KR20080111062A - (1 oxoxa or 1 thiathia) - Google Patents

Abstract

The present invention provides a carboxy protected 7β-amino-7α-methoxy- (1-oxa- or 1-thia-) 3- (1-substituted-1H-tetrazol-5-yl) thiomethyl-3-cepem- A method for producing 4-carboxylic acid. The process comprises (a) reacting a carboxy-protected 7-amino-3-chloromethyl- (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid with alkyl- or aryl-sulphenyl chloride To; (b) reacting the corresponding 7-alkyl- or aryl-thioimino derivative with 1- (alkyl- or ω-hydroxyalkyl-) 1H-tetrazol-5-ylthiol; (c) the corresponding 7- (alkyl- or aryl-) thioimino-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- (1-oxa- or 1-thia-) 3- Reacting the cefem with methanol in the presence of aluminum trichloride and triphenylphosphine neutralized with base. Carboxyprotected 7β-amino-7α-methoxy- (1-oxa- or 1-thia-) 3- (1-substituted-1H-tetrazol-5-yl) thiomethyl-3-cepem-4 obtained -Carboxylic acid is reacted with activated 2- (cyanomethylthio) acetic acid or 2- (difluoromethylthio) acetic acid, after the final removal of the protective ester group, cefemethazole and flomoxef are respectively obtained. . 7- (alkyl- or aryl) thioimino-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl-1-dethia-1-oxa-3-cepem intermediate is a novel compound.

Description

(1Xoxa or 1xthiazine) 3.The preparation method of a cefefem derivative {PREPARATION OF (1-OXA- OR 1-THIA-) 3-CEPHEM DERIVATIVES}

The present invention relates to a process for the preparation of (1-oxa- or 1-thia-) 3-cepem derivatives which are useful intermediates in the preparation of (1-oxa- or 1-thia-) cephalosporins. More specifically, the present invention provides a carboxy protected 7β-amino-7α-methoxy-3- [1- (alkyl- or ω-hydroxy alkyl-) 1H-tetrazol-5-yl] thiomethyl- (1- Preparation of oxa- or 1-thia-) 3-cepem-4-carboxylic acid and conversion of this compound to therapeutically of interest (1-oxa- or 1-thia-) cephalosporin, in particular Conversion to flomoxef

And a method for converting cefmetazole of the following formula (B).

In the context of the present invention, in order to simplify the nomenclature, the more commonly used expression "(1-dethia-) to indicate the nucleus of the structural formula (a) using the traditional numbering of cephalosporin chemistry despite anomalous 1-oxa) -3-cepem or 3-cepem "and" (5-oxa- or 5-thia-) 1-azabicyclo [4.2.0] oct-2-ene "instead of" (1-oxa- or 1-thia-) 3-cepem "is used.

Wherein X is oxygen or sulfur.

The compounds flomoxef and cefmetazole are 7β-acylamino-7α-methoxy-cephalosporin-type antibiotics used as antibacterial drugs.

Plomoxef is an oxacefem described in US Pat. No. 4,532,233, wherein the key intermediate is carboxy-protected 7β-amino-7α-methoxy-3- [1- (2-hydroxyethyl) -1H-tetra Sol-5-yl] thiomethyl-1-dethia-1-oxa-3-cepem-4-carboxylic acid. This compound protects the primary hydroxyl group of the hydroxyethyl radical bound to the tetrazole ring, subsequently condenses with activated 2- (difluoromethylthio) acetic acid and removes the hydroxy- and carboxy-protecting groups. It is converted to flow Mokseop. A multi-step process for producing flomoxep is described in A. Kleemann, J. Engel, "Pharmaceutical Substances", G. Thieme Verlag, 4 Ed, 2001, Flomoxef-6515-S (A. Kleemenn et al.).

Cefmethazole is the cefem described in GB 1449420, and the corresponding carboxy-protected 7 β-amino-7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3- Cefem-4-carboxylic acid is prepared by reacting by condensation with activated 2- (cyanomethylthio) acetic acid and removing carboxy-protecting groups. For synthesis, see H. Nakao et al. J. Antibiot. (Tokyo), 1979, 32, 320-329.

Flomoxef and cefmethazole each contain 7β- (substituted-thio) acetamido-7α-methoxy-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- (1-oxa Or 1-thia-) 3-cepem-4-carboxylic acid. Their synthesis is carboxy-protected 7β-amino-7α-methoxy-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- (1-oxa- or 1-thia-) 3- Preparation of cefem-4-carboxylic acids and condensation of these with activated (substituted-thio) acetic acid.

The two 7β- (substituted-thio) acetamido-7α-methoxy-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- (1-oxa- or 1-thia-) Synthesis of 3-cefe-4-carboxylic acid is enantiomerically pure carboxy-protected 7β-amino-7α-methoxy-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- Consideration should be given to the preparation of (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid.

Moreover, the synthesis of phlomoxef must take into account the presence of 2-hydroxyethyl substitution on the tetrazole residues, which involves the protection of primary hydroxyl groups during condensation with activated difluoromethyl thioacetic acid.

Enantiomerically pure carboxy-protected 7β-amino-7α-methoxy-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- (1-oxa- or 1-thia-) 3 Cefem-4-carboxylic acid is a carboxy-protected 7-benzamido-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- (1 in the presence of t-butyl hypochlorite It is known that it can be prepared by reacting -oxa- or 1-thia-) 3-cepem-4-carboxylic acid with lithium methoxide (Kleemann et al. And DE2806457). Another method for converting 7-benzamido groups to 7β-amino-7α-methoxy functional groups using chlorine or lithium methoxide is disclosed in WO 2006/006290.

