KR810000117B1 - Process for preparing cefarosphorin compound - Google Patents

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Description

Preparation of Cephalosporin Compound

The present invention relates to a method for producing the cephalosporin compound of the general formula (I).

(Wherein R ¹ represents a hydrogen or acyl group and R ² represents a residue of a nucleophilic compound.)

That is, the present invention is characterized in that the following compound of formula (II) is reacted with a nucleophilic compound to prepare a compound of formula (I), or a compound of formula (III) Reacting with a compound of formula (II) to obtain a compound of formula (II), and then reacting with a nucleophilic compound to prepare a method for preparing the cephalosporin compound of formula (I), or a compound of formula (III) It is a method of manufacturing the compound of General formula (II) characterized by reacting with the compound of Formula (IV).

Where

X represents an organic moiety,

R ³ represents hydrogen or an acyl group,

R ¹ is as described above.

The 3-hydroxymethyl body represented by the above general formula (III) generally removes the 3-acetyl group of the cephalosporin having a 3-acetoxymethyl group enzymatically, or in the culture of cephalosporin C. Although only obtained by separation from living organisms, 7- (D-5-aminodipineamido) -3-hydroxymethyl-3-cepem-4-carboxylic acid (deacetylcephalosporin C, DCPC) has recently been fermented. It becomes possible to produce in high unit by (Natura 246/154 (1973), Japanese Patent Laid-Open No. 491/1974) and attention as a raw material which leads to more antibacterial cephalosporin compound with cephalosporin C It came to be.

The reaction between compound (III) and compound (IV) is a 0-acylation reaction by compound (IV) with 3-hydroxymethyl group of compound (III).

However, until now, acylating 3-hydroxymethyl groups of 3-hydroxymethyl bodies such as cephalosporadesinic acid has not been easy. For example, E.van Heyningen (J. Med. Chem., 8.22 (1965), Advan. Drug Res. 4.28 (1968)) shows that the 0-acylation of cephalosporadesin is an excess of alloline. It is only possible by the use of monochloride (yield 32% 57%), but it is reported that ketene, aliphatic acid salts, acetic anhydride do not become 0-acylated or lactone ring formation takes place. In addition, Kukolja (J.Med. Chem. 13. 1114 (1970) reports a method of specifically 0-acylating 3-hydroxymethyl-2-cefe bodies followed by isomerization to 3-cefe bodies to synthesize 0-acyloxymethylcephalosporins. , U.S. Patent No. 3,532,694 and Belgian Patent No. 719,711 protect the method of zero-acylating after protecting 4-carboxyl groups of cephalosporadesin acid with an ester or the like to prevent lactonation. No. 42792/1972 describes a process for 0-acylating cephalosporadesinic acid with azolide.

However, these methods have low yields, are difficult to operate, and cannot be said to be industrially advantageous methods such as using expensive reagents.

That is, for example, the esterification reaction of cephalosporadesin cannot be achieved by the transesterification or lactonation of double bonds as a conventional esterification means.

Only a diazo compound, such as diazomethane, diazoethane, diphenyl diazomethane, phenyl diazomethane, can be introduced with methyl, ethyl, diphenylmethyl, benzyl, etc. After acylation, it is difficult to deesterify without causing side reactions such as cleavage of the β-lactam ring and transition of the double bond.

On the other hand, the reaction of substituting the 3-acetoxymethyl group of the cephalosporin compound with the nucleophilic reagent also causes decomposition of the raw material, the intermediate value and the product during the reaction, resulting in a long reaction time resulting in lower yield [A.B. Taylor J. chem. Soc. 7020 (1965)], and derivatives are more preferable than acetoxy groups.

The present inventors have conducted various studies in order to overcome the above-mentioned problems. As a result, when the compound (IV) is used as the acylating agent, the present inventors can induce the compound (II) with high yield. It was found that the derived compound (I) was very easily substituted by a nucleophilic agent.

The zero-acylation of cephalosporadesinic acid, which has been difficult to date, is achieved in good yield by cheap compound (IV), and the compound (I) derived from compound (II) thus synthesized is 3-acetoxymethylacetate. Substitution reactions with nucleophilic compounds are faster than that of palosporins.

In the method of the present invention, the best raw material compound (III) is generally advantageously obtained by being easily obtained by fermentation production, or easily derived from them by chemical or enzymatic treatment.

Thus, R ³ includes hydrogen or phenylacetyl, phenoxyseryl, 5-amino-5-carboxybutyryl and its amino or carboxyl groups, but the sixth or seventh position of the penicillin and cephalosporin derivatives thereof. For example, aliphatic carboxylic acid acyl groups such as port mill, acetyl, propionoyl, hexanoyl, butanoyl, heptanoyl, octanoyl, cyclopentanoyl, phenylacetyl, 2-thienylacetyl, tetra Zolylthioacetyl, tetrazolylacetyl, cyanoacetyl, phenoxyacetyl, acetoacetyl, 4-methylthio-3-oxobutyryl, 4-carbamoylmethylthio-3-oxobutyryl, α-phenoxypropionyl , α-phenoxybutyroyl, P-nitrophenylacetyl, α- (2-pyridyloxy) acetyl, α- (3-pyridyloxy) acetyl, α- (4-pyridyloxy) acetyl, 2- (2-oxo-4-thiazolin-4-yl) acetyl, 2- (2-imino-4-thiazolin-4-yl) acetyl, 4-pyri Monosubstituted aliphatic carboxylic acids such as thioacetyl, 2- (3-sidone) acetyl, 1-pyrazolylacetyl, 2-furylacetyl, 6- (2'-oxo-3'-methylpyridazinyl) thioacetyl Real group, α-carboxyphenylacetyl, α-aminophenylacetyl, mandelyl, α-sulfophenylacetyl, α-sulfo- (P-aminophenyl) acetyl, phenylglycyl, 1-cyclohexenyl glycyl, thienylglycol Aromatic acryl groups, such as di-substituted aliphatic carboxylic acid acyl groups, such as a lysyl, a furyl glycyl, cyclohexanedienyl glycyl, (alpha)-((beta) -methylsulfonylethoxycarbonyl) -aminophenyl acetyl, benzoyl, P-nitrobenzoyl, etc.). Heterocyclic acyl groups, such as a real group, 5-methyl-3- phenyl- 4-isoxazolylcarbonyl, and 3- (2, 6- dichlorophenyl) -5-methyl- 4-isoxazolyl carbonyl, etc. may be sufficient. Moreover, functional groups, such as an amino group and / or a carboxyl group in these acyl groups, also include what is suitably protected. For example, as the protecting group of the amino group, for example, phthaloyl, benzoyl P-nitrobenzoyl, toluoyl, naphthoyl, P-ert-butylbenzoyl, P-tert-butylbenzenesulfonyl, phenylacetyl, benzenesulfonyl, phenoxy Aromatic acyl groups such as cyacetyl, toluinsulfonyl, chlorobenzoyl, acetyl, valeryl, caprylyl, n-decanoyl, acryloyl, pivaloyl, camphorsulfonyl, methanesulfonyl, chloroacetyl and the like Esterified carboxyl groups such as aliphatic acyl groups, ethoxycarbonyl, isobornyloxy carbonyl, phenyloxy carbonyl, trichloroethoxycarbonyl, benzyloxy carbonyl, methylcarbamoyl, phenylcarbamoyl, naph Carbamoyl groups, such as tilcarbamoyl, or the same thiocarbamoyl group, etc. are used. Moreover, as a protecting group of the carboxyl group in the organic residue represented by said R <^3> , and the 4th position carboxyl group of a cefe ring, for example, methyl, ethyl, tert- butyl, tert-amyl, benzyl, Pnitrobenzyl, P-methoxybenzyl, Benzhydryl, 1-indanyl, phenacyl, phenyl, P-nitrophenyl, methoxymethyl, aoxymethyl, benzyloxymethyl, astaxoxymethyl, pivaloyloxymethyl, β-methylsulfonylethyl, methylthio Silyl groups such as methyl, trityl, β, β, β-trichloroethyl, trimethylsilyl, dimethylsilyl and the like are used. In addition, these carboxyl groups are alkali metals such as lithium, sodium, potassium and magnesium, alkaline earth metals such as calcium, for example, various amines and inorganic salts such as dicyclohexylamine, triethylamine, pyridine and tributylamine. Even if it becomes an organic salt, it can be used.

