KR810000980B1 - Process for preparing 3-acetoxymethyl-7-(iminoacetamido)cephalosporanic acid derivatives - Google Patents

Abstract

Title compds. [I; R = H, trityl; R1 = H, trityl, C1-4 alkyl, alkenyl, C1-4 alkynyl; A = H, Na, Et2N; line means OR1 is located in syn or anti position (preferably syn) were prepd. by reaction of 7-aminocephalosporanic acid and II or its reactive derivs. Thus, N-methylmorpholine was added to II (R,R1 = H) which was prepd. by 3 steps from ethyl-γ-chloro-α-oxyiminoacetyllacetate as starting material, followed by reaction with 7-aminocephalosporanic acid to give I(R,R1,A = H).

Description

Method for preparing 3-acetoxymethyl-7- (iminoacetamido) -cephalosporanic acid derivative

The present invention relates to a process for preparing a new 3-acetoxymethyl-7- (iminoacetamido) -cephalosporanic acid derivative as in general formula (I).

선은 OR¹가 두 가능한 syn-또는 anti- 위치에 있을 수 있음을 의미한다. 산가수분해나 가분해에 의해 용이하게 제거될 수 있는 그룹들로서는 3차-부톡시카보닐, 트리틸, 벤질, 디벤질, 트리클로로에틸, 카보벤질옥시, 포르밀, 트리클로에톡시카보닐, 또는 2-테트라히드로피라닐들을 들수 있다. R¹로서는 메틸, 에틸, 프로필, 이조프로필, 부틸 2차 부틸, 3차 부틸, 비닐, 프로페닐, 부테닐, 에티닐, 프로파질등과 같은 알킬, 알케닐, 혹은 알키닐을 들 수 있다. A의 보기로는 수소, 나트륨, 칼륨, 리튬, 칼슘, 마그네슘, 트리메틸아민, 트리에틸아민, 메틸아민, 프로필아민, N,N-디메틸 에타놀아민,트리스-(하이드록시메틸)-아미노메탄, 알기닌 또는 라이신을 들 수 있다. 산가수 분해나 가수소분해에 의해 용이하게 제거될 수 있는 일반적인 그룹들은 3차 부톡시 카보닐, 트리틸, 디벤질, 트리클로로에틸, 카보벤질옥시들이다.Wherein R is selected from a hydrogen atom or a group which can be easily removed by acid hydrolysis or hydrogenation, R 'is a hydrogen atom, alkyl having 1-4 carbon atoms, alkynyl and alkenyl having 2-4 carbon atoms And can be easily removed by acid hydrolysis or hydrogenation, which is selected from the group, where A is a hydrogen atom, an alkali metal, or an equivalent amount of an alitometal or magnesium or organic amine base and R ¹ is acid hydrolyzed. In the case of a group which can be easily removed by hydrogenation, R is the same group. When R ¹ represents a hydrogen atom, R also represents a hydrogen atom. And

The line means that OR ¹ can be in two possible syn- or anti-positions. Groups which can be easily removed by acid hydrolysis or hydrolysis include tert-butoxycarbonyl, trityl, benzyl, dibenzyl, trichloroethyl, carbenzyloxy, formyl, trichloroethoxycarbonyl, Or 2-tetrahydropyranyl. Examples of R ¹ include alkyl, alkenyl, or alkynyl such as methyl, ethyl, propyl, dizopropyl, butyl secondary butyl, tertiary butyl, vinyl, propenyl, butenyl, ethynyl, and propazyl. Examples of A include hydrogen, sodium, potassium, lithium, calcium, magnesium, trimethylamine, triethylamine, methylamine, propylamine, N, N-dimethyl ethanolamine, tris- (hydroxymethyl) -aminomethane, arginine or Lysine. Common groups that can be easily removed by acid hydrolysis or hydrogenolysis are tert-butoxy carbonyl, trityl, dibenzyl, trichloroethyl, carbenzyloxys.

Compounds of structure (I) may exist in syn-position isomers such as structure (I ′) or in anti-isomer forms such as structure (I ′).

However, OR ¹ groups are generally preferred to be syn position isomers.

Generally, in structure (I), R is hydrogen atom or trityl, R ¹ is hydrogen atom, alkyl having 1 to 4 carbon atoms, or alkenyl; alkynyl having 2 to 4 carbon atoms, A is hydrogen, sodium Or diethylamine.

Examples of the compound preferred as the compound of the structure (I)

3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxy amino acetamido] -cep-3-m-3-carboxylic acid; Sodium 3-acetoxy methyl-7- [2- (2-amino-4-thiazolyl) 2-methoxy imino acetamido] -sef-3-m-4-carboxylate; Syn position isomer of 3-acetoxy methyl 7- [2- (2-amino-4-thiazolyl) -2-methoxy amino acet amido] -cep-3-m-4-carboxylate.

3-acetoxy methyl 7- [2- (2-amino-4-thiazolyl) 2-methoxy imino acetamido] -cep-3-m-4-carboxylic acid as obtained by the process of Example 4 ; Sodium 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) -2-methoxy imino acetamido] -cep-3-m-4- as obtained by the process of Example 7 Carboxylates; Syn position isomer of crystalline sodium 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxyiminoacetamido] -sep-3-m-4-carboxylate; Syn-position isomer of 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-ethoxyimino acetamide] -cep-3-m 4-carboxylic acid and its alkali metals, alkaline earth metals and magnesium And organic amine salts; 3-Ryuacetoxymethyl 7- [2- (2-amino 4-thiazolyl) -2- (2-propenyl) oxymino) acetamide] -cep-3-m-4-carboxylic acid synposition isomer Alkali metals, alkaline earth metals, magnesium and organic amine salts; 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) -2- (2-propenyl) oxymino) acetamide] -cep-3-m-4-carboxylic acid synposition isomer and its alkali Metals, alkaline earth metals, magnesium and organic amine salts; Syn-position isomer of 3-acetoxyethyl 7- [2- (2-amino 4-thiazolyl) 2- (1-methylethoxyimino) acetamide] -cep-3-m 4-carboxylic acid and its alkali metals , Alkaline earth metals magnesium and organic amino salts.

The products of the present invention may exist in the form of structure (I) or in the form of structure (Iz).

In the preparation of the compound of structure (I), in the process of the present invention, 7-amino-cephalosporanic acid is reacted with an acid of structure (II) or a derivative thereof to form a compound of structure (Ia) and acid hydrolysis thereof. The compound of structure (I) is obtained by hydrogenation.

In structure (II), R ₁ is a group that can be easily removed by acid hydrolysis or hydrogenolysis, and R ₁ 'is a group that can be easily removed by acid or hydrolysis. Phosphorus alkyl, alkenyl and alkynyl groups having 2-4 carbon atoms.

In one improved process according to the invention, in the preparation of a compound such as structure (Ib), a compound of structure (Ic) is reacted with an acid or a derivative thereof such as structure (II) to obtain a compound of structure (XI) Or further treated with an acid hydrolysis or hydrogenating agent or thiourea to obtain a compound of structure (Ib).

In structure (Ib), R ₁ 되며 is selected from the group consisting of hydrogen, alkyl having 1-4 carbons, alkenyl, and alkynyl having 2-4 carbons, and in structure (Ic) A ₁ is acid hydrolyzed. Or a group that is easily removable by hydrogenolysis.

Examples of groups that can be easily removed by acid hydrolysis or by hydrogenolysis include tert-butoxycarbonyl, trityl, benzyl, dibenzyl, ethyl chloride, carbenzyloxy, or formyl. However, 2-tetrahydro pyranyl and ethoxycarbonyl chloride can also be used.

In the general form of this process, the compound of structure (Ic) reacts with the derivative of the acid of structure (II). Other acid halides or other mixed anhydrides formed by action with other alkylchloro formates or dicycloalkyl carbodiimides or alkyl carbodiimides can also be used. Other acid derivatives can be used with active esters or active amides of acids formed with hydroxy sucinimid, paranitrophenyl or 2-4 dinitrophenol.

When acid halides or acid anhydrides are used together with isopropylchloroformate, the reaction is generally carried out in the presence of a basic agent.

As the basic agent, alkali metal carbonate, N-methylmorpholine, pyridine as tertiary organic amine, triethylamine or the like as trialkylamine can be used.

Compounds of structure (XI) are converted to compounds of structure (Ib). In the compound of the structure (Ib), R ₁ and A ₁ are substituents which can be substituted with hydrogen and R ₁ ′ is a group that can be easily released by acid hydrolysis or hydrogenolysis. When R ₁ ′ is replaced with hydrogen, the compound of structure (IX) is changed to the compound of structure (Ib). For this purpose, the compounds of structure (XI) are groups in which R ₁ and A ₁ are easily released by acid hydrolysis, and when R ₁ ′ is a group easily released by acid hydrolysis or alkyl, one or more acid number groups Treated with a decomposition agent, where R ₁ and A ₁ are groups that are easily released by hydrogenolysis, and when R ₁ ′ is a group that is easily released by hydrogenolysis or alkyl, one or more hydrogenolysis agents do.

Finally, the compound of structure (XI) is treated with one or more acid hydrolysis sites or a hydrogenolysis agent and thiourea when at least one of R ₁ and R ₁ ′ is acetyl chloride. Acid hydrolysis is performed with formic acid, trifluoroacetic acid or acetic acid. These acids can be used in anhydrous form or in aqueous solution. Zinc-acetic acid systems are also useful.

To remove tertiary butoxycarbonyl or trityl groups of R ₁ or R ₁ ′ or to remove benzohydryl or tertiary butyl of A ₁ , trifluoroacetic anhydride, aqueous formic acid, or acetic acid is used as an acid agent. Commonly used.

Zinc-acetic acid system, R _1, R ₁ 'trichloromethyl of are primarily used to remove the acetate group, R _1, R _1' of benzyl, dibenzyl, carbonyl benzyloxy group singer a catalyst catalyst to subdivision singer cattle Removed by decomposition. The reaction of thiourea with a compound of structure (XI) having at least one chloroacetyl is preferably carried out in neutral or acidic catalysts. This type of reaction is mentioned by MaSaki (JACS, Vol 190 (1968) P4508).

In the present invention, a compound of structure (II) is reacted with thiourea and the product obtained therefrom is treated with a base to form a compound of structure (IV), and derivatives of the group which can be easily released by acid hydrolysis or hydrogenolysis. The process of preparing a compound of structure (II) by treating with a compound of structure (V) followed by a base followed by an acid is described.

Wherein R 'is the same as above and Alk is alkyl having 1-4 carbon atoms.

The base used to treat the compound of structure (IV) is generally potassium acetate, but alkali metal carbonates or dicarbonates, or dilute sodium hydroxide or potassium hydroxide may also be used. Preferred derivatives of the group which can be easily released by acid hydrolysis or hydrolysis are triethylamine or trityl chloride in the presence of tertiary amine bases such as pyridine, N-methylmorpholine, or other trialkyl amines.

The base used to treat the compound of structure (V) is usually sodium hydroxide, but potassium hydroxide or barium hydroxide may also be used. The acid used to obtain the compound of structure (II) is usually dilute hydrochloric acid, but other acids such as acetic acid or formic acid may also be used.

In another process for producing a compound of structure (II), the compound of structure (IV) is first treated with a base and then with an acid to obtain a compound of structure (XII) and reacted with a derivative of R ₁ to give structure (II) To obtain the compound.

The base used for saponification is usually sodium hydroxide, but potassium hydroxide or barium hydroxide is also used. Dilute hydrochloric acid is usually used, and acetic acid and formic acid are also useful. Derivatives of R ₁ are generally trityl chloride used in the presence of triethylamine or other tertiary amines such as other trialkylamines, pyridine or N-methylmorpholine. Also, tert-butyl chloroformate, tert-butyl azido formate, ethyl trichloride or benzyl chloroformate, or mixed formyl acetic anhydride, benzyl or dibenzyl chloride, phthalic anhydride, or N-carboethoxy phthalate Easily leaving derivative groups such as imides are likewise usefully employed.

