HU184815B - Process for preparing 7alpha-methoxy-7beta-/cyano-methyl-acetamido-3-cefem-4-carboxylic acid derivatives - Google Patents

Abstract

An improved process for producing a 7.alpha.-methoxy-cephalo-sporin of the formula <IMG> wherein R1 and A are as defined hereinafter, or an ester, salt or amide thereof, which comprises reacting a compound of the formula <IMG> wherein R2 is as defined hereinafter, or an ester, salt or amide thereof, with a halogenating agent in the presence of methanol and an alkali metal salt of methanol and reacting the resulting corresponding 7.alpha.-methoxy compound or an ester, salt or amide thereof, with a thiol of the formula R1--SH or a salt thereof.

Description

The present invention relates to a process for the preparation of 7a-methoxy-3-cephem-4-carboxylic acid derivatives. More particularly, the present invention relates to an improved process for the preparation of 7 amethoxy-3-acephem-4-carboxylic acid derivatives of the formula I and their salts, wherein

R ₃ is R, S or R ₂ SO ₃ - wherein

R 1 is a 5 or 6 membered heterocyclic radical optionally substituted with hydroxy, phenyl and / or carboxyl, containing 1 or 2 nitrogen atoms and optionally one sulfur atom, or a C 1-4 alkyl or naphthyl group substituted with a phenyl or cyano group,

R _{2 is C} 1 -C 4 alkyl, C 2 -C 4 alkenyl or benzyl, or phenyl or naphthyl optionally substituted with C 1 -C 3 alkyl,

C14 alkyl optionally substituted with C 1-4 alkanoyloxy or tetrazolylthiomethyl substituted with C 1-4 alkyl, and

R _{4 is} hydrogen or C 1-6 alkyl.

Methoxy-3-cephem-4-carboxylic acid derivatives 7a and their salts are known as antimicrobial agents. In particular, 7a-methoxy-7β- (cyanomethylthioacetamido) -3- (1-methyl-1 H -tetrazol-5-yl) thiomethyl-3-cfem-4-carboxylic acid and 7α-methoxy-7 (3- (1) 2,

Thia-diazol-2-yl-thioacetamido) -3- (1-methyl-H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid is an effective antimicrobial agent against a number of bacteria [53-59890. Japanese Patent Publication No. Kokai (Kokai); J. Antibiotics 29/9, 969 (1976)].

Many processes are known for the preparation of 7a-methoxy-3-cephem-4-carboxylic acid derivatives, but these processes are not commercially available for the preparation of the above compounds. For example, in J. Antibiotics 29/9, 969 (1976), 7α-methoxy-7β- (cyanomethylacetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl -cephene-4-carboxylic acid is prepared according to the procedure outlined in Scheme 1. However, our own experiments have shown that the intermediate of formula 4 in this scheme is not stable and thus difficult to handle.

Studying the preparation of 7a-methoxy-3-cephem-4-carboxylic acid derivatives, it has been found that the compound of formula III, which contains only the R ₂ SO ₃ CH ₂ CO substituent at the 7-position of the amino group, is preferably converted 7a-methoxy derivative of formula II, and the resulting 7a-methoxy derivative can be advantageously used to prepare the 7 amethoxy-3-acephem-4-carboxylic acid derivatives of formula I without deprotection.

Thus, according to the present invention, there is provided a process for the preparation of compounds of formula II wherein R ₂ and A are as defined above or their salts and C 1-6 alkyl esters. Accordingly, the compound of formula III, wherein R ₂ and A are as defined above, or a C 1 -C 6 alkyl ester or salt thereof is reacted with a halogenating agent in the presence of methanol and an alkali metal salt of methanol (alkali metal methanolate).

The present invention provides a process for the preparation of compounds of formula I wherein: And R ₃ and A are as defined above and salts thereof. These compounds are prepared by reacting a compound of formula III, wherein R ₂ and A are as defined above, or a C 1 -C 6 alkyl ester or salt thereof, with a halogenating agent, in the presence of methanol and an alkali metal methanolate, to give a compound of formula II. - aho ^! R ₂ and A are the above - or a C 1 -C 6 alkyl ester 5 or a salt thereof with a thiol of the formula R 1 -SH IV - wherein R 1 is as defined above - or a salt thereof.

In a preferred embodiment the second compound, esters and salts are prepared by the general formula of the compound or an ester or a 10 salt III methanol alkali metal salt is reacted with methanol at a temperature of -95 ° C to -1Ö ^Q C in an inert solvent, and then a halogenating agent is added at the above temperature. The reaction is usually completed in a short time, such as 5 minutes to 2 hours. Then, 15 carboxylic acids, such as formic acid or acetic acid, are added to the reaction mixture to decompose the excess alkali metal methanolate. If the reaction mixture contains an unreacted halogenating agent, a reducing agent such as trimethylphosphine, triphenylphosphine or sodium thiosulfate is added to the reaction mixture before or after the addition of the carboxylic acid to decompose the unreacted halogenating agent. If either the starting material or the product is unstable and can be degraded by the alkali metal methanolate or the halogenating agent, the alkali metal methanate and the halogenating agent are preferably added two or more times so as to avoid degradation.