Enantiomerically pure carboxy-protected 7β-amino-7α-methoxy-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid, corresponding 7-methyl- or 7- (4-tolyl) -thioimino derivatives are described in EM Gordon et al. in J. Am. Chem. Soc. 1977, 99 (16) 5504-5 and ibid . It is also known that it can be prepared by reacting with methanol in the presence of triphenylphosphine and mercury acetate in dichloromethane as disclosed in 1980, 102 (5), 1690-1702. However, the presence of mercury salts in the reaction mixture makes the purification of the product difficult.

Finally, carboxy-protected 7β-amino-7α-methoxy-3- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thiomethyl-1 to prepare flomoxef precursors Condensation of -dethia-1-oxa-3-cepem-4-carboxylic acid with activated 2- (difluoromethylthio) acetic acid indicates that the primary hydroxyl group on the tetrazole moiety is 4-methylbenzoyloxycar It is known to protect as a bonyl ester, which is subsequently removed using SnCl ₄ (Kleeman et al.).

Summary of the Invention

Starting from carboxy-protected 7-amino-3-chloromethyl-1- (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid, it is reacted with alkyl- or aryl-sulphenyl chloride To give the corresponding 7-thioimino derivative, which is reacted with a suitable 1- (alkyl- or ω-hydroxyalkyl-) 1H-tetrazol-5-ylthio or salt thereof to produce the corresponding 7- (alkyl- or Aryl-) thioimino-3-[(1-substituted) -1H-tetrazol-5-yl] thiomethyl- (1-oxa- or 1-thia-) 3-sepime is obtained, which is aluminum trichloride Treatment with methanol in the presence of triphenylphosphine and sodium bicarbonate to give the corresponding carboxy protected 7β-amino-7α-methoxy-3- [1- (alkyl- or ω-hydroxyalkyl-) 1H- Modification with tetrazol-5-yl] thiomethyl- (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid has now been found.

Carboxyprotected 7β-amino-7α-methoxy-3- [1- (alkyl- or ω-hydroxyalkyl-) 1H-tetrazol-5-yl] thiomethyl- (1-oxa- or 1 thus obtained -Thia-) 3-cepem-4-carboxylic acid is a carboxy protected 7β-amino-7α-methoxy-3- [1- (alkyl- or ω-hydroxy alkyl-) 1H-tetra which is carboxy protected in the presence of a silylating agent. Carboxyl by traditional condensation of sol-5-yl] thiomethyl- (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid with suitably activated 2- (difluoromethylthio) acetic acid Plomoxef, obtained by deflomoprotection after deprotection, or by cefmethazole after deprotection of carboxyl by conventional condensation of suitably activated 2- (cyanomethylthio) acetic acid. Intermediates important in the preparation of Formula A) and cefemethazole (Formula B) or analogs thereof.

It is therefore an object of the present invention to provide a process for the preparation of (1-oxa- or 1-thia-) 3-cepem derivatives of formula (I) or salts thereof,

(a) a carboxy-protected 7-amino-3-chloromethyl- (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid or a salt thereof of formula (II) Treated with (alkyl- or aryl) sulphenyl chloride,

(b) the corresponding carboxy-protected 7- (alkyl- or aryl-) thioimino-3-chloromethyl- (1-oxa- or 1-thia-) 3-cephem- of the formula (IV) 4 carboxylic acids are treated with [1-alkyl or 1- (ω-hydroxyalkyl)]-1H-tetrazol-5-ylthiol or an alkali metal salt thereof,

(c) the corresponding 7- (alkyl- or aryl-) thioimino-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- (1-oxa) of the formula (VI) Or treating ₁ -thia-) 3-cepem with methanol in the presence of base neutralized aluminum trichloride and triarylphosphine or tri (C ₁ -C ₆ ) alkylphosphine, and the compound of formula (I) Separation by itself or as an addition salt thereof, neutralized with free base or not neutralized, includes:

Wherein X is oxygen or sulfur, Y is an alkyl group having 1 to 3 carbon atoms or an ω-hydroxyalkyl group having 2 to 3 carbon atoms, R ° represents a carboxy-protecting group, and W is one carbon atom Or a benzyl group unsubstituted or substituted with alkyl having 1 to 3 carbon atoms, or a phenyl group unsubstituted or substituted with alkyl having 1 to 3 carbon atoms. In the formulas (III) and (VI), the alkyl substituent on the benzyl group is preferably in the benzene ring. The compound of formula (I) thus obtained is in enantiomerically pure form.

In step (c), sodium bicarbonate is preferably used as the base to neutralize aluminum trichloride. In the same step (c), the expression “triarylphosphine or tri (C ₁ -C ₆ ) alkylphosphine” means that the three hydrogen atoms are monocyclic, by substituted or unsubstituted phenyl groups such as phenyl or tolyl, Reference is made to phosphines which have been replaced by aromatic heterocyclic groups such as furyl or thienyl or by (C ₁ -C ₆ ) alkyl groups such as n-butyl.

As protecting groups that can be easily removed, in particular 7-amino-3-chloromethyl- (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid esterified in acidic medium is used as starting material . The protecting groups used according to the invention and methods for their removal are described, for example, in Theodora W. Greene, Peter GV Wuts in "Protetive Groups in Organic Synthesis", III ed., John Wiley & Sons, Inc., 1999, pages 373-431. Preferred esters are trifluoroacetic acid and anisole in dichloromethane or 4-methoxybenzyl and diphenylmethyl (benzhydryl) esters which can be easily removed with aluminum trichloride and anisole in dichloromethane.