The present invention also deals with the preparation of compounds such as structures (Vc).

In the above, R ₁ and R ＂c can be easily removed by acid hydrolysis or hydrogenolysis, which represents a group or ethyl chloride, and Alk represents an alkyl group having 1 to 4 carbon atoms.

This reaction consists of reacting a compound of structure (X) with a functional derivative of R ＂c. R ₁ is usually trityl and the functional derivative of R ＂c is dihydro pyranyl.

In another process of the invention for preparing compounds of structure (I) wherein A and R are hydrogen and R 'is hydrogen, alkyl having 1 to 4 carbon atoms, or alkenyl or alkynyl having 2 to 4 carbon atoms, R ₁ is Acid salts of compounds of structure (Ia) consisting of alkyls having 1 to 4 carbon atoms and R 'consisting of alkenyl and alkynyl or alkynyl groups, which can be easily separated by hydrolysis, are treated with an acid to obtain the desired compound. Hydrolysis of the salt of the compound of structure (la), in which R ₁ is a group that can be easily released by hydrogenolysis, yields the desired compound in the form of a salt.

In one modified process for preparing compounds such as structure (IVa), compounds of structure (VI) are treated with alkylating agents to obtain compounds of structure (V), which are reacted with bromination agents to obtain compounds of structure (X). This is reacted with thiourea and then with a base to obtain a compound of structure (IVa).

Alkylating agents used to treat compounds of structure when carrying out this process include alkyl sulfates having 1 to 4 carbon atoms or alkyl chlorides, brominated and iodide as alkyl halides.

The brominating agent used to react the compound of structure (IV) is usually bromine, and the base used to obtain the product of structure (IV) is primarily an alkali metal carbonate or bicarbonate, but dilute sodium hydroxide or potassium hydroxide or potassium. It can be used as an acetate.

In one modified process of a compound of structure (IIa) wherein A and R are hydrogen and R 'is hydrogen, alkyl having 1-4 carbon atoms, alkynyl having 2-4 carbon atoms, or alkenyl, The lanic acid is reacted with a compound having the same structure as that of the structure (IIa) to obtain a compound like the structure (VII), and then reacted with thiourea to obtain the compound of the structure (I).

Wherein R 에서 a is selected from the group consisting of chloroacetyl, alkyl having 1-4 carbons, and alkynyl and alkenyl having 2-4 carbons.

The reaction with 7-amino-cephalosporanic acid is carried out under the same conditions as in the reaction with the compound of structure (II). The reaction with thiourea is described in the form of the reaction mentioned by Masaki [J.A.C.S., Vol. 90 (1968), P4508], in neutral or acid medium.

In the process of preparing a compound such as structure (IIa), a derivative of chloroacetic acid is reacted with a compound such as structure (IVb) to obtain a compound of structure (Va), which is first treated with a base and then an acid to give structure (IIa). It consists of obtaining the compound of.

Wherein R ₁ 'is hydrogen, alkyl having 1-4 carbon atoms, or alkynyl or alkenyl having 2-4 carbon atoms, alk is alkyl having 1-4 carbon atoms, and R'a is as described above.

Derivatives of chloroacetic acid are generally chloroacetic anhydride or chloroacetyl halides such as chlorine. If acid halides are used, they are made in the presence of a reaction base agent. The base used to treat the compound of structure (Va) is usually sodium hydroxide, but other bases such as potassium hydroxide and barium hydroxide may also be used. The acid used to obtain the compound of structure (IIa) is usually dilute hydrochloric acid, but acetic acid and formic acid are likewise useful.

One modified process for obtaining compounds such as structure (Vb) involves treating compounds such as structure (IV) with derivatives of groups that can be easily released by acid hydrolysis to obtain compounds of structure (VIII) and alkylate them. Reaction with an agent to obtain a compound of structure (Vb).

Such derivatives are usually trityl chloride used in the presence of a base such as triethylamine, but N-methyl-morpholine, pyridine, or other trialkylamines can also be used. The arylating agent is usually an alkyl halide such as alkylsulfate or iodine.

The syn or anti arrangement of the products of structure (I) is determined by the arrangement of products such as structure (IV) because the arrangement of the products of structure (IV) is maintained during synthesis.

This is true for the products of structures IVa, IVb and IVV, because they fall within the category of structure IV. The arrangement of the products of structure (IV) depends on the number of variables in the process of making these products.

It is known that the action of the products of structure (III) and thiourea can take place in aqueous solvents such as aqueous acetone or aqueous ethanol or react at room temperature for 1-3 hours with the amount of thiourea in stoichiometric ratio. do.

The process of the present invention for preparing the products of structure (IV) in the Syn form is that thiourea is reacted with a mixture of structure (III ′).

X represents chlorine or bromine, R ¹ b is a group which can be easily removed by acid hydrolysis or hydrogenolysis, alkyl having 1-4 carbons or alkenyl and alkynyl having 2-4 carbons, etc. Alk is alkyl having 1-4 carbons.

The antibiotic compositions of the present invention consist of at least one compound (I) and a pharmaceutical carrier. There are various forms of the composition such as tablets, granules, injection solutions, suspensions, creams, pomades, gels, and the like.

Examples of suitable pharmaceutical carriers include starch, talc, gum gum, lactose, magnesium stearate, cacao butter, vegetable and animal fats, paraffin derivatives, glycols, various humectants, dispersants, emulsifiers and the like.

Compositions of the present invention containing compounds of structure (I) have very good antibiotic titers against Gram-positive bacteria, such as Staphylococcus aureus, Streptococci, and in particular Penicillin-resistant cyanobacteria, and Gram-negative bacteria, especially Escherichia coli, It has good antibiotic potency against Klebsilella, Salmonella, and other strains.

Due to these properties, the compositions can be used for diseases caused by susceptible microorganisms, especially staphylococcal infections, such as staphylococcal sepsis, malignant facial or skin staphylococcal infections, purulent dermatitis, rot or purulent inflammation, anthrax, cellulitis, It is useful for the treatment of single disease, acute primary or influenza staphylococcal infections, bronchial lungs and pneumonia.

These compositions can also be used for infections caused by enterobacterial and associated infectious diseases, infections caused by erythritis, salmonella and other Gram-negative bacteria. Among common compositions are those in which the compound of structure (I) is contained in its Syn isomer form.

Usually R is a hydrogen atom, R 'is a hydrogen atom, an alkyl group having 1-4 carbon atoms, alkynyl and alkenyl having 2-4 carbon atoms, and A is a hydrogen or sodium atom. Typical compositions contain the following active ingredients. Namely 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxyimino acetamido] -cep-3-m 4-carboxylic acid Syn isomer (this material is used in Examples 4,6, 20 or 22) or a narium salt thereof (this material is specifically mentioned in Example 7) or at least one of its crystalline natrutic salts or products, ie 3-acetoxymethyl 7- [2- (2 -Amino 4-thiazolyl) -2-ethoxyimino acetamido] -sef-3-m 4-carboxylic acid, Syn isomer thereof and its pharmaceutically acceptable alkali metals, alkaline earth metals, magnesium or organic amino bases Salts with,

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) -2- (2-propenyl) -oxymino) -acetamido) -cep-3-em carboxylic acid Syn-isomer and its Salts with pharmaceutically acceptable alkali metals, alkaline earth metals, magnesium or organic amino bases,

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) -2-((1-methyl ethoxy) -imino) -acetamido) -cep-3-m 4-carboxylic acid, its Salts of the Syn isomer and its pharmaceutically acceptable alkali metals, alkaline earth metals, magnesium or organic amino bases. Such complexes may be administered via the topical route by oral, rectal, or parenteral administration, or by external application to the skin and mucous membranes.

The dose to be administered may vary according to disease, person, route of administration, product, and the like. The usual daily dose is 5-80 mg / kg.

Among the new intermediate compounds of the present invention are compounds of the structure

R ₂ is selected from the group consisting of a hydrogen atom and a group that can be easily removed by acid hydrolysis or hydrogenolysis, and R ¹ ₂ is easily removed by a hydrophobic atom, acid hydrolysis or hydrogenolysis. It may be selected from the group consisting of alkyl groups having 1-4 carbon atoms, alkynyl or alkenyl groups having 2-4 carbon atoms. When R ₂ is other than hydrogen, R ¹ ₂ cannot represent a hydrogen atom.

In addition, an intermediate compound having the following structure can be obtained.

R ' ₁ is a group which can be easily removed by acid hydrolysis or hydrogenolysis, and is selected from the group consisting of alkyl having 1-4 carbons, alkenyl and alkynyl having 2-4 carbons, and Alk has 1 carbon atom. The alkyl group of -4 is shown.

In addition, intermediate compounds such as the following structures can be obtained.

Wherein R _a ＂is selected from the group consisting of chloroacetyl, alkyl having 1-4 carbons, alkynyl having 2-4 carbons and alkenyl.

In the present invention, an intermediate compound having the following structure can also be obtained.

R ₁ , R ' ₁ , and A ₁ are the same as before.

-염화-

-옥시미노-아세틸아세테이트로 시작해서 제조될 수 있다. R'가 탄소수 1-4의 알킬이나 탄소수 2-4의 알키닐 또는 알케닐인 화합물을 얻기 위해서는 상기의 에틸에스테르를 그 그룹의 기능유도체들과 반응시킨다.Compounds of unknown structure (III) are described in J. Medical Chem, Vol. Ethyl referred to in 16 NO, 9 (1973)

Chlorine

It can be prepared starting with -oxymino-acetylacetate. In order to obtain a compound in which R 'is alkyl having 1 to 4 carbon atoms, alkynyl or alkenyl having 2 to 4 carbon atoms, the above ethyl ester is reacted with the functional derivatives of the group.

X is a bromine atom, the product of R _'b is structure (Ⅲ represents hydrogen atom') can be prepared by reaction with brominating agent under the same conditions as when the compounds of the process of the next frame structure (Ⅶ) a compound of.

In addition to the products mentioned in the examples, the materials obtainable by the present invention include the following.

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-furophylloxyimino acetamido] ceph-3-M 4-carboxylic acid, Syn-isomer and its alkyllimetals, alkaline earth Salts with metals, magnesium, or organic amino bases,

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-butyloxyimino acetamido] -cep 3-M 4-carboxylic acid Syn isomer and its alkali and alkaline earth metals, magnesium or Organic amino bases,

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (2-methylpropyloxy imino) -acetamido) -sef-3-M 4-carboxylic acid, Syn isomer and its isomer Alkali metals, alkaline earth metals, magnesium or organic amino bases and salts;

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl)-2- (1,1-dimethylethoxy imino) -acetamido] -cep-3-m 4-carboxylic acid Syn isomer Alkali metals, alkaline earth metals, magnesium or organic amino bases and salts thereof;

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (2-butenyloxy imino) -acetamido] -cep-3-m 4-carboxylic acid, Syn isomer and its isomer Alkali metals, alkaline earth metals, magnesium or organic amino bases and salts;

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (2-butenyloxy imino) -acetamido] -cep-3-m 4-carboxylic acid, Syn isomer and its Alkali metals, alkaline earth metals, magnesium or organic amino bases and salts;

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (2-butenyloxy imino) -acetamido] -cep-3-m 4-carboxylic acid, Syn isomer and its Alkali metals, alkaline earth metals, magnesium or organic amino bases and salts;

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (2-butenyloxy imino) -acetamido] -cep-3-m 4-carboxylic acid, Syn isomer and its Alkali metals, alkaline earth metals, magnesium or organic amino bases and salts;

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (2-butenyloxy imino) -acetamido] -cep-3-m 4-carboxylic acid, Syn isomer and its Alkali metals, alkaline earth metals, magnesium or organic amino bases and salts;

Other embodiments are not intended to limit the invention but to describe the invention in more detail.

