KR880001029B1 - 6-(substituted)methyenepenicillanic acid and 6-(substituted)hydroxymethyl penicillanic acids and derivatives thereof - Google Patents

Abstract

6-(substituted) methylene penicillanic acid and 6(substituted) hydroxymethyl penicillanic acid and their esters or salts as β- lactamase inhibitors are prepared. For methylene penicillanic acid, compound (V) reacts with compound (A) in organic solvent at -100 -- +50≰C to give compound (I).

Description

Process for preparing 6- (substituted) methylenephenicylanic acid and 6- (substituted) hydroxymethylphenylphenic acid and derivatives thereof

The present invention provides the preparation of novel 6- (substituted) methylenephenicylic acid, novel 6- (substituted) hydroxymethylphenicylic acid, specific esters thereof and pharmaceutically acceptable salts useful as beta-lactamase inhibitors. It is about a method.

One of the most widely known and used antibacterial agents is a class known as beta-lactam antibiotics. These compounds are characterized by having a nucleus consisting of a thiazolidine ring or a 2-azetidinone (beta-lactam) ring attached to a dihydro-1 or 3-thiazine ring. When the nucleus contains a thiazolidine ring, the compound is usually referred to as penicillin, and when the nucleus contains a dihydrothiazine ring, it is referred to as cephalosporin. Representative penicillins commonly used in clinical trials include benzylphenicillin (penicillin G), phenoxymethylphenicillin (penicillin V), ampicillin and carbenicillin; Representative cephalosporins are cephalotin, cephalexin and cefazoline.

However, despite the widespread use and recognition of beta-lactam antibiotics as important chemotherapeutic agents, some of these groups have the major drawback of being inactive against certain microorganisms. In many instances, the resistance of certain microorganisms to existing beta-lactam antibiotics is considered to be due to the microorganisms producing beta-lactamase.

The latter is an enzyme that breaks down the beta-lactam rings of penicillin and cephalosporin to produce products without antibacterial activity. However, certain substances have the ability to inhibit beta-lactamase, and the use of beta-lactamase inhibitors in combination with penicillin or cephalosporin can increase or enhance the antibacterial efficacy of penicillin or cephalosporin against certain microorganisms. . Antibacterial efficacy is considered to be enhanced when the antibacterial activity of a mixture of beta-lactamase inhibitors and beta-lactam antibiotics is much greater than the sum of the antibacterial activities of the individual components.

Thus, according to the present invention there is provided a novel compound 6- (substituted) methylenephenicsilane acid, its 1-oxide, 1, 1-dioxide and its esters which can be easily hydrolyzed in vivo. These novel peniclanic acids and their esters that can be easily hydrolyzed in vivo are potent inhibitors of beta-lactamase by microorganisms. Thus, there is also provided a method of enhancing the efficacy of beta-lactam antibiotics using these novel acids, salts thereof and certain esters thereof that can be readily hydrolyzed.

Also provided are derivatives of 6- (substituted) methylenephenicanoic acid, its 1-oxides with carboxy protecting groups and 1,1-dioxide, which are compounds useful as chemical intermediates.

Also provided are 6- (substituted) hydroxymethylphenicylic acid, 1-oxide, 1, 1-dioxide and salts and esters thereof useful as chemical intermediates and beta-lactamase inhibitors.

EP 50, 805 describes compounds of general formula (III) useful as beta-lactamase inhibitors.

In the above formula,

n is 0, 1 or 2,

R ₁ is CN or a specific carbonyl moiety,

R ₂ is hydrogen, lower alkyl or halogen,

R ₃ is hydrogen or a group that can be easily hydrolyzed.

This document also discloses 6-oxophenic silane esters, the corresponding sulfoxides and sulfones, as well as reacting them with phospholanes of the general formula R ₁ R ₂ C = P (C ₆ H ₅ ) Also described are methods for preparing the compounds.

British Patent Application GB 2, 053, 220A, among which n is 2, R ₁ and R ₂ are each hydrogen, optionally substituted alkyl, aryl, optionally substituted cycloalkyl, aralkyl or optionally substituted amino group, or R ₁ And specific 6-methylene-1, 1-dioxophenicsilane acids of the general formula (III) wherein R ₂ together with the carbon atom to which they are attached form a 3-7 membered carbocyclic ring or hetero-cyclic ring; And esters are described.

(여기에서 R₃는 H 또는 알카노일이고, R₄는 H,(C₂-C₄)알킬, 페닐, 벤질 또는 피리딜이다)인, 베타-락타마제 억제제로 유용한 특정 6-치환된 페니실란산 1, 1-디옥사이드 및 이의 에스테르가 기술되어 있다.In U.S. Patent Nos. 4, 287, 181, 6-substituents

In which R ₃ is H or alkanoyl and R ₄ is H, (C ₂ -C ₄ ) alkyl, phenyl, benzyl or pyridyl). Specific 6-substituted penicsilanes useful as beta-lactamase inhibitors. Acids 1, 1-dioxide and esters thereof are described.

The present invention relates to novel 6- (substituted) methylenepheniclanates of formula (I), or pharmaceutically acceptable acid addition salts of these compounds when R ² or R ³ is a group containing a basic nitrogen atom, or If R ¹ is hydrogen or R ² or R ³ contains a carboxy group, pharmaceutically acceptable cationic salts of the compounds are provided.

In the above formula,

n is 0, 1 or 2,

R ¹ is R ^a or R ^b , where R ^a is tetrahydropyranyl, allyl, benzyl, 4-nitrobenzyl, benzhydryl, 2, 2, 2-tri-chloroethyl, tert-butyl and pen Is a residue of a carboxy protecting group selected from acyl, R ^b is hydrogen, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl,

Is a residue of an ester group that can be readily hydrolyzed in vivo, wherein R ⁴ and R ⁵ are each hydrogen or CH ₃ , R ⁶ is (C ₁ -C ₅ ) alkyl, and R ¹⁴ is

Wherein X ₂ is a 3-substituent of a known cephalosporin beta-lactam antibiotic and R ¹⁵ is a 6- or 7-substituent of a known penicillin or cephalosporin beta-lactam antibiotic, respectively. Particularly preferred R ¹⁴ is R ¹⁵ is 2-phenylacetamino, 2-phenoxyacetamide, D-2-amino-2-phenyl-acetamino, D-2-amino-2- (4-hydroxy-phenyl) acetamino, 2-carboxy-2-phenylacet-amino, 2-carboxy-2- (2-thienyl) acetamino, 2-carboxy-2- (3-thienyl) acetamido, D-2- (4-ethyl -2,3-dioxopyrerazinocarbonylamino) -2-phenylacetamido, D-2- (4-ethyl-2,3, -dioxopiperazinocarbonylamino) -2- (4-hydr Oxy-phenyl) acetamido or the penicillin moiety that is 2,2-dimethyl-4-phenyl-5-imidazolidinon-1-yl]

One of R ² and R ³ is hydrogen and the other is CL, CH ₂ OH, vinyl, (C ₂ -C ₄ ) alkylthio, (C ₁ -C ₄ ) alkylsulfonyl, furyl, thienyl, N-methyl Pyrrolyl, N-acetylpyrrolyl, R ⁷ C ₆ H ₄ , R ⁷ C ₆ H ₄ S, —CH (R ⁴ ) NR ¹⁶ R ¹⁷ ,

[Where n is 2 or 3, P is 0 or 1, t is 0.1 or 2 and X ₁ is S, O or NR ¹¹ (where NR ¹¹ is hydrogen, CH ₃ , C ₂ H ₅ or CH ₃ CO) and R ⁷ is hydrogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, allyloxy, hydroxyl, carboxyl, (C ₂ -C ₅ ) alkoxycarbonyl, (C ₁ -C ₅ ) alkylcarbonyl, phenyl, benzyl, naphthyl, pyridyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NHCOR ¹⁰ , NO ₂ , CL, Br, CF ₃ or SR ⁸ and wherein <R ⁸ and R ⁹ is hydrogen, (C ₁ -C ₄ ) alkyl, phenyl or benzyl and R ¹⁰ is (C ₁ -C ₄ ) alkyl, CF ₃ or phenyl>, R ¹⁶ and R ¹⁷ are each H, (C ₁ -C ₄ ) alkyl or (C ₂ -C ₄ ) hydroxyalkyl, or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocyclic group, particularly preferred heterocyclic Groups include pyrrolidino, pyrrididino, morpholino, thiomorpholino or 4-methylaryrerazino ].

The compounds wherein R ¹ is R ⁸ are useful as intermediates in the preparation of compounds in which R ¹ is R ^b . The latter compound is the active benta-lactamase inhibitor of the present invention.

The present invention also relates to 6- (R ¹² R ¹³ -substituted) hydroxymethylphenicylic acid of formula (II), 1-oxide, 1, 1-dioxide and esters thereof, or pharmaceutically acceptable acid moieties thereof. Provide salt or carboxylate.

n and R ¹ are as defined in the compound of formula (I),

X ₃ is H or Br,

One of R ¹² and R ¹³ is hydrogen, the other is vinyl, (C ₁ -C ₄ ) alkylsulfonyl, furyl, thienyl, N-methylpyrrolyl, N-acetylpyrrolyl, R ⁷ C ₆ H ₄ , CH (R ⁴ ) NR ¹⁶ R ¹⁷ ,

이고 P가 0이면, R⁷은 H 또는 CH₃가 아니고 R¹⁸은 H, (C₂-C₅)알카노일, (C₂-C₅) 알콕시카보닐, 피라진카보닐, 벤조일, CF₃CO 또는 CONR⁸R⁹이고 m, P, t, R⁷, R⁸, R⁹, R¹¹, R¹⁶, R¹⁷및 X¹은 전술한 바와 같다.Provided that R ¹² or R ¹³

And P is 0, R ⁷ is not H or CH ₃ and R ¹⁸ is H, (C ₂ -C ₅ ) alkanoyl, (C ₂ -C ₅ ) alkoxycarbonyl, pyrazinecarbonyl, benzoyl, CF ₃ CO Or CONR ⁸ R ⁹ and m, P, t, R ⁷ , R ⁸ , R ⁹ , R ¹¹ , R ¹⁶ , R ¹⁷ and X ¹ are as described above.

The compounds of formula (II) are all useful as chemical intermediates for the preparation of the 6- (substituted) methylene-1, 1-dioxophenisilanate of the corresponding general formula (I). However, compounds of general formula (II) wherein R ¹ is also a residue of a hydrogen or ester group (R ^{b as described above} ) which can be readily hydrolyzed in vivo, especially when used in combination with beta-lactam antibiotics It is useful for lactase inhibitory activity.

Particularly preferred compounds of formula (I) are those in which n is 0 or 2, one of R ² and R ³ is hydrogen and the other is furyl, thienyl, CH ₂ OH, phenyl, methylsulfonyl, N-methylpyrrolyl,

Compound.

Particularly preferred compounds of formula (II) are those in which n is 0 or 2, one of R ¹² and R ¹³ is H and the other is vinyl, 2-furyl, 2-thienyl, N-methylpyrrole-2-yl, N Acetylpyrrole-2-yl, 3-hydroxy-2-pyridyl, 4-methoxy-2-pyridyl,

R ¹⁸ is a compound that is H or CH ₃ CO.

Particularly preferred carboxy protecting groups, R ^a are allyl, benzyl, tert-butyl and 2, 2, 1-trichloroethyl, of which more particularly preferred group is allyl, since it is relatively easy to selectively prepare and separate .

Particularly preferred as residues of ester groups which can be readily hydrolyzed in vivo, namely R ^b as described above

R ⁴ and R ⁵ are each hydrogen and R ⁶ is as described above.

In addition to the process for preparing compounds of formulas (I) and (II), the present invention comprises administering to a mammal a compound of formula (I) wherein an antibacterial effective amount of R ¹ is R ⁶ . Also provided are methods of treating bacterial infections in mammals.

Also provided is a pharmaceutical composition for the treatment of a bacterial infection in a mammal, including the human body, consisting of a compound of formula (I) in which an antibacterial effective amount of R ¹ is R ^b .

Compounds of formulas (I) and (II) wherein R ¹ is R ^b are useful as inhibitors of beta-lactamase enzymes. By this mechanism, the compounds produce beta-lactam antibiotics, particularly against microorganisms that are resistant to or partially resistant to beta-lactam antibiotics by producing enzymes (beta-lactamases) that degrade or partially degrade beta-lactam antibiotics. Enhances the activity of (penicillin and cephalosporin). By this method the activity spectrum of beta-lactam antibiotics is increased.

In addition, the present invention is characterized by administering to a mammal an antibacterial effective amount of penicillin or cephalosporin (particularly below) and a beta-lactamase inhibitory amount of a compound of formula (I) or (II) to a mammal. Also provided are methods for treating bacterial infections in mammals.

While the compounds of the present invention are generally effective for enhancing the activity of beta-lactam antibiotics, their preferred use is penicillin or cephalosporins with conventional clinical efficiency, namely amoxicillin, ampicillin, apalcillin, azolocillin, azu Threonam, bacampicillin, carbenicillin, carbenicillin indanyl, carbenicillin phenyl, cephaclo, cephadroxyl, cephaloram, cephamandol, cephamandol nafate, sephaparol, cephatrizin, cephaa Sleepy, cefebuferazone, cenisid, cefenoxime, cedizime, cefeperazone, celanide, cephalacime, ceftiom, cepocithin, ceftyramide, ceftirom, ceftulinine, ceftazidime, Ceftizone, ceftriaxone, cepuroxime, cephacetyl, cephalexin, cephalo-glycine, cephaolidine, cephalotin, cefapirine, cepradine, cyclolaline, epicillin, furazlocillin, heta Cylin, Ren Ampicillin, Levo Lophylcillin, mescillin, mezlocillin, penicillin G, penicillin V, peneticillin, piperacillin, fibenicillin, pibampicillin, samoxicillin, sapicillin, suncillin, deampicillin and ticacillin, And pharmaceutically acceptable salts thereof.

In addition, the beta-lactamase inhibitors of the present invention may be treated with 7-[(2-amino-4-thiazolyl) -2methoxyiminoacet-amido] -3- (5, 6-dihydro-4-pyridinium) Methyl-3-cepem-4-carboxylate (HR-810), 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3- (N-methylpy Lolidinium) methyl-3-cepem-4-carboxylate (BMY-28, 142) and 7- [D- (2- [4-carboxy-5-amidazolecarbox-amido])-2-phenylacet It can also be used with amido] -3- [4- (2-sulfonato-ethyl) pyradinium] -3-cefe-4-carboxylic acid.

Although the compounds of the present invention can be administered separately from beta-lactam antibiotics, combination dosage forms are preferred. Oral or parenteral pharmaceutical compositions consist of beta-lactamase inhibitors and beta-lacta antibiotics of the general formula (I) or (II) in a 1: 3 to 3: 1 weight ratio and are successful in bacterial infection of mammals. It may consist of a single dose or more usually a combined dose having a total amount sufficient for treatment.

-톨루엔설폰산,

-클로로벤젠설폰산 및 2-나프탈렌설폰산이 있다.According to the invention, compounds of the general formulas (I) and (II) in which one of the groups R ² , R ³ , R ¹² or R ¹³ contain a basic nitrogen atom can form acid addition salts. Salts with such pharmaceutically acceptable acids also fall within the scope of the present invention. Examples of such acids are hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, saccharic acid, benzene-sulfonic acid,

Toluenesulfonic acid,

-Chlorobenzenesulfonic acid and 2-naphthalenesulfonic acid.

In addition, compounds of formulas (I) and (II) wherein R ¹ is hydrogen form cationic salts, and salts with such pharmaceutically acceptable cations also fall within the scope of the present invention. Examples of such cations include sodium, potassium, ammonium, calcium, magnesium, zinc; And substituted ammonium salts formed with amines such as diethanolamine, clean, ethylenediamine, ethanolamine, N-methylglucamine and procaine.

The present invention relates to a derivative of peniclanic acid represented by the following structural formula.

은 치환체가 핵의 평면 아래에 있음을 나타낸다. 이러한 치환체는 알파-배위에 있다고 말해진다. 역으로, 비사이클릭 핵에 결합된 치환체의 넓은선

은 치환체가 핵의 평면위에 있을 나타낸다. 이러한 배위는 베타-배위로 지칭된다. 또한 비사이클릭핵에 결합된 치환체의 직선

은 치환체가 알파-배위이거나 베타-배위일 수 있음을 나타낸다.In derivatives of peniclanic acid, hatched lines of substituents bound to the acyclic nucleus

Indicates that the substituent is below the plane of the nucleus. Such substituents are said to be in alpha-coordination. Conversely, a broad line of substituents bound to the acyclic nucleus

Indicates that the substituents will be on the plane of the nucleus. This coordination is referred to as beta-coordination. Also, the straight line of the substituent bound to the acyclic nucleus

Indicates that the substituents may be alpha- or beta-coordinated.

The compounds of the present invention are prepared, for example, by one or more of the following general methods.

의 비티히염은 공지의 화합물이거나, 예를 들어 하기한 바의 통상적 합성방법에 의해 시판용 선구물질로부터 쉽게 제조된다.General formula used in Method A above

The biti salts of are known compounds or are readily prepared from commercial precursors, for example, by the usual synthetic methods as described below.

Primary alcohols of the general formula R ³ CH ₂ OH are converted to the corresponding chloromethyl compounds by reaction with equimolar amounts of thionyl chloride at room temperature or in room temperature in the presence of a reaction inert solvent such as chloro-form or methylene chloride. . The product is separated, for example, by neutralization and extraction of the reaction mixture.

The chloromethyl compound (R ³ CH ₂ CL) is then reacted, for example with an equimolar amount of triphenylphosphine, to convert to the desired Vitis salt. Typically this step is carried out at elevated temperature, preferably at reflux, in a solvent such as toluene. The desired product forms a precipitate which is collected by filtration.

