KR820001565B1 - Process for preparing oxim derivatives of 3-acetoxymethyl 7-aminothiazolyl acetamido cephalosporanic acid - Google Patents

Abstract

Bactericidal title compds. [I; R1 = -CO2R1' (R1' = C1-3 alkyl, H, alkali metal, alkali earth metal, Mg, ammonium, organo amino salt), nitryl, CONH2; A = H, alkali metal, alkali earth metal, Mg, ammonium, organo amino salt; R', R" = same or different H, C1-3 alkyl) were prepd. by 5 steps.

Description

Method for preparing oxime derivative of 3-acetoxymethyl 7-aminothiazolyl acet amido cephalosporan acid

The present invention relates to a method for producing an oxime derivative of 3-acetoxy methyl 7-amino thiazolyl acetamido cephalosporan acid represented by the following general formula (I).

The present invention is also a divisional application of 1978 Patent Application No. 818.

기는 Syn 위치에 존재하며, 이때 R는 CO₂R´₁기(여기에서 R1´은 수소원자를 나타냄)를 나타내는 경우 A는 수소원자를 나타내고, R1이 CO₂R´₁기(여기에서 R´1은 알칼리금속, 알칼리토금속, 마그네슘, 암모늄 또는 유기아미노 염기의 등가물)을 나타냄)를 나타낼 경우, A는 알칼리금속, 알칼리토금속, 마그네슘, 암모늄 또는 유기아미노염기의 등가물을 나타낸다.(R ₁ is -CO _{2 R'1} group (which represents the equivalent of this eseoeun 1-3 carbon atoms alkyl group, a hydrogen atom, having from, or alkali metal alkaline earth metal, magnesium, ammonium or an organic amino base in the structural formula), or knit Represents a radical group or a carbamoyl group CONH ₂ , A represents a hydrogen atom or an equivalent of an alkali metal, alkaline earth metal, magnesium, ammonium, or an organic amino base, and R ′ and R ′ are the same or different hydrogen atoms Or an alkyl group having 1-3 carbon atoms,

Group is present at the Syn position, where R represents a CO ₂ R ' ₁ group (where R1' represents a hydrogen atom), A represents a hydrogen atom, and R1 represents a CO ₂ R ' ₁ group (here R' 1 represents an equivalent of an alkali metal, alkaline earth metal, magnesium, ammonium or an organic amino base), and A represents an equivalent of an alkali metal, alkaline earth metal, magnesium, ammonium or an organic amino base.

Examples of R ' ₁ include methyl, ethyl, propyl or isopropyl groups.

Suitable examples of the R ′ ₁ group include equivalents of sodium, potassium, lithium, calcium, or magnesium. Among the organic bases, trimethylamine, diethylamine, methylamine, propylamine, and NN-dimethylethanolamine tris. (Hydroxymethyl) aminomethane, arginine or lysine.

A can represent any of the equivalents of alkali metal, alkaline earth metal, magnesium, ammonium or organoaminobase mentioned for R ' ₁ .

Examples of R 'and R' include methyl, ethyl, propyl or isopropyl groups.

An object of the present invention is in particular the equivalent of R ₁ is CO _{2 R'1} group (where R'1 is an alkyl group having 1 to 3 carbon atoms, a hydrogen atom or an alkali metal, alkaline earth metal, magnesium, ammonium or an organic amino base, And R 'and R' each represent a method for producing the above-described product of formula (I), each representing a hydrogen atom.

Among the compounds represented by the general formula (I), the following compounds which are specifically dealt with in the following examples are mentioned.

-7- [2- (2-aminothiazol-4-yl) 2-carbathoxy methyloxyimido] 3-acetoxymethylcepa-3-m 4-carboxyl, syn isomer, -7- [ 2- (2-bodyaminothiazol-4-yl) 2-hydroxy carbonylmethyloxyiminoacetamido] 3-acetoxymethyl sepha-3-m 4-carboxylic acid, syn isomer, -3- Acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-// (cyanomethyl) oxy / amino / acetyl / amino / cepha-3-M 4-carboxylic acid, syn isomer , -3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-/// (aminocarbonylmethyl) oxy / imino / acetyl / amino / cepha-3-em 4 -Carboxylic acids, syn isomers, and 3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-// (1-carboxy-1-methyl ethyl) oxy / imi No / acetyl / amino / cepha-3-m 4-carboxylic acid, syn isomers and salts with alkali metals, alkaline earth metals, magnesium, ammonia and organoamino bases and more specifically Water; -7- / 2- (2-aminothiazol-4-yl) 2-hydroxycarboylmethyloxy iminoacetamido / 3-acetoxy methyl sefa-3-m 4-carboxylic acid, syn isomer Disodium salt; -3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-// (cyanomethyl) oxy / imino / acetyl / amano / cepha-3-M 4-carboxyl Acid, sodium salt of syn isomer, and 3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-/// (amino carbonyl) methyl / imino / acetyl / amino Sodium salt of / cepha-3-m 4-carboxylic acid, syn isomer,