Example 1

3-acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2-tritylhydroxy amino-acet amido] -cep-3-m 4-carboxylic acid

Step A: ethyl 2- (2-amino 4-thiazolyl) -2-hydroxyiminoacetate

2 g of ethyl gamma-chloro-alpha-oxyminoacetylacetate was added to 5 cm 3 ethanol and 0.76 g of thiourea and the whole was stirred at room temperature for 16 hours. The hydrochloride is then precipitated. Dilution of the whole with 5 cm 3 of ether followed by vacuum filtration and washing with 1: 1 ethanol-ether mixture followed by ether again yields 1.55 g of hydrochloride.

The resulting 1.55 g hydrochloride was dissolved in 8 cm 3 of 40-50 ° C. water and neutralized to pH 5-6 by adding sodium acetate to precipitate free amine. The whole was cooled, washed with water after vacuum filtration and dried to obtain 1.22 g of an inverted isomer (melting point: 154 ° C).

The mother liquor and washings from the above experiments are collected, concentrated, taken with water, washed with ether and neutralized. The whole was washed with water after vacuum filtration to give 1.0 g of the product, which was shown by two layers by thin layer chromatography, and the two spots on silica were eluted and purified by ether. Once pure isomers of the isomers are collected, they are concentrated, axially made of ether, vacuum filtered, and dried to yield 50 mg of the isomers.

Step B: ethyl 2- (2-tritylamino 4-thiazolyl) 2-tritylhydroxy imino acetate

After dissolving 5.4 g of the product prepared in step A in a mixture of 54 cm 3 of chloroform and 7.5 cm 3 of triethylamine, 30 cm 3 of 15 g of trichlorochloride solution of tritylchloride was added at + 10 ° C.

After leaving for one hour, the whole was washed with 40 cm 3 of water, and then washed again with 20 cm 3 of water containing 4 cm 3 of normal hydrochloric acid to remove the homolog, and then dried and concentrated to dryness. The residue is taken up with 10 cm 3 ether and 50 cm 3 methanol is added, the whole is washed with methanol after stirring and vacuum filtration to give 14.2 g of the desired product.

Step C: 2- (2-tritylamino 4-thiazolyl) 2-tritylhydroxy imino acetic acid

10.5 g of the ester obtained in step B are suspended in 55 cm 3 dioxane under reflux and 17 cm 3 2N sodium hydroxide is slowly added. The whole is cooled while continuing gentle reflux and the resulting salt is vacuum filtered. The resulting salt is taken up with 60 cm 3 of methylene chloride, 20 cm 3 of water, and 2 cm 3 of acetic acid mixture, which is vacuum filtered and washed with water to give an acid of 7 as the first yield.

After dioxane was evaporated from the mother liquor, 20 cm 3 of methylene chloride, 10 cm 3 of water, and 1 cm 3 of acetic acid were added. As a second yield 1.5 g of the same product are isolated. The whole is 8.5g.

Composition: C ₄₃ H ₃₃ O ₃ N ₃ D, O, 5H ₂ O

Calculated Value (%): C 75.85 H 5.03 N 6.17 S 4.7

Found (%): 75.8 4.9 5.9 4.6

Step D: 3-Acetoxymethyl 7- [2- (2-tritylamino-4-thiazolyl) 2-trityl hydroxyimino acetamido] -cep-3-m 4-carboxylic acid

8.5 g of the acid prepared in step C is suspended in 50 cm 3 of methanol, and after stirring, 5 cm 3 of N-methylmorpholine is added. The whole was stirred at 30 ° C. for 10 minutes and then 30 cm 3 of methylene chloride was added, the whole was concentrated and then 100 cm 3 of ether was added. The whole was decomposed, vacuum filtered and washed with ether to give 7.2 g of salt in the first yield.

The filtrate is concentrated to dryness and taken with ether to give a second yield of the same material.

4.24 g of the morpholine salt described above is suspended in 60 cm 3 of methylene chloride under inert gas while stirring.

After stirring for 5 minutes, the mixture was left at -5 ° C for 15 minutes, cooled to -20 ° C, and then 1.36 g of 7-amino sephalosporranic acid was added to 25 cm3 of methylene chloride and 1.4 cm3 of triethylamine. After adding the dissolved solution, the whole was allowed to stand at room temperature for 1 hour, washed with 50 cm 3 of water containing 10 cm 3 of normal hydrochloric acid, vacuum filtrate was collected, washed with water, concentrated to dryness, and then triturated with ether and vacuum filtered ether. Washing yields 4.5 g of crude product. This crude product is dissolved in 10 cm 3 of methylene chloride, stirred at + 10 ° C. for 1 hour, and the insolubles are vacuum filtered and then washed with methylene chloride. 50 cm 3 of ether was added to the filtrate and then stirred to wash the precipitate with ether after vacuum filtration to give 2.29 g of the expected product. In addition, a second yield of 0.856 g can be obtained, yielding an expected target of 3.14 g as a whole.

Example 2

3-acetoxymethyl 7-[(2- (2-amino 4-thiazolyl) 2-hydroxy imino-acetamido] -cep-3-m 4-carboxylic acid

2.29 g of the product obtained in Example 1 are suspended in 50% aqueous formic acid solution and brought to 55 ° C. for 16 minutes with good stirring.

After cooling, 10 cm 3 of water was added, the whole was vacuum filtered, washed with water, concentrated in vacuo, acetone was added, the whole was vacuum filtered, and 30 cm 3 of ether was added. The whole was stirred well, vacuum filtered and washed with ether to give 0.665 g of product. 0.123 g of product was precipitated by the second yield operation, which is 0.788 g.

0.735 g of the product was dissolved in 7.5 cm 3 of ethanol and 7.5 cm 3 of acetone, followed by 70 mg of carbon black, the whole was vacuum filtered, the solvent was removed, the residue was triturated in ethanol and washed with ethanol. A first yield is obtained, yielding 0.105 g as a second yield.

Example 3

3-acetoxymethyl 7- [2- (2-tritylamino-4-thiazolyl) 2-methoxyminoacet amido] -cep-3-m 4-carboxylic acid

Step A: ethyl 2- (2-amino 4-thiazolyl) 2-methoxymino acetyl acetate

1 g of ethyl-gamma-chloro-alpha-methoxymino acetylacetate, 3 cm 3 of pure alcohol, 0.42 g of pulverized thiourea are mixed together, stirred at room temperature for about 2 hours, and diluted with 60 cm 3 of ether to give hydrochloride. The precipitate is precipitated, and the whole is stirred, vacuum filtered, washed, and dried to yield 685 mg of hydrochloride. This is dissolved in 4 cm 3 of water at 50 ° C., and then added with acetate until pH is 6, the amine precipitates out.

After cooling the whole, vacuum filtration, the residue was washed with water and dried to obtain 270 mg of product (melting point: 161 ° C).

The resulting product has an equilateral arrangement.

RMN (CDCl ₃ 60 MHz) ppmi4 (NOCH ₃ )

6,7 (proton of thiazole ring)

Step B: ethyl 2- (2-tritylano-4-thiazolyl) 2-methoxyimino acetate

The product of 4.6g prepared in the previous step was dissolved in methylene chloride in degrees 30 °, 92cm ^3, and the solution was added a total of triethylamine 2.9cm ³ after cooling to -10 ° Celsius to -35 ° Celsius, Cool. Another 6.1 g of trityl chloride was added over 16 minutes, and the whole was left to stand at room temperature over about 2 hours 30 minutes, washed with water, washed with 0.5N hydrochloric acid and with an aqueous sodium acetate solution, then dried and concentrated. Take it with ether, concentrate it again, dissolve in methanol and add water and ether. On standing, crystals are precipitated, which are washed with ether after vacuum filtration to give the expected product of 6.15 g (melting point: 120 ° C).

The product obtained has an isotope structure.

Step C: 2- (2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid

After dissolving 7.01 g of the ester obtained in step B in 35 cm 3 of dioxane, the solution was brought to 110 ° C. in an oil bath, and 9 cm 3 of 2N caustic soda was added over 5 minutes, followed by stirring for 30 minutes under reflux. prevent. Sodium salts are then precipitated. The whole is cooled, vacuum filtered, washed with dioxane, and then washed with ether to yield 5.767 g of a first yield. Concentration of the mother liquor again yielded a salt of 1.017 g in secondary yield. The yield of the whole is 6.784 g.

3.06 g of salt is dissolved in 65 cm 3 of methylene chloride and 6.5 cm 3 of 2N hydrochloric acid, and the whole is washed with water, dried and concentrated to dryness to obtain some free acid. The product obtained has an isotope structure.

RMN (DMSO, 60MHz) ppm: 3.68 (N-OCH ₃ ), 6,6 (thiazole ring proton)

Step D: 3-acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2-methoxyimino-acetamido] -cep-3-m 4-carboxylic acid

The dry acid obtained in step C is dissolved in 30 cm 3 of dry methylene chloride. 0.78 g of dicyclohexylcardiodine was added, the whole was stirred for 1 hour at room temperature, and the resulting dicyclohexylurea was vacuum filtered, the filtrate was cooled to -10 ° C, and 1.01 g of 7-amino cephalosporranic acid was added to 13 cm 3. A solution dissolved in a mixture of methylene chloride and 0.9 cm 3 triethylamine is added.

After leaving the whole to room temperature, 1cm 3 of acetic acid was added and the whole was vacuum filtered, and the residue was washed with water containing hydrochloric acid, again washed with water, dried and concentrated, taken as 10cm 3 dioxane, 1cm 3 water and 3cm 3 hydrogen carbonate Saturated sodium solution is added. The whole is stirred, vacuum filtered, washed and melt dried.

It is taken up with methylene chloride, washed with 10 cm3 water, washed with 5 cm3 normal hydrochloric acid, discarded with homologous solution, washed with water, dried and triturated in ether to give 1.747 g of crude product, which is dissolved in ethyl acetate and recrystallized from ether. This yields 1.255 g of pure product. The structure of the obtained product is isoform.

-클로로-

-메톡시미노 아세틸아세테이트가 다음과 같이 제조 되었다.Ethyl- used as starting material in Example 3

-Chloro-

-Methoxymino acetylacetate was prepared as follows.

-클로로-

-옥시미노 아세틸 아세테이트를 100㎤의 염화메틸렌에 넣고 그 전체를 빙조 놓은 뒤 275㎤의 디아조메탄 담수용액(ℓ당 21.6g함유)을 교반하면서 서서히 가하고 5분동안 접촉시킨 후 과량의 디아조메탄은 소량의 알루미나로 파괴 시킨다. 나머지는 농축시키고, 실리카 상에 염화메틸렌으로 용리시켜 정제하면 11.93g의 기대하는 산물이 얻어진다.22.5 g of ethyl

-Chloro-

Add oxymino acetyl acetate to 100 cm 3 of methylene chloride, place the whole with an ice bath, slowly add 275 cm 3 of diazomethane freshwater solution (containing 21.6 g per liter) with stirring and contact for 5 minutes. Is destroyed with a small amount of alumina. The remainder is concentrated and purified by eluting with methylene chloride on silica to give 11.93 g of the expected product.

Ethyl 2- (2-amino-4-thiazolyl) 2-methoxyamino acetate used in Example 3 was prepared as follows.

단계 : 에틸 2-아세틸 2-메톡시이미노 아세테이트My

Steps: ethyl 2-acetyl 2-methoxyimino acetate

180 g of crude ethyl 2-acetyl 2-hydroxyimino acetate was added to 900 cm 3 of pure acetone, and 234 g of calcium carbonate was added under 10 ° C and nitrogen gas. Then, 103 cm 3 of dimethyl sulfate was added and the whole was stirred at room temperature for 3 hours. After adding ice, the whole is poured into 4 liters of water, extracted with methylene chloride, washed with water, dried and evaporated to evaporate the solvent to yield 185 g of the expected product.

