KR830000566B1 - Method of Preparation of 3-Halomethyl Sepem - Google Patents

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Description

Method of Preparation of 3-Halomethyl Sepem

The present invention relates to the preparation of 3-halomethyl cefem of formula (I), which is an intermediate useful for the preparation of cephalosporin-based antibiotics.

Wherein X is fluorine, chlorine, bromine or iodine,

q is 1 or 0,

R is a carboxylic acid protecting group,

R ₁ is hydrogen or methoxy

R ₂ is (1) an imide group of the following formula (IV)

Wherein R ₄ is C ₂ -C ₄ alkenylene, 1,2-phenylene or 1,2-cyclo hexenyl

(2) Amido groups of the following formula (V)

[Where R ₃ is

(a) hydrogen, C ₁ -C ₃ alkyl, halomethyl, 3- (2-chlorophenyl) -5-methyl isoxazol-4-yl or 4-protected amino-4-protected carboxybutyl

(b) benzyloxy, 4-nitro benzyloxy, 2,2,2-trichloro ethoxy, tert-butoxy or 4-methoxy benzyloxy

(c) -R '' group wherein R '' is 1,4-cyclo hexadienyl, phenyl or halogen, protected hydroxy, nitro, cyano, trifluoromethyl, C ₁ -C ₃ alkyl or Phenyl substituted one or two with C ₁ -C ₇ alkoxy)

(d) an arylalkyl group of the following formula (VI)

R ''-(O) _m- (CH ₂ )-(VI)

(Where R '' is as described above and m is 0 or 1)

(e) a substituted arylalkyl group of the formula

(R '' 'is R' ', 2-chienyl, 3-chienyl bromo-2-chienyl or bromo-3-chienyl as described above and W is protected hydroxy or Protected amino)

Or (f) a heteroarylmethyl group of the formula

R '''-CH _2- (Ⅷ)

(R '' 'in this case is 2-chienyl, 3-chienyl, 2-furyl, bromo-2-chienyl, bromo-3-chienyl, bromo-2-furyl, 2-thiazolyl, 5-tetrazolyl, or 1-tetrazolyl)

Or (3) an imidazolidinyl group of the following formula (IX).

(Wherein R '' 'is as described above and Y is acetyl or nitrozo)

∼20℃에서 활성할로겐화제 존재하에 3-메틸텐 세팜을 저급알코올의 알칼리 금속염 또는 바이 사이클릭 아미딘 염기와 반응시킴을 특징으로 하는 신규방법에 의해 제조된다.3-halomethyl-3-cepem is -80

Prepared by a novel process characterized by reacting 3-methyltencepam with an alkali metal salt of lower alcohol or a bicyclic amidine base in the presence of an active halogenating agent at -20 ° C.

내지 0℃에서 활성브롬화제 존재하에 3-메틸렌 세팜을 저급인 제1급 알코올의 알칼리 금속염과 반응시켜 제조한다.Especially 7-alkoxy-3-bromomethyl-3-cepem is -80

Prepared by reacting 3-methylenecepam with an alkali metal salt of a lower primary alcohol in the presence of an active brominating agent at from 0 ° C.

내지 0℃에서 제3급-부틸 하이포클로 라이트 존재하에 3-메틸렌 세팜의 저급인 제1급 알코올의 알칼리 금속염과 반응시켜 제조한다.In addition, 7-alkoxy-3-chloro methyl-3-cepem is -80

Prepared by reacting with an alkali metal salt of a lower primary alcohol of 3-methylene sepam in the presence of tert-butyl hypochlorite at -0 ° C.

3-halomethyl cefem is a substance known to the cephalosporin family and has proven to be a useful intermediate for the preparation of many cephalosporin antibiotics by nucleophilic substitution of halogen atoms. 3-halomethyl cefem is prepared by allylic halogenation of the corresponding desceroxe cephalosporin compound (see US Pat. Nos. 3,637,678 and 3,705,897) or halogenation of the corresponding descececeloposporin (see US Pat. No. 3,658,799). Has been. Recently, 3-acetomethyl and 3-carbamoyloxymethylcepem were digested with halogenated hydrochloric acid to prepare 3-halomethylcepem.

The preparation of 3-halomethylcepem as described in British Patent No. 1,407,348 first involves reacting 3-methylenecepam with free halogen and then reacting the resulting 3-halo-3-halomethylcepam with a base. Coppell and Kohler have announced a process for the 3-acetoxymethyl cefem to 7-methoxylization with lithium methoxide and tert-butyl hypochlorite. (See J. Am. Chem. Soc. 95, 2403-04 (1973)).

∼20℃에서 불환성 유기용 매중에서 반응시켜 상기 일반식(Ⅰ)의 3-할로메틸세펨 화합물을 제조하는 신규 방법에 관한 것이다. 이때 사용되는 할로겐화제는3급-부틸 하이포클로라이트, 브롬, 3급-부틸 하이포브로마이트, 요오다인 모노브로마이드, 1,5-디아자바이사이클로 [5,4,0] 운덱-5-엔, 하이드로-브로마이드 퍼브로마이드, 요오드, 요오다인 모노클로라이드, 3급-부틸 하이포요오다이트 및 퍼클로릴 플루오라이드 중에서 선택한다.The present invention relates to 3-methylcepam having the following structural formula (II) in the presence of 1-6 equivalents of an active halogenating agent, or a 3-6 equivalent alkali metal salt of secondary C ₁ -C ₇ alcohol or primary or tertiary C ₁ -C ₇ -1 equivalent to 3 equivalents of alkali metal salt of alcohol or bicyclic amidine base of the following structural formula (III)

It relates to a novel process for producing 3-halomethylcefem compound of the general formula (I) by reacting in a non-cyclic organic solvent at -20 ℃. The halogenating agent used here is tert-butyl hypochlorite, bromine, tert-butyl hypobromite, iodidine monobromide, 1,5-diazabicyclo [5,4,0] undec-5-ene, hydro -Bromide perbromide, iodine, iodide monochloride, tert-butyl hypoiodite and perchloryl fluoride.

(Wherein z is 3,4 or 5 and q, R, R ₁ are as described above and R ₅ is the same as R ₂ )

However, when using alkali metal salts of primary C ₁ -C ₇ alcohols with tert-butyl hypochlorite, R ₁ must be methoxy and R ₅ is bromochienyl acet in the compounds of formulas (I) and (II). Neither amido nor bromofuryl acetami.

In the above definition of the invention, "C ₁ -C ₃ alkyl" is methyl, ethyl, n-propyl or isopropyl. "C ₁ -C ₇ alkoxy" is a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, cyclohexyl oxy or benzyl oxy. Examples of `` alkali metal salts of C ₁ -C ₇ alcohols '' are lithium methoxide, sodium ethoxide, potassium ethoxide, lithium butoxide, sodium benzyloxide or sodium n-propoxide. Representatives of “alkali metal salts of secondary C ₁ -C ₇ alcohols” are sodium isopropoxide, lithium secondary-butoxide, sodium cyclohexylside and potassium cyclohexyloxide. Examples of “alkali metal salts of tert-C ₁ -C ₇ alcohols” include potassium tert-butoxide, sodium 1-methylcyclohexyloxide, potassium 2-methyl-2-butoxide and lithium tert-butoxide. .

A "halomethyl" group is, for example, fluoromethyl, chloromethyl, bromomethyl or iodomethyl. Immersion groups in which R ₄ is C ₂ -C ₄ alkenylene are for example maleimido, 3-ethylmaleimido or 3,4-dimethylmaleimido R ₄ is 1,2-cyclohexenylene or 1,2- Imido groups which are phenylene are 2,3,5,6-tetrahydro phthalimido or phthalimido, respectively.

In the above definition, when R '' is a substituted phenyl group, R '' is 4-chloro phenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl 3,4-dichloro phenyl, 3-chlorophenyl, 3-bromo Mono- or di-substituted halophenyl groups such as phenyl, 4-bromo phenyl, 3,4-dibromophenyl, 3-chloro-4-fluoro phenyl or 2-fluoro phenyl, or 4-benzyl oxyphenyl, 3- Benzyloxyphenyl, 4-tert-butoxyphenyl, 4-tetra hydropyranyl oxyphenyl4- (4-nitro-benzyloxy) phenyl 2-phenacyloxyphenyl, 4-benzhydryloxyphenyl or 4-tri Protected hydroxyphenyl groups such as yloxyphenyl or cyanophenyl groups such as 3-nitrocyanophenyl or 4-methylphenyl, 2,4-dimethylphenyl, 2-ethylphenyl 4-isopropylphenyl, 4-ethylphenyl or 3-n Mono or dialkyl substituted phenyl groups such as -propylphenyl or mono or dialkoxyphenyl groups (e.g., 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4- Is a butoxy phenyl or 3-ethoxy-4-methoxyphenyl) propoxy-phenyl, 4-tert. In addition, R '' is a disubstituted phenyl group and the substituents may be different from each other, for example, 3-methyl-4-methoxyphenyl, 3-chloro-4-benzyloxyphenyl, 2-methoxy-4-bromo Phenyl 4-ethyl-2-methoxyphenyl, 3-chloro-4-nitrophenyl or 2-methyl-4-chlorophenyl.

"Protected amino" in the above definition means tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitro-benzyloxycarbonyl or 2,2,2-trichloroethoxycarbon It refers to an amino group substituted with one of the amino protecting groups commonly used, such as a silyl group. Conventional amino protections described by J. W., Barton are recognized to be suitable and are described in “Protective Groups in Organic Chemistry”, J.F.W. McOmie, Ed. Plenum Press, New York, N.Y., 1973, Chapter 2.

"Protected hydroxy" means formyloxy group, chloroacetoxy group, benzyloxy group, benzhydryloxy group, tritylbenzyloxy group, 4-nitrobenzyloxy group trimethylsilyloxy group, phenacyloxy group, tertiary part It means a group that is easily decomposed to form a hydroxyl group, such as a oxy group, a methoxy methoxy group, a tetrahydropyranyloxy group, and the like. Other hydroxy protecting groups described by C, B, Leeds in "Protective Groups in Organic Chemistry", supra, Chapter 3 also belong to the "protected hydroxy" used in the present invention.