와 5∼6 원환을 형성할 수 있는 탄소 쇄이며, 그 탄소 쇄의 중간에 이중결합, 산소 혹은 황을 갖고 있어도 좋고, 또 그 탄소 상에 적당한 치환기를 갖고 있어도 좋다.Moreover, the organic residue represented by X in compound (IV) is normally

And a carbon chain capable of forming a 5 to 6 membered ring, and may have a double bond, oxygen or sulfur in the middle of the carbon chain, and may have an appropriate substituent on the carbon.

Examples of such carbon chain substituents include carboxyl groups, halogens, nitro groups, for example, alkyl groups such as methyl, ethyl, propyl, methylene and ethylene, aralkyl groups such as benzyl and phenethyl, and aryl groups such as phenyl and tolyl. Substituted hydroxy group or mercapto group (for example, methoxy, P-chlorophenylthio etc.) etc. are used. When these substituents are two or more, you may form the ring with a carbon chain.

Therefore, specific examples of compound (IV) include maleic anhydride, succinic anhydride, phthalic anhydride, glutaric anhydride, diglycolic anhydride, thiodiglycolic acid anhydride, P-chlorophenyl succinic anhydride, methylene succinic anhydride, 3-nitrile. Phthalic anhydride, trimellitic anhydride and the like.

It is generally appropriate to react the compound (III) with the mixture (IV) in the presence of a suitable inert solvent.

Frequently used solvents are, for example, dichloromethane, chloroform, dichloroethane, ethyl acetate, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylacetamide, dioxane, ether or mixtures thereof and the like. This reaction is equimolar, and it is sufficient to use an equimolar amount of compound (IV) with respect to compound (III), but even if compound (IV) is used excessively in consideration of shortening of reaction time, decomposition of compound (IV), etc. good. The reaction is generally carried out at room temperature under ice cooling (for example, -10 to 40 ° C), preferably at 0 to 30 ° C, and usually proceeds for a short time (within 2 hours), but depending on the reaction temperature to some extent In order to complete the reaction completely, the reaction is usually carried out for 0.5 to 15 hours. If necessary, amines such as triethylamine may be added to the reaction system, and when an alkali metal salt is used as the starting material (III), hydrochloric acid and the like of triethylamine may be added in an equimolar amount and reacted with salt exchange. have. Moreover, when raw material (III) has an unprotected amino group, it acylates by acyl group similarly to acylation of the hydroxy group of a 3rd position on this reaction condition.

Compound (II) thus obtained not only has antimicrobial property per se, but can also be deacylated by a conventional method, if necessary, and then easily reacted with nucleophilic compound to lead to compound (I). As the nucleophilic compound used in this reaction, any compound substituted with 3-acetoxy group of cephalosporin can be used, and the reaction proceeds almost quantitatively at a rate of 4-16 times that of 3-acetoxy. .

기 등의 다가기를 거쳐서 여러가지의 치환기를 갖는 것이 사용된다. 다가기가 저급알킬렌기인 경우에는, 이 치환분은 수산기, 메트캅토기, 아미노기, 모르폴리노기, 카르복실기, 술포기, 카르바모일기, 알콕시카르보닐기, 저급알킬카르바모일기, 알콕시기, 알킬티오기, 알킬술포닐기, 아실옥시기, 모르폴리노카르보닐기 등이어도 좋다.The nucleophilic compound contains, for example, one or more nitrogen atoms which may be oxidized, but other than nitrogen, for example, it is a nitrogen-containing heterocyclic thiol which may contain atoms such as oxygen and sulfur. It also includes a substituent. As such a nitrogen-containing heterocyclic group of thiols, for example, pyridyl, N-oxide pyridyl, pyrimidyl, pyridazinyl, N-oxide pyridazinyl, pyrazolyl, diazolyl, thiazolyl, 1,2 , 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2 , 4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl and the like are frequently used. Substituents on these nitrogen-containing heterocyclic groups include, for example, hydroxyl group, mercapto group, amino group, carboxyl group, carbamoyl group and lower alkyl group (e.g., methyl, ethyl, trichloromethyl, propyl, isopropyl, butyl). Monovalent, such as isobutyl, lower alkoxy groups (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy), halogen atoms (eg chlorine, bromine), or lower Alkylene group, -S-,

The thing which has various substituents through polyvalent groups, such as a group, is used. In the case where the polyvalent group is a lower alkylene group, the substitution may be a hydroxyl group, a metcapto group, an amino group, a morpholino group, a carboxyl group, a sulfo group, a carbamoyl group, an alkoxycarbonyl group, a lower alkyl carbamoyl group, an alkoxy group or an alkylthio group. , Alkylsulfonyl group, acyloxy group, morpholinocarbonyl group and the like.