단계 : 에틸 4-브로모 2-메톡시이미노 아세틸아세테이트 197g의

단계에서 얻어진 산물을 1ℓ의 염화메틸렌에 넣고 20㎎의 파라톨루엔 설폰산을 가한 다음 191g의 순수 브롬을 200㎤의 염화메틸렌에 용해시킨 용액의 1/20을 섭씨 20°에서 가한다. 반응이 시작하면 나머지 브롬용액을 약 섭씨 20°에서 한 시간에 걸쳐 도입시킨다. 전체를 방치, 온도가 섭씨 25°로 올라하면 반응이 종결된다. 이것을 빙수로 세척하고 염화 메틸렌으로 추출, 건조하고 용매를 증발 축출시키면 목적물 268g을 얻는다.My

Steps: 197 g of ethyl 4-bromo 2-methoxyimino acetylacetate

The product obtained in the step is placed in 1 L of methylene chloride, 20 mg of paratoluene sulfonic acid is added, and then 1/20 of a solution in which 191 g of pure bromine is dissolved in 200 cm 3 of methylene chloride is added at 20 ° C. When the reaction starts, the remaining bromine solution is introduced at about 20 ° C. over one hour. The reaction is terminated when the whole is left to stand and the temperature rises to 25 ° C. It is washed with ice water, extracted with methylene chloride, dried and the solvent is evaporated to yield 268 g of the desired product.

단계 : 에틸 2-(2-아미노 4-티아졸릴) 2-메톡시 이미노아세테이트My

Steps: ethyl 2- (2-amino 4-thiazolyl) 2-methoxy iminoacetate

Add 80 g of thiourea to 270 cm ³ ethanol and 540 cm ³ . 268 g of the product obtained in step β are placed in 270 cm ³ ethanol over 30 minutes under nitrogen gas. The whole is stirred at 20 ° C. for one hour, cooled to about 15 ° C., and the bicarbonate is added in small portions until pH is reached. The whole was vacuum filtered, washed with water and dried to obtain 133.8 g of the desired product. The obtained target product is the same as that obtained in step A.

Example 4

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] -cep-3-m 4-carboxylic acid

0.975 g of the product obtained in Example 3 are stirred for 10 minutes at 55 ° C. in 4 cm 3 of 50% aqueous formic acid solution. 4 cm <3> of water is added and the whole is vacuum filtered and concentrated in vacuo. This was again triturated in 2 cm 3 ethanol, vacuum filtered and washed with ethanol and ether to give 0.428 g of pure product.

Analysis: C ₁₆ H ₁₇ O ₇ N ₅ S ₂

Calculated Value: C% 42.19 H% 3.76 N% 15.37 S% 14.08

Found: 42.3 4.1 15.2 13.8

The product obtained is an isostructure.

Example 5

Diethylamine salt of 3-acetoxymethyl 7- [2- (tritylamino 4-thiazolyl) 2-methoxyimino) -acetamido] -cep-3-m 4-carboxylic acid

Example from the condensation of di (cyclohexyl carbodiimide) with 2- (2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid in anhydride form prepared using 40.8 g of 7-amino sephalosporonic acid 350 cm 3 di of crude 3-acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2-methoxyimino) -acet amido-sef-M 4-carboxylic acid obtained as illustrated in 3 It is dissolved in a solution of oxane and 350 cm 3 ether sulfate and slowly added 33 cm 3 of diethylamine with stirring. The whole was stirred for 20 minutes and the diethylamine salt of 2- (2-tritylamino 4-thiazolyl) -2-methoxyiminoacetic acid precipitated was vacuum filtered. This salt was washed twice with 30 cm 3 of the dioxane-ether mixture to give 62.6 g of salt. The filtrate is concentrated to syrup form and about 2.5 liters of sulfuric acid ether is added.

Stirring and vacuum filtration of the whole yielded 110.3 g of the desired diethylamine salt. The product obtained is isotopic.

Example 6

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (methoxy imino) -sef-3-m-4-carboxylic acid

After adding 36 g of the product obtained in Example 5 to 180 cm 3 of 50% formic acid aqueous solution maintained at 50 ° C., the whole was stirred at 50 cm 3 for 20 minutes, followed by vacuum filtration of triphenylcarbinol formed and 180 cm 3 of ethanol. The whole is concentrated to dryness under reduced pressure, and the residue is taken up as a mixture of 100 cm 3 and 20 cm ethanol, concentrated again, and taken up with 100 cm 3 of water, stirred at 15 ° C. for 15 minutes, vacuum filtration, washed with water, and ether washed. 15.6 g of the desired product is obtained. The product was the same as obtained in Example 4.

Example 7

Sodium of 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (methoxyimino) -acetamido] -cep-3-m 4-carboxylic acid

Pure 3-acetoxymethylshi 7-2- (2-mino 4-thiazolyl) 2- (methoxyimino) acetamido cef-3-em 4-carboxylic acid obtained according to the process in Example 4 or 6 45.55 g is mixed with 100 cm 3 of distilled water and 8 sodium bicarbonate is added while adding about 20 cm 3 ethanol. It was washed with 80 cm 3 of ethanol and concentrated to dryness in vacuo. This was again taken up in 100 cm 3 ethanol and concentrated to dryness. The residue was dissolved in 100 cm 3 methanol, 2 L acetone was added and the whole was stirred vigorously, vacuum filtered, washed with acetone and washed with ether. Vacuum drying yields 43.7 g of white product, which is hydrated in air, resulting in a final weight of 45.2 g.

analysis:

Calculated Value: C% 40.24 H% 3.38 N% 14.67 S% 13.43 Na% 4.81

Found: 40.3 3.8 14.4 13.3 4.84

The product obtained is isotopic.

NMR (60 MHz D ₂ O) ppm; 2.01 (COCH ₃ )

doublet is 9.53 at J = 8HZ (NHCO) 6.75 (thiazole quantum)

Example 8

3-acetoxymethyl 7 [2- (2-tritylamino 4-thiazolyl) 2- (2-propenyl) -oxyimino) -acetamido] -cep-3-m 4-carboxylic acid

Step A: ethyl (2 (2-amino 4-thiazolyl) 2-((2-propenyl) oxyimino) -acetate

a) 9.7 g of ethyl 2-hydroxy imino 4-chloro acetyl acetate, 30 cm 3 acetone, and 9.15 cm 3 3-iodopurene mixture were cooled with ice, 27.5 cm 3 of 2-sodium hydroxide was added and the whole was Leave at room temperature for an hour and a half.

b) 3.8 g of thiourea was added to the reaction mixture, which was kept at 60 ° C. for 15 minutes, and the phases were left for 45 minutes. After stirring, the supernatant was decanted and extracted, dried and concentrated to dryness with methylene chloride to obtain 9.75 g of a residue, which was chromatographed on silica and eluted with ether to separate 27 g of product. This was taken with dizopropyl ether, and the crystals were vacuum filtered, washed and dried to give 783 mg of the desired product.

Melting point is 100 degrees Celsius, the product obtained is isotropic.

Step B: ethyl 2- (2-tritylamino 4-thiazolyl) 2- (2-propenyl) oxymino acetate

511 mg of the product prepared in step A, 0.92 cm 3 of dimethylpoamide, 1.8 cm 3 of methylene chloride, and 0.29 cm 3 of triethylamine are mixed. The mixture was cooled to -15 [deg.] C. and 615 mg trityl chloride were added. The whole was left at room temperature for 1 hour and a half, and 2 cm 3 of 1N hydrochloric acid and 5 cm 3 of water were added to discard the supernatant, and then dried and concentrated to dryness to obtain 1.28 g of crude product. The product obtained is isotopic.

Step C: 2- (2-tritylamino 4-thiazolyl) 2- (2-propenyl) oxyimino) acetic acid

1.28 g of the product obtained in step B, 6.2 cm 3 of dioxane, and 3 cm 3 of 2N-sodium hydroxide are mixed, heated to 120 ° C., and refluxed for one hour to precipitate sodium, which is vacuum filtered, ether- Washing and drying with a dioxane mixture separates 805 mg of product. This is taken up with 10 cm 3 of methylene chloride and 3 cm 3 of 1N hydrochloric acid mixed solution, stirred until a solution is obtained. Thus, the resultant is concentrated to dryness, taken with ether and vacuum filtered to give 715 mg of the desired product. Melting point; 170 ° C The product is isotropic.

Step D: 3-acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2-((2-propenyl) -oxyimino) acetamido] -sef-3-m 4- Carboxylic acid

470 mg of the product prepared in step C, 5 cm 3 of methylene chloride, and 130 mg of dicyclohexylcarbodiimide were mixed and washed with a small amount of methylene chloride, stirred at room temperature for one hour, and the resulting dicyclohexyl urea formed. Vacuum filtration, the filtrate was cooled, 136 mg of 7-amino sephalosporranic acid solution of 2.4 cm 3 methylene chloride and 0.14 cm 3 triethylamine mixed solution was added under inert gas, and then left at room temperature for an hour and a half. 1N hydrochloric acid and water are added. The whole was stirred, decanted, washed with water, dried and concentrated to yield 610 mg of crude product. The product obtained is isotopic.

Example 9

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-((2-propenyl) -oxyimino) -acetamido] -cep-3-m 4-carboxylic acid

610 mg of the product obtained in Example 8 and 3 cm 3 of 50% formic acid aqueous solution were heated at 60 ° C. for 15 minutes, and 4 cm 3 of water was added thereto, followed by shaking, vacuum triphenylcarbonyl was washed with water, and the filtrate was vacuumed. Drying, taking with water, grinding, vacuum filtration and washing give 120 mg of the desired product.

Melting point is 160 ° Celsius

Ultraviolet spectrum

NMR (DMSO 90 MHZ) p.p.m. 2.02 (OAC) 6.68 (thiazole proton) The product is thus isotopic.

Example 10

3-acetoxymethyl 7 [2- (2-tritylamino 4-thiazolyl) -2- (ethoxyimino) -acetamido] -cep-m 4-carboxylic acid

Step A: ethyl 2- (2-amino 4-thiazolyl) 2-ethoxyiminoacetate

-클로로

-옥시이미노 아세토아세 테이트를 60㎤아세톤과 14.3㎤디에틸설페이트 혼액에 넣고 전체를 10분 동안 빙조에서 냉각시키고, 55㎤의 2N-산화나트륨을 30분간에 걸쳐 가한 후 40분동안 진탕시킨다.a) 19.4 g of ethyl-

-Chloro

-Oxyimino acetoacetate is placed in a mixture of 60 cm 3 acetone and 14.3 cm 3 diethylsulfate, cooled in an ice bath for 10 minutes, 55 cm 3 of 2N-sodium oxide is added over 30 minutes and shaken for 40 minutes.

b) 7.6 g of thiourea is added to the reaction medium and the acetone is evaporated when heated at 55 ° C for 20 minutes. The remainder is taken up with ethyl acetate, and 6.9 g of calcium carbonate is added, which is then shaken, decanted, ethyl acetate, extracted, dried and concentrated to dryness to separate 17.4 g of the residue which is chromatographed on silica and eluted with ether. The target product is collected, taken as dizobutyl ether, vacuum filtered and washed to obtain 2.8 g of the target product. Melting Point: 129 ° C The product is isotropic.

Stage B: ethyl 2 (2-tritylamino 4-thiazolyl) 2-ethoxyimino acetate

3.16 g of the product obtained in step A, 6 cm 3 of dry dimethylpoamide, 12 cm 3 of methylene chloride, and 1.89 cm 3 of triethylamine were placed under inert gas and the mixture cooled to -15 ° C., 3.98 g of tree Tylchloride is added slowly. If the whole is left for one and a half hours, the temperature rises to +10 degrees Celsius, and it is left to stand for three and a half hours at room temperature. 13 cm 3, 1N hydrochloric acid was added thereto, shaken, decanted, washed with 1N hydrochloric acid, washed with water, extracted with methylene chloride, dried and concentrated to dryness to obtain 7.89 g of crude residue. The product is isotopic.

