KR870000526B1 - Process for preparing azetidinone suifinic acid from cephalosporin sulfones - Google Patents

Abstract

New cepham sulphones of fomula(I) [R1=carboxylic acyl; R2=H, alkoxy or alkylthio; R3=removable ester-forming gp. were prepd. by reduction of corresp. 3-acetoxy-methyl-3-cephems. Thus, a corresp. 3- acetoxymethyl-3-cephem was reacted with activated Zn, Mg, activated Mg or amalgamated Mg in presence of a bound proton source in solvent at -30≰C to 30≰C to give cepham deriv. (II) [n=1 or 2 . (II) are intermediates in the prepn. of antibacterial cephalosporins, esp. the 1-oxides and 1-oxado-thiacepahlosporins.

Description

Method for preparing azetidinone sulfinic acid

The present invention relates to a process for preparing azetidinone sulfinic acid of the general formula (I) which is useful for the synthesis of cephalosporin antibiotics.

In the above formula,

R ¹ is an acyl residue of carboxylic acid,

R ² is hard, lower alkoxy or lower alkylthio,

R ³ is a removable ester forming group.

The present invention provides a process for converting a novel 3-exomethylene cepam sulfone into azetidinone sulfinic acid useful for synthesizing 1-oxadetia cephalosporin antibiotics.

A new class of antibiotics has recently been developed that have been found to be very effective against a broad spectrum of bacterial infections. This new class of compounds, 1-oxadetiacephalosporin, is a cephalosporin homologue having an oxygen atom at the sulfur atom in the cephalosporin nucleus.

This compound is described in the literature. [See Sheehan et al., In J. Heterocyclic Chemistry, Vol. 5, page 779 (1968); Christensen et al., In j. Am. Chem. soc. Vol. 96. page7582 (1974); And US Patent Nos. 4, 138, 486 to Narisada et al.]

In the reported synthesis of 1-oxadetiacephalosporin, haloazetininone, in particular 4-chloroazetidinone, was used. See US Pat. Nos. 4, 013, 653, 4, 234, 724 and No. 4, 159, 984]. This haloazetidinone starting material is typically prepared by reacting penicillin with a halogen molecule or a halogenating agent such as N-halosuccinamide. [US Patent No. 4, 159, 984] Nafisada et al. Described a method for synthesizing chloroazetidinone from methylthioazetidinone induced with penicillin. [US Patent No. 4, 138] , 486]. To date, haloazetidinone has not been obtained from the cephalosporin starting material.

The present invention provides a chemical process for converting cephalosporin sulfone to azetidinone sulfinic acid, which can be converted to haloazetidinone, wherein the haloazetidinone is 1-oxadetia. It can be converted to cephalosporin antibiotics.

The azetidinone sulfinic acid of general formula (I) according to the present invention may be prepared by activating zinc, magnesium, activated magnesium or amalgam in a solvent having a temperature of about 20 ° C. to about 100 ° C. Prepared by reaction with magnesium sulfide and proton.

In the above formula,

R ¹ , R ² and R ³ are as described above.

The method is carried out using, for example, a protonic acid in combination with an amine compound. Particularly preferred bound protic acid is ammonium chloride.

Another preferred embodiment is to carry out the process on sulfones of the general formula (II) wherein R ¹ is a group as follows.

In the above formula,

R ⁴ is hydrogen, amino, protected-amino, hydroxy, protected-hydroxy, tetrazolyl, carboxy, or protected-carboxy,

R ⁵ is hydrogen, phenyl, substituted phenyl, cyclohexadienyl or a 5- or 6-membered monocyclic heterocyclic ring containing one or more oxygen, sulfur, nitrogen atoms in the ring, which ring is substituted with hydrogen or amino )

Y is oxygen or a direct bond,

R ⁶ is hydrogen, phenyl, substituted phenyl, alkyl or substituted alkyl.

The process is typically carried out using a 3-exo methylene sepam substrate, wherein R ¹ is mentioned below.

Preferred metals that can be used in the present invention are activated zinc. Preferred reaction solvents are N, N-dimethyl formamide. The solvent used should be non-reactive under the reaction conditions used.

R <^1> of the said general formula is an acyl residue of carboxylic acid. The R ¹ group is not critical to the process because the process of the invention acts on the nucleus of the cephalosporin starting material. Several acyl residues of carboxylic acids are known in the cephalosporin and penicillin arts and both groups can be used in the present invention. Representative acyl moieties are described in US Pat. Nos. 4, 052, 387 and 4, 243, 588 by reference.

Preferred cephalosporin sulfones that can be used in this process are those in which R ¹ is

Wherein Y is oxygen or a direct bond, R ⁴ is hydrogen, amino, protected amino, hydroxy, protected-hydroxy, tetrazolyl, carboxy or protected carboxy; R ⁵ is hydrogen, phenyl, substituted Phenyl, cyclohexadienyl or 5- or 6-membered heterocyclic ring). The terms "protected-amino""protectedhydroxy" and "protected-carboxy" used have definitions recognized in each field. For example, "protected-amino" refers to an amino group derived from a decomposable group that can prevent side reactions of undesired amino groups in the course of the process, or to aid in the dissolution of an amino-containing substrate. Groups used as protecting groups for amino, hydroxy and carboxy moieties are known and many are exemplified in the literature. Chapters 2, 3 and 5 of Protective Groups in Organic Chemistry, McOmie, Ed. York, NY (1973) and Protective Group in Organic Synthesis, Greene, Ed. John Wiley and Sons, New York, NY, (1981).

Representative amino-protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl and 1-carbonmethoxy-2-propenyl group do. Commonly used hydroxy-protecting groups include acyl groups (eg formyl, acetyl, chloroacetyl), arylalkyl groups (eg benzyl and 4-nitrobenzyl) and alkyl groups (eg methoxy methyl and tertiary- Butyl). Groups commonly used to protect carboxy groups (which are referred to as "removable ester-forming groups") include alkyl groups such as methyl, tert-butyl, or C ₂ -C ₆ alkanoyls. Oxymethyl) and aralkyl groups such as diphenylmethyl, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, tri (C ₁ -C ₃ alkyl) silyl, succinimidomethyl) and related groups. When referring to hydroxy, amino or carboxy groups, one also considers each protected group. It is intended that such groups can be substituted with conventional blocking groups used to temporarily protect against undesired side reactions and promote dissolution of the compounds containing such groups. Such protected groups can be converted to the corresponding freehydroxy, carboxy or amino groups by conventional and known methods.

The term “substituted phenyl” means a phenyl group having one or two substituents, selected from lower alkyl (eg C ₁ -C ₄ alkyl), amino, hydroxy or lower alkoxy.

로 정의된 카복실산아실 잔기의 예로는 페닐아세틸, 페녹시아세틸, 4-시아노페닐아세틸, 4-3급-부톡시페닐아세틸, α-하이드록시페닐아세틸, α-아미노페닐아세틸, α-3급-부톡시카보닐아미노페닐아세틸, α-에톡시카보닐페닐아세틸, 또는 4-니트로페녹시아세틸 또는 이의 보호된 유도체를 포함할 수 있다.

Examples of carboxylic acid acyl residues defined as include phenylacetyl, phenoxyacetyl, 4-cyanophenylacetyl, 4-tert-butoxyphenylacetyl, α-hydroxyphenylacetyl, α-aminophenylacetyl, and α-tertiary. Butoxycarbonylaminophenylacetyl, α-ethoxycarbonylphenylacetyl, or 4-nitrophenoxyacetyl or protected derivatives thereof.

[여기에서 R6는 수소, 알킬(예 : C₁-C₆알킬), 페닐, 치환된 페닐 또는 치환된 알킬이다]이다. 용어 "치환된 알킬"에는 하이드록시, 아미노, 카복시 또는 알쿡시와 같은 하나이상의 치환기를 함유하는 C₁-C₆알킬그룹이 포함된다. 전형적인

그룹은 포르밀, 아세틸, n-부티릴, 5-아미노펜타노일, 벤조일, 4-아미노벤조일, 3-하이드록시벤조일, 4-메틸벤조일, 2, 6-디에틸벤조일 또는 이의 보호된 유도체이다.Another preferred R ¹ carboxylic acyl residue is

Where R 6 is hydrogen, alkyl (eg C ₁ -C ₆ alkyl), phenyl, substituted phenyl or substituted alkyl. The term "substituted alkyl" includes C ₁ -C ₆ alkyl groups containing one or more substituents such as hydroxy, amino, carboxy or alkoxy. Typical

The group is formyl, acetyl, n-butyryl, 5-aminopentanoyl, benzoyl, 4-aminobenzoyl, 3-hydroxybenzoyl, 4-methylbenzoyl, 2, 6-diethylbenzoyl or protected derivatives thereof.