"Protected carboxy" refers to a carboxy group protected with one of the commonly used carboxylic acid protecting groups, wherein the protecting group blocks or protects the function of the carboxylic acid while allowing other functional groups of the compound to react. Such protected carboxyl groups should be readily degraded by hydrolysis or hydrocracking to the corresponding carboxylic acids. Examples of carboxylcin ester protecting groups include methyl, tert-butyl, benzyl, 4-methoxybenzyl, C ₂ -C ₆ alkanoyloxymethyl, 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl (benz hydryl), Phenacyl, 4-halofenacyl, 2,2,2-trichloroethyl, succinimidomethyl and tri (C ₁ -C ₃ alkyl) silyl. This has been recognized by Hasram as a suitable carboxyprotector of other bases described in "Protective Groups in Organic Chemstry", supra, Chapter 5. The nature of these ester forming groups is not a problem as long as the specific ester formed is stable under the reaction conditions described later. Suitable as carboxylic ester protecting groups are tert-butyl, 4-methoxybenzyl, benzhydryl, 4-nitrobenzyl and 2,2,2-trichloroethyl.

In the above definition, hydroxy, amino and carboxy protecting groups are not fully defined. The function of these groups should be removed without damaging the reaction product after preparation to protect the reaction functionality during the preparation of the desired product. Many of these protecting groups are well known in the art and it is also suitable to use other groups which are equally applicable to the process of preparing the compounds of the present invention.

In addition, the properties of the side chain groups R ₂ and R ₆ are not a problem in the preparation of the compound of the present invention, that is, the process of converting 3-methylenecetim to 3-halomethylcefe. However, care should be taken because some side-chain groups, especially those having chienyl or furyl groups, are prone to halogenation of heteroaryl groups under the reaction conditions of the preparation process of the present invention. However, special care should be taken, such as using halogen removers, preferably with lowering reaction temperatures, to minimize the possibility of halogenation of the side chains involved during the manufacturing process of the present invention as described below. The side chain halogenation that may occur because the side chains on the product and the compounds derived therefrom are often continuously degraded and the resulting nuclear esters are acylated again does not affect the process of the invention. .

Representative examples of the amido group of the structural formula (V) as defined above are acetamido, propionamido, butylamido, 2-pentenoylamido, chloroacetamido, bromoacetamido and 5-3 grade Butoxycarbonylamino-5-tert-butoxycarbonyl valeramido.

Examples of specific amido groups of formula (V) wherein R ₃ is R '' include benzamido, 2,6-dimethoxybenzamido, 4-chlorobenzamido, 4-methylbenzamido, 3,4- Dichlorobenzamido, 4-cyanobenzamido, 3-bromobenzamido and 3-nitrobenzamido.

Amido groups of formula (V) wherein R ₃ is formula (VI) and m is 0, for example cyclohexa-1,4-dienylacetamido, phenylacetamido, 4-chlorophenylacetamido, 3 -Methoxyphenylacetamido, 3-bromophenyl acetamido, 3-methoxyphenylacetamido, 4-nitrophenylacetamido, and 3,4-dimethoxyphenyl acetamido with m being 1 Representative amido groups are phenoxyacetamido, 4-cyanophenoxyacetamido, 4-chlorophenoxyacetamido, 3,4-dichlorophenoxy cyacetamido, 2-chlorophenoxy acetamido, 4 -Methoxyphenoxy acetamido, 2-ethoxyphenoxy acetamido, 3,4-dimethylphenoxy acetamido, 4-isopropylphenoxy acetamido, 3-cyanophenoxy acetamido and 3 Nitrophenoxy acetamido.

Examples of the amido group of the structural formula (V) when R ₃ is the structural formula (VII) and W is hydroxy protected are 2-formyloxy-2-phenylacetamido, 2-benzyloxy-2- (4-meth Methoxyphenyl) acetamido, 2- (4-nitrobenzyloxy) -2- (3-chlorophenyl) -acetamido, 2-chloroacetoxy-2- (4-methoxyphenyl) acetamido, 2 -Benzyloxy-2-phenylacetamido, 2-trimethylsilyloxy-2- (4-chlorophenyl) acetamido and 2-benzhydryloxy-2-phenylacet amido. Examples of the amido group of structural formula (V) when W is an amino group protected include 2- (4-nitrobenzyloxycarbonylamino) -2- (2-chienyl) acetamido, 2- (2,2, 2-trichloroethoxycarbonylamino) -2-phenylacetamido, 2-chloroacetamido-2- (1,4-cyclo hexadien-1-yl) acetamido, 2- (4-meth Methoxy benzyloxy carbonylamino-2- (4-methoxyphenyl) -acetamido, 2-benzhydryloxycarbonylamino-2- (3-chienylacetamido and 2- (1-carbomethoxy -2-propenyl) amino-2-phenylacet amido.

Examples of the amido group of the structural formula (V) when R ₃ is a structural formula (V) include chienyl acetamido, 3-chienyl acetamido, 2-furyl acetamido, and 2-chiazolyl of the following structural formula Acetamido.

1-tetrazolylacetamido of the formula

5-tetrazolylacetamido of the formula

Or 3- (2-chlorophenyl) -5-methylisoxazol-4-ylamido group of the following structural formula.

Representative examples when R ₂ and R ₅ are imidazolidinyl groups of the formula ( ₂ ) include 2,2-dimethyl-3-nitrozo-5-oxo-4-phenyl-1-imidazolidinyl group, 2, 2-dimethyl-3-acetyl-5-oxo-4- (4-cyclohexadien-1-yl) -1-imidazolidinyl group and 2,2-dimethyl-3-nitrozo-5-oxo-4- (2-chienyl) -1-imidazolidinyl group.

Preferred amido groups are formamido, acetamido, 4-nitrobenzyloxy carbonylamido, phenoxyacetamido, phenylacetamido and 2-chienylacetamido; phenylacetamido and phenoxy acetami Is most preferred.

Generally, 7-alkoxy-3-bromomethylcepem is prepared by reacting 3-exo methylenecepam with an alkoxide base in the presence of an active brominating agent according to the process of the present invention.

The properties of the 7-alkoxy substituents on the cefe as a product are determined by the particular primary alkoxide base used in the reaction process. Thus, for example, using lithium ethoxide produces 7-ethoxy-3-halomethylcefem.

3-exomethylenecepam of formula (II), the starting material in the process of the present invention, was first disclosed as a generic class in US Pat. No. 3,275,626. 7-amino and 7-acylamido 3-exo methylenecepam can be used to electroreduce the corresponding cephalosporin compounds having a 3-substituted methyl group such as acyloxymethyl, acylthiomethyl or quaternary ammonium methyl (pH 2-7). (See US Patent No. 3,792,995). Optionally, the starting material of the present invention, exomethylenecepam, is described in Al. Journal of Organi Chemistry, 38, 2994 (1973). egg. Schaubet and P. a. It can be prepared by the process of Pennington, where 3-methylenecepam may be prepared from cephalosporanic acid, first containing sulfur-containing nucleophilic acid selected from thiourea, thibenzoic acid, potassium ethyl xanthate or sodium thiosulfate. The drug is reacted with cephalosporranic acid and then the reaction product, C _3- (substituted) chimethylcepem derivative, is prepared by reduction with Raney nickel or zinc in formic acid-dimethylformamide solution in aqueous ethanol solution. The cephalosporranic acid derivatives are also converted to 3-exo methylenecepam when treated with a crop (II) salt in a solvent. 3-exo methylenecepam sulfoxide, the starting material used in the process of the present invention, is prepared by oxidation of the corresponding sulfide with an equivalent amount of metachloro and benzoic acid. 3-exo-methylenecepam having a 7-methoxy group can be prepared by the same method as described in the literature cited above for the production of unsubstituted 3-exo methylenecepam compound from the corresponding 7-methoxy sephalosporan acid. have.

The living organism of the process of the present invention is 3-halo methylcefe. "Halomethyl" refers to chloromethyl, bromomethyl, uridomethyl, or fluoromethyl, and whether the living organism is any derivative of chlorine, cancellation, iodine or fluorine depends upon the choice of active halogenating agent used in the present invention. Suitable active halogenating agents for the process of the present invention are: tert-butylhypochlorite to form 3-chloromethylcepem; bromine to form 3-bromomethylcepem, 1,5-diazabi Cyclo [5,40] undec-5-enhydrobromide perbromide, iodide monobromide and tert-butylhypobromite; iodine to form 3-ureth methylcefem, iodide mornechloride and tert-butyl hypo Iodide and perchloryl fluoride to form 3-fluoromethyl cefem.

Although the method of mixing the reaction reagent used in the process of the present invention is not a problem, it is most preferable not to react the starting material exo methylenecepam with a base in the absence of a halogenating agent. However, it should be noted that the base used in the process of the present invention reacts with exomethylene cepam and forms desacetoxymethyl cephalosporin without changing the reaction rate depending on the reaction temperature without a halogenating agent. Such conversions are reported in the following chemical literature.

[R. See R. Chauvette and P. A. Pennington, Journal of Organic Chemistry, 38, 2994 (1973)]

Therefore, if the base is mixed with exomethylenecepam, it is preferable to add the halogenating agent to the mixture in advance, or to add the halogenating agent immediately after mixing. The conversion of 3-exo-methylenecepam to 3-halomethylcepem typically involves the actuation of a substrate, 3-exo methylenecepam, with an alkali metal salt of bicyclic amidine base or C ₁ -C ₇ alcohol in an organic solvent. It is carried out by adding to the reaction solution of the halogenating agent.

Any of a wide range of inert organic solvents can be used as the medium for the halogenation process of the present invention. The term "inert organic solvent" as used herein refers to an organic solvent that does not cause any reaction with reactants or living organisms under the conditions of the manufacturing process. What aprotic organic solvents are preferred. Very small amounts of water present in commercially available anhydrous solvents can be tolerated, but in general the process of the present invention is preferably carried out under anhydrous conditions.

Suitable organic solvents include, for example, aromatic hydrocarbons such as benzene, chlorobenzene, toluene, ethylbenzene, xylene; Aliphatic hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane (ethylene collide), 1,1,2-trichloroethane and 1,1-dibromo-2-chloroethane; Aliphatic nitriles such as acetonitrile or propion nitrile; Esters such as ethyl acetate and butyl acetate; ; Esters such as 1,4-dioxane, tetrahydrofuran, diethyl ether and dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide or hexamethyl formalicamide (HMPA); And other suitable aprotic solvents. Preferred solvents or mixed solvents are those having a freezing point of -10 deg. Very preferred solvents for the process of the invention are methylene chloride, chloroform, 1,2-dichloroethane and tetrahydrofuran. Especially, tetrahydrofuran is the most preferable.

