4 -C 8 alkylene amino, C 2 -C 6 dialkylamino, C 14 -C 20 diarylalkylamino optionally substituted with an inert group such as alkyl or halogen. The amino group has the advantage over the various substituents in that it facilitates the desired halogenation and hydrolyzes under the mildest conditions as explained below.

The most preferred starting compounds of the formulas IV and V are the following formulas IVa and

Va

_/ CH ₂ Hal \ y

R

I ^ ^C \

N S

C = C

I cox

CH ₂ Hal

Y (IVa) (Va) wherein A is phenylacetyl or phenoxyacetyl, B is hydrogen, R is hydrogen, methoxymethyl, carbobenzoxy, cyclopropylmethoxycarbonyl or benzothiazol-2-ylthio, Hal is chlorine or bromine, X is methyl, benzyl, p nitrobenzyl, benzhydryl or 2,2,2-trichloroethyl, Y is piperidino, morpholino or dimethylamino and R 'is benzyl or phenoxymethyl.

The starting materials of formulas VII, VIII and IX and X can be prepared from penicillin-1-oxide by reaction of phosphitesters, acetic anhydride and the like to form alpha-isopropenylazetidine-1-acetic acid and derivatives thereof that are oxidized by ozone to produce a starting material wherein The alpha substituent is 1-hydroxyethylidene or 1-acetyl, which provides the corresponding starting materials by acylating agents, amination reactions, reactive nitrogen introducing agents and the like. Further, starting materials can also be prepared from the azetidin-2-one derivative and reactive acetoacetic acid derivatives.

The halogenation of the compounds of formulas XIII and XIV is carried out with a halogen cation or a halogen radical or equivalents thereof. Representative halogenating agents fall into the following categories:

X ₂ ', BrCl, IBr, C ₉ H _{11 I} X', C ₆ N ₁₁ H X ', X', C ₆ H ₅ N (CH ₃ ) ₂ X 'X', (alkyl) gSC 14 HX ', CuX 8.

2. -OX '(alkyl) OX', HOX ', (acyl) OX'.

3. = NX '(alkyl) ₄ NX'. X ₂ , NO ₂ x ', (acyl) NHX', (acyl) ₂ 'X'.

4. -SX 'sx ₂ , s + x ₂ .

. 5. -cx '

XgCHOCH ^ CX _4, alpha-haloketone, a-halosulfones, or like reagents, where alkyl and acyl contain 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 and the like) 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 carbonate, sodium, pyridine, quinoline, lutidine, diethylamine, triethylamine and the like). The onion ion of the starting compound formed is easier to halogenate to give the desired compound in higher yield under mild conditions.

When these halogenating agents are used over the carbanions of the parent compound, the parent 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 a carbanion followed by reaction with a halogenating agent. The reaction is preferably carried out in an aprotic solvent at a lower temperature so as to avoid side reactions.

The reactions of the starting materials with the halogenating agents are preferably carried out in an inert solvent.

Solvents include hydrocarbons (pentane, hexane, benzene, toluene, etc.), halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, dichlorobenzene, etc.), esters * (ethyl acetate, butyl acetate, methyl benzoate, etc.), ketones (acetone, cyclohexanone, benzophenone and the like). .), ethers (diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, tetrahydropyran, dioxane, morpholine, anisole, etc.), alcohols (methanol, ethanol, ethylene glycol, benzyl alcohol, etc.), carboxylic acids (acetic acid, propionic acid, etc.), bases (butylamine, triethylamine, pyridine, picoline and the like), amides (dimethylphosphamide, dimethylacetamide, hexamethylphosphoric triamide, etc.), nitriles (acetonitrile, benzonitrile, etc.), nitrocarbons, sulfoxides (dimethylsulfoxide and the like), water, liquid ammonium solvent and other solvents and mixtures thereof .

Particularly preferred solvents are aromatic hydrocarbons, halogenated hydrocarbons, esters, ethers, amides and acids.

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

Halogenations of compounds represented by the formula, provided that Y is other than amino, in some cases proceed smoothly and difficult in other cases. The main difficulty is the position into which halogen atoms are introduced. In other words, the priority of the desired position over other positions in the halogen molecule is rather low and varies from one compound to another. Another factor limiting Y to the above range is not in halogenation but in subsequent reactions, for example i) ease of deprotection to form a compound wherein Y is hydroxyl and ii) ease of cyclization to produce the desired cephem compound. The compounds represented by formulas XIII and XIV, provided that Y is a group other than hydroxyl, cyclize inefficiently or insignificantly. Of these findings, Y is limited to a substituted amino group, as explained above.

The products are unstable to alkalis and oxidation. Therefore, the reactions and work-ups are carried out without subjecting the reaction mixture to these conditions. *

Further, the preparation of the mercapto compound IV by elimination of the thiol substituent R, which is a carbon acyl, can be carried out by reacting compound VI with a Lewis acid according to the reaction scheme

CH ₂ Hal cox \

M ei_i

Lewis acid B

(VI)

Ί wherein A, Β, X, Υ and Hal have the above entry and R 'is hydrocarbyl of Γ to 20 carbon atoms, optionally substituted with an inert group such as halogenated arylalkyl, nitro, alkoxy or alkyl of 1 to 5 carbon atoms or carbalkoxy. The carbon acyl may be carbobenzoxy, tert-butoxycarbonyl, cyclopropylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, methanesulfonylethoxycarbonyl, isobornyloxycarbonyl, and the Lewis acid may be boron halide, aluminum halide, titanium halide and titanium alkanoate conditions. yield.

The cyclization can be carried out by reacting a compound of formula II with

i) acid ii) base or iii) solvent, optionally in the presence of a catalyst or under conditions that cyclize the ejection of material to the 3-cephem core. The starting compounds tend to cyclize almost automatically and under various mild conditions, whereby the cephem compounds can be isolated in good yield. The mercapto group at the 4-position of the starting materials may be in the form of a mercaptide anion. Kenya is required to use an isolated starting material II for the reaction, and any method that provides a starting material from the above intermediates wherein R is hydrogen can be used for the reaction. Typical examples of the method are the reaction of alpha- [3-phenoxymethyl or benzyl) -7-oxo-2,6-diaza-4-thiabicyclo [3.2.0] hept-2-en-6-yl] -alpha- ( 2-haloacetyl) acetic acid, alpha- [4-mercapto-3-phenoxyacetyl or phenylacetyl) -amino-2-oxoazetidin-1-yl] -alpha- (2-haloacetyl) acetic acid or a carboxylic acid derivative or an enamine derivative thereof in the alpha- (2-haloacetyl) group under aqueous acidic conditions. The reaction is carried out under the cyclization conditions outlined above for (i) and the product obtained is cephem compound Ia.

Acids used to acidify the reaction medium include mineral acids (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 weak base salts (such as aromatic or aliphatic bases, ammonia, alkaline earth metals, aluminum, silver) or their salts with common bases including alkali metal salts. The Lewis wads can also be used, preferably in an aprotic solvent.

Bases used for basic media preferably include these weak bases. Strong bases (e.g. alkali metal hydroxide, alkali metal carbonate, tertiary ammonium hydroxide) can 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, high polarity solvents 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 the solvent mentioned above under 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 eephem or cepham compounds are obtained in high yields.

The reaction products can be isolated from the reaction mixture by conventional methods, for example by removing unreacted materials, by-products, solvents, and the like, and purified by conventional methods, for example, by crystallization, chromatography, or reprecipitation.

The final product is 3-hydroxy-3-cephem-4-carboxylic acid or 3-oxocepham-4-carboxylic acid Ia or Ib. In some cases, the substituents at the 3 or 7 position of the cephem ring vary during the reaction or treatment and, as a result, the corresponding substituents in the starting and resulting materials are different. Optionally, these substituents can be converted back or converted to others by known methods. These cases are also included within the scope of the present invention.

In the cephem core of the products, the double bond is attached to the carbon atom at the 3-position. The double bond may be directed to the 2, 4 or 3-oxo substituent or, depending on the reaction conditions and processing method, may be a mixture thereof. These cases are also included within the scope of the present invention, usually the major product has a 3-cephem- or 3-oxo-double bond.