1327(1967). 상기 산을 일반식( IV )의 카복시 보호된 유도체로 전환시킨다. 카복시 보호그룹은 특별히 정해져 있지 않다. 카복시 보호그룹 R^a에 대한 요건은 다음과 같다 : ( i ) 6-옥소페니실라네이트 에스테르 (V) 형성 및 이의 비티히 시약과의 반응에 의한 일반식 (VI, R¹=R^a)의 6-(치환된 메틸렌페니실라네이트 형성에 사용된 산화조건에 안정해야 하고 ; ( ii ) 베타-락탐 및 6-(치환된) 메틸렌그룹이 거의 그대로 남는 조건을 사용하여 일반식(VI, R¹=R^a)의 화합물로부터 선택적으로 제거할 수 있어야 하고 ; (iii) 일반식(VII)의 설폰 또는 상응하는 설폭사이드를 형성하는 화합물(VI, R¹=R^a)의 산화에 안정해야 한다. 상기 요건을 충족시키는 대표적 카복시 보호그룹에는 테트라하이드로피라닐그룹, 벤질그룹, 벤즈히드릴그룹, 2, 2, 2-트리클로로에틸그룹, 알릴그룹, 3급-부틸그룹 및 펜아실 그룹이 있다(참조 : 미합중국 특허 제3, 632, 850 및 3, 197,466호 ; 영국 특허 제1, 041, 985호, Woodward등, Journal of the Americam Chemical Society, 88, 852(1966) ; Chauvette, Journal of Organic Chenlistry, 36, 1259(1971) ; Sheehan등, Journal of Organic Chemistry 29, 2006(1964) ; 및“Cephalosporin and Penicillins, Chemistry and Biology”, edited by H.E.Flynn, Academic Press, Inc., 1972). 특히 바람직한 그룹은 알릴, 벤질 및 2, 2, 2-트리클로로에틸이고, 더욱 특히 바람직한 그룹은 알릴인데 이는 제조 및 선택적 분리의 용이성 때문이다.6-alpha-hydroxyphenicsilane acid is a known compound (see Hauser et al.,

1327 (1967). The acid is converted to the carboxy protected derivative of formula (IV). The carboxy protection group is not specifically defined. The requirements for the carboxy protecting group R ^a are as follows: (i) 6 of the general formula (VI, R ¹ = R ^a ) by the formation of the 6-oxophenylanate ester (V) and its reaction with a Wittig reagent. -(Stable to the oxidative conditions used to form the substituted methylenephenicylanate; (ii) using the conditions under which the beta-lactam and 6- (substituted) methylene groups remain almost intact, with the general formula (VI, R ¹ = Must be capable of being selectively removed from the compound of R ^a ) and (iii) be stable to oxidation of the compound (VI, R ¹ = R ^a ) which forms sulfones of the general formula (VII) or the corresponding sulfoxides. Representative carboxy protecting groups that meet the requirements are tetrahydropyranyl groups, benzyl groups, benzhydryl groups, 2, 2, 2-trichloroethyl groups, allyl groups, tert-butyl groups and phenacyl groups (see : US Pat. Nos. 3, 632, 850 and 3, 197,466; UK Patents 1, 041, 985, Wood ward et al., Journal of the Americam Chemical Society, 88, 852 (1966); Chauvette, Journal of Organic Chenlistry, 36, 1259 (1971); Sheehan et al., Journal of Organic Chemistry 29, 2006 (1964); and “Cephalosporin and Penicillins , Chemistry and Biology ”, edited by HEFlynn, Academic Press, Inc., 1972. Particularly preferred groups are allyl, benzyl and 2, 2, 2-trichloroethyl, and more particularly preferred groups are allyl, which are prepared and selectively separated. Because of its ease.

Oxidation of the carboxy protected 6-alpha-hydroxyphenicilanate (IV) to the corresponding 6-oxophenicilanate ester (X) typically results in about equimolar amounts of trifluoro-acetic anhydride and molar excess of dimethylsulfoxide. The reaction with the side is carried out in the presence of a reaction inert solvent such as chloroform or methylene chloride. The reaction is preferably carried out at a temperature of about -80 ° to -7- ° C. After the reaction mixture is neutralized, for example, by the addition of a tertiary amine, such as triethylamine, the mixture is separated, for example, by partitioning between water and the water immiscible solvent and evaporation of the organic layer.

의 비티히 시약과 반응시킨다. 이 반응은 반응 불활성 유기용매, 예를 들어 탄화수소류(예 : 펜탄, 헥산, 벤젠, 톨루엔 또는 크실렌), 할로겐화 탄화수소류(예 : 메틸렌 클로라이드, 클로로포름, 사염화탄소, 1, 2-디클로로에탄, 1, 2-디브로모에탄 또는 클로로벤젠) 또는 에테르(예 : 테트라하이드로푸란, 디옥산, 디에틸 에테르, 1, 2-디메톡시에탄 또는 3급-부틸메틸에테르)존재하에 수행하는 것이 바람직하다. 한편 이 반응을 약 -100°태지 +50℃의 온도 범위 이상에서 수행할 수 있지만, 바람직한 온도범위는 약 -78°내지 25℃이다.Subsequently the 6-oxophenylanate ester of formula (V)

React with the Wittich reagent. This reaction is carried out by reaction inert organic solvents such as hydrocarbons (e.g. pentane, hexane, benzene, toluene or xylene), halogenated hydrocarbons (e.g. methylene chloride, chloroform, carbon tetrachloride, 1, 2-dichloroethane, 1, 2 Dibromoethane or chlorobenzene) or ethers such as tetrahydrofuran, dioxane, diethyl ether, 1, 2-dimethoxyethane or tert-butylmethylether. On the other hand, the reaction can be carried out at a temperature range of about -100 ° to + 50 ° C or higher, but a preferred temperature range is about -78 ° to 25 ° C.

The desired product of formula (VI, R ¹ = R ^a ) is separated by known techniques, for example by the addition of aqueous ammonium chloride, the reaction is cooled, extracted with a water immiscible solvent and the solvent is evaporated. The product obtained is purified, if necessary, according to conventional methods known to those skilled in the art, such as column chromatography on silica gel.

Subsequently, an ester of the general formula (VI, R ¹ = R ^a ), wherein R ^a is ^a carboxy protecting group as defined above, is a compound of formula (VI, R, wherein R ^b is hydrogen or an ester forming moiety that can be readily hydrolyzed in vivo The corresponding acid or ester of ¹ = R ^b ) can be converted. Typically, the carboxy protecting group is removed from the intermediate compound of formula (VI, R ¹ = R ^a ) to form the corresponding carboxylic acid. The particular method chosen for the removal of the carboxy protecting group depends on the nature of the ester moiety R ^a , but a suitable method will be readily appreciated by those skilled in the art.

As mentioned above, the particularly preferred carboxy protecting group R ^a is allyl. This group can be removed with satisfactory results by a weakly acidic or alkaline hydrolysis process, with a particularly preferred removal method using a soluble palladium (0) complex, i.e. tetrakis (triphenylphosphine) palladium (0) as catalyst. (See Jeffrey and Mccombie, J. Org. Chem., 47, 587-590 (1982). In a typical process, allyl esters in reaction inert solvents such as ethylene dichloride, chloroform, ethyl acetate), A catalytic amount of tetrakis (triphenylphosphine) palladium (0) (eg about 1-5 mole percent based on allyl ester), and about the same weight of triphenylphosphine are mixed under a nitrogen atmosphere. The sodium or potassium salt of ethylhexanoate is added in an equimolar amount relative to the starting allyl ester, and the resulting mixture is completed, for example, the precipitation of the desired salt of formula (VI) wherein R ¹ is Na or K. Until Stir at ambient temperature Usually the reaction is almost complete in about 2 to 20 hours The salts are then collected, for example by filtration.

The sulfoxides or sulfones of the present invention (e.g. compounds of formula (I) wherein n is 1 or 2) are required by using any oxidizing agent known in the art for the oxidation of sulfoxides to sulfones. Oxide the sulfide of (VI). However, particularly convenient reagents are metal permanganate salts such as alkali metal permanganate salts and alkaline earth metal permanganate salts and organic peroxy acids such as organic peroxycarboxylic acids. Typical reagents are sodium permanganate, potassium permanganate, 3-chloroperbenzoic acid and peracetic acid.

Particularly preferred group of oxidants is organic peroxy acid, and preferred organic peroxy acid is 3-chloroperbenzoic acid.

If the desired oxidation product is a sulfoxide of general formula (I) with n equal to 1, then use about molar equivalents of sulfide (n = 0) and an oxidizing agent. If the desired product is a sulfone of general formula (I), for example n is, the sulfide is reacted with at least 2 molar equivalents of oxidizing agent. Alternatively, sulfoxide can, of course, be used as a starting material for the preparation of the corresponding sulfone, in which case at least about equimolar amounts of oxidant are used.

For example, an organic peroxy acid: To (for example, peroxy acids) R ^a is oxidized to the compound of formula formula (VII) to the corresponding compound of ^{(VI, R 1 = R a} ) as previously described In this case, the reaction is usually carried out by reacting a compound of general formula (VI, R ¹ = R ^a ) in ^a reaction-inert organic solvent with about 2 to about 4 molar equivalents of oxidizing agent. Representative solvents are chlorinated hydrocarbons (eg dichloromethane, chloroform and 1, 2-dichloroethane) and ethers (eg diethyl ether, tetrahydrofuran and 1, 2-dimethoxy-ethane). The reaction is usually carried out at a temperature of about -20 ° to about 50 ° C, preferably about 25 ° C. A reaction time of about 2 to about 16 hours at about 25 ° C. is commonly used. The solvent is evaporated off in vacuo to separate the product. The product can be purified by conventional methods known in the art.

In the oxidation process, it is preferable that the carboxy group use a starting material protected with the carboxy protecting group R ^a . Removal of the carboxy protecting group from the product sulfoxide or sulfone is carried out in a manner customary to the particular protecting group used, for example as described above in compounds (VI, R ¹ -R ^a ).

(여기에서 R⁴, R⁵및 R⁶는 전술한 바와 같다)의 그룹에서 선택될 경우, 이들은 R¹이 수소인 적절한 발명 화합물을 일반식 R^bQ의 할라이드, 즉 3-프탈리딜 할라이드, 4-크로토노락토닐 할라이드, 감마-부티로락톤-4-일 할라이드, 또는 일반식According to the present invention, for example, compounds of formula (I) or (II), in which R ¹ is an ester forming moiety that can be readily hydrolyzed in vivo, are compatible with those in which R ¹ is hydrogen by conventional evaporation processes. It can be prepared directly from the compound. The particular method chosen depends on the specific structure of the ester forming residue, but the appropriate method will be readily selected by one skilled in the art. R ¹ is 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, and general formula

When selected from the group of R ⁴ , R ⁵ and R ⁶ as described above, these are suitable compounds of the invention wherein R ¹ is hydrogen, halides of the general formula R ^b Q, ie 3-phthalidyl halide, 4-crotonolactonyl halide, gamma-butyrolactone-4-yl halide, or general formula

-에틸피페리딘, N,

-디메틸아닐린 및

-메틸모르폴린 염) 및 4급 암모늄염(예 : 테트라메틸암모늄 및 테트라부틸 암모늄염)이다. 반응은 약 0내지 100℃, 보통 약 25℃의 온도에서 수행한다. 반응완결시간은 여러 요인, 예를 들어 반응물의 농도 및 시약의 반응성에 따라 달라진다. 따라서 할로화합물을 고려할 경우, 요오다이드는 브로마이드보다 빨리 반응하고, 브로마이드는 클로라이드보다 빨리 반응한다. 실제로 클로로 화합물 사용시, 1몰당량의 알칼리 금속 요오다이드를 가하는 것이 때때로 유리하다. 이는 반응을 가속화시키는 효과를 갖는다. 상기 요인들을 고려할때, 약 1내지 약 24시간 반응시간이 통상사용된다.It can be prepared by alkylation with a compound of the formula wherein Q is halo and R ⁴ , R ⁵ are as described above. The terms “halide” and “halo” herein refer to derivatives of chlorine, bromine and iodine. The reaction typically dissolves a salt of a compound of formula (I) or (II) in which R ¹ is hydrogen in an appropriate polar organic solvent (e.g., N, N-dimethylformamide), followed by about 1 molar equivalent of a suitable halide ( R ^b Q) is performed. When the reaction is almost complete, the product is separated by standard fixation. It is often sufficient to dilute the reaction medium with excess water, extract the product with a water-immiscible organic solvent and then recover by solvent evaporation. Commonly used salts of starting materials include alkali metal salts (e.g. sodium and potassium salts), tertiary amine salts (e.g. triethylamine,

Ethylpiperidine, N,

Dimethylaniline and

-Methylmorpholine salts) and quaternary ammonium salts such as tetramethylammonium and tetrabutyl ammonium salts. The reaction is carried out at a temperature of about 0-100 ° C., usually about 25 ° C. The reaction completion time depends on several factors, for example the concentration of the reactants and the reactivity of the reagents. Therefore, when considering halo compounds, iodide reacts faster than bromide and bromide reacts faster than chloride. In practice, when using chloro compounds, it is sometimes advantageous to add 1 molar equivalent of alkali metal iodide. This has the effect of accelerating the reaction. In view of these factors, about 1 to about 24 hours reaction time is commonly used.

As described above, when used in the preparation of a compound of formula (II) or a compound of formula (VII) wherein n is 2 and X ₃ and R ¹⁸ are each hydrogen, 6-alpha-bromo-1, 1 -Dioxophenylanate ester starting material (IX) is added in an equimolar amount of low molecular weight Grignard reagent (e.g. methylmagnesium bromide, ethylmagnesium chloride or n-butylmagnesium iodide) and an ethereal solvent, preferably tetrahydro Conversion to Grignard reagent is carried out in furan or ethyl ether at a temperature of −80 to 25 ° C., typically −78 ° C. After stirring for a few minutes, an equivalent molar amount of aldehyde of the general formula R ¹² R ¹³ C═O is added and stirring is continued at the same temperature, usually for about 10 minutes to about 4 hours, until the reaction is almost complete. The ester (n = 2) of the general formula (II) is then separated by standard procedures. For example, the reaction is cooled with aqueous ammonium chloride and the product is extracted with a water immiscible solvent. Compound (II), the product obtained, is further purified by, for example, silica gel chromatography.

The secondary alcohols of formula (II) (n = 2, X ₃ = H) were then dehydrated to give the corresponding 6- (substituted) methylene-1, 1-dioxophenisilanate compounds of formula (VII). Can provide. While various dehydration methods of secondary alcohols to olefins known in the art have been successfully used to carry out this step, preferred methods are reactions with at least equimolar amounts of acetic anhydride and pyridine to convert the alcohol to acetate and then at room temperature. It is made to stir for 10 to 10 hours to allow the formation of olefins at the actual mass. Usually the reaction is cooled with water and the desired product (II) (n = 2) is separated by extraction and purified if necessary.

The product of formula (II) or (VII) obtained is an ester wherein R ¹ is the carboxy protecting group R ^{a as described above} or the residue R ^b of an ester group which can be readily hydrolyzed in vivo. Esters in which R ¹ is R ^a are converted to the corresponding carboxylic acid (R ^b is hydrogen) according to the above method. Of course, if necessary, the carboxylic acids of formulas (II) and (VII) are also converted according to the above methods to the corresponding compounds wherein R ¹ is a residue of an ester group which can be readily hydrolyzed in vivo.

Representative starting materials 6-alpha-bromo-1, 1-dioxophenicylanate ester (IX) are 6,6-dibromo-1,1-dioxophenicsilane acid, sodium bicarbonate and sodium bisulfite After reacting with acid, it is prepared. The 6-alpha-bromo-1,1-dioxophenicsilane acid obtained is then converted to the ester of formula (IX).

-부틸 리튬, 3급-부틸 리튬 또는 메틸 리튬)과 반응시켜 리티오페니실린 중간체를 수득한다. 이를 즉시 등몰량의 알데히드 R¹²R¹³Co(여기서 R¹²R¹³은 전술한 바와 같다)와 반응시키고, 혼합물을 -100내지 -50℃, 바람직하게는 -78℃에서 약 1내지 4시간 교반시킨다. 이어서 반응물을 냉각시키고, 일반식(XI)의 브로모히드린 중간체를 예를 들어 물과 용매사이의 분배로 분리시키고 실리카겔 또는 플로리실(마그네슘 실리케이트)상의 컬럼 크로마토그라피로 추출물을 정제한다.The ester of general formula (X) used as starting material in the above method C is a known compound (US Pat. No. 4,234,579). In a representative process carried out in the above manner, the ester (X) in a reaction inert solvent (e.g. toluene, xylene, pentane, tetra-hydrofuran, ethyl ether or mixtures thereof) at low temperature equimolar alkyl lithium reagent (e.g.

-Butyl lithium, tert-butyl lithium or methyl lithium) to obtain a thiophenicillin intermediate. This is immediately reacted with an equimolar amount of aldehyde R ¹² R ¹³ Co (where R ¹² R ¹³ is as described above) and the mixture is stirred at -100 to -50 ° C, preferably at -78 ° C for about 1 to 4 hours. . The reaction is then cooled, the bromohydrin intermediate of formula (XI) is separated, for example by partitioning between water and solvent and the extract is purified by column chromatography on silica gel or florisil (magnesium silicate).

Alternatively, the dibromo ester of general formula (X) is reacted with a low molecular weight Grignard reagent of equimolar with the same reagents and conditions as described in Method B above to bromoheid of general formula (XI) Obtain a bite.

Acylation of bromohydrin (XI) can yield the corresponding compound (XII) wherein R ¹⁸ is as described above (except hydrogen). Typically, acylation is carried out by reacting equimolar amounts of acyl chloride, acyl bromide or the corresponding acid anhydride, bromohydrin intermediate of formula (XI) and tertiary amines (e.g. pyridine, N-methyllofoline, etc.). , Preferably by reaction at room temperature or lower in the presence of methylene chloride, tetrahydrofuran or ethyl acetate. The diester of the general formula (XII) is then separated by known methods such as extraction and the solvent is evaporated and purified by column chromatography if necessary.

The bromohydrin ester intermediate (XI) or bromo diester (XII) is then introduced under hydrolysis conditions to remove bromine atoms. This is done using a variety of known reducing agents and conditions, for example by introducing bromohydrin into hydrogen in the presence of a noble metal catalyst or by reducing to a particular organotin hydrolide.

Preferred organotin hydride reducing agents are dialkyltin dihydrides, where each alkyl group contains 1 to 6 carbon atoms, and triaryltin hydride, where aryl is phenyl or nitro, or alkyl having 1 to 3 carbon atoms. Or phenyl substituted with alkoxy). Particularly preferred are triphenyltin hydride and tri-n-butyltin hydride, with the latter being more particularly preferred for economics and efficiency.

The reaction using the tin hydride is usually carried out in the presence of a reaction inert solvent. Suitable solvents for use with the organotin hydride reducing agent are those which substantially dissolve the starting compound of formula (XI) or (XII) but do not react with the hydride reducing agent. Examples of such solvents include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and naphthalene, and ethers such as ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and 1, 2-dimethoxyethane. have. Particularly preferred solvents for economics and efficiency are beenegen and toluene.

In carrying out the hydrogenolysis using an organotin hydride reducing agent, equimolar amounts of bromohydrin (XI) or bromodiester (XII) and hydride are theoretically required. In practice, often excess hydrides (eg 5 to 50% molar excess) are used to complete the reaction.

The hydrogenolysis reaction with organotin hydride is almost complete under the desired conditions without the use of a catalyst. However, the reaction is facilitated through a source of free radicals (eg ultraviolet or catalytic amounts of azobisisobutyronitrile or peroxides such as benzoyl peroxide). In this reaction, a catalytic amount of azobisisobutyronitrile is the preferred source of free radicals.

Typically, a compound of formula (XI) or (XII) is dissolved in a reaction inert solvent and the solution is maintained under an inert atmosphere (e.g. nitrogen or argon atmosphere), followed by an appropriate amount of organotin hydride and, optionally, free radicals. Source (e.g. azobisisobutyronitrile) is added and the resulting mixture is stirred at the desired temperature between about 0 ° C and the solvent boiling point. The reaction is usually complete in a few minutes to about several hours (eg, 5 minutes to benzene at about 20 hours at 0 ° C.). The product of formula (III, X ₃ = H) is then separated according to methods known to those skilled in the art, such as evaporation of solvents and silica gel chromatography of residues.

Compounds of the general formula (II, X ₃ = H) formed by organotin hydride debromination as described above are mainly 6-beta isomers, ie 6-R ¹² R ¹³ C (OR ¹⁸ ) substituents in beta-coordination. It turned out to be a compound.