Suitable bases that can be used to effect halogenation of the process of the present invention are bicyclic amidine base groups and alkali metal salts of C ₁ -C ₇ alcohols. Bicyclic amidine bases are represented by structural formula (III) and examples of such bases are 1,4-diaza bicyclo [4,3,0] -5-ene (DBN) and 1,5-diazabicyclo [5,4,0] undec-5-en (DBU).

"Alkali metal salts of C ₁ -C ₇ alcohol" means primary, secondary, such as methanol, ethanol, isopropanol, secondary-butanol, tert-butanol, n-propanol, cyclohexanol, benzyl alcohol or n-hexanol, Sodium, potassium and lithium salts of tertiary-C ₁ -C ₇ alcohols. Examples of such alkoxide bases suitable for the process of the invention are lithium methoxide, sodium methoxide potassium ethoxide, sodium benzyl oxide, potassium tert-butoxide, lithium isopropoxide, sodium n-propoxide and sodium cyclohexyl Oxide.

Among the bases used in the process of the present invention, lithium salts of bicyclic bases and secondary alcohols are preferred, with DBU and lithium isopropoxide being most preferred.

When the starting material of the structural formula (I) wherein the C ₇ substituent on exomethylenecepam (R _{1 in the} above formula) is hydrogen and the alkali metal salt of C ₁ -C ₇ primary alcohol as the base are used in this step, the halogenating agent is 3 It should be noted that it must be something other than butyl-hypochlorite. If tert-butyl hypochlorite is used with a primary alkoxide base, C-7 alkoxylation occurs incidentally with the desired C-3 ′ halogenation. Thus, for example, only C-3 ′ chlorination occurs when using DBU or potassium tert-butoxide as the base and tertbutyl hypochlorite as the halogenating agent. However, if lithium methoxide is used instead of DBU or potassium tert-butoxide, C-3 'chlorination and C-7 methoxylation occur simultaneously, resulting in 7-methoxy-3-chloro-methylcepem.

In carrying out the process of the present invention for converting 3-exo methylenecepam of formula (II) to 3-halomethylcepem of formula (I), secondary to every equivalent of exo methylenecepam in the presence of 1-6 equivalents of a halogenated halogenating agent C ₁ -C ₇ or an alkali metal salt 3-6 equivalents of a primary or tertiary C ₁ -C ₇ between an alkali metal or bicyclic amidines of the alcohol of the alcohol is reacted with 1-3 equivalents of a base. Generally, when using primary or tertiary alkoxides or bicyclic amidine bases, the reaction is carried out using 2-3 equivalents of base and 3-4 equivalents of halogenating agent. Preferably, the reaction is carried out using 3 equivalents of base and 3 equivalents of halogenating agent per 3 equivalents of 3-exo methylenecepam, which is formula (II). However, the use of secondary alkoxide bases is typically carried out using 4-6 equivalents of base and halogenating agent per equivalent of exomethylenecepam of Structural Formula (II), preferably 6 equivalents of each. It should be noted that as the amount of halogenating agent decreases to less than 2.5 equivalents per exomethylenecepam, the corresponding amount of desacetoxy cephalosporin in the reaction organism increases.

When the alkali metal salt of C ₁ -C ₇ alcohol is used as the base in the process of the present invention, it is preferable to add an excess of protic acid to the reaction mixture before the reaction mixture is warmed to above 0 ° C. This optional but preferred procedure is necessary to rule out any undesirable side reactions between the excess base and the living 3-halo methylcepem in the reaction mixture. Both organic and inorganic protic acids are suitable, for example formic acid, acetic acid, propionic acid, trifluoroacetic acid methanesulfonic acid. p-toluenesulfonic acid, hydrochloric acid and sulfuric acid.

C ₇ -alkoxylated-C ₃ '-brominated according to the present invention is 4-8 equivalents of the active bromating agent of exomethylene sepam of formula (II), and 4-8 equivalents of alkali metal salt of primary C ₁ -C ₇ alcohol in the presence of And the product is 7-alkoxybromomethylcepem. It was found that the best yield was obtained when 8 equivalents of an alkoxide base and a brominating agent were used per equivalent of Sepam substrate in the conversion process, and a halogen scavenger (described later on this property) was used.

In the novel process of the invention, 3'-chlorination and C ₇ -alkoxylation occur simultaneously. This conversion reaction is carried out by reacting exo methylenecepam with 1 to 5 equivalents of an alkali metal salt of primary or secondary C ₁ -C ₇ alcohol in the presence of 1 to 5 equivalents of tert-butyl hypochlorite. Preferably, the base and the tert-butyl hypochlorite are reacted by using 3 equivalents each of the equivalent of exo methylenecepam.

∼20℃에서 수행하는데 -80

∼0℃에서 수행하는 것이 바람직하다. 일반적으로 -10

∼40℃의 반응온도가 가장 바람직하다. 그러나 구조식(Ⅱ)인 세팜의 측쇄기도 할로겐화 특히 브롬화시킬 경우에는 본 발명 공정을 -40℃이하의 온도에서 수행하는 것이 바람직하다. 이러한 할로겐화 반응성이 있는 C-7 측쇄로는 2-치에닐-아세트아미도, 3-치에닐아세트 아미도와 2-푸릴아세트아미도가 있다.The process of the present invention is -80

-80 at -20 ° C

It is preferable to carry out at -0 degreeC. Typically -10

The reaction temperature of -40 degreeC is the most preferable. However, in the case of halogenation, especially bromination, of the side chains of the sefam which is the formula (II), it is preferable to carry out the process of the present invention at a temperature of -40 ° C or lower. Such halogenated reactive C-7 side chains include 2-chienyl-acetamido, 3-chienylacet amido and 2-furylacetamido.

It is also preferable to add a halogen scavenger to the reaction mixture when the halogenating agent is a brominating agent, in addition to the fact that it is desirable to carry out the process of the invention at low temperatures when the starting material has substituents reactive with such halogens. Halogen scavenger is used to remove or continuously reduce the possibility of side reactions that may occur between the side chain reactive with halogen and excess halogenating agent present on the starting material and the product, 3-halo methylcepem. To destroy them.

`` Halogen remover '' described in the process of the present invention refers to a sephalt substance, a sebaceous substance, and a reagent capable of reacting with a halogenating agent without reacting with the cefem product of the process of the present invention. Is to ensure that the excess halogenating agent does not react with the 3-halo methylcepem which is the product of the process of the present invention The halogen scavenger typically used in the process of the present invention is a halogen reducing agent and Other halogen scavengers are also suitable, which may optionally prevent further reactions, suitable diols include di (C ₁ -C ₆ alkyl) sulfides, tri (C ₁ -C ₆ alkyl) phosphites, olefins and acetylenes. Similarly, aqueous solutions of known reducing inorganic salts, such as bisulfite, metabisulfite, thiosulfate and dithionite salts, are effective. It can be used.

Sulphite and phosphite halogen scavengers useful in the process of the present invention are, for example, dimethylmesulfide, di-n-propylsulfide, dicyclohexylsulfide, methylethylsulfide, trimethylphosphite, triethylphosphite and tri- n-butyl phosphite.

Examples of olefins and acetylenes that can be used as removal agents in the process of the present invention are vinyl ethyls such as diethyl acetylene dicarboxylate, methyl vinyl ether and ethyl vinyl ether, vinyl esters such as vinyl acetate. Examples of suitable reducing inorganic salts are sodium bisulfite, potassium bisulfite, sodium metabisulfite, potassium thiosulfate and sodium dithiionite.

Halogen scavengers are typically added to the reaction mixture after the halogenation reaction has ended (eg, identified by thin layer chromatography) and preferably added before warming to the reaction mixture above 0 ° C. When the aqueous solutions of the reducing inorganic salts described above are used as removal agents, they are typically added as a first step when treating the reaction mixture. However, when the reaction temperature is less than -20 ℃ can be added to the reaction mixture before the halogen reaction to the organic halogen remover described above. Thus, for example, 1 equivalent of 4'-methoxybenzyl-7- (2- in a solution prepared by dissolving 3 equivalents of DBU, 3 equivalents of bromine and 5 equivalents of trimethylphosphite in tetrahydrofuran at -40 ° C. 4'-methoxybenzyl 7- (2-chienylacetamido) -3- by adding a solution made by dissolving chienyl acetamido) -3-methylenesepam-7-carboxylate in tetrahydrofuran. Bromomethyl-3-cepem-4-carboxylate can be prepared. Trimethyl phosphite is not reactive with halogenating agents at low reaction temperatures, but when the reaction mixture is warmed above the reaction temperature after completion of halogenation, trimethyl phosphite reacts with excess bromine in the mixture.

The main product of the above example performed without a halogen scavenger is 4'-methoxybenzyl-7- [2- (5-bromochienyl) acetamido] -3-bromomethyl-3-cepem-4-carboxylate to be. Although halogenation of the side chains is not generally preferred, it should be noted that the 3-halo methylcefe product produced in this reaction is extremely useful for preparing other 3-halomethylcefe compounds. Thus, for example, 4'-methoxybenzyl-7- [2- (5-bromochienyl) acetamido] -3-bromomethyl-3-cepem-4-carboxylate is subjected to conventional side chain decomposition. Degradation under conditions (PCl ₅ , pyridine / methanol) can yield 4'-methoxybenzyl-7-amino-3-bromomethyl-3-cepem-4-carboxylate, which is an ester on the corresponding nucleus. Can be reacylated as desired. It is therefore contemplated that the conversion of 3-methylenecepam to 3-halomethylcepem having a halogen substituent in addition to the side chain is also within the scope of the present invention.

The amount of remover used is not a problem as long as a sufficient amount is added to inactivate the excess halogenating agent in the reaction mixture. Generally 1-10 times or more halogen scavenger is used.

The product, 3-halomethylcepem, is generally obtained in high yield when using such a remover. Therefore, halogen scavengers are typically used in the process of the present invention even when the starting material exo methylenecepam does not have a side chain that is reactive with halogen. Therefore, it is preferable to use a halogen scavenger generally in the course of the present invention.