According to the method of the present invention, 3-exomethylene-1,1-dioxocepam (ie, cephalosporin sulfone) is reacted with azetidinone sulfide by reaction with a metal such as activated zinc, activated magnesium, magnesium or magnesium amalgamated and a protonic acid. Prepares finic acid. Preferred metals used in the process are activated zinc. Activated zinc is generally a zinc metal without an oxide layer. Commercially available zinc metal powders usually have one or more zinc oxide coatings. This is easily removed by washing the zinc with a rare inorganic acid (eg 1N hydrochloric acid or sulfuric acid). The activated metal formed may be washed with a solvent for use in the process, although general laboratory solvents may be used. Representative solvents that may be used in this process may be polar solvents such as N, N-dimethyl formamide (DMF), formamide, dimethylsulfoxide, hexamethylphosphotriamide or N, N-dimethylacetamide. Optionally less polar organic solvents such as alcohols (eg methanol, ethanol, isopropanol), ethers (eg diethylether, methylethyl ether, tetrahydroputane) and ketones (eg acetone or methyl ethyl ketone ) Can be used. Preferred solvent for use in the process is N, N-dimethylformamide. One or more solvents may be used if necessary and a mixture of N, N-dimethylformamide and water (volume ratio about 80:20) is a particularly preferred solvent system.

The process of the present invention is carried out in the presence of a protic acid and a number of conventional amphoteric acids can be used. Typical amphoterics commonly used include inorganic acids (e.g. hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid) and organic amphoterics (e.g. formic acid, acetic acid, trifluoroacetic acid, chloroacetic acid, methanesulfonic acid or benzoic acid). .

In some cases, the protic acid may be used in the form of a bound proton, such as an amine acid addition salt. Representative amines used to bind protic acids include ammonia and lower alkylamines (methylamine, dimethylamine, triethylamine) and cyclic and aromatic amines (pyrrolidine, piperizine or pyridine). Ammonia is particularly preferred and hydrochloric acid is the preferred protic acid used to bind ammonia.

Each amount of metal and protic acid used in the process is not critical, but it is preferred to use about equimolar amounts or excessive amounts, respectively, in order to promote full conversion of 3-exomethylene cephalosporin sulfone. Typically about 1 to about 50 molar excess of metal and acid are used relative to the sefamsulfone starting material, and some of the excess is insignificant and can be used as the case may be.

The reaction of 3-exo methylene sulfone, metal and protic acid is typically carried out at about 20 ° C to about 100 ° C, more typically about 25 ° C to about 60 ° C. When carried out at this temperature, the reaction is usually complete after 2 to 24 hours.

This process product, azetininone sulfinic acid, is easily separated by conventional methods. For example, the reaction mixture can be filtered to remove excess metal and the filtrate can be concentrated to dryness. If desired, the product formed can be further purified by conventional methods, including salting and crystallization. The product of this process is not most conveniently separated, but rather reacts further with a halogenating agent (e.g., N-chlorosuccinimide or N-bromosuccinimide) in its original form to yield the halo of Formula (VI) Produces azetidinone.

In the above formula,

R ¹ , R ² and R ³ are as defined above,

X is halo such as fluoro, chloro, bromo or iodo.

Such haloazetidinones are useful for the synthesis of 1-oxadethiacephalosporin compounds that can act as antibiotics themselves or can easily be converted to antibiotics, for example by removing any protecting groups present. The conversion of halo azetidinone to 1-oxadetia cephalosporin is described in US Pat. Nos. 4, 103, 653 and 4,234,724.

The process of the present invention can likewise be performed well using sefamsulfone, in which the 7-acyl amido side chain is naturally occurring or β-span, or α- or epiarray. Throughout the process the arrangement of acylamido groups is maintained so that the azetidinone sulfinic acid product has an acylamido side chain of the same arrangement as the starting material used. Thus, according to the present invention, natural azetidinone-4-sulfinic acid (A) and epi-azetidinone-4-sulfinic acid (B) are produced.

Formula (II) compounds used as starting materials in the preparation of the above-mentioned compounds of formula (I) are novel compounds. Therefore, this invention also provides the manufacturing method of the following general formula (III) compound containing the compound of general formula (II). [The compound of General formula (II) is a compound whose n is 2 in general formula (III) compound.]

In the above formula,

R ¹ , R ² , and R ³ are as described above and n is 1 or 2.

Cephalosporins containing 3-exomethylene groups are important intermediates in the synthesis of cephalosporins with antimicrobial activity. Chauvette described that ozone digestion of 3-exomethylenecepam yields 3-hydroxy-3-cepem, which is then halogenated to yield 3-halo-3-cepem antibiotics. 3, 925, 372]. One of these, 3-chloro-3-cepem, is commonly known as cefaclor.

Several methods of synthesizing 3-exomethylenecepam are known. Chauvette and pennington are described in the following literature by reacting 3-acetoxy-3-cefe (cephalosporan acid derivative) with a sulfur nucleophile, such as thiourea, to form a 3-thiomethyl-3-cefem derivative. The method of obtaining the corresponding 3-exomethylenecepam by reducing the obtained compound with zinc in formic acid and dimethylformamide was described. See J. Org. chem., 38, 2994 (1973). Ochiai et al. Described in US Pat. No. 3, 792, 995 a method of electroreductively degrading 3-acetoxy groups of cephalosporanic acid derivatives to obtain 3-exomethylenecepam. Teijin described in Japanese Patent No. 51, 141, 889 a method for preparing 3-exomethylene cepam by reacting 3-trifluoroacetoxy-3-methylsepam with a strong acid such as methanesulfonic acid. . Kukolja describes a method of converting monocyclic azetidinone-2-sulfinyl chloride to 3-exomethylenecepam by reacting a monocyclic azetidinone-2-sulfinyl chloride with a Friedel-Craft catalyst. Ponticello et al., In US Pat. Nos. 3, 883, 518, reduce 3-carbamoyloxymethyl or 3-acetoxymethyl cephalosporin with zinc and acetic acid to yield the corresponding 3-exomethylenecepam. How to do this was described.

All these prior methods of preparing 3-exomethylenecepam have several problems. The use of C-3 derivatives other than acetoxy is uneconomical as it requires an additional reaction process from the product. The method requiring acid for a long time has a problem that △ ³ isomerization occurs. Moreover, the yield of 3-exomethylenecepam of the prior art method is usually low.

In accordance with the present invention, an improved process for preparing 3-exomethylene cepam from 3-acetoxymethyl-3-cepem is provided. The present invention differs from the prior art in that 3-exomethylenecepam is obtained in high yield. In addition, since there is no free acid in the reaction mixture, there is little risk of undesired side reactions.

According to the present invention, the compound of formula (III) is prepared from about -30 ° C to about +30 in the presence of a bound proton source in a solvent of 3-acetoxymethyl cefem of another formula (IV) Prepared by reaction with activated zinc, magnesium, activated magnesium or amalgamated magnesium at a temperature of &lt; RTI ID = 0.0 &gt;

In the general formula, R ¹ , R ² , R ³ and n are as described above.

This preferred method is to use 3-acetoxymethyl-3-cepem-1-oxide in which n is 1 in the above general formula (IV) as starting material, 3-acetoxymethyl-3- in which n is 2 It is also preferable to use cefem-1,1-dioxide.

Preferred in this process is the use of ammonium chloride as the bound proton source.

In a preferred embodiment, especially when n is 1, N, N-dimethylformamide and water (water volume of about 10% to 20%) are used as reaction solvent.

When n is 2, it is preferable to use it with alcohol solvents, such as ethanol.

The most preferred metal that can be used is activated zinc.

In a preferred embodiment, 3-exomethylenecepam of formula (III) is prepared from compounds of formula (IV) wherein R ₁ is an acyl residue of a carboxylic acid selected from the following formula:

In the above formula,

R ⁴ , R ⁵ , R ⁶ are as defined above,

X has the same definition as Y described above.

An embodiment for preparing the general formula (III) compound of the present invention is carried out using 3-acetoxymethyl-3-cepem, in which the side chain defined by R ^{1 is} as follows.

In the general formula, R ¹ is an acyl residue of carboxylic acid. Since the method of the present invention includes only the acetoxymethyl group bonded to the 3-position of the cephalosporan acid derivative, the 7-amino group bound to the 7-amino group of cephalosporin is not important for the process. Several acyl residues of carboxylic acids are known in the art of cephalosporins and penicillins and 3-acetoxymethyl cephalosporins with such acyl residues can be used. U.S. Patent Nos. 4, 052, 387 describe representative acyl residues used in the field of cephalosporins.

그룹 (여기에서 X, R⁴및 R⁵는 전술한 바와 같다). 대표적인 아실잔기는 R⁴가 수소 또는 아미노이고 R⁵가 페닐 또는 치환된 페닐인 것이다.The most common acyl residue defined by R ¹ is the general formula

Group wherein X, R ⁴ and R ⁵ are as described above. Representative acyl residues are those wherein R ⁴ is hydrogen or amino and R ⁵ is phenyl or substituted phenyl.