기인 경우에는, 치환분은 저급알킬기 및 상기 치환분을 갖는 저급알킬렌기 등이어도 좋다. 다가기가

인 경우에는, 또한 카르복실기, 알콕시카르보닐기, 아실기, 카르바모일기, 저급알킬카르바모일기 등의 치환분이 연결되어 있어도 좋다. 구체적으로는, 예를들면 카르복시메틸, 카르바모일메틸, N-저급알킬카르바모일 메틸(예를들면 N,N-디메틸카르바모일메틸), 하이드록시저급알킬(예를들면, 하이드록시메틸, 2-하이드록시에틸), 아실옥시저급알킬(예를들면, 아세톡시메틸, 2-아세톡시에틸), 알콕시카르보닐메틸(예를들면, 메톡시카르보닐메틸, 헥실옥시카르보닐메틸, 옥틸옥시카르보닐메틸), 메틸티오메틸, 메틸술포닐메틸, N-저급알킬아미노저급알킬(예를들면, N,N-디메틸아미노메틸, N,N-디메틸아미노에틸, N,N,N-트리메틸암모늄에틸), 모르폴리노메틸 등의 치환알킬기, 저급알킬아미노(예를들면, 메틸아미노), 술포저급알킬아미노(예를들면, 2-술포에틸아미노), 히드록시저급알킬아미노(예를들면, 히드록시에틸아미노), 저급알킬아미노-저급알킬아미노(예를들면, 2-디메틸아미노에틸아미노, 2트리메틸암모늄에틸아미노), 아실아미노(예를들면, 아세틸아미노), 2-디메틸아미노아세틸아미노, 2-트리메틸암모늄 아세틸아미노, 저급알콕시카르보닐아미노(예를들면, 메톡시카르보닐아미노) 등의 치환아미노기, 메틸티오, 2-히드록시에틸티오, 2-아실옥틸시에티오(예를들면, 2-아세톡시에틸티오, 2-페닐아세톡시에틸티오, 2-카프로일옥시에틸티오), 카르복시메틸티오, 알콕시카르보닐메틸티오(예를들면, 메톡시카르보닐 메틸티오, 헥실옥시카르보닐메틸티오), 카르바모일메틸티오, N-저급알킬카르바모일메틸티오(예를들면, N,N-디메틸카르바모일메틸티오), 아세틸메틸티오, N-저급알킬아미노저급알킬티오(예를들면, 2-N,N-디메틸아미노에틸티오, 2-N,N,N-트리메틸암모늄에틸티오), 모르폴리노카르바모일메틸티오, 2-술포에틸티오등의 치환티오기를 들 수 있다. 구체적으로는, 예를들면 테트라졸티올, 메틸테트라졸티올, 페닐테트라졸티올, 메틸티아디아졸티올, 히드록시에틸티오티아디아졸티올, 메틸티오티아디아졸티올, 티아디아졸티올, 카르바모일아미노티아디아졸티올, 카르바모일메틸티오티아디아졸티올, 티아졸티올, 메틸티아졸티올, 카르복시메틸티아졸티올, 트리아졸티올, 디메틸트리아졸티올, 피라졸티올, 에톡시카르보닐메틸트리아졸티올 이미다졸티올, 메틸옥사디아졸티올, 피리딘티올, 피리미딘티올, 메틸피리다진티올, 트리아진티올 등의 복소환티올이 있다. 그외, 메탄티올, 에탄티올, 티오페놀 등의 지방족, 방향족티올, 티오요소, N메틸티오요소, N-메틸-N'-피리딜티오요소 등), 티오요소유도체, 티오세미카르바지드, 티오아세트아미드, 티오벤즈아미드 등의 티오아미드유도체, 티오황산나트륨, 아지화나트륨 등, 또한, 예를들면 피리딘퀴놀린, 피콜린, 니코틴산, 니코틴산아미드, 이소니코틴산아미드, 이소니코틴산하이드라지드, m-브로모피리딘, 피리딘슬폰산, 피리딘-m-카르비놀(3-히드록시메틸피리딘), 피리딘알데히드, 퀴놀린, 이소퀴놀린 등의 피리딘유도체, 피라진, 피라진산아미드(2-카르바모일피라진), 피리다진, 피리미딘, 이미다졸, 1-메틸이미다폴 등의 함질소복소환화합물 등이 사용된다. 또, 3위치와의 치환반응이 곤란하게 되는 탄소구핵시약도 사용할 수 있다. 이와같은 탄소구핵시약의 예로서는, 시아나이드, 피롤, 트리아세틸메탄, 치환피롤, 인돌, 아세틸렌, 활성메틸렌화합물, 예를들면 아세틸아세톤, 아세토초산에스테르, 말론산에스테르, 시클로헥산-1,3-디온, 트리아세틸메탄이나 에나민화합물을 들수 있다. 또, 메탄올, 에탄올, 프로탄올과 몇개의 알코올류도 본 반응에 사용할 수 있다. 이들의 구핵성 화합물과 화합물(Ⅱ)와의 치환반응은 통상 용매 중에서 행해진다. 용매로서는, 물이 가장 빈번히 사용되지만, 반응에 관여하지 않는 친수성 유기용매, 예를들면 아세톤, 테트라히드로푸란, 디메틸포름아미드, 메탄올, 에탄올, 디메틸 술폭사이드 등의 반응에 관여하지 않는 극성이 높은 용매와 물과의 혼합용매 같은 수용성 용매가 바람직하게 사용된다.To approach -S-,

In the case of a group, a substitution may be a lower alkyl group, a lower alkylene group which has the said substitution, etc. Approaching

In the case of, further, substituents such as a carboxyl group, an alkoxycarbonyl group, an acyl group, a carbamoyl group, and a lower alkylcarbamoyl group may be connected. Specifically, for example, carboxymethyl, carbamoylmethyl, N-lower alkylcarbamoyl methyl (eg, N, N-dimethylcarbamoylmethyl), hydroxy lower alkyl (eg, hydroxymethyl , 2-hydroxyethyl), acyloxy lower alkyl (eg, acetoxymethyl, 2-acetoxyethyl), alkoxycarbonylmethyl (eg, methoxycarbonylmethyl, hexyloxycarbonylmethyl, Octyloxycarbonylmethyl), methylthiomethyl, methylsulfonylmethyl, N-lower alkylamino lower alkyl (e.g., N, N-dimethylaminomethyl, N, N-dimethylaminoethyl, N, N, N- Substituted alkyl groups, such as trimethylammonium ethyl) and morpholinomethyl, lower alkylamino (for example, methylamino), sulfo lower alkylamino (for example, 2-sulfoethylamino), hydroxy lower alkylamino (for example, Hydroxyethylamino), lower alkylamino-lower alkylamino (eg, 2-dimethylaminoethylamino 2trimethylammoniumethylamino), acylamino (for example, acetylamino), 2-dimethylaminoacetylamino, 2-trimethylammonium acetylamino, lower alkoxycarbonylamino (for example, methoxycarbonylamino), etc. A substituted amino group of, methylthio, 2-hydroxyethylthio, 2-acyloctylthiothio (eg 2-acetoxyethylthio, 2-phenylacetoxyethylthio, 2-caproyloxyethylthio), Carboxymethylthio, alkoxycarbonylmethylthio (e.g. methoxycarbonyl methylthio, hexyloxycarbonylmethylthio), carbamoylmethylthio, N-lower alkylcarbamoylmethylthio (e.g., N, N-dimethylcarbamoylmethylthio), acetylmethylthio, N-lower alkylamino lower alkylthio (e.g. 2-N, N-dimethylaminoethylthio, 2-N, N, N-trimethylammonium Substituted thio groups, such as ethylthio), morpholinocarbamoyl methylthio, and 2-sulfoethylthio, are mentioned. There. Specifically, for example, tetrazolthiol, methyltetrazolethiol, phenyltetrazolethiol, methylthiadiazolthiol, hydroxyethylthiothiadiazolthiol, methylthiothiadiazolthiol, thiadiazole thiol, carba Moylaminothiadiazolthiol, carbamoylmethylthiothiadiazolthiol, thiazolethiol, methylthiazolthiol, carboxymethylthiazolthiol, triazolethiol, dimethyltriazolethiol, pyrazolethiol, ethoxycarbonylmethyl Heterocyclic thiols, such as a triazole thiol imidazole thiol, methyloxadiazole thiol, a pyridine thiol, a pyrimidine thiol, a methyl pyridazine thiol, and a triazine thiol, are mentioned. And aliphatic such as methanethiol, ethanethiol, thiophenol, aromatic thiol, thiourea, Nmethylthiourea, N-methyl-N'-pyridylthiourea, etc.), thiourea derivatives, thiosemicarbazide, and thiou Thioamide derivatives such as acetamide and thiobenzamide, sodium thiosulfate, sodium azide, and the like, and examples thereof include pyridinequinoline, picoline, nicotinic acid, nicotinic acid amide, isoninicotinic acid amide, isonicotinic acid hydrazide, and m-bromo Pyridine derivatives such as pyridine, pyridinesulfonic acid, pyridine-m-carbinol (3-hydroxymethylpyridine), pyridinealdehyde, quinoline, isoquinoline, pyrazine, pyrazine acidamide (2-carbamoylpyrazine), pyridazine, Nitrogen-containing heterocyclic compounds, such as pyrimidine, imidazole, and 1-methyl imidapol, are used. Moreover, the carbon nucleus reagent which becomes difficult to carry out substitution reaction with a 3-position can also be used. Examples of such carbon nucleophilic reagents include cyanide, pyrrole, triacetylmethane, substituted pyrrole, indole, acetylene, active methylene compounds, for example acetylacetone, acetoacetic acid ester, malonic acid ester, cyclohexane-1,3-dione And triacetylmethane and enamine compounds. Moreover, methanol, ethanol, protanol, and some alcohols can also be used for this reaction. Substitution reaction of these nucleophilic compound and compound (II) is normally performed in a solvent. As the solvent, water is most frequently used, but a hydrophilic organic solvent that does not participate in the reaction, such as acetone, tetrahydrofuran, dimethylformamide, methanol, ethanol, dimethyl sulfoxide, etc., is a highly polar solvent. A water-soluble solvent such as a mixed solvent of water and water is preferably used.