It is also preferred to add excess protic acid to the reaction mixture before the reaction mixture is warmed to about 0 ° C. or higher in the process of the present invention. This optional but preferred procedure inhibits unwanted side reactions that occur between the 7-alkoxy-3-bromomethylcepem product and the excess base in the reaction mixture. Both organic and inorganic protic acids are suitable here. Examples of such acids are formic acid, acetic acid, propionic acid, trifluoro acetic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and similar organic and inorganic protic acids.

The reaction time generally depends to some extent on the particular reactant, solvent used and the temperature at which the reaction is carried out, in the range of 2 minutes to 1 hour. Usually the reaction is complete after contacting the reactants at the desired temperature for 5-15 minutes. The endpoint of the reaction mixture can be easily examined, for example, using comparative thin layer chromatography to know when the halogenation reaction is complete.

Examples of conversion reactions carried out by the process of the present invention are as follows.

Tert-Butyl 7-phenylacetamido-3-bromomethyl- in tert-butyl 7-phenylacetamido-3-methylenecepam-4-carboxylate using DBN and tert-butyl hypobromite Preparation of 3-Cefem-4-carboxylate

Benzyl-7- (4-nitrobenzyl in benzyl 7- (4-nitrobenzyloxycarbonylamino) -3-methylenecepam-4-carboxylate using potassium tert-butoxide and tert-butyl hypochlorite Preparation of Oxy Carbonylamino) -3-Chloromethyl-3-cepem-4-carboxylate.

4'-nitrobenzyl 7-acetamido-3-iodomethyl-3-cepem-4-carboxyl to 4'-nitrobenzyl 7-acetamido-3-methylenecepam-4-carboxylate using iodine and DBU Preparation of Rate.

2 in 2 ', 2', 2 ',-trichloroethyl 7- (2-phenyl-2-benzyloxy-acetamido) -3-methylenecepam-4-carboxylate using iodine and sodium methoxide Preparation of ', 2', 2'-trichloroethyl-7- (2-phenyl-2-benzyloxy acetamido) -3-iodomethyl-3-cepem-4-carboxylate.

Benzhydryl 7-formamido-3-methylenecepam-4-carboxylate 1-oxide using 1,5-diazabicyclo [5,4,0] -undec-5-enhydrobromide perbromide and DBU Preparation of benzhydryl 7-formamido-3-bromomethyl-3-cepem-4-carboxylate 1-oxide in.

2'-iodoethyl 7- (in 2'-iodoethyl 7- (2-formyloxy-2-phenylacetamido) -3-methylenecepam-4-carboxylate using perchloryl fluoride and DBN Preparation of 2-formyloxy-2-phenylacetamido) -3-fluoromethyl-3-cepem-4-carboxylate.

4'-methoxybenzyl 7-phenoxyacetami to 4'-methoxybenzyl 7-phenoxyacetamido-7-methoxy-3-methylene sefam-4-carboxylate using lithium cyclohexyloxide and bromine Figure 7-Preparation of methoxy-3-bromomethyl-3-cepem-4-carboxylate.

Benzhydryl 7- (2,2-dimethyl-3-nitrozo-5-oxo-4-phenyl-1-imidazolinyl) -3-methylenecepam- using DBU and tert-butyl hypochlorite Benzhydryl 7- (2,2-dimethyl-3-nitrozo-5-oxo-4-phenyl-1-imidazolinyl) -3-chloromethyl-3-cepem-4-carboxyl at 4-carboxylate Preparation of Rate.

2 ', 2', 2'-trichloroethyl 7- [2- (4-nitrobenzyloxycarbonylamino) -2-phenylacetamido] -3-methylenecef with DBU and perchloryl fluoride 2 ', 2', 2'-trichloroethyl 7- [2- (4-nitrobenzyloxycarbonylamino) -2-phenylacetamido] -3-fluoromethyl-3- at -4-carboxylate Preparation of Cefem-4-carboxylate.

4'-nitrobenzyl 7- (5-bromo-2- in 4'-nitrobenzyl 7- (2-furylacetamido) -3-methylenecepam-4-carboxylate using iodine monobromide and DBN Preparation of furylacetamido) -3-bromomethyl-3-cepem-4-carboxylate.

Tert-Butyl 7- (4-chlorophenylacetami) in tert-butyl 7- (4-chlorophenylacet amido) -3-methylenecepam-4-carboxylate 1-oxide with lithium ethoxide and bromine Figure 3) Preparation of 3-bromomethyl-3-cepem-4-carboxylate 1-oxide.

4'-methoxybenzyl 7-chloroacetamido-7-methionate at 4'-methoxybenzyl 7-chloroacet amido-7-methoxy-3-methylenecepam-4-carboxylate using DBU and iodine Preparation of oxy-3-iodomethyl-3-cepem-4-carboxylate.

Tert-Butyl 7-phenylacet Amido-7-ethoxy in tert-butyl 7-phenylacet amido-3-methylenecepam-4-carboxylate using lithium ethoxide and tert-butyl hypobromite Preparation of 3-bromomethyl-3-cepem-4-carboxylate.

Benzyl 7- (4-nitrobenzyl oxycarbonyl amino) in benzyl 7- (4-nitro benzyloxycarbonyl amino-3-methylenecepam-4-carboxylate using lithium methoxide and tert-butylhypobromite Preparation of -7-methoxy-3-bromomethyl-3-cepem-4-carboxylate.

4'-nitro benzyl 7-acet amido-7-n-propoxy- in 4'-nitro benzyl 7-acet amido-3-methylenecepam-4-carboxylate using bromine and sodium n-propoxide Preparation of 3-bromomethyl-3-cepem-4-carboxylate 1-oxide.

2 ', 2 in 2', 2 ', 2'-trichloroethyl 7- (2-phenyl-2-benzyl oxyacetamido) -3-methylenecepam-4-carboxylate using bromine and sodium methoxide Preparation of ', 2'-trichloroethyl-7- (2-phenyl-2-benzyloxyacetamido) -7-methoxy-3-bromomethyl-3-cepem-4-carboxylate.

Preparation of benz hydryl 7-form amido-3-methyllinesepam-4-carboxylate using 1,5-diazabicyclo [5.4.0] undec-5-ene hydrobromide perbromide and lithium methoxide.

2'-Urinary in 2'-Iodoethyl 7- (2-formyloxy-2-phenylacet amido) -3-methylenecepam-4-carboxylate using tert-butylhypobromite and lithium benzyloxide Preparation of ethyl 7- (2-formyloxy-2-phenylacetamido) -7-benzyloxy-3-bromomethyl-3-cepem-4-carboxylate.

4'-methoxybenzyl-7-phenoxy acetamido-7- in 4'-methoxybenzyl-7-phenoxy acet amido-3-methylenecepam-4-carboxylate using lithium methoxide and bromine Preparation of Methoxy-3-bromomethyl-3-cepem-4-carboxylate.

2 ', 2', 2'-trichloroethyl-7- [2- (4nitrobenzyl oxycarbonylamino) -2-phenylacetamido] using lithium propoxide and tert-butyl hypobromite 2 ', 2', 2'-trichloroethyl 7- [2- (4-nitrobenzyl oxycarbonylamino) -2-phenylacetamido] -7-pro in -3-methylenecepam-4-carboxylate Preparation of Foxy-3-bromomethyl-3-cepem-4-carboxylate.

4'-nitrobenzyl 7- (2-furylacetyl) in 4'-nitrobenzyl 7- (2-furylacetamido) -3-methylenecepam-4-carboxylate using bromine, lithium methoxide and trimethylphosphite Amido) -7-methoxy-3-bromomethyl-3-cepem-4-carboxylate.

Tert-butyl 7- (4-chlorophenyl acetamido)-in tert-butyl 7- (4-chlorophenylacetamido) -3-methylenecepam-4-carboxylate using lithium ethoxide and bromine Preparation of 7-ethoxy-3-bromomethyl-3-cepam-4-carboxylic acid.

4'-methoxybenzyl 7-chloroacetamido-3-methylenecepam-4-carboxylate to 4'-methoxybenzyl 7-chloroacetamido-7- using lithium ethoxide and iodide monobromide Preparation of oxy-3-chloromethyl-3-cepem-4-carboxylate.

Tert-Butyl 7-phenylacetamido-7-ethoxy in tert-butyl 7-phenylacetamido-3-metallenecepam-4-carboxylate using lithium ethoxide and tert-butyl hypochloride Preparation of 3-Chloromethyl-3-cepem-4-carboxylate.

Benzyl 7- (4-nitrobenzyl oxycarbonylamino in benzyl 7- (4-nitrobenzyl oxycarbonylamino-3-methylenecepam-4-carboxylate using lithium methoxide and tert-butyl hypochlorite ) -7-methoxy-3-chloromethyl-3-cepem-4-carboxylic acid.

4'-nitrobenzyl 7-acetamido-7 in 4'-nitrobenzyl 7-acetamido-3-methylenecepam-4-carboxylate using tert-butyl hypochlorite and sodium n-propoxide Preparation of Propoxy-3-chloromethyl-3-cepem-4-carboxylate 1-oxide.

2 ', 2', 2'-trichloroethyl 7- (2-phenyl-2-benzyl oxyacetamido) -3-methylenecepam-4-carboxyl with tert-butyl hypochlorite and sodium methoxide Of 2 ', 2', 2'-trichloroethyl-7- (2-phenyl-2-benzyloxyacetamido) -7-methoxy-3-chloromethyl-3-cepem-4-carboxylate at rate Produce.

Benzhydryl 7-formamido-7-methoxy-3-chloro in benzhydryl 7-formamido-3-methylenecepam-4-carboxylate using tert-butyl hypochlorite and lithium methoxide Preparation of Methyl-3-cepem-4-carboxylate.

2'-Urinary in 2'-Iodoethyl 7- (2-formyloxy-2-phenylacetamido) -3-methylenecepam-4-carboxylate using tert-butyl hypochlorite and lithium benzyl oxide Preparation of ethyl 7- (2-formyloxy-2-phenylacetamido) -7-benzyloxy-3-chloromethyl-3-cepem-4-carboxylate

4'-methoxybenzyl-7-phenoxy acetyl in 4'-methoxybenzyl 7-phenoxyacetamido-3-methylenecepam-4-carboxylate using lithium methoxide and tert-buyfochlorite Preparation of Amido-7-methoxy-3-chloromethyl-3-cepam-4-carboxylate.