The term "substituted phenyl" refers to a phenyl group having one or more substituents, such as lower alkyl (eg, C ₁ -C ₄ alkyl), amino, hydroxy, or lower alkoxy. If a hydroxy group is present, it is preferred to derivatize it with one of the usual hydroxy-protecting groups to facilitate dissolution and prevent any unwanted side reactions that may occur. Typical hydroxy protecting groups are the easily decomposed hydroxy commonly used in formin, acetyl, diphenylmethyl, 4-methylbenzyl, trimethylsilyl, tert-butyl, methoxymethyl and cephalosporin and penicillin chemistry. It is a protection group.

Particular amino groups present in the 3-acetoxymethyl cephalosporin starting material are preferably combined with the derivative (ie, protected). This also prevents side reactions and facilitates dissolution. As with hydroxy-protecting groups, "amino-protecting groups" are recognized in the cephalosporin and penicillin arts. Groups used as protecting groups for amino, hydroxy and carboxy residues are known and many are exemplified in the literature [Sections 2, 3 and 5 of Protective Groups in Organic Chemistry, McOmie, Ed, Plenum Press, New York] , NY, (1973) and Protective Groups in Organic Synthesis John Wiley & Sons, New York, NY, 1981].

로 정의된 카복실산 아실잔기의 예로는 페닐아세틸, 페녹시아세틸, 4-메틸페닐아세틸, 4-3급-부톡시페닐아세틸, 3,4-디에틸페닐아세틸, 2-푸릴아세틸, 2-티에닐아세틸, 3-티에닐아세틸, 시클로헥사디에닐아세틸, 4-3급-부톡시페녹시아세틸, α-아세트아미도페닐아세틸, α-에톡시카보닐페닐아세틸 및 다른 관련 카복실산 아실 잔기가 포함될 수 있다.

Examples of carboxylic acyl residues defined as include phenylacetyl, phenoxyacetyl, 4-methylphenylacetyl, 4-tert-butoxyphenylacetyl, 3,4-diethylphenylacetyl, 2-furylacetyl, 2-thienylacetyl , 3-thienylacetyl, cyclohexadienylacetyl, quaternary-butoxyphenoxyacetyl, α-acetamidophenylacetyl, α-ethoxycarbonylphenylacetyl and other related carboxylic acyl residues may be included. .

이다. 이 그룹의 예로는 벤조인, 4-메틸벤조일, 3-에틸-벤조일, 포르밀, 아세틸, 아미노아세틸, 메톡아세틸, 4-에틸페닐아세틸, 부티릴, 페타노일, 5-아미노펜타노일, 5-카복시펜타노일, 5-아미노-5-카복시펜타노일, 5-3급-부틸아미노-5-디페닐메틸카복시펜타노일 및 관련 카복실산 아릴 잔기 또는 이의 보호된 유도체를 들 수 있다.In the general formula (III) compound production process, the preferred carboxylic acyl residue is

to be. Examples of this group are benzoin, 4-methylbenzoyl, 3-ethyl-benzoyl, formyl, acetyl, aminoacetyl, methoxyl, 4-ethylphenylacetyl, butyryl, petanoyl, 5-aminopentanoyl, 5- Carboxypentanoyl, 5-amino-5-carboxypentanoyl, 5-tert-butylamino-5-diphenylmethylcarboxypentanoyl and related carboxylic acid aryl residues or protected derivatives thereof.

R ² of the above formula includes lower alkoxy such as methoxy and ethoxy and lower alkylthio such as methylthio, ethylthio or n-butylthio. The process is preferably carried out with a compound wherein R ² is hydrogen.

As mentioned above, R ³ is a "removable ester forming group". This term refers to a plurality of carboxylic acid-protecting groups which are easily removed by conventional means. All such are known in the art and may include groups such as diphenylmethyl, silyl, benzyl, P-methoxybenzyl, phenacyl or tetrahydropyranyl. Preferred, removable ester forming groups are diphenylmethyl. US Pat. No. 4, 052, 387 describes another removable ester forming group.

3-exomethylene cepam of general formula (III) is prepared by converting 3-acetoxylentyl-3-cepemsulfoxide or sulfone. This conversion process is carried out by reacting 3-acetoxymethyl-3-cepem with activated zinc, magnesium, activated magnesium or amalgamated magnesium in the presence of bound protons in an intersolvent at a temperature of about -30 ° C to about + 30 ° C. . Certain 7-acylamido cephalosporinic derivatives may be used as substrates.

The terms "activated zinc" and "activated magnesium" refer to metals which are generally free of acidic coatings. For example, commonly useful zinc powders are coated with one or more layers of chlorine oxide. Zinc oxide coatings can be removed by treatment with inorganic acids (eg hydrochloric acid or hydrobromic acid) to produce activated zinc. This is usually done before washing the zinc powder with an aqueous solution of acid (e.g. 1N hydrochloric acid) and then zinc into water or an organic solvent, preferably a solvent (e.g. N, N-dimethylformamide) used in the process. Clean. Activated zinc or activated magnesium can optionally be air dried and used directly in the process of the present invention. For example, activated zinc can be added to a reaction mixture consisting of a 3-acetoxymethyl-3-cepem substrate and bound protons in a suitable reaction solvent. The exact amount of activated zinc or other metal used is not critical to the process but it is preferred to use an equivalent weight or more preferably greater than 1 to 5 weights relative to 3-acetoxymethyl-3-cepem. As mentioned above, magnesium, activated magnesium and amalgamated magnesium can also be used in the present invention.

The process of the present invention requires the use of a combined quantum source. The term “bound proton” refers to a reagent capable of releasing protons useful in the presence of activated zinc or such other metals and 3-acetoxymethyl-3-cefem compounds. Such bound proton sources may typically include protic acid addition salts of amines. Amines, for example ammonia, readily form acid addition salts with organic and inorganic protic acids. Examples of bound protons thus formed are ammonium chloride, ammonium bromide, ammonium acetate, ammonium benzoate, ammonium formate, ammonium sulfate, ammonium phosphate and related ammonium salts. Other amines such as triethylamine, trimethylamine, n-butylamine, glycine, di-n-butylamine, N, N-dimethylcyclohexylamine, methylamine, dimethylamine, aniline, guanidine and isopropylamine are likewise protons Reacts with the acid to form ammonium and ammonium salts, which can be used to form the bound protons for use in the process of the present invention.

Aromatic amines (e.g. pyridine) and non-aromatic cyclic amines (e.g. pyrrolidine) can form acid addition salts to act as bound protons in this process. Protons react with metals and 3-acetoxymethyl-3-cepem substrates but the reaction mixture should be largely free of acid. In other words, the pH of the reaction mixture should not be more than about 3.0 and not more than about 8.5. Ideally the pH of the reaction mixture will be about 4.5 to about 8.0 preferably about 5.5 to about 7.5.

Many solvents can be used as appropriate reaction solvents in the general formula (III) compound preparation process. Preferred are solvents in which the 3-acetoxymethyl-3-cepem substrate is largely soluble, but this is not critical to the present invention. Commonly used solvents are polar solvents such as N, N-dimethylformamide (DMF), N, N-diethylformamide, dimethylsulfoxide, N-methylformamide or N, N-dimethylacetamide. Less polar solvents may also be used, such as alcohols (eg methanol, ethanol, isopropanol) and ethers (eg tetrahydrofuran, dioxane or methylethyl ether). In some cases, one or more solvents containing water may be used. Preferred solvent systems are mixtures of DMF and water in a volume ratio of about 4: 1. Such solvent systems are particularly preferred when using sulfoxide substrates. When using sulfone as a substrate, an alcohol solvent is more preferable. The process for preparing the compound of formula III is carried out at a temperature below room temperature, typically from about −30 ° C. to about + 30 ° C. Higher reaction temperatures have been found to promote isomerization so that large amounts of 3-methyl-3-cepem are produced from the first 3-exomethylene cepam. This applies especially in the case of sulfoxide substrates, so low temperatures are preferred when the process is carried out on sulfoxides.

The 3-acetoxymethyl-3-cepem starting material is only partially soluble in some solvents, so the cephalosporin substrate is mixed with the cephalosporin substrate, solvent and bound protons at temperatures above + 10 ° C., for example at room temperature or above room temperature. It is preferable to promote dissolution of the. If the substrate is 3-acetoxymethyl-3-cepem sulfoxide, it is preferred to cool the reaction mixture to about −10 ° C. or lower before adding activated zinc or other metals. Once the metal is added, the reaction is carried out at about -20 ° C to about 0 ° C. In the case of sulfones, the entire reaction can be carried out at high temperatures, for example at room temperature (ie about 25 ° C.).

In carrying out the general formula (III) compound preparation process, it may be desirable to add to the reaction mixture an additive that acts as a free base (ie, free amine) remover or buffer that may be present in the reaction mixture. For example, when DMF (particularly with water) is the preferred process solvent, conventional DMF often contains dimethylamine as an impurity. Since the free base in the reaction mixture promotes the production of the 3-methyl-3-cepem product, it is not critical, but preferred, to have a reagent in the reaction mixture which can complex or bind with the particular free base present. Commonly used base removers include Lewis acids such as zinc chloride, zinc bromide, ferric chloride, tin tin chloride, aluminum chloride, boron trifluoride. Preferred Lewis acids for use in the present invention are zinc chloride. Other buffers include ethylenediaminetetraacetic acid (EDTA), which is particularly desirable when the process is performed on a cephalosporin sulfone substrate.