During cyclization, it is certain that they form the compounds as an intermediate regardless of whether they are isolated or not.

Halogenation, deprotection and cyclization can be carried out in one step, namely without isolation of intermediates and without removal of reaction solvents. The reaction is therefore carried out simply in one reaction step (see Examples 2 (2) and (3) and Examples 9 to 17 of Part III, cyclization).

Some starting materials are prepared by the following procedures.

Preparation

To a solution of methyl alpha- [4-mercapto-3-phthalimido-2-oxoazetidin-1-yl] -alpha- (1-hydroxyethylidene) acetate (100 mg) in tetrahydrofuran (3 mL) was added benzyl chloroformate (100 mg) and the mixture is cooled to -65 ° C. To the solution was added triethylamine (60 mg) and the reaction mixture was stirred for one hour. After warming to room temperature, the mixture was evaporated. Purification of the residue by silica gel chromatography gave methyl alpha - [4-benzyloxycarbonylthio-3-phthalimido-2-oxoazetidin-1-yl] -alpha- (1-benzyloxycarbonylethylidene) acetate (160 mg). Yield 94 The product does not contain an alpha isomer.

lc: in ° ^X ^ 3 1790, 1780, 1730 cm '. NMR: δ CDCl-δ 8.00 - 7.50 m, 4H, 7.40 s, 9H,

7.30 s, 5H, 6.27d, (5Hz), 1H, 5.90d, (5Hz), 1H, 5.27s, 2H, 5.17s, 2H, 3.70s, 3H,

2.47 s. 3H.

Preparation 2. To a solution of methyl alpha- (4-mercapto-3-phthalimido-2-oxoazetidin-1-yl) -alpha- (1-hydroxyethylidene) acetate (50 mg) in tetrahydrofuran (2 mL) was added cyclopropylmethyl chloroformate (50 mg), and the mixture was cooled to -65 ° C, then triethylamine (30 mg) in tetrahydrofuran (0.5 mL) was added. After stirring for 1 hour, the mixture was slowly warmed to room temperature, evaporated under reduced pressure and purified by silica gel chromatography using benzene containing 5% ether to give methyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phthalimido-2-oxoazetidin-1-yl] -alpha- (1-cyclopropylmethoxycarbonyloxyethylidene) acetate (61 mg), yield 79 *

The product was a mixture of geometric Ismeri substituent in the alpha position (about 3: 2). · ^{Lc: max 1790 L3 '780> 1730 cm -1} ·

NMR: δ CDCl3 8.00-7.60, m, 4H, 6.18, d, (5Hz), 3 / 5H, 6.10, d, (5Hz), 2 / 5H, 5.85, d, (5Hz) ), 3 / 5H, 5.78, d, (5Hz), 2 / 5H, 4.30-3.80, m, 4H, 3.87, s, 6 / 5H, 3.82, s, 9 / 5H, 2.53, s, 6 / 5H, 2.47, s, 9 / 5H, 1.60-0.90, m, 2H, 0.90-0.10, m, 8H.

Preparation 3

To a solution of 2,2,2-trichloroethyl alpha [4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-dihydroxyethylidene) acetate in tetrahydrofuran is added acid chloride and triethylamine and allowed to react for 1 to 3 hours, worked up in a conventional manner to give the following esters:

(1) 2,2,2-Trichloroethyl alpha [4- (2-benzothiazolyl) dithio-3-phenoxacetamido-2-oxoazetidin-1-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate; , 1,795, 1,753,

698, 1640, 1660 cm -1. NMR: δ CDCl ₃ 2.70, s, 3H, 3.38, s, 3H, 4.6, m, 4H, 5.25, d, (5Hz), 1H, 5.78, d, (5Hz 1 H, 6.8-8.0, m, 10H;

(2) 2,2,2-trichloroethyl alpha- [4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-toluene-p-sulfonyloxyethylidene) acetate, IR: v ^ ⁸¹ 3 3 420, 1780, 1770,

685 cm NMR: δ CDCl ₃ 2.28, s, 3H, 2.50, s, 3H, 4.55, s, 2H, 4.63, ABq, (12Hz), 2H,

5.08, dd, (7.5Hz), 1H, 5.78, d, (5Hz), 1H, 6.65-8.22, m, 14H;

(3) p-nitrobenzyl a- [4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2-oxo-azetidin-1-yl] -a- (1-cyklopropylmethoxykarboxylethyliden) acetate, i ^{*: n} _AX 3 3420 , 1,780, 1,685,

640 cm ^-1 . NMR: δ CDCl ₃ 0.05 - 1.52, m, 5H, 2.47, s, 3H, 3.95 + 4.02, d, (2H), 4.50 + + 4.58, s, 2H, 4.80-5.40, m, 4H, 6.67-8.13, m, 14H;

(4) 2,2,2-trichloroethyl alpha- [4- (2-benzothiazolyl) -dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-cyclopropylmethoxycarboxyethylidene) acetate, IR: v / v ^ 3,450, 1,790,

690, 1650 cm -1. NMR: δ CDCl ₃ 0.13-1.55, m, 5H, 2.52, s, 3H, 4.10, d, (7Hz), 2H, 4.53, ABq, (12Hz), 2H, 4 , 62, s, 2H, 5.11, dd, (7.5Hz), 1H, 5.75, d, (5Hz), 1H, 6.72 - 8.07, m,

10H.

Preparation 4

To a solution of p-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-hydroxyethylidene) acetate (904 mg) in a mixture (9.5 mL) of tetrahydrofuran and hexamethylphosphoric triamide (20 mL). 1) methanesulfonyl chloride (0.26 mL) and triethylamine (0.37 mL) were added. After two hours, the reaction mixture was quenched into ice water and extracted with chloroform. The chloroform solution was washed with water and evaporated to give p-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate (1.12 g). Yellow foam. IČ: v 3,426, 1,785, 1,722-1,704br,

640, 1601, 1160, 1175, 986 cm @ -1. NMR: δ CDCl 3 0.32-1.25, m, 5H, 2.57, s, 3H, 2.72, s, 3H, 3.99, d, (7Hz), 2H, 4.55, s, 2H, 5.33-5.99, m, 4H, 6.82-7.62, m, 7H, 8.21, d, (8.5Hz), 2H.

The following compounds were prepared by similar acylation;

(1) p-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-methoxycarbonyloxyethylidene) acetate, IR; ^v Jjax ^ 1,780, 1,731, 1,643,

612, 1 601 cm ¹ . NMR: δ CDCl ₃ 0.2 - 1.33, m, 5H, 2.34, s, 3 / 2H, 2.50, s, 3 / 2H, 3.74, s, 3 / 2H, 3.83 s, 3 / 2H, 3.97, d, (7Hz), 2H, 4.52, s, 2H, 5.26, s, 2H, 5.53-6.00, m, 2H,

6.79-8.24, m, 9H;

(3) 2,2,2-trichloroethyl alpha- [4- (o-nitrophenyl) dithio-3'-phenoxyacetamido-2-oxoazetidine] CFIP1

-1-yl] - .alpha .- (1-cyclopropylaethoxycarbonyloxyethylidene) acetate, IC: 3430, 1781,

750sh, 1685, 1640, cm ^-1 . NMR: δ CDCl3 0.2-1.4, m, 5H, 2.50, s, 3H, 4.13, d, (8Hz),

2H, 4.53, ABq, (12Hz), 2H, 4.56, s, 2H, 5.15, dd, (5.8Hz), IH, 5.43, d, (5Hz), 1H,

6.8-8.4, m, 10H.

Preparation 5

To a solution of 2,2,2-trichloroethyl alpha- [4-mercapto-3-phenoxyaoetamido-2-oxoazetidin-1-yl] -alpha- (1-hydroxyethylidene) acetate silver salt (695 mg) in hexamethylphosphoric triamide (8 mL) was added. mixture with cyclopropylmethyl chloroformate (480 mg) and triethylamine (180 mg) was added and the mixture was stirred for one hour. The reaction mixture was poured into ice water and extracted with benzene. The extract was washed with water, dried and evaporated to give the product which was purified; Chromatography on silica gel gave 2,2,2-trichloroethyl alpha- [4-cyclopropylmethylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-cyclopropylmethoxycarbonyloxyethylthio) acetate (650 mg). Yield 64.4%.