In step (a), the carboxy-protected 7-amino-3-chloromethyl- (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid itself or its hydrocrolides, in turn, corresponds to Methyl- or aryl-disulfide is reacted separately with chlorine in an inert organic solvent such as toluene or dichloromethane at room temperature (20 ° ÷ 30 ° C), in the presence of a hydrogen chloride acceptor such as, for example, 1,2-epoxypropane React with the prepared methyl- or aryl-sulphenyl chloride. Methylsulphyl chloride (Formula III, W = methyl), phenylsulphenyl chloride (Formula III, W = phenyl) and p -tolylsulphenyl chloride (Formula III, W = 4-methylphenyl) are preferred methyl- or aryl-sulphates Phenyl chloride. Thus obtained 7- (alkyl- or aryl-) thioimino-3-chloromethyl- (1-oxa- or 1-thia-) 3-cefe of formula (IV), for example sodium bicarbonate ( Separation is carried out according to a conventional method by neutralization with a base such as an aqueous solution of NaHCO ₃ ), removal of salts and extraction with a suitable solvent such as dichloromethane.

In step (b), 7- (alkyl- or aryl-) thioimino-3-chloromethyl- (1-oxa- or 1-thia-) 3-cepem of the formula (IV) thus obtained is preferably sodium Treatment with 1-alkyl- or 1- (ω-hydroxyalkyl) -1H-tetrazol-5-ylthiol in salt form. The reaction is carried out in the presence of a quaternary ammonium salt such as tetra-n-butylammonium bromide in a two-phase system with an inert organic solvent such as dichloromethane or toluene and water at a temperature of 20 ° to 30 ° C. After 5-10 hours, the reaction was terminated and 7- (alkyl- or aryl-) thioimino-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- (of formula (VI) obtained ( 1-oxa- or 1-thia-) 3-cepem, for example, is used to separate the phases, wash the organic phase with water, dry, evaporate the solvent, and crystallize the residue with alcohol, for example methanol. By the usual method.

1-methyl-1H-tetrazol-5-ylthiol or 1- (2-hydroxyethyl) -1H-tetrazol-5-ylthiol as the sodium salt is 1-substituted-1H-tetrazol-5-yl It is preferable to use as thiol. Said sodium salts can be prepared, for example, according to known methods for reacting 1-substituted-1H-tetrazol-5-ylthiol with sodium 2-ethylhexanoate in acetone.

The 7- (alkyl- or aryl-) thioimino-3-chloromethyl (1-oxa- or 1-thia-) 3-cepem compound of formula (VI), wherein X obtained at the end of step (b) is oxygen It is a novel and useful intermediate in the preparation of flomoxef and is a further object of the present invention.

In step (c), 7- (alkyl- or aryl-) thioimino-3-chloromethyl (1-oxa- or 1-thia-) 3-cepem of formula (VI) obtained at the end of step (b) Is reacted with methanol in the presence of triarylphosphine or tri (C ₁ -C ₆ ) alkylphosphine and aluminum trichloride neutralized with a base in an inert organic solvent such as dichloromethane or toluene.

In general, methanol contains sodium bicarbonate as the base neutralizing aluminum trichloride. Preferably triarylphosphine or tri (C ₁ -C ₆ ) alkylphosphine is triphenylphosphine, tri ( o -tolyl) phosphine, tri (2-furyl) phosphine and tri ( n -butyl) force Selected from the group consisting of pins.

Indeed, a solution of aluminum trichloride in methanol, prepared beforehand at a temperature of 10 ° 15 ° C. and neutralized with a base such as sodium bicarbonate, has been added to the compound (VI) and triphenylphosphine, tri (o), the solvents mentioned above. Add to a solution of either tolyl) phosphine, tri (2-furyl) phosphine or tri (n-butyl) phosphine. The compound of formula (I) thus obtained is added glacial acetic acid to the obtained suspension at the end of the reaction, the phases are subsequently separated, the organic phase is dried, and the product of formula (I) with a solvent such as dichloromethane or toluene Extraction and separation by optionally adding HCl in isopropanol, HBr in isopropanol, methanesulfonic acid, p-toluene sulfonic acid or naphthalene-2-sulfonic acid to the organic solution.

Instead of sodium bicarbonate, alkali metal methoxides such as lithium methoxide or sodium methoxide and alkali metal acetates such as sodium or potassium acetate are also preferred neutralizing bases.

By extracting the product and evaporating the solvent, the compound of formula (I) is separated as a free base, which is dissolved, for example, by silica gel, a suitable resin or in a polar solvent such as dimethylacetamide and methanol or isopropanol It may be purified according to a known method of precipitation with an alcohol such as.

By separation of the salt form, for example as hydrochloride, hydrobromide, methanesulfonate, p-toluenesulfonate or naphthalene-2-sulfonate, the compounds of formula (I) so chlorided are already in pure form and corresponding Pure free base can be readily obtained by neutralization.

The compounds of the formula (II) used as starting materials are known or for example the corresponding carboxy-protected 7-acylamido-3-chloromethyl- (1 as disclosed in DE 2806457 (see also US 4,366,316). It can be readily prepared by treating -oxa- or 1-thia-) 3-cepem-4-carboxylic acid by reaction with PCl ₅ in the presence of pyridine.

Specifically, the present invention provides a process as described above, at the end of step (c), wherein the compound of formula (I ') is separated:

Wherein X 'is oxygen, Y' is 2-hydroxyethyl and R ° is a carboxy-protecting group, preferably benzhydryl or 4-methoxybenzyl. Compound (I ′) is obtained in enantiomerically pure form.