As mentioned above, the use of Lewis acids or other buffers is not critical to the process. When such a reagent is used, it is typically used about equal to the 3-acetoxymethyl-3-cepem substrate. Excess 10 to 50% by weight is not harmful to the progress of the reaction and may be used in some cases.

The conversion of 3-acetoxymethyl-3-cepem of the present invention to the corresponding 3-exomethylenecepam is typically carried out within about 2 to about 48 hours when the reaction is carried out at a temperature of about -30 to about + 30 ° C. Is completed. Many 3-acetoxymethyl-3-cepem sulfoxide compounds are reacted at about 2 to about 5 hours at temperatures of 0 to + 10 ° C. and 3-isomethylenecepam can be separated after that time. In a preferred embodiment, the sulfoxide is reacted with a metal and bound proton source at about −20 ° C. to about + 10 ° C. at such temperature the reaction is typically complete after about 2 to 24 hours. The 3-acetoxy-3-cepem sulfone substrate reacts more quickly than sulfoxide and typically completes the process in about 15 minutes to about 2 hours when performed at room temperature. Sulfonation occurs less with 3-methyl-3-cefem than with sulfoxide.

Upon completion of the reaction, 3-exomethylenecepam product is easily separated by filtering the reaction mixture to remove metals and other insolubles and extract the product from the filtrate. For example, the highly volatile material is evaporated, the filtrate is concentrated, diluted with water and extracted with a water miscible organic solvent (eg, ethyl acetate, dichloromethane, or chloroform). The solvent is removed from the mixed extract by evaporation under reduced pressure to give the desired 3-exomethylenecepam product. The product can be purified by chromatography and removal of 3-methyl-3-cepem or other impurities that may be present using standard methods of crystallization with solvents such as methanone, isopropanol or benzene. As mentioned above, the starting material 3-exomethylene cepam prepared by the process of the present invention is useful as an intermediate in the synthesis of cephalosporins with antimicrobial activity. 3-exomethylstyrenecepam-1-oxide is particularly useful as an intermediate. The present invention includes a process for converting 3-acetoxymethyl-3-cepem sulfoxide to 3-exomerene palm sulfoxide. 3-exomethylenecepam sulfoxide is particularly useful for 3-hydroxy cephalosporin synthesis, which can be easily converted to 3-halosephalosporin by known methods. For example, 3-zonemethylenecepam sulfoxide derived from an appropriately protected cephalosporin C derivative can be subjected to ozone degradation to yield the corresponding 3-hydroxysepam sulfoxide and reacted with a reducing agent to produce the corresponding 3- Convert to hydroxycepam sulfide. The hydroxycepam sulfide is halogenated at 3-position, for example by reacting with a halogenating agent (e.g., phosphorus chloride) to give 3-chloro-3-cepem sulfide. Removal of the protecting group or dechaining and reacylation yields cephalosporin antibiotics such as cephaclo. This reaction is described in more detail in US Pat. Nos. 3, 925, 372.

3-exomethylene sulfone, the starting material of the present invention, is useful as an intermediate in the synthesis of 1-oxadethiacephalosporin antibiotics. For example, this compound is typically converted to azetidinone sulfinic acid by reaction with zinc which is then converted to chloroazetidinone and oxazoline, which are converted to 1-oxadethiacephalo by the methods described in the literature. Useful for the synthesis of sporin [Tsuji, et al., US Pat. No. 4, 220, 766, Narisada, et al. United States Patents 4, 323, 567 and United States Patents 4, 138, 486, 4, 013, 653 and 4, 159, 894.

The following examples further illustrate the invention, which is not intended to limit the invention.

Example 1

Activation of Zinc Powder

Approximately 5 grams of zinc metal powder is placed in a sintered glass funnel and ground with 20 ml of 2.5 percent (v / v) aqueous hydrochloric acid. The aqueous acid is removed by filtration and fresh acid solution is added. The aqueous acid is removed again by filtration and the zinc powder is polished several times with N, N-dimethylformamide.

Example 2

Diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1-oxide-4-carboxylate

Diphenylmethyl 7-β- (4-methylphenylcarboximido) -3-acetoxymethyl-3-cepem-1 in 5 ml of water containing 2.0 grams of ammonium chloride and 25 ml of N, N-dimethylformamide (DMF) 1.14 gram (2 mmol) solution of oxide-4-carboxylate is stirred under nitrogen atmosphere and cooled to 0-5 ° C. in an ice / water bath. 2.5 grams of activated zinc are added to the reaction mixture at once and the slurry is vigorously stirred at 0-5 ° C. The zinc is removed by filtration and washed with 50 ml of ethyl acetate, and then the filtrate is washed with 50 ml of water and 5% (v / v) aqueous hydrochloric acid and finally saturated aqueous sodium chloride. The organic layer is treated with charcoal and dried over magnesium sulfate. The drying agent was removed by filtration, and the filtrate was evaporated under reduced pressure to obtain 1.0 gram of white cellum. The foam was triturated with 10 ml of methanol and cooled at 0 ° C. for 12 hours to yield 610 mg (59.2) of diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylene cepam-1-oxide-4-carboxylate. %) Is obtained.

NMR (CDCl ₃ ) is a product consisting of about 94% of pure 3-exomethylenecepam and about 6% of 3-methyl-3-cepem isomer (s4.9, doublet, exomethylene; s2.1, singlet 3-methyl) Prove it is. High pressure liquid chromatography confirms that the product consists of about 94% pure 3-exomethylenecepam.

Diphenylmethyl 7-β- (4-methyl-phenylcarboxamido) -3-acetoxymethyl-3-cepam-1-oxide-4-carboxylate 1.14 grams of N-methylformamide at 25 ° C. under nitrogen Dissolve in 25 ml and repeat the reaction of Example 2. Two grams of ammonium chloride are added to the reaction mixture which is cooled to 4 ° C. in an ice / water bath and stirred. 2.5 grams of activated lead is added to the reaction mixture at a time and stirring is continued at 4 ° C. for 31/2 hours. The progress of the reaction is examined by thin layer chromatography.

When the reaction is complete, zinc is removed by filtration and washed with 25 ml of clean methylformamide. The filtrate is diluted with 100 ml of water and 100 ml of ethyl acetate. 2 milliliters of acetic acid is added to break up the formed emulsion and to separate the ethyl acetate layer. The aqueous layer is washed with clean ethyl acetate and the combined organic layers are washed with aqueous sodium chloride, treated with charcoal and dried. The solvent was removed by evaporation to give a foam which was crystallized from 10 ml of methanol to give 560 mg (55) of diphenylmethyl 7-β- (4-methylphenyl-carboxamido) -3-exomethylene cefe-1-oxide-4-carboxylate. %) Is obtained.

Example 4

5.72 grams (10 mmol) of diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-acetoxymethyl-3-cepem-1-oxide-4-carboxylate in 175 ml of DMF and 25 ml of water 10.0 grams of ammonium chloride are added all at once. The reaction mixture is stirred under nitrogen and cooled to −10 ° C. in an ethanol / ice bath. 12.5 grams of activated zinc are added to the cooled stirred reaction mixture at once. The reaction mixture is stirred vigorously for 9 1/2 hours at a temperature maintained at -10 to -5 ° C. The reaction mixture is stored at -20 ° C for 12 hours and stirred at -10 ° C for 2 hours. The solid is removed by a filter and washed with 250 ml of ethyl acetate. The filtrate is washed with 375 ml of water and 125 ml of 5% hydrochloric acid followed by 500 ml of water and 100 ml of saturated aqueous sodium chloride. The organic layer is washed again with 300 ml of water, 200 ml of saturated brine, and finally 100 ml of clean water. The organic layer is dried and the solvent is evaporated off under reduced pressure to yield a white solid. Crystallize the solid with 30 ml of methanol to afford 3.15 grams (61.3%) of diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1-oxide-4-carboxylate.

NMR (CDCl 3) demonstrates that the product is 94% 3-exomethylene and 6% 3-cefem isomer. This ratio is confirmed by high pressure liquid chromatography.

Example 5

The product of Example 4 is further purified by suspending 2.0 grams of the mixture in 25 ml of isopropyl alcohol and heating the mixture in a steam bath. Dichloromethanol is added until all solids are dissolved. Cooling the solution yields a white crystalline product, yielding 1.6 g of pure diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1-oxide-4-carboxylate.