When the hydrogenolysis step is carried out in the presence of a noble metal catalyst using hydrogen, a conventional method for carrying out this modification is the presence of a noble metal hydrolysis catalyst under hydrogen or a hydrogen atmosphere mixed with an inert diluent such as nitrogen or argon. Stirring or shaking the solution of the compound of formula (XI) or (XII). Suitable solvents for this hydrocracking reaction are those which dissolve little of the starting mixture of the general formula (XI) or (XII) but are not hydrogenated or hydrogenated. Examples of such solvents include ethers such as diethyl ether, tetrahydro-furan, dioxane and 1, 2-dimethoxyethane, low molecular weight esters such as ethyl acetate and butyl acetate, tertiary amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone), water and mixtures thereof. In addition, it is often desirable to buffer the reaction mixture to work at a pH of about 4-9, preferably about 6-8. Borate, bicarbonate and phosphate buffers are commonly used. Introduction of hydrogen gas into the reaction medium is usually effected by carrying out the reaction in a closed vessel containing a compound of formula (XI) or (XII), a solvent, a catalyst and hydrogen. The internal pressure of the reaction vessel may be about 1 to about 100kg / ㎠. If the internal atmosphere of the reaction vessel is almost pure hydrogen, the preferred pressure range is about 2 to about 5 kg / cm 2. Hydrolysis is generally carried out at a temperature of about 0 ° to about 60 ° C, preferably about 25 ° to about 50 ° C. Using the desired temperature and pressure, hydrolysis generally occurs within several hours, for example about 2 to about 20 hours. Preferred precious metal catalysts used in the hydrocracking reaction are types of reagents known in the art for this kind of modification, for example nickel, palladium, platinum, and rhodium. Palladium is particularly preferred. The catalyst is usually present in an amount of about 0.01 to about 25% by weight, preferably about 0.1 to about 10% by weight, based on the compound of formula (XI). It is often convenient to immobilize the catalyst on an inert support, and a particularly convenient catalyst is palladium immobilized on an inert support such as carbon.

When the hydrogenolysis is almost complete, the desired product of formula (II, X ₃ = H) is separated by standard methods, for example the catalyst is removed by filtration and the solvent is evaporated and the product crystallized or chromated if necessary. Purification by known methods such as graffiti.

If the starting mixture of formula (XI) or (XII) is a benzyl ester (R ¹ = R ^a = benzyl), the catalytic hydrolysis process may result in the decomposition of the benzyl group, where the product is X ₃ And R ¹ are each a compound of hydrogen general formula (II).

6- (substituted) hydroxymethylphenicylic acid or ester of general formula (XII) or (II, X ₃ = H) where n is 0 is a known method for converting sulfides to sulfoxides and sulfones (e.g. Oxidation using any one of 3-chloroperbenzoic acid) to give the corresponding sulfoxide or sulfone of general formula (XII) or (II, X ₃ = H), wherein n is 1 or 2, respectively. do. However, a preferred method for obtaining the sulfones of general formula (XI), (XII) or (II) is a suitable 6, 6-dibromo-1, 1-dioxophenicylanate ester (X) wherein n is 2 above. It is used as starting material in Method C.

Aldehydes of the general formula R ¹² R ¹³ CO as R ¹² and R ¹³ as described above are commercially available or can be easily prepared by methods known in the art from commercially available starting materials, for example as follows.

1. Catalytic oxidation of a primary alcohol corresponding to, for example, an oxidizing agent (eg potassium dichromate, chromic acid / pyridine) correspondingly in the presence of a noble metal (manganese dioxide) as in the Wittich reagent precursor.

2. Reaction of the corresponding methyl substituted aromatic hydrocarbons with, for example, selenium dioxide.

3. Metal hydride reduction of the corresponding C ₁ -C ₄ alkoxycarbonyl compound at low temperature, examples of suitable metal hydrides include lithium aluminum hydride and diisobutylaluminum hydride (DIBAL-H). have.

4. Reaction of appropriate aromatic hydrocarbon precursors with n-butyl lithium and dimethylformamide.

As noted above, compounds of formula (I) or (II) wherein R ¹ is H and mixtures of salts thereof with beta-lactam antibiotics exhibit synergy in in vitro antibacterial tests. This action is indicated by measuring the minimum inhibitory concentration (MIC'S, mcg / ml) for various microorganisms. The following process is recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (see Ericcson and Sherris Acta, Pathologica et Microbiologia Scandinav, Supp, 217, Section B: 64-68 [1971). ]), Brain injection (BHI) agar and inoculation device is used. Overnight the growth tube is diluted 100-fold for use in standard vaccination (20,000 to 10 000 cells in about 0.002 ml are placed on the agar surface: 20 ml BHI agar / dish). A 2-fold dilution of 12 test compounds is used with an initial concentration of test drug of 200 mcg / ml. Single colonies are ignored when reading plates at 37 ° C. after 18 hours. The sensitivity of the test microorganism (MIC) is considered to be the lowest concentration of the test compound or mixture of compounds that can result in a complete suppression of the diet determined by the naked eye.

Mixtures of compounds of formulas (I) and (II) in which R ¹ is H with known beta-lactam antibiotics include industrial fungicides (eg water treatment, mucus control, paint preservation and wood preservation) and disinfectants for topical application. Useful as In the application of the compounds for such applications, it is often convenient to mix the active ingredient with a nontoxic carrier such as vegetable oil, mineral oil or softening cream. Similarly, they can be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most cases it is appropriate to use a concentration of from about 0.1 to about 10% by weight of active ingredient, based on the total composition.

As also mentioned above, compounds of formulas (I) and (II) wherein R ¹ is R ^b are particularly important as potent inhibitors of beta-lactamases by microorganisms. In accordance with this mechanism, they enhance the antibacterial efficacy of beta-lactam antibiotics (penicillins and cephalosporins) against many microorganisms, especially those that produce beta-lactamases. The ability of a compound of formula (I) or (II) to enhance the efficacy of a beta-lactam antibiotic was determined by measuring the MIC values of the antibiotic alone and the compound of formula (I) or (II) where R ¹ is hydrogen. This can be seen. These MIC values are then compared with the MIC values obtained from a mixture of a given antibiotic and a compound of formula (I) or (II) wherein R ¹ is hydrogen. If the antibacterial efficacy of the mixture is much greater than the individual components can be foreseen from the potency, it is considered that enhanced activity has been achieved. MIC values of the mixtures are measured using the methods described by Barry and sabath (see “Manual of clinical Microbiology”, edited by Lenette, Spaulding and Truant, 2nd Edition, 1974, American. Society for Microbiology).

Compounds of formulas (I) and (II), wherein R ¹ is hydrogen or a residue of an ester group that can be readily hydrolyzed in vivo, enhance the antibacterial efficacy of beta-lactam antibiotics in vivo. That is, they lower the amount of antibiotics needed to protect mice against the lethal vaccination of certain beta-lactamases that produce bacteria. To measure this activity, mice are intraperitoneally inoculated with standardized cultures of test microorganisms suspended in 5% swine gastric spots resulting in acute experimental infection in mice. The infectivity is normalized to provide caterpillar microorganisms (lethal dose is the minimum inoculation of microorganisms required to thoroughly kill 100% infected and untreated control rats). Mixtures of test compounds and antibiotics are administered to groups of mice infected orally or intraperitoneally at various concentration levels. At the end of the test, the activity of the mixture is assessed by calculating the residual water in rats treated at a given dose. Activity is expressed as the percentage of mice remaining at a given dose or calculated as PD ₅₀ (a dose protecting 50% of mice from infection).

The ability of the compounds of formulas (I) and (II) to enhance the potency of beta-lactam antibiotics on beta-lactamase to produce bacteria has been shown in combination with beta-lactam antibiotics in the treatment of bacterial infections in mammals, particularly humans. Important for co-administration In the treatment of bacterial infections, compounds of formula (I) or (II) are mixed with beta-lactam antibiotics or R ^b is CH (R ⁴ ) OCOR ¹⁴ , wherein R ⁴ and R ¹⁴ are Beta-lactam antibiotics can be chemically bound to a combination of Formula (I) or (II) to administer two agents simultaneously. Alternatively, compounds of formula (I) or (II) may be administered separately during treatment with beta-lactam antibiotics. In some instances it is advantageous to pre-administer the compound of formula (I) or (II) to the patient before initiating treatment with beta-lactam antibiotics.

In order to enhance the efficacy of beta-lactam antibiotics, when a compound of formula (I) or (II) wherein R ¹ is R ^b as described above, a mixture of the compound or beta-lactam antibiotics, or R ^b is In the case of CH (R ⁴ ) OCOR ¹⁴ the compounds of the invention are administered alone, preferably in combination with standard pharmaceutical carriers or diluents. Pharmaceutical compositions consisting of pharmaceutically acceptable carriers, beta-lactam antibiotics and / or compounds of general group (I) or (II) usually contain from about 5 to about 80% by weight of a pharmaceutically acceptable carrier. .

When the compound of formula (I) or (II) is used in conjunction with another beta-lactam antibiotic, the compound may be administered orally or parenterally (eg intramuscularly, subcutaneously or intraperitoneally). Although the physician will finally determine the dose to be used for the patient, the daily dose ratio of the compound of formula (I) or (II) to beta-lactam antibiotics in which R ¹ is R ^b is usually about 1: 3 to 3: 1 weight ratio. . In addition, when a compound of formula (I) or (II) is used with beta-lactam antibiotics, the daily oral dose of each component is usually about 10 to about 200 mg / kg body weight, and the daily parenteral dose of each component is usually weight About 10 to about 400 mg per kg. These daily doses are usually administered in divided doses. In some cases, doctors may determine doses beyond these limits.

As will be appreciated by those skilled in the art, some beta-lactam compounds are effective for oral or parenteral administration, while others are effective only for parenteral administration. When the compounds of formula (I) or (II) are used simultaneously (ie mixed together) with beta-lactam antibiotics that are effective only parenterally, appropriate formulations for parenteral administration are required. Alternatively, when the compounds of formula (I) or (II) are used simultaneously (mixed together) with beta-lactam antibiotics effective for oral or parenteral administration, preparations suitable for oral or parenteral administration can be prepared. It is also possible to orally administer a preparation of the active compound of formula (I) or (II) while at the same time parenteral administration of beta-lactam antibiotics; Parenteral administration of the formulations of compounds of formula (I) or (II) may also be oral administration of beta-lactam antibiotics at the same time.

The invention is illustrated by the following examples. However, the present invention is not limited to the following specific examples. Proton and C ¹³ nuclear magnetic resonance spectra were 60, in deuterochloroform (CDCl ₃ ), deuterium oxide (C ₂ O), perdutero acetone (CD ₃ COCD ₃ ) or perduterodimethyl sulfoxide (CMSO-d ₆ ) solution. Measured at 90, 250 or 300 MHz, peak positions are expressed in parts per million (ppm) based on tetramethylsilane. Use the following abbreviations. : S, singlet: d, doublet; dd, doublet doublet; t, triplet; q, quartet; m, multiplet; b, broad.

Example 1

6-alpha-hydroxyphenicylanate ester

A. allyl ester

A 85 g 6-alpha-hydroxyphenicsilane acid ^* (0.39 mol) solution in 300 ml dimethylformamide was reacted with 34 ml (0.39 mol) allyl bromide, 54 ml (0.39 mol) triethylamine and 2 g sodium bicarbonate, and the mixture was allowed to room temperature. Stir for 15 hours. After the reaction was cooled with water and extracted with ethyl ether, the mixed ether layers were washed with saturated sodium bicarbonate solution and water, dried (MgSO ₄ ) and concentrated in vacuo to give 43 g of crude product. The crude was purified by silica gel column chromatography eluting with chloroform / ethyl acetate (9: 1) to afford 22.75 g (23%) of allyl ester. ¹ H-NMR (CDCl ₃ ) PPm (delta): 1.42 (s, 3H), 1.60 (s, 3H), 4.45 (s, 1H), 4.5 to 5.0 (m, 3H), 5.2 to 6.2 (m, 4H ).

^* Manufactured according to the method of Hauser et al. (See: Helv. Chim. Acta, 50, 1327 (1967)

)).

B. Pivaloyloxymethyl Ester

9 g (0.041 moles) 6-alpha-hydroxyphenicylic acid, 40 ml dimethylformamide, 7.4 ml (0.0

41 mol) a mixture of diisopropylethylamine, 6 ml (0.041 mol) chloromethyl pivalate and 6.15 g (0.041 mol) sodium iodide is stirred at room temperature for 15 hours. Water is added and the mixture is extracted with ethyl ether and the extract is dried and concentrated to give 9 g of crude ester, which is purified on a silica gel column eluting with chloroform / ethyl acetate (9: 1). The amount of mixed product fraction is 4.384 g (32%).

C. Benzyl Ester

12.0 ml (20 g (0.092 mole) 6-alpha-hydroxyphenicylic acid, 12.9 ml (0.092 mole) triethylamine, 1.105 g (0.013 mole) sodium bicarbonate and 200 ml dimethylformamide (DMF)

0.101 mol) benzyl bromide is added. The mixture is stirred at rt for 20 h, partitioned between ethyl ether and water and the aqueous phase is introduced at pH 2.0 with 6N hydrochloric acid. The layers are separated and the aqueous layer is extracted twice with ether and the mixed ether layers are washed with sodium bicarbonate solution and water, dried and the solvent is evaporated. The residue is crystallized from hot chloroform / hexanes to give 9.1 g of colorless crystals (melting point 165-167 ° C.).

D. (5-Methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester

A mixture of 15 g (0.078 mole) (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl bromide and 18.7 g (0.078 mole) sodium 6-alpha-hydroxyphenicilanate in 225 ml DMF was added. Stir at room temperature for 4 hours, pour into ice and finish as described above to afford the desired ester.

Example 2

6-oxophenicylanate ester

A. Allyl 6-Oxophenicylanate

A mixture of 2.84 ml (0.04 mole) dimethylsulfoxide, 3.67 ml (0.026 mole) trifluoroacetic anhydride and 50 ml methylene chloride is stirred at −78 ° C. for 10 minutes. 5.14 g (0.02 mole) allyl 6-alpha-hydroxyphenicilanate solution in 10 ml methylene chloride is added at -78 ° C and the resulting mixture is stirred for 40 minutes. Triethylamine (7.24 ml, 0.052 mol) is added at the same temperature and the mixture is gradually warmed to room temperature and cooled with water. After extraction with methylene chloride the mixed organic layers are washed with water (3X), dried and the solvent is evaporated in vacuo to afford the title compound as a yellow oil. 5.1 g (100%). ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.60 (s, 6H), 4.75 (m, 2H), 4.82 (s, 1H), 5.1 to 6.3 (m, 3H), 5.82 (s, 1H).

B. Pivaloyloxymethyl Ester

A mixture of 0.36 ml (5.06 mM) dimethylsulfoxide, 0.47 ml (3.29 mM) trifluoroacetic anhydride, 839 mg (2.53 mM) pivaloyloxymethyl 6-alpha-hydroxyphenicylanate and 5 ml methylene chloride After stirring for 30 min at 0.9 ° C., 0.92 ml (6.58 mM) triethylamine are added. Finish the product as in A above to yield 788 mg (95%) of the desired ketone. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.3 (s, 9H), 1.65 (s, 6H), 4.85 (s, 1H), 5.8 (m, 3H).

Example 3

Allyl 6 (E)-(2-pyridyl) methylenephenicylanate

A mixture of 2.64 g (6.8 mM) of 2-ml anhydrous tetrahydrofuran (THF) strain, 2-picolyl triphenylphosphonium olidine and 0.265 g (6.8 mM) sodium amide is stirred at room temperature for 30 minutes. The resulting brown suspension was cooled to -78 ° C and 1.8 g (7.0 mM in 4 ml anhydrous THF)

) Allyl 6-oxophenicylanate solution is added in one portion and the mixture is stirred at -78 ° C for 3 minutes. After adding the saturated ammonium chloride solution to cool the reaction and extracting with ethyl acetate, the mixed organic layer is washed with water (3 ×), dried (MgSO ₄ ) and concentrated in vacuo to yield 3.3 g of red oil. This oil was purified by chromatography on a silica gel column to give 1.35 g.

(60.7%) of the desired product is obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.50 (s, 3H), 1.58 (s, 3H), 4.57 (s, 1H), 4.65 (d, 2H), 5.15 to 6.15 (m, 3H), 6.17 (d, 1H, J = 1 Hz), 6.87 (d, `H, J = 1 Hz), 7.2 to 7.4 (m, 2H), 7.60 (t of d, 1H), 8.62 (d of d):

¹³ C-NMR (CDCl ₃ ) ppm (delta): 26.04, 32.99, 62.77, 65.75, 70.01, 70.54, 119.10, 123.24, 124.02, 125.86, 131.06, 136.34, 144,66, 149.94, 152.13, 167.54, 168.73.

Example 4

의 비티히 시약을 사용하여 다음 화합물을 수득한다.General formula suitable for 2-piccolyl phenylphenylphosphonium chloride in the process of Example 3

The following compound is obtained using the Wittich reagent.

^* A = hexanes / ethyl acetate (9: 1),

A ¹ = hexanes / ethyl acetate (7: 3).

B = chloroform

C = chloroform / ethyl acetate (9: 1),

D = chloroform / ethyl acetate (99: 1).

- 이성체 (R³가 베타-락탐에 안티이다)

Isomers (R ³ is anti-beta-lactam)

Z-isomer (R ³ is a god in beta-lactam)

Example 5

Sodium 6 (E)-(2-pyridyl) methylenephenicylanate

A mixture of 0.120 g (0.38 mM) allyl 6- (E)-(2-pyridyl) methylenephenylanate, 20 mg tetrakis (triphenylphosphine) palladium (O) and 20 mg triphenylphosphine was added to 3 ml ethyl acetate. To this was added 0.76 ml (0.38 mM) 0.5 mol of sodium 2-ethylhexanoate in ethyl acetate under nitrogen atmosphere. The mixture is stirred at rt for 2 h, the precipitates are collected by filtration, washed with ethyl acetate and dried in vacuo to give 57 mg (48%) of the title compound as a yellow solid. ¹ H-NMR (D ₂ O) ppm (delta): 1.55 (s, 6H), 4.33 (s, 1H), 6.17 (d, 1H, j = 0.5 Hz), 7.03 (d, 1H, J = 0.5 Hz ), 7.17 to 8.07 (m, 3H), 8.57 (m, 1H): IR spectrum (KBr): 3433, 1756, 1605 cm ^-1 .

Example 6

Using the appropriate starting material selected from the allyl ester obtained in Example 4, the following sodium salts are obtained by the process of Example 5.

Example 6A

6-phenylthiomethylene peniclanic acid

A mixture of 93 mg (0.26 mM) allyl 6-phenylthiomethylenephenicilanate (isomer) and 10 mg each of tetrakis (triphenylphosphine) palladium (O) and triphenylphosphene were dissolved in 1 ml ethyl acetate and ethyl 0.52 ml, 0.5 M sodium 2-ethylhexanoate in acetate is added at room temperature and the resulting mixture is stirred under nitrogen for 10 hours. Since very small amounts of salt precipitate, the mixture is cooled with water and extracted with methylene chloride. The aqueous layer is acidified (pH 3.5) and extracted with methylene chloride. The dried extract is concentrated in vacuo to give 63 mg (75%) of free acid as an isomer mixture. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.5 (s, 2.1H), 1.55 (s, 0.9H), 1.6 (s, 2.1H), 1.65 (s, 0.9H), 4.4 (s, 0.7 H), 4.5 (s, 0.3H), 5.38 (d, 0.7H), 5.7 (s, 0.3H), 6.7 (s, 0.3H), 7.1 (d, 0.7H), 7.5 (m, 5H).