For example, the alkali metal salt of methanol is lithium methanolate, potassium methanolate or sodium methanolate, and lithium methanolate is preferred. These alkali metal salts are prepared in a conventional manner, for example, by adding the alkali metal to methanol or to an inert solvent containing excess methanol and using the reaction mixture without isolating the alkali metal salt of methanol.

In the process of the present invention, about 2 to about 10 equivalents of an alkali metal methanolate are reacted with 1 equimolar amount of the compound of Formula III, or derivatives thereof, in the presence of at least 1 equimolar amount of methanol, but preferably in a large excess.

The solvent used in the process is, for example, dimethylformamide, dimethylacetamide, hexamethylphosphoric triaramide, ethyl acetate, toluene, tetrahydrofuran, dichloroethylene, aceto45 nitrile, acetone, chloroform or mixtures thereof.

Halogenating agents are, for example, chlorine, bromine, N-haloamides such as N-chloroacetamide or N-bromoacetamide; N-halogenimide such as N-chlorosuccinimide 5C or N-bromosuccinimide; N-halosulfonamide such as N-chlorobenzenesulfonamide; and alkyl hypohalite such as tert-butyl hypochlorite. Of these, tert-butyl hypochlorite is particularly preferred.

The 7a-methoxy-3-cephem455 carboxylic acid derivatives of formula I wherein R _{3 is} R ₃ S - and salts thereof are prepared by reacting a compound of formula II or an ester or salt thereof with a thiol of formula IV or a salt thereof. . The process is generally carried out in the presence of a base in an inert solvent, but if the starting material of formula II or the thiol is used in a salt form, the reaction may be carried out without the addition of a base. There are no particular limitations on the reaction temperature, but preferably the reaction is carried out at or below room temperature.

For example, dlmethylform-21 is used as a solvent in the process

184,815, which are used in the form of dimethylacetamide, water, acetone, dioxane, methanol, ethanol, acetonitrile, methylene chloride, chloroform, tetrahydrofuran, dichloroethane, benzene, toluene, pyridine, ethyl acetate or a mixture thereof.

The reaction mixture of the above process can be obtained without isolation of the product to obtain the compound of formula I or salts thereof. In this case, the thiol or its salt is added directly to the reaction mixture when the reaction of the compound of formula II with the halogenating agent in the presence of methanol and alkali metal methanol is carried out, and this process is highly preferred for the industrial preparation of the compound of formula.

As thiol salts, alkali metal salts (e.g. lithium, sodium or potassium salts), amine salts (e.g. triethylamine salt, N, N-dimethylbenzylamine salt, N, N-dimethylcyclohexylamine salt, or dicyclohexylamine salt) and quinoline salt.

In general, the compounds of the formulas II and III and their derivatives are very soluble in the above solvents and thus very convenient for use in the process of the invention, but some of their salts, such as the dicyclohexylamine salt, have relatively low solubility. In this case, the salt is further reacted by dissolving an equimolar amount of an acid such as p-toluenesulfonic acid in a solvent.

The compound of formula III and its carboxyl-substituted derivative are prepared by reacting a compound of formula V, wherein A is as defined, or a derivative thereof.

R, SO ₃ CH ₂ COOH

With a compound of formula VI wherein R! or a reactive derivative thereof.

Derivatives of the compound of formula V include those compounds of formula V wherein the amino or carboxyl group is substituted. Such derivatives include amino-substituted salts such as hydrochloride, acetate or íoluolszulfonát or V. It is generally ^one general silicone compound! Formed reaction product of a compound such as bis (trimethylsilyl) acetamide. Examples of the carboxyl substituted derivatives of the compound of formula VI include acid anhydrides, acid halides, acid azides and active esters. Of these, halides (e.g. chloride) are preferred.

The reaction is generally carried out in an inert solvent such as water, acetone, dioxane, dimethylformamide, acetonitrile, methylene chloride, tetrahydrofuran, chloroform, dichloroethane, pyridine and the like at room temperature or below (e.g. actually not critical. When the compound of formula VI is used in the process as the free acid or salt, the reaction is preferably carried out in the presence of a condensing agent such as phosphorus trichloride or cyclohexylcarbodiimide. In addition, it may be advantageous to carry out the reaction in the presence of a base such as an alkali metal bicarbonate, trialkylamine, dialkylaniline, pyridine or dicyclohexylamine.

Compound II can also be prepared according to Scheme 2, in substantially the same manner as Compound III is prepared from Compound V as described above,

The compound of formula II is advantageously used to prepare the compound of formula I and can also be used as a broad spectrum antimicrobial agent.

The following examples illustrate the invention in more detail without limiting the scope of the invention.