Elemental analysis: C ₂₈ H ₂₅ N ₂ O ₄ S

Theoretic value: C, 67.69; H, 5.0 9; N, 5.44; 0, 15.55; S, 6.23

Found: C, 67.80; H, 5. 14; N, 5.18; 0, 15.79; S, 6.16

IR (CHCl ₃ ): 1780 cm-1 β-lactam carbonyl

1740cm-1 ester carbonyl

1670cm-1 amidecarbonyl

NMR (CDCl ₃ ): s3.57 (quartet, 2H, C-2); s5.43, s5.78 (2-single line, 2H, 3-exomethylene)

s5.33 (single line, 1H, C-4)

s4.89 (double line, 1H, C-6)

s6.13 (quartet, 1H, C-7)

s2.36 (single line, 3H, -CH ₃ )

s6.83 (single line, 1H, diphenylmethyl-CH)

s7.1 to 7.7 (multiline, 15H, aliphatic and -NH).

Example 6

Diphenylmethyl 7-β-phenoxyacet amido-3-exo methylenecepam-1-oxide-4-carboxylate

To a cold (0 ° C.) stirred solution of 2.35 grams (4 mmol) of diphenylmethyl 7-β-phenoxyacetamido-3-exo methylenecepam-1-oxide 4-carboxylate in 50 ml of DMF containing 10 ml of water Add 2.72 grams (2 mmol) of zinc chloride, 4.0 grams of ammonium chloride, and finally 5.0 grams of activated zinc powder. The reaction mixture is stirred for 36 h at 0-5 [deg.] C., then the solids are removed by filtration and washed with ethyl acetate. The filtrate is extracted with 200 ml of ethyl acetate and the organic phase is washed three times with 250 ml of water containing a small amount of 6N hydrochloric acid to break up the emulsification. The organic layer is washed with brine, dried and the solvent is evaporated off under reduced pressure to give a white foam. The foam was triturated with 25 ml of methanol and air dried to give 95% pure diphenylmethyl 7-β-phenoxyacetamido-3-exomethylenecepam-1-oxide-4-carboxylate (approximately 5% present in 3-cefem). ) 1.65 g.

NMR (CDCl ₃ ): s3.50 (quartet, 2H, C-2)

s5.43, 5.77 (2-single line, 3-exomethylene)

s5.30 (single line, 1H, C-4)

s4.80 (double line, 1H, C-6)

s5.95 (quartet, 1H, C-7)

)s4.50 (single line, 2H,

)

s6.84-7.50 (multiline, 16H, aliphatic and diphenylmethyl)

s8.08 (double line, 1H, NH)

Example 7

Diphenylmethyl 7-β-phenoxyacetamido-3-exomethylenecepam-1-oxide-4-carboxylate

A solution containing 2.28 grams (4 mmol) of diphenylmethyl 7-β-phenylacetamido-3-acetoxymethyl-3-cepam-1-oxide-4-carboxylate in 75 ml of DMF and 10 ml of water was stirred and iced / Cool down to 0-5 [deg.] C. in a water bath. To the cooled reaction mixture was added 2.7 grams of zinc chloride, 4.0 grams of ammonium chloride and 5.0 grams of activated zinc powder. The reaction mixture is stirred at 0-5 ° C. for 6 hours and then stored at 0 ° C. for 6 days. The solid is removed by filtration and washed several times with ethyl acetate. The ethyl acetate layer is separated with filtrate and the aqueous DMF layer is extracted several times with clean ethyl acetate. The ethyl acetate extract and the washing solution are mixed, washed with brine and dried. The solvent was evaporated to remove about 90% of diphenylmethyl 7-β-phenyl acetamido-3-exomethylenecepam-1-oxide-4-carboxylate and diphenylmethyl 7-β-phenylacetamido-3-methyl 1.27 grams of solid product is obtained, which is about 10% of 3-Cefe-1-oxide-4-carboxylate. The mixture is separated by high pressure liquid chromatography to give 540 mg of pure 3-exomethylenecepam product.

NMR (CDCl ₃ ): s3.42 (quartet, 2H, C-2)

s5.33, 5.67 (2-single line, 2H, 3-exomethylene)

s5.23 (single line, 1H, C-4)

s4.70 (double line, 1H, C-6)

s5.84 (quartet, 1H, C-7)

)s3.52 (single line, 2H,

)

s6.77 (polyline, 1H, diphenylmethyl-CH)

s7.23 (polyline, 16H, aromatic and -NH)

Example 8

Diphenylmethyl 7-β- (4- (methylphenylcarboxamido) -3-exomethylenecepam-1-oxide-4-carboxylate

A solution of 2.7 grams (20 mmol) of zinc chloride in 50 ml of DMF containing 10 ml of water is stirred under nitrogen and cooled to about 3 ° C. in an ice / water bath. Four grams of ammonium chloride were added to the cold reaction mixture at a time, followed by dichloromethyl 7-β- (4-methylphenylcarboxamido) -3-acetoxymethyl-3-sepam-1-oxide-4-carboxylate. 4 mmol) are added all at once. 5.0 grams of activated zinc powder is added to the cold stirred reaction mixture. The reaction mixture is stirred at about 3 ° C. for 6 hours and then at 0 ° C. for 48 hours. Thin layer chromatography analysis confirmed the reaction was complete and the product was largely a single compound.

The reaction mixture is filtered and the solid is washed with 200 ml of ethyl acetate. The filtrate is diluted with 250 ml of water and dilute hydrochloric acid is added to adjust the pH of the mixture to 7.0. The organic layer is separated and the aqueous layer is extracted several times with clean ethyl acetate. Ethyl acetate fractions are mixed, washed with chlorine and dried. The solvent is evaporated off under reduced pressure to yield 1.9 grams of a white solid. High pressure liquid chromatography confirms that the product is about 92% pure 3-exomethylenecepam. The product is crystallized from 12.5 ml of methanol to give 1.28 grams of diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1-oxide-4-carboxylate (61%).

Example 9

Diphenylmethyl 7-β- [α- (tert-butoxycarbonylamino) phenylacetamido] -3-exomethylenecepam-1-oxide-4-carboxylate

Diphenylmethyl 7-β- [α- (tert-butoxycarbonylamino) phenylacetamido] -3-acetoxymethyl-3-cepem-1-oxide-4-carboxylate in 50 ml of DMF and 10 ml of water To 2.75 grams (4 mmol) of cold (0-5 ° C.) stirred solution, 2.7 grams of zinc chloride, 4.0 grams of ammonium chloride and 5.0 grams of activated zinc powder are added. The reaction mixture is stirred for 6 hours at 0-5 ° C. and then stored at 0 ° C. for 12 hours. The reaction mixture is filtered and the solid is washed with ethyl acetate. The filtrate is extracted several times with clean ethyl acetate. The extract is mixed, washed with water and brine and dried. The solvent was evaporated off under reduced pressure to give an oil which was crystallized from 25 ml of methanol to give 90% pure diphenylmethyl 7-β- [α- (tert-butoxycarbonylamino) -phenylacetamido] -3-exomethylene Obtain 1.70 grams of cefam-1-oxide-4-carboxylate. The product is further high pressure liquid chromatography to give 100% pure 3-exomethylene product.

NMR (DMSO-d ₆ )

s3.80 (quartet, 2H, C-2)

s5.23 to 5.94 (multiline, 5H, exomethylene, C-4, C-7, acetamidomethine)

s5.08 (double line, 1H, C-6)

s1.43 (single line, 9H, tert-butyl)

s6.92 (single line, 1H, diphenylmethylmethine)

s7.43 (broad single line, 15H, aliphatic)

s8.35 (double line, 1H, -NH)

Example 10

According to the method of Example 9, 5.4 grams (40 mmol) of zinc chloride were dissolved in 100 ml of DMF at room temperature under nitrogen (which caused some exothermic reaction). The solution is stirred and cooled to 0-5 ° C. in an ice / water bath. Diphenylmethyl 7-β- [α- (tert-butoxycarbonylamido) phenylacetamido] -3-acetoxymethyl-3-cepem-1-oxide-4-carboxylate 5.5 in cold stirring solution Gram (8 mmol), 10 ml of water, 8.0 grams of ammonium chloride, 10 grams of active zinc powder (zinc is activated by washing three times with 3N hydrochloric acid and then washing three times). The reaction mixture is stirred at 0-5 ° C. under nitrogen and stored at −10 ° C. for 12 hours. The reaction mixture is warmed to 0-5 ° C. and stirred at that temperature for 10 hours and then stored again at −10 ° C. for 12 hours. Thin layer chromatography analysis (1: 1 v / v ethyl acetate-toluene) yielded the product by diphenylmethyl 7-β- [α- (tert-butoxycarbonylamino) phenylacetamido] -3-exomethylenecepam It is confirmed that -1-oxide-4-carboxylate is at least 90% (a small amount of 3-sepi isomer).

The reaction mixture is filtered and the filtrate is partitioned between ethyl acetate and water. The organic layer is separated, washed with water and brine, dried and the solvent is evaporated off to yield a white foam. The foam was ground with isopropyl alcohol to obtain approximately 90% pure diphenylmethyl 7-β- [α- (tert-butoxycarbonylamino) phenylacetamido] -3-exomethylenecepam-1-oxide-4- Obtain a carboxylate.