Step C: 2- (2-tritylamino-4-thiazoli) 2-ethoxyiminoacetic acid

789 g of the product obtained in step B, 40 cm 3 of dioxane and 19.5 cm 2 of 2N sodium hydroxide mixture are heated at 110 ° C. for 1 hour, the mixture is vacuum filtered, washed with ether-dioxane mixture, washed again with ether and dried. . 6.25 g of sodium salt are obtained, which is then taken up in 60 cm 3 of methylene chloride and 20 cm 3 of 1N-hydrochloric acid to shake the head phase and 5.85 g of pure 2- (2-tritylamino 4-thiazolyl) -2-ethoxyimino Acetic acid is separated.

The product obtained is isotopic.

Step D: 3-acetoxymethyl 7-2- (2-tritylamino 4-thiazolyl) 2- (ethoxy imino) -acetamido-sef-3-m 4-carboxylic acid

3.43 g of 2- (2-tritylamino 4thiazolyl) 2-ethoxyiminoacetic acid prepared in step C was added to 34 cm 3 methyl chloride, suspended and cooled, and 970 mg of dicyclohexylcarbodiimide was cooled. After addition, it is washed with methylene chloride and shaken for 1 hour at room temperature.

The formed dicyclohexylurea was vacuum filtered and the filtrate was cooled to -20 ° C, and a 1.02 g 7-aminocephalosporonic acid solution of a mixture of 18 cm 3 of methylene chloride and 1.06 cm 3 triethylamine was cooled to -20 ° C. Combine together. The whole was heated for 1 and a half hours, 1.8 cm 3 acetic acid was added, 9 cm 3 1 N-acetic acid was added, the whole was washed with shaking, decant, water, extracted with methylene chloride, dried and concentrated to obtain 4.56 g of the desired product. Brother.

Example 11

3-acetoxymethyl 7- [2-amino 4-thiazolyl) 2- (ethoxyimino) -acetamido] cef-3-m 4-carboxylic acid

4.56 g of the product obtained in Example 10 was added to 23 cm 3 of a 50% formic acid aqueous solution, heated at 55 ° C. for 15 minutes, diluted with 30 cm 3 of water, triphenylcarbyol was vacuum filtered, the filtrate was concentrated to dryness, taken with water, shaken, Vacuum filtration and washing with water yield 116 mg of crude product. A secondary yield of 674 mg of crystalline product is obtained by concentrating the filtrate. The total amount is 790 mg.

This is followed by the following purification process.

1.063 g of crude product was made into 5 cm 3 of water and then heated, cooled, shaken, vacuum filtered, washed and dried for 30 minutes at 70 ° C. to separate 815 mg of purified product. Take 3 cm 3 of acetone mixture and warm it up slightly, then filter the insolubles, add 3 cm 3 of water, heat to 60 ° C, acetone evaporate off nitrogen, wash the formed particles with water, wash the ether, and 438 mg of the target is separated. do.

analysis; C ₁₇ H ₁₉ O ₉ N ₅ S ₂

Calculated value; C% 43.49 H% 4.08 N% 14.92 S% 13.66

Found; 44.5 4.4 14.8 13.3

The product is isotopic.

NMR (60MHZ DMSO) p.p.m; 2.05 (OAC)

6.75 (proton thiazole)

Example 12

3-acetoxymethyl 7 [2- (2-tritylamino 4-thiazolyl) 2- (1-methylethoxy imino) -acetamido] -cep-3-m 4-carboxylic acid

Step A: 39.8 g of ethyl 2-acetyl-2- (1-methyl ethoxyimino) -acetate was added to 200 cm 3 of pure acetone, and the whole was cooled in an ice bath, 52 g of Caliper carbonate is added and 25 cm 3 of 2-iodine furophan is added over 30 minutes. The whole was shaken for 2 hours, 800 cm 3 of water and 500 cm 3 of methylene chloride were added, followed by extraction with shaking, decant, and methylene chloride, followed by drying under vacuum filtration to separate 41.5 g of the target product.

Step B: ethyl 4-bromo 2- (1-methyl ethoxyimino) -acetylacetate

41.5 g of the product obtained in the preceding step is added to 190 cm 3 of methylene chloride containing a small amount of paratoluene sulfonic acid, and the whole is shaken and 11.9 cm 3 bromine and 50 cm 3 methylene chloride solution are added at room temperature over an hour. The whole was added with shaking ice water, the whole was decanted, extracted with methylene chloride, washed with ice water and concentrated to dryness to obtain 55 g of the target product.

Step C: ethyl 2- (2-amino 4-thiazolyl) 2- (1-methyl ethoxyimino) -acetate

Into a mixture of 55 cm 3 ethanol and 105 cm 3 water of 14.9 g Trourera, add 55 cm 3 of 55 g of the ethanol solution prepared in step B over 40 minutes. The whole was shaken at room temperature for 2 and a half hours, and after adding 220 cm 3 of 10% aqueous sodium bicarbonate solution, shaking, vacuum filtration and drying, 42.15 g of crude product was separated and chromatographed on silica to elute with ether. A large portion of the recovered concentrated crystals were taken with dizopropyl ether and washed with vacuum filtration to obtain 10.75 g of the desired product. The product obtained is isotopic.

Stage D: ethyl 2- (2-tritylamino, 4-thiazolyl) 2- (1-methylethoxyimino) -acetate

11 g of the product obtained in the step C were added to a mixture of 20 cm 3 dry dimethylformamide 40 m 3 methylene chloride and 6.2 cm 3 triethylamine, and the mixture was cooled, slowly added 13.2 g of triethyl chloride, followed by shaking and normal for 2 and a half hours. 43 cm3 hydrochloric acid is added, washed with shaking, decant, 40 cm3 water, extracted with methylene chloride and concentrated to dryness in vacuo to give 27.7 g of the desired product.

The product obtained is isotopic.

Step E: 2- (2-tritylamino 4-diazolyl) 2- (1-methylethoxyimino) -acetic acid

The mixture of 27.7 g, 150 cm 3 dioxane and 65 cm 3 2N sodium hydroxide obtained in the step D is refluxed for 2 hours, and sodium salt precipitates as crystals, the mixture is cooled, vacuum filtered, and 1: 1 ether-dioxane. Washing with a mixture and drying gives 16.85 g of crude sodium salt.

15.9 g of this sodium salt is dissolved in 15.9 g of dimethyl amide, 100 cm 3 water of about 500 cm 3 methanol mixture, and then 30 cm 2 2N hydrochloric acid is added. After the methanol is removed, the excess is diluted with water, vacuum filtered, washed with water and dried to obtain 9.8 g of a viscous product, which is taken as a 50: 50 methylene chloride and methanol mixture 200 cm 3, taken as a concentrated dry ether, and the resulting crystals are vacuum filtered. When washed with water and dried, 49 g of the desired product is obtained. Melting point: 170 ° C. The analytical sample is obtained by dissolving 300 mg of crude product in a mixture of 2 cm 3 methylene chloride and 1 cm 3 methanol. The whole is diluted with water and methylene chloride, shaken, and the resulting crystals are vacuum filtered and methylene chloride. After washing, washing with water and drying again, 230 mg of analytical pure product is separated.

analysis :

Calculation: C% 68.77 H% 5.34 N% 8.91 S% 6.8

Found: 68.6 5.5 8.8 6.8

The product obtained is isotopic.

Step F: 3-acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2- (1-methylethoxyimino) -acetamino] cef-3-m 4-carboxylic acid

After dissolving 4.89 g of the acid obtained in the step E under argon gas in 13.5 cm 3 of dimethylformamide, the solution is cooled in an ice bath and a 16 cm 3 methylene chloride solution of 1.62 g dicyclohexylcarbodiimide is added. Dicyclohexyl urea precipitates as crystals and the mixture is washed with agitation, vacuum filtration, methylene chloride and dried in an ice bath to obtain 1.424 g of dicyclohexyl urea. The filtrate was cooled in a methanol-ice bath and a solution of 1.41 g 7-aminocepharosporanic acid dissolved in 30 cm 3 of methylene chloride and 1.45 cm 3 of triethylamine turbidity was added. After shaking for 3 hours at room temperature, 20 cm 3 hydrochloric acid was added. do.

The whole was extracted again with shaking, decant, methylene chloride, dried and vacuum filtered to give 9.05 g of the mixture of the desired and starting materials. It is taken up with methylene chloride and crystallized under shaking. The crystals are vacuum filtered, washed with water and dried to obtain 1.6 g of starting material. The filtrate is concentrated to dryness with vigorous shaking with isopropyl ether and 4.91 g of insoluble viscous product expected as the target is separated. The object obtained is isotropic.

Example 13

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (1-methylethoxyimino) -acetamido] -cep-3-m 4-carboxylic acid

4.91 g of the crude product obtained in Example 12 was poured into a 30 cm 3 50% formic acid aqueous solution, and the whole was shaken in a 60 ° C water bath, diluted with water, and vacuum filtered and washed with triphenyl carbinol to obtain 800 mg of the target product. The analytical sample is prepared by dissolving 972 mg of the crude product in 4 cm 3 of methanol, which is diluted with 20 cm 3 of ether, and the insolubles are vacuum filtered, washed with water, and dried to obtain 404 mg of pure target. Melting Point: 200 ° C

Analysis

Calculation: C% 44.71 H% 4.38 N% 14.48 S% 13.26

Found: 44.5 4.5 14.1 13.2

The product is isotopic.

NMR (60MHZ DMSO) ppm; 2.01 (CH ₃ CO); doublet is 9.46 J = 8 Hz (CONH); 6.7 (proton of thiazole ring)

Example 14

3-acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2-ethoxyimino-acetamido] -cep-3-m 4-carboxylic acid

Step A: ethyl 2- (2-tritylamino 4-thiazolyl) 2-hydroxyacetate inverse isomer

Ethyl 2- (2-amino 4-thiazolyl) 2-hydroxyimino acetate, inverse isomer, 90 ml of dry dimethylpoamide, 24 cm 3 of triethylamine prepared by step A of Example 1 were mixed and tritylchloride A small amount of 47.6 g is added over a period of 30 minutes, followed by heating and leaving for 2 and a half hours, followed by adding 150 cm 3 of 2N hydrochloric acid and 600 cm 3 of water.

After shaking the whole for 15 minutes, it was made three times with ether and then mixed with methanol triethylamine and water, followed by shaking, vacuum filtration, washing with water and drying to obtain 60.2 g of the target substance.

Recrystallization of 3.4 g of the crude product from the methylene chloride-methanol mixture gave 3 g of pure product. Melting point is 260 ° C

Step B: ethyl 2- (2-triaminoamino 4-thiazolyl) 2-ethoxyimino acetate, inverse isomer;

11.5 g of the product obtained in step A and 5.85 g of carbonate carbonic acid 25 cm 3 were mixed together, cooled to 15 ° C., 16.7 cm 3 of ethyl sulfate was added and left at room temperature for 4 hours, followed by water 420 cm 3 and ethyl acetate 250. After adding 3 cm 3 of the mixture, the whole was extracted with shaking, decant, washing with ethyl acetate, dried, vacuum filtered and extracted with ethanol. The mixture was left to precipitate, washed with water, dried and dried to obtain 6.6 g of the target substance. Melting point is 165 ° C

This product can be recrystallized as follows;

797 mg was dissolved in a 50:50 mixture of methylene chloride and ethanol, and the solution was vacuum filtered and concentrated to evaporate methylene chloride. The product was recrystallized. The mixture is vacuum filtered, washed with water and dried to give 596 mg of pure product.

Step C: 2- (2-tritylamino 4-thiazolyl) 2-ethoxyimino acetic acid, inverse isomer

7.29 g of the product prepared in step B was added to a mixture of 45 cm 3 of dioxane and 9 cm 3 of 2N sodium hydroxide, and the mixture was heated at 50 ° C. for 1 hour and 50 minutes while shaking, followed by cooling. The crystals were vacuum filtered and washed with 4.2 g of sodium salt. The salt was taken in a mixture of 50 cm 3 of methylene chloride, 40 cm 3 of water and 11 cm 3 of normal hydrochloric acid. The mixture was extracted with shaking, decant, methylene chloride, extracted, washed, dried, vacuum filtered and concentrated. Water was washed with ether after vacuum filtration to obtain 3.27 g of the target.