Example 1 Preparation of g Tosylglycolic acid

Glycolic acid (38 g, 0.5 mol) was dissolved in water (150 mL) and sodium hydroxide (20 g, 0.5 mol) was added gradually. The solution was cooled in ice to 0-10 ° C for 15 minutes and simultaneously with p-toluenesulfonyl chloride (143 g, 0.75 mol) dissolved in ether (500 mL) under vigorous stirring and 20% w / w aqueous sodium hydroxide solution (100 g) was added. After stirring for 3 hours at 0-10 ° C, the solution was partitioned between aqueous and organic layers. The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid to give white crystals.

The crystals were filtered off with a suction filter, washed with water (500 ml) and dried at 60-80 ° C under reduced pressure to give 92 g of tosylglycolic acid.

135-137 ° C (known value 137 ° C).

Infrared (IR) (nujol): 1710 cm ^1st

Synthesis of 7β - [2- (p-Toluenesulfonyloxy) acetamido] cephalosporanic acid and its salt 30 p-Toluenesulfonyloxyacetic acid (2.3 g, 0.01 mol) in methylene chloride (4.6 g) and dimethylformamide (0.02 g) and thionyl chloride (1.9 g, 0.01 mol) was added and the suspension was stirred and refluxed for 3 to 5 hours.

After the suspension had become a nearly homogeneous solution, the solution was cooled to give a solution of p-toluenesulfonyloxyacetyl chloride in methylene chloride.

In a separate vessel, 90% pure 7-aminocephalosporanic acid (2.72 g) was suspended in dimethylformamide (10 g) and dissolved in triethylamine (1.515 g, 0.015 mol) with stirring. The solution is cooled in an ice / sodium chloride bath to -10 ° to 0 ° C and the above methylene chloride solution is added dropwise over 30-60 minutes with vigorous stirring. Stirring was then continued for another 60 minutes. The resulting triethylamine hydrochloride was filtered off, washed with dimethylformamide (2 g) and the filtrates were combined.

Acetone (50 g) was added to the combined filtrate followed by dicyclohexylamine (1.81 g, 0.01 mol) under stirring, which resulted in immediate crystallization. After stirring for 1 to 2 hours, the crystals were filtered off, washed with acetone and dried under reduced pressure to give the dicyclohexylamine salt of the target compound (4.8 g, 80%, based on 7-aminocephalosporanic acid).

173-175 ° C (dec.).

Nuclear Magnetic Resonance Spectrum (CF3 COOH): δ 1-2.5 (2OH),

2.3 (3H),

2.5 (3H),

3.4 (2H),

3.7 (2H),

4.8 (2H),

184,815

5.2-5.5 (3Η),

5.9 (1 Η),

7.7 (7Η),

8.2 (1H).

Synthesis of 7α-Methoxy-7 (3- [2- (ρ-toluenesulfonyloxy) -acetamido-cephalosporanic acid and its salts)

The dicyclohexylamine salt of 7- [2- (p-toluenesulfonyloxy) acetamido] -cephalosporanic acid (10.7 g) was treated with dimethylformamide (40 mL), tetrahydrofuran (16 mL) and ethyl acetate (40 mL). ml) and p-toluenesulfonic acid (2.75 g) was added with stirring. The solution was cooled to -60 ° C and a solution of lithium inethanolate prepared from lithium (0.48 g) and methanol (26 mL) was added dropwise over 20 minutes. Stirring was continued at -60 ° C for 30 minutes and a mixture of tert-butyl hypochlorite (3.75 g) and ethyl acetate (26 mL, diluent) was added dropwise over 25 minutes. After stirring at -60 ° C for 10 minutes, the reaction was quenched by the addition of triphenylphosphine (13 g) in ethyl acetate (60 mL) and acetic acid (2.1 mL). The solution was stirred at 5 ° C for 40 minutes, the insoluble material was filtered off and washed with acetone (50 mL). The filtrates were combined and ethyl acetate (600 mL) was added. The precipitate was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give the lithium salt of the target compound. Yield: 85%.

IR (nujol): nC = O 1780 cm ^-1 (δ-lactam).

NMR (CH ₃ COOH):

2.30 (3H, s),

2.55 (3H, s),

3.60 (2H, bs),

3.73 (3H, s),

4.86 (2H, s),

5.3-5.5 (3 H, m),

7.40-8.10 (4H, q),

8.50 (1H, s).

Melting point: 179 ° C (dec.).

Example 2

Synthesis of [2- (p-Toluenesulfonyloxy) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 carboxylic acid and its salt p-Toluenesulfonyloxyacetic acid (23 (g) Suspended in a mixture of methylene chloride (75 g) and dimethylformamide (0.2 g) and after addition of thionyl chloride (11.9 g), the suspension was stirred and refluxed for 3-5 hours.

When the suspension becomes a nearly homogeneous solution, the solution is cooled to give p-toluenesulfonyloxyacetyl chloride in methylene chloride.