The present invention also provides the above described process wherein at the end of step (c), the compound of formula (I ") is separated:

Wherein X ″ is oxygen, Y ″ is methyl and R ° is a carboxy-protecting group, preferably benzhydryl or 4-methoxybenzyl. The compound (I ″) is obtained in enantiomerically pure form.

Carboxy-protected 7β-amino-7α-methoxy-3- [1-alkyl of formula (I) wherein R ° thus obtained is a carboxy-protecting group as described above, preferably benzhydryl or 4-methoxybenzyl Or 1- (ω-hydroxyalkyl) -1H-tetrazol-5-yl] thiomethyl- (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid, a hydrogen chloride acceptor, For compounds of formula (I), for example in the presence of a tertiary amine such as pyridine and Y is ω-hydroxyalkyl having 2 to 3 carbon atoms, it is also possible to use hexamethyldisilazane and / or trimethylchlorosilane Condensation with 2- (difluoromethylthio) acetic acid or 2- (cyanomethylthio) acetic acid suitably activated in the presence of a silylating agent such as can be readily converted to flomoxef or cefmethazole. In the preparation of flomoxef, the intermediate compound used has formula (I) wherein X is oxygen and Y is 2-hydroxyethyl. In the case of ceftmethazole, the intermediate compound has formula (I) wherein X is sulfur and Y is methyl.

Accordingly, a further object of the present invention is to further react and treat a compound of formula (I ') with 2- (difluoromethylthio) acetic acid activated in the presence of a silylating agent to treat a compound of formula (VII') To provide a process as described above, to obtain:

Wherein X 'is oxygen, Y' is 2-hydroxyethyl and R ° is a carboxy-protecting group that is removed to separate flomoxef.

According to a preferred embodiment, 7β-amino-7α-methoxy-3- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thiomethyl-1-dethia-1-oxa-3 -Diphenylmethyl or 4-methoxybenzyl ester of cefem-4-carboxylic acid is treated with a silylating agent such as hexamethyldisilazane and trimethylchlorosilane and then 2- (in dichloromethane in the presence of pyridine. React with difluoromethylthio) acetyl chloride (F ₂ CH-S-CH ₂ COCl) at -10 ° -25 ° C. At the end of the reaction, the product is added, for example, water to the reaction mixture, the phases are separated, the organic phase is evaporated, and the residue consisting of diphenylmethyl or 4-methoxybenzyl ester of flomoxef is dissolved in dichloromethane. And the solution thus obtained is separated in accordance with known techniques by treatment with trifluoroacetic acid and anisole. Plomoxef of 98% purity thus obtained is added water to the reaction mixture, the phases are separated and the product in acidic form is recovered by concentration of the organic phase or the organic phase is treated with sodium or potassium 2-ethylhexanoate. By separating the product in the form of a sodium or potassium salt.

The sodium salt of flomoxef is obtained by dissolving an aqueous solution of pH 5.8 ÷ 6.2 through a column containing silica gel or a resin such as Amberlite (Amberlite ^® XAD 1180) to deionized or deionized water and an alcohol such as ethanol or It can be further purified by passage through eluting the mixture.

According to another embodiment, the present invention further provides a process as described above, wherein said compound of formula (I ") is further reacted and treated with activated 2- (cyanomethylthio) acetic acid and a compound of formula (VII") To provide:

Wherein X ″ is sulfur, Y ″ is methyl and R ° is a carboxy-protecting group that is removed to separate cemetazole.

According to another preferred embodiment, diphenylmethyl or 4-methoxybenzyl 7β-amino-7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4 The carboxylate is treated with 2- (cyanomethylthio) acetyl chloride (NCCH ₂ SCH ₂ COCl) in dichloromethane in the presence of pyridine at a temperature of -10 to -25 ° C. At the end of the reaction, the product is added, for example, water to the reaction mixture, the phases are separated, the organic phase is evaporated and the residue consisting of benzhydryl or 4-methoxybenzyl ester of ceftmethazole with dichloromethane It is dissolved and the solution thus obtained is separated according to a known method by treating with trifluoroacetic acid and anisole or aluminum trichloride and anisole. The 99% pure cemetazole thus obtained is obtained by adding water to the reaction mixture, separating the phases and recovering the product in acidic form by condensation of the organic phase or treating the organic phase with sodium or potassium 2-ethylhexanoate. Separated by recovery of the product as a sodium or potassium salt.

Finally, a further object of the present invention is a novel 7- (alkyl- or aryl-) thioimino-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- of formula (VI) To provide a (1-oxa- or 1-thia-) 3-cepem compound:

Wherein X is oxygen, Y is an alkyl group having 1 to 3 carbon atoms or an ω-hydroxyalkyl group having 2 to 3 carbon atoms, and W is an alkyl having 1 to 3 carbon atoms and 1 to 3 carbon atoms A benzyl group unsubstituted or substituted with personal alkyl, or a phenyl group unsubstituted or substituted with alkyl having 1 to 3 carbon atoms, and R ° is a carboxy-protecting group. The alkyl substituent on the benzyl group is preferably present in the benzene ring.

Preferred compounds are those of the formula (VI '), wherein X' is oxygen, Y 'is 2-hydroxyethyl, R ° is benzhydryl or 4-methoxybenzyl, and W is methyl, benzyl or p -tolyl to be.

The following examples illustrate the present invention without restricting it.