2 ', 2', 2'-trichloroethyl 7- [2- (4-nitrobenzyl oxycarbonylamino) -2-phenylacetamido] using lithium propoxide and tert-butyl hypochlorite In 3-methylenecepam-4-carboxylate, 2 ', 2', 2'-trichloroethyl 7- [2- (4-nitrobenzyl oxycarbonylamino) -2-phenylacetamido] -7- Preparation of Propoxy-3-chloromethyl-3-cepem-4-carboxylate.

4'-nitrobenzyl in 4'-nitrobenzyl 7- (2-furylacetamido) -3-methylene-sefam-4-carboxylate using tert-butylhypochlorite, lithium methoxide and trimethylphosphite Preparation of 7- (2-furylacetamide) -7-methoxy-3-chloromethyl-3-cepem-4-carboxylate

Tert-butyl 7- (4-chlorophenyl in tert-butyl 7- (4-chlorophenylacetamido-3-methylenecefe-4-carboxylate using lithium ethoxide and tert-butyl hypochlorite Acetamido) -7-Ethoxy-3-Chloromethyl-3-cepem-4-carboxylate.

4'-methoxybenzyl 7-chloroacetamido 7 in 4'-methoxybenzyl 7-chloroacetamido-3-methylene sefam-4-carboxylate using lithium ethoxide and tert-butyl hypochlorite Preparation of ethoxy-3-chloromethyl-3-cepem-4-carboxylate.

The product made according to the process of the present invention can be separated and purified by conventional experimental techniques. Such techniques include chromatographic separation, filtration, crystallization and recrystallization.

The 3-halomethylcefem compound of formula (I) is useful as an intermediate for preparing antibiotics. The sulfoxides can be prepared in the known manner, ie, by reducing in dimethylformamide with phosphorus tribromide or phosphorus trichloride to produce the corresponding 3-halomethylcepem. 3-halomethylcepem esters are converted to active antibiotics by breaking down ester groups. (US Pat. No. 3,658,799) Deesterification can occur in one of several recognized ways, depending on the nature of the ester group. The method comprises (1) treatment with an acid such as trifluoro acetic acid, formic acid or hydrochloric acid, (2) treatment with an acid such as formic acid, acetic acid or hydrochloric acid and zinc, or (3) palladium, platinum, rhodium or compounds containing them. Hydrogenated on suspension or on a carrier such as barium sulfate, carbon or alumina. Optionally, the 3-halomethylcepem may be converted to another 3- (substituted) methylcefem compound by nucleophilic substitution of the halo group. This method is recognized by those skilled in the art to prepare a wide variety of known active 3-heteroarylthio methylcefe compounds.

The invention is further illustrated by the following examples. The present invention is not to be limited in scope by these examples.

값[parts/million (ppm)]으로 표시하였고 커플링 상수(J)는 cycles/second로 표시하였다.In the following examples, nuclear magnetic resonance (NMR) spectra were measured with a Varian Associates T-60 Spectrometer using tetramethylsilane as a control standard. Chemical Shift

Values [parts / million (ppm)] and coupling constants (J) are expressed in cycles / second.

Example 1

4'-nitrobenzyl 7-phenoxy acetamido-3-bromomethyl-3-cepem-4-carboxylate

(A) 0.109 mL of bromine is added to a solution of 248 g of DBN dissolved in 20 mL of tetrahydrofuran (THF) at -78 ° C. Immediately thereafter, a solution of 0.483 g of 4'-nitrobenzyl 7-phenoxy acetamido-3-methylenecepam-4-carboxylate is dissolved in 15 ml of tetrahydrofuran.

The reaction mixture is stirred at −78 ° C. for 10 minutes, warmed to 0 ° C. and then the mixture is stirred at 0 ° C. for 10 minutes. Then 0.118 ml of trimethyl phosphite is added. The reaction mixture was evaporated to dryness in vacuo to give a reddish brown, foamy material which was then dissolved in methylten chloride, subsequently washed with 5% hydrochloric acid and saturated sodium chloride solution, dehydrated with anhydrous magnesium sulfate and then evaporated to dryness in vacuo. To give 536 mg (95%) of the title product in the form of a pink foam.

3.6(bs, 2, C₂-H), 4.46(bs, 2, C₃-CH₂Br), 4.58(s, 2, 측쇄의 CH₂), 5.05(d, 1, J=5Hz, C₆-H), 5.40(s, 2, 에스테르 CH₂), 5.95(q, 1, =5 및 9Hz, C₇-H). 6.8-8.3(ArH).NMR (CDCl ₃ )

3.6 (bs, 2, C ₂ -H), 4.46 (bs, 2, C ₃ -CH ₂ Br), 4.58 (s, 2, side chain CH ₂ ), 5.05 (d, 1, J = 5 Hz, C ₆ -H), 5.40 (s, 2, ester CH ₂ ), 5.95 (q, 1, = 5 and 9 Hz, C ₇ -H). 6.8-8.3 (ArH).

(B) 0.12 ml of bromine is added to a solution prepared by dissolving 0.336 g of potassium tert-butoxide in tetrahydrofuran at -80 ° C. Then a solution made by dissolving 0.483 g of 4'-nitrobenzyl 7-phenoxy acetamido-3-methylene sefam-4-carboxylate in 4 ml of tetrahydrofuran is added. The reaction is allowed to warm the mixture to 0 ° C. and then stirred at 0 ° C. for 10 minutes and 10 drops of trimethyl phosphite are added. The reaction mixture was evaporated to dryness in vacuo and the residue obtained was treated with ethylene chloride, and subsequently washed with 5% hydrochloric acid, washed twice with brine, dehydrated with magnesium sulfate and evaporated to dryness in vacuo. The product thus obtained is purified by preparative thin layer chromatography, to yield 0.50 g of the title product. The NMR of the product obtained at this time is the same as the NMR of the product obtained by the method of (a) mentioned above.

(C) A solution of 14.4 ml of bromine and 38.64 g of 4'-nitrobenzyl 7-phenoxy acetamido-3-methylenese palm-4-carboxylate was dissolved in 160 ml of tetrahydrofuran. Is added to a solution prepared by dissolving in 820 ml of tetrahydrofuran. After 10 minutes at −80 ° C., 14.4 ml of trimethylphosphite was added dropwise over 6 minutes. The reaction mixture is then warmed up to 0 ° C. 60 ml of trimethylphosphite is further added to the reaction mixture, evaporated in vacuo to almost dryness and the residue is dissolved in methylene chloride. The methylene chloride solution is subsequently washed with 5% hydrochloric acid and saturated brine, passed through silica gel and activated charcoal filter, and the filtrate is evaporated to dryness in vacuo to give 35.6 g (80%) of the title product.

(D) 0.18 ml of bromine is added to a solution of 0.456 g of DBU dissolved in 15 ml of tetrahydrofuran. Then a solution made by dissolving 0.483 g of 4'-nitrobenzyl 7-phenoxy acetamino-3-methylenecepam-4-carboxylate in 4 ml of tetrahydrofuran is added. The reaction mixture is warmed up to 0 ° C. and stirred at 0 ° C. for 10 minutes, and then the reaction mixture is filtered through Merck silica gel using ethyl acetate as eluent. The eluates were collected and evaporated to dryness in vacuo to confirm by NMR to give the title compound.

Example 2

4'-nitrobenzyl-7-phenoxy acetamido-3-bromomethyl-3-cepem-4-carboxylate

내지 -15℃에서 30분간 교반한 다음 메틸렌클로라이드 50ml와 메타중아황산 나트륨 수용액 150ml를 가한다. 유기용매층을 분리하고 중아황산 나트륨 용액으로 2회 세척한 후 진공하에 증발건조시켜 수득한 생성물 2.90g을 염화메틸렌 75ml에 용해시킨다. 이 용액을 염화수소 /5% 염산 포화용액으로 3회 세척한 다음 무수황산나트륨으로 탈수시키고 진공에서 건조한다. 이때 수득된 생성물을 2시간 동안 디에틸 에테르 50ml에 녹여 슬러리로 만든 다음 이를 여과하여 상기 제목의 생성물 1.71g(60.8%)을 수득한다.(A) 0.82 ml of bromine was added to a solution made by dissolving 2.28 g of DBU in 50 ml of tetrahydrofuran at -20 ° C, and 4'-nitro-benzyl 7-phenoxyacetamido-3-methylenecepam-4- A solution of 2.415 g of carboxylate dissolved in 20 ml of tetrahydrofuran is added immediately. -20 to reaction mixture

After stirring at -15 ° C for 30 minutes, 50 ml of methylene chloride and 150 ml of aqueous sodium metabisulfite solution are added thereto. The organic solvent layer was separated, washed twice with sodium bisulfite solution and evaporated to dryness in vacuo to dissolve 2.90 g of the product in 75 ml of methylene chloride. The solution is washed three times with saturated hydrogen chloride / 5% hydrochloric acid solution, then dehydrated with anhydrous sodium sulfate and dried in vacuo. The resulting product was dissolved in 50 ml of diethyl ether for 2 hours to make a slurry, which was then filtered to give 1.71 g (60.8%) of the title product.

(B) A compound of the title was obtained in 59.4% yield by the same method as described in (A) of Example 2, except that sodium bisulfite was used instead of meta sodium bisulfite.

Example 3

4'-nitrobenzyl 7-phenoxy acetamido-3-bromomethyl-3-cepem-4-carboxylate

(A) Add 0.082 ml of bromine at -78 ° C (dry ice / acetone) to a solution of 0.228 g of DBU dissolved in 20 ml of methylene chloride, and immediately add 4'-nitrobenzyl 7-phenoxy acetamido-3-methylenecepam- A solution of 0.241 g of 4-carboxylate dissolved in 15 ml of methylene chloride is added. The reaction mixture is stirred at −78 ° C. for 10 minutes and then warmed to 0 ° C. and further stirred at this temperature for 10 to 15 minutes. Dimethyl sulfide (0.07 ml) is added to the reaction mixture. The reaction mixture is evaporated to dryness in vacuo to dissolve the resulting residue in methylene chloride. The methylene chloride solution is washed with 5% hydrochloric acid / saturated saline solution, dehydrated with anhydrous sodium sulfate and evaporated to dryness in vacuo to yield 300 mg of a brown foamy material. Comparative thin layer chromatography and NMR data showed that the title compound was the main component.