Example 7

Allyl 1,1-dioxo-6 (E)-(2-pyridyl) methylenephenicylanate

To 1.30 g (4.09 mM) allyl 6 (E)-(2-pyridyl) methylenephenicylanate solution in 15 ml methylene chloride was added 1.70 g (8.2 mM) of 80-85% pure m-chloroperbenzoic acid It is stirred for 3 hours at room temperature under nitrogen. After cooling with saturated sodium thiosulfate solution and water, the mixture was extracted with methylene chloride and the organic layer was adjusted to pH 7.5 with saturated sodium bicarbonate solution, washed with water and dried (MgSO ₄ ) and the solvent was evaporated under vacuum to 1.4 g (98). %) Of the product is obtained as a yellow oil. This oil is purified by silica gel column chromatography, eluting with hexanes / ethyl acetate (7: 3) to afford 0.78 g (55%) of the title sulfone as colorless crystals. ¹ H-NMR (CDCL ₃ ) ppm (delta): 1.48 (s, 3H), 1.63 (s, 3H) 4.45 (s, 1H), 4.73 (d, 2H), 5.1 to 6.2 (m, 3H), 5.77 (d, 1H, J = 0.5 Hz), 7.1 to 8.1 (m, 3H), 8.6 (m, 1H): ¹³ C-NMR (CDCl ₃ ) ppm (delta): 18.53, 20.43, 63.18, 64.25, 66.63, 72.04, 119.91, 124.64, 126.03, 130.68, 132.83, 136.77, 150.31, 166.86, 168.11. IR (KBr) cm ^-1 : 1323, 1586, 1759, 1783, 3437.

Example 8

Allyl, 1,1-dioxo-6- (E)-(2-hydroxyethylidene) phenylanate

To a solution of 0.190 g (0.6 mM) allyl 1,1-dioxo-6 (E) -formylmethylenephenicylate in 4 ml anhydrous tetrahydrofuran, 0.61 ml (0.61 mM) of 1M diisobutylaluminum hydride in hexane Ride is added at -78 ° C. The mixture is stirred at −78 ° C. for 10 minutes, then cooled with methanol, stirred at room temperature for 20 minutes and then filtered. The filtrate is concentrated in vacuo to afford 0.258 g of crude product, which is diluted with water, extracted with chloroform and the organic layer is dried (MgSO ₄ ). Evaporate chloroform to afford 160 mg of material, which is purified by silica gel column chromatography, eluting with chloroform / ethyl acetate (4: 1) to afford 113 mg (60%) of the title compound. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.40 (s, 3H), 1.60 (s, 3H), 2.60 (bs, 1H), 4.3 (m, 2H), 4.4 (s, 1H), 4.7 ( d, 2H), 5.1 to 6.0 (m, 3H), 5.25 (d, 1H), 6.38 (m, 1H).

Example 9

The appropriate 6-methylenephenicilanate ester (n = 0) provided in Example 4 is used as starting material in the process of Example 7 to afford the following compounds.

^{In the} following reaction, eluting from the silica gel column with 2% ethyl acetate-chloroform to give 29% yield of sulfone (n = 2), the more polar fractions were identified as sulfoxide (n = 1) as 27% yield. It became.

Example 9A

Allyl 6- (E)-[(1-oxoquinolin-2-yl) methylene] -1,1-dioxophenicylanate

Allyl 6 (E)-[(quinolin-2-yl) methylene] -1-oxophenicylanate (obtained as a by-product in the preparation of the corresponding sulfone, see Example * above) (124 mg, 0.313 mM) in 5 ml methylene chloride Dissolve in and add 195 mg (0.904 mM) of 80% m-croperbenzoic acid. The mixture is stirred for 48 hours at room temperature, cooled with water and extracted with methylene chloride. The extracts were washed separately with saturated sodium bicarbonate solution and water, dried and concentrated in vacuo to yield a yellow oil. This oil is purified by silica gel column chromatography to yield 45 mg (35%) of the title N-oxide as a yellow solid. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.45 (s, 3H), 1.6 (s, 3H), 4.45 (s, 1H), 4.7 (m, 2H), 5.0 to 6.0 (m, 3H), 5.85 (d, 1H), 7.3 to 8.0 (m, 7H).

Example 10

Sodium 1,1-dioxo-6- (E)-(2-pyridyl) methylenephenicylanate

Allyl 1,1-dioxo-6 (E)-(2-pyridyl) methylenephenicylanate (0.14 g, 0.4 mM), 20 mg tetrakis (triphenylphosphine) palladium (O) and 20 mg triphenylphosphine Was dissolved in 2 ml ethyl acetate and 0.8 ml (0.4 mM) 0.5 M sodium 2-ethyl hexanoate solution in ethyl acetate was added under nitrogen. The resulting mixture is stirred at room temperature for 5 minutes. The precipitate obtained is filtered, washed with ethyl acetate and dried to give 0.13 g (95%) of sodium salt as a yellow solid. ¹ H-NMR (D ₂ O) ppm (delta): 1.50 (s, 3H), 1.60 (s, 3H), 4.23 (s, 1H), 5.90 (d, 1H, J = 1 Hz), 7.1 to 8.0 ( m, 4H), 8.57 (m, 1 H). IR spectrum (KBr) cm ⁻¹ : 1590, 1621, 1770, 3454.

Example 11

Allyl 1,1-dioxo-6 (E)-(1-oxo-2-pyridyl) methylenephenicylanate

Treatment of allyl 1,1-dioxo-6- (E)-(2-pyridyl) methylenephenicylate (100 mg, 0.286 mM) solution in 5 ml methylene chloride with m-chloroperbenzoic acid (120 mg, 0.59 mM) And stirred at room temperature for 3 days. The mixture is cooled with saturated sodium thiosulfate solution and extracted with methylene chloride. The organic layer is neutralized with saturated sodium bicarbonate solution, washed with water, dried and concentrated to give 82 mg of yellow oil. This yellow oil was purified by silica gel column chromatography using ethyl acetate as eluent to give 22 mg (21%) of the title compound and 14 mg (13%) by-product [2,3-epoxypropanyl 1,1-dioxo -6 (E)-(1-oxo-2-pyridyl) methylenephenicylanate]. Allyl 1,1-dioxo-6 (E)-(1-oxo-2-pyridyl) methylene peniclanate: ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.5 (s, 3H), 1.6 ( s, 1H) 4.45 (d, 1H), 4.7 (d, 2H), 5.1 to 6.0 (m, 3H), 5.8 (s, 1H), 7.1 to 8.4 (m, 5H).

Example 12

Compounds of the following general formula are obtained by hydrolyzing the appropriate allyl ester according to the method of Example 10.

Potassium 2-ethylhexanoate is used instead of sodium, 2-ethyl-hexanoate to obtain the potassium salt corresponding to the above general formula.

Example 13

Pivaloyloxymethyl 6 (E)-(methylthio) methylenephenicylate

A mixture of 2.4 mM (methylthiomethyl) triphenylphosphonium chloride and 2.4 mM sodium amide in 5 ml anhydrous tetrahydrofuran (THF) is stirred for 20 minutes at room temperature. To the obtained yellow solution, a 788 mg (2.4 mM) pivaloyloxymethyl 6-oxophenicylanate solution in 10 ml anhydrous THF was stirred at -78 DEG C for 1 minute, poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried (Na ₂ SO ₄ ) and the solvent was evaporated in vacuo to afford 774 mg of crude product, which was purified by silica gel column chromatography while eluting with chloroform to give 220 mg (24.5%) of pure product. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.25 (s, 9H), 1.50 (s, 3H), 1.65 (s, 3H), 2.45 (s, 3H), 4.45 (s, 1H), 6.85 ( m, 3H), 7.0 (d, 1H).

Example 14

Pivaloyloxymethyl 6 (E) -methylsulfonylmethylenephenylanate 1-oxide (A) and the corresponding 1,1-dioxide (B)

To 215 mg (0.58 mM) pivaloyloxymethyl 6 (E)-(methylthiomethyl) methylenephenicilanate solution in 5 ml methylene chloride was added 375 mg (1.74 mM, 3 equiv) of 80% m-chloroperbenzoic acid. . The mixture is stirred at rt for 4 h, cooled with water, saturated sodium thiosulfate solution and sodium bicarbonate and extracted with chloroform. The organic phase is washed three times with water, dried (MgSO ₄ ) and concentrated in vacuo to yield 200 mg of mixed product. The crude mixture is purified by silica gel chromatography, eluting with chloroform / ethyl acetate (9: 1) to afford 25 mg of the 1-oxide (A) and 45 mg of the 1,1-dioxide product (B). (A): ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.21 (s, 9H), 1.3 (s, 3H), 1.7 (s, 3H), 3.1 (s, 3H), 4.7 (s, 1H ), 5.8 (AB Quetet, 2H), 5.85 (d, 1H), 7.1 (d, 1H): IR spectrum (CHCl ₃ ) cm ^-2 : 1333, 1759, 1807, 2927, 2960. (B): ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.2 (s, 9H), 1.45 (s, 3H), 1.6 (s, 3H), 3.15 (s, 3H), 4.5 (s, 1H), 5.6 (d , 1H), 5.8 (AB quartet, 2H), 7.2 (d, 1H): IR spectrum (CHCl ₃ cm ^-1 : 1324, 1758, 1800, 2929, 2956.

Example 15

Allyl 6-alpha- (N-methylpyrrole-2-yl) hydroxymethyl-1,1-dioxophenicylanate

Allyl 6-alpha-bromo-1,1-dioxophenicylanate (520 mg, 1.48 mM) is dissolved in 10 ml anhydrous tetrahydrofuran (THF) and cooled to -78 ° C. Methylmagnesium bromide solution (0.52 ml, 2.85 M in THF) is added and the mixture is stirred at −78 ° C. for 5 minutes. N-methylpyrrole-2-carboxaldehyde (162 mg, 0.16 ml) is added and stirred at −78 ° C. for 20 minutes. The mixture is poured into saturated ammonium chloride solution, extracted with ethyl acetate and the organic layer is dried (MgSO ₄ ). The solvent was evaporated in vacuo to afford 466 mg of crude product, which was purified by silica gel chromatography eluting with chloroform / ethyl acetate (9: 1) to afford 180 mg (32%) of the pure title compound. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 3H), 1.62 (s, 3H), 3.68 (s, 3H), 4.0 to 4.4 (m, 1H), 4.42 (s, 1H), 4.5 to 4.8 (m, 3H), 5.0 to 6.0 (m, 4H), 6.0 to 6.7 (m, 3H).

Example 16

Allyl 6 (E)-(N-methylpyrrole-2-yl) methylene-1,1-dioxophenicylanate

Allyl 6-alpha- (N-methylpyrrole-2-yl) hydroxymethyl-1,1-dioxophenylsilanate (180 mg, 0.47 mM) is dissolved in 3 ml tetrahydrofuran and 0.15 ml acetic anhydride and 0.2 ml pyridine Add. The mixture is stirred at room temperature for 1 hour. The reaction is cooled with water and extracted with ethyl acetate. The organic layer is dried and the solvent is evaporated in vacuo to yield 162 mg of material which still contains the starting material. It is dissolved in methylene chloride (3 ml) and 0.15 ml acetyl chloride and 0.2 ml pyridine are added. The mixture was stirred at room temperature for 2 hours and finished as in the above example to afford 140 mg of crude product which was purified by silica gel column chromatography to give 72 mg (42%) of pure product. Recrystallization from ethyl acetate gives colorless needles. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.45 (s, 3H), 1.65 (s, 3H), 3.7 (s, 3H), 4.4 (s, 3H), 4.6 to 4.9 (m, 2H), 5.1 to 6.4 (m, 4H), 6.6 to 7.0 (m, 2H), 7.5 (dd, 1H).

Example 17

Sodium 6- (E)-(N-methylpyrrole-2-yl) methylene-1,1dioxophenicylanate

46 mg allyl 6 (E)-(N-methylpyrrole-2-yl) methylene-1,1-dioxophenicylanate, 5 mg tetrakis (triphenylphosphine) palladium (O), 4 mg triphenylphosphine and 1 ml The solution of methylene chloride is stirred for 5 minutes under nitrogen. The resulting mixture is diluted with 1 ml ethyl acetate and 0.25 ml sodium 2-ethyl hexanoate in ethyl acetate is added. After stirring for 1 hour at room temperature, the mixture is filtered and the precipitate is washed with ethyl acetate and ethyl ether to give 30 mg of yellow solid. ¹ H-NMR (D ₂ O) ppm (delta): 1.50 (s, 3H), 1.60 (s, 3H), 3.65 (s, 3H), 4.10 (s, 1H), 5.4 (s, 1H), 6.1 To 6.5 (m, 1H), 7.0 (s, broad, 2H), 7.2 to 7.4 (m, 1H): IR (KBr) cm ⁻¹ : 1568, 1616, 1660, 1745, 3465.

Example 18

In the process of Example 15 the appropriate aldehyde of the general formula R ¹³ CHO is used to obtain the corresponding compound of the general formula

^* A-chloroform / ethyl acetate (9: 1)

B-ethyl acetate / chloroform (7: 3)

C-chloroform / ethyl acetate (19: 1)

D-chloroform / methanol (19: 1)

E-chloroform

F-chloroform / ethyl acetate (1: 1)

G-ethyl acetate

Example 19

Allyl 6- (furan-2-yl) methylene-1,1-dioxo-penicilanate, (E)-and (Z) -isomers

0.14 ml (1 mM) triethylamine and 0.1 ml (0.92) in 310 mg (0.84 mM) allyl 6-alpha- (furan-2-yl) hydroxymethyl-1,1-dioxophenicylanate solution in 5 ml methylene chloride mM) trifluoromethylsulfonyl chloride is added and the mixture is stirred at room temperature under nitrogen for 2 hours. The reaction is cooled with water, extracted with methylene chloride, the extract is dried (MgSO ₄ ) and the solvent is evaporated in vacuo to yield 330 mg of crude product. Purification by silica gel column chromatography eluting with chloroform gave 130 mg of product, which was evaluated by a mixture of the HPLC (E)-and (Z) -isomers (4: 1). ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.47 (s, 3H), 1.61 (s, 3H), 4.47 (s, 1H), 4.75 (d, 2H), 5.1 to 6.2 (m, 4H), 5.52 (dd, 1H), 6.8 (m, 1H), 7.15 (d, 1H), 7.6 (d, 1H).

Example 20

Allyl 6 (E)-(N-acetylpyrrole-2-yl) methylene-1,1-dioxophenylsilanate

A. Allyl 6- (N-acetylpyrrole-2-yl) acetoxymethyl-1,1-dioxophenicylanate

Allyl 6- (N-acetylpyrrole-2-yl) hydroxymethyl-1,1-dioxophenicilanate (210 mg, 0.51 mM) is dissolved in 3 ml tetrahydrofuran and 0.16 ml acetic anhydride and 0.2 ml pyridine The mixture is stirred for 24 hours at room temperature. The reaction was cooled with water, extracted with methylene chloride and the extract dried and concentrated to yield 171 mg (75%) of yellow crystals. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H), 2.15 (s, 3H). 2.55 (s, 3H), 4.15 to 4.3 (dd, 1H), 4.4 (s, 1H), 4.6 to 4.8 (m, 3H), 5.1 to 6.0 (m, 3H), 6.1 to 6.6 (m, 2H), 6.6 to 7.4 (m, 2 H).

B. 170 mg (0.38 mM) of N, O-diacetate product obtained from A was dissolved in methylene chloride and 47 mg (0.38 mM) 1.5-diazabicyclo [4. 3. Add 0.] non-5-ene (DBN). The mixture is stirred at room temperature for 1 hour. Water is added to extract the mixture with methylene chloride. The extract was dried and concentrated to give 158 mg of oil and purified by silica gel chromatography using 2% ethyl acetate in chloroform as eluent to afford 108 mg of the product as pale yellow oil. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.5 (s, 3H), 1.6 (s, 3H), 2.55 (s, 3H), 4.4 (s, 1H), 4.65 (d, 2H), 5.0 to 5.0 6.0 (m, 4H), 6.3 (t, 1H), 6.8 (dd, 1H), 7.2 (m, 1H), 8.2 (d, 1H).

Example 21

Allyl 6 (E) -phenylmethylene-1,1-dioxophenicylanate and the corresponding (Z) -isomer

A. 0.7 g (84%) of allyl 6 according to the method of Example A above using 1.98 mM allyl 6-phenylhydroxymethyl-1,1-dioxophenicylanate, 4.2 mM acetyl chloride and 0.4 ml pyridine -Phenylacetoxymethyl-1,1-dioxophenicylanate is obtained with a light yellow gum. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.3 and 1.4 (s, 3H), 1.62 (s, 3H), 2.08 and 2.2 (s, 3H), 4.2 (dd, 1H), 4.4 (s, 1H ), 4.5 (d, 1H), 4.65 (d, 2H), 6.25 (m, 1H), 7.3 (m, 5H).

B. 0.25 ml (1.67) in a solution of product A (0.7 g, 1.66 mM) in methylene chloride

mM) 1.5-diazabicyclo [5.4.0] undec-5-ene (DBU) is added and the mixture is stirred at room temperature for 10 minutes. Water and methylene chloride are added, the layers are separated and the organic extract is washed with 0.1N hydrochloric acid, brine and water. The extract was dried (Na ₂ SO ₄ ) and the solvent was evaporated to give 660 mg of crude product, which was purified by column chromatography on 100 g silica gel, eluting with chloroform to give 68 mg (11%) of the (Z) -isomer. do. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.45 (s, 3H), 1.60 (s, 3H), 4.45 (s, 1H), 5.37 (d, 1H), 5.1 to 6.05 (m, 3H), 7.35 (d, 1 H), 7.45 (s, 1 H).

In the subsequent elution fraction 100 mg (16.7%) of the (E) -isomer of the title compound are obtained as colorless oil and left to crystallize. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.45 (s, 3H), 1.58 (s, 3H), 4.45 (s, 1H), 4.75 (d, 2H), 5.45 (d, 1H), 5.2 to 5.2 6.2 (m, 3 H), 7.36 (d, 1 H). 7.45 (s, 5 H).

Example 22

The following compounds are prepared according to the process of Example 19 from an appropriate hydroxy compound selected from the compounds provided in Example 18.

Example 23

Starting from the allyl 6-R ³ -methylene-1,1-dioxophenicilanate ester provided in Examples 19-22, the following sodium salts are obtained according to the method of Example 17. The corresponding potassium salt is obtained using potassium 2-ethyl hexanoate.

Example 24

6 (E) -phenylmethylenephenic silane acid-1,1-dioxide

0.1 g (0.28 mM) allyl 6 (E) -phenylmethylene-1,1-dioxophenicylanate, 20 mg triphenylphosphine and 20 mg tetrakis (triphenylphosphine) palladium (O) solution in 3 ml ethyl acetate To this was added 0.57 ml 0.5 M sodium 2-ethyl hexanoate and the mixture was stirred at room temperature for 1 hour. No precipitate formed after 65 hours in the refrigerator. The mixture was diluted with ethyl acetate and water and the separated aqueous layer was diluted with dilute hydrochloric acid to pH1.8, extracted with fresh ethyl acetate, the extract was dried (Na ₂ SO ₄ ) and the solvent was evaporated under vacuum to 62 mg (69%). The product of is obtained as yellow crystals. (From acetone). ¹ H-NMR (CD ₃ COCD ₃ ) ppm (delta): 1.55 (s, 3H), 1.65 (s, 3H), 4.43 (s, 1H), 5.93 (d, 1H), 7.3 to 7.9 (m, 6H ), 8.7 (bs, 1 H): IR spectrum (KBr) cm ^-1 : 1327, 1685, 1737, 1772, 2929, 2961, 3108, 3477.