-3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-// (1-carboxyoxy 1-methylethyl) oxy / imino / acetyl / amino / cepha-3- M 4-carboxylic acid, disodium salt of syn isomer.

The compound represented by the above general formula (I) is in the form represented by the general formula (I) or the form of the compound represented by the following general formula (Iz).

The present invention also relates to a process for preparing compounds of the general formula (I ′), syn isomers. This method is represented by the following general formula (V) in the presence of a base.

(Wherein Hal represents a halogen atom and R ′, R ″ and R ₃ have the same meanings as above), and the compound represented by the following general formula (IV), syn isomer.

(Wherein R ₂ and A ′ have the same meaning as described above), a compound of the general formula (I ′) and syn isomer is obtained.

In a suitable method of carrying out the above process, the compound of formula (V) is reacted with a compound of formula (IV) in the presence of a base such as triethylamine, pyridine or silver oxide. The reaction is suitably carried out in a solvent such as methylene chloride, benzene, acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, chloroform or dimethylformamide.

In the present invention, the following general formula

Isopropenyl methyl ether represented by the following general formula (IV), syn isomer compound.

(Wherein R ₂ represents a group or a chloroacetyl group that can be easily removed by acid hydrolysis or hydrogenolysis), followed by the following general formula

Obtain a compound represented by the following formula and the acid of this compound or functional derivative of this acid is represented by the general formula (II)

A 'represents a hydrogen atom or an ester group which can be easily removed by acid hydrolysis or hydrogenolysis.

(Wherein R ₂ and A 'have the same meaning as described above), a compound of the formula (VII) wherein A' represents a hydrogen atom is esterified according to a conventional method if necessary, and A ' After obtaining a compound of the general formula (에스테르) representing an ester group that can be easily removed by acid hydrolysis or hydrogenolysis, the compound represented by the general formula (Ⅸ) is treated with an acid under appropriate conditions as follows. General formula (Ⅳ)

It relates to a method for producing a compound represented by.

The reaction of isopropenylmethylether to the compound of formula (IV) can be carried out in the presence of an acid, for example paratoluene sulfonic acid. As a starting compound, as an inorganic acid salt of the compound represented by general formula (IV), a thing like hydrogen chloride water can be used. In this case, the presence of an acid is not necessary, and by the end of the reaction with a base such as pyridine, free amine is obtained.

Condensation of any one of the compounds of formula (VII) with esters of 7-amino cephalosporonic acid or the compound represented by formula (II) is a compound represented by formula (III) and the general formula of The reaction is carried out under the same reaction conditions as those used for the reaction with the compound represented by (II).

The esterification of the compound represented by the general formula (VIII) in which A 'represents a hydrogen atom is performed under normal conditions. For example, diazo derivatives such as diazodiphenyl methane can be used.

The purpose of converting the compound of formula (VII) to the compound of formula (IV) is to cleave the protecting group from 1-methyl-1-methoxy-ethyloxime. This reaction is carried out in the acidic medium under conditions suitable for the protecting groups R ₂ and A ′ which can be cleaved in the acidic medium.

To this end, the reaction is carried out using an aqueous hydrochloric acid solution of about 1 or 2N at room temperature, for example for about 30 minutes to several hours. Tertiary-butoxy carbonyl, trityl, benzyl, benzhydryl, trichloroethyl, carbobenzyloxy, formyl, trichloro as R ₂ groups that can be easily removed by acid hydrolysis or hydrogenolysis Ethoxy carboyl, 2-tetrahydropyranyl group, etc. are mentioned.

Examples of the ester group R ₁ ″ which can be easily removed by acid hydrolysis or hydrogenolysis include benzhydryl, tertiary butyl, benzyl paramethoxybenzyl and trichloroethyl group.