The product is a mixture (about 4: 3) of the geometric isomers of the substituent at the alpha position.

ID: v ® “® ^X 3 3 440, 1 785, 1 720 cm ¹ . NMR: δ CDCl 3 0.1-1.3, m, 10H, 2.4, s, 3H, 4.0, m, 3H, 4.60, s, 2H, 4.83, s, 2H, 5, 2-6.1, m, 2H, 6.8-7.5, m, 6H.

Preparation6

To a solution of p-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate (1.12 g) in benzene (11 mL) was added morpholine (0.26 mL) with cooling and the mixture was kept at 10 ° C overnight. The reaction mixture was washed with water, dried and evaporated under reduced pressure. Purification of the obtained residue (1 g) by chromatography on silica gel (10 g) using a mixture of benzene and ethyl acetate (1: 2) gave p-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyaoetamido-2-oxoazetidin-1-yl] - alpha- (1-morpholinoethylidene) acetate (602 mg). Foam. ID: v 3,430, 1,774,

694br, 1 604, 1 150 cm ^-1 . NMR: δ CDCl 3 0.22, m, 5H, 2.27 + 2.40, s, 3H, 3.43, m, 4H, 3.77 m, 4H, 4.02, d, (6.4 Hz) ), 2H, 4.57, s, 2H, 5.05-5.27, m, 3H, 5.89, d, (5.4Hz), 1H, 4.12-7.65, m, 7H, 8.23, d, (8.4Hz), 2H.

The following compounds were similarly obtained from the corresponding methanesulfonates by the procedure described above.

(1) 2,2,2-Trichloroethyl alpha- [4- (benzothiazolyl) dithio-3-phenoxyacetamido-2-oxoazetidine

-1-yl] - .alpha .- (1-piperidinoethylidene) acetate, IR: .delta. 3440, 1773, 1690, 1600 cm ^-1 .

NMR: δ CDCl3 1.68, brs, 6Ii, 2.4, brs, 3H, 3.36, brs, 4H, 4.63, m, 4H, 5.0-5.7, m, 2H,

6.8 - 8.0, m, 10H.

(2) p-Nitrobenzyl alpha- [4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-piperidinoethylidene) acetate, NMR: δ CDCl 3 1.63, brs, 6H, 2.33, brs, 3H, 3.3, brs, 4H, 4.53, s, 2H, 5.0-5.5, m, 4H, 6.8-8.2, m, 14H.

Similarly, the following compounds were prepared from the corresponding chlorides.

(1) 2,2,2-Trichloroethyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-piperidinoethylidene) acetate. ID No: θ ^ ¹ 3 3 440, 1 780, 1 710,

695 cm ¹ . NMR: δ 0.2-1.3, m, 5H, 1.67, brs, 6H, 2.40 or 2.27, s, 3H, 3.35, brs,

4H, 3.98, d, (7Hz), 1H, 4.57, s, 2H, 4.73, s, 2H, 5.13-6.07, m, 2H, for isomers.

(2) 2,2,2-Trichloroethyl alpha- [4- (benzothiazolyl) dithio-3-phenoxyacetamido-2-axoazetidin-1-yl] -alpha- (1-piperidinoethylidene) acetate mentioned above.

1

Preparation of a 7-solution of p-nitrobenzyl .alpha .- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabieyclo [3.2.0] hept-2-en-6-yl] -alpha- (1- hydroxyethylidene) 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 over magnesium sulphate 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.

I WANT 1

The product does not contain the geometric isomer at the alpha position. IC: _{ν max} 3 1780, 1730 cm.

NMR: δ CDCl ₃ 2.60, s, 3H, 3.18, s, 3H, 4.58, + 4.88, ABq, (14Hz), 2H, 5.24, s, 2H, 5.92 i + 6.08, ABq, (5Hz), 2H, 6.73-8.20, m, 9H.

Preparation8

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 toluene-p-sulfonyl 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 [3.2.0] hept-2-en-6-yl] -alpha- (1-toluene-). p-sulfonyloxyethylidene) acetate (644 mg).

IR: £ ₃ HC1, _{785 (, 735 cm} -1 _t jjjjjj. _{8 CDC1} 3 _2j 45, _{S @ 3 H 4> 75 + 4 (20j ABq> (14Hz))} 2H;

5.15, s, 2H, 5.77, b, 2H, 8.30-6.60, m, 13H.

Preparation 9

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) of 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 (MgSO 4) 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 alpha position.

IR: v 1,768, 1,685, 1,612, 1,623 cm ^-1 . NMR: δ CDCl-δ 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 10

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 obtained 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, (12Hz), 2H, 4.95, s,

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

Preparation 11

To a stirred solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thla-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 ice-cooling, methyl chloroformate (200 mg) and triethylamine (216 mg).

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-methoxycarbonyloxyethyl) acetate (546 mg). Foam. Yield 97%.

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

IR: [delta] 1773, 1732, 1642, 1612, 1600 cm &^lt; -1 ^>. NMR: δ CDCl-δ 1.95, s, 1H, 2.47, s, 2H, 3.68, s, 1H, 3.80, s, 2H, 4.54 + 4.86, ABq, (Ι4Ηζ) ), 4 / 3H, 4.86, s, 2 / 3H, 5.25, s,

3H, 5.73-6.03, m, 2H, 6.70-8.16, m, 9H.

Preparation 12

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 methanesulfonyl chloride (0.093 mL) and triethylamine (0.48 mL) at -25 ° C and held at this temperature for 40 minutes. To the resulting solution of 2,2,2-trichloroethyl alpha- [3-benzyl-]

Morpholine (0.112 mL) was added dropwise to -7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate, and Stir 1.3 hours. The reaction mixture is washed with water, dried and the residue obtained 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: δ CDCl ₃ 1.67, s, +2.35, s, (3H), 2.83-4.00, 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 13

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

The product does not contain a geometric isomer in alpha position.

t

IR: 3 ° ≤ ¹ 1784, 1728, 1700, 1614 cm ^1st NMR: δ CDCl-δ 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.

Preparation14 *

To a solution of p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en6-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate ( 609 mg) in methylene chloride (3 mL) was added morpholine (0.2 mL) at -15 ° C 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. The purified foam obtained (569 mg) was chromatographed on silica gel (25 g) to obtain p-nitrobenzyl .alpha .- [3-benzyl-7-oxo-4-thia-2] eluting with 2: 1 benzene / ethyl acetate. 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.

IR: C-j ^, _{778 (, 695j, 615 cm} - \ _NKJR; CDC1 ₃ δ 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 conform to the following formulas XV and XVI R '

C = C

COX (XVI) ₃ '' wherein A, B, R, 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 aromatic or aliphatic sulfonyl having 1 to 20 carbon atoms. *

Compounds XV or XVI wherein Y is a disubstituted amino group can be prepared by the following reactions by conventional methods as set forth in the preparations above.

SR acylation with sulfonyl acid acceptor

CH,

Ό-sulfonyl

SR .CH, cox> -N _{K from} ^ch 3

O ^X C = C <-.

I pcox wherein A, B, R, X is as defined above, at a temperature of from -30 ° C to 0 ° C.

The process may be carried out in a single vessel, in particular it is not necessary to isolate the intermediates from the enamine preparation steps.

The preparation of enamines by the above process and halogenation, 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 cephem compound I from compound XV or XVI, wherein Y 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 carbon solvents (e.g. chloroform, methylene chloride and dichloroethane).

As mentioned above, the present invention exhibits higher yields and is a simpler procedure of cheaper penicillins for the preparation of key intermediates of 3-hydroxy-3-cephem compounds.

The following examples illustrate the invention without limiting it in any way. The description of the double bond bound at position 3 includes the presence of the positional isomers relative to the double bond bound at position 3.

Part I. Halogenation.