Example 25

Potassium 6- (E)-(1-methylimidazol-2-yl) methylene-1,1-dioxophenicylanate

A. Allyl 6- (1-methylimidazol-2-yl) acetoxymethyl-1,1-dioxophenicylanate

6- (1-methylimidazol-2-yl) hydroxymethyl-1,1-dioxophenicylanate (472 mg, 1.23 mM) was acylated according to the method of Example 20A to give 392 mg (75%) of Acetoxy compound is obtained as a mixture of two isomers. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 1.5H), 1.5 (s, 1.5), 1.6 (s, 1.5H), 1.7 (s, 1H), 2.2 (s, 3H), 3.7 (s, 1.5H), 3.75 (s, 1.5H), 4.0 to 6.0 (m, 8H), 6.3 to 6.5 (m, 1H), 6.8 (m, 1H), 7.0 (m, 1H).

B, allyl 6- (E)-(1-methylimidazol-2-yl) methylene-1,1-dioxophenicylanate

The product obtained in A (392 mg, 0.920 mM), 5 ml methylene chloride and 0.115 ml 1.5-diazabicyclo [4.3.0] non-5-ene (DBN) were obtained in 53% yield according to the method of Example 20B. Convert to ester. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.5 (s, 3H), 1.6 (s, 3H), 3.7 (s, 3H), 4.35 (s, 1H), 4.7 (m, 2H), 5.0 to 5.0 6.1 (m, 3H), 5.7 (d, 1H), 6.9 (m, 1H), 7.1 (d, 1H), 7.2 (m, 1H).

C. The allyl ester (163 mg, 0.45 mM) obtained in B is converted to the title potassium salt according to the method of Example 17 using potassium 2-ethylhexanoate instead of the corresponding sodium salt. The product is 143 mg (87% yield) of the single (E) isomer. ¹ H-NMR (DMSO) ppm (delta): 1.38 (s, 3H), 1.45 (s, 3H), 3.8 (s, 4H), 5.68 (s, 1H), 7.15 (s, 1H), 7.35 (m , 2H),: ¹³ C-NMR (DMSO) ppm (delta): 18.5, 20.2, 32.5, 64.4, 66.2, 70.55, 115.2, 124.6, 129.9, 130.6, 141.2, 167.9, 1690.0 IR spectrum (KBr) cm ^-1 : 1614, 1762, 3428.

Example 26

Using 5.2 mg triphenylphosphine, 5.2 mg tetrakis (triphenylphosphine) palladium (O) and 0.24 mM potassium 2-ethylhexanoate (2 molar equivalents of starting material allyl ester) in 1.5 ml ethyl acetate The process of Example 10 was repeated with 50 mg (0.12 mM) allyl 6- (3-allyloxy-2-pyridyl) methylene-1,1-dioxophenicylanate and the resulting mixture was stirred for 18 hours. The ethyl acetate was removed with a pipette and the residue was washed twice with 1 ml of ethyl acetate to give 43 mg of a blackish solid, which was 6 (E)-(3-hydroxy-2-pyridyl) methylene-1,1-di It was found to be the dipotassium salt of oxophenic silane acid. ¹ H-NMR (D ₂ O) ppm (delta): 1.56 (s, 3H), 1.62 (s, 3H), 4.27 (s, 1H), 6.00 (d, 1H), 7.29 (m, 2H), 7.80 (d, 1 H), 8.04 (d, 1 H).

Example 27

Allyl 6 (E)-(2-pyrimidinyl) methylenephenicylanate

A. 2-hydroxymethylpyrimidine

A slurry of sodium ethoxide prepared from 7.44 g (323 mM) sodium metal and 300 ml anhydrous ethanol was cooled at room temperature, and 18 g (163 mM) hydroxyacetamidine hydrochloride and 8.06 ml (81 mM) 3-dimethylaminoacrolein were added to the mixture. Heat to reflux. Ethanol is added periodically to slowly distill off dimethylamine while maintaining solvent volume. After refluxing for 9 hours the mixture is stirred for 18 hours at room temperature. The solvent is evaporated under reduced pressure and left on a silica gel column to elute with ethyl acetate / methanol (19: 1) to yield 4.1 g of product (46% yield).

B. 2-pyrimidinylmethyltriphenylphosphonium chloride

4.096 g (37.2 mM) of 2-hydroxymethylpyrimidine are dissolved in 80 ml methylene chloride and 8.6 ml (37.2 mM) thionyl chloride is added dropwise (exothermic reaction). The mixture is stirred for 15 minutes, neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride. The extract is dried and the solvent is evaporated to yield 3.67 g of 2-chloromethylpyrimidine. ¹ H-NMR (CDCl ₃ ) ppm (delta): 4.82 (s, 2H), 7.3 (±, 1H), 8.9 (d, 2H).

A mixture of 3.565 g (27.7 mM) 2-chloromethyl pyrimidine and 7.269 g (27.7 mM) triphenylphosphine in 30 ml toluene is heated to reflux for 18 hours. The precipitate obtained is collected by filtration and dried to yield 9.06 g (65% in two steps).

C. A mixture of the Wittich reagent obtained from B, 218.4 mg (5.32 mM) of sodium amide and 30 ml anhydrous tetrahydrofuran (THF) is stirred at room temperature for 1.5 hours. A solution of 1.44 g (5.65 mM) allyl 6-oxophenicilanate in 10 ml anhydrous THF was added at -78 ° C in one portion, and the resulting mixture was stirred for 5 minutes, poured into saturated ammonium chloride solution and extracted with chloroform. The organic phase is washed with saturated ammonium chloride and brine, dried (MgSO ₄ ) and the solvent is evaporated in vacuo. The oil was purified by column chromatography on silica gel, eluting with chloroform / ethyl acetate (9: 1) to afford 560 mg of pure product. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.5 (s, 3H), 1.6 (s, 3H), 4.6 (s, 1H), 4.7 (m, 2H), 5.1 to 6.3 (m, 3H), 6.2 (d, 1H), 7.0 (d, 1H), 7.0 to 7.35 (m, 1H), 8.8 (d, 2H).

Example 28

Allyl esters and potassium salts of 1,1-dioxo-6 (E)-(2-pyrimidinyl) -methylenephenicylanic acid

A. Allyl 6 (E)-(2-pyrimidinyl) -methylenephenicylanate (560 mg, 1.69 mM) and 730 mg (3.38 mM) of 3-chloroperbenzoic acid are dissolved in 10 ml methylene chloride and stirred for 4 hours under nitrogen atmosphere. Let's do it. The resulting mixture was cooled with water, extracted with methylene chloride and the extract washed with sodium thiosulfate, neutralized with sodium bicarbonate, washed with brine, dried and concentrated in vacuo to afford 460 mg of crude oil. The oil is purified by silica gel column chromatography, eluting with chloroform / ethyl acetate (9: 1) to afford 180 mg of the desired allyl ester as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.45 (s, 3H), 1.65 (s, 3H), 4.5 (s, 1H), 4.75 (m, 2H), 5.2 to 6.3 (m, 3H), 5.75 (s, 1 H), 7.1 to 7.5 (m, 2 H), 8.9 (d, 2H).

B. The reactant of the allyl ester and triphenyl phosphine, tetrakis (triphenylphosphine) palladium (O) and potassium 2-ethyl hexanoate were reacted by the method of Example 10 to give the desired potassium salt 89 Obtained as a pale pink solid in% yield. ¹ H-NMR (D ₂ O) ppm (delta): 1.6 (s, 3H), 1.68 (s, 3H), 4.4 (s, 1H), 6.1 (s, 1H), 7.48 (s, 1H), 7.54 (±, 1H). 8.88 (d, 2H):

¹³ C-NMR (D ₂ O) ppm (delta): 20.9, 22.7, 68.8, 68.9, 74.6, 124.5, 132.5, 139.9, 160.9, 163.2, 172.5, 175.5. IR spectrum (KBr) cm ^-1 : 1560, 1615, 1771, 3439.

Example 29

A. Add 50 mg diisopropylcarbodiimide and 0.5 ml 2,2,2-trichloroethanol to 1.0 g 6-alpha-hydroxyphenicylic acid in 25 ml methylene chloride. The mixture is stirred overnight and the solvent is evaporated off in vacuo and the crude product is purified by column chromatography on silica gel to give 2,2,2-trichloroethyl 6-alpha-hydroxyphenicylanate.

-톨루엔 설폰산 및 0.4g 디하이드로피란을 가하고 혼합물을 50℃로 가온시킨 후, 밤새 실온에서 교반시킨다. 용매를 증발시키고 실리카겔 커러럼 크로마토그라피로 정제하여 2-테트라하이드로피라닐 6-알파-하이드록시페니실라네이트를 수득한다.B. 0.5 g to 1.0 g 6-alpha-hydroxyphenicylic acid in 50 ml dioxane

Toluene sulfonic acid and 0.4 g dihydropyran are added and the mixture is allowed to warm to 50 ° C. and then stirred at room temperature overnight. The solvent is evaporated and purified by silica gel column chromatography to give 2-tetrahydropyranyl 6-alpha-hydroxyphenicilanate.

Example 30

Benzyl 6-Oxophenicylanate

To a 1.8 ml (0.025 mol) dimethylsulfoxide solution of 2 ml methylene chloride strain is added dropwise a solution of 2.12 ml (0.015 mol) trifluoroacetic anhydride in 5 ml methylene chloride at -60 ° C. The mixture is stirred 20 min at -60 ° C and a 350 mg (1.14 mM) benzyl 6-alpha-hydroxy penicilanate solution in 5 ml methylene chloride is added and stirred at -60 ° C for 60 min. Triethylamine (0.50 ml) is added and the ice bath is removed, the mixture is warmed to 0 ° C., poured into ice water and extracted with methylene chloride. The organic layer is dried and concentrated in vacuo to make a small amount which is diluted with benzene and washed three times with ice water. The benzene layer is dried and the solvent is evaporated in vacuo to give 230 mg (67%) of the product as yellow crystals. Proton-NMR spectra in CDCl ₃ showed that the product was very pure.

Example 31

Benzyl 6- (2-pyridyl) hydroxymethylphenicylanate

A. Benzyl 6-Bromo-6 (2-pyridyl) hydroxymethylphenicylanate

A 9.0 g (0.02 mole) benzyl 6,6-dibromophenicylanate solution in 200 ml of freshly distilled toluene is cooled to −78 ° C. and 9 ml 2.2M tert-butyllithium in pentane is added dropwise. The resulting mixture was stirred for 30 minutes and 2.14 g (0.02 mol) 2-pyridine-carboxaldehyde was added and stirred for 40 minutes. Acetic acid in toluene is added dropwise to cool the reaction. After stirring for 1 hour and removing the bath, the mixture is warmed to −10 ° C., diluted with 200 ml toluene, washed with water (5 times) and dried (Na ₂ SO ₄ ). Toluene solution is loaded into a column of Florisil (1 kg) and eluted with toluene / ethyl acetate (2: 1). The product fractions are mixed and evaporated under vacuum to 4.2 g of brown syrup which is used for the next step.

B. Dissolve the brown syrup (4.2 g) of A in 50 ml benzene and add 2.65 g tributyltin hydride. The mixture is heated to reflux for 2 hours and additional tributyltin hydride (1.65 g) is added to reflux overnight. The solvent was evaporated in vacuo and the residue washed with hexane and placed in a column containing 500 g silica gel and eluted with toluene / ethyl acetate (2: 1) to afford 425 mg of the title compound. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.35 (s, 3H), 1.7 (s, 3H), 4.0 (dd, 1H), 4.5 (s, 1H), 5.1 (s, 2H), 5.2 ( d, 1H), 5.4 (d, 1H), 7.0 to 7.8 (m, 3H), 8.5 (m, 1H)

[Example 32]

6- (2-pyridyl) hydroxymethylphenicylic acid 1,1-dioxide

A. Benzene 6- (2-pyridyl) hydroxymethyl-1,1-dioxophenicylanate

-클로로퍼벤조산을 가하고 혼합물을 실온에서 1시간 교반시킨다. 박층 크로마토그라피 결과, 혼합물은 약간의 설폭사이드를 함유하는 것으로 밝혀졌다. 추가의 0.2g

-클로로퍼벤조산을 가하고 혼합물을 밤새 교반시킨다 메틸렌 클로라이드로 혼합물을 희석하고, 포화 티오황산나트륨 용액, 물 및 포화 중탄산나트륨 용액으로 차례대로 세척하고 유기층을 진공하에 농축시킨다. 잔사를 에틸 아세테이트에 용해시키고 중탄산나트륨 용액, 물 및 염수로 세척하고 건조시킨다(Na₂SO₄). 용매를 증발시켜 330mg의 목적한 벤질 에스테르를 갈색 오일로 수득하고, 에틸 아세테이트/헥산(11 : 9)으로 용출시키면서 실리카겔 컬럼 크로마토그라피로 정제하여 60mg의 황색 오일을 수득한다.¹H-NMR(CDCl₃)ppm(델타) : 1.25(s, 3H), 1.52(s, 3H), 4.1(dd, 1H), 4.5(s, 1H), 4.72(d, 1H), 5.5(d, 2H), 5.8(d, 1H), 7.1 내지 8.0(m, 3H), 8.5(m, 1H).0.20 g in 0.40 g benzyl 6- (2-pyridyl) hydroxymethylphenicylate solution in 5 ml methylene chloride

-Chloroperbenzoic acid is added and the mixture is stirred at room temperature for 1 hour. Thin layer chromatography showed that the mixture contained some sulfoxide. 0.2g additional

Add chloroperbenzoic acid and stir the mixture overnight Dilute the mixture with methylene chloride, wash sequentially with saturated sodium thiosulfate solution, water and saturated sodium bicarbonate solution and concentrate the organic layer in vacuo. The residue is dissolved in ethyl acetate, washed with sodium bicarbonate solution, water and brine and dried (Na ₂ SO ₄ ). The solvent was evaporated to afford 330 mg of the desired benzyl ester as a brown oil, which was purified by silica gel column chromatography eluting with ethyl acetate / hexanes (11: 9) to give 60 mg of yellow oil. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.25 (s, 3H), 1.52 (s, 3H), 4.1 (dd, 1H), 4.5 (s, 1H), 4.72 (d, 1H), 5.5 ( d, 2H), 5.8 (d, 1H), 7.1 to 8.0 (m, 3H), 8.5 (m, 1H).

B. Prehydrogenation of 118 mg 10% Pd / C catalyst suspension in 10 ml tetrahydrofuran (THF) and 4 ml water for 20 minutes at 3 atm hydrogen pressure. To this was added 130 mg benzyl ester in the same THF / water mixture obtained in A above. This was hydrogenated at 50 psi (3.5 km / cm ² ) for 30 minutes. An additional 129 mg of 10% Pd / C was added and hydrogenated at 50 psi for 2 hours. The catalyst is removed by filtration, the solvent is evaporated in vacuo and the residue is partitioned between water and ethyl acetate. The aqueous layer is lyophilized to yield 85 mg of the desired acid. ¹ H-NMR (D ₂ O) ppm (delta): 1.3 (s, 3H), 1.5 (s, 3H), 4.4 (s, 1H), 5.0 to 5.35 (m, 2H), 5.9 (d, 1H) : IR spectrum (KBr) cm ^-1 : 1620, 1731, 3407.

-클로로퍼벤조산(등몰량)을 사용하는 것을 제외하고 상기 공정을 수행할 경우, 분리된 생성물은 상응하는 알파-및 베타-설폭사이드의 혼합물이다.C. 175 mg total in A

When carrying out the above process except using -chloroperbenzoic acid (equal molar amount), the separated product is a mixture of the corresponding alpha- and beta-sulfoxides.

Example 33

The following materials are mixed in the following weight ratios to obtain a powder of homogeneous composition:

(a) Potassium (6-alpha, 8R) -6- (thiazol-2-yl) acetoxymethyl-1,1-dioxophenicylanate 1.0

(b) Ampicillin Trihydrate 1.0

(c) lactose 0.5

(d) polyethylene glycol, average molecular weight, 400 3.0

The mixture (1375 mg) is filled into hard gelatine capsules of appropriate size to give a capsule of each active ingredient of 250 mg titer. Proper control of the capsule size and fill weight produces high or low titer capsules. By adjusting the comparative increase of the active ingredient to prepare a different active ingredient ratio, for example, by mixing the active ingredient in the weight ratio of 0.75, 1.5, 0.5 and 3.0 respectively 1700m

g Fill weight / capsules to obtain capsules with (a) of 225 mg titer and (b) of 450 mg titer.

In a similar manner, other beta-lactamase inhibitors of the invention are formulated for oral use with other conventional beta-lactam antibiotics.

Alternatively, components (a) and (b) in the formulation were prepared by 2 parts by weight of 6- [D- (2-amino-2-phenylacetamido)] phenylananoyloxymethyl 6- (2-pyridyl) Substitute with methylene-1,1-dioxophenicylanate hydrochloride.

Example 34

Injection preparations

Equal parts of cellular ferrazone sodium and potassium 1,1-dioxo-6 (E)-(2-pyrazinyl) methylenephenicylanate are mixed with 20 parts by weight of water. Using standard methods in the pharmaceutical art, the solution is sterile filtered, filled into vials, and the vials are loosely capped and lyophilized on trays. Filling capacity is that a lyophilized vial sealed under vacuum contains 500 mg of each active ingredient. Inject 10 ml of sterile water for injection through a rubber stopper and shake to dissolve each vial before injection. The injected 1-10 ml solution is removed by subcutaneous injection through a rubber stopper.

Example 35

Allyl 6- (2-thiazolyl) acetoxymethyl-1,1-dioxophenicylanate

0.396 g (3.88 mM) acetic anhydride and 0.307 g (3.88) in 5 ml tetrahydrofuran

mM) acetylation of 0.5 g (1.29 mM) allyl 6- (2-thiazolyl) hydroxymethyl-1,1-dioxophenicylanate (obtained in Example 18) with pyridine, obtained in Example 20A. It is carried out with stirring for 4 hours at room temperature according to the method. The mixture is then diluted with methylene chloride, washed with water until neutral (pH 6.0 to 6.5), the organic phase is dried (Na ₂ SO ₄ ) and the solvent is evaporated to yield 0.688 g of the desired acetate. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.52 (s, 3H), 1.70 (s, 3H), 2.35 (s, 3H), 4.4 to 4.6 (m, 2H), 4.6 to 5.0 (m, 3H ), 5.2 to 6.4 (m, 3H), 6.65 (d, 1H), 7.4 (d, 1H), 7.8 (d, 1H).