A ′ represents any of the ester groups which can be easily removed by acid hydrolysis or hydrogenolysis as mentioned for R ₁ ″.

The purpose of converting the compound represented by the general formula (I ') to the compound of the general formula (Ia) is to substitute substituent R ₂ as a hydrogen atom and a substituent representing an ester group which can be easily removed by acid hydrogenolysis or hydrogenolysis. Hydrogen atom is used to replace R ₁ ″ with a R ₂ ″ group representing a hydrogen atom and substituent A ′ representing an ester group that can be easily removed by acid hydrolysis or hydrogenolysis.

To do so, R ₂ represents a group that can be easily removed by acid hydrogenolysis, and R ₃ represents CO ₂ R ₁ ″ (where R ₁ ″ represents an ester group that can be easily removed by hydrocracking). ), And when A 'represents an ester group or a hydrogen atom which can be easily removed by acid hydrolysis, one or more acid hydrolysis agents are used.

R ₂ represents a group that can be easily removed by hydrogenolysis, and R ₃ represents a CO ₂ R ₁ ″ group where R ₁ ″ represents an ester group that can be easily removed by acid hydrolysis. And when A 'represents an ester group which can be easily removed by hydrogen atom or hydrogenolysis, one or more hydrogenolysis is used.

Compounds of formula (I ′) are treated with one or more acid hydrolytic agents, at least one of R ₂ , R ₁ ″ and A ′ represents a group that can be readily removed by acid hydrolysis, and these substitutions If at least one of the agents represents a group that can be easily removed by hydrogenolysis, it is treated with at least one or more hydrogenolysis agents.

General formula (I ') a compound of is treated with thiourea, R ₂ is R ₁ "and A case represent an chloroacetyl, can be treated as one, depending on the value of the on or off one or more of the acid value of the water or the hydrolysis subdivision release .

Formic acid, trifluoroacetic acid, or acetic acid can be used as the acid hydrolysis agent that can be used for the compound of the general formula (I '). These acids can be used in anhydrous form or in aqueous solution. Zinc acetic acid systems may also be used.

Anhydrous trifluorine to remove tert-butoxycarbonyl or trityl groups which the R ₂ group may represent or to remove benzhydryl, tert-butyl or paramethoxybenzyl groups which the A ′ and R ₁ ″ groups may represent It is suitable to use an acid hydrolysis agent such as acetic acid or aqueous formic acid solution or aqueous acetic acid solution.

It is suitable to use a zinc / acetic acid system to remove the trichloroethyl group represented by R ₂ , R ₁ ″ and A ′.

In order to remove the benzhydryl and carbobenzyloxy groups which the R ₂ groups may represent or to remove the benzyl groups which the R ₁ ″ and A ′ groups may represent, it is suitable to use a hydrogenolysis agent such as hydrogen in the presence of a catalyst.

The reaction of thiourea with respect to the compound of general formula (I ') in which R ₂ represents a chloroacetyl group is preferably carried out in a neutral or acidic medium. This type of reaction was described by Masaki (JACS, 90, 4508 (1968)).

Salification of the compound represented by general formula (Ia) can be performed in accordance with a conventional method. Salicylation is for example the action of inorganic bases such as sodium hydroxide, potassium hydroxide, or sodium bicarbonate, or of substituted or unsubstituted aliphatic carboxylic acids such as diethylacetic acid, ethylhexanoic acid, or more specifically acetic acid. By the action of a salt. Among the salts of the foregoing acids are sodium salts.

Salicylation is also accomplished by the action of ammonia or by organic bases such as triethylamine, diethylamine, trimethylamine, propylamine, N, N-dimethylethanolamine, or tris (hydroxymethyl) aminomethane. Can lose. Salicylation can also be obtained by the action of arginine or lysine. Solvents of free acid can be used as raw compound instead of free acid to prepare salts.

Salylation is suitably carried out in a single solvent or in a mixture of solvents such as water, ethyl ether, methanol, ethanol or acetone.

Obtained in amorphous or crystalline form depending on the reaction conditions using the salt. Crystalline salts are suitably prepared by reacting the free acid with one of the aliphatic carboxylic acid salts described above, usually sodium acetate.

In the production of the sodium salt, the reaction is carried out in a suitable organic solvent such as methanol, or in a solvent containing a small amount of water.