Example 1-1

Dissolve p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabieyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) acetate (939 mg) in tetrahydroduran (14 mL), the solution was cooled to -40 ° C, triethylamine (0.67 mL) and methanesulfonyl chloride (0.187 mL) were added, and the reaction 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 extract with 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-acetyl acetate (81.7 mg, yield: 7.5 35), ₍ 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 [3.2.1] hept-2-en-6- yl] - alpha .alpha .- (1-morpholinoethylidene) acetate (120.5 mg, 11.2% yield).

Example 2-1

Dissolve p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -aflo- (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 16 minutes. Then N-chlorosuccinimide (97 mg) was added, the reaction mixture was stirred at -20 ° C for two hours, washed with water, dried and evaporated. Purification of the obtained residue (368 mg) by silica gel chromatography with 10% water (18.4 g) using benzene / ethyl acetate (1: 1) afforded p-nitrobenzyl-alpha-β-phenoxymethyl-7-oxo-4-thia- 2,6-diazabieyclo [3,2,0] hept-2-en-6-yl] -alpha- (1-morpholino-2-chloroethylidene) acetate (106 mg, 31.2%) 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 (134 mg, 42 , 0%).

Example 3-1

Dissolve p-nitrobenzyl-alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -1-hydroxyethylidene) acetate ( 940 mg) in dichloromethane (14 mL), 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 solution, and water, dried and evaporated. Purification of the resulting residue (1457 mg) was chro _(HPLC on silica gel containing 10% water (100 g) using benzene-ethyl acetate (2: 1) to afford p-nitrobenzyl a- [3-7-fenoxyme.thyl oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha-methanesulfonyl-alpha- (dibromoacetyl) 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- t)

morpholino-2-bromoethylidene acetate (1033.5 mg, 83.7%).

Example 1 a d 4-1

Dissolve p-nitrobenzyl .alpha .- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabioylclo [3.2.1] hept-2-en-6-yl] - .alpha .- (1-hydroxyethylidene) acetate ( 940 mg) in dichloromethane (14 mL), the solution was cooled to -25 ° C, triethylamine (0.61 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 mol) dissolved in carbon tetrachloride (2.2 mL) was added and after 30 minutes at -25 ° C. A 5% aqueous sodium bicarbonate solution was added to the ° C, washed with a defect, dried and evaporated. Purification of the obtained residue (1.134 g) by chromatography on silica gel with 10 ΐ water (100 g) using benzene / ethyl acetate (3: 1) afforded p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2]. 6-diazabicyclo 13,2,0] 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-en76-yl] -alpha-methanesulfonyl-alpha-acetylacetate (1,332.2 mg, 12.2%) ).

Example 5-1

Dissolve the p-nitrobenzyl a- [4-methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl] -a ^a- (1-hydroxyethylidene) acetate (1.06 g) in tetrahydrofuran (10 ml) solution of After cooling to -40 ° C under a nitrogen atmosphere, triethylamine (489 mg) dissolved in tetrahydrofuran (1 mL) and methanesulfonyl chloride (252 mg) dissolved in tetrahydrofuran (1 mL) were added and the reaction mixture was stirred at -40 ° C for 30 min. and 45 minutes at 0 ° C. To this solution was added morpholine (209 mg) dissolved in tetrahydrofuran (1 mL), the reaction mixture was maintained at 0 ° C for two hours, N-bromosuccinimide (392 mg) was added, and the reaction mixture was maintained at 0 ° for 1.5 hours. C, water was added, the oily material precipitated and extracted with ethyl acetate. The extract and the separated oily material were combined, dried (MgSO4) and evaporated, purifying the residual oil (1.4 g) by chromatography on silica gel with 5% water (20 g) to give p-nitrobenzyl alpha- [4-methoxymethylthio-3-phenoxyacetamido 2-oxo-azetidin-1-yl] -alpha- (1-morpholino-2-bromoethiidene) acetate (700 mg, 52% yield) and p-nitrobenzyl alpha- [4-methoxymethylthio-3-phenoxyacetamido-2-oxo -azetidin-1-yl] -alpha- (1-morpholinoethylidene) acetate (170 mg, 14% yield).

Stir the first product (100 mg) with 10% hydrochloric acid (0.3 mL) in a mixture of methanol (2 mL) and tetrahydrofuran (1 mL) at 0 ° C for 90 minutes and then isolate by diluting with water, evaporating, dissolving in chloroform, washing water, drying over magnesium sulfate and evaporation gave p-nitrobenzyl alpha- [4-methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl] -alpha- (1-hydroxy-2-bromoethylidene) acetate (70 mg) . Yield 78%.

Example 6-1

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, a solution of methanesulfonyl chloride (1 M in methylene chloride 2.2 mL) and a solution of triethylamine (1 M in methylene chloride, 2.2 mL) were added, the reaction mixture was stirred for 90 minutes, cooled to -25 ° C, morpholine (0.35 mL) was added, stirred for 65 minutes, N-bromosuccinimide (340 mg) was added, 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 gave p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.1] hept-2-en-6-yl] alpha - (1-morpholino-2-bromoethylidene) acetate (710 mg). Yield 65%.

Example 7-1

The azetidineacetic acid derivatives (1) are dissolved in a solvent, optionally an additive is added, the brominating agent is added, and allowed to react for a given period of time at said temperature. The solution was washed with water, dried and evaporated.

Purification of the obtained residue by chromatography on silica gel containing 10% water and evaporation of fractions containing the desired compounds afforded brominated azetidineacetic acid derivatives (2).

The reaction conditions are given in Table I and the physical constants are given in Table XI.

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Example 8-1

In a manner similar to that described in Examples 1 to 7, the following compounds were prepared:

(1) p-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-thienylacetamido-2-oxo-azetidin-1-yl] -alpha- (1-morpholino-2-bromoethylidene) acetate;

(2) 2,2,2-trichloroethyl alpha- [4-methylsulfonylethylthio-3-carbobenzoxyamido-2-oxo-azetidin-1-yl] - alpha - (1-piperidino-2-bromoethylidene) acetate;

(3) phenacyl alpha- [4-ethoxycarbonylmethylthio-3- (2,2,2-trichloroethoxycarbonyl) amino-2-oxoazetidin-1-yl] -alpha- (1-morpholino-2-bromoethylidene) acetate;

(4) alpha - [4-isobutyrylthio-3R (o-nitrophenylsulfenyl) amino-2-oxo-acetidin-1-yl] - alpha - (1-acetoxy-2-bromoethylidene) acetic acid sodium salt;

(5) pivaloyloxymethyl alpha - [4-benzoylthio-3- (N-tert-butoxycarbonyl-alpha-phenylglycinamido) -2-oxo-azetidin-1-yl] - alpha - (1-dimethylamino-2-chloroethylidene) acetate;

_f (6) 2,2,2-Trichloroethyl alpha- [4-chloroacetylthio-3- (N-trichloroethoxycarbonyl-alpha-phenylglycinamido) -2-oxo-azetidin-1-yl] -alpha- (1-chloro-2- bromoethylidene) acetate;

(7) alpha - [4-benzylthio-3- (2,2-dimethyl-4-phenyl-5-oxoimidazolidin-1-yl) -2-oxo-azetidin-1-yl] - alpha - (1-methoxy- 2-bromoethylidene) acetic acid;

(8) 2,2,2-trichloroethyl alpha [4-anilinothio-3- (o-hydroxybenzylidene) amino-2-oxo-azetidin-1-yl] -alpha- (1-diphenylphosphinyl-2-bromoethylideneacetate) and (9) alpha- [3-methyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-chloro-) diisopropylidene hydrazide. 2-bromoethylidene) acetic acid.

Example 9-1

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 -15 to -20 ° C for one hour. To the resulting solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-methanesulfonyloxyethylidene) 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 [3.2.0] hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate, which is cooled to -15 ° C, pyridine (0.174 mL) was added and then after 5 minutes a solution of bromine in carbon tetrachloride (1 mol / liter, 2.1 mL) was stirred for 15 minutes at the same temperature, poured into a | water (50 mL) and extracted with ethyl acetate (50 mL).

The extract was washed with water, dried over magnesium sulphate and evaporated to give 1.7 g of a residue. Purification of the residue by chromatography on silica gel with 10% water yielded p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diabicyclo [3] fractions eluting with 2: 1 benzene / ethyl acetate. 2,0] hept-2-en-6-yl] -alpha- (2-bromo-1-morpholinoethylidene) acetate (1.109 g, yield 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, yield 7, 7%).