Example 36

Allyl 6- (2-thiazolyl) methylene-1,1-dioxophenicylanate and its hydrolysis to potassium salts

A. The acetoxy ester (0.688 g, 1.29 mM) was mixed with 0.16 g (1.29 mM) 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 5 ml methylene chloride to give 1 Stir for time. The resulting mixture is diluted with methylene chloride, washed with water (2 × 50 ml), dried (Na ₂ SO ₄ ) and the solvent is evaporated to give an oil. The oil was chromatographed on a silica gel column eluting with ethyl acetate / hexanes (1: 1) to yield 0.189 g (39%) of a light yellow oil. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.53 (s, 3H), 1.65 (s, 3H), 4.33 (s, 1H), 4.55 (d, 2H), 5.0 to 5.4 (s, 1H), 5.45 (s, 1 H), 5.4 to 6.0 (m, 1 H), 7.1 (m, 1 H), 7.75 (m, 1 H), 7.65 (d, 1 H).

B. The allyl ester obtained according to the method of Example 25C above was hydrolyzed to give 84.7% yield of potassium 6- (2-thiazolyl) methylene-1,1-dioxophenisilanate as a yellow solid. ¹ H-NMR 250 MHz (DMSO-d ₆ ) ppm (delta): 1.40 (s, 3H), 1.45 (s, 3H), 3.80 (s, 1H), 5.83 (s, 1H), 7.66 (s, 1H) , 8.04 (m, 2 H).

Example 37

Tetrabutylammonium 6- [D- (2- [1-methyl-2-methoxycarbonylvinylamino] -2-phenylacetamido)] phenylanate

To 300 ml chloroform, 39.3 g 6- [D- (2-amino-2-phenylacetamido)] phenic acid trihydrate and 50 ml of water were added, and 40% aqueous tetrabutylammonium hydroxide was added to the pH of the mixture. Is adjusted to 8.5. The layers are separated and the aqueous layer is saturated with sodium sulfate and extracted with fresh chloroform. The extract and the initial bottom layer are mixed and the solvent is evaporated to a total volume of about 250 ml.

To this was added 39.3 g of anhydrous magnesium sulfate to 150 ml chloroform. The mixture is heated to reflux for 3 hours and left to pour off the warm organic layer. The clear chloroform solution is cooled to give crystals of the title compound having a melting point of 182 to 184 ° C. (decomposition) in 52% yield. ¹ H-NMR (CDCl ₃ ) ppm (delta): 0.8 to 2.0 (m, 4H), 1.88 (s, 3H), 3.1 to 3.6 (m, 8H), 3.6 (s, 3H), 4.17 (s, 1H ), 4.58 (s, 1H), 5.05 (d, 1H), 5.38 to 5.6 (m, 2H), 6.78 (d, 1H), 7.35 (s, 5H), 9.4 (d, 1H).

Example 38

Tetrabutylammonium 6- [D- (2- [1-methyl-2-methoxycarbonylvinylamino] -2- [4-hydroxyphenyl] acetamido)] pheniclanate

To 300 ml of dichloromethane 41.9 g of 6- (2-amino-2- [4-hydroxyphenyl] acetamido} phenicylic acid trihydrate and 50 ml of water were added followed by 40% aqueous tetrabutylammonium hydroxide. The pH is adjusted to 8.5 using three layers are obtained, the upper layer is separated, saturated with sodium sulfate and extracted with dichloromethane The extract is mixed with the middle layer and the lower layer and the resulting mixture is evaporated under vacuum to give an oil To obtain 44.6 g of tetrabutylammonium 6- (2-amino-2- [4-hydroxyphenyl] acetamido) phenylanate.

The salt is added to 150 ml of methyl aceto acetate and the suspension is heated to about 65 ° C. to give a clear solution (8 minutes). After cooling the mixture the solid is recovered by filtration. The solid was washed sequentially with methyl aceto acetate and diethyl ether to give 49.25 g of tetrabutylammonium 6- (2- [1-methyl-2-methoxycarbonylvinylamino] -2- [4-hydroxyphenyl] Acetamido) phenicilanate crystals are obtained.

Example 39

A. Potassium (6-alpha, 8s) -6- (pyrimidin-2-yl) hydroxymethyl-1,1-dioxophenicylanate

300 mg (0.79 mM) of a primary eluted isomeric solution of allyl 6-alpha- (pyrimidin-2-yl) hydroxymethyl-1,1-dioxophenicylanate (obtained in Example 18) in 4 ml ethyl acetate

) Is added 30 mg tetrakis (triphenylphosphine) palladium (O) and 30 mg triphenylphosphine. The mixture is stirred under nitrogen to dissolve the reagent (5 to 10 minutes) and 1.57 ml (0.79 mM) potassium 2-ethylhexanoate in ethyl acetate is added. After stirring 20 minutes at room temperature, the mixture is filtered and the cake is washed with ethyl acetate and dried to give 53 mg of a yellow solid. The filtrate is treated with ethyl ether and precipitated to give 152 mg of second yield in 69% yield in total. ¹ H-NMR, 250 MHz, (DMSO-d ₆ ) ppm (delta): 1.33 (s, 3H), 1.44 (s, 3H), 3.77 (s, 1H), 3.95 (dd, J = 2, J = 6 , 1H), 4.89 (d, J = 2, 1H), 5.1 (d, J = 6, 1H), 6.33 (s, 1H), 7.48 (±, J = 4, 1H), 8.84 (d, J- 4, 2H).

B. Potassium (6-alpha, 8R) -6- (pyrimidin-2-yl) hydroxymethyl-1,1-dioxophenicylanate

300 mg (0.79 mM) of a secondary eluted isomeric solution of allyl 6-alpha- (pyrimidin-2-yl) hydroxymethyl-1,1-dioxophenicylanate (obtained in Example 18) were subjected to the above procedure. Conversion to its potassium salt yields 236 mg (79%) of product. ¹ H-NMR, 250 MHz, (DMS

Od ₆ ) ppm (delta): 1.30 (s, 3H), 1.42 (s, 3H), 3.65 (s, 1H), 4.60 (dd, J = 2, J = 8, 1H), 4.75 (d, J = 2, 1H), 5.15 (d, J = 8, 1H), 7.47 (t, J = 4, 1H), 8.85 (d, J = 4, 2H).

Example 40

A. Allyl (6-alpha, 8S) -6- (pyrimidin-2-yl) acetoxymethyl-1,1-dioxophenicylanate

To 785 mg (2.1 mM) of the first eluted isomeric solution of allyl 6-alpha- (pyrimidin-2-yl) hydroxymethyl-1,1-dioxophenicylanate (obtained in Example 18) of 4 ml methylene chloride 0.45 ml (5.6 mM) pyridine and 0.53 ml (5.6 mM) acetic anhydride are added and the mixture is stirred at room temperature for 2.5 hours. The mixture is diluted with 30 ml methylene chloride, extracted with water (7 x 60 ml), dried over anhydrous magnesium sulfate and filtered. 813 m by evaporation under vacuum

g (92%) of the title compound is obtained. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H), 2.2 (s, 3H), 4.45 (s, 3H), 4.45 (dd, 1H), 4.75 ( m, 2H), 4.95 (d, 1H), 5.2 to 5.6 (m, 2H), 5.7 to 6.3 (m, 1H), 6.45 (d, 1H), 7.35 (t, 1H), 8.85 (d, 1H) .

B. Allyl (6-alpha. 8R) -6- (pyrimidin-2-yl) acetoxymethyl-1,1-dioxophenicylanate

According to the method, the secondary eluted isomer of ali 6-alpha- (pyrimidin-2-yl) hydroxymethyl-1,1-dioxophenicylanate (obtained in Example 18) was acetylated to give 88% yield. To give the title compound. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H), 4.45 (s, 1H), 4.50 (dd, J = 1, J = 8, 1H), 4.75 (m, 2H), 4.8 (d, J = 1, 1H), 5.25 to 5.6 (m, 2H), 5.7 to 6.3 (m, 1H), 6.4 (d, J = 8, 1H), 7.35 (t, J = 6, 1H), 8.8 (d, J = 6, 1H).

Example 41

A. Potassium (6-alpha. 8S) -6- (pyrimidin-2-yl) acetoxymethyl-1,1-dioxophenicylanate

A 789 mg (1.86 mM) allyl (6-alpha, 8S) -6- (pyrimidin-2-yl) acetoxymethyl-1,1-dioxophenifylanate solution in 4 ml ethyl acetate was prepared according to the process of Example 54. Reaction gave 342 mg (43%) of the desired potassium salt, which was purified by preparative MPLC * eluting with water / acetonitrile (9: 1) to yield 105 mg of product (HPLC analysis 85% purity).

B. Potassium (6-alpha, 8R) -6- (pyrimidin-2-yl) acetoxymethyl-1,1-dioxophenicylanate

666 mg (1.57 mM) allyl (6-alpha, 8R) -6- (pyrimidin-2-yl) acetoxymethyl-1,1-dioxophenicylanate solution was reacted according to the above procedure to give 339 mg (51%) A crude product of was obtained and purified by preparative MPLC * eluting with water / acetonitrile (9: 1) to afford 162 mg of pure isomers. ¹ H-NMR, 250 MHz, (DMSO-d ₆ ) ppm (delta): 1.34 (s, 3H), 1.44 (s, 3H), 2.17 (s, 3H), 3.65 (s, 1H), 4.15 (dd, J = 2, J = 8, 1H), 4.97 (d, J = 2, 1H), 6.27 (d, J = 8, 1H). 7.50 (t, J = 5, 1H), 8.85 (d, J = 5, 2H).

* MPLC is medium pressure liquid chromatography.

HPLC is high pressure liquid chromatography.

Example 42

The following acetate esters are prepared according to the method of Example 20 or 55 using the appropriate 6-R ¹³ CHOH-substituted -1,1-dioxophenicilanate ester provided in Example 18.

Example 43

The 8-acetoxy-3-carbonyloxyallyl esters provided in Examples 25A and 57 are converted to potassium salts of the general formula following the method of Example 54.

* C ¹⁸ used, (C ₁₈ is monooctadecyl silicate) column.

Example 44

The 8-acetoxy ester obtained from above was converted to the corresponding 6-methylene compound according to the method of Example 20B and the allyl group was removed according to the method of Example 54, wherein R ¹ is potassium Obtain potassium salt.

Example 45

Potassium 6- (imidazol-2-yl) hydroxymethyl-1,1-dioxophenicylanate

141 mg (0.38 mM) allyl 6- (imidazol-2-yl) hydroxymethyl-1,1-dioxophenicylanate (isomer mixture obtained in Example 18), 12 mg tetrakis (triphenyl phosphine) palladium (O), a mixture of 12 mg triphenylphosphine, 0.76 ml (0.38 mM) potassium 2-ethylhexanoate and 2 ml ethyl acetate is stirred under nitrogen for 1 hour. The precipitated product was recovered by filtration to give 143 mg (100%) of a yellow solid, which was found to contain two isomers by high pressure liquid chromatography analysis. IR (KBr): 3382, 1780, 1728 and 1615 cm ^-1

Example 46

A. Benzyl 6- (2-thiazolyl) hydroxymethyl-1,1-dioxophenicylanate

A 17.79 g (44 mM) benzyl 6-alpha-bromo-1,1-dioxophenisilanate solution in 250 ml anhydrous tetrahydrofuran was reacted with equimolar amount of methylmagnesium bromide at -78 ° C, stirred for 1 minute, and the like. Molar amount of thiazole-2-carboxaldehyde is added and stirred for a further 10 minutes. Then equimolar amount of acetic acid is added and stirred for 5 minutes and the mixture is poured into 500 ml water. Extract with ethyl acetate and wash the extract with water, dry (MgSO ₄ ) and evaporate the solvent under vacuum to afford 16.93 g (89%) of crude product, which showed two spots on TLC. The crude product was purified by silica gel column chromatography, eluting with chloroform / ethyl acetate (96: 4) to afford 4.72 g of more polar isomers, 2.98 g of less polar isomers and 0.5 g of isomer mixture (total Yield 43%).

More polar isomers: ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.25 (s, 3H), 1.55 (s, 3H), 4.3 (dd

, 1H), 4.45 (s, 1H), 4.65 (bs, 1H), 4.9 (d, 1H), 5.2 (m, 2H), 5.55 (d, 1H), 7.35 (m, 6H), 7.75 (

d, 1H).

Less polar isomers: ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.2 (s, 3H), 1.5 (s, 3H), 4.35 (m, 2H), 4.75 (d, 1H). 5.1 (m, 2H), 5.55 (d, 1H), 7.2 (m, 6H), 7.6 (d, 1H).

B. Diphenylmethyl 6- (2-thiazolyl) hydroxymethyl-1,1-dioxophenicylanate

The process was repeated with 20 mM diphenylmethyl 6-alpha-bromo-1,1-dioxophenicylanate, purified by silica gel chromatography eluting with chloroform / ethyl acetate (9: 1). 2.464 g of less isomeric (LP) isomer and 3.029 g of more polar (MP) isomer are obtained.

More polar isomers: ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.06 (s, 3H), 1.52 (s, 3H), 4.1-4.3 (m, 1H), 4.42 (s, 1H), 4.76 ( d, 1H), 5.45 (d, 1H), 6.83 (s, 1H), 7.05-7.3 (m, 11H), 7.56 (d, 1H).

Less polar isomers: ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.2 (s, 3H), 1.65 (s, 3H), 4.35 (dd

, 1H), 4.55 (s 1H), 4.83 (d, 1H), 5.65 (dd, 1H), 6.95 (s, 1H), 7.2-7.4 (m, 11H), 7.75 (d, 1H).

Example 47

Using the appropriate acid chlorides or corresponding acid anhydrides of the general formula R ¹⁸ Cl as obtained above, and the appropriate 6-R ¹³ CHOH-substituted-1,1-dioxophenicylanate esters, the following compounds were prepared in Example 20A Manufacture according to.

Example 48

A. (6-alpha, 8R) -6- (thiazol-2-yl) propionyloxymethyl-1,1-dioxophenicsilane acid

A mixture of 1.89 g of 10% carbonaceous palladium catalyst in a mixture of 20 ml, tetrahydrofuran (THF) and water (9: 7, V / V) was saturated with hydrogen and 689 mg (1 ml) in 13 ml THF and 7 ml water.

.4 mM) benzyl (6-alpha, 8R) -6- (thiazol-2-yl) propionyloxymethyl-1,1-dioxophenicylanate solution is added. The mixture obtained is hydrogenated at 3 bar pressure for 20 minutes, then the catalyst is removed by filtration, the filtrate is extracted with ethyl acetate (3x200 ml) and the extract is dried (MgSO ₄ ). The solvent is evaporated in vacuo to yield 330 mg of a yellow solid.

B. (6-alpha, 8R) -6- (thiazol-2-yl) benzoyloxymethyl-1,1-dioxophenicsilane acid

This process affords the title compound in 57% yield from the corresponding benzyl ester.

¹ H-NMR (D ₂ O) ppm (delta): 1.38 (s, 3H), 1.55 (s, 3H), 4.25 (s, 1H), 4.44 (dd, 1H), 5.05 (d, 1H), 6.68 (d, 1H), 7.4 (t, 7H), 7.55 (t, 1H), 7.58 (d, 1H), 7.7 (d, 1H), 7.95 (d, 1H), IR (KBr): 3473, 1782, 1729, 1622 cm ^-1

Example 49

A. (6-alpha, 8S) -6- (thiazol-2-yl) ethoxycarbonyloxymethyl-1,1-dioxophenicsilane acid

0.62 in 557 mg (0.954 mM) diphenylmethyl (6-alpha, 8S) -6- (thiazol-2-yl) ethoxycarbonyloxymethyl-1,1-dioxophenicylanate solution in 5 ml methylene chloride Add ml (5.72 mM) anisole. The mixture is cooled to -5 ° and slowly added 382 mg (2.86 mM) anhydrous aluminum chloride and 2 ml nitromethane for 15 minutes. The reaction mixture is diluted with 50 ml ethyl acetate and adjusted to pH 7.5 by addition of water. The aqueous layer is separated, acidified to pH 3 and extracted with ethyl acetate. The solvent is evaporated to give a residual glass which is dissolved in ethyl ether, filtered and hexane is added to the filtrate to effect precipitation. After filtration the solids are recovered and dried to yield 211 mg (35%) of product.

¹ H-NMR, 300 MHz, (CDCl ₃ ) ppm (delta): 1.40 (t, 3H), 1.53 (s, 3H), 1.67 (s, 3H), 4.28-4.42 (m, 3H), 4.50 (s, 1H), 4.92 (s, 1H), 6.58 (d, .1H), 7.53 (d, 1H), 7.93 (d, 1H), IR (KBr): 3443, 1797, 1754cm ^-1

B. 6- (thiazol-2-yl) ethoxycarbonyloxymethyl-1,1- using the (6-alpha, 8R) -isomer of the diphenylmethyl ester provided in Example 62 according to the above procedure The corresponding (6-alpha, 8R) -isomer of dioxophenicsilane acid is obtained.

¹ H-NMR, 300 MHz, (CDCl ₃ ) ppm (delta): 1.34 (t, 3H), 1.53 (s, 3H), 1.65 (s, 3H), 4.2-4.4 (m, 3H), 4.44 (s, 1H), 5.04 (s, 1H), 6.67 (d, 1H), 7.53 (d, 1H), 7.90 (d, 1H), IR (KBr): 3418, 1803, 1750cm ^-1

Example 50

Using the appropriate allyl ester provided in Example 62 as starting material, the following potassium salts are obtained according to the method of Example 60.

Example 51

A. Allyl 6-bromo-6- (2-thiazolyl) hydroxymethyl-1,1-dioxophenicylanate

8.84 g (20 mM) allyl 6,6-dibromo-1,1-dioxophenislanate solution in 100 ml anhydrous tetrahydrofuran was cooled to -78 ° C and the mixture was added 7.02 ml (20 mM) methylmagnesium bromide Stir for 5 minutes. 2.26 g (20 mM) thiazole-2-carboxaldehyde solution in 10 ml solvent as described above is added at -78 ° C and the resulting mixture is stirred for 20 minutes. Acetic acid (1.2 ml) is added and the mixture is poured into water and extracted with ethyl acetate and chloroform. The mixed organic layer is dried (Na ₂ SO ₄ ) and the solvent is evaporated in vacuo to give 8.5 g of crude product as glass. The crude glass was purified by column chromatography on silica gel, eluting with chloroform / ethyl acetate (89: 11) to give 6.2 g (72%) of pure isomers which were found to be single isomers.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H), 4.0 (bs, 1H), 4.42 (s, 1H), 4.6 (d, 2H), 5.3 ( s, 1H), 5.55 (s, 1H), 5.1-6.3 (m, 3H), 7.35 (d, 1H), 7.75 (d, 1H).

B. Benzyl 6-Bromo-6- (2-thiazolyl) hydroxymethyl-1,1-dioxophenicylanate

The title compound of the organic foam is obtained in quantitative yield following the above process using benzyl 6,6-dibromo-1,1-dioxophenicylanate in place of allyl ester.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.32 (s, 3H), 1.60 (s, 3H), 4.5 (s, 2H), 5.2-5.8 (m, 4H), 7.3 (d, 1H), 7.4 (s, 5 H), 7.8 (d, 1 H).

C. The following compounds are prepared following procedures analogous to A above.

Example 52

A. The compounds provided in the above examples were acylated according to the method of Example 57 or 62 to afford the following compounds.