Finally, when the reaction for converting the compound of formula (Ia) to the compound of formula (Ia) is carried out using an acid such as trifluoroacetic acid, the compound of formula (Ia) It has been found that it can be liberated in the form of an amine salt of an aminothiazole ring. Examples of such compounds are shown in more detail in the Examples described later. The free base of the compound of general formula (I ′) is obtained by the action of about 1 equivalent of a base such as pyridine, if necessary.

Compounds of formula (I) are on the one hand Gram-positive bacteria, such as staphylococci and streptococci, in particular penicillin-resistant staphylococci and, on the other hand, coliform bacteria, klebsiella and Salmonella sp. It has a very good antibiotic effect against Gram-negative bacteria such as Salmonella and proteus.

This property is characterized by the above-mentioned pharmacologically acceptable compounds of the general formula (I) for the treatment of diseases caused by infectious bacteria, in particular staphylococcal infectious diseases, for example, staphylococcal septic tumors or skin staphylococcal infectious, purulent dermatitis. It makes effective use of drugs, in particular antibiotics, for the treatment of sepsis or purulent salts, anthrax, cellulitis alone, acute early or post-influenza A. infections, bronchial pneumonia and sepsis.

This compound can also be used as a medicament for the treatment of Escherichia coli epidemic and infectious diseases, Pronews, Klapsiella spp. And Salmonel spp. And other diseases caused by Gram-negative bacteria.

Of these drugs, it is suitable to use the following:

-7- / 2- (2-aminothiazol-4-yl) 2-caraethoxymethyloxyamino acetamido / 3-acetoxymethylcepa-3-m 4-carboxylic acid, syn isomer.

-7- / 2- (2-aminothiazol-4-yl) 2-hydroxycaraboylmethyloxy aminoacetamido / 3-acetoxymethylcepa-3-m 4-carboxylic acid, syn isomer.

-3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-// (cyanomethyl) oxy / imino / acetyl / amino / cepha-3-M 4-carboxyl Acid, syn isomer,

-3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-/// (aminocarbonanylmethyl) oxy / imino / acetyl / amino / cepa-3-em 4- Carboxylic acid, syn isomer,

-3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-//-1-carboxy-1-methylethyl) oxy / imino / acetyl / amino / cepha-3 M-carboxylic acids, syn isomers and alkali metal, alkaline earth metal, magnesium or organic aminobases and pharmacologically acceptable salts thereof, and more particularly, -7- / 2- (2-aminothiazole-4- Yl) 2-hydroxycarbonyl methyloxyaminoacetamido / 3-acetoxymethylcepa-3-m 4-carboxylic acid, sodium salt of syn isomer,

-3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-// (cyano methyl) oxy / imino / acetyl / amino / cepha-3-M 4-carboxyl Acid, sodium salt of syn isomer,

-3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-/// (aminocarmethyl) methyl / oxy / acetyl / amino / cepha-3-M 4-carboxyl Acid, sodium salt of syn isomer,

3-acetoxymethyl 7-// 2- (2-aminothiazol-4-yl) 2-// (1-bonyl 1-methylethyl) oxy / imino / acetyl / amino / cepha 3M 4-cara Sodium salt of acid, Syn isomer,

-7- / 2- (2-aminothiazol-4-yl) 2-hydroxycarboyl methyloxyamino setamido / 3-acetoxy methylcepa-3-m 4-carboxylic acid, di-isomer of Syn isomer Sodium salts have an extremely good effect on Gram-negative bacteria.

The pharmacologically acceptable compound of general formula (I) can be used in preparation by the agent containing at least 1 or more of the compounds mentioned as an active ingredient.

These agents can be administered topically to the rectal, oral, parenteral or intramuscular routes or topical routes and to the skin and mucous membranes.

These agents are solid or liquid, and can be formulated in the form of drugs commonly used in medicines such as conventional tablets or dragees, gelatin capsules, granules, suppositories, injections, ointments, creams and gels. Is prepared according to a conventional method. Active ingredients include excipients commonly used in these agents, such as active, gum arabic, lactose, starch, magnesium stearate, cocoa butter, water soluble or non-aqueous colorants animal or vegetable fatty substances bluefin derivatives, glycols, various hydrating agents, dispersants Or mixed with emulsifiers and / or preservatives.

The dosage will vary depending on the disease to be treated, the patient, the route of administration and the compound under consideration. For example, the compounds described in Examples 1 or 2 are between 0.250 g and 4 g per day for oral administration to adults, and three doses per day between 0.500 g and 1 g for intramuscular administration.