Although compound (II) may be liberated, it is suitable to provide to reaction as organic amine salt, such as alkyllithium salt, such as sodium and potassium, triethylamine, and trimethylamine, for example.

Nucleophilic compounds are also provided to the reaction as free or alkali metal salts, organic amine salts, and the like. As for the quantity of the nucleophilic compound used for reaction, 1 equivalent or more is suitable with respect to compound (II). Although the optimum pH varies depending on the type of nucleophilic compound and compound (II), the reaction is generally preferably performed in a weakly acidic to weakly alkaline nature.

Although reaction temperature is not specifically limited, 40-70 degreeC is preferable. The reaction time is not particularly limited because it depends on the reaction temperature, pH, and the like, but the reaction is generally completed at 60 ° C. for 30 minutes-2 hours. Moreover, you may react by adding inorganic salts, such as chloride, such as lithium, sodium, potassium, and ammonium, a bromide, an iodide, a thiocyanide, and a nitrate, to reaction liquid.

Compound (I) thus prepared is known per se (for example, Japanese Patent Application Laid-Open No. 13862/1966, 40899/1970, 34387/1972, 95292/1975, 96591 / 1975, US Pat. No. 35079/1975, US Pat. No. 3,632,578, etc.) and the like to cleave the acyl group at the seventh position, and lead to a compound wherein R ¹ is hydrogen, thereby producing the desired compound (I) of the present invention. .

The cephalosporin compound (I) thus obtained can be isolated and purified by known means, for example, solvent extraction, liquid conversion, distillation, distillation, crystals, recrystallization, chromatography, and the like in its free state or as a salt thereof, or Although various esters are used as antimicrobial substances per se, they are also useful as raw material compounds for producing stronger antimicrobial substances. For example, the cephalosporin compound (I) is reacted with 4-halogeno-3-oxobutyrylhalogenide to form 4-halogeno-3-oxobutyrylamide, followed by reaction with thiourea, 7 Compounds obtained by reacting a-[2- (2-imino-4-thiazolin-4-yl) acetamide with a nucleophilic reagent may vary somewhat depending on the kind of the third-position substituent, It is particularly useful, for example, having a 1-methyltetrazol-5-yl-thiomethyl group in the third position, and having about 1/5 the amount of cefazoline. have.

Example 1

7β- (2-thienylacetamido) -3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid

7β- (2-thienylacetamido) -3-hydroxymethyl-3-cepam-4-carboxylic acid triethylamine salt (4.55 g) was dissolved in dichloromethane (30 mL), and succinic anhydride ( 1.50 g) is added and stirred at room temperature for 2 hours. Dichloromethane was distilled off, 3% aqueous phosphate solution (100 mL) was added to the residue, extraction was performed with ethyl acetate (150 mL), and the ethyl acetate layer was washed with saturated brine (100 mL x 2) and dehydrated (magnesium sulfate phase). The mixture was concentrated under reduced pressure, and ether was added to obtain a powder. The powder was filtered off, and then washed with etheto, and then concentrated under reduced pressure on phosphorus pentoxide to 7β- (2-thienylacetamido) -3- (3-carboxypropionyloxymethyl) -3-cepem-4-carboxylic acid ( 4.00 g) was obtained.

IR (KBr, cm ⁻¹ ): 1872 (β-lactam), 1733 (-CO ₂ H)

NMR (d ₆ -DMSO):

), 9.10(1H, d, J=8Hz, -CONH-)δ.50 (4H, -CO (CH ₂ ) _2- ), 340 3.63 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 3.75 (2H, s, -CH ₂ CONH-), 4.71 5.07 (2H , ABq, J = 13 Hz, 3-CH ₂ ), 5.07 (1H, d, J = 5 Hz, 6-H), 5.68 (1H, dd, J = 5 8 Hz, 7-H) 6.90 7.30 (3H,

), 9.10 (1H, d, J = 8 Hz, -CONH-)

Example 2

7β- (2-thienylacetamido) -3- (2-carboxybenzoyloxy methyl-3-cepem-4-carboxylic acid

7β- (2-thienylacetamido) -3-hydroxymethyl-3-cepem-4-carboxylic acid triethylamine salt (3.60 g) was dissolved in dichloromethane (25 mL), and phthalic anhydride ( 1.80 g) was added and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was treated in accordance with Example 1 to obtain 7β- (2-thiynylacetamido) -3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid (3.44 g).

IR (KBr): 1777, 1724, 1650 (Shoulder) cm ^-1

NMR (d ₆ -DMSO):

), 7.64(4H,

), 9.12(1H, d, J=8Hz -CONH-)δ 3.50 3.70 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 3,77 (2H, s, -CH ₂ CO-), 4.91 5.29 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 5.10 (1H, 6, J = 5 Hz, 6-H), 5.70 (1H, dd, J = 5 8 Hz, 7-H), 6.92 7 32 (3H,

), 7.64 (4H,

), 9.12 (1H, d, J = 8 Hz -CONH-)

Example 3

7β-mandelirylamido-3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid:

Dichloromethane (40 ml) was dissolved in 7β-mandelamido-3-hydroxymethyl-3-cepem-4-carboxylic acid triethylamine salt, to which succinic anhydride (1.50 g) was added. It stirred at room temperature for 1 hour and a half.

After the reaction was completed, the same process as in Example 1 was carried out to obtain 7β-mandelyl amido-3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid (4.45 g).

DIR (KBr): 1776, 1737, 1684, (Shoulder) cm ^-1

NMR (d ₆ -DMSO):

), 5.06(1H, d, J=5Hz, 6-H), 5.68(1H, dd, J=5 8Hz, 7-HO, 7.35(5H,

), 9.31(1H, d, J=8Hz,

).δ 2.48 (4H, -CO (CH ₂ ) ₂ 3.3-3.7 (2H, 2-CH ₂ ), 4.69 5.03 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 4.99 (1H,

), 5.06 (1H, d, J = 5 Hz, 6-H), 5.68 (1H, dd, J = 5 8 Hz, 7-HO, 7.35 (5H,

), 9.31 (1H, d, J = 8 Hz,

).