In another flask, 7-amino-3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid (32.8 g) was suspended in dimethylformamide (95 g), cooled to -10 ^° C. To C and dropwise, bis (trimethylsilyl) acetamide (44.7 g) is added gradually. The slurry is then warmed to room temperature and stirred until the suspended acid is completely dissolved. The aqueous solution was cooled to -30 ° C to -40 ° C, diethylaniline (14.9 g) was added and the methylene chloride solution prepared above (30-60 minutes) was added dropwise and stirring continued for 1 hour. The solution was poured into a mixture of ethyl acetate (200 mL) and distilled water (500 mL), the aqueous layer was adjusted to pH 2.0-2.5 if necessary, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The extracts and the above ethyl acetate layer were combined, washed with a saturated aqueous sodium chloride solution (60 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to a volume of 170 mL. Crystals are precipitated after addition of dicyclohexylamine (18.1 g).

After stirring for 1 h, the crystals were collected by filtration, washed with ethyl acetate, ethyl acetate and dried under reduced pressure to give the dicyclohexylamine salt of the target compound (67 g).

NMR (CF ₃ COOH):

δ 1.0-1.3 (20H, m),

2.51 (3H, s),

3.1-3.7 (2 H, m),

3.83 f2H, broad s),

4.16 (3H, s),

4.3 - 4.9 (4H, m),

5.32 (1H, d),

5.92 (1H, q),

7.4-8.0 (4H, q),

8.12 (1H, d).

Synthesis of 7a-Methoxy-70- [2- (p-toluenesulfonyloxy) -acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid and its salt

- [2- (p-Toluenesulfonyloxy) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt (23.1 g) and p-toluenesulfonic acid (5.5 g) was dissolved in a mixture of dimethylformamide (96 mL) and ethyl acetate (96 mL). The solution was cooled to -60 ° C and lithium methanolate in lithium (0.672 g) and methanol (49 mL) was added dropwise over 35 minutes. The solution was then stirred at -60 ° C for 30 min and a mixture of tert-butyl hypochlorite (6.95 g) and ethyl acetate (48 mL, diluent) was added dropwise over 45 min. After stirring at -60 ° C for a further 20 minutes, a solution of lithium methanolate in lithium metal (0.224 g) and methanol (16.5 ml) was added dropwise over 20 minutes. After stirring at the above temperature for 20 minutes, a mixture of tert-butyl hypochlorite (1.74 g) and ethyl acetate (12 mL, diluent) was added dropwise over 15 minutes. The solution was stirred for an additional 15 minutes and a solution of triphenylphosphine (13 g) in ethyl acetate (60 mL) and acetic acid (4.5 mL) was added dropwise. The solution was then poured into a mixture of distilled water (800 mL) and ethyl acetate (600 mL), the pH of the aqueous layer was adjusted to 2.5 with 1N hydrochloric acid, and the ethyl acetate layer was separated from the aqueous layer. The aqueous layer was extracted with ethyl acetate (2 x 200 mL). All ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to a volume of 260 ml. Dicyclohexylamine (5.9 g) was added followed by carbon tetrachloride (630 mL). The precipitate was collected by filtration, washed with carbon tetrachloride and dried under reduced pressure to give the dicyclohexylamine salt of the target compound (19.2 g).

IR (nujol): 1778 cm <^-1> .

NMR (CF ₃ COOH): δ 1.0 - 2.3 (2OH, m),

2.49 (3H, s),

3.1 - 3.6 (2H, m),

184,815

3.60 (2Η, wide),

3.67 (3H, s),

4.10 (3H, s),

4.58 (2H, bs),

4.76 (2H, broad),

5.23 (1H, s),

7.35-7.93 (4H, q),

8.23 (1H, s).

Melting point: 150 ^o C (dec).

Example 3

Synthesis of 7a-Methoxy-7 / 1- (2- (4-pyridylthio) acetamido] 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem 4-carboxylic acid

The dicyclohexylamine salt (1.81 g) obtained in Example 2 and 4-mercaptopyridine (0.233 g) were dissolved in a mixture of methylene chloride (30 ml) and dimethylsulfoxide (0.2 ml) and stirred for 24 hours. . The precipitate was collected by filtration, washed with methylene chloride and dried under reduced pressure to give the title compound of high purity. Yield: 100%.

NMR (CF3 COOH): δ 3.69 (5H, s),

4.15 (3H, s),

4.30 (2H, bs),

4.3-4.9 (2H, q),

30 (lH, s);

7.8-8.7 (4H, q),

8.5 (1H, broad s).

Melting point: 135 DEG C. (dec.).