Example 11

Diphenylmethyl 7-β-[(5-heptanamido-5-di-phenylmethoxycarbonyl) valermido] -3-exomethylenecepam-1-oxide-4-carboxylate

A solution of 2.7 grams (20 mmol) of zinc chloride in 10 ml of water and 100 ml of DMF is stirred under nitrogen and cooled to 0-5 ° C. in an ice / water bath. 4 grams of ammonium chloride was added to the stirred solution, and the stirring was continued for 10 minutes, followed by diphenylmethyl 7-β-[(5-heptanamido-5-diphenylmethoxy-carbonyl) valermido] -3-acetoxymethyl 3.5 grams (4 mmol) of 3-cefe-1-oxide-4-carboxylate are added in one portion. With continued stirring, activated zinc (activated as in Example 1) was added to the reaction mixture all at once and the mixture was stirred at 0-5 ° C. for 8 hours. Thin layer chromatography analysis confirms that the reaction is not complete. The mixture is stored at -20 [deg.] C. for 12 h and then further stirred at 0-5 [deg.] C. for 8 h. The solid is removed from the reaction mixture by filtration (using a Hi-Flo filter aid) and the filtrate is diluted with ethyl acetate and water. The ethyl acetate layer was separated, washed with water, brine, dried and the solvent was evaporated off under reduced pressure to afford 2.8 grams of product as an oil. The oil was crystallized with diethyl ether to give diphenylmethyl 7-β-[(5-heptanamido-5-diphenylmethoxycarbonyl) valeramido] -3-exomethylenecepam-1-oxide-4-carboxyl 2.8 grams of product are obtained, which is about 80% of the rate and about 20% of the 3-methyl-3-cepem isomer. The yield of 3-exomethylenecepam was found to be about 68%.

NMR (CDCl ₃ ): s3.45 (quartet, 2H, C-2)

s5.40, 5.74 (2-single line, 2H, exomethylene)

s5.32 (single line, 1H, C-4)

s4.75 (dual line, 1H, C-6)

s5.84 (quartet, 1H, C-7)

s6.84 (2-single line, 2H, diphenylmethyl methine)

s0.80 to 2.40 (multiline, 19H, aliphatic)

s7.10 to 7.50 (broad singlet, 20H, aromatic)

s4.67 (multiline, 1H, methine)

Example 12

Diphenylmethyl 7-β-formamido-3-exomethylene-cepam-1-oxide-4-carboxylate

To a cooled (0-5 ° C.) stirred solution of 1.35 grams of zinc chloride and 2.0 grams of ammonium chloride in 25 ml of DMF and 5 ml of water, diphenylmethyl 7-β-formamido-3-acetoxymethyl-3-cepam-1- 970 milligrams (2 mmol) of oxide-4-carboxylate are added in one portion. The reaction mixture is vigorously stirred at 0-5 ° C. under nitrogen while 2.5 milligrams of activated zinc are added all at once. After continuing stirring for 5 hours, the mixture is stored at -10 ° C for 12 hours. The reaction mixture is filtered and the filtrate is added to ethyl acetate and water. The ethyl acetate layer was separated, washed with water and brine, dried and the solvent was evaporated off under reduced pressure to yield 85% pure diphenylmethyl 7-β-formamido-3-exomethylenecepam-1-oxide-4-carboxylate. 400 milligrams is obtained. The yield of 3-exomethylene is about 58%.

NMR (CDCl ₃ ): s3.53 (quartet, 2H, C-2)

s5.43, 5.77 (2-single line, 2H, exomethylene)

s5.33 (single line, 1H, C-4)

s4.84 (double line, 1H, C-6)

s5.95 (quartet, 1H, C-7)

s8.17 (single line, 1H, formyl H)

s6.84 (single line, 1H, diphenylmethyl H)

s7.00-7.50 (single line, 11H, aliphatic and -NH)

Example 13

Diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1,1-dioxide-4-carboxylate

To a stirring solution of 294 milligrams (0.5 mmol) of diphenylmethyl 7-α- (4-methylphenylcarboxamido) -3-acetoxymethyl-3-cepem-1,1-dioxide-4-carboxylate in 25 ml of ethanol. Add 500 milligrams of ammonium chloride all at once, followed by 750 milligrams of activated zinc (2x 20 ml of 2.5% aqueous hydrochloric acid and zinc washed several times with ethanol). The reaction mixture is stirred vigorously for 2 hours at room temperature under nitrogen. Thin layer chromatography analysis confirmed that the reaction mixture contains predominantly 3-exomethylene sepam product. Zinc was removed by filtration and ethanol was removed from the filtrate by evaporation to diphenylmethyl 7-α- (4-methyl-phenylcarboxamido) -3-exomethylenecepam-1,1-dioxide-4-carboxylate To obtain.

NMR (CDCl ₃ ): s2.28 (single line, 3H, -CH2)

s7.1 to 7.8 (polyline, 15H, aromatic and -NH)

s6.88 (single line, 1H, diphenylmethylmethine)

s4.9 to 5.60 (two singlets, 5H, C-4, C-6, C-7 and exomethylene, overlapped by two polylines)

s3.60 (br singlet, 2H, C-2).

Example 14

Diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1,1-dioxide-4-carboxylate

To a stirred suspension of 2.35 grams (4 mmol) of diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-acetoxymethyl-3-sepam-1,1-dioxide-4-carboxylate in 100 ml of ethanol. Add 4.0 grams of ammonium chloride all at once, then add 5.0 grams of activated zinc powder. The reaction mixture is stirred at room temperature under nitrogen for 1 hour. The solid is removed by filtration and the solvent is evaporated off from the filtrate under reduced pressure to give a white solid. The solid is dissolved in 50 ml of ethyl acetate, washed twice with 50 ml of water, dried and the solvent removed to give a white foam. The foam is dissolved in hot methanol and cooled to form a crystalline product which is collected by filtration. High performance liquid chromatography resulted in 90% diphenyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1,1-dioxide-4-carboxylate and 10% 3-methyl-3 It has been shown to be a cefe isomer.

Elemental analysis: C ₂₉ H ₂₆ N ₂ O ₆ S

Theoretic value: C, 65.65; H, 4.94; N, 5.28; 0, 18.09; S, 6.04

Found: C, 65.49; H, 4.99; N, 5.19; 0, 17.91; S, 6.12

NMR (CDCl ₃ ): s3.67 (single line, 2H, C-2)

s5.36, 5.46 (2-single line, 2H, exomethylene)

s5.36 (double line, 1H, C-4)

s5.14 (double line, 1H, C-6)

s6.23 (double of doublets, 1H, C-7)

s2.28 (single line, 3H, methine)

s6.80 (single line, 1H, dimenylmethyl methine)

s7.00-7.87 (multiline, 15H, aliphatic and -NH).

Example 15

Dimenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1,1-dioxide-4-carboxylate

While adding 2.0 grams of ammonium chloride in one portion, dimenylmethyl 7-β- (4-methylphenylcarboxamido) -3-acetoxymethyl-3-cepem-1,1-dioxide-4-carboxylate in 50 ml of tetrahydrofuran The 1.18 gram (2 mmol) solution is stirred at room temperature under nitrogen and then 2.5 grams of activated zinc is added. The reaction mixture is stirred at rt for 48 h and then filtered. The filtrate is concentrated to a solid by evaporating the solvent. The solid was dissolved in dichloromethane, filtered and the solvent was evaporated to remove the foam, which was then crystallized from 25 ml of methanol to give dimenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1,1 700 milligrams of dioxide-4-carboxylate is obtained. This product was found to contain about 10% of the 3-methyl-3-cepem isomer.

Example 16

-(4-메틸페닐카복스아미도)-3-엑소메틸렌세팜-1,1-디옥사이드-4-카복실레이트는 상응하는 3-아세톡시메틸-3-세펨을 활성아연 및 결합 양자원과 반응시켜 제조된다. 반응을 디메틸포름아미드 및 물(80 : 20 v/v) 중에서 수행하고 pH 약 5 내지 6이 유지되도록 에틸렌디아민테트라아세트산을 사용한다. 고압 액체 크로마토그래피로 반응 혼합물을 분석하여 목적하는 3-엑소메틸렌생성물, 3-메틸-3-세펨 화합물 및 3-아세톡시메틸-3-세펜(출발물질)의 퍼센트 농도를 측정한다. 여러 가지 연구 결과를 다음 표에 나타낸다.Several experiments are conducted to determine the effect on the response of a specific bound quantum source. Dimenylmethyl 7-

-(4-methylphenylcarboxamido) -3-exomethylenecepam-1,1-dioxide-4-carboxylate is prepared by reacting the corresponding 3-acetoxymethyl-3-cepem with active zinc and binding protons do. The reaction is carried out in dimethylformamide and water (80:20 v / v) and ethylenediaminetetraacetic acid is used to maintain a pH of about 5-6. The reaction mixture is analyzed by high pressure liquid chromatography to determine the percent concentrations of the desired 3-exomethylene product, 3-methyl-3-cefem compound and 3-acetoxymethyl-3-cepene (starting material). The results of various studies are shown in the following table.