The compound of formula (V), which is not yet known, is represented by the following formula

위치에서 표준법에 따라 할로겐화에 의해 제조할 수 있다.Wherein R ₇ represents a CO ₂ R ₈ group, where R ₈ represents an alkyl group or a hydrogen atom, or a nitrile group.

In situ can be prepared by halogenation according to standard methods.

Compounds of formula (V) wherein R ₃ represents an OCNH ₂ group can be obtained by amidating the corresponding acid.

The following examples illustrate the invention in more detail and the invention is not limited to these examples.

Example 1

Diphenylmethyl 3-acetoxymethyl 7-// 2- (2-trityl aminothiazol 4-yl) 2-// (tert-butoxycarboylmethyl) oxy / imino / acetyl / amino / cepha 3-M 4-carboxylate, Syn isomer.

Step A: 2- (2-tritylamino thiazol 4-yl) 2- (1-methyl 1-methoxy ethoxyimino) acetic, Syn isomer.

12.9 g of 2-/ (hydroxy) imino / 2- (2-tritylaminothiazol 4-yl) acet and Syn isomer in 120 cm 3 of methylene chloride and 12 cm 3 of 2-methoxypropene were mixed at room temperature for 20 minutes. After stirring, the mixture was concentrated to dryness and further stirred for 30 minutes in 60 cm 3 of methylene chloride and 12 cm 3 of methoxypropene, and then concentrated to dryness under reduced pressure. From this the desired product is obtained and used in this state.

Step B: 3-acetoxymethyl 7-// 2- (2-tritylaminothiazol 4-yl) 2- / 1-methoxyethoxy / imino / acetyl / aminocepa-3-em 4-car Diethylamine salt of acid, Syn isomer.

2- (2-tritylaminothiazol 4-yl) 2- (2-tritylaminothiazol 4-yl prepared according to the method described in step A above starting with 47.25 g of 2-hydroxy aminoacetic acid ) 2- (1-methyl 1-methoxyethoxy imino) acetic acid and Syn isomer were dissolved in 230 cm 3 of methylene chloride. 12.5 g of dicyclo hexyl carbodiimide was added thereto, and the mixture was stirred at room temperature for 1 hour.

The dicyclohexyl urea formation was filtered off with a vacuum-filter, which was washed with a small amount of methylene chloride to yield 9.82 g of product. To the filtrate was added 13.6 g of 7-aminocephalosporanic acid dissolved in 70 cm 3 of methylene chloride and 14 cm 3 of triethylamine, which was stirred at an acid temperature for 2 hours. This was washed with a separatory funnel with 350 cm3 of normal hydrochloric acid, decanted and washed again with water and then concentrated to dryness. After the residue was dissolved in 100 cm 3 of ethyl acetate, crystallization occurred. The crystals were left for 30 minutes and then filtered through a vacuum-filter to give 5.5 g of starting product.

The filtrate was concentrated to dryness and the residue was stirred with 200 cm 3 of isopropyl ether for 30 minutes. Vacuum-filtration followed by drying gave 37.35 g of crude concentrate. The purification was carried out as follows.

The product was dissolved in 148 cm 3 of ethyl acetate, 5.5 cm 3 of diethylamine was added to this solution, and 650 cm 3 of ether was added thereto, followed by rapid stirring and drying to obtain 26.35 g of the target product.

This filtrate was then concentrated to dryness and dissolved in 50 cm 3 ether. Thin layer chromatography gave 2.8 g of a second yield similar to the first yield. The diethylamine salt was used as follows.

(a) = 1.54 p. p. m.

(b) = 3.27 p. p. m.

Proton of thiazole ring: 6.68 p. p. m.

Step C: Diphenylmethyl 3-acetoxymethyl 7-// 2- (2-tritylaminothiazol 4-yl) 2- / 1-methyl 1-methoxyethoxy / imino / acetyl / aminocepa- 3-M 4-carboxylate, Syn isomer.

4.15 g of the diethylamine salt obtained in step B was introduced into 40 cm 3 of methylene chloride and 55 cm 3 of 0.1N hydrochloric acid.

It was stirred at room temperature for 10 minutes and decanted to wash the organic phase twice with 25 cm 3 of water. It was dried, vacuum-filtered and washed with methylene chloride.