Melting point = decomposing to about 200 ° C

NMR (60 MHz CDCl 3) p.p.m. = 7.66 (protons of thiazole rings)

7.36 (protons of trityl)

Stage D: 3-acetoxymethyl 7-2- (2-tritylamino 4-thiazolyl) 2-ethoxyimino acet amido-sef-3-m 4-carboxylic acid, inverse isomer

41 g of the acid obtained in step C, 36 cm 3 of tetrahydrofuran, 27 cm 3 of methylene chloride and 0.99 cm 3 of N-methylmorpholine were mixed under argon gas, cooled to -20 ° C. and 1.17 cm 3 of dizobutylchloroformate was added one by one. do.

The whole was left at this temperature for 3 minutes, cooled to -13 ° C, and a solution of 2.45 g of 7-aminocephalosporranic acid was dissolved in a mixture of 4.5 cm 3 of methylene chloride and 2.52 cm 3 of triethylamine, and the whole was added for 2 hours 30 minutes. The solvent is removed and the excess is taken up to pH 1-2 with a mixture of methylene chloride, water and normal hydrochloric acid, and the whole is extracted with methylene chloride, washed, dried, vacuum filtered, concentrated, taken with ethyl acetate and diluted with dizopropyl ether. After shaking, shaking, vacuum filtration, and washing to obtain 4.87 g of the target inverse isomer. Purification is as follows;

4.87 g of the above product was heated, and the solution dissolved in 10 cm 3 of ethyl acetate was slowly diluted with isoprophyl ether, shaken, vacuum filtered, washed with water and dried to obtain 4.53 g of purified product.

Example 15

3-acetoxymethyl 7-2- (2-amino 4-thiazolyl) 2-ethoxyimino acetamido-sef-3-M 4-carboxylic acid, inverse isomer.

4.27 g of the purified product obtained in Example 14 was placed in 20 cm 3 of a 50:50 formic acid aqueous solution, and the mixture was shaken at 60 ° C. on a water bath for 20 minutes, cooled, diluted with water, shaked for 10 minutes, and the formed triphenyl carbinol was vacuumed. Filtration with water affords 1.44 g of triphenylcarbinol. Ethanol was added, the whole was concentrated in vacuo, the residue was taken up with ethanol, and ethanol was again removed under vacuum, and 30 cm 3 of water was added to the residue. .

The purification process is as follows.

After dissolving 2.06 g of the above product in a mixture of 5 cm3 of 10% thick water and 5 cm3 of water, vacuum filtration of the cloudy liquid and 3-4 drops of pure formic acid after washing were carried out. Filtration, washing and drying yield 1.73 g of pure product.

Melting point = about 200 ° C with decomposition

NMR (60 MHz DMSO) ppm = 2.04 (CH ₃ CHO)

7.5 (proton of thiazole ring)

Example 16

3-acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2- (1-methylethoxy imino) -acetamido] ceph 3-M 4-carboxylic acid inverse isomer

Step A: Ethyl 2- (2-tritylamino 4-thiazolyl) 2- (1-methyl ethoxyimino) -acetate, inverse isomer Ethyl 2- (2- prepared by step A of Example 14 A mixture of tritylamino 4-thiazolyl) -hydroxyiminoacetate, 6.86 g of reverse isomers, 15 cm3 of dimethylpoamide with 3.5 g of carbonate, and 7.7 cm3 of dizopropyl oxide was mixed for 4 hours and a half. After standing, 250 cm3 of distilled water and 150 cm3 of ethyl acetate were added, and the whole was shaken, decanted, washed, extracted with ethyl acetate, dried, vacuum filtered, concentrated and dried, and then taken up with ethanol, and left to crystallize. Make 3.26g of the target. Melting point = 182 ° C

Step B: 2- (2-tritylamino 4-thiazolyl) 2- (1-methylethoxyimino) acetic acid, inverse isomer

6.8 g of the product obtained in step A was added to 41 cm 3 of dioxane and 8.15 cm 3 of 2N sodium hydroxide, and the whole was heated at 55 ° C. for 2 hours in a water bath, and after cooling, 9.5 cm 3 of 2N hydrochloric acid was added to obtain pH 23-3.

After dioxane is removed, the residue is crystallized, diluted with water, shaken, washed with ether and dried to obtain 5.87 g of the target substance. Melting point = 240 ° C with decomposition

NMR (60 MHz CDCl 3) p.p.m. = 7.66 (protons of thiazole rings)

7.31 (protons of trityl)

Step C: 3-acetoxymethyl 7-2- (2-tritylamino 4-thiazolyl) 2- (1-methylethoxyimino) -acetamido-cef-3-m-4-carboxylic acid, inversion Isomers

5.66 g of the acid obtained in step B was added to a mixture of 48 cm 3 of tetrahydrofuran, 48 cm 3 of methylene chloride and 1.32 cm of N-methylmorpholine, and the whole was dissolved. The solution was cooled to -20 ° C., and 1.56 cm 3 of dizobutyl chloroformate. After the addition of the mixture, the whole was left at -20 ° -10 ° C for 10 minutes, cooled to -35 ° C again, and 3.26 g of 7-amino sepharosephosphoric acid was added to 60 cm3 of methylene chloride and 3.36 cm3 of dry triethylamine. The whole is heated, shaken for 3 hours and 30 minutes, the solvent is removed, and the excess is taken as an emacetate to dissolve. The whole was diluted with zofuru, diluted with filether, shaken, vacuum filtered, washed and dried to obtain 5.42 g of the target substance.

The product is purified as follows.

5.82 g of the product obtained in the above step was dissolved in 20 cm 3 of ethyl acetate while heating, and then diluted and dried with 200 cm 3 of zofurophyl ether to obtain 4.82 g of the desired product.

Example 17

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (1-methylethoxyimino) acetamido] -cep-3-m 4-carboxylic acid, inverse isomer

3.62 g of the product obtained in Example 16 and 16 cm 3 of a 50:50 formic acid aqueous solution were mixed together, and the mixture was heated to 60 ° C. for 20 minutes, cooled, and 16 cm 3 of water was added to shake the mixture, and the resulting triphenylcarbinol was vacuum filtered. After washing with water, 1.23 g of triphenylcarbinol is obtained. The resultant was concentrated, dried in vacuo, taken with ethanol, taken out of the solvent (under vacuum), again with water, shaken and cooled to precipitate crystals, and the obtained crystal-rubber mixture was washed with vacuum and washed to obtain 168 g of a crude molar.

Pure samples are obtained by the following operations.

2 g of the product was dissolved in 5 cm ³ of 10% aqueous sodium bicarbonate solution and 5 cm ³ of water, followed by shaking, vacuum filtration and washing for 10 minutes, adding formic acid to PH = 3, followed by shaking, vacuum filtration and washing for 1 hour in an ice bath. After dissolving in ethanol 100cm ³ while heating, cooling with ice water, vacuum filtration, washing with ethanol and ether washing to obtain 748 mg of purified product. Crystalline product can also be observed in the filtrate (it is diluted with ether without causing precipitation) and the crystals are vacuum filtered, washed with ethanol-ether compound and washed with ether to give 177 mg of pure crystals (reverse isomers). . Melting point = about 200 ° C with decomposition

NMR (DMSO 60 MHZ) p.p.m. = 7.46 (protons of thiazole rings)

4.43 (third proton of zopropyl group)

Example 18

3-acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2- (2-furophenyloxymino) -acetamide] -cep-3-m 4-carboxylic acid, inverse isomer

Step A: ethyl 2- (2-tritylamino 4-thiazolyl) 2- (2-propenyloxyamino) -acetate inverse isomer

6.86 g of the reverse isomer ethyl 2- (2-tritylamino 4-thiazolyl) 2-hydroxy amino acetate, prepared by step A of Example 14, 3.51 g of carbonate carbonate, 15 cm 3 of dimethylpoamide, aryloxide After shaking 3 cm under argon and shaking the whole at room temperature for 5 hours and adding 250 cm 3 of water and 150 cm 3 of ethyl acetate, the whole was shaken, decanted, washed, extracted with ethyl acetate, dried, vacuum filtered and concentrated to dryness and then ethanol. Crystals precipitate.

The whole is cooled in ice water, crystallized with shaking for 30 minutes, vacuum filtered and the crystals washed with water to give 4.72 g of the desired product. The product is purified as follows.

That is, 215 mg of the above product is dissolved in 2 cm 3 of ethanol and 2 cm 3 of ethylene chloride, the filtrate is concentrated, diluted with ethanol, and crystallized, filtered, washed with ice and dried to obtain 70 mg of purified product.

Melting point; 90 ° Celsius (Atmosphere), 160 ° Celsius (Pure Water)

Step B: 2- (2-tritylamino 4-thiazolyl) 2- (2-propenyl oxyimino) acetic acid, inverse isomer

3.71 g of the product obtained in step A was added to 22 cm 3 of dioxane and 4.5 cm 3 of 2N sodium hydroxide, and the mixture was heated and heated to 55 ° C. for 1 hour and 50 minutes in a water bath, and 5.25 cm 2N hydrochloric acid was added to PH = 2. After distilling the dioxane, gum is obtained, which is diluted with water, cooled with ice water, vacuum filtered, washed with water, and then made three times with an ether to obtain 2.85 g of the target substance.

Melting Point = 198 ° C (decomposition)

NMR (CDCl ₃ ) ppm = 7.64 (protons of thiazole ring)

7.27 (trityl quantum)

Step C: 3-acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2-furophenyl oxingmino) -acetamido] -sef-3-m 4-carboxylic acid, inverse isomer

2.82 g of the acid obtained in the step B was dissolved in 24 cm 3 of dry tetrahydrobutane and 24 cm 3 of methylene chloride, and then 0.66 cm of N-methylmorpholine was added, the whole was cooled to -20 ° C., and 0.78 cm 3 of dizobutylchloroformate was added. do. The whole was stirred at -20 ° C for 3 minutes, then cooled to -35 ° C, and a solution obtained by dissolving 1.63 g of 7-aminocepharosporanic acid in 30 cm 3 of methylene chloride and 1.68 cm 3 of triethylamine was added thereto, and the whole was heated and solvent After removal, the excess is taken up with methylene chloride and normal hydrochloric acid, shaken, decant, washed with water, extracted with methylene chloride, dried, vacuum filtered, washed with methylene chloride, concentrated to dryness, taken with ethyl acetate, diluted with isoprofil ether, shaken, After vacuum filtration, washing with zofurophyl ether gives 3.08 g of the target product. The purification process is as follows.

3.29 g of the product obtained above was dissolved in 15 cm 3 of ethyl acetate, diluted with isofurophyl ether, stirred, and precipitated in vacuo and washed with isofurophyl ether to obtain 3.33 g of purified product.

Example 19

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2- (2-propenyloxyimino) -acetamido] -cep-3-m 4-carboxylic acid, inverse isomer

2.53 g of the product obtained in Example 18 was added to 11.5 cm 3 of 50:50 formic acid aqueous solution, and the mixed solution was heated to 60 ° C. for 20 minutes, diluted with water, cooled to room temperature, vacuum filtered, and washed to form triphenylcarbinol. 963 mg is obtained.

The mother liquors were concentrated to dryness in vacuo, ethanol was added, and the gum produced after solvent extraction was taken with 15 cm 3 of water and ground, vacuum filtered, washed with water and dried to obtain 1.275 g of the target substance.

The product is purified as follows. 1.63 g of the crude product was suspended in 15 cm 3 of ethanol, and the whole was refluxed and washed with ethanol after heating under vacuum filtration to recover 877 mg of insoluble matter.

20 cm 3 of ether is added to the filtrate, and the insoluble matters are vacuum filtered and washed with a 1: 1 ethanol-ether mixture to dry, thereby obtaining 97 mg of the second insoluble component.