(B) Perform the same process as described in (A), except that toluene is used as a solvent instead of methylene chloride. Thin layer chromatography and NMR data showed that the compound was converted into the title. 256 mg of impure product are obtained.

(C) Carry out the same general procedure as described above under (a) except that: 1,1,2-trichloroethane is used as solvent instead of methylene chloride; Use liquid nitrogen / aceto nitrile baths (-41 ° C.) instead of dry ice / acetone baths to prevent solvent freezing; Trimethylphosphite is used instead of dimethylsulfide as a scavenger. Thin layer chromatography and NMR data showed that about 100 mg of the title compound was produced.

(D) Perform the same process as described in (A), except that methane is used as solvent and trimethyl phosphite is used instead of dimethylsulfide as eliminator. Thin layer chromatography on the crude product (229 mg) showed favorable conversion to the title compound.

(E) Carry out the same process as described in (a) except as follows: Use hexamethylphosphoric triamide in place of methylene chloride as the reaction solvent, and use liquid nitrogen / instead of dry ice / acetone bath. An acetonitrile bath (-41 ° C.) is used and trimethyl phosphite is used instead of dimethyl sulfide as the remover. It was found that about 150 mg of the title compound was produced by thin layer chromatography.

(F) Carry out the same steps as described in (a), except as follows. Use 1,4-dioxane instead of methylene chloride as a reaction solvent: use ice bath instead of dry ice / acetone bath to prevent solvent freezing; use trimethyl phosphide instead of dimethyl sulfide as remover. It was found that thin layer chromatography produced the title compound (yield: about 150 mg).

(G) Carry out the same general procedure as described in (a), except as follows: Use 1,2-dimethoxyethanol instead of methylene chloride as a reaction solvent: dry ice to prevent any solvent A liquid nitrogen / aceto nitrile bath (-41 ° C.) is used instead of the acetone bath; trimethyl phosphite is used instead of dimethyl sulfide as a remover. Thin layer chromatography showed clear and complete conversion to 279 mg of the title compound.

(H) The same process as described in (A) is carried out, except that dimethyl formamide is used instead of methylene chloride as the reaction medium and trimethylphosphite is used instead of dimethyl sulfide as the removal agent. Thin layer chromatography on the final crude product showed that the compound was converted to the title.

Example 4

4'-nitrobenzyl 7-phenoxy acetamido-3-bromoethyl-3-cepem-4-carboxylate

To a solution made by dissolving 64 mg of methanol in 20 ml of tetrahydrofuran, 1.15 ml of 1.75 mol of methyllithium was added at -80 ° C. At this time, 0.11 ml of bromine was added to the tetrahydrofuran solution of lithium methoxide generated after 5 minutes. Then a solution prepared by dissolving 0.483 g of 4'-nitrobenzyl 7-phenoxy acetamido-3-methylenecepam-4-carboxylate in 4 ml of tetrahydrofuran is added dropwise. The tetrahydrofuran solution of methylenecepam, the starting material, is completely added and then the mixture is stirred for 5 minutes at -80 ° C and warmed up to 0 ° C. After 10 minutes at 0 ° C., 4 drops of trimethylphosphite are added. The residue obtained by evaporating to dryness in vacuo the reaction mixture is then treated with methylene chloride. The methylene chloride solution thus obtained is subsequently washed with 5% hydrochloric acid solution, water and saturated saline solution.

The organic layer is then separated, dehydrated with anhydrous sodium sulfate and evaporated to dryness in vacuo. The product thus obtained is purified by preparative thin layer chromatography (adsorbent: silica gel) developed with benzene / ethyl acetate (7: 3) solution. 126 mg of the title compound is isolated. The NMR spectrum of the isolated product is identical to the spectrum of the product described in Example 1.

Example 5

4'-nitrobenzyl 7-phenoxy acetamido-3-bromomethyl-3-cepem-4-carboxylate 1-oxide

To the solution of 0.912 g of DBU dissolved in 15 ml of tetrahydrofuran, 0.36 ml of bromine was added at -80 ° C. Then a solution of 0.499 g of 4'-nitrobenzyl 7-phenoxy acetamido-3-methylenecepam-4-carboxylate 1-oxide was dissolved in 4 ml of hexamethylphosphoric triamide. After 10 minutes, 0.186 ml of trimethyl phosphite is added. The reaction mixture is allowed to warm to 0 ° C. and then 5 ml of trimethyl phosphite is added after 5 minutes. The reaction mixture is then evaporated to dryness in vacuo to dissolve the residue in methylene chloride. The methylene chloride solution is subsequently washed twice with 5% hydrochloric acid, water and saturated brine, then dehydrated with anhydrous sodium sulfate and evaporated to dryness in vacuo to purify the product obtained by preparative thin layer chromatography: 60 mg of the compound of the title is isolated. do.

3.96(bs, 2, C₂-H), 4.57(s, 2, C₃-CH₂Br), 4.73(s, 2, 측쇄 CH₂), 5.09(d, 1, J=5Hz, C₆-H), 5.50(s, 2, 에스테르 CH₂), 6.10(q, 1, J=10 및 5Hz, C₇-H) 및 6.9-8.2(ArH).NMR (DMSOd-6)

3.96 (bs, 2, C ₂ -H), 4.57 (s, 2, C ₃ -CH ₂ Br), 4.73 (s, 2, branched CH ₂ ), 5.09 (d, 1, J = 5 Hz, C _6- H), 5.50 (s, 2, ester CH ₂ ), 6.10 (q, 1, J = 10 and 5 Hz, C ₇ -H) and 6.9-8.2 (ArH).

Example 6

4'-nitrobenzyl 7- (2-chienyl acetamido) -3-bromomethyl-3-cepem-4-carboxylate

To a solution of 9.12 g of DBU dissolved in 200 ml of anhydrous tetrahydrofuran, 3.5 ml of bromine was added at -78 ° C (dry ice / acetone). The resulting mixture was stirred at −78 ° C. for 10 minutes, and then 9.46 g of 4′-nitrobenzyl 7- (2-chienylacetamido) -3-methylenecepam-4-carboxylate was dissolved in 100 ml of tetrahydrofuran. The resulting solution is added dropwise over 5 minutes. After the complete dropping of the substrate solution, the mixture is stirred for 10 minutes at -78 ° C, replaced by an ice-water bath instead of a dry ice / acetone bath, the mixture is stirred for 6 minutes, and then 5.0 ml of trimethylphosphite is added.

3.80(bs, 4, 측쇄 CH₂+C₂-H)4.55(bs, 2, -CH₂Br), 5.20(d, 1, J=4.5Hz, C₆-H), 5.82(dd, 1, J=4.5 및 9Hz, C₇-H) 및 6.9-8.4(ArH).The mixture is stirred for 10 minutes and then evaporated to dryness in vacuo to obtain the black residue. The residue is treated with methylene chloride and the solution is subsequently washed with water, 5% hydrochloric acid and brine and then dehydrated with anhydrous sodium sulfate. Approximately 10 g of Darco G-60 is added and the solution is filtered to evaporate to dryness in vacuo. The residue thus obtained is recrystallized in methylene chloride / hexane to give 6.96 g (63%) of the title compound: NMR (DMSOd-6).

3.80 (bs, 4, branched CH ₂ + C ₂ -H) 4.55 (bs, 2, -CH ₂ Br), 5.20 (d, 1, J = 4.5 Hz, C ₆ -H), 5.82 (dd, 1, J = 4.5 and 9 Hz, C ₇ -H) and 6.9-8.4 (ArH).

Example 7

Benzhydryl 7- (2-chienyl acetamido) -3-bromomethyl-3-cepem-4-carboxylate

4.91 g of benzhydryl 7- (2-chienyl acetamido) -3-methylenecepam-4-carboxylate are treated by the method described in Example 6 to convert to the compound of the title.

3.50(bs, 2, C₂-H), 3.84(s, 2, 측쇄 CH₂), 4.30(s, 2, C₃-CH₂Br), 4.98(d, 1, J=4.5, C₆-H), 5.86(q, 1, J=4.5 및 9Hz, C₇-H), 6.84(d, 1, J=9Hz, 측쇄 NH) 및 7.0-7.6(ArH).NMR (CDCl ₃ )

3.50 (bs, 2, C ₂ -H), 3.84 (s, 2, branched CH ₂ ), 4.30 (s, 2, C ₃ -CH ₂ Br), 4.98 (d, 1, J = 4.5, C ₆ − H), 5.86 (q, 1, J = 4.5 and 9 Hz, C ₇ -H), 6.84 (d, 1, J = 9 Hz, branched NH) and 7.0-7.6 (ArH).

Example 8

4'-nitrobenzyl 7- (2-chienylacetamido) -3-bromomethyl-3-cepem-4-carboxylate

DBU hydrobromide perbromide is prepared as follows: To a solution of 20.3 g of DBU dissolved in 100 ml of 48% hydrobromic acid, 32.06 g of bromine is added dropwise over 10 minutes at -5 ° C. The orange precipitate formed is separated and washed with acetic acid and water and dissolved in methylene chloride. The methylene chloride solution is washed with water and then dehydrated with anhydrous sodium sulfate. Ethyl acetate is added to the methylene chloride solution while cooling until crystallization begins to occur. The solution is left at 0 ° C. for 2 hours, then the perbromide is separated by filtration and washed with ethyl acetate and ether. Receive 22.6 g. Melting point 11-122 ° C. The filtrate is concentrated and cooled to further precipitate 9.5 g of perbromide into orange crystals. (Melting point 118-121 ° C). A total of 32.1 g (61%) are read.

0.946 g of 4'-nitrobenzyl 7- (2-chienylacetamido) -3-methylenecepam-4-carboxylate in a solution of 2.35 g of DBU hydrobromide perbromide and 0.34 g of DBU dissolved in 20 ml of tetrahydrofuran. And 20 ml of tetrahydrofuran are added at room temperature. This solution immediately turns black. After 2 minutes 0.5 ml of trimethylphosphite is added and the reaction mixture is immediately evaporated to dryness in vacuo. The residue thus obtained is dissolved in methylene chloride and the solution is washed with 5% hydrochloric acid and saturated brine, dehydrated with anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue is crystallized in methylene chloride / ethanol to yield 0.92 g of the title compound as pink crystals. The structure of this compound was confirmed by NMR and TLC data.