15 cm 3 of 8% diazodiphenylmethane in benzene was added to the stirring sand over 10 minutes or more, stirred at room temperature for 15 minutes, and the solvent was evaporated under reduced pressure at 30 ° C. It was dissolved again with isopropyl ether, vacuum-filtered and washed. It was dried again to give 4.41 g of the desired product.

NMR: CDCl ₃ 60MHz

a = 1.53p.p.m.

b = 2.01p.p.m.

c = 3.26p.p.m.

d = 6.78p.p.m.

(e) = 7.33p.p.m.

Step D: diphenylmethyl 3-acetoxymethyl 7-// 2- (2-tritylaminothiazol-4-yl) 2- (hydroxy) imino / acetylamino cepha-3-em 4-carboxyl Latex, Syn isomer.

2.775 g of the product obtained in step C was added to 14 cm 3 of acetone and 4.5 cm 3 of hydrochloric acid, stirred at room temperature for 2 hours, and then acetone was removed under reduced pressure.

20 cm 3 of ethyl acetate was added thereto, stirred, and decanted.

The organic phase was washed four times with 10 cm 3 of some brine and the wash water was extracted with 5 cm 3 of ethyl acetate.

The organic fractions were combined and dried. It was vacuum-filtered, washed with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was dissolved in ether to crystallize.

It was separated again, vacuum-filtered and washed with ether. After drying, 1.88 g of the desired product was obtained.

NMR: CDCl ₃ 60MHz

6.88p.p.m: Proton of thiazole ring.

7.33 p. p. m: proton of phenyl nucleus.

Rf = 0.5 (an ether containing 20% of acetone = developer).

Step E: Diphenylmethyl 3-acetoxymethyl 7- / 2- (2-tritylamino thiazol 4-yl) 2-3 tert-butoxy carboyl methyloxyimino / acetyl aminocepa-3m 4-cow Carboxylates, Syn isomers.

0.85 g of the product prepared in step D was introduced into 4 cm 3 of dimethylformamide and 0.8 cm 3 of tert-butylbromoacetate. After stirring for 5 minutes in an ice bath, 1.7 g of silver oxide was added.

After removing the ice bath, it was stirred for 1 hour, vacuum-filtered and washed with ethyl acetate. 80 cm 3 of water was added to the filtrate, the solution was decanted, and the aqueous phase was extracted twice with 20 cm 3 of ethyl acetate.

The organic phase was washed twice with 50 cm 3 of brine and dried in the presence of 80 mg of activated carbon. It was vacuum filtered and washed with ethyl acetate. It was removed under reduced pressure and the residue was dissolved in isopropyl ether.

It was decomposed, vacuum-filtered and rinsed with isopropyl ether. After drying, 0.274 g of the desired product was obtained.

Rf = 0.34 (methylene chloride containing 5% ether).

Example 2

3-acetoxymethyl 7- / 2- (2-aminothiazol 4-yl) 2-carboxyethyloxy imino / acetylaminocepa-3M 4-carboxylic acid, Syn isomer (trifluoroacetate form).

Cooled with an ice bath of methanol and 5 cm 3 of trifluoroacetic acid. 0.482 g of the product obtained in Example 1 was added and stirred for 15 minutes after the bath was removed. After 5 minutes degradation was observed. The acid was removed under reduced pressure, 20 cm 3 of isopropyl ether was added thereto, stirred for 5 minutes, and washed with isopropyl ether.

After drying, 0.277 g of the desired trifluoroacetate was obtained.

Example 3

Disodium salt of 3-acetoxymethyl 7- / 2- (2-aminothiazol 4-yl) 2-carboxymethyloxyimino / acetylamino sepha-3m 4-carboxylic acid, Syn isomer.

The salt obtained in Example 2 was dissolved in 0.5 cm 3 of methanol, and 1.5 cm 3 of a solution of sodium acetate in water dissolved in methanol was slowly added thereto. After decomposition, 5 cm 3 of ethanol was slowly added. It was vacuum-filtered, washed twice with ethanol and then with ether.

After drying it, 0.178 g of the desired disodium salt was obtained.

Example 4

Tert-butyl-3-acetoxymethyl 7-// 2- (2-tritylaminothiazol-4-yl) 2-tert-butoxycarbonanyl methyloxyimino / acetyl.aminocepha-3-em 4 Carboxylates, Syn isomers.