Example 17

A series of reactions were carried out in the same manner as in Example 16 to measure the solvent effect in the reaction. The binding proton source used in each reaction is ammonium chloride.

Example 18

The same series of reactions as in Example 16 were carried out to determine the effect of the various metals on the reaction. For each reaction, DMF-water 80:20 is used as the solvent, ammonium chloride as the binding proton source, and EDTA as the pH regulator. The results are shown in the following table.

In the study as described in Examples 16 to 18, it was proved that ammonium chloride as the binding proton source, N, N-dimethylformamide as the reaction solvent and activated zinc as the water and metal were preferred.

Example 19

Preparation of 7-β- [2-amino-2- (4-hydroxyphenyl) acetamido] -3-chloro-3-cepem-4-carboxylate from 7-ACA

A) 18.9 kg of sodium carbonate in 62 liters of water are added dropwise to 64.26 kg of a stirred solution of 7-aminocephalosporranic acid (7-ACA) in 117 liters of acetone and 148 liters of water. The reaction mixture is stirred at 5-10 ° C. until all 7-ACA is dissolved. To the cooled reaction mixture is added dropwise a solution of 11.73 liters of 4-methylbenzoyl chloride in 55 liters of acetone over one hour. After the addition is complete, the reaction mixture is stirred at 5-10 ° C. for 30 minutes and heated to 35 ° C. Acetone is removed from the reaction mixture by evaporation under reduced pressure, and concentrated hydrochloric acid is added to adjust the pH to 7.0. The aqueous layer is washed with ethyl acetate and diluted with hydrochloric acid to pH 2.0. The precipitate formed is collected by filtration and washed with a mixture of ethyl acetate and water. The precipitate is air dried at 35 ° C. to give 26.10 kg of 7-β- (4-methylphenylcarboxamido) -3-acetoxymethyl-3-cepem-4-carboxylic acid.

B) stirring 36.0 kg of 7-β- (4-methylphenylcarboxamido) -3-acetoxymethyl-3-cepem-4-carboxylic acid (prepared as described in A) in 460 liters of acetone and 46 liters of water 16.1 liters of peracetic acid was added dropwise over 45 minutes to the cooled (0-5 ° C.) solution. The reaction mixture is stirred at 0-5 ° C. for 12 hours. A 30.7 kg solution of benzophenone hydrazone in 140 liters of acetone is added in small portions over 30 minutes to the stirred cold reaction mixture. After the addition was complete the reaction mixture was further stirred at 0-5 ° C. for 30 minutes and then warmed to 25 ° C. and stirred for 12 hours. The reaction mixture is cooled to 17-20 [deg.] C. and 9.2 liters of trimethyl phosphite are stirred during the dropwise addition over 1 hour. The acetone solvent is removed into the reaction mixture by evaporation under reduced pressure, then 440 liters of isopropyl alcohol are added to the mixture and the mixture is cooled to 0-5 ° C. for 16 hours. The precipitated solid was collected by filtration and washed with clean isopropyl alcohol to diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-acetoxymethyl-3-cepem-1-oxide-4-carboxyl. Obtained 41.65 kg of rate.

C) Diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-acetoxymethyl-3-cepem-1-oxide-4-carboxy in 90 liters of water containing 36 kg of ammonium chloride and 630 liters of DMF 45 kg of activated zinc powder is added to a cold (-8 ° C.) stirred (under nitrogen) solution of 20.6 kg of silates. The reaction mixture is stirred at about −8 ° C. for 12 hours and then filtered. The solid is washed with ethyl acetate and the filtrate is withdrawn several times with ethyl acetate. The exports and washes are mixed, washed with water and brine, dried and the solvent is evaporated off under reduced pressure to give a solid. The solid is crystallized with methanol to yield 9.94 kg of diphenylmethyl 7-8- (4-methylphenylcarboxamido) -3-exomethylenecepam-1-oxide-4-carboxylate.

D) 8.0 kg solution of diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1-oxide-4-carboxylate in 156 liters of dichloromethane was cooled to -70 ° C and 14 hours While ozone gas is bubbled into the solution while stirring. With continued stirring at −70 ° C., the reaction mixture is diluted by dropwise addition of a 4.5 liter solution of triphenyl phosphite in 4.5 liters of dichloromethane over 15 minutes. The reaction mixture is concentrated to a volume of 60 liters and 73 liters is added thereto. The reaction mixture is stirred at 30 ° C. for 5 minutes and then the remaining dichloromethane is removed by evaporation while maintaining the temperature at 10-15 ° C. The reaction mixture is cooled to -43 [deg.] C. and subjected to a small addition of 3.4 liters of phosphorus trichloride over 10 minutes. The reaction mixture is warmed to −26 ° C. and stirred at that temperature for 15 minutes. The reaction mixture is then warmed to 25 ° C. and stirred for 2 hours. Dichloromethanol is evaporated off under reduced pressure and the remaining solution is diluted with 39 liters of methanol and 39 liters of water. The precipitate formed was collected by filtration and dried at 50 ° C. to yield 3.38 kg of diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-chloro-3-cefe-4-carboxylate.

E) Diphenylmethyl 7-β- (4-methylphenylcarboxamid) in a cold (-10 to -15 ° C) stirred solution of 2.43 liters of triphenylphosphite in 28.5 liters of methylene chloride containing 756 g of chlorine gas and 875 ml of pyridine 3.25 kg of 3-chloro-3-cepem-4-carboxylate are added in small portions over two hours.

After addition the reaction mixture is diluted with 434 g of hydrogen chloride and then warmed to room temperature and stirred for 2 hours. The reaction mixture is diluted with 35 liters of water and the aqueous mixture is stirred for 10 minutes. The organic layer is removed once separated, dried over 1 kg of calcium chloride and the solvent is evaporated off under reduced pressure. The product is crystallized with diethyl ether containing concentrated hydrochloric acid to give 1.96 kg of 7-amino-3-chloro-3-cef-4-carboxylic acid diphenylmethyl ester hydrochloride.

F) The obtained hydrochloride salt is converted to the free base by reaction with 1500 ml of 20% aqueous sodium carbonate solution. Sodium 3-[(α-carboxy-P-hydroxybenzyl) amino] crotonic acid methyl ester in 10.91 liters of ethyl acetate containing 13.1 ml of methanesulfonsal, 13.5 ml of N, N-dimethylbenzylamine and 181.1 ml of methylchloroformate 875 g of diphenylmethyl 7-amino-3-chloro-3-cepem-4-carboxylate are added in portions to a stirred, cold (-45 to -50 ° C.) solution of 672.1 g of salt. The reaction mixture is allowed to warm to room temperature and stirred for 2 hours. The solvent is removed from the filtrate by filtration and evaporation under reduced pressure to give a white powder. The powder was dissolved in 16.86 liters of chloromethane and 455 g of P-toluene sulfonic acid was added all at once with stirring. The reaction mixture was cooled to 0 ° C. and 175 ml of ethanethione was added with stirring followed by the dropwise addition of 336 ml of boron trifluoride diethyl etherate. The reaction mixture is allowed to warm up to room temperature and stirred for 3 hours. The mixture is filtered and the solvent is evaporated off to yield 608.2 g of 7-β-2-amino-2 (4-hydroxyphenyl) acetamido-3-chloro-3-cepem-4-carboxylic acid hydrate.

Example 20

Diphenylmethyl 7-β-phenylacetamido-7-α-methoxy-3-exomethylenecepam-1,1-dioxide-4-carboxylate

Diphenylmethyl 7-β-phenylacetamido-7-α-methoxy-3-acetoxymethyl-3-cepem-1,1-dioxide-4-carboxyl in 50 ml of N, N-dimethylformamide and 10 ml of water To a stirred, cooled (0 ° C.) solution of rate 2.48 grams, 2.7 grams (20 mmol) of zinc chloride, 4.0 grams of ammonium chloride and finally 5.0 grams of active zinc powder are added in portions. The reaction mixture is stirred at 0-5 ° C. for 5 hours, stored at −10 ° C. for 72 hours and then further stirred at 0-5 ° C. for 3 hours. The reaction mixture was filtered and the filtrate was added to 200 ml of ethyl acetate, washed twice with 200 ml of water and once with 200 ml of brine. The organic layer is separated, dried and concentrated to dryness to afford an oil. The oil was crystallized with 25 ml of methanol to give 530 mg (24% yield) of diphenylmethyl 7-β-phenylacetamido-7-α-methoxy-3-exomethylenecepam-1,1-dioxide-4-carboxylate. do. The second product is crystallized from the mother liquor to give 620 mg of adduct (52% total yield).