Example 4

7a · Synthesis of methoxy-70- (cyanomethyl-thioacetamido) · 3 (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4 carboxylic acid and its sodium salt

A mixture of cyanomethylisothiourea hydrochloride (3.03 g) and dimethylformamide (15 ml) was cooled with stirring to -50 ° C and a solution of lithium methanolate in lithium metal (0.280 g) and methanol (21 ml) was added dropwise. is added dropwise over 10 minutes. The solution was then stirred at -30 ° C for a further 10 minutes and poured into dimethylformamide (20 ml) containing the dicyclohexylamine salt of Example 2 (7.51 g) at 30 ° C with stirring. The reaction proceeds at -20 ° C for 1 hour. Acetic acid (2.4 mL) was added and the solution was poured into a mixture of distilled water (100 mL) and ethyl acetate (100 mL) and the pH of the aqueous layer was adjusted to 2 with 2N hydrochloric acid. The ethyl acetate layer was separated from the aqueous layer and the aqueous layer was extracted with ethyl acetate (2 x 40 mL). All ethyl acetate layers were combined, washed with 2 x 40 mL of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to a volume of 80 mL. Sodium 2-ethylhexanoate (2.01 g) dissolved in ethyl acetate (20 mL) was gradually added dropwise. The precipitate was collected by filtration and dried under reduced pressure to give the high purity sodium salt of the target compound. Yield: 80%.

IR (Nujol): 1775 ^cm-first

NMR (CF3 COOH): δ 2.27 (3H, s),

3.55-3.85 (6H, not clear due to overlapping peaks),

3.72 (3H, s),

5, ΐ 2-5.56 (2H, q),

5.31 (1.1, s),

8/5 (1H, s).

Example 5

Synthesis of 7a-Methoxy-70 - ((4-carboxy-3-hydroxy-isoriaazol-5-yl) -thioacetanedo] -ephephalosporanic acid

7a-Methoxy-70- [2- (p-toluenesulfonyloxy) -acetamido'-cephalosporanic acid (9.7 g) was dissolved in methanol (90 mL) and the solution was cooled to 5 ° C. A solution of 4 carboxy-3-hydroxy-5-mercaptoisothiazole trihydrate (5.94 g) dissolved in distilled water (20 mL) was gradually added dropwise to the solution under ice-cooling. The solution was then stirred at 0-5 ° C for 2 hours. The methanol was removed under reduced pressure, the solution was acidified to pH 2 with 2N hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed twice with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the ethyl acetate under reduced pressure gave the target compound as a powder. Yield: 75%.

Example 6

Synthesis of 7a-Methoxy-70-2- (1,3,4, -thia-diazolyl) thioacetamido -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 cephem-4 carboxylic acid and its sodium salt

A mixture of 2-mercapto-1,3,4-thiadiazole (0.36 g) and dimethylformamide (2.5 mL) was cooled with stirring to -30 ° C and lithium (0.021 g) and methanol (1). Lithium methanolate (5 ml) was added dropwise. This solution of sodium 7a-methoxy-70- [2- (p-toluenesulfonyloxy) acetamido] -3- (1-methyl-1H-tetrazole-5) in dimethylformamide (12 mL) was dissolved at -30 ° C. - yl-thiomethyl) -3-cephem-4-carboxylate (1.78 g). The reaction was continued at -30 ° C for 1 hour and then at ~ 10 ° C for 3.5 hours. After adding acetic acid (0.2 mL), the solution was poured into a mixture of distilled water (150 mL) and ethyl acetate (100 mL) and the pH of the aqueous phase was adjusted to 2.5 with 2N hydrochloric acid. The organic layer was separated from the aqueous layer and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed twice with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After evaporation, the residue is crystallized from isopropyl alcohol containing sodium 2-ethylhexanoate. The crystals were collected by filtration and dried under reduced pressure to give the sodium salt of the target compound. Yield: 75%.

IR (Nujol): 1775 ^cm-first

NMR (DMSO-d6): δ 3.1-3.8 (2H, q),

3.41 (3H.s),

3.93 (3H, s),

4.15-4.40 (4H, m),

4.93 (1H, s).

9.48 (111, s),

9.57 (1H, s).

-5 ₁ 184815

Example 7

Synthesis of Ία-Methoxy-Ίβ- (danomethyl-thioacetamido) -3 (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4 carboxylic acid and its sodium salt