Step A: tert-Butyl-3-acetoxymethyl 7-// 2- (2-tritylaminothiazol-4-yl) 2- / 1-methyl 1-methoxy ethoxy / imino / acetyl / Amino sefa-3-em 4-carboxylate, Syn isomer.

Dissolves 2- (2-trityliminothiazol 4-yl) 2- (1-methyl 1-methoxy ethoxyamino) acetic acid and Syn isomer prepared in step A of Example 1 in 120 cm 3 of methylene chloride. 9.84 g of 3-butyl esters of 7-aminocephalosonic acid were added thereto. It was cooled to + 10 ° C. and 6.5 g of dicyclohexyl carbodiimide was added thereto. The cooling bath was removed and left to stand for 3 hours under stirring at room temperature. The resulting dicyclohexylurea (4 g) was vacuum-filtered and concentrated to dryness, and then the residue was dissolved in 25 cm 3 of ethyl acetate. 100 cm 3 of ether was added thereto and washed with 100 cm 3 of 0.2N hydrochloric acid, 100 cm 3 of water and 20 cm 3 of a molar solution of sodium carbonate. Thus sodium was precipitated from the starting product which was vacuum-filtered and dried to give 3.9 g. It was washed with water, dried, vacuum-filtered and then concentrated to dryness.

This was dissolved in 50 cm 3 of ether to cause crystallization, and then 50 cm 3 of isopropyl ether was charged to terminate the crystallization. This gave 10.8 g of the product. Melting point = 160 ° C.

NMR: CDCl ₃ 60MHz

Proton of thiazole: 6.76p.p.m.

Stage B: tert-Butyl 2-acetoxymethyl 7-1 / 2- (2-tritylaminothiazol 4-yl) 2- (hydroxy) imino / acetyl / aminocepa-3-m 4-cara Carboxylates, Syn isomers.

0.812 g of the product obtained in step A was dissolved in 4 cm 3 of acetone and 1 cm 3 of normal hydrochloric acid under stirring at ambient temperature for 3 hours. 1 cm 3 of molar aqueous solution of sodium carbonate, 10 cm 3 of water and 5 cm 3 of ethyl acetate were added thereto. 0.551 g of the desired product was obtained.

Melting Point ~ 200 ℃

Analysis: C ₃₈ H ₃₇ O ₇ N ₅ S ₂

Calculated Value: C% 61.69 H% 5.04 N% 9.47 S% 8.66

Found: 61.5 5.0 9.1 8.4

NMR: CDCl ₃ 60MHz 6.86ppm: Proton of Thiazole

1.55p.p.m. : Tert-butyl

Step C: tert-Butyl 3-acetoxymethyl 7-// 2- (2-tritylaminothiazol 4-yl) 2-tert-butoxycaraboylmethyloxyimino / acetyl / aminocepa-3- M 4-carboxylate

0.074 g of the product prepared in step B, 0.7 cm 3 of dimethylformamide and 0.5 cm 3 of tert-butylbromoacetate were mixed and 0.5 g of silver oxide was introduced at 20 ° C. It was stirred for 30 minutes, vacuum-filtered and washed with ethyl acetate. 10 cm 3 of water was added thereto, decanted, extracted with 5 cm 3 of ethyl acetate, and the organic phase was washed with 5 cm 3 of brine. It was dried over magnesium sulfate, vacuum-filtered, washed with ethyl-acetate, the solvent removed and the residue dissolved in isopropyl ether. It was decomposed, vacuum-filtered and rinsed with isopropyl ether. After drying, 0.02 g of product was obtained.

Rf = 0.34 (methylene chloride containing 5% ethyl acetate).

Example 5 Injectables were prepared with the following ingredients: -7- / 2- (2-amino-4-thiazolyl) 2-hydroxycarboyl methyloxyiminoacet amido / 3-acetoxymethyl Sepha-3-M 4-carboxylic acid. 500 mg of disodium salt of Syn isomer-aqueous solution of medium phase excipient. 5 cm3

Example 7: A gelatin capsule was prepared with the following components: -7- / 2- (2-amino-4-thiazolyl) 2-hydroxycarboyl methyloxyiminoacetamido / 3-acetoxy Methylcepa-3-m 4-carboxylic acid. Disodium salt of Syn isomer 250 mg-excipient for gelatin capsule 400 mg

Example 8: Injections were prepared with the following ingredients

3-acetoxymethyl 7-// 2- (2-aminothiazol 4-yl) 2-// (cyanomethyl) oxy / imino / acetyl / amino / cepha-3-em 4-carboxylic acid. 500 mg of sodium salt of Syn acid isomer-5 cm3 of excipient solution

Example 9 A gelatin capsule was prepared by the following ingredients.