Example 4

7β- (2-thienylacetamido) -3- (4-carboxybutyryloxy) methyl-3-cepem-4-carboxylic acid sodium:

7β- (2-thienylacetamido) -3-hydroxymethyl-3-cepem-4-carboxylic acid triethylamine salt (0.68 g) is dissolved in dichloromethane (7 ml), and anhydrous glutarium is added thereto. An acid (0.34 g) was added and the mixture was stirred at room temperature for 2 and a half hours.

Dichloromethane was distilled off, 3% aqueous phosphate solution (15 mL) was added to the residue, extraction was performed with ethyl acetate (25 mL), the ethyl acetate layer was washed with saturated brine (15 mL x 2), and dehydrated (magnesium sulfate). And 2N-2-ethylhexane sodium isopropyl alcohol solution (1.50 ml) were added dropwise to obtain a powder. The powder was filtered off, washed with crude ethyl ether, and dried under reduced pressure over phosphorus pentoxide to obtain 7β- (2-thienylacetamido) -3- (4-carboxybutyryloxy) methyl-3-cepem-4-carr Disodium carbonate (0.42 g) was obtained.

IR (KBr): 1760, 1736 (Shoulder), 1661, 1609 cm ^-1

NMR (D ₂ O):

), 4.4 4.9(2H, 3-CH₂), 4.98(1H, d, J=5Hz, 6-H), 5.60(1H, d, J= 5Hz, 7-H), 6.95 7.28(3H,

)δ 1.90 (2H, -CH ₂ CH ₂ CH _2- ), 2.28 (4H, -CH ₂ CH ₂ CH _2- ), 3.21 3.61 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 3.78 (2H, s,

), 4.4 4.9 (2H, 3-CH ₂ ), 4.98 (1H, d, J = 5 Hz, 6-H), 5.60 (1H, d, J = 5 Hz, 7-H), 6.95 7.28 (3H,

)

Example 5

7β- [D-5- (D-t-butylbenzamido) -5-carboxyvalerylamido] -3- (3-carboxycopionyloxy) methyl-3-cepem-4-carboxylic acid:

7β- [D-5- (P-tert-butylbenzamido) -5-carboxyvalerylamido] -3-hydroxymethyl-3-cepem-4-carboxylic acid ditriethylamine salt (7.35 g) It was dissolved in dimethylformamido (50 mL), succinic anhydride (1.50 g) was added thereto, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 3% aqueous phosphoric acid solution (250 ml) was added, extracted with ethyl acetate (500 ml), and the ethyl acetate layer was washed with water (250 ml x 2), dehydrated (magnesium sulfate), concentrated under reduced pressure, and ether was added. Powder was obtained. The powder was filtered off, washed with ether, and dried under reduced pressure on phosphorus pentoxide to give 7β- [D-5- (P-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (3- Carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid (6.20 g) was obtained.

IR (KBr): 1779, 1732, 1640 cm ^-1

NMR (d ₆ -DMSO):

), 1.73 2.24(6H, -(CH₂)₃-), 2.50(4H, -COCH₂CH₂CO-), 3.38 3.63(2H, ABq, J=18Hz, 2-CH₂), 4.37(1H, -CH-NH-), 4.71 5.60(2H, ABq, J=13Hz, 3-CH₂), 5.04(H, d, J=5Hz, 6-H), 5.66(1H, dd, J=5 8Hz, 7-H), 7.44 7.81(4H,

), 8.43(1H, d, J=8Hz,

CONH-), 8.80(1H, d, J=8Hz, -CONH-)δ 1.28 (9H, s,

), 1.73 2.24 (6H,-(CH ₂ ) _3- ), 2.50 (4H, -COCH ₂ CH ₂ CO-), 3.38 3.63 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 4.37 (1H, -CH-NH-), 4.71 5.60 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 5.04 (H, d, J = 5 Hz, 6-H), 5.66 (1H, dd, J = 5 8 Hz, 7-H), 7.44 7.81 (4H,

), 8.43 (1H, d, J = 8 Hz,

CONH-), 8.80 (1H, d, J = 8 Hz, -CONH-)

Example 6

7β- [D-5-p-t-butylbenzamido) -5-carboxyvalerylamido] -3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid:

7β- [D-5- (pt-burylbenzamido) -5-carboxylerylamido] -3-hydroxymethyl-3-cepem-4-carboxylic acid ditriethylamine salt (7.35 g) It was dissolved in formamide (50 mL), and phthalic acid (1.63 g) was added thereto, followed by stirring at room temperature for 30 minutes. After the reaction was completed, the same process as in Example 5 was carried out to obtain 7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (2-carboxybenzoyloxy) methyl- 3-cepem-4-carboxylic acid (6.70 g) was obtained.

IR (KBr): 1784, 1726, 1642 cm ^-1

NMR (d ₆ -DMSO):

), 1.72 2.22(6H -(CH₂)₃-), 3.46 3.71(2H, ABq, J=18Hz 2-CH₂), 4.37(1H,

), 4.89 5.27(2H, ABq, J=13Hz, 3-CH₂), 5.08(1H, d, J=5Hz, 6-H), 5.67(1H, dd, J=5 8Hz, 7-H), 7.43 7.81(4H,

), 7.62(4H,

), 8.42(1H, d, J=8.Hz, -CHNHCO-), 8.80(1H, d, J=8Hz, -CONH-)1.27 (9 H, s,

), 1.72 2.22 (6H-(CH ₂ ) _3- ), 3.46 3.71 (2H, ABq, J = 18 Hz 2-CH ₂ ), 4.37 (1H,

), 4.89 5.27 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 5.08 (1H, d, J = 5 Hz, 6-H), 5.67 (1H, dd, J = 5 8 Hz, 7-H), 7.43 7.81 (4 H,

), 7.62 (4H,

), 8.42 (1H, d, J = 8.Hz, -CHNHCO-), 8.80 (1H, d, J = 8 Hz, -CONH-)

Example 7

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3-carboxyacryloyloxy) methyl-3-cepem-4-carboxylic acid:

7β- [D-5- (pt-butylbenzamido) -5-carboxyvalerylamido [-3-hydroxymethyl-3-cepem-4-carboxylic acid ditriethylamine salt (7.35 g) in dimethyl It was dissolved in formamide (50 mL), maleic anhydride (1.49 g) was added thereto, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the same process as in Example 5 was carried out to obtain 7β- [D-5- (pt-butylbenzamido) -5-carboxyvalerylamido] -3- (3-carboxyacryloyloxy) methyl 3-Cefe-4-carboxylic acid (6.05 g) was obtained.

IR (KBr): 1780, 1727, 1640 cm ^-1

NMR (d ₆ -DMSO):

), 1.77 2.26(6H, -(CH₂)₃-), 3.41 3.65(2H, ABq, J=18Hz, 2-CH₂), 4.37(1H,

), 4.80 5.16(2H, ABq, J=13Hz, 3-CH₂), 5.02(1H, d, J=5Hz, 6-H), 5.66(1H, dd, J=5 8Hz, 7-H), 6.34(2H, -CH=CH-), 7.44 7,82(4H,

), 8.40(1H, d, J=8Hz, -CHNHCO-), 8.80(1H, d, J=8Hz,-CONH-).δ 1.32 (9H, s,

), 1.77 2.26 (6H,-(CH ₂ ) _3- ), 3.41 3.65 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 4.37 (1H,

), 4.80 5.16 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 5.02 (1H, d, J = 5 Hz, 6-H), 5.66 (1H, dd, J = 5 8 Hz, 7-H), 6.34 (2H, -CH = CH-), 7.44 7,82 (4H,

), 8.40 (1H, d, J = 8 Hz, -CHNHCO-), 8.80 (1H, d, J = 8 Hz, -CONH-).