A similar reaction using N, N-dimethylformamide (14 mL) instead of tetrahydrofuran gave the same products (90 mg, 73.6% and 100 mg, 9.0%).

Example 10-1

Suspend p-nitrobenzyl alpha- [3-benzyl-7-oxo-ethylidene) -2,6-diaza-4-thiabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1) -hydroxyethylidene acetate (2.265 g) in anhydrous tetrahydrofuran (30 ml), and a solution of triethylamine (1.11 g) and methanesulfonyl chloride (630 mg) in tetrahydrofuran (2 ml) was added dropwise at 1 to 2 ° C and the reaction mixture was stirred at room temperature. Stir 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-7-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-benzyl-7-oxo-2,6-diaza-4- thiabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-morpholinoethylidene) acetate, which was cooled to -20 ° C, pyridine (396 mg) and a solution of bromine in carbon tetrachloride were added (1 mol / liter, 5 ml), after 15 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-1-morpholinoethylidene) acetate (2.36 g). Yield 78%.

"and

The product, without isolation from the solution, can be diluted with 5% hydrochloric acid (10 mol equivalents) and methanol and stirred at room temperature for 3 hours to give p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate in more than 70 % yield.

EXAMPLE 11-1

Dissolve diphenylmethyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) acetate ( 4.84 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, and the reaction mixture was allowed to react 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-methanesulfonyloxyethylidene) acetate , 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, -bromine is added, (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.

To this solution was added dropwise 5% hydrochloric acid (72 ml) and methanol (60 ml), the reaction mixture was stirred at room temperature for 3 hours, and allowed to stand overnight in the refrigerator.

The reaction mixture was evaporated, the residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate and evaporated. Purification of the obtained residue (5.83 g) by chromatography on silica gel with 10% water (150 g) afforded diphenylmethyl 7-phenylacetamido-3-hydroxy-3 from the fractions eluted with benzene / ethyl acetate (4: 1) after crystallization from n-hexane. -cephem-4-carboxylate (3.51 g), mp 93-96 ° C. Yield 70%. 10: ^ 3 3410, 1782, 1674, 1610 cm ^-1 . NMR: δ CDCl 3

3.20, s, 2H, 3.64 s, 2H, 4.97, d, (· 4Ηζ), IH, 5.66, dd, (9: 4), IH, 6.77, d, (9Hz) ), 1H,

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

«

Example 12-1

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 mixture was 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 obtained residue (461 mg) by silica gel chromatography (25 g) yielded p-nitrobenzyl .alpha .- [3-benzyl-7-oxo-4-thia-2,6-] from a fraction eluted with a 2: 1 mixture of benzene and ethyl acetate. diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (2-bromo-1-morpholinoethylidene) acetate (289 mg).

Yield 54.5%. ·δ: ^{v 1 77θ} > ^{1 69} °>' ^{610 cm} ' ¹ · NMR: δ ^CDCl 3 3.00-3.74, m, 8H,

5.52, s, 2H, 4.47 + 4.71, ABq, 03Hz), 2H, 5.23, s, 2H, 5.68, d, (4Hz), 1H, 5.94d (4Hz) 1H , 7.20-8.25, m, 9H.

Part II. Removal of protecting groups

Example 1 —II

To a solution of 3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-ene (200 mg) in a mixture of methylene chloride (8 mL) and acetone (8 mL) was added 30% aqueous perchloric acid solution (1.0 mL) and the mixture was stirred at room temperature for 40 minutes. After dilution with excess water, the reaction mixture was extracted with methylene chloride. The extract was washed with water, dried over sodium sulfate and concentrated. A white crystalline 4-beta-mercapto-3-beta-phenoxyacetamido-2-oxoazetidine, m.p. 137-138 ° C, is obtained as a residue.

[α] ²³ + 38.0 ± 3) 0 ⁰ [c = 0.261, CHCl 3 + CH 2 OH (4: 1)] ¹ C: ^ν max ^{01 3 290} > ^{3 200} ' ^{2 562} >' ^{757, 1 65S} >' ^{549 cm_1} · ™ ^{W : 5 d} 6 ^DMS0 3,17, brs,

1H 4.58, s, 2H, 5.00, brs, 1H, 5.32, dd, (9 &apos; 5Hz), 1H, 6.80-7.43, m, 6H.

Example 2-II

To a solution of (R ³ ) alpha- [3-substituted (R ') -7-oxo-4-thia-2,6-diazabicyclo [3.2.1] hept-2-en-6-yl] -alpha. -substituted ⁽² R) -acetic acid (5) in a solvent acid was added and the mixture was stirred at that temperature for the indicated time. The reaction mixture was diluted with water and extracted with methylene chloride. The extract was washed with water, dried over sodium sulfate to give the desired (R ³ ) alpha- [4-mercapto-3-substituted amino-4 -CONH-R-oxoazetidin-1-yl] -alpha-substituted (R ² ) acetic acid ester (6).

Table III gives the reaction conditions and Table IV gives the physical constants of the product (6). Table III shows the weight yield of the crude products. The products are almost pure according to thin layer chromatography and NMR spectra. Some of them were purified by crystallization.

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Example 3-II

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-isopropenyl acetate (200 mg) in tetrahydrofuran (5 ml) oxalic acid (200 mg) and water (0.5 ml) were added and the mixture was stirred at room temperature for three hours. The chromatogram of the reaction mixture showed the presence of β-nitrobenzyl alpha- [4-mercapto-3-phenoxyacetamido-2-oxo-azetidin-1-yl] -alpha-isopropenylacetate and the starting material.

Example 4-II

Following the procedure of Example 2, the following compounds were prepared:

(1) 4-mercapto-3-thienylacetamido-2-oxo-1-acetylazetidine from 6-acetyl-3-thienylmethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2 (2) 4-mercapto-3-benzamido-2-oxo-1-trifluoroacetyl azetidine from 6-trifluoroacetyl-3-phenyl-7-oxo-thia-2,6-diazabicyclo [3.2.0] hept- (3) 4-mercapto-3-acetamido-2-oxo-1-methylazetidine from 3,6-dimethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept (4) 4-mercapto-3- (alpha-phenyl-alpha-chloroacetamido) -2-oxo-1-carbethoxycarbonylazetidine from 6-carbethoxycarbonyl-3-phenyl-chloromethyl-7-oxo-4-thia -2,6-diazabicyclo [3.2.0] hept-2-ene, (S) alpha- [4-mercapto-3-formamido-2-oxoazetidin-1-yl] -alpha-isopropylidene acetic acid and from alpha- [7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] - [alpha] -isopropylidenoic acid and (6) 4-mercapto-3-benzylthiocarbonylamino-2 -oxo-1-p-toluenesulfonylazetidine from 3-benzylthio-6-p-toluenesulfonyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-ene.

Part III. Deprotection and cyclization

Example 1-III

1. To a solution of methyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phthalimido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-cyclopropylmethoxycarbonyloxyethylidene) acetate (500 mg) in methylene chloride (20 mL) is added in one portion aluminum chloride (510 mg) and the mixture was stirred at room temperature. After one hour, the mixture was poured into cold 3% hydrochloric acid (20 mL) and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and evaporated to give methyl alpha- [4-mercapto-3-phthalimido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate (252 mg) . Yield 72.5%.

However, in CHCl 3, 790, 1783, 1728, 1670, 1620 cm -1. NMR: δ ^CDCl3 1.80, d, (11Hz), 1H, 3.87, s, 3H, 4.22 + 4.56, AB2, (10Hz), 2H, 5.38, dd, (11; 5Hz), 1H, 5.70, d, (5Hz), 1H, 7.76, m, 4H, 12.3, s, 1H.

2. Methyl alpha [4-mercapto-3-phthalimido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate (a) is reacted under the following conditions to give methyl 3-hydroxy -7-phthalimido-3-cephem-4-carboxylate (b), mp 223-226 ° C, IR: [delta] 1797, 1779,

728, 1667, 1716 cm ^-1 .