NMR (CDCl ₃ )

s3.32 (s, 3H); s3.65 (s, 2H)

s3.81 (s, 2H); s5.1 to 5.5 (s, 6H)

s6.5 (s, 1H); s7.33 (s, 15H)

Example 21

Preparation of Diphenylmethyl 3-methyl-2- (2-sulfinyl-4-oxo-3- (4-methylbenzoylamino) -1-azetidinyl) -2-butenoate from 3-exomethylenesulphone

3.18 g (6 mM) of diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1,1-dioxide-4-carboxylate in 35 ml of N, N-dimethylformamide and 5 ml of water The suspension of is stirred at 25 ° C. under a blanket of nitrogen. Six grams of ammonium chloride are added to the reaction mixture at a time and 7.5 g of zinc metal powder (washed with 50 ml of IN hydrochloric acid) are added. The reaction mixture is stirred at 25 ° C. for 24 hours and filtered through a Hiflo filter aid. The filter cake was washed with 20 ml of N, N-dimethylformamide followed by 200 ml of ethyl acetate. The filtrate is washed three times with 100 ml of 5% (v / v) aqueous hydrochloric acid. The organic layer was separated, washed with brine, dried and the solvent was evaporated and removed under reduced pressure to give a white foam of diphenylmethyl 3-methyl-2- (2-sulfinyl-4-oxo-3- (4-methylbenzoylamino) 3.5 g of-(-azetidinyl) -2-butenoate are obtained.

IR (CHCl ₃ ): 1778cm-1

NMR (CDCl ₃ ): s2.01 to 2.25 (three singlets, 3H each)

s4.70 (d, 1H); s5.60 (dd, 1H)

s6.1-7.9 (m, 16H); s9.35 (s, 1 H).

Example 22

Preparation of Diphenylmethyl 3-methyl-2- (2-sodium sulfonyl-4-oxo-3- (4-methylbenzoylamino) -1-azetidinyl) -2-butenoate from 3-exomethylene sulfone

3.18 g (6 mmol) of diphenylmethyl 7-β- (4-methylphenylcarboxamido) -3-exomethylenecepam-1,1-dioxide-4-carboxylate in 35 ml of N, N-dimethylformamide and 5 ml of water 6.0 g of ammonium chloride is added to a stirred solution of) followed by 7.5 g of activated zinc (activated by washing twice with dilute hydrochloric acid and twice with water). The reaction mixture is stirred for 24 hours at 25 ° C. under a blanket of nitrogen and the reaction mixture is filtered through a Hiflo filter aid and the filter cake is washed with 100 ml of ethyl acetate. The filtrate is washed with 5% aqueous hydrochloric acid and dried. While stirring the solution, a solution of 1 g (6 mmol) of sodium 2-ethylhexanoate in 20 ml of ethyl acetate was added all at once. The reaction mixture is stirred at 25 ° C. for 16 hours and then the solvent is evaporated off under reduced pressure to yield an oil. The oil was crystallized in 50 ml of chloroform to form diphenylmethyl 3-methyl-2 (2-sodiumsulfonyl-4-oxo-2- (4-methylbenzoylamino) -1-azetidinyl) -2-part of the general formula 1.0 g of tenoate is obtained.

IR (KBr): 1776cm ^-1

NMR (DMSO-d ₆ ): s2.05 (s, 3H)

s2.18 (s, 3H); s2.39 (s, 3H)

s4.56 (d, 1H); s5.56 (dd, 1 H)

s7.3 to 7.5 (m, 13 H)

s7.70 (d, 2H); s8.71 (d, 1 H).

Example 23

Diphenylmethyl α- [4-chloro-3- (4-methylcarboxamido) -2-oxazetidin-1-yl] -α-isopropylidene acetate

Diphenylmethyl 3-methyl-2- [2-sulfinyl-4-oxo-3- (4-methylphenylcarboxamido) -1-azetidinyl] 2-part in 25 ml of ethyl acetate and 10 ml of saturated aqueous sodium bicarbonate 530 mg of N-chlorosuccinimide is added to 1.07 g (2 mmol) of a mixture of tenoate (Schilling Example 1). The reaction mixture is stirred at 25 ° C. for 16 h. The organic layer was separated, washed with water and brine, and the solvent was evaporated and removed under reduced pressure to yield 900 mg of oil. The oil is chromatographed on silica coated plates. Remove the appropriate band, wash with acetone and evaporate the acetone to remove diphenylmethyl α- [4-chloro-3- (4-methylcarboxamido) -2-oxazetidin-1-yl] -α- Isopropylidene acetate is obtained.

IR (CHCl ₃ ): 1780 cm ^-1 (β-lactam)

Example 24

Benzyl 3-methyl-2- [2-sulfinyl-4-oxo-3-methoxy-3-phenylacetamido) -1-azetidinyl) -2-butenoate

Solution containing 2.5 g (5.15 mmol) of benzyl 7-β- (phenylacetamido) -7-α-methoxy-3-exomethylenecepam-1,1-dioxide-4-carboxylate in 20 ml of DMF and 75 ml of ethanol Is heated to 65 ° C., and 8.25 g (154.97 mM) of ammonium chloride are added in one portion with stirring, followed by 16.83 g (257.5 mmol) of activated zinc. The reaction mixture is stirred at 65 ° C. for 3 hours and then cooled to about 30 ° C. 100 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed six times with 20 ml of 1N hydrochloric acid and once with brine. The organic solution was dried and concentrated to dryness to yield benzyl 3-methyl-2- [2-sulfinyl-4-oxo-3-methoxy-3-phenylacetamido) -1-azetidinyl) -2-butenoate To obtain.

The physical properties of benzyl 7-β- (phenylacetamido) -7-α-methoxy-3-exomethylenecepam-1,1-dioxide-4-carboxylate used as starting materials in this example are as follows. same.

Elemental analysis: C ₂₄ H ₂₄ N ₂ O ₇ S ₁

Calc .: C, 59.49; H, 4.99; N, 5.78; S, 6.62; O, 23.11.

Found: C, 59.47; H, 5. 14; N, 6.08; S, 6.70; O, 22.90.

IR (KBR): 1785 (β-lactam) 1735 (ester) 1343, 1127 (SO2) cm ^-1

Claims (14)

3-exomethylene sulfone of formula (II) is reacted with activated zinc, magnesium, activated magnesium or amalgamated acid and protonic acid at a temperature of about 20 ° C. to about 100 ° C. in a solvent. A process for preparing azetidinone sulfinic acid of formula (I).

In the above formula, R ¹ is an acyl residue of carboxylic acid, R ² is hydrogen, lower alkoxy or lower alkylthio, R ³ is a removable ester forming group. The method of claim 1, R ¹ is

or

How to be. [In the above formula, R ⁴ is hydrogen, amino, protected amino, hydroxy, protected hydroxy, tetrazolyl, carboxy or protected carboxy, R ⁵ is hydrogen, phenyl, substituted phenyl or cyclohexadienyl, or a 5- or 6-membered monocyclic heterocyclic ring having one or more oxygen, sulfur or nitrogen atoms in the ring, which ring is substituted with hydrogen or amino ) Y is oxygen or a direct bond, R ⁶ is hydrogen, phenyl, substituted phenyl, alkyl or substituted alkyl.] According to claim 1 or 2, R ¹ is

How to be. The method of claim 3 wherein activated zinc is used. The process according to claim 4, wherein N, N-dimethylformamide is used as the reaction solvent. The compound of formula (IV) is reacted with activated zinc, magnesium, activated magnesium or amalgamated magnesium in a solvent at a temperature of about -30 ° C to about + 30 ° C in the presence of a binding resource. And the method for preparing the compound of the following general formula (III).

In the above formula, R ¹ is an acyl residue of carboxylic acid, R ² is hydrogen, lower alcohol or lower alkylthio, R ³ is a removable ester forming group, n is 1 or 2. The method of claim 6, wherein ammonium chloride is a binding proton. The process according to claim 6 or 7, wherein N, N-dimethylformamide is used as the solvent. The method of claim 8, wherein n is 1. 8. The method of claim 7, wherein the alcohol is used as the solvent. The method of claim 10, wherein n is two. The method of claim 6, R ¹ is

or

How to be. [In the above formula, R ⁴ is hydrogen, amino, protected amino, hydroxy, protected hydroxy, tetrazolyl, carboxy or protected carboxy, R ⁵ is hydrogen, phenyl, substituted phenyl or cyclohexadienyl, or a 5- or 6-membered monocyclic heterocyclic ring having one or more oxygen, sulfur or nitrogen atoms in the ring, which ring is substituted with hydrogen or amino ) R ⁶ is hydrogen, phenyl, substituted phenyl, alkyl or substituted alkyl, X is oxygen or a direct bond] The method of claim 12, R ¹ is

How to be. [In the above formula, R ⁵ is hydrogen, phenyl, substituted phenyl or cyclohexadienyl, or a 5- or 6-membered monocyclic heterocyclic ring having one or more oxygen, sulfur or nitrogen heteroatoms in the ring (the ring being hydrogen or amino Is substituted.] The method of claim 12,

How to be.