Example 8

7- [D-5- (pt-butylbenzamido) -5-carboxyvalericamido] -3- [3-carboxy-3- (or 2) (p-chlorophenylthio) propionyloxy] methyl -3-cefe-4-carboxylic acid:

Dichloroethylamine salt (1.47 g) of 7- [D-5- (pt-butylbenzamido) -5-carboxyvaleryl amido] -3-hydroxymethyl-3-cepem-4-carboxylic acid ditriethylamine salt It dissolved in methane (20 mL), p-chlorophenyl thio succinic anhydride (0.51 g) was added here, and it stirred at room temperature for 1 hour. After completion of the reaction, the mixture was treated according to Example 1, and then 7β- [D-5- (pt-butylbenzamido) -5-carboxyvalerylamide] -3- [3-carboxy-3 (or 2)-(p -Chlorophenylthio) propionyloxy] methyl-3-cepem-4-carboxylic acid (1.50 g) was obtained.

IR (KBr): 1778, 1728, 1636 cm ^-1

NMR (d ₆ -DMSO):

), 1.74 2.24(6H, -(CH₂)₃-), 2.73(2H,

), 3.3 2.8(2H, 2-CH₂), 4.03(1H,

), 4.40(1H, CH-NH), 4.73 5.07(2H, ABq, J=13Hz, 3-CH₂), 5.02(1H, d, J=5Hz, 6-H), 5.68(1H, dd, J=5 8Hz, 7=H), 7.42(4H,

), 7.44 7.82(4H,

), 8.44(1H, d, J=8Hz, -CHNHCO-), 8.82(1H, d, J=8Hz, -CONH-),δ 1.28 (9H, s,

), 1.74 2.24 (6H,-(CH ₂ ) _3- ), 2.73 (2H,

), 3.3 2.8 (2H, 2-CH ₂ ), 4.03 (1H,

), 4.40 (1H, CH-NH), 4.73 5.07 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 5.02 (1H, d, J = 5 Hz, 6-H), 5.68 (1H, dd, J = 5 8 Hz, 7 = H), 7.42 (4H,

), 7.44 7.82 (4 H,

), 8.44 (1H, d, J = 8 Hz, -CHNHCO-), 8.82 (1H, d, J = 8 Hz, -CONH-),

Example 9

7β- (D-3-phthalimido-5-carboxyvalerylamido) -3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid:

Dichloromethane (50 mL) of 7β- (D-5-phthalimido-5-carboxyvaleryl amido) -3-hydroxymethyl-3-cepem-4-carboxylic acid ditriethylamine salt (7.05 g) Was dissolved in, and succinic anhydride (1.50 g) was added thereto, followed by stirring at room temperature for 1 hour and a half. After the completion of the reaction, the treatment according to Example 1 was carried out to obtain 7β- (D-5-phthalimido-5-carboxyvalderylamido) -3- (3-carboxypropionyloxy) methyl-3-cepem-4-car Obtained the main acid (5.43 g).

IR (KBr): 1777, 1710, 1644 cm ^-1

NMR (d ₆ -DMSO):

), 8.78(1H, d, J=8Hz, -CONH-)δ 1.52 2.17 (6H,-(CH ₂ ) _3- ), 2.50 (-1H,-(CH ₂ ) _2- ), 3.3-3.8 (2H, 2-CH ₂ ), 4.70 5.03 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 4.72 (1H, t, J = 7 Hz, CH-), 5.01 (1H, D, J = 5 Hz, 6-H), 5.62 (1H, dd, J = 5 8 Hz, 7- H), 7.86 4H, s,

), 8.78 (1H, d, J = 8 Hz, -CONH-)

Example 10

7β- (D-5-phthalimido-5-carboxyvalerylamido) -3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid:

7β- (D-5-phthalimido-5-carboxyvaleryl amido) -3-hydroxymethyl-3-cepem-4-carboxylic acid ditriethylamine salt (7.05 g) in dichloromethane (150 mL) It melt | dissolved in and added to it, the phthalic anhydride (2.22g), and stirred for 1 hour and a half at room temperature. After the completion of the reaction, the mixture was treated in accordance with Example 1 to obtain 7β- (D-5-phthalimido-5-carboxyvaleryl amido) -3- (2-carboxybenzoyloxy) methyl-3-cepem-4-car Main acid (6.39 g) was obtained.

IR (KBr): 1772, 1714, 1643 cm ^-1

NMR (d ₆ -DMSO):

), 8.81(1H, d, J=8Hz, -CONH-)δ 1.52 2.18 (6H,-(CH ₂ ) _3- ), 3.42 3.69 (2H, ABp, J = 18 Hz, 2-CH ₂ ), 4.74 (1H, t, J = 8 Hz, -CH-), 4.89 5.28 ( 2H, ABq, J = 13 Hz, 3CH ₂ ), 5.06 (1H, d, J = 5 Hz, 6-H), 5.66 (1H, dd, J = 5 8 Hz, 7-H), 7.64 (4H, ), 7.86 (4H, s,

), 8.81 (1H, d, J = 8 Hz, -CONH-)

Example 11

7β- [D-5- (pt-butylbenzamido) -5-carboxyvalderylamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4- Carboxylic acid:

7β- (D-5- (pt-butylbenzamido) -5-carboxyvalerylamido] -3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid (1.27 g), 5-mercapto-1-methyl-1H-tetrazole (0.25 g) and sodium hydrogencarbonate (0.68 g) were dissolved in water (12 mL) and stirred at 60 ° C. for 1 hour and the reaction liquid was returned to room temperature. Aqueous solution of 4% phosphoric acid was added (30 ml), extracted with ethyl acetate (60 ml), and the ethyl acetate layer was washed with brine (40 ml x 2), dehydrated (magnesium sulfate) and concentrated under reduced pressure. Obtained.

The powder was filtered off, washed with ether, and dried under reduced pressure on phosphorus pentoxide to give 7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (1- Methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (1.02 g) was obtained.

IR (KBr) 1776, 1727, 1640 cm ^-1

NMR (d ₆ -DMSO):

), 11.70 2.21(6H, -(CH₂)₃-), 3.54 3.77(2H, Abq, J=18Hz, 2-CH₂), 3.91(3H, s,

), 4.20 4.37(2H, Abq, J=13Hz, 3-CH₂), 4.39(1H,

), 5.02(1H, d, J=5Hz, 6-H), 5.64(1H, dd, J=5 8Hz, 7-H), 7.43 7.81(4H,

), 8.42(1H, d, J=8Hz, -CHNHCO-), 8.79(1H, d, J=8Hz, -CONH-)δ 1.28 (9H, s,

), 11.70 2.21 (6H,-(CH ₂ ) _3- ), 3.54 3.77 (2H, Abq, J = 18 Hz, 2-CH ₂ ), 3.91 (3H, s,

), 4.20 4.37 (2H, Abq, J = 13 Hz, 3-CH ₂ ), 4.39 (1H,

), 5.02 (1H, d, J = 5 Hz, 6-H), 5.64 (1H, dd, J = 5 8 Hz, 7-H), 7.43 7.81 (4H,

), 8.42 (1H, d, J = 8 Hz, -CHNHCO-), 8.79 (1H, d, J = 8 Hz, -CONH-)

Example 12

7β- [D-5-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3- Sepem-4-carboxylic acid:

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (3-carboxyacryloyloxy) methyl-3-cepem-4-carboxylic acid (1.26 g), 5-mercapto-1-methyl-1H-tetrazole (0.25 g) and sodium hydrogencarbonate (0.68 g) were dissolved in water (12 mL) and stirred at 60 ° C for 2 hours.