Example 1

(a) 60 g (0.138 mmol) of benzhydryl 7-amino-3-chloromethyl-1-dethia-1-oxa-3-cepem-4-car in 1800 ml of dichloromethane cooled to -5 ° C. 96 g (1.65 m) of 1,2-epoxypropane were added to the solution of cyclate for 5 minutes. Of CH ₃ SCl in dichloromethane, then obtained by treating 26 g (0.276 m) of dimethylsulfide in 800 ml of dichloromethane with 200 ml of a 10% chlorine solution in dichloromethane at a temperature of −5 ° C. to 0 ° C. The solution was added here. The mixture was stirred for 30 minutes at a temperature of -5 ° C to 0 ° C, then brought to a temperature of 20 ° C and stirring was continued for 1 hour. The mixture was treated with a solution of 80 g sodium bicarbonate in 1200 ml of water, the phases were separated and the aqueous phase was washed with 200 ml of dichloromethane. The phases were separated and the collected organic phase was washed with 600 ml of water, the organic phase was extracted with 200 ml of dichloromethane and then the organic phase was collected and dried under reduced vacuum. The residue was crystallized with 225 ml of methanol to yield benzhydryl 7-methylthioimino-3-chloromethyl-1-dethia-1-oxa-3-cefe-4-carboxylate. Yield: 88% of theory.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.9 (s, 3H); 4.4 (2d, 2 H); 4.5 (2d, 2 H); 5.2 (s, 1 H); 6.9 (s, 1 H); 7.2 ÷ 7.6 (m, 10 H).

(b) 11.5 g (0.026 m) of intermediate benzhydryl 7-methylthio imino-3-chloromethyl-1-dethia-1-oxa-3- obtained in step (a) in 150 ml of dichloromethane. To a solution of cefe-4-carboxylate, a solution of 7 g (0.041 m) of sodium 1- (2-hydroxyethyl) -1H-tetrazol-5-ylthiolate in 150 ml of water at 20 ° C Added. Then 1.2 g tetra-n-butyl ammonium bromide was added and the reaction mixture was stirred at a temperature of 20 ° C.-25 ° C. for 8 hours. The phases were separated and the organic phase was washed with 50 ml of water. The organic phase was concentrated in vacuo and the residue was dissolved in 30 ml of methanol. The mixture was cooled and the solid product was filtered and dried to give benzhydryl 7-methylthioimino-3- [1- (2-hydroxyethyl) -1 H-tetrazol-5-yl] thiomethyl-1-dethia- 1-oxa-3-cefe-4-carboxylate was obtained. Yield: 85% of theory.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.90 (s, 3H); 3.9 (t, 2 H); 4.3 (t, 2 H); 4.35 (s, 2 H); 4.6 (2d, 2 H); 5.2 (s, 1 H); 6.9 (s, 1 H); 7.4 (m, 10 H).

(c) 51.4 g (0.093 m) of intermediate benzhydryl 7-methylthio imino-3- [1- (2-hydroxyethyl) obtained in step (b) in 800 ml of dichloromethane cooled to 5 ° C. To a solution of) -1H-tetrazol-5-yl] thiomethyl-1-dethia-1-oxa-3-cepem-4-carboxylate, 30 g of triphenylphosphine (0.1143 m) was added and The mixture was stirred at a temperature between 0 ° C. and 5 ° C. for 15 minutes, then neutralized with 24.6 g (0.29 m) sodium bicarbonate, a solution of 13.12 g (0.097 m) of aluminum trichloride in 200 ml of methanol Was added here. The mixture was stirred at 25 ° C. for 30 minutes, then it was cooled to a temperature of 0 ° C. to 5 ° C., diluted with 50 ml of methanol and stirred at 8 ° C. ± 1 ° C. for 3 hours. At the end of the reaction, the mixture was treated with 17 ml of glacial acetic acid, stirred at a temperature of 15 ° C. to 20 ° C. for 15 minutes, then treated with 250 ml of water containing 5% sodium chloride and stirred for a further 10 minutes. The phases were separated and the organic phase was washed with 250 ml of water containing 5% acetic acid and 250 ml of water containing 5% sodium chloride. The organic phase was collected, concentrated in vacuo to a small volume, and the residue dissolved in a methanol / dichloromethane mixture. The solid was filtered off, washed with isopropyl ether and dried to benzhydryl 7β-amino-7α-methoxy-3- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thiomethyl- 1-dethia-1-oxa-3-cepem-4-carboxylate was obtained. Yield: 82% of theory.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.45 (s, 3H); 3..7 (t, 2 H); 4.2 and 4.3 (2d, 2 H); 4.35 (m, 2 H); 4.6 (2d, 2 H); 5.1 (t, 1 H); 5.2 (s, 1 H); 6.9 (s, 1 H); 7,25-7,65 (m, 10 H).

Example 2

(a) (b) Benzhydryl 7-amino-3-chloromethyl-3-cepem-4-carboxyl under the same conditions, by working as described in steps (a) and (b) of Example 1; Starting from the rate, reacted with CH ₃ SCl to react benzhydryl 3-chloromethyl-7-methyl thiimino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4- A carboxylate is obtained, which is reacted with sodium 1-methyl-1H-tetrazol-5-ylthiolate to yield benzhydryl 7-methyl thiimino-3- (1-methyl-1H-tetrazol-5-yl ) Thiomethyl-3-cepem-4-carboxylate was obtained. Melting point: 211 ° ÷ 212 ° C.