Ίβ- [2- (p-Toluenesulfonyloxy) acetamido] -3- (1-methyl-III-tetrazol-5-yl) thiomethyl-3-cephem-4 carboxylic acid (2.16 g) in dimethylformamide (24 ml) was dissolved with stirring. The solution was cooled to -50 ° C and gradually lithium methanolate solution from lithium metal (0.056 g) and methanol (4 ml) was added, followed by stirring for 30 minutes with tert-butyl hypochlorite (0.434 g), and g) and a solution of lithium methanolate in methanol (2 mL), after stirring for 30 min, a solution of tert-butyl hypochlorite (0.434 g) was added dropwise to the reaction mixture. After 20 minutes, a solution of lithium cyanomethyl mercaptide (NCCH ₂ SLi) is added to the solution [NCCH ₂ SLi solution is prepared by adding lithium methanolate made from metal lithium (0.17 g) and methanol (12 mL). under stirring with a mixture of cyanomethyl isocarbamide hydrochloride (1.82 g) and dimethylformamide (9 ml)]. The solution was stirred at -3 ° C for 5 hours and at -10 ° C for a further 20 minutes. After adding acetic acid (2 in), the solution was poured into a mixture of distilled water (200 mL) and ethyl acetate (100 mL) and the pH of the aqueous layer was adjusted to 2.5 with 2N hydrochloric acid. After separation of the organic layer g, the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, washed twice with saturated brine, dried over anhydrous magnesium sulfate and treated with charcoal. After concentration under reduced pressure, the residue is crystallized from isopropanol containing sodium 2-ethylhexanoate as the sodium salt. The crystals were collected by filtration and dried under reduced pressure to give sodium Ία · methoxy - Ίβ - cyanomethylthioacetamido - 3 (1 - methyl - 1H - tetrazol - 5 - yl) thiomethyl - 3 - cephem - 4 - carboxylate. The IR and NMR spectra of this compound were identical to those of Example 4. Yield: 85%.

The compounds of the formula RSO ₃ CH ₂ COOH are those of formula I. or Acta Chem. Scand. 22, 20 2043 (1968). The following starting materials were prepared as described in Examples 1 and 2, and the following target compounds were prepared from the starting materials as described in Example 1.5s 2.

Starting compound of formula VII: The target compound of formula Vili

R THE Starting compound target W is the group of Formula NMR (CF ₃ COOH): 5 1.0-2.4 (2OH, m); W '= Na IR (Nujol): 1768 ^cm-1 vC = O 2.37 (3H, s), NMR (CF ₃ COOH): δ tolyl methyl 2.52 (3H, s), 2.41 (3H, s), 3.2-3.7 (2 H, m), 2.50 (3H, s), 3.53 (2H, bs), 3.2-3.5 (2 H, m). 4.70 (2H, s), 3.63 (3H, s), 5.23 (1H, d), 4.78 (2H, broad s), 5.71 (1H, q), 5.23 (1H, s), 7.4-8.0 (4H, q), 7.4-7.9 (4H, q), 8.10 (1H, d) 8.35 (1H, s). Melting point: 175-180 ° C Yield: 75% (Dec) W is a group of the formula W 'is a group of the formula 1-naphthyl acetoxymethyl NMR (CF ₃ COOH): δ 1.0-2.3 (2OH, mL, IR (nujol): ν C-Q 1780 cm ^-1 2.30 (3H, s), NMR (CF ₃ COOH): 6 3.0-3.6 (2 H, m), 1.0-2.4 (2OH, m), 3.4-3.8 (2H, q), 2.30 (3H, s), 4.74 (2 H, s). 3.1-3.6 (2 H, m), 5.07-5.47 (3 H, m), 3.3-3.8 (2H, not due to overlap 5.85 (1H, q), clean) 7.5-8.7 (8H, m) 3.60 (3H, s), 4.82 (2H, broad s), 5.19 (1H, s), 5.12-5.55 (2H, q), 7.5-8.7 (8H, m) Melting point: Yield: 70%. 170-180 ° C (dec.)

184,815

Starting compound of formula VII

Vili is the target compound

R THE Starting compound: target W = a group of the formula W '= Well NMR (CF ₃ COOH): δ IR (nujol): υ C-0 1.0-2.3 (2OH, m), 1772 cm ^-1 1-naphthyl (L-methyl-tetrazol-5-yl) - 3.1-3.6 (2 H, m), NMR _(CF3 CQQH): <$ thiomethyl 3.78 (2H, broad s), 3.52 (3H, s), 4.13 (3H, s), 3.5-3.6 (2H, not due to overlap 4.2-4.8 (4H, m), clean) 5.19 (1H, d), 4.08 (3H, s), 5.82 (1H, q), 4.52 (2H, broad), 7.5-8.7 (8H, m) 4.70 (2H, bs), 5.13 (1H, s), 7.5-8.7 (8H, m), Mp 185 ° C Yield: 73%. (Dec) W is isobutyl W 'isobutyl NMR (CDCl ₃ ): δ IR (nujol): v C = O 1.55 (9H, s), 1785 cm ^-1 p-tolyl acetoxymethyl 2.07 (3H, s), NMR (CDCl ₃ ): δ 2.45 (3H, s), 1.55 (9H, s), 3.2-3.7 (2H, q), 2.06 (3H, s), 4.52 (2H, bs), 2.44 (3H, s), 4.7-5.2 (3H, m), 3.1-3.7 (2H, overlap 5.77 (1H, q), not clear), 7.28-7.85 [5H: (4H, q) + 1H] 3.50 (3H, s), 4.53 (2H, bs), 4.7-5.1 (2H, q), 5.00 (1H, s), 7.29-7.86 [5H: (4H, q) + 1H] Yield: 75% Melting point: 150 ° C (dec.) W = a group of the formula W '= a group of the formula NMR (CF ₃ COOH): δ IR (nujol): v C = O 1.0-2.3 (2OH, m), 1780 cm ^-1 methyl (1-Methyl-1H-tetrazol-5-yl) - 3.1-3.6 (2 H, m), NMR (CF ₃ COOH): δ thiomethyl 3.27 (3H, s), 1.0-2.3 (2OH, m), 3.70 (2H, bs), 3.1-3.5 (2 H, m), 4.12 (3H, s), 3.28 (3H, s), 4.2-4.8 (2H, q), 3.63 (2H, broad s), 5.00 (2H, s), 3.69 (3H, s), 5.26 (1H, d), 4.10 (3H, s), 5.89 (1H, q), 4.57 (2H, bs), 8.03 (1H, d) 5.00 (2H, s), 5.25 (1H, s), 8.24 (1H, s) Melting point: Yield: 80%. 170 ° C (dec.)