When the filtrate is concentrated in half, crystals are precipitated, and the result is vacuum filtration, washed with ethane, and dried to give 162 mg of an inverse isomer. Melting Point: 180 ° Celsius

NMR (DMSO 60 MHZ) p.p.m. = 7.48 (protons of thiazole rings)

2.40 (proton of trityl group)

Example 20

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] -cep-3-m 4-carboxylic acid, isomer

Stage A: ethyl 2- (2-chloroacetamido or thiazolyl) 2-methoxy aminoacetate, isomer.

The isotope ethyl 2- (2-amino 4-thiazolyl) 2-methoxyiminoacetate 45.8 prepared in Example 3 was added to 200 cm 3 of methylene chloride, 20 cm 3 of which was distilled and removed, and then 10 ° C. After cooling to 50, 50 cm 3 of pyridine is added, then monochloroacetic anhydride is added and the whole is slightly warmed to dissolve.

After standing for 6 hours at 20 ° C. under nitrogen, 5 cm 3 of water was added and the whole was shaken and poured into 300 cm 3 of cooled 2N hydrochloric acid.

The whole was extracted with decant, methylene chloride, washed, dried with sodium and carbonate, concentrated through charcoal, and 300 cm3 of izofurofil ether was added to precipitate crystals. It is concentrated until it becomes a mass, cooled, vacuum filtered, washed with isoprofil ether and dried to obtain 45.4 g of product. Melting point = 113 ° C

Pure samples are obtained by recrystallization from a mixture of methylene chloride and isoprophylether. Melting point = 118 ° C

Stage B: 2- (2-chloroacetamido 4-thiazolyl) 2-methoxy iminoacetic acid, isomers

46 g of the product obtained in step A was added to 230 cm 3 of pure ethanol and 30 cm 3 of pure concentrated sodium carbonate solution was added at 20 ° C. under nitrogen to dissolve the product. Sodium salt began to precipitate crystals, causing the medium to lump in a mass. do.

After 16 hours, the resultant was filtered by vacuum, washed with ethanol, dissolved in water, cooled, added 100 cm 3 of 2N hydrochloric acid, saturated with sodium chloride, extracted with ethyl acetate containing 10% ethanol, passed through dry charcoal, and vacuum dried. Water was extracted with benzene, extra was taken up with methylene chloride, evaporated to dryness, and again taken up with methylene chloride, cooled, vacuum filtered, washed with methylene chloride and dried to give 34.5 g of the desired product. Melting point = 200 ° C

The product is recrystallized from an acetone-isofurophylether mixture.

Analysis: C ₈ H ₈ O ₄ N ₃ ClS = 277.68

Calculated Value: C% 34.60, H% 2.90 N% 15.13 Cl% 12.77 S% 11.55

34.81 2.8 14.8 12.6 11.5

Step C: 3-Acetoxymethyl 7- [2- (2-chloroacetamido 4-thiazolyl)) 2-methoxyimino acetamido] -cep-3-m 4-carboxylic acid, isomer.

15.3 g of the product obtained in step B are added to 80 cm 3 of methylene chloride. Triethylamine is added at 50 ° C. and 3.8 cm 3 of thionyl chloride and 26 cm 3 of methylene chloride are added again at 0 ° C. under nitrogen. The whole was left at 0 ° C. for 15 minutes, and 7 cm 3 of triethylamine was added thereto.

A solution of 13.6 g of 7-aminocephalosporranic acid dissolved in 100 cm 3 of methylene chloride and 14 cm 3 of triethylamine is introduced at 0 ° C. under nitrogen. The whole is brought back to 20 ° C, stirred for 1 hour, evaporated to dryness under vacuum at about 30-35 ° C, the residue is dissolved in 250cm3 of water, passed through charcoal and 50cm3 of 2N hydrochloric acid is added.

The crude product obtained by vacuum filtration and washing with water was suspended in 80 cm 3 of ethanol, 7 cm 3 of triethylamine was added at 5 ° C., and stirred at 5 ° C., and 15 cm 3 of 4N sulfuric acid was added at once to precipitate crystals after 15 minutes. . This was vacuum filtered, washed with an atlas, washed again with ether, and dried in vacuo to obtain 18.6 g of the target substance.

Step D: 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxyimino acetamido] -cep-3-m 4-carboxylic acid isomer

5.32 g of the acid obtained in step C are added to a suspension of 10.6 cm 3 of water and 912 mg of thiourea, and 1 g of potassium dicarbonate is added at 20 ° C.

After dissolution, the whole is nitrogen and stirred at about 20 ° C. for 6 hours to begin to produce a gum-like precipitate after about 1 hour and 30 minutes. 30 cm 3 of water and 3 cm 3 of formic acid were added, the whole was cooled to 5 ° C., vacuum filtered, washed with water containing 10% of formic acid, the residue was washed with water containing triethylamine, and the residue was triethylamine. It is dissolved in about 30 cm 3 of water at about 5 ° Celsius.

3 cm3 of formic acid is added at 5 ° C and the precipitate formed is vacuum filtered, which is then washed with water containing formic acid to form an atherosclerosis and the dark brown gum is removed. The aqueous phase is collected and treated with charcoal to give a clear yellow solution. After saturating with ammonium sulfate, the precipitate is vacuum filtered, and the precipitate is vacuum-filtered with water to obtain precipitate A.

The mother liquors are then saturated with ammonium sulfate to precipitate a precipitate which is washed three times with a small amount of water after vacuum filtration to obtain precipitate B. The precipitates A and B are collected together, taken with ethanol, stirred at 20 ° C. for 1 hour, left at 0 ° C. for 16 hours, vacuum-filtered ethanol washing, ether washing and drying in vacuo to obtain 3.47 g of the target isomer.

This product is the same as that obtained in Examples 4 and 6.

Example 21

Diethylamine salt of 3-acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2-methoxyimino acet amido] -cep-3-m 4-carboxylic acid, isotope

Step A: ethyl 2-acetyl 2-methoxy imino acetate

4.69 kg of ethyl 2-acetyl 2-hydroxy amino acetyl acetate corresponding to 4.21 kg of pure product was added to 21 L of pure acetone, and 6.1 kg of potassium carbonate was added at 20 ° C-25 ° C, and the suspension was shaken for 10 minutes. Then add 3.72 kg of dimethylsulfate at 20 ° -25 ° C. The whole was stirred at 20 ° -25 ° C. for 3 hours, poured into 126 liters of demineralized water, extracted four times with 5 liters of methylene chloride, and extracted again with 2 liters. The whole was washed with 10 liters of demineralized water, dried and vacuum filtered. Rinse with 2 L and dry in vacuo to obtain 4.88 kg of the desired product.

Rf = 0.7 (in silica phase thin layer chromatography, eluent = 9: 1 methyl chloride-ethyl acetate_

단계에서 얻어진 것과 동일하다.The product of Example 3

Same as that obtained in the step.

Step B: ethyl-4-bromo 2-methoxy imino acetyl acetate

3.53 kg of the product obtained in step A was added to 18.6 L of methylene chloride and 3.5 g of paratoluene sulfonic acid, and dissolved in it. A 3.5 L methylene chloride solution of 2.96 kg bromine was added over 30 minutes, wherein the temperature was 22 ° C ± 1 ° C. Maintain °. Fifteen minutes after introduction, hydrogen bromide gas is liberated. The whole is shaken at 22 ° C for 45 minutes, then transferred to another flask and washed twice with 14 L of cooled demineralized water. The washings were extracted twice with 3.5 L of methylene chloride, dried, filtered, washed with methylene chloride and distilled under vacuum to obtain 4.73 kg of the target substance.

The product was identical to that obtained in step B of Example 3.

Step C: ethyl 2- (2-amino 4-thiazolyl) 2-methoxy iminoacetate, isomer

1.43 kg of thiourea is added to 3.55 L of ethanol and 7.1 L of demineralized water. The whole is shaken for 10 minutes at 20 ° C., and then 4.730 kg of 3.55 L ethanol solution of the product obtained in the above step at 25 ° C. is added. The whole was shaken at 20 ° -25 ° C. for 3 hours, neutralized to pH 7 with about 1.6 L of 22 ° C. ammonia. The whole was further shaken again at 20 ° -25 ° C. for 15 minutes, followed by vacuum filtration and washing 5 times with 1.8 L of demineralized water to obtain 2.947 kg of the desired product. (Melting point: 162 ° C)

단게에서 얻어진 것과 동일하다.The product was the same as A in Example 3

It is the same as that obtained in the step.

Stage D: ethyl 2- (2-tritylamino 4-thiazolyl) 2-methoxyiminoacetate, isomer

3.41 kg of the product obtained in the step C was added to a mixture of 17 l of methylene chloride and 2.275 l of triethylamine, and the whole was shaken for 15 minutes, and 4.5 kg of trityl chloride was added over an hour while shaking was continued.

When the whole is stirred under nitrogen at 20 ° -25 ° C. for 20 hours, triethylamine hydrochloride crystal is precipitated.

The liquid was poured into another flask, washed with cooled 0.5 N hydrochloric acid and 10.2 liters, washed twice with 10.2 liters of demineralized water, and extracted with 1.7 liters of methylene chloride, dried, filtered and washed with 1.7 liters of methylene chloride. Vacuum drying under vacuum at temperatures below 50 ° C. yields 8.425 kg of crude product.

This product was dissolved again in 20 liters of 8.4 liters of methanol at 20 ° -25 degrees Celsius, and 2.8 liters of demineralized water was added over an hour at 20 degrees -25 degrees Celsius and the crystals began to precipitate. Further shaking and vacuum filtration were made into atherosclerosis twice with 1.7 L of methanol containing 25% water and dried at 40 ° C. to obtain 7.165 kg of the desired product.

The product was the same as that obtained in Step B of Example 3.

Step E: 2- (2-tritylamino 4-thiazolyl) 2-methoxy amino acet amido acid, isotope

4.175 kg of the product obtained in the above step D was added to 20.9 L of ethanol and the whole was refluxed under shaking and nitrogen. Complete solution is obtained from 55 ° C.

After the introduction of approximately 5.235 L of 2N-sodium hydroxide while refluxing under nitrogen, crystals precipitate rapidly. The whole is stirred under reflux while refluxing under nitrogen and kept at 20 ° -25 ° C for about 2 hours. After holding again for about 2 hours at -25 °, washed 4 times with 2.1 L of ethanol and dried after vacuum filtration to obtain 4.02 kg of the target product.

Stage F: 2- (2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid, isomers

500 g of the product obtained in the above step E (commercially used in 440 g of the dried product) were added to 2.5 l of methylene chloride, and then, approximately 2 L of 1N hydrochloric acid was added under nitrogen at 2 ° C. for 2 minutes while stirring, and the whole was added under nitrogen. Further shake for 2 hours at 20 ° -25 ° C. The methylene chloride phase is discarded and the washing solution washed three times with 2 L of demineralized water is collected, extracted with 1 L methylene chloride, dried and 25 g of charcoal is added. After vacuum filtration, the mixture is washed with methylene chloride and evaporated to dryness to obtain crude product 481 g. They were taken in 2.1 L of dizopropyl ether, vacuum filtered, washed twice with 420 cm 3 of izofuropropyl ether, and dried in vacuo until constant weight was obtained to obtain 424.6 g of the target product.

The product was identical to that obtained in step C of Example 3.

Step G: 3-Acetoxymethyl 7- [2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acet amido] -CE-3M 4-carboxylic acid, isoisomeric diethylamine salt

200 g of 2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acetate and 1200 cm 3 of methylene chloride obtained in step F above were added to a flask.