(c) 25.2 g (0.047 m) of intermediate benzhydryl 7-methylthioimino-3- (1-methyl-1H-tetrazol-5 obtained in step (a) (b) above in 400 ml of dichloromethane To a stirred solution of -yl) thiomethyl-3-cepem-4-carboxylate, at 5 ° C., 15.18 g (0.058 m) of triphenylphosphine was added under stirring, followed by a temperature of 0 ° C. to 5 ° C. Agitation was continued for 15 ÷ 20 minutes at to reach complete dissolution. To the solution was added a solution of 6.64 g (0.097 m) of aluminum chloride in 105 ml of methanol, neutralized with 12.45 g (0.29 m) of sodium bicarbonate. The mixture was cooled to a temperature between 0 ° C. and 5 ° C., diluted with 25 ml of methanol and stirred at 8 ° C. ± 1 ° C. for 3 hours. At the end of the reaction (HPLC control), the mixture was treated with 8.6 ml of glacial acetic acid and stirred at 20 ° 25 ° C. for 20 minutes, then with 130 ml of water containing 5% sodium chloride and stirred for an additional 10 minutes. It was. The phases were separated and the organic phase was washed with 130 ml of water containing 5% acetic acid and 130 ml of water containing 5% sodium chloride. The organic phase was dried and concentrated in vacuo to a volume of 145-155 ml. The remaining solution was diluted with 210 ml of methanol and concentration resumed in vacuo until the volume was 210-230 ml. The mixture was allowed to crystallize for 15 hours at a temperature of 0 ° C to 5 ° C. The solid product was filtered off, washed with cold methanol and dried in vacuo at 30 ° C. to benzhydryl 7β-amino-7α-methoxy-3- (1-methyl-1H-tetrazole having a melting point of 127 ° ÷ 128 ° C. -5-yl) thiomethyl-3-cepem-4-carboxylate was obtained. Yield: 84% of theory.

Example 3

(a) 80.7 g (0.15 m) benzhydryl 7β-amino-7α-methoxy-3- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] in 250 ml of dichloromethane A suspension of thiomethyl-1-dethia-1-oxa-3-cefe-4-carboxylate was prepared, followed by 103.3 g (0.64 m) of hexamethyldisilazine and 34.75 g (0.32 m) of trimethylchloro Silane was added here. The mixture was stirred for 30 minutes to give a clear solution, which was cooled to a temperature of -5 ° C to -10 ° C and treated with 30.2 g (0.38 m) pyridine. To this mixture, 52.8 g (0.25 m) of phosphorus pentachloride (PCl ₅ ) was added to a solution of 32.8 g (0.213 m) of sodium 2- (difluoromethylthio) acetate in 625 ml of dichloromethane at 0 ° ÷ 2. A solution of 2- (difluoromethylthio) acetyl chloride obtained by addition at 캜 was added. The reaction mixture was stirred for 30 minutes at a temperature between -10 [deg.] C. and -15 [deg.] C., 440 ml of water was added thereto and stirring continued for an additional 15 minutes. After phase separation, the organic phase was washed with 260 ml of 2N hydrochloric acid, then with 5% aqueous solution of sodium bicarbonate, and finally with 260 ml of water. The organic phase was concentrated in vacuo to a dense oil, which was dissolved in methanol and left to crystallize for 15 hours. The solid was filtered off, washed with cold methanol and dried under vacuum to yield benzhydryl 7β- [2- (difluoromethylthio) acetamido] -7α-methoxy-3- [1- (2-hydroxy Ethyl) -1H-tetrazol-5-yl] thiomethyl-1-dethia-1-oxa-3-cepem-4-carboxylate was obtained. Yield: 79% of theory.

¹ H-NMR (DMSO-d 6) δ ppm: 3.45 (s, 3H); 3.65 (2d, 2 H); 3.7 (t, 2 H); 4.25 (2d, 2 H); 4.3 (m, 2 H); 4.6 (2d, 2 H); 5.1 (t, 1 H); 5.2 (s, 1 H); 6.9 (s, 1 H); 7.35 (t, 1 H); 7.25-7.65 (m, 10 H); 9.4 (s, 1 H).

(b) 58 g (0.088 m) of benzhydryl 7β- [2- (difluoromethylthio) obtained in step (a) in 250 ml of dichloromethane, cooled to a temperature of -30 ° C to -35 ° C. Acetamido] -7α-methoxy-3- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thiomethyl-1-dethia-1-oxa-3-cefe-4 To the solution of carboxylate intermediate 17.1 g (0.15 m) trifluoroacetic acid and 32 g (0.29 m) anisole were added. The reaction mixture was stirred at the same temperature for 2-3 hours and then the temperature was raised to 20 ° ÷ 25 ° C. The mixture was washed with 45 ml of 5% HCl and then with 45 ml of water. The separated organic phase was dried and concentrated in vacuo. The residue was crystallized from ethyl acetate and the solids were filtered to give 7β- [2- (difluoromethylthio) acetamido] -7α-methoxy-3- [1- (2-hydroxyethyl) -1H- Tetrazol-5-yl] thiomethyl-1-dethia-1-oxa-3-cepem-4-carboxylic acid (flomoxef free acid) was obtained. Yield: 92% of theory.

¹ H-NMR (DMSO-d 6) δ ppm: 3.4 (s, 3H); 3.65 (s 2 H); 3.7 (t, 2 H); 4.2 (s, 2 H); 4.3 (t, 2 H); 4.5 (s, 2 H); 5.1 (s, 1 H); 7.05 (t, 1 H); 9.2 (s, 1 H).