-7184 815

The starting compound of formula VII is the target compound of formula MII

R THE Starting compound target W = a group of the formula W * = b group of formula IR (Nujol): v C = O 1780 ^cm-1 NMR (CF3 COOH): δ NMR (CF ₃ COOH): δ 1.0-2.3 (20, m), 2.24 (3H, s), 2.25 (3H, s). 2.93 (6H, d), 3.0-3.6 (2 H, m), 3.29 (3H, s), 3.28 (3H, s), 3.3-3.7 (2H, overlap 3.44-3.89 (2H, q), not clear), methyl acetoxymethyl 4.8-5.5 (5H, ni), 3.68 (3H, s), 5.93 (1H, q), 4.32 (2H, d), 8.03 (1H, d) 5.01 (2H, bs) 5.26 (1H, s), 5.0-5.5 (2H, not clear due to overlap), 7.3-7.6 (5 H, m), 8.29 (1H, bs) Melting point: Yield: 80%. 165 ° C (dec.) W = a group of the formula W '= a group of the formula IR: i> C = 0 1760 cin ' ¹ IR: t> C = O 1770 cm ^-1 NMR (CF ₃ COOH): δ NMR (CF ₃ COOH): δ 1.43 (3 H, t). 1.43 (3H, t), 1.0-2.4 (20H, m), 1.0-2.4 (2OH, m), ethyl (1-methyl-1H-tetrazol-5-yl) - 3.1-3.6 (2 H, m), 3.0-3.6 (2 H, m), thiomethyl 3.40 (2H, q), 3.42 (2H, q). 3.80 (2H, broad), 3.6 (2H, overlap) 4.13 (3H, s), not clear), 4.1-4.8 (4H, m), 3.67 (3H, m), 4.97 (2H, bs), 4.12 (3H, s), 5.23 (1H, d), 4.55 (2H, bs), 5.90 (1H, q), 4.97 (2H, bs), 8.00 (1H, d) 6.0-6.9 (2H, bs), Yield: 75%. 8.23 (1H, s) W = H W '= a group of the formula NMR (CF ₃ COOH): δ NMR (CF ₃ COOH): δ 3.80 (2H, s), 1.0-2.3 (2OH, m), 4.10 (3H, s), 3.0-3.6 (2 H, m), benzyl (L-methyl-lH-tetrazol-5-yl) - 4.57 (2H, s), 3.5-3.7 (5H, overlapping) thiomethyl 4.65 (2H, s), not clear), 4.67 (2H, s), 4.06 (3H, s), 5.23 (1H, d), 4.55 (2H, s), 5.86 (1H, q), 4.61 (2H, s), 7.46 (5H, s), 4.67 (2H, s), 7.93 (1H, d) 5.18 (1H, s), 7.43 (5H, s), Yield: 71%. 8.03 (1H, s)

184,815

Starting compound VII: VII. is a target compound of the general formula

R THE Space compound target vinyl (1-methyl-lH-tetrazol-5-yl) - W = (a) NMR (CF ₃ COOH) δ 1.0 - 2.3 (2OH, m), 3.0 - 3.6 (2H, broad s), 3.70 (2H, s), W '= a group NMR (CF ₃ COOH): δ 1.0-2.3 (2OH, m), 3.1-3.6 (2H, bs), 3.65 (2H, s), thiomethyl 4.13 (3H, s), 3.72 (2H, s), Yield: 68%. 4.33-4.76 (2H, q), 4.87 (2H, s), 5.24 (1H, d), 5.90 (1H, q), 6.3-6.7 (3 H, m), 8.13 (1H, d) 4.13 (3H, s), 4.61 (2H, s), 4.90 (2H, s), 5.27 (1H, s), 6.31-6.94 (3 H, m), 8.28 (1H, s) W = group W * is a group of the formula allyl (1-Methyl-1H-threzol-5-yl) - NMR (CF ₃ COOH): d 1.0-2.3 (2OH, m), 3.1-3.6 (2H, br s); NMR (CF ₃ COOH): δ 1.0-2.3 (2OH, m), 3.1-3.6 (2H, bs), thiomethyl 3.77 (2H, s), 3.65 (2H, s), 4.0-4.2 (5 H, m), 4.3-4.7 (2H, q), 4.97 (2H, s), 5.20 (1H, d), 5.43-6.17 (4 H, m), 7.99 (1H, d) Yield: 70%. 3.72 (3H, s), 4.13 (3H, s), 4.15 (2H, d), 4.62 (2H, s), 5.03 (2H, s), 5.27 (1H, s), 5.47-6.17 (3H, m), 8.22 (1H, s)

The compounds of Examples 1 and 2 and thiols are prepared as described in Examples 3-6. The compounds of Table 1 were prepared.