NMR & C® ° 3 ^X 3.26 and 4.5, ABq (14), 2H, 5.60, s, 3H, 5.63 + 6.15, ABq, (4), 2H, 7.16 , m, 4H.

i) To a solution of (a) (80 mg) in benzene (8 mL) was added N, N-dimethylaniline (20 mg) and the mixture was heated to boiling under nitrogen. After 30 minutes, the reaction mixture was cooled, acidified with 5% hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated. The residue (71 mg) was treated with ethyl acetate (1 mL), allowed to stand for a while, yielding (b) mp 223-226 ° C. Yield 38.9% ii) A solution of (a) (150 mg) in hexamethylphosphoric triamide (1 ml) was stirred at room temperature for one hour. The reaction mixture was treated with ice water (6 ml) and ether (0.5 ml) to give crystals (b) (50 mg) which were filtered off. Yield 40.8%.

iii) Solution (a) (200 mg) was applied to a pre-prepared preparative chromatography plate (silica gel F-254) from Merck AG. and developed with a 2: 1 mixture of benzene and ethyl acetate. The main belt was extracted with ethyl acetate containing 3% methanol and the extract was evaporated under reduced pressure. The residue was dissolved in chloroform, freed from insoluble matter and evaporated to give compound (b) (62 mg). Yield 37.9%.

Methyl 3-oxo-7-phthalimidocepham-4-carboxylate (b) prepared by the above methods was dissolved in dioxane, treated with a solution of diazomethane in ether and stirred for one hour (at room temperature. The reaction mixture was evaporated under reduced pressure to give methyl 3-methoxy-7-phthalimido-3-cephem-4-carboxylate in almost quantitative yield Crystallization from acetone / ether gave pure crystals of mp 225-227 ° C.

Example 2-XII

1. To a solution of 2,2,2-trichloroethyl-alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha [2-bromo-1- (piperidin-1-yl) ethylidene] of acetate (573 mg) in methanol (30 mL) was added, 0% hydrochloric acid (7 mL), and the mixture was stirred at room temperature or at 40-45 ° C. After 30 minutes, the reaction mixture was poured into ice water and extracted with benzene. The extract was washed with water, dried and evaporated to give 2,2,2-trichloroethyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate ( 434 mg). Yield 83.5%.

IR: HC1 ° _{3 3 450j, 7g0 (, 72Qi, 720} (infiex), ₇₀₀ cm ^- '. NMR δ ^CDG1 3 0.1 to 1.4, m, 7H, 3.98, d. (7Hz ), 2H, 4.27, d, (5Hz), 2H, 4.57, s, 2H, 4.82, d, (3Hz), 2H, 5.27, d, (6.8Hz), 1H, 5.93, d, (5Hz), 1H, 6.8-7.5, m, 6H, 11.67, brs, 1H.

2. To a stirred solution of 2,2,2-trichloroethyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyaoetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate (330 mg) in methylene chloride (6 mL) was added aluminum chloride (330 mg) at room temperature and the mixture was stirred for 60 minutes. The reaction mixture was poured into iced dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water, dried and evaporated to give 2,2,2-trichloroethyl 7-phenoxyacetamido-3-oxooefam-4-carboxylate (300 mg). Foam. ICV ^{G "G1} 3 3420, 1780, 1685 cm ^- '. NMR: δ ^CDCl 3 3.37, s, 2H, 4.53, s, 2H,

4.85, s, 2H, 5.07, d, (4), 1H, 5.20-5.73, m, 2H, 6.8-7.7 m, 6H.

Example 3-IH

Using the method described in Example 2 (1), 2,2,2-trichloroethyl alpha- [4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- [2-bromo-1- (piperidin-1-) yl) ethylidene] acetate hydrolyzed in methanolic hydrochloric acid to give 2,2,2-trichloroethyl alpha- [4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) ) acetate and the product was cyclized with aluminum chloride in methylene chloride to give 2,2,2-trichloroethyl 7-phenoxyacetamido-3-oxocepham-4-carboxylate, which is identical to the product of Example 2 (2).

Example 4-III

1. To a solution of p-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- [2-bromo-2- (morpholin-4-yl) ethylidene] acetate (300 mg) with a mixture of methanol (22 ml) and methylene chloride (3.5 ml), 10% hydrochloric acid (4 ml) was added and the mixture was stirred under nitrogen at room temperature. After two hours, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried to give p-nitrobenzyl-4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxo-afla- (2-bromo-1-hydroxyethylidene) azetidine-1-acetate (252 mg). Foam. Yield 92.8%.

^{lc: max L3 3426> '782> 1} ° ^{71' 69} ° ^{1 '601 cm'} '· M ⊕ ^{5 * 8 CDC1} 3 0.23 to 1.33, m, 5H, 3.84 - 4.36, m, 4H, 4.55, s, 2H, 5.10-5.32, m, 3H, 5.88, d, (5Hz), 1H, 6.83-8.33, m, 9H, 12.0, s, 1 H.

2. To a solution of p-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl-alpha- (2-bromo-1-hydroxyethylidene) acetate (218 mg) in methylene chloride (2.1) ml) aluminum chloride (220 mg) was added under ice-cooling, and the mixture was stirred under argon. After 35 minutes, the reaction mixture is poured into ice-cold water

N hydrochloric acid (4 mL), stirred for 10 minutes and extracted with chloroform. The extract was washed with water, dried and evaporated to give β-nitrobenzyl alpha- [4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate (150 mg), yellow foam. Yield 94.6%. IR: v 3400, 1780, 1692, 1610, 1623 cm ^-1 . NMR: δ ^CDCl 3 2.25, d, (1OHZ), 1H, 4.25, d, (2Hz), 2H, 4.58, s, 2H, 5.20-5.37, m, 4H, 6 , 84-8.24, m, 9H, 12.1, s, 1H.

3. To a solution of p-nitrobenzyl alpha- [4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene acetate (106 mg) in benzene (5 mL) is added Silica gel F-254 (500 mg) from E. Merck, AS and shaken at room temperature for one hour, insoluble material was filtered off and washed several times with chloroform. The filtrate and washed solution were combined and evaporated under reduced pressure to give a p- nitrobenzyl 3-hydroxy-7-phenoxyacet

Qmido-3-cephem-4-carboxylate (60 mg). Yield 66.3%, mp 95.5-99.5 ° C. IR: v2 ^8C1 3400 pnn max

785, 1685, 1 605. NMR: .delta. 2.03, s, 2H, 4.60, s, 2H, 5.07 + 5.37, ABq, (4), 2H, 5.37, d, (4), 1H, 5.68, dd, (9.4), 1H, 6.83-8.32, m, 9H.

4. A solution of p-nitrobenzyl alpha- [4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate (70 mg) was prepared according to the method of Example 4 (2). ) in a mixture of methylene chloride (2 mL) and methanol (2 mL) and stirred at room temperature for three hours. The reaction mixture 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 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (42 mg), identical to the product of Example 4 (3). Yield 70%.

5. A solution of p-nitrobenzyl alpha- [4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate prepared as in Example 4 (2) (70 mg) in a mixture of methylene chloride (2 mL), methanol (2 mL) and 10% hydrochloric acid (0.3 mL) was stirred at room temperature for two hours. The reaction mixture 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 3-oxo-7-phenoxyacetamidocaphan-4-carboxylate (44.5 mg) identical to the product of Example 4 (3). Yield 74%.

* Example 5-III

A solution of p-nitrobenzyl alpha- [4-carbobenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- [2-bromo-1- (morpholin-4-yl) ethylidene] acetate (469 mg) in a mixture of methylene chloride (4 ml), methanol (4 ml) and 10% hydrochloric acid (0.8 ml) was stirred at room temperature for two hours. The reaction mixture was diluted with ice water and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and evaporated to give p-nitrobenzyl207654 alpha- [4-carbobenzoxythio-3-phenoxacetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate (426 mg) ). Quantitative yield, ΐδ: μ ^c ^ ^cl 3 3 408, 1 788, 1 725, 1 696,

615, ¹⁶⁶⁰ cm NMR: δ ^{υ υχ} 3 4.27, d, (3Hz), 2H, 4.48, s, 2H, 5.16, s, 2H, 5.22, s, 2H,

5.29, m, 1H, 5.86, d, (5Hz), 1H, 6.74-8.20, m, 9H.