Example 9

4'-nitrobenzyl 7- [2- (5-bromochienylacetamido)]-3-bromomethyl-3-cepem-4-carboxylate

To a solution of 4.56 g of DBU dissolved in 50 ml of tetrahydrofuran, 1.8 ml of bromine was added at -78 ° C.

After stirring the mixture for 15 minutes at -78 ° C, 4.73 g of 4'-nitrobelzyl 7- (2-chienylacetamido) -3-methylenecepam-4-carboxylate was dissolved in 40 ml of tetrahydrofuran. Add. The mixture is warmed to -15 [deg.] C. over 30 minutes. 250 ml of water and 150 ml of methylene chloride are added to the reaction mixture. The organic layer is separated, washed with 5% hydrochloric acid, washed with water and then dehydrated with anhydrous sodium sulfate.

The methylene chloride solution is passed through 150 g of silica gel using methylene chloride as eluent. The eluate containing the main reaction product is evaporated to dryness in vacuo. The residue thus obtained is crystallized in methylene chloride / hexane to obtain 370 mg of the title compound as pale yellow crystals. Melting Point 144-146 ° C (Decomposition):

6.79 및 7.05(d's, 각각 1, J=3.5Hz, 치오펜 C₃와 C₄-프로톤).λ _EtOH ^max 260 μm (19,600); NMR (DMSOd-6)

6.79 and 7.05 (d's, 1, J = 3.5 Hz, respectively, Ciophen C ₃ and C ₄ -protons).

Analysis of C ₂₁ H ₁₇ N ₃ O ₆ S ₂ Br ₂

Calc .: C 39.01; H 2.63; N 6.50; Br 24.76

Found: C 40.22; H 2.57; N 6.59; Br 24.37

Example 10

4'-nitrobenzyl 7-phenoxyacetamido-3-chloromethyl-3-cepem-4-carboxylate

3.60(bs, 2, C₂-H), 4.58(s, 4, C₃-CH₂Cl+측쇄의 CH₂), 5.03(d, 1, J=5Hz, C₆-H), 5.38(s, 2, 에스테른 CH₂), 5.93(q, 1, J=5와 9Hz, C₇-H) 및 6.8-8.4(ArH).A solution of 0.312 g DBU dissolved in 15 ml of tetrahydrofuran was added 0.286 ml of tert-butyl hypochlorite at -80 ° C. 0.483 g of 4'-nitrobenzyl 7-phenoxy acetamido-3-methylenecepam-4-carboxylate is added to a cooled (-80 ° C) mixture of 4 ml of tetrahydrofuran. The reaction mixture is stirred at -80 ° C for 10 minutes and then 10 drops of trimethylphosphite are added. The reaction mixture is warmed to 0 ° C. and then evaporated to dryness in vacuo. The solution obtained by dissolving the residue in methylene chloride was washed with 5% hydrochloric acid and saturated brine, separated, dehydrated with anhydrous sodium sulfate and evaporated to dryness in vacuo to give 260 mg of the title compound. NMR (CDCl ₃ )

_{3.60 (bs, 2, C 2} -H), 4.58 (s, 4, C 3 -CH 2 CH 2 Cl + in the side chain), 5.03 (d, 1, J = 5Hz, C 6 -H), 5.38 (s, 2, ester CH ₂ ), 5.93 (q, 1, J = 5 and 9 Hz, C ₇ -H) and 6.8-8.4 (ArH).

Example 11

4'-nitrobenzyl 7-phenoxyacetamido-3-fluoromethyl-3-cepem-4-carboxylate

A solution of 0.483 g of 4'-nitrobenzyl 7-phenoxy acetamido-3-methylenecepam-4-carboxylate in 30 ml of anhydrous tetrahydrofuran was added to a perchlorylfluoride gas under anhydrous nitrogen stream at -78 ° C. 25 ml of perchloryl fluoride-dimethylformamide anhydrous saturated solution (4.7 g FClO ₃ / liter, 25 ° C.) prepared by passing the dimethylformamide at room temperature for 10 minutes is added thereto. The solution of methylenecepam and perchloryl fluoride thus obtained was dissolved in 5 ml of anhydrous tetrahydrofuran at 0.178 g of DBU at -78 ° C over 5 minutes. After complete addition of the DBU solution, the mixture is stirred for 3 minutes at -78 ° C and 0.118 g of trimethylphosphite is added. The reaction mixture is then almost evaporated to dryness in vacuo. The resulting liquid sand is dissolved in methylene chloride and the solution is subsequently washed with 1N hydrochloric acid, water and twice with saturated brine.

3.56(bs, 2, C₂-H), 4.55(s, 2, 측쇄 CH₂), 5.0(d, 1, J=5Hz, C₆-H), 5.35(d, ABq's, 2, J_F=47Hz, C₃-CH₂F), 5.32(s, 2, 에스테르CH₂), 5.91(q, 1, J=5와 9Hz, C₇-H) 및 6.7-8.2(ArH) : 불소자기공명(CDCl₃) : 트리플렛, J_H=47Hz.The washed methylene chloride solution was dehydrated with anhydrous sodium sulfate and evaporated to dryness in vacuo to give 443 mg of a colorless foamy material. After first purification using high pressure liquid chromatography, the compound was finally purified using preparative thin layer chromatography. A preparative TLC plate made of silica gel was developed with a benzene / ethylacetate (7: 3) solvent. Subsequent extraction of this site with methylene chloride afforded 21.1 mg of the title compound as a colorless resin: NMR (CDCl ₃ )

3.56 (bs, 2, C ₂ -H), 4.55 (s, 2, branched CH ₂ ), 5.0 (d, 1, J = 5 Hz, C ₆ -H), 5.35 (d, ABq's, 2, J _F = 47 Hz, C ₃ -CH ₂ F), 5.32 (s, 2, ester CH ₂ ), 5.91 (q, 1, J = 5 and 9 Hz, C ₇ -H) and 6.7-8.2 (ArH): Fluorine magnetic resonance ( CDCl ₃ ): triplet, J _H = 47 Hz.

[Example 12]

Banshydryl 7- (2-chienylacetamido) -3-fluoromethyl-3-cepem-4-carboxylate

187 mg of the title compound is obtained in benzhydryl 7- (2-chienylacetamido) -3-methylenecepam-4-carboxylate following the procedure described in Example 11.

3.44(s, 2, C₂-H), 3.08(s, 2, 측쇄 CH₂), 4.89(d, 1, J=5Hz, C₆-H), 4.84 및 5.64(2bs's, 각각 1, J_F=48Hz, C₃-CH₂F), 5.86(q, 1, J=5와 9H_z), 6.65(d, 1, J=9Hz, 측쇄 NH) 및 6.8-7.5(ArH)NMR (CDCl ₃ )

3.44 (s, 2, C ₂ -H), 3.08 (s, 2, branched CH ₂ ), 4.89 (d, 1, J = 5 Hz, C ₆ -H), 4.84 and 5.64 (2bs's, 1, J _F , respectively) = 48 Hz, C ₃ -CH ₂ F), 5.86 (q, 1, J = 5 and 9H _z ), 6.65 (d, 1, J = 9 Hz, branched NH) and 6.8-7.5 (ArH)

Example 13

4'-nitrobenzyl 7-phenoxyacetamido-3-uridomethyl-3-cepem-4-carboxylate

To a solution made by dissolving 0.456 g of DBU in 15 ml of tetrahydrofuran, 0.84 g of iodine was added at -80 ° C in 4 ml of tetrahydrofuran, followed by 4'-nitrobenzyl 7-phenoxy acetamido-3-methylenecepam-4-carboxylate. A solution of 0.483 g dissolved in 4 ml of tetrahydrofuran was added dropwise. After 5 minutes at −80 ° C., 0.983 ml of trimethyl phosphite is added and the reaction mixture is allowed to warm to 0 ° C. After about 10 minutes, 1 ml more trimethylphosphite is added. The reaction mixture is then evaporated to dryness in vacuo and the residue obtained is dissolved in methylene chloride and subsequently washed with 5% hydrochloric acid, water and twice with saturated brine. The methylene chloride solution was then dehydrated with anhydrous sodium sulfate and evaporated to dryness in vacuo to give an impure product which was chromatographed on a silica gel column to give 260 mg of the title compound: NMR (CDCl ₃ ) 3.44 and 3.82 (ABq, 2). , J = 18 Hz, C ₂ -H), 4.40 (s, 2, C ₃ -CH ₂ I), 4.54 (s, 2, branched CH ₂ ), 4.98 (d, 1, J = 5 Hz, C ₆ -H ), 5.34 (s, 2, ester CH ₂ ), 5.82 (q, 1, J = 5 and 9 Hz, C ₇ -H) and 6.8-8.4 (ArH).

Example 14

4'-nitrobenzyl 7-phenoxyacetamido-3-chloromethyl-3-cepem-4-carboxylate

To a solution made by dissolving 0.12 g of isopropanol in 20 ml of tetrahadrofuran, 1.1 ml of a solution made of 1.84 M of methyllithium in tetrahydrobutane is added at 0 ° C. The resulting solution was cooled to -80 ° C and 0.286 ml of tert-butyl hypochlorite and 0.483 g of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepam-4-carboxylate were added to 4 ml of tetrahydrofuran. Continue adding the dissolved solution. The semi-fused mixture is warmed to 0 ° C., and then left at 0 ° C. for 10 minutes, and then 1 ml of acetic acid and 1 ml of trimethyl phosphite are added. The mixture obtained by evaporation to dryness in the air is dissolved in methylene chloride, washed with potassium bicarbonate solution, and the methylene chloride solution is dehydrated and evaporated to dryness in vacuo. The product thus obtained is purified by preparative thick layer chromatography (silica gel plate / benzene-ethyl acetate solvent) to give 100 mg of the title compound:

3.63(br, s, 2, C₂-H), 4.58(s, 4, C₃'-H와 측쇄의 CH₂), 5.05(d, 1, J=5Hz, C₆-H), 5.38(s, 2, 에스테르 CH₂), 5.94(dd, 1, J=5와 9Hz) 및 6.8-8.4(m, 9, ArH).NMR (CDCl ₃ )

3.63 (br, s, 2, C ₂ -H), 4.58 (s, 4, C ₃ '-H and side chain CH ₂ ), 5.05 (d, 1, J = 5 Hz, C ₆ -H), 5.38 ( s, 2, ester CH ₂ ), 5.94 (dd, 1, J = 5 and 9 Hz) and 6.8-8.4 (m, 9, ArH).