When the suspension is stirred and heated under argon etc., 600 cm 3 of methylene chloride is distilled off at normal pressure. The excess is stirred for 1 hour at 18-20 degrees Celsius, and at this temperature 61.4 g of 7-amino sephalosporanic acid is dissolved in 900 cm 3 of methylene chloride and 63 cm 3 of triethylamine, and an immediate solution is added for 15 minutes. These were stirred for 1 hour and 30 minutes at 20 ° C. (pH = 6.5-7), 50 cm 3 of acetic acid was added and stirred at 20 ° C. for 15 minutes, followed by vacuum filtration to remove the first 7-amino sephalosporonic acid. do. It is then washed four times with 200 cm 3 of methylene chloride. The organic solution is washed three times with 400 cm 3 of demineralized water and then dried over magnesium sulfate. Vacuum filtration, washing twice with 200 cm 3 of methylene chloride, distilling under vacuum argon and the like to dry. The dried oily residue is dissolved by stirring in 700 cm 3 of dioxane at 20 ° -25 ° C. under argon. 300 cm 3 of the dioxane-methylene chloride mixture is distilled under vacuum at 30 ° C. or lower under argon. The remainder was added to 500 cm 3 of emulsified ether and 52 cm 3 of diethylamine while maintaining the temperature at 20 ° ± 2 ° Celsius. After about 10 minutes the diethylamine salt of 2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acetic acid is crystallized. It is left to stand for 1 hour at 20 ° C under argon and then vacuum filtered and washed three times with 100 cm 3 of dioxane-emulsified ether solution. 113.6 g of dried dimethylamine salt was dried. The organic solution is precipitated in 3.25 L of dizopropyl ether with stirring for at least 30 minutes, and again for 15 minutes with stirring for 15 minutes, followed by stirring for 15 minutes and vacuum filtration under vacuum. It was washed twice with 400 cm 3 of dizopropyl ether and dried under vacuum to afford 182 g of the same product as obtained in Example 5.

Example 22

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy iminoacet amido] -sef-3-m 4-carboxylic acid, isomer

As the material obtained in Example 21 182g at 28 ° -30 ° stirred under argon to a 347cm ³ of acetic acid and deionized mineral can 87cm ^3. Dissolution and crystallization of triphenyl chitenol occurs. After stirring under argon for 2 hours and 30 minutes at 28 ° -30 ° C, the mixture was precipitated with 1740 cm 3 of demineralized water and 847 g of ammonium sulfate for at least 15 minutes, followed by stirring for 30 minutes. Vacuum filtration and washing twice with 174 cm 3 of demineralized water followed by vacuum drying at 25 ° -30 ° C. yield 147 g of a mixture of the expected material and triphenyl carbinol.

Vacuum filtration, washing twice with 147 g of emulsified ether and drying at 25 ° -30 ° C. yielded 89 g of the expected material.

The foreign material is stirred and made into an ointment in 445 cm3 of ethanol under nitrogen. The suspension is maintained at 45 ° -50 ° C. with stirring and in this state for 1 hour. This was vacuum vacuumed, washed twice with 45 cm 3 of ethanol and vacuum dried at 20 ° C. to yield 76.85 g of the expected material. This material is added to 230 cm 3 of acetic acid, stirred for 15 minutes under nitrogen, etc., 77 cm 3 of demineralized water is added, and 700 cm 3 of water is added to the solution. Stir for 1 hour at 18 ° -20 ° C, add 269 g of ammonium sulfate for at least 10 minutes, leave for 15 minutes, and add 3.85 g of activated carbon. The mixture was stirred for 15 minutes and again filtered through a vacuum to agitate 25% acetic acid, followed by vacuum filtration and washing with 77 cm 3 of deaerated water containing 25% acetic acid.

154 cm 3 of acetic acid is stirred and added at 15 ° -20 ° C and the first amount of the final material crystallizes. The mixture is left for 2 hours with stirring at 18 ° -20 ° C, and then left for 2 hours at 0 ° -5 ° C. After vacuum filtration, washing four times with 77 cm 3 of demineralized water containing 5% acetic acid and then vacuum drying at 20 ° -25 ° C. yielded 49.45 material in acetate form.

The resulting acetate was prepared as an ointment in ethanol 250 cm 3 with stirring for 1 hour at 45 ° -50 ° C and then left at 18 ° -20 ° C for 1 hour. Vacuum filtration and wash twice with 50 cm 3 of ethanol. Drying under vacuum at 20 ° C. and then left at 35 ° -40 ° C. for 10-15 hours yielded 45.45 g of the expected material.

=+64.5°Non-luminescence

= + 64.5 °

(At a concentration of 0.5% in water containing 0.5% of sodium bicarbonate)

This material is the same as that obtained in Examples 4, 6 and 20.

Example 23

Crystalline sodium salt of 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxyamino acetamino] -cep-m 4-carboxylic acid, isomer

Isotopes obtained in Examples 4, 6, 20 or 22,

19.8 g of 3-acetoxymethyl 7- [2- (2-4-thiazolyl-2-methoxy amino acet amido] -sef-3-m4-carboxylic acid is dissolved in 65 cm 3 of a mixed solution of sodium acetate and methanol The mixture was left to crystallize at room temperature for 35 minutes, and 40 cm3 of ethanol was added for 1 hour or more, followed by stirring for 2 hours and 30 minutes in a cold bath, followed by vacuum filtration, followed by 10 cm3 of methanol-ethanol (1: 1) mixed solution. Twice, twice with 10 cm 3 of ethanol and twice with 20 cm 3 of ether, 16 hours of drying in a desiccator under vacuum at sulfuric acid for 2 hours under vacuum at 45 ° C. to give 16.191 g of crystalline material.

To avoid contact with atmospheric humidity, the physical constant of the material is:

Moisture Content (Knife.Fitshire) = 0.2%

Assay: C ₁₆ H ₁₆ O ₇ N ₅ S ₂ Na = 477.5

Calculation: C% 40.24 H% 3.38 N% 14.67 S% 13.43 Na% 4.81

39.9 3.5 14.5 13.1 4.8

If left in the air, rehydration occurs.

X-ray spectra (Debbie Scheller) can confirm the crystalline nature of the product. Izofuropanol can be used equally in place of ethanol for the expected crystallization of the product.

Example 24

Crystalline sodium salt of 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy aminoacet amido] -cep-3-m 4-carboxylic acid, isomer

Stage A: Methyl 7-acetoxy- [2 (2-amino 4-thiazolyl) 2-methoxy amino acet amido] -cep-3-m 4-carboxylic acid, isomers and acetic acid

Diethylamine of 3-acetoxy-methyl 7- [2- (2-tritylamino 4-thiazolyl) 2-methoxy amino acetamido] -cep-3-m 4-carboxylic acid prepared in Example 5. 87.2 g of salt is added to the mixed solution of 200 cm 3 pure pure acid and 220 cm 3 water with slight stirring. Stir at 50 ° C. for 30 minutes, cool and filter to remove 30.1 g of triphenyl carbinol.

450 cm 3 of water is sparged into the filtrate and some precipitate is removed with carbon. And concentrated at 40 ° C. under vacuum until a precipitate is formed. 200 cm 3 of absolute ethanol are added, cooled with ice, filtered, washed with ethanol and ether and dried in vacuo.

Analysis: C ₁₆ N ₁₇ N ₅ O ₇ S ₂ HCO ₂ HH ₂ O; Molecular Weight = 541.5

Calculation: C% 39.3 H% 4.08 N% 13.48 S% 12.34 H2O 3.46

Stage B: Crystalline Sodium Salt

15 g of the pure solvent obtained in the step A was dissolved in 75 cm 3 of methanol, and the solution was treated with 4.5 g of acetonitrile and 3 g of activated carbon, filtered, and kyoba, and 5 cm 3 of zopropane was added. After 16 hours at 0 °, the crystals are separated, washed with ethanol and ether and dried for 2 hours under reduced pressure at 50 ° C to yield 7.95 g of product. It keeps its shape in air for a while and disassembles as follows.

C ₁₆ H ₁₆ N ₅ NaO ₇ S ₂ = 495.5

Calculation: C% 38.78 H% 3.66 N% 14.14 Na 4.64 S% 12.94

38.6 3.7 13.8 4.6 13.2

Example 25

Amorphous sodium salt of 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acet amido] -sef-3-M 4-carboxylic acid isomer

a) 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acet amido] -cep-3-m 4-carboxylic acid

52 g of the mixture of acetic acid and the solvent obtained in step 24A and ethanol in an isotropic group was dissolved in a mixture of 3 L of 96% ethanol and 350 cm 3 of water, and concentrated in vacuo until the volume reached 300 cm 3. Crystallization begins to occur during concentration, after cooling for 1 hour in a cold bath, filtration, washing with a small amount of ethanol and vacuum drying at atmospheric temperature in the presence of concentrated sulfuric acid to give 44 g of product.

Analysis: C ₁₆ H ₁₇ N ₅ O ₇ S ₂ 0.8 C ₂ H ₅ OH; Molecular Weight = 492.3

Calculation: C% 42.94 H% 4.46 N% 14.23 S% 13.02

43.0 4.4 14.1 12.9

B) amorphous sodium salt

3 g of the solvent obtained in step A is dissolved in 60 cm 3 of water at 0 ° C with ethanol, and 0.0504 g of sodium bicarbonate dissolved in 6 cm 3 of water is added with stirring, maintaining its form in air for a while and decomposing as follows: .

C ₁₆ H ₁₆ N ₅ NaO ₇ S ₂ 1.5H ₂ O; Molecular Weight = 504.47

Calculation: C% 38.09 H% 3.8 N% 13.88

38.2 3.8 13.6

Example 26

Crystalline sodium salt of 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acet amido] -CE-3M 4-carboxylic acid, isomer

3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] -cep-3-M 4-carboxylic acid obtained by Examples 4,6,20,22 5 cm 3 of ethanol is added to 4.95 g of isomers, and 10 cm 3 of an aqueous sodium bicarbonate solution is added to the mixture with stirring on a cold water bath. After dissolution, 15 cm 3 of ethanol is added, concentrated in vacuo at 30 ° C., and dissolved in 15 cm 3 of ethanol to initially crystallize. If left in the refrigerator overnight, 3.407 g of crystallized product is separated.

Example 27

Crystalline sodium salt of 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy aminoacet amido] -cep-3-m 4-carboxylic acid, isomer

0.1 g of the amorphous sodium salt obtained in Example 25 was dissolved in 20 cm 3 of methanol and slowly added with stirring of 0.25 cm 3 of n-butanol.

It is cooled to 6 ° C. in the refrigerator for 48 hours. The crystals were washed with mild cold methanol and dried in vacuo at 40 ° C. for 3 hours in vacuum to yield 0.2 g of crystalline product.

The product stays in shape for a while in the air.

Analysis: C ₁₆ H ₁₆ N ₅ NaO ₇ S ₂ 1.5H ₂ O; Molecular Weight = 504.47

Calculation: C% 38.09 H% 3.8 N% 13.88 O% 26.96

38.2 3.8 13.6 27.1

Similar operation results in slightly different forms of crystals, for example, containing 0.5 mole of water, 1 mole of water, and 1 mole of methanol.

The product obtained above is confirmed by X-ray spectra (Debbie Schiller).

Example 28

The following formulations are prepared for injection.

Example 29

Injectable preparations with the following ingredients:

Example 30

Injectable preparations with the following ingredients

Example 31

Injectable preparations of the following prescription

Example 32

Gelatin capsules by the following prescription

Example 33

Gelatin capsules by the following prescription;

Example 34

Gelatin capsules of the following prescription;

Claims (1)

3-acetoxymethyl-7- (imino acetamido) as represented by the following formula (I) characterized by reacting a 7-amino cephalosporranic acid with an acid as represented by the following formula (II) or a reactive derivative thereof -Preparation method of cephalosporan acid derivatives.

In the above structural formula, R is hydrogen or a group selected from the group which can be easily removed by acid hydrolysis or hydrogenolysis, and R ₁ is hydrogen C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl or alky It can be easily removed by nil or acid hydrolysis or hydrogenolysis. It is a group selected from the group. A is an alkaline earth metal, magnesium, or an organic amine base such as hydrogen or an alkali metal, except that R ¹ is acid hydrolysis. R is the same group if the group can be easily removed by hydrogenolysis, and R is hydrogen when the R ¹ is hydrogen.

Means that the OR ¹ group can be geometrically in the syn- or anti-position.