2. To a solution of ρ-nitrobenzyl alpha- [4-carboxybenzoxythio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate (480 mg) in methylene chloride (5 mL) containing A solution of aluminum chloride (270 mg) in methylene chloride containing 20% nitromethane (4 mL) was added to 20% nitromethane, and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into dilute hydrochloric acid and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and evaporated to give p-nitrobenzyl alpha- [4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate (376 mg) ). Yield 99.5%.

Example 6-IXI

To a solution of p-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl] -alpha- [2-bromo-1- (morpholin-4-yl) ethylidene] acetate (151 mg) ) in methylene chloride (1.5 mL) was added aluminum chloride (142 mg) and the mixture was stirred under ice-cooling for 50 minutes. The mixture was diluted with ice water (2 mL), stirred for 5 minutes, then stirred with the mixture (15 mL). methanol and methylene chloride (5: 1) to which was added 10% hydrochloric acid (3 mL) at room temperature for 80 minutes. The reaction mixture was diluted with ice water and extracted with chloroform. The solution was washed with water, dried over magnesium sulfate and evaporated to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (63 mg). Yield 63% ·

This product is identical to the product of Example 4 (3) prepared by hydrolyzing the 4-morpholino group to the corresponding hydroxy group.

Example 7-III

To a solution of 2,2,2-trichloroethyl alpha- [4-phenyzothiazol-1-yl) dithio-3-phenoxyacetamido-2-oxo-azetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate (100 mg) in ethanol (10 mL) was added sodium borohydride (5 mg) under ice-cooling, and the mixture was stirred for 15 minutes. The reaction mixture was neutralized with a few drops of glacial acetic acid and water and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was dissolved in N, N-dimethylformamide (4 mL), treated with triphenylphosphine (30 mg), stirred at room temperature for 1.5 h, and diluted with ethyl acetate. This solution was washed with water, dried and evaporated.

The resulting 2,2,2-trichloroethyl 7-phenoxyacetamido-3-oxocepham-4-kerboxylate was dissolved in roethylene chloride (4 ml), treated with a solution of diazobethane in ether and stirred at room temperature for 25 minutes. The solution was evaporated and the residue obtained by thin-layer chromatography 2,2,2-trichloroethyl 7-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylate. The IR spectrum and Rf values in thin layer chromatography are identical to those of an authentic sample prepared by other methods.

Example 8-III

The following compounds were prepared according to the preceding examples:

(1) methyl 7-phthalimido-3-hydroxy-3-cephem-4-carboxylate; (2) 2,2,2-trichloroethyl 7-phenoxyacetamido-3- (morpholin-4-yl) -3-cephem-4- (3) p-methoxybenzyl 7- (2,2-dimethyl-3-nitroso-4-phenyl-5-oxoimidazolidin-1-yl) -3-hydroxy-3-cephem-4-carboxylate; -nitrobenzyl 7- (N-tert-butoxycarbonyl-alpha-phenylglycyl) amino-3-oxocepham-4-carboxylate; 31 (5) 2,2,2-trichloroethyl 7-thienylacetamido-3-hydroxy-3-oefem-4 (6) p-nitrobenzyl-7-salicylideneamino-3-hydroxy-3-cephem-4-carboxylate, (7) 2,2,2-trichloroethyl 7-bemzyloxycarbonylamino-3-hydroxy-3-cephem-4- (8) p-nitrobenzyl 7- (2,2,2-trichloroethoxycarbonyl) amino-3-hydroxy-3-cephem-4-carboxylate.

Example 9-IXI

To a solution of 2,2,2-trichloroethyl [alpha] - [3-phenoxymethyl-7-oxo-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha [ 2-Bromo-2- (morpholin-4-yl) ethylidene acetate (6.00 g) in a mixture of chloroform (150 ml) and methanol (200 ml) was added at room temperature 10% hydrochloric acid (40 ml) and the mixture was stirred 60 minutes. The reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried and evaporated to give 2,2,2-trichloroethyl-3-oxo-7-phenoxyacetamidocapham-4-carboxylate (4.70 g). Foam. Yield 99.8%.

Example 10-III

To a solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-1,6-diazabicyclo [3.2.0] hept-2-en-6-yl-alpha- [2-bromo-1] - (Morpholin-4-yl) ethylidene] acetate (64 mg) in a mixture of methanol (4 ml) and methylene chloride (3 ml) was added 10% hydrochloric acid (0.38 ml) and the mixture was stirred at room temperature for 75 minutes. The reaction mixture was poured into water and extracted with methylene chloride. The extraxt was washed with water, dried over magnesium sulfate and evaporated to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (41 mg), mp 95.5-99.5 ° C. Yield 82.9 a.

Example 11-III

To a solution of p-nitrobenzyl alpha- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.1] hept-2-en-6-yl] -alpha [2-chloro-1- (morpholin-4-yl) ethylidene] acetate (106 mg) in a mixture (6 mL) of methanol and methylene chloride (2: 1) was added 2 N hydrochloric acid (0.93 mL) and the mixture was stirred under argon at room temperature. . After 40 minutes, the reaction mixture was diluted with ice water and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate and evaporated to give a yellow oil (94 mg). Purification of the oil by silica gel thin layer chromatography gave p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (20 mg) from the eluted fractions of benzene / ethyl acetate (1: 2). Yield 22%.

Example 12-III

To a 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 [ 2-bromo-1- (morpholin-4-yl) ethylidene acetate (117 mg) in a mixture (4 ml) of methanol and chloroform (1: 1) was added 10% hydrochloric acid (0.5 ml) and the mixture was stirred for two hours at room temperature. The reaction mixture was extracted with chloroform. The extract was washed with water, dried and evaporated. Purification of the residue by silica gel chromatography afforded 2,2,2-trichloroethyl 3-oxo-7-phenylacetamidocapham-4-carboxylate (41 mg). Yield 44%. NMR: δ ^CD3 3.33, S, 2H, 3.60, s, 2H, 4.83, s, 2H, 5.00, d, (5), 1H, 5.13-5.70, m , 2H, 6.82, d, (8), 1H, 7.25,

5H.

Example 13-III

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 [2-bromo-1- (morpholin-4-yl) ethylidene acetate (248 mg) in a mixture of methanol (8 ml) and methylene chloride (6 ml) was added 10% hydrochloric acid (1.5 ml) under ice-cooling, and the mixture was stirred for 2 hours. The reaction mixture was poured into ice water and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulphate and evaporated to give 184 mg of extract. Purification of the residue by silica gel chromatography with 10% water (10 g) gave p-nitrobenzyl 7-phenylacetamido fractions eluted with benzene / ethyl acetate (2: 1). 3-hydroxy-3-cephem-4-carboxylate (66 mg). Oil. Yield 35%. IR: [delta] 3,400, 1,782, 1,678, 1,612

NMR: .delta. 3.32, d, 2H, 3.63, s, 2H, 4.97, d, 1H, 5.34, sd, H, 5.60, q, 1H, 7.3, m , 6H,

7.47 - 8.30, q, 4H.

Example 14-III

The following compounds were prepared according to the preceding examples:

(1) 7-acetamido-3-oxocepham-4-carboxylic acid 1,2-diisopropylhydrazide, (2) diphenylmethyl 7-phenoxyacetamido-3-hydroxy-3-eephem-4-carboxylate, (3) 7 phenylacetamido-3-hydroxy -3-Cephem-4-carboxylic acid.

Example 15-IXI

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- [2- bromo-1- (morpholin-4-yl) ethylidene] acetate (580 mg) in tetrahydrofuran (10 mL was added at -10 ° C 60% aqueous perchloric acid solution (1.5 mL) and the mixture was stirred for 30 minutes. The reaction mixture was diluted with water and extracted with methylene chloride.