[Example 15]

4'-nitrobenzyl 7-phenoxyacetamido-3-bromomethyl-3-cepam-4-carboxylate

0.360 g of isopropanol was dissolved in 25 ml of tetrahydrofuran, and 3.26 ml of a solution dissolved in 1.84 mol of methyllithium in tetrahydrofuran was added at 9 ° C.

The mixture was cooled to -80 ° C, and a solution of 0.36 ml of bromine and 0.483 g of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylphencepam-4-carboxylate dissolved in 4 ml of tetrahydrofuran was continued. Add. The reaction mixture was warmed up to 0 ° C., after 10 minutes, 1 ml of acetic acid and 2 ml of trimethylmethylphosphite were added, followed by evaporation to dryness in vacuo. The resulting product was dissolved in methylene chloride and washed with aqueous potassium bicarbonate solution and 5% hydrochloric acid. The solution was filtered through Merck silica gel and the filtrate was evaporated to dryness under reduced pressure to yield 0.374 g (67%) of the title compound.

Example 16

4'-nitrobenzyl 7-phenylacetamido-3-bromomethyl-3-cepem-4-carboxylate

A small amount of bromine is added to a tetrahydrofuran solution of DBU at low temperature followed by a tetrahydrofuran solution of 4'-nitrobenzyl 7-phenylacetamido-3-methylenecepam-4-carboxylate. The reaction mixture is stirred for a short time at a constant low temperature and a small amount of trimethylphosphite is added. Treatment of this reaction mixture as described in Example 1 yields a compound of the title in significant yield.

Example 17

4'-nitrobenzyl 7-phenoxyacetamido-7-methoxy-3-bromomethyl-3-cepem-4-carboxylate

To a solution of 0.256 g of anhydrous methanol in 15 ml of tetrahydrobutane was added 4.17 g of 1.85 N-methiumlithium dissolved in tetrahydroputane at -80 ° C. The mixture is stirred for 5 minutes and then 0.44 ml bromine is added. To the resulting mixture was added 0.483 g of 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepam-3-carbosylate in 4 ml of tetrahydrofuran. The reaction mixture is allowed to warm to 0 ° C., then stirred at this temperature for 15 minutes and 3 ml of trimethylphosphite are added. The residue obtained by evaporating to dryness in vacuo the reaction mixture is dissolved in methylene chloride. The methylene chloride solution is then washed three times with saturated brine, once with dilute sodium thiosulfate solution, twice with sodium bicarbonate solution and once with saturated saline solution. The washed solution is dehydrated and evaporated to dryness in vacuo resulting in an impure product. Purification of this by preparative thin layer chromatography using a benzene / ethyl acetate solvent yielded 140 mg of the title compound:

3.53(s, 5, C₂-H와 C₆-OCH₃), 4.42(bs, 2, C₃-CHBr), 4.62(s, 2, 측쇄의 CH₂), 5.14(s, 1, C₆-H), 5.42(s, 2, 에스테트 CH₂), 6.8-8.4(ArH).NMR (CDCl ₃ );

3.53 (s, 5, C ₂ -H and C ₆ -OCH ₃ ), 4.42 (bs, 2, C ₃ -CHBr), 4.62 (s, 2, side chain CH ₂ ), 5.14 (s, 1, C ₆ -H), 5.42 (s, 2, ester CH ₂ ), 6.8-8.4 (ArH).

The structure of the product was prepared using 4'-nitrobenzyl 7-phenoxyacetamido-3-bromomethyl-3-cefe-4-carboxylate at -80 ° C in lithium methoxide and tert-butyl. It was compared with the standard 4'-nitrobenzyl 7-phenoxyacetamido-7-methoxy-3-bromomethyl-3-cepem-4-carboxylate prepared by reacting hypochlorite with 7-methoxylation. .

Example 18

2-benzhydryl 7- (2-chienylacetamido) -7-methoxy-3-bromomethyl-3-cepem-4-carboxylate

Benzhydryl 7- (2-chienylacetamido) -3-methylenecepam-4-carboxylate according to the method described in Example 17 in tetrahydrofuran solution in the presence of 8 equivalents of bromine at −80 ° C. Reaction with 8 equivalents of lithium methoxide gives a compound of the title:

3.41(bs, 2, C₂-H), 3.46(s, 3, C₇-OCH₃), 3.83(s, 2, 측쇄의 CH₂), 4.20, 3.34(ABq, 2, C₃-CH₂Br), 5.06(s, 1, C₆-H) 및 6.8-7.6(m, 14, 방향족 수소와 벤즈하이드릴 CH).NMR (CDCl ₃ );

3.41 (bs, 2, C ₂ -H), 3.46 (s, 3, C ₇ -OCH ₃ ), 3.83 (s, 2, side chain CH ₂ ), 4.20, 3.34 (ABq, 2, C ₃ -CH ₂ Br), 5.06 (s, 1, C ₆ -H) and 6.8-7.6 (m, 14, aromatic hydrogen and benzhydryl CH).

Example 19

Benzhydryl 7- (2-chienylacetamido) -7-methoxy-3-chloromethyl-3-cepem-4-carboxylate

2 ml of methanol is added to a solution made by dissolving 2 ml of 1.85 M methyllithium in 25 ml of tetrahydrofuran. The mixture is cooled to −80 ° C. in a dry ice / acetone bath and 0.15 ml of tert-butyl hypochlorite are added. Then a solution made by dissolving 0.504 g of benzhydryl 7- (2-chienyl-acetamido) -3-methylenecepam-4-carboxylate in 4 ml of tetrahydrofuran is added. After 20 minutes 3 ml of acetic acid are added at -80 ° C, then the mixture is warmed to 0 ° C. The reaction mixture is evaporated to dryness in vacuo and the resulting residue is dissolved in methylene chloride. The methylene chloride solution was continuously washed with 5% hydrochloric acid, water and saturated brine, dehydrated with anhydrous sodium sulfate, vacuum dried and evaporated to dryness in vacuo to give the title compound:

3.38(bs, C₂-H), 3.46(s, 3, C₇-OCH₃), 3.82(s, 2, 측쇄의 CH₂), 4.34(s, 2, C₃-CHCl), 5.04(s, 1, C₆-H), 6.8-7.6(ArH).NMR (CDCl ₃ )

3.38 (bs, C ₂ -H), 3.46 (s, 3, C ₇ -OCH ₃ ), 3.82 (s, 2, side chain CH ₂ ), 4.34 (s, 2, C ₃ -CHCl), 5.04 (s , 1, C ₆ -H), 6.8-7.6 (ArH).

Example 20

4'-nitrobenzyl 7-phenoxyacetamido-7-methoxy-3-chloromethyl-3-cem fem-4-carboxylate

Compounds of the above title are prepared from the 4'-nitrobenzyl 7-phenoxyacetamido-3-methylenecepam-4-carboxylate according to the method described in Example 19.

3.52(s, 5, C₇-OCH₃, C₂-H), 4.52(m, 2, C₃-CH₂Cl), 4.61(s, 2, 측쇄의 CH₂), 5.10(s, 1, C₆-H), 5.37(s, 2, 에스테르 CH₂) 및 6.9-8.2(ArH).NMR (CDCl ₃ )

3.52 (s, 5, C ₇ -OCH ₃ , C ₂ -H), 4.52 (m, 2, C ₃ -CH ₂ Cl), 4.61 (s, 2, side chain CH ₂ ), 5.10 (s, 1, C ₆ -H), 5.37 (s, 2, ester CH ₂ ) and 6.9-8.2 (ArH).

Claims (1)

-80

Tert-butyl hypochlorite, bromine, tert-butyl hypobromite, iodide monobromide, 1,5-diazabicyclo [5,4,0] undec-5-ene hydrobromide perbromide 3-methylenecepam of the following formula (II) in an inert organic solvent in the presence of 1-6 equivalents of an active halogenating agent selected from iodine, iodide monochloride, tert-butyl hypoiodite and perchloryl fluoride 3 to 6 equivalents of C ₁ -C ₇ alcohol alkali metal salt or 1 to 3 equivalents of primary or tertiary C ₁ -C ₇ alcohol alkali metal industry or by reacting with a bicyclic amidine base of the following structural formula (III) A process for preparing 3-halomethylcefem compound of formula (I).

In the above structural formula, X is fluorine, chlorine, bromine or iodine z is 3,4 or 5, q is 1 or 0, R is a carboxylic acid protecting group, R ₁ is hydrogen or methoxy, R ₂ and R ₅ (1) is already an imide group of the following structural formula (IV)

Wherein R ₄ is C ₂ -C ₄ alkenylene, 1,2-phenylene or 1,2-cyclohexenylene (2) is an amido group of the following structural formula (V)

Where R ₃ is (a) hydrogen, C ₁ -C ₃ alkyl, halomethyl, 3- (2-chlorophenyl) -5-methylisoxazol-4-yl or 4-protected amino-4-protected carboxybutyl (b) benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichloro ethoxy, tert-butoxy or 4-methoxybenzyloxy (c) -R '' group wherein R '' is 1,4-cyclohexahexanyl, phenyl or halo, protected hydroxy, nitro, cyano, triomethyl, C ₁ -C ₃ alkyl and C Or phenyl substituted with one or each other two substituents selected from _1- C ₇ alkoxy) (d) an arylalkyl group of the following formula (VI) R ''-(O) m- (CH ₂ )-(VI) Where R '' is as defined above and m is 0 or 1 (e) a substituted arylalkyl group of the formula

Wherein R '' 'is R' ', 2-thienyl, 3-thienyl, bromo-2-thienyl or bromo-3-thienyl as defined above and W is protected hydroxy or protected Amino) Or (f) a heteroarylmethyl group of the following structural formula (iii). R '''-CH _2- (Ⅷ) Wherein R '' ''. 2-thienyl, 3-thienyl, 2-furyl, bromo-2-thienyl, bromo-3-thienyl, bromo-2-furyl, 2-thia Zolyl, 5-tetrazolyl or 1-tetrazolyl)] or (3) It is an amidazolidinyl group of following structural formula.

Wherein R '' 'is as defined above and Y is acetyl or nitrozo)