After the reaction was completed, the reaction was carried out according to Example 11, and then 7- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (1-methyl-1H-tetrazol- 5-yl) thiomethyl-3-cepem-4-carboxylic acid (0.88 g) was obtained.

IR (KBr) and NMR (d ₆ -DMSO) are consistent with those obtained in Example 11.

Example 13

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem- 4-carboxylic acid:

7β- [D-5- (pt-butylbenzamido) -5-carboxyvalerylamido] -3- (2carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid (1.36 g), 5- Mercapto-1-methyl-1-tetrazole (0.25 g) and sodium hydrogencarbonate (0,68 g) were dissolved in water (12 ml) and stirred at 60 ° C for 2 hours.

After the completion of the reaction, the same process as in Example 11 was carried out to obtain 7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (1-methyl-1H-tetra Sol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (0.97 g) was obtained.

IR (KBr) and NMR (d ₆ -DMSO) were consistent with those obtained in Example 11.

Example 14

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamide] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4 Carbonic acid:

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- [3-carboxy-3 (or 2)-(p-chlorophenylthio) propionyloxy Methyl-3-cepem-4-carboxylic acid (1.55 g), 5-mercapto-1-methyl-1H-tetrazole (0.25 g) and sodium hydrogencarbonate (0.68 g) were dissolved in water (12 mL), It stirred at 60 degreeC for 1 hour and a half. After the reaction was completed, the same treatment as in Example 11 was carried out to provide the following treatment: 7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- (1-methyl-1H-tetra Sol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (0.99 g) was obtained.

IR (KBr) and NMR (d ₆ -DMSO) were consistent with those obtained in Example 11.

Example 15

7β- (D-5-phthalimido-5-carboxyvalerylamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid:

7β- (D-5-phthalimido-5-carboxyvalerylamido) -3- (3-carboxypropylonyloxy) methyl-3-cepem-4-carboxylic acid (1.21 g), 5-mercapto- 1-methyl-1H-tetrazole (0.25 g) and sodium hydrogencarbonate (0.68 g) were dissolved in water (12 mL), and the mixture was stirred at 60 ° C for 1 hour and a half. After completion of the reaction, the reaction was carried out in accordance with Example 11 to be treated with 7β- (D-5-phthalimido-5-carboxyvalerylamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl- 3-cepem-4-carboxylic acid (1,00 g) was obtained.

IR (KBr): cm ^-1 3325, 1780, 1730, 1715, 1650 1545

NMR (d ₆ -DMSO):

δ 1.40 to 1.76 (m, 2H), 2.0 to 2.4 (m, 4H), 3.64 (AB pattern, 2H, J = 19 cps), 3.93 (s, 3H), 4.30 (Ab pattern, 2H, J = 15 cps), 4.73 (t, 1H, J = 8cps), 5.01 (d, 1H, J = 5cps), 5.62 (q, 1H, J = 5.9cps), 7.85 (s, 4H), 8.80 (d, J = 9cps) ppm

Example 16

7β- (D-5-phthalimido-5-carboxyvalerylamino) -3- (1-methyl-1H-tetrazol-3-yl) thiomethyl-3-cepem-4-carboxylic acid:

7β- (D-5-phthalimido-5-carboxyvalerylamido) -3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid (1.30 g), 5-mercapto-1 -Methyl-1H-tetrazole (0.25 g) and sodium hydrogencarbonate (0.68 g) were dissolved in water (12 mL), and the mixture was stirred at 60 ° C for 1 hour and a half. After the reaction was completed, the same treatment as in Example 15 was carried out to obtain 7β- (D-5-phthalimido-5-carboxyvalerylamido) -3- (1-methyl-tetrazol-5-yl) thiomethyl- 3-cepem-4-carboxylic acid (0.94 g) was obtained. IR (KBr) and NMR (d ₆ -DMSO) were consistent with those obtained in Example 15.

Example 17

7β- (2-thienylacetamido) -3-carboxyacryloyloxy) methyl-3-cepem-4-carboxylic acid:

It synthesize | combined according to Example 1.

IR (KBr): 1780, 1725, 1638 cm ^-1

NMR (d ₆ -DMSO):

), 9.10(1H, d, J=8Hz, -CONH-)δ 3.43 3.74 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 3.75 (2H, 2H, s, -CH ₂ CO-), 4.79 5.14 (2H, ABq, J = 13 Hz, 3-CH ₂ ) , 5.07 (1H, d, J = 5 Hz, 6-H), 5.68 (1H, dd, J = 5 8 Hz, 7-H), 6.35 (2H, s, -CH = CH-), 6.90 7.29 (3H,

), 9.10 (1H, d, J = 8 Hz, -CONH-)

Example 18

7β- [D-5- (p-tert-butylbenzamido) -3-carboxyvalerylamido] -3- (2-carboxy-4 (or 5) -nitrobenzoyloxy) methyl-3-cepem- 4-carboxylic acid:

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3-hydroxymethyl-3-cepem-4-carboxylic acid ditriethylamine salt (2.20 g) Dichloromethane (15 mL) and triethylamine (0.42 mL) were added and dissolved in 3-nitrophthalic anhydride (1.16 g), and the mixture was stirred at room temperature for 1 hour and a half. After the completion of the reaction, dichloromethane was maintained under reduced pressure, and 3% aqueous phosphoric acid solution (120 mL) and ethyl acetate (160 mL) were added to the residue. The ethyl acetate layer was washed with water (80 ml x 2), dehydrated (magnesium phase) and concentrated under reduced pressure, and ether was added to obtain a powder. The powder was filtered off, washed with ether, and dried under reduced pressure on phosphorus pentoxide to give 7β- (D- (p-tert-butylbenzamido) -5-carboxyvalerylamido) -3- (2-carboxy- 4 (or 5) -nitrobenzoyloxy) methyl-3-cepem-4-carboxylic acid (2.10 g) was obtained.

IR (KBr): 1783, 1735, 1640 cm ^-1

NMR (d ₆ -DMSO)

), 7.8∼8.4(3H,

), 8.40(1H, d, J=8Hz,

), 8.84(1H, d, J=8Hz, -CONH-)δ 1.28 (9H, s, -C (CH ₃ ) ₃ ), 1.53 2.23 (6H,-(CH ₂ ) _3- ), 3.43 3.70 (2H, -ABq, J = 18 Hz, 2-CH ₂ ), 4.37 ( 1H, -CH-), 4.96 5.41 (2H, Abq, J = 13 Hz, 3-CH ₂ ), 5.07 (1H, d, J = 5 Hz, 6-H), 5.68 (1H, dd, J = 5 8 Hz, 7-H), 7.42 7.80 (4H,

), 7.8-8.4 (3H,

), 8.40 (1H, d, J = 8 Hz,

), 8.84 (1H, d, J = 8 Hz, -CONH-)

Example 19

7β- (D-5-phthalimido-5-carboxyvalerylamido) -3- (2-carboxy-4 (or 5) -nitrobenzoyloxy) methyl-3-cepem-7-carboxylic acid:

7β- (D-5-phthalimido-5-carboxy valerylamido) -3-hydroxymethyl-3-cepem-4-carboxylic acid ditriethylamine salt (2.12 g), 3-nitrophthalic anhydride ( Dichloromethane (15 mL) triethylamine (0.42 mL) was added and dissolved in 1.16 g), and the mixture was stirred at room temperature for 1 hour and a half. After the reaction was completed, the same procedure as in Example 18 was carried out to obtain 7β (D-5-phthalimido-5-carboxyvalerylamido) -3- (2-carboxy-4 (or 5) -nitrobenzoyloxy) methyl 3-Cefe-4-carboxylic acid (0.08 g) was obtained.