-3-acetoxymethyl 7-1 / 2- (2-aminothiazol 4-yl) 2-/// (aminocarbonyl) methyl / oxy / imino / acetyl / amido / sepha-3-em 4 -Carabou. 500 mg of sodium salt of Syn isomer-5 cm3 for excipients

Example 10: Injections were prepared with the following ingredients

-3-acetoxymethyl 7-// 2- (2-aminothiazol4-yl) 2-// (cyanomethyl) oxy / imino / acetyl / amido / sepha-3-em 4-carboxyl mountain. Sodium salt of Syn isomer 250 mg-excipient for gelatin capsule 400 mg

Claims (1)

The isopropenyl methyl ether of the following structural formula (a) is reacted with the Syn isomer of the following structural formula (IV) to give the product of the following structural formula (VII), and the acid or functional derivative of this product is treated with the product of the following structural formula (II) To obtain the product of the following structural formula (A), where A 'is esterified in a conventional manner to represent an ester group that can be easily removed by acid hydrolysis or hydrogenolysis, and then treated with an acid under ordinary conditions to give the following structural formula (VI) To obtain the product of and react the Syn isomer of the product with the product of the following formula (V) in the presence of a base to obtain the Syn isomer of the following formula (I '), which is converted into an acid hydrolysis and hydrolysis agent, and thiourea Treatment with one or more agents selected from the group consisting of gives the compounds of formula (Ia) or again dimers according to conventional methods Production method of the chloride by the following structural formula (Ib) with the following structural formula (I), characterized in that for obtaining the compounds 3-acetoxymethyl 7-amino-thiazolyl acetamide sepal oxime derivative of Los Incubation acid

In the above structural formula R 1 is —CO ₂ R 1 ′ group, where R 1 is an alkyl group of 1-3 carbon atoms, a hydrogen atom or an equivalent of an alkali metal, an alkaline earth metal, magnesium, ammonium or an organic amine Or nitrile group, Or carbamoyl group CONH ₂ , A represents a hydrogen atom, or an equivalent amount of an alkali metal, an alkaline earth metal, magnesium ammonium, or an equivalent amount of an organic amino base, and R 'and R' are the same or different and represent a hydrogen atom or an alkali group having 1-3 carbon atoms. ,

When the group is at the Syn position and R ₁ represents a CO ₂ R ₁ 'group (R ₁ ' is a hydrogen atom), A is hydrogen and R ₁ is an equivalent amount of CO ₂ R ₁ 'group (R ₁ ' is equivalent Is an equivalent amount of the same alkali metal, alkaline earth metal, magnesium, or organic amino base, and A 'is used for hydrogen atom or acid hydrolysis or hydrogenolysis. easily removed represents an ester group by, R ₂ represents an acid hydrolysis or hydrolysis small removable group facilitated by the decomposition or chloroacetyl, R ₃ is CO ₂ R ₁ ˝ a group (wherein R ₁ ˝ carbon atoms Is an alkyl group having 1 to 3, or an ester group which can be easily removed by acid hydrolysis or hydrolysis), or a nitrile group or a carbamoyl group, and R ₄ represents a CO ₂ R ₂ ˝ group, wherein R ₂ ˝ Is hydrogen or an alkali having 1-3 carbon atoms Im) or a nitrile group, a carbamoyl group, or represents a CONH _2, R ₅ is CO ₂ R ₃ ˝ group (wherein R ₃ ˝ having a carbon number of 1 to 3 alkyl groups, or an alkali metal, alkaline earth metal, magnesium, ammonium, organic Equivalent to an amino base), a nitrile group, or a carbamoyl group CONH ₂ , and A˝ represents an equivalent amount of an alkali metal, alkaline earth metal, magnesium, ammonium, or an organic amino base, and R ₅ is CO ₂ R ₃ When R ₃ group represents an equivalent amount of alkali metal, alkaline earth metal, magnesium, ammonium, or organic amino base A 'is the equivalent of alkali metal, alkaline earth metal, magnesium, ammonium, or organic amino base, and Hal is a halogen atom.