A. When R ^a is yl and R ¹⁸ is CH ₃ CO:

B. When R ^a is benzyl and R ¹⁸ is CH ₃ CO:

C. The compounds of the above general formulas are also prepared according to the method of example 66 by acylating the reaction mixture before separating the product by the following general method: 1.0 equivalent of 6,6-di in tetrahydrofuran. 1.3 equivalents of methylmagnesium bromide are added to the bromophenicylanate ester solution at -78 ° C, dissolved in the same solvent and the mixture is stirred for 5-10 minutes. 1.3 equivalents of the appropriate aldehyde (R ¹³ CHO) in the same solvent are added at -78 ° C to -68 ° C and the reaction mixture is stirred for 30 to 60 minutes. Then 1.3 equivalents of acetyl chloride are added and stirred at −78 ° C. for 10 minutes, after which the product is poured into ice / water, extracted with ethyl acetate, dried and separated by evaporation of the solvent under vacuum.

When R ¹⁸ is CH ₃ CO

Example 53

A. Benzyl 6-beta- (thiazol-2-yl) acetoxymethyl-1,1-dioxophenicylanate

43.99 g (151.2 mM) tri-n- in a solution of 74.6 g (134 mM) benzyl 6-bromo-6- (thiazol-2-yl) acetoxymethyl-1,1-dioxophenicylanate in 850 ml benzene Butyltin hydride is added. The mixture is heated to reflux for 5.5 hours and left overnight. The solvent is evaporated in vacuo and the residue is dissolved in hexane and extracted with acetonitrile (2x250 ml). The acetonitrile layer was evaporated, the residue slurried in ethyl ether, filtered and the cake washed with ether to give 33.28 g of colorless crystals. The filtrate is also evaporated to dryness to afford 2.8 g. The residue is dissolved in benzene and 10 g of tri-n-butyltin hydride are added. The mixture is refluxed for 1 hour and the first product is finished; Mixed yield 56.3%

The first product is purified by column chromatography on silica gel, eluting with chloroform / ethyl acetate (9: 1). The product fractions are concentrated, slurried with ethyl ether / ethyl acetate (4: 1), filtered and washed with ether to give 22.6 g of a white solid. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.25 (s, 3H), 1.53 (s, 3H), 2.1 (s, 3H), 4.58 (

s, 1H), 4.80 (d, 1H), 5.2 (dd, 1H), 5.22 (q, 2H), 6.75 (d, 1H), 7.35 (s, 5H), 7.4 (d, 1H), 7.8 (d , 1H). ¹³ C-NMR (CDCl ₃ ) ppm (delta): 17.7, 19.9, 20.5, 54.5, 63.06, 63.6, 63.8, 64.5, 68.1, 121.8, 128.8, 128.9, 134.3, 142.6, 164.6, 166.5, 169.2, 170.5.

B. Debromination of the residual compound provided in Example 67 affords the following compounds.

Example 54

A. The benzyl ester prepared above was hydrogenated on a palladium on carbon catalyst according to the method of Example 63 to convert to the corresponding carboxylic acid of the general formula wherein R ^b is H.

Example 54

B. The 6-beta- (thiazol-2-yl) acetoxymethyl-1,1-dioxophenicsilane acid obtained in A was treated with an aqueous slurry of acid and potassium bicarbonate in equimolar amounts of water to give a corresponding Conversion to potassium salt and purification with medium pressure liquid chromatography on a C ₁₈ * column eluting with water / acetonitrile (9: 1) afforded the corresponding potassium salt in 60% yield.

¹ H-NMR (DMSO-d ₆ ) ppm (delta): 1.37 (s, 3H), 1.48 (s, 3H), 2.07 (s, 3H), 3.80 (s, 1H), 4.92 (dd, 1H), 5.12 (d, 1 H), 6.55 (d, 1 H), 7.89 (m, 2 H), IR (KBr): 3454, 1788, 1630 cm ^-1 .

* C ₁₈ is octadecylsilicate.

Example 55

A. A mixture of 6- (benzothiazol-2-yl) methylene-1,1-dioxophenicsilane acid, E and Z isomers

To a solution of 400 mg (0.91 mM) 6- (benzothiazol-2-yl) acetoxymethyl-1,1-dioxophenicsilane acid in 5 ml water was added 0.15 g (1.82 mM) sodium bicarbonate solution in 2 ml water and obtained. The mixture is stirred for 2 hours. The reaction mixture (pH 7.55) is lyophilized. The lyophilisate is dissolved in 8 ml water, adjusted to pH 3.5 with dilute hydrochloric acid, extracted with ethyl acetate, the organic layer is dried (MgSO ₄ ) and the solvent is evaporated in vacuo. As a result of NMR spectrum, the obtained product was found to be a mixture of (E) and (Z) of 60:40.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.55 (s, 1.2H), 1.6 (s, 1.8H), 1.65 (s, 1.2H), 1.67 (s, 1.8H), 4.55 (s, 0.6 H), 4.58 (s, 0.4H), 5.38 (s, 0.4H), 5.74 (s, 0.6H), 7.44 (s, 0.4H), 7.48 (s, 0.6H), 7.5 (m, 4H), 7.89 (d, 1 H), 8.07 (d, 0.4 H), 8.15 (d, 0.6 H).

B. Similarly treating the appropriate 6-R ¹³ -CH (OAC) -substituted-1,1-dioxophenicsilane acid obtained above to obtain a compound of the following general formula as a mixture of (E) and (Z) isomers do.

Example 56

A. Potassium 6-bromo-6- (thiazol-2-yl) acetoxymethyl-1,1-dioxophenicylanate

96 mg (0.2 mM) allyl 6-bromo-6- (thiazol-2-yl) acetoxymethyl-1,1-dioxophenylsilanate (obtained in Example 67) was prepared according to the method of Example 60 React for a minute and finish as described to give 46 mg (48%) of a yellow solid product.

¹ H-NMR (D ₂ O) ppm (delta): 1.45 (s, 3H), 1.6 (s, 3H), 4.4 (s, 1H), 5.55 (s, 1H), 6.85 (s, 1H), 7.72 (d, 1 H), 7.86 (d, 1 H).

B. Potassium 6-bromo-6- (thiazol-2-yl) hydroxymethyl-1,1-dioxophenicylanate (obtained in Example 66) was reacted for 20 minutes according to the above method for 52% yield. The title salt of is obtained as a pale yellow solid.

¹ H-NMR (DMSO-d ₆ ) ppm (delta): 1.34 (s, 3H), 1.47 (s, 3H), 3.75 (s, 0.4H), 3.83 (s, 0.6H), 5.3 (d, 0.4 H), 5.32 (d, 0.6H), 5.45 (s, 0.6H), 5.5 (s, 0.4H), 7.6-8.0 (m, 2H).

IR (KBr): 3442, 1794, 1633cm ^-1

Example 57

Potassium (6-beta, 8s) -6- (thiazol-2-yl) hydroxy-methylphenicylanate

A. Allyl 6-bromo-6- (thiazol-2-yl) hydroxymethyl-penicylate

To a solution of 9.971 g (24.99 mM) allyl 6,6-dibromophenicilanate in 150 ml anhydrous tetrahydrofuran was added 8.77 ml of 2.85 M (24.99 mM) methylmagnesium bromide in THF under nitrogen at −78 ° C. and the mixture was added. Stir for 15 minutes. 2.824 g (24.99 mM) thiazole-2-carboxaldehyde solution in 5 ml THF is added and the mixture is again stirred at −78 ° C. for 20 minutes. 1.43 ml (24.99 mM) glacial acetic acid is added to cool the reaction, the mixture is stirred for 10 minutes and allowed to warm to room temperature. It is then poured into water, extracted with 2 x 250 ml ethyl acetate, the extract is washed with water (2 x 250 ml), dried (MgSO ₄ ) and the solvent is evaporated in vacuo to give 10.36 g of orange oil. The oil was purified by column chromatography on silica gel, eluting with chloroform / ethyl acetate (9: 1) to afford 4.54 g yellow solid (mixture of isomers) and 0.443 g yellow foam (more polar isomers) (total yield 46%). ).

For yellow foam: ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.56 (s, 3H), 1.76 (s, 3H), 4.60 (s, 1H), 4.7 (m, 2H), 4.9-6.4 ( m, 6H), 7.45 (m, 1 H), 7.8 (m, 1 H).

B. Allyl 6-beta- (thiazol-2-yl) hydroxymethyl penicillate

200 mg (0.462 mM) of the more polar isomer obtained from A were dissolved in 1 ml benzene and 0.183 ml (0.693 mM, 1.5 equiv) of tri-n-butyltin hydride in benzene was added. The mixture is heated to reflux for 3 hours and allowed to stand overnight at room temperature. The solvent is evaporated in vacuo and the residue is dissolved in acetonitrile, washed with hexane and evaporated to small amounts, then left on a silica gel column and eluted with chloroform to give 73 mg (45%) of the desired product. ¹ H-NMR (CDCl ₃ ) ppm (delta): 1.65 (s, 3H), 1.87 (s, 3H), 3.8-4.4 (m, 1H), 4.05-4.3 (dd, 1H), 4.65 (s, 1H ), 4.78 (m, 2H), 5.3-5.6 (m, 2H), 5.6-6.3 (m, 3H), 7.45 (m, 1H), 7.85 (m, 1H).

C. 73 mg (0.206 mM) of product obtained from B above were converted to potassium salt according to the method of Example 60 to give 58 mg (80%) of the title compound.

¹ H-NMR, 300 MHz, (D ₂ O) ppm (delta): 1.36 (s, 3H), 1.55 (s, 3H), 4.13 (dd, 1H), 4.18 (s, 1H), 5.32 (d, 1H ), 5.41 (d, 1 H), 7.56 (d, 1 H), 7.60 (d, 1 H).

Example 58

A. Using the appropriate aldehyde R ¹³ CHO instead of thiazole-2-carboxaldehyde in the process of Example 72-A, the corresponding compounds of the following general formula are obtained.

B. Debromination of the compound according to the method of Example 72B affords the following compounds.

C. The allyl ester obtained above was reacted according to the method of Example 60 to obtain the following potassium salt.

Production Example A

6-chloropyridin-2-ylmethyltriphenylphosphonium chloride

(i) 6-chloro-2-methylpyridine-1-oxide

To a solution of 5.1 g (40 mM) 6-chloro-2-piclin in 50 ml methylene chloride is added 8.625 g (40 mM) of 80% m-chloroperbenzoic acid and the mixture is stirred at room temperature for 15 hours. The reaction is cooled to 0.5 ml saturated sodium thiosulfate and adjusted to pH 7.5 using sodium bicarbonate solution. The organic layer is washed with water, dried (Na ₂ SO ₄ ) and the solvent is evaporated to yield 4.84 g of N-oxide.

¹ H-NMR (CDCl ₃ ) ppm (delta): 2.6 (s, 3H), 7.0-8.0 (m, 3H).

(ii) 6-chloro-2-acetoxymethylpyridine

A solution of 4.8 g (0.035 moles) of Sykes N-oxide in 15 ml acetic anhydride is heated at 100 ° C. for 1 hour and distilled under vacuum to yield 2.39 g of the desired product as colorless oil, having a boiling point of 125 to 128 ° / 0.7 mm. .

¹ H-NMR (CDCl ₃ ) ppm (delta): 2.1 (s, 3H), 5.1 (s, 2H), 7.0-7.8 (m, 3H).

(iii) 6-chloro-2-pyridylmethanol

The product obtained in (ii) in 10 ml 2N hydrochloric acid was hydrolyzed at −70 ° C. for 1 hour, then neutralized, extracted with K ₂ CO ₃ ) chloroform and the solvent was evaporated from the dry extract to give 1.87 g of crude alcohol. This was purified by column chromatography on silica gel to yield 0.982 g of pure material.

¹ H-NMR (CDCl ₃ ) ppm (delta): 4.8 (s, 2H), 5.3 (bs, 1H), 7.0-7.8 (m, 3H).

(iv) 6-chloro-2-chloromethylpyridine

0.982 g (6.84 mM) of 6-chloro-2-pyridylmethanol in 10 ml methylene chloride was treated with 0.814 g of thionyl chloride for 1 hour at room temperature. The mixture is neutralized with saturated sodium bicarbonate solution, extracted with methylene chloride, the extract is dried and the solvent is evaporated to yield 815 mg of the product as colorless crystals. ¹ H-NMR (CDCl ₃ ) ppm (delta): 4.7 (s, 2H), 7.1-8.0 (m, 3H).

(v) 815 mg (5 mM) and 1.318 g (5 mM) triphenylphosphine obtained in (iv) above were dissolved in toluene, and the mixture was heated to reflux for 6 hours to prepare a Wittig reagent. The precipitated product was collected by filtration to give 1.368 g (65%) of the title component.

¹ H-NMR (CDCl ₃ ) ppm (delta): 5.5 (s, 1H), 5.8 (s, 1H), 7.2-8.2 (m, 18H).

(vi) 4-methoxypyridin-2-ylmethyltriphenylphosphonium chloride

2.5 containing about 25% 5-acetoxy-2-methyl-4-methoxypyridine starting from 2-methyl-4-methoxypyridine-1-oxide (2.1 g) in the process of (ii) above g of 2-acetoxymethyl-4-methoxypyridine is obtained. This mixture is dissolved in methanol (10 ml) containing 1.118 g (20.7 mM) sodium methoxide and stirred under reflux for 1 hour. Methanol is evaporated in vacuo and the residue is diluted with water, neutralized with dilute hydrochloric acid and extracted with chloroform. The organic layer is washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to afford 853 mg (41%) of 2-hydroxymethyl-4-methoxypyridine.

¹ H-NMR (CD "T-51") ppm (delta): 3.9 (s, 3H), 4.72 (s, 2H), 5.35 (bs, 1H), 6.7 (dd, 1H), 6.95 (d, 1H) ), 8.3 (d, 1H).

The hydroxymethyl compound obtained is converted to 2-chloromethyl-4-methoxypyridine according to the method of (iv) to give 0.895 g (5.68 mM). This is reacted with equimolar amount of triphenylphosphine in toluene (10 ml) for 20 hours under reflux. The precipitated product is filtered to give 860 mg of the title compound as a yellow solid.

Preparation Example B

2-quinolinylmethyltriphenylphosphonium chloride

6.26 g (0.035 mol) and 9.20 g (0.035 mol) triphenylphosphine solution in 80 ml toluene are heated to reflux for 3 hours. The precipitated solids are collected in a filter and dried under vacuum to yield 3.5 g (23%) of the product as a brown solid.

Preparation Example C

3-allyloxy-2-pyridylmethyltriphenylphosphonium chloride

(i) 3-allyloxy-2-hydroxymethylpyridine

To sodium methoxide, a methanol mixture prepared from 1.43 g (62 mM) sodium metal and 100 ml methanol, 5.9 g (31 mM) 3-hydroxy-2-hydroxymethylpyridine is added and the methanol is removed under vacuum. The obtained residue was dissolved in 80 ml dimethylsulfoxide (DMSO) and 3.0 ml (34.7 mM) allyl bromide in 20 ml DMSO was added at room temperature for 20 minutes. The mixture is stirred for 2 hours and DMSO is distilled under vacuum to break up the residue into chloroform / water. The aqueous phase is adjusted to pH 7.5 and extracted three times with chloroform. The combined organic layers are washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated to yield 3.48 g (68%) of the desired ether.

(ii) 3-allyloxy-2-chloromethylpyridine

The product of A (3.43 g 20.8 mM) in 20 ml methylene chloride is treated with 1.5 equivalents (2.5 ml) of thionyl chloride and the mixture is stirred under nitrogen for 2 hours. The volatiles are removed in vacuo and the residue is broken down in methylene chloride and water. The aqueous layer is adjusted to pH 7.5 and extracted with fresh methylene chloride. The mixed extract is washed with water and brine, dried (Na ₂ SO ₄ ) and the solvent is evaporated in vacuo to yield 3.28 g (86%) of the desired product which is used in the next step.

(iii) the product of (ii) (3.28 g, 17.9 mM) was dissolved in 30 ml toluene and 4.69 g (17.9)

mM) triphenylphosphine is added. The mixture is stirred at reflux for 3 hours and then at room temperature for 12 hours. The product is isolated by filtration and washed with toluene to yield 3.89 g (49%) of the desired Wittich reagent.

Preparation Example D

Allyl 6-alpha-bromo-1,1-dioxophenicylanate

(i) 6-alpha-bromophenic silane acid 1,1-dioxide

20.26 g (0.0517 mole) 6,6-dibromo-phenicylic acid suspension in 80 ml water is added dropwise with 13 g (0.155 neck) of solid sodium bicarbonate. Ethyl acetate is added to control the vigorous gas release. 6.76 g (0.062 mol) of solid sodium disulfide are then added dropwise and the resulting mixture is stirred for 35 minutes and adjusted to pH 1.0 with concentrated hydrochloric acid. The acidified mixture is diluted with ethyl acetate and the organic phase is washed with brine and dried (Na ₂ SO ₄ ) and the solvent is evaporated in vacuo. The residue was triturated with chloroform and filtered to yield 6.72 g of a pale yellow solid. The filtrate is concentrated and the residue is treated with chloroform to give another 3.2 g of product.

(ii) To 6.352 g of the product in 20 ml dimethylformamide, 1.76 ml (20.3 mM) allyl bromide, 2.83 ml (20.3 mM) triethylamine and 0.2 g sodium bicarbonate are added and the mixture is stirred at room temperature under nitrogen for 15 hours. Water is added and the mixture is extracted with ethyl ether, the extract is washed with water and dried (Na ₂ SO ₄ ) and the solvent is evaporated in vacuo to give 4.60 g (64%) of the desired ether as an oil.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H), 4.4 (s, 1H), 4.6 (d, 1H), 4.7 (d, 2H), 5.15 ( d, 1H), 5.1-5.95 (m, 3H).

(iii) allyl 6,6-dibromophenicylanate

According to the above process, 0.417 mol of 6,6-dibromophenic carboxylic acid was esterified to 140

g (84%) of allyl ester is obtained as an oil.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.5 (S, 3H), 1.65 (s, 3H), 4.6 (s, 1H), 4.75 (m, 2H), 5.3-5.6 (m, 2H), 5.85 (s, 1 H), 5.8-6.3 (m, 1 H).

Production Example E

2-formyl-1-methylimidazole

(i) 2-hydroxymethyl-1-methylimidazole

50 g 1-methylimidazole and 100 ml 37% formaldehyde (specific gravity 1.08) are placed in a stainless steel bomb (300 ml) and heated at 150 ° C. (bath is 17 hours). The bomb is then cooled with ice, the mixture is separated, concentrated in vacuo and the residue stored at 4 ° C. overnight. The mixture of crystals and oil obtained is filtered and washed with ethyl acetate. Colorless crystals are dried under vacuum to afford 14.60 g of product. The mother liquor is retreated to give a second 6.48 g of product. The total yield is 21.08 g (31%).

(ii) To 4.96 g (43.9 mM) 2-hydroxymethyl-1-methylimidazole solution in 50 ml dioxane, 4.90 g (44.1 mM) selenium dioxide was added and the mixture was stirred at 85 to 90 DEG C for 5 hours at room temperature. Stir for 8 hours at 85 ° C. and finally 15 hours at room temperature. The reaction mixture is filtered and the solvent is evaporated in vacuo to yield 4.81 g of crude aldehyde which is distilled to yield 2.11 g of product as colorless crystals having a boiling point of 65 ° C. at 2.8 mm Hg.