Example 4

(a) 60 g (0.113 m) benzhydryl 7β-amino-7α-methoxy-3- [1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem in 150 ml of dichloromethane A suspension of -4-carboxylate was prepared, then 13.5 g (0.17 m) pyridine was added and the mixture was cooled to 0 ° 3 ° C. To this mixture, a solution of 25 g (0.213 m) of sodium 2- (cyanomethylthio) acetate in 150 ml of dichloromethane with 35 g (0.168 m) of phosphorous pentachloride (PCl ₅ ) at 0 ° ÷ 2 ° C To the 2- (cyanomethylthio) acetyl chloride solution obtained by addition to was added. The reaction mixture was stirred for 30 minutes at a temperature between -10 ° C and -35 ° C and then 100 ml water was added thereto. The phases were separated and the organic phase was washed with 10% aqueous NaCl solution followed by water. The dried organic phase was concentrated to a residue in vacuo and it was dissolved in 250 ml of methanol. The product was allowed to crystallize at 10 ° 15 ° C. for 15 hours and then the mixture was cooled to 5 ° C. The solid was filtered off, washed with cold methanol and dried to benzhydryl 7β- [2- (cyanomethylthio) acetamido] -7α-methoxy-3- (1-methyl-1H-tetrazol-5 -Yl) thiomethyl-3-cepem-4-carboxylate was obtained. Yield: 86% of theory.

(b) To 100 ml of anisole, 37.5 g (0.28 m) of aluminum trichloride was added at 20 ° 25 ° C. and the mixture was diluted with 250 ml of dichloromethane to give a solution. Alternatively, 50 g (0.078 m) of benzhydryl 7β- [2- (cyanomethylthio) acetamido] -7α-methoxy-3- (1-methyl) in step (a) in 800 ml of dichloromethane A solution of -1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylate intermediate was prepared, cooled to -5 ° C and added to the solution obtained above. The resulting mixture was stirred at 0 ° C. for 40 minutes and then poured in a mixture of 500 ml of water, 750 ml of acetone and 25 ml of 35% HCl. After stirring for 30 minutes, the phases were separated. To the organic phase, 28 g NaCl and 75 ml ethyl acetate were added. The organic phase was separated and washed with 200 ml of 10% NaCl solution. The collected organic phases were treated with 500 ml of 5% NaHCO ₃ . The organic phase was collected, brought to pH 6 with 40 ml of 35% HCl, then 15 g of activated alumina was added and the mixture was stirred for 30 minutes. The alumina was filtered off and washed with water. An aqueous solution with 100 g of NaCl and 300 ml of ethyl acetate was added and 50% H ₃ PO ₄ and 50 ml of methyl isobutyl ketone were added to bring the pH to 3.5-3.6. 50% H ₃ PO ₄ was added to bring the pH to 2.2 slowly for 2 hours and the product was left to crystallize for 15 hours in the cold. The solid was filtered off, washed and dried in vacuo to afford 7β- [2- (cyanomethylthio) acetamido] -7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thio Methyl-3-cepem-4-carboxylic acid (cepmethazole) was obtained. Yield: 97% of theory.

Example 5

40 g (0.742 m) of benzhydryl 7-methylthioimino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylate are 640 at room temperature under stirring. was added to ml of dichloromethane. The mixture was cooled to 5 ° C. and 24 g (0.0914 m) triphenylphosphine was added thereto under stirring. The mixture was kept at 0 ° 5 ° C. for 15 minutes to give a clear solution (solution A). Separately, 16.4 g (0.078 m) of anhydrous aluminum trichloride was added to 160 ml of methanol, partially cooled to 10 ° 15 ° C. previously, under a nitrogen atmosphere. After stirring for 5 minutes, 19.68 g (0.234 m) of sodium bicarbonate are added in portions at 10 ° ÷ 15 ° C. for 10-15 minutes and the mixture is left under stirring at 25 ° C. for 30 minutes to give a suspension Was obtained (suspension B). Suspension B was added to Solution A at 0 ° ÷ 5 ° C. and the reaction mixture was stirred for about 3 hours at 8 ° C. ± 1 ° C. following reaction progress by TLC (eluent: ethyl acetate / toluene 1/1). At the end of the reaction, the mixture was treated as described in Example 2 (c) to give 32 g of benzhydryl 7β-amino-7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl 3-Cefe-4-carboxylate was obtained as a crystalline powder. Melting point: 127 ° ÷ 128 ° C.

Claims (29)

(a) a carboxy-protected 7-amino-3-chloromethyl- (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid or a salt thereof of formula (II) Treated with (alkyl- or aryl-) sulphenyl chloride, (b) the corresponding 7- (alkyl- or aryl-) thioimino-3-chloromethyl- (1-oxa- or 1-thia-) 3-cepem of the formula (IV) thus obtained is converted to Treated with [1-alkyl or 1- (ω-hydroxyalkyl-)]-1 H-tetrazol-5-ylthiol or an alkali metal salt thereof, (c) the corresponding 7- (alkyl- or aryl-) thioimino-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- (1-oxa- or 1) of formula (VI) -Thia-) 3-cepem is treated with methanol in the presence of base neutralized aluminum trichloride and triarylphosphine or tri (C ₁ -C ₆ ) alkylphosphine and the compound of formula (I) Or a process for preparing a (1-oxa- or 1-thia-) 3-cepem derivative of formula (I) or a salt thereof, including obtaining in the form of an acid addition salt thereof:

Wherein X is oxygen or sulfur, Y is alkyl having from 1 to 3 carbon atoms or ω-hydroxyalkyl having from 2 to 3 carbon atoms, R ° represents a carboxy protecting group, and W is from 1 to 1 carbon atoms Benzyl unsubstituted or substituted with 3 alkyl, alkyl having 1 to 3 carbon atoms, or phenyl unsubstituted or substituted with alkyl having 1 to 3 carbon atoms. The process of claim 1, wherein in step (a) the alkyl- or aryl-sulphenyl chloride has the formula (III), wherein W is methyl, phenyl or p-tolyl. The carboxy-protected 7-amino-3-chloro of formula (II) according to claim 1 or 2, wherein in step (a), X is oxygen or sulfur and R is benzhydryl or p-methoxybenzyl. Methyl- (1-oxa- or 1-thia-) 3-cepem-4-carboxylic acid or salt thereof is used. The [1-alkyl- or 1- (ω-hydroxyalkyl-)] 1H-tetrazol-5 of formula (V) according to claim 1, wherein in step (b), Y is methyl or 2-hydroxyethyl. How the thiol is used. The [1-alkyl- or 1- (ω-hydroxyalkyl)-] 1H-tetrazol-5-ylthiol of formula (V) according to claim 4, wherein Y is methyl or 2-hydroxyethyl. In salt form. The [1-alkyl- or 1- (ω-hydroxyalkyl-)] 1H- of formula (V) according to claim 1, wherein in step (b), Y is methyl or 2-hydroxyethyl. Tetrazol-5-ylthiol and 7- (alkyl- or) of formula (IV) wherein X is oxygen or sulfur, R ° is benzhydryl or 4-methoxybenzyl, and W is methyl, phenyl or p-tolyl Aryl-) thioimino-3-chloromethyl- (1-oxa- or 1-thia-) 3-cepem is used. The process of claim 1, wherein in step (c), X is oxygen or sulfur, R ° is benzhydryl or 4-methoxybenzyl, Y is methyl or 2-hydroxyethyl, and W is methyl, phenyl or 7- (alkyl- or aryl-) thioimino-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl- (1-oxa- or 1-thia) of p-tolyl -) 3-cepem is used. The process of claim 1, wherein in step (c), X is oxygen or sulfur, Y is methyl or 2-hydroxyethyl and R ° is a carboxy protecting group. The method of claim 1, wherein in step (c), the triarylphosphine or tri (C ₁ -C ₆ ) alkylphosphine is triphenylphosphine, tri ( o -tolyl) phosphine, tri (2-furyl) force Pin and tri ( n -butyl) phosphine. The method of claim 8, wherein the R ° group is benzhydryl. The method of claim 8, wherein the R ° group is 4-methoxybenzyl. The method of claim 1 wherein the base is sodium bicarbonate. The process according to claim 1, wherein in step (c), the compound of formula (I) is separated in its salt form, neutralized with free base or not neutralized. The method of claim 13, wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, methanesulfonate, p -toluenesulfonate and naphthalene-2-sulfonate salts. The process of claim 1, wherein in step (c), the compound of formula (I ') is isolated: Wherein X 'is oxygen, Y' is 2-hydroxyethyl and R ° is a carboxy protecting group. The process of claim 1, wherein in step (c), the compound of formula (I ") is isolated:

Wherein X ″ is sulfur, Y ″ is methyl and R ° is a carboxy protecting group. The method of claim 15, wherein the carboxy protecting group R ° is benzhydryl. The method of claim 15, wherein the carboxy protecting group R ° is 4-methoxybenzyl. The method of claim 16, wherein the carboxy protecting group R ° is benzhydryl. The method of claim 16, wherein the carboxy protecting group R ° is 4-methoxybenzyl.  17. The process of claim 16, wherein the compound of formula (I ') is further reacted and treated with 2- (difluoromethylthio) acetic acid activated in the presence of a silylating agent to obtain a compound of formula (VII') :

Wherein X 'is oxygen, Y' is 2-hydroxyethyl and R ° is a carboxy protecting group that is removed by known methods to separate flomoxef. 22. The method of claim 21, wherein the silylating agent consists of hexamethyldisilazane and trimethylchlorosilane. The method of claim 21, wherein the carboxy protecting group R ° is benzhydryl or 4-methoxybenzyl, the removal of which is carried out by treatment with trifluoroacetic acid and anisole in dichloromethane. 17. The process of claim 16, wherein the compound of formula (I ") is further reacted and treated with activated 2- (cyanomethylthio) acetic acid to obtain a compound of formula (VII"):

Wherein X ″ is sulfur, R ″ is methyl and R ° is a carboxy protecting group which is removed by known methods to separate cefmetazole. The method of claim 24, wherein the carboxy protecting group R ° is benzhydryl or 4-methoxybenzyl, the removal of which is carried out by treatment with trifluoroacetic acid and anisole in dichloromethane. The process of claim 24, wherein the carboxy protecting group R ° is benzhydryl or 4-methoxybenzyl, the removal of which is carried out by treatment with aluminum trichloride and anisole in dichloromethane. 7- (alkyl- or aryl-) thioimino-1-dethia-1-oxa-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl-3- of formula (VI ′) Sepem:

Wherein X 'is oxygen, Y' is alkyl having 1 to 3 carbon atoms or ω-hydroxyalkyl having 2 or 3 carbon atoms, and W is 1 to 3 carbon atoms unsubstituted or substituted with a phenyl group Or a phenyl group unsubstituted or substituted with personal alkyl or alkyl having 1 to 3 carbon atoms, and R ° is a carboxy protecting group. The compound of formula (VI ') according to claim 27, wherein X' is oxygen, Y 'is 2-hydroxyethyl, W is methyl, phenyl or p-tolyl, and R ° is benzhydryl or 4-methoxybenzyl. 7- (alkyl- or aryl-) thioimino-1-dethia-1-oxa-3- (1-substituted-1H-tetrazol-5-yl) thiomethyl-3-cepem. Benzhydryl 7-methylthioimino-3- [1- (2-hydroxyethyl) -1H-tetrazol-5-yl] thiomethyl-1-dethia-1-oxa-3-cepem-4-car Carboxylate.