The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give a pale yellow foam (512 mg). The foam was purified by silica gel chromatography with 10% water (50 g) and p-nitrobenzyl .alpha .- [3-phenoxymethyl-7-oxo-4-thia-2,6-diazsbicyclo was obtained from the fractions eluted with benzene and ethyl acetate (1: 1). [3,2,0] hept-2-en-6-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate (foam: 207 mg, 40% yield). IR: v ^X 3 1781 cm ^-1 . NMR: δ ^CDCX 3 3.75 + 3.95, ABq, (10Hz), 2H, 4.72, s, 2H, 5.25, s, 2H, 5.73, d, (4Hz), 1H, 6 10.7 d, (4Hz), 1H, 6.73-8.15, m, 9H, 12.07, s, 1H.

Also, p-nitrobenzyl alpha- [3-phenoxyacetamido-4-mercapto-2-oxo-azetidin-1-yl] -alpha- (2-bromo-1-hydroxyethylidene) acetate can be isolated from the fractions as a by-product.

The previous major product (84 mg) was dissolved in tetrahydrofuran (2 mL), treated with 2 N hydrochloric acid (0.2 mL) and allowed to stand at 0 ° C for 30 min and at room temperature for 60 min. The reaction mixture was diluted with water, extracted with methylene chloride. The extract was washed with water, dried over sodium sulfate and evaporated. The residue (75 mg) was identified by IR and NMR as p-nitrobenzyl 7-phenoxyacetamido-3-oxocepham-4-carboxylate.

Example 16-III

Dissolve diphenylmethyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-hydroxyethylidene) acetate ( 4.84 g) in tetrahydrofuran (60 ml), cooled to -20 ° C, triethylamine (2.84 ml) was added and methanesulfonyl chloride (0.82 ml) was added dropwise with stirring, and the reaction was allowed to proceed 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-methanesulfonyloxyethylidene) acetate morpholine (0.96 mL) was added at -40 ° C, the reaction 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, bromine (0, 49 ml) and 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.

To this solution was added dropwise 5% hydrochloric acid (72 mL) and methanol (60 mL) at room temperature over three hours, and the reaction mixture was allowed to stand in the refrigerator overnight.

AND

The reaction mixture was evaporated, the residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate and evaporated. Purification of the obtained residue (5.83 g) by chromatography on silica gel with% water (150 g) was obtained after crystallization from n-hexane diphenylmethyl 7-phenylacetamido-3-hydroxy-3- from fractions eluting with benzene / ethyl acetate (4: 1). cefem-4-carboxylate (3.51 g)

mp 93-96 ° C. Yield 70%. IR: .delta. 3443, 1782, 1674, 1610 cm ^-1 . NME: ^CDC1 3

IHuX

3.20, s, 2H, 3.64, s, 2H, 4.97, d, (4Hz), 1H, 5.66, dd, (9: 4Hz), 1H, 6.77, d, (9Hz) 1 H, 6.90, s, 1H, 7.35, m, 15H.

Example 17-III

Triethylamine (5.68 mL) was added to a suspension of p-nitrobenzyl alpha- [3-benzyl-7-oxo-4-thia-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl 1 H -alpha (1-hydroxyethylidene) acetate (9.06 g) in tetrahydrofuran (120 mL) stirred under nitrogen at -20 ° C to give a clear solution to which was added methanesulfonyl chloride (1.65 mL), reaction the mixture was stirred at the same temperature for 30 minutes, morpholine (1.92 mL) was added, the reaction mixture was warmed to 0 ° C, stirred for five hours, cooled to -30 ° C to -35 ° C, pyridine ( 1.54 ml) and bromine (3.2 g), stirred for 20 minutes, warmed to ice bath temperature, 5% hydrochloric acid (144 ml) and methanol (120 ml) were added, the reaction mixture was stirred for three hours Stir at room temperature and not allow to stand overnight at. Low: 14 ° C. The precipitated crystals were filtered from the reaction mixture to give p-nitrobenzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (6.678 g), mp 201 ° C.

1. To a solution of diphenylmethyl alpha- [3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (1-chloro- 2-Propen-2-yl) acetate (160 mg) with a mixture of methylene chloride (32 mL) and methanol (0.3 mL) in a cooled dry ice / acetone bath was introduced with ozone until the reaction mixture turned blue. Excess ozone was removed with oxygen, the reaction mixture was treated with an aqueous solution of 95% sodium bisulfite (100 mg) and warmed to room temperature to decompose the ozonide. After 1.5 hours, the solution was washed with 5% sodium bicarbonate solution and water, dried and concentrated to remove methylene chloride. The resulting oil (132 mg) was purified by thin layer chromatography (Merck 60F-254) using a 1: 1 mixture of benzene and ethyl acetate as eluent to give diphenylmethyl alpha- [3-phenoxymethyl-7-oxo-2,6- Diaza-4-thiabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (2-chloro-1-hydroxyethylidene) acetate (44 mg) as a glassy product. IR: ^X ^ 3 1784, 1672, 1620, 1603 cm ^-1. NMR: δ ^CDCl 3 4.00, s, 2H, 4.66 + 4.96, ABq, (14Hz), 2H, 5.23, s, 2H.

2. To an ice-cooled solution of diphenylmethyl alpha- [3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo [3.2.0] hept-2-en-6-yl] -alpha- (2- chloro-1-hydroxyethylidene) acetate (36 mg) in methanol in tetrahydrofuran (1: 1) (1.1 mL) was added 1 N hydrochloric acid (0.39 mL), the reaction mixture was warmed to room temperature and the mixture was allowed to warm to room temperature. Stir 1.5 hours. The reaction mixture was poured into ice water and extracted with methylene chloride. The extract was washed with 5% aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. Purification of the obtained residue by thin layer chromatography using a 3: 2 mixture of benzene and ethyl acetate gave diphenylmethyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate (6 mg), mp 125-126 ° C.

IR: _3420, 1788, 1738, 1692, 1600 cm ^-1. NMR: δ ^CDCl 3 3.33, _s , 2H, 4.54, s,

2H, 5.02, d, (4Hz), 1H, 5.26, s, 2H, 5.62, dd, (10: 4Hz), 1H, 6.81-7.45, m, 10H, 11 , 5, brs, 1 H.

Example 18-III

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- (2-bromo- 1-dimethylaminoethylidene) acetate (380 mg) in tetrahydrofuran (10 ml) was added 5% sulfuric acid (2 ml) and methanol (10 ml) and the mixture was stirred at room temperature for two hours. The reaction mixture was kept overnight at 0 ° C and p-nitrobenzyl-7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (240 mg) was isolated, mp 201 ° C.

Example 19-III

To a solution of p-nitrobenzyl alpha- [4-methoxymethylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (2-bromo-2-hydroxyethylidene) acetate (200 mg) in dioxane (5 ml) and ethanol (2 mL), a solution of mercuric chloride (300 mg) in water (2 mL) was added and the mixture was stirred at 50 ° C for 12 h. The reaction mixture is concentrated under reduced pressure, extracted with ethyl acetate, washed with water, dried and evaporated to give a residue which is dissolved in a mixture of methylene chloride and methanol, washed with a layer of silica gel, concentrated and treated with ether. P-nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate is obtained in the form of a foam which is identical to an authentic sample.

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Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of 7-acylamino-3-hydroxy-3-cephem-4-carboxylic acid derivatives or their oxoforms of the general formula Ia or Ib A wherein A and B are hydrogen atoms or a group N- is phenylacetamino, phenoxyacetamido or phthalimido, X is hydroxyl, methoxy, 2,2,2-triethloroethoxy, benzyloxy, p-nitrobenzyloxy or diphenylmethoxy, characterized in that the compound of formula II is cyclized CH, Hal / ^{2 X} OH (II) wherein A, B, and X are as defined above and Hal is a halogen atom, such as a chlorine or bromine atom, by reaction with an acid or base or a solvent optionally in the presence of a catalyst. 2. A process according to claim 1, wherein the acid is a mineral acid, a sulfonic acid or a carboxylic acid, a base is a weak base or a solvent is an amide, an alcohol or water. 3. The process of claim 1 wherein the catalyst is neutral or basic silica gel, alumina or diatomaceous earth. 4. Process according to claims 1-3, characterized in that the reaction is carried out at a temperature from -10 ° C to + 80 ^OJ C, preferably from 0 ° C to 40 ° C for 30 minutes to 20 hours.