Production Example F

6-methyl-2-pyridylmethyltriphenylphosphonium chloride

(i) 6-methyl-2-hydroxymethylpyridine

6-Methylpyridine-2-carboxaldehyde (0.44 mM) in 50 ml methanol is reduced with 20.6 mM sodium borohydride at 0-5 ° C. After completion of the reduction, the mixture is neutralized with 2N sulfuric acid (pH 7.5), filtered and the filtrate is concentrated and partitioned between chloroform and water. The solvent is evaporated from the organic layer to yield 3.32 g of reddish brown oil which is used in the next step.

(ii) 2-chloromethyl-6-methylpyridine

3.32 g (0.27 mM) of this product in 20 ml methylene chloride are treated with 1.94 ml (27 mM) thionyl chloride for 1 hour at room temperature. The mixture is neutralized (NaHCO ₃ ) and extracted with chloroform. The solvent is evaporated to give 3.22 g of product as an oil which is used for the next step.

(iii) 3.22 g of the oil of (ii) and 5.96 g of triphenylphosphine solution in 30 ml toluene are heated to reflux for 4 hours. The precipitate is filtered to yield 3.93 g of Wittich reagent as a brown solid.

Production Example G

2-pyrazinylmethyltriphenylphosphonium chloride

(i) 2-hydroxymethylpyrazine

2.0 g of 52.6 mM lithium aluminum hydride in a solution of 11.29 g (79.2 mM) 2-pyrazinecarbonyl chloride (prepared by treating the corresponding 2-carboxylic acid at molar excess of thionyl chloride at reflux) in 100 ml tetrahydrofuran ( 95% purity) is added dropwise for 20 minutes. The mixture is stirred for 10 minutes and left warm at room temperature. The reaction is cooled with 2M sodium hydroxide, filtered and washed with methanol. The filtrate is concentrated in vacuo to yield 4.12 g of a blackish solid which is used in the step.

(ii) The darkish solid 94.12 g, 37.8 mM) is dissolved in methylene chloride and 2.8 ml of thionyl chloride are added at 0 ° C. The mixture is allowed to warm to room temperature, stirred for 30 minutes, water is added, the mixture is neutralized and the methylene chloride is extracted to give 2.29 g of yellow oil which is used in the next step.

(iii) 2.29 g of the oil in 40 ml toluene are added to 4.70 g triphenylphosphine and the mixture is refluxed for 3 hours. Finished in the usual manner to yield 1.995 g of Wittich reagent as a brown solid.

Production Example H

4-formylpyrimidine

A 4-methylpyrimidine (10 g, 0.106 mol) solution in 100 ml dioxane is treated with 11.8 g selenium dioxide at room temperature and the mixture is heated at 100 ° C. for 15 hours. 2.5 g of selenium dioxide is added, then heated for 1 hour, the mixture is cooled, filtered and the cake is washed with ethyl acetate. The filtrate and washings are evaporated to dryness in vacuo. The remaining thick oil is dissolved in methylene chloride, filtered and the solvent is evaporated. The residue is crystallized with a small amount of methylene chloride to give the title aldehyde.

¹ H-NMR (CDCl ₃ ) ppm (delta): 7.87 (dd, 1H), 9.06 (d, 1H), 9.43 (d, 1H), 10.0 (s, 1H).

Preparation Example I

Diphenylmethyl 6-alpha-bromo-1,1-dioxophenicylanate

To a solution of 21.557 g (0.1 mole) diphenyldiazomethane in 400 ml anhydrous tetrahydrofuran is added 31.2 g (0.1 mole) 6-alpha-bromo-1,1-dioxophenicsilane acid dropwise dropwise. The reaction is slightly exothermic. The mixture is stirred for 1 hour, the solvent is evaporated and the residue is dissolved in ethyl acetate (50 ml). Ethyl ether (400 ml) is added and the resulting mixture is stored at 4 ° C. After 18 hours no crystals formed. The mixture is then concentrated in vacuo to give 51.2 g of a yellow solid which is chromatographed on silica gel eluting with chloroform to give 14.86 g of a colorless product as glass.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.26 (s, 3H), 1.57 (s, 3H), 4.55 (s, 1H), 4.70 (d, 1H), 5.13 (d, 1H), 6.9 ( s, 1 H), 7.27 (s, 10 H).

Production Example J

Benzothiazole-2-carboxaldehyde

A freshly distilled (bp82 ° C., 2 tor) benzothiazole 910 g, 0.074 mole in 250 ml tetrahydrofuran is cooled at -78 ° C. under nitrogen and stirred for 15 minutes at the same temperature. To this was added 29.6 ml (0.074 mol) 2.5M n-butyllithium dropwise for 15 minutes, stirring continued for 25 minutes, and 8.6 ml (0.111 mol) dimethylformamide was added and the reaction mixture was stirred for 1 hour. The mixture is allowed to warm to room temperature, 200 g of ice is added and the solvent is evaporated in vacuo. The aqueous residue was extracted with 5 × 100 ml ethyl acetate, the extract was dried (MgSO ₄ ), concentrated in small amounts and chromatographed on a silica gel column eluting with chloroform / ethyl acetate (96: 4) to 8.4 with a solvent of 74.5 to 75 ° C. Obtain the desired aldehyde of g.

¹ H-NMR (CDCl ₃ ) ppm (delta): 7.54 (m, 2H), 7.79 (m, 1H), 8.21 (m, 1H), 10.1 (s, 1H).

The following aldehydes are prepared in a similar manner to the above process.

Prepared as a solid in 37% yield by reaction of 1H-1,2,4-triazine and methyl iodide in ethanol sodium ethoxide.

** Prepared from imidazole and ethyl orthoformate according to the following method [Curtis et al., J. Org. Chem. 45, 4038 (1980).

Production Example K

Pyrazine-2-carboxaldehyde

The pyrazine-2-carboxylic acid is esterified for 5 hours under reflux with methanolic sulfuric acid. Methanol is evaporated in vacuo, diluted with methylene chloride and neutralized with sodium bicarbonate. (pH 7.5). The dry organic layer was concentrated to give methylpyrazine-2-carboxylate as 84% yield as a grayish white solid, which was recrystallized from isopropanol and ethyl ether to give a yellow needle.

¹ H-NMR (CDCl ₃ ) ppm (delta): 4.1 (s, 3H), 8.93 (m, 2H), 9.47 (m, 1H).

20 g (0.145 mole) of methyl ester are dissolved in 600 ml anhydrous tetrahydrofuran, cooled to -78 ° C and 5.8 g 98% lithium aluminum hydride solution in THF is added dropwise for 15 minutes. The mixture is stirred for 30 min at -78 ° C, 20 ml acetic acid is added and the mixture is concentrated under reduced pressure. The residue was partitioned between 2N hydrochloric acid (30 ml) and chloroform and the mixed organic layers washed with water, dried and evaporated to yield 8.53 g of crude product, which was passed through a silica gel column eluting with methylene chloride / ethyl acetate (4: 1). To give 5.02 g of pale yellow needles.

¹ H-NMR (CDCl ₃ ) ppm (delta): 8.38 (m, 2H), 8.7 (bs, 1H), 9.7 (s, 1H).

Preparation Example L

2-phenyl-1,2,3-triazole-4-carboxaldehyde

(i) 0.34 ml mol acetone dicarboxylic acid in 100 ml water was reacted with 0.58 mol sodium nitrite at 0 ° C 10 ° C, and diluted nitrous acid was added to the precipitate to give 46% yield of dioxime (1,3-dioxymino-). 2-oxopropane) to give as tan crystals.

(ii) The dioxime (0.158 mol) in ethanol 9170 ml) was reacted with equimolar amounts of phenylhydrazine hydrochloride and sodium acetate at 70 ° C. for 30 minutes. Water (170 ml) is added and the mixture is heated to 85 ° C., reduced to 250 ml volume and cooled to yield 24.7 g of phenylhydrazone.

¹ H-NMR (CD ₂ COCD ₂ ) ppm (delta): 7.3 (m, 5H), 7.9 (s, 1H), 8.6 (s, 1H), 10.5 (bs, 1H), 11.4 (bs, 1H), 12.3 (s, 1 H).

(iii) 24.7 g (0.119 mol) of the dioxylphenylhydrazone are stirred with 500 ml of acetic anhydride for 30 minutes at room temperature, the mixture is poured into water, stirred for 20 minutes and filtered. The crude solid obtained is recrystallized from benzene / ethyl acetate to give 15.47 g (52%) of monoacetate (HON = CH-C (= NNHC ₆ H ₅ ) CH = NOCOCH ₃ ) as a yellow powder.

¹ H-NMR (CDCl ₃ , Acetone): 1.85 (s, 3H), 7.09 (m, 5H), 7.95 (s, 1H), 8.3 (s, 1H), 10.9 (bs, 1H), 12.25 (s, 1H).

(iv) A solution of 15.40 g (0.062 mol) monoacetate and 22.16 g (0.068 mol) cesium carbonate obtained in 400 ml tetrahydrofuran was stirred at room temperature for 1 hour, filtered and the filtrate was concentrated to give a yellow residue. The residue was dissolved in 700 ml of hot isopropyl ether / cyclohexane (1: 2) and concentrated to 200 ml to give 9.41 g (80%) of 2-phenyl-1,2.3-triazole-4-carboxaldehyde oxime as a yellow powder. Obtained as and used in the next step.

(v) A mixture of 9.41 g (0.0497 moles) of oxime, 4.48 g S-trioxane and 300 ml 2N hydrochloric acid is heated to reflux for 3.5 hours. The aqueous phase is extracted with ethyl ether, the mixed ether layers are washed with water and dried (MgSO ₄ ) and the ether is evaporated in vacuo to give 6 g of crystalline aldehyde.

¹ H-NMR (CDCl ₃ ) ppm (delta): 7.6 (m, 3H), 8.25 (m, 3H), 10.25 (s, 1H): mp66-67 ° C.

Production Example M

5-methylisoxazole-3-carboxaldehyde

(i) ethyl 5-methylisoxazole-3-carboxylate

A mixture of 0.16 mole ethyl 2,4-dioxovalerate and 0.08 mole hydroxylamine sulfate, 50 ml ethanol and 70 ml toluene is stirred at 40 ° C. for 4 hours. The mixture is cooled to 15-20 ° C. and 1.8 g of concentrated ammonium hydroxide is added and stirred at room temperature for 60 hours. The mixture is poured into water / toluene and the aqueous layer is extracted with toluene, the organic layers are mixed, washed with brine and dried (Na ₂ SO ₄ ). The solvent is evaporated in vacuo to give a yellow liquid which is distilled at 30 Torr to give 14.68 g of product having a boiling point of 120 to 124 ° C. which is left to crystallize.

(ii) 2.0 g (14.4 mM) of the ethyl ester obtained in 75 ml toluene are reduced with-equimolar amount of 1 M diisobutylaluminum hydride in hexane at -75 to -70 DEG C under nitrogen. After stirring for 30 minutes, the reaction is cooled with ammonium chloride solution, warmed to room temperature and the solvent is evaporated in vacuo. The residue is triturated with hot methanol and evaporated to yield 0.85 g of product as colorless oil.

¹ H-NMR (CDCl ₃ ) ppm (delta): 2.4 (s, 3H), 6.3 (d, 1H), 9.0 (s, 1H).

Claims (19)

A compound of formula (I) or a pharmaceutically acceptable acid addition salt or cationic salt thereof.

In the above formula, n is 0 or 2: R ¹ is R ^a or R ^b where R ^a is allyl or benzyl and R ^b is hydrogen; one of R ² and R ³ is hydrogen, the other is CL, CH ₂ OH, (C ₁ -C ₄ ) alkylthio, phenylthio, phenyl, pyridyl, pyrazinyl, quinolyl, chloropyridyl, methoxypyridyl, allyloxypyridyl, dimethylpyrimidyl, methylpyridyl, 1,2,3-thiadiazolyl, methyl-1,2,4-oxadiazolyl, furyl, vinyl, 2-thiazolyl, pyrimidyl, 2-phenyl-1,2,3-triazol-4-yl , 2-imidazolyl, pyridazinyl, methyl-2-pyridyl, methyl-2-thiazolyl, 1,2,3, -thiadiazol-4-yl, 1,2, -isothiazole-3 -Yl, 1-oxoquinolin-2-yl, 1-oxo-2-pyridyl, methylsulfonyl, N-methylpyrrole-2-yl, N-acetylpyrrole-2-yl, thienyl, 1-methyl Midazol-2-yl or 3-methyl-1,3,4, -triazol-2-yl. The compound of claim 1, wherein one of R ² and R ³ is hydrogen and the other is pyridyl, allyloxypyridyl, pyrazinyl or methoxypyridyl. A compound of formula (II) or a pharmaceutically acceptable acid addition salt or cationic salt thereof.

Wherein n is 0 or 2 and: X ₃ non-H or Br and R ¹ is R ^a or R ^b where R ^a is allyl or benzyl and R ^b is hydrogen: R ¹² and R ¹³ One is hydrogen, the other is 1,3-thiazolyl, benzothiazolyl, pyrazinyl, 1,2,3, -thiadiazolyl, methyl-1,3-thiazolyl, dimethyl-1,3-thia Zolyl, methyl-1,2-isoxazole, methyl-1,2,4-oxadiazolyl, furyl, phenyl, pyridyl, vinyl, N-methyl-2-imidazolyl, 2-thiazolyl, pyrimidyl, 2-phenyl-1,2,3-triazol-4-yl, 2-imidazolyl, pyridazinyl, 1,2-isothiazol-3-yl, N-methylpyrrole-2-yl, N- Acetylpyrrole-2-yl, pyrazinyl, 3-methyl-1,3,4-triazol-2-yl or thienyl: R ¹⁸ is H, (C ₂ -C ₅ ) alkanoyl, (C _2- C ₅ ) alkoxycarbonyl, benzoyl or pyrazinoyl. The compound of claim 3, wherein R ¹⁸ is H or CH ₃ CO. 2. A compound according to claim 1 or a pharmaceutically acceptable diacid salt thereof, wherein R ^b is H. A pharmaceutical composition for treating bacterial infection, comprising the compound of claim 5 and a β-lactam antibiotic in a weight ratio of 1: 3 to 3: 1. 4. A compound according to claim 3, or a pharmaceutically acceptable cationic salt thereof, wherein R ^b is H. A pharmaceutical composition for treating bacterial infection, comprising the compound of claim 7 and a β-lactam antibiotic in a weight ratio of 1: 3 to 3: 1. The compound of general formula (V) is reacted with the Wittisch reagent of general formula (A) at a temperature of -100 to + 50 ° C. in the presence of a reaction inert organic solvent to obtain a compound of general formula (I) wherein n is 0. Characterized in that a compound of formula (I) or a pharmaceutically acceptable acid addition salt or cationic salt thereof.

In the above formula, n is 0 or 2: R ¹ is R ^a or R ^b (where R ^a is allyl and R ^b is hydrogen): one of R ² and R ³ is hydrogen, the other is Cl, CH ₂ OH, (C ₁ -C ₄ ) alkylio, phenylthio, phenyl, pyridyl, pyridyl-N-oxide, pyrazinyl, quinolyl, quinolyl-N-oxide, chloropyridyl, methoxypyridyl, allyl Oxypyridyl, dimethylpyrimidyl or methylpyridyl. The compound of formula (X) is reacted in equimolar amounts of (C ₁ -C ₄ ) alkyl magnesium halide in the presence of a reaction inert solvent, wherein the halide is Cl, Br or I) or ( C ₁ -C ₄ ) A compound of formula (I ′) or (II), characterized in that it reacts with an alkyl lithium reagent and an aldehyde of formula (C) to give a compound of formula (XI). Process for preparing acid addition salts or cationic salts thereof.

In the above formula, n is 0 or 2: X ³ is H or Br: R ¹ is allyl, benzyl or hydrogen, provided that in general formula (X), R ¹ is benzyl or allyl, and R ¹⁸ is H or (C ₂ -C ₅ ) alkanoyl: one of R ¹² and R ¹³ is hydrogen, the other is 1,3-thiazolyl, benzothiazolyl, pyrazinyl, 1,2,3-thiadiazolyl, methyl-1, 2,3-triazolyl, methyl-1,3-thiazolyl, dimethyl-1,3-thiazolyl, methyl-1,2-isoxazole or methyl-1,2,4-oxadiazolyl. A compound of formula (IX) is reacted with an equimolar amount of (C ₁ -C ₄ ) alkyl magnesium halide in an ethereal solvent at a temperature of -80 to 25 ° C. to obtain a compound of formula (VII ′). To prepare the compound of formula (VII) or (II ').

In the above formula, R ¹ is allyl, diphenylmethyl, benzyl or hydrogen, provided that in general formula (IX) R ¹ is not H: one of R ¹² and R ¹³ is hydrogen and the other is N-methyl-2- Pyrrolidyl, furyl, N-acetyl-2-pyryl, phenyl, pyridyl, thienyl, vinyl, N-methyl-2-imidazolyl, 2-thiazolyl, pyrimidyl, 2-phenyl-1,2, 3-triazol-4-yl, 2-imidazolyl, pyridazinyl, methyl-2-pyridyl, pyrazinyl, methyl-2-thiazolyl, 1,2,3-thiadiazol-4-yl or 1,2-isothiazol-3-yl: R ¹⁸ is hydrogen, (C ₂ -C ₅ ) alkanoyl, (C ₂ -C ₅ ) alkoxycarbonyl, benzoyl or pyrazinoyl. The starting compound according to any one of claims 9 to 11, wherein the starting compound wherein R ¹ is allyl is carried out in an equimolar amount with a catalytic amount of tetrakis (triphenylphosphine) palladium (O) and triphenylphosphine in the presence of a reaction inert solvent. Reacting with sodium or potassium salt of 2-ethylhexanoic acid to convert to the corresponding compound wherein R ¹ is H, Na or K. 10. The process of claim 9, wherein the compound of formula (I) wherein n is 0 is oxidized to a compound of formula (I) wherein n is 2 using 3-chloroperbenzoic acid. The method of claim 9, wherein the compound of formula (I) wherein R ¹ is R ^a is converted to a compound of formula (I) wherein R ¹ is R ^b . 11. A compound according to claim 10, wherein the compound of formula (XI) is acylated with a corresponding acid anhydride in the presence of an equimolar amount of tertiary amine and a reaction inert organic solvent, wherein R ¹⁸ is (C ₂ -C ₅ ) alkanoyl A process for converting to a compound of formula (II). A compound of formula (II) wherein R ¹⁸ is (C ₂ -C ₅ ) alkanoyl and X ₃ is Br is subjected to hydrogenolysis using organotin hydride in the presence of a reaction inert solvent to form R. ¹⁸ is a conversion to a compound of formula (II) wherein (C ₂ -C ₅ ) alkanoyl and X ₃ is hydrogen. The process of claim 10, wherein the compound of formula (II) wherein X ₃ is hydrogen and R ¹⁸ is (C ₂ -C ₅ ) alkanoyl is deacylated to convert to a compound of formula (I ′). The method of claim 11, wherein the general formula R ¹⁸ is hydrogen in the general formula (II ') equal to the molar amount of the tertiary, such as the compounds of the amines and the reaction was acylated with an acid anhydride or acid chloride in the presence of an inert solvent R ¹⁸ other than hydrogen A method of converting to a compound of (II ′). 12. The process of claim 11, wherein R ¹⁸ is (C ₂ -C ₅ ) alkanoyl or hydrogen to dehydrate or deacylate the compound of formula (II ') to a compound of formula (VIII).