In Table 1, the formulas of the prepared target compounds are shown in the form of the free acid, since the metal salts formed on the 4-carboxyl group are readily converted to the free acids.

The NMR (delta) and yields of the target compounds (A) - (K) of the table are given below.

Compound of Formula (A):

NMR _(DMSO-d6) delta: 2.15 (3H, s), 3.22 (2H), 3.45 (2H), 3.5 (5H), 5.06 (2H, s) .

Yield: 85%.

A compound of formula (B);

NMR (CD ₃ CN) delta: 2.00 (3H, s), 3.4 (2H), 3.42 (2H), 3.52 (3H, s), 3.60 (2H); 4.9 (2H), 5.03 (1H, s).

Yield: 90%.

Compound of Formula C:

NMR (DMS0-d _é) delta: 3.43 (3H, s), 3.45 (2H), 3.99 (3H, s), 4.02 (2H), 4.35 (2H) , 4.93 (2H, s), 7.3 (2H).

Yield: 85%.

Compound of Formula D:

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ ) delta 3.42 (3H, s), 3.6 (2H), 3.9 (2H), 3.92 (3H, s), 4.3 (2H) , 5.01 (1H, s), 7.5 (5H, m).

Yield: 80%.

Compound of Formula (E):

Nuclear Magnetic Resonance Spectrum (CD ₃ CN + D ₂ O), δ 2.01 (3H, s), 3.35 (3H, s), 3.4 (2H), 3.76 (2H), 4.80 (2H), 5.00 (1H, s), 7.10 (2H, s).

Yield: 90%.

Compound of Formula (F):

Nuclear Magnetic Resonance Spectrum (CD ₃ CN + D ₂ O) δ 3.30 (3H, s), 3.6 (2H, 3.7 (2H), 3.84 (3H, s), 4.5 ( 2H), 4.96 (1H, s), 7.6 (1H, m).

Yield: 95%.

Compound of Formula (G):

NMR _(DMSO-d6) delta: 2.00 (3H, s), 3.40 (3H, s), 3.2-3.7 (6H), 4.6-4.9 (2H ), 5.02 (1H, s), 7.07.2 (5H, m).

Yield: 90%.

184,815 Compound (H):

Nuclear Magnetic Resonance Spectrum (DMSO-d ₆ ), delta 2.01 (3H, s), 3.40 (3H, s), 3.3-3.9 (4H), 4.8 (2H), δ 11 (2H, s), 7.36 (2H), 8.40 (2H).

Yield: 95%.

Compound of Formula (K):

Nuclear Magnetic Resonance Spectrum (CD ₃ COCD ₃ ), δ 1.55 (9H, s), 2.04 (3H, s), 3.5 (2H), 3.50 (3H, s), 3.58 ( 2H), 3.73 (2H), 4.95 (2H), 5.11 (1H, s).

Yield: 80%.

Claims (1)

A patent claim A process for the preparation of compounds of formula I or salts thereof, wherein: R ₃ is R ₃ or R ₂ SO ₃ - wherein R j is a 5 or 6 membered heterocyclic radical optionally substituted with hydroxy, phenyl and / or carboxyl, containing 1 or 2 nitrogen atoms and optionally one sulfur atom, or a (1-4C) alkyl or naphthyl group substituted with phenyl or cyano, R _{2 is C} 1 -C 4 alkyl, C 2 -C 4 alkenyl or benzyl, or phenyl or naphthyl optionally substituted with C 1 -C 3 alkyl, C 1-4 alkyl optionally substituted with C 1-4 alkanoyloxyoxy or tetrazolylthiomethyl substituted with C 1-4 alkyl, and R 4 is hydrogen or C 1-6 alkyl, characterized in that: 15) a compound of formula III wherein R ₂ and A are reacted with the above or C 1-6 alkyl ester or a salt thereof with a halogenating agent in the presence of methanol and an alkali metal methanolate and, if desired, the resulting compound of formula II - wherein R ₂ and A above -, With a C 1 -C 6 alkyl ester or a salt thereof, with a thiol or a salt thereof R 2 -SH, or ₂ ) a compound of the formula Π wherein R ₂ and A are the same C 1 -C 6 alkyl esters or a salt thereof; With a thiol or a salt of the formula R 1 -SH.