IR (KBr): 1775 (sh), 1718, 1642 cm ^-1

NMR (d ₆ -DMSO):

), 4.98 5.42(2H, ABq, J=18Hz, 3-CH₂), 5.06(1H, d, J=5Hz, 6-H), 5.66(1H, dd, J=5 8Hz, 7-H), 7.7∼8.4(3H,

), 7.86(4H, s,

), 8.81(1H, d, J=8Hz, -CONH-)δ 1.54 2.19 (6H,-(CH ₂ ) _3- ) 3.40 3.68 (2H, ABq, J = 18 Hz, 2-CH ₂ ), (4.73 (1H, t, J = 7 Hz,

), 4.98 5.42 (2H, ABq, J = 18 Hz, 3-CH ₂ ), 5.06 (1H, d, J = 5 Hz, 6-H), 5.66 (1H, dd, J = 5 8 Hz, 7-H), 7.7-8.4 (3H,

), 7.86 (4H, s,

), 8.81 (1H, d, J = 8 Hz, -CONH-)

Example 20

7β- [D-5 (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (2,4 (or 5) -dicarboxybenzoyloxy) methyl-3-cepem-4- Carboxylic acid:

7β- [D-5 (p-tert-butylbenzamido) -5-carboxy valerylamido] -3-hydromethyl-3-cepem-4-carboxylic acid ditriethylamine salt (2.20 g), anhydrous Dichloromethane (15 mL) and triethylamine (0.84 mL) were added and dissolved in trimellitic acid (1.15 g), and it stirred at room temperature for 1 hour. After the completion of the reaction, the mixture was treated according to Example 18, and 7β- [D-5 (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- (2,4 (or 5) -carboxy Benzoyloxy) methyl-3-cepem-4-carboxylic acid (2.14 g) was obtained.

IR (KBr): 1777, 1724, 1636 cm ^-1

NMR (d ₆ -DMSO):

), 4.95 5.30(2H, ABq, J=13Hz, 3-CH₂), 5.11(1H, d, J=5Hz, 6-H, 5.70(1H, dd, J=5 8Hz, 7-H), 7.43 7.82(4H,

), 7.7∼8.3(3H,

), 8.43(1H, d, J=18Hz,

), 8.84(1H, d, J=8Hz, -CONH-)δ 1.29 (9H, s, -C (CH ₃ ) ₂ ), 1.54 2.25 (6H,-(CH ₂ ) _3- ), 3.99 3.72 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 4.38 (1H ,

), 4.95 5.30 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 5.11 (1H, d, J = 5 Hz, 6-H, 5.70 (1H, dd, J = 5 8 Hz, 7-H), 7.43 7.82 (4 H,

), 7.7-8.3 (3H,

), 8.43 (1H, d, J = 18 Hz,

), 8.84 (1H, d, J = 8 Hz, -CONH-)

Example 21

7β- [D-5- (2-carboxy-4 (or 5) -nitrobenzamido-5-carboxyvalerylamido] -3- (2-carboxy-4 (or 5) -nitrobenzoyloxy) methyl -3-cefe-4-carboxylic acid:

Deacetylcephalosporin (2.16 g) was suspended in dimethylformamide (10 ml), and concentrated ice hydrochloric acid (0.83 ml) was added to dissolve under ice-cooling.

Moreover, dimethylformamide (10 ml), triethylamine (4.0 ml), and 3-nitrophthalic anhydride (3.86 g) were added, and it stirred at room temperature for 2 hours. After the reaction was completed, 3% aqueous phosphate solution (150 mL) was added, extraction was performed with ethyl acetate (250 mL x 2), and the ethyl acetate layer was washed with water (200 mL) and saturated brine (200 mL), and dehydrated (magnesium sulfate). Phase), concentrated under reduced pressure, and ether was added to obtain a powder. The powder was filtered off, washed with ether, and dried under reduced pressure on phosphorus pentoxide to give 7β- [D-5- (2-carboxy-4 (or 5) -nitrobenzamido) -5-carboxyvaleramido)- 3- (2-carboxy-4 (or 5) -nitrobenzoyloxy) methyl-3-cepem-4-carboxylic acid (3.77 g) was obtained.

IR (KBr): 1780 (sh), 1729, 1638, 1534, 1348cm ^-1

NMR (d ₆ -DMSO):

), 8.78(1H, d, J=8Hz, -CONH-)δ 1.67 2.23 (6H,-(CH ₂ ) _3- ), 3.60 (2H, 2-CH ₂ ), 4.39 (1H, -CH-), 4.97 5.40 (2H, ABq, J = 13 Hz, 3-CH ₂ ) , 5.08 (1H, d, J = 5 Hz, 6-H), 5.68 (1H, dd, J = 5 8 Hz 7-H), 7.5 8.5 (7H,

), 8.78 (1H, d, J = 8 Hz, -CONH-)

Example 22

7β- [D-5- (2-carboxy-4 (or 5) -nitrobenzamido) -5-carboxyvalerylamido] -3- (1-methyl-1H-tetrazol-5-yl) thio Methyl-3-cepem-4-carboxylic acid:

7β- [D-5- (2-carboxy-4 (or 5) -nitrobenzamido) -5-carboxyvalerylamido] -3- (2-carboxy-4 (or 5) -nitrobenzoyloxy) Methyl-3-cepem-4-carboxylic acid (0.78 g), 5-merfato-1-methyl-1H-tetrazole (0.12 g) and sodium hydrogencarbonate (0.42 g) are dissolved in water (6 ml), It stirred at 60 degreeC for 30 minutes. After completion of the reaction, the product was treated in accordance with Example 11 to obtain 7β- [D-5- (2-carboxy-4 (or 5) -nitrobenzamido) -5-carboxyvalerylamido] -3- (1- Methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (0.50 g) was obtained.

IR (KBr): 1782, 1731, 1645, 1537, 1351cm ^-1

NMR (d ₆ -DMSO):

), 4.32(2H, 3-CH₂), 4.52(1H, -CH-), 5.06(1H, d, J=5Hz, 6-H), 5.67(1H, dd, J=5 8Hz, 7=H), 7.6∼8.4(4H,

NO₂

), 8.79(1H, d, J=8Hz, -CONH-)δ 1.73 2.26 (6H,-(CH ₂ ) _3- ) 3.69 (2H, 2-CH ₂ ), 3.94 (3H, s,

), 4.32 (2H, 3-CH ₂ ), 4.52 (1H, -CH-), 5.06 (1H, d, J = 5 Hz, 6-H), 5.67 (1H, dd, J = 5 8 Hz, 7 = H ), 7.6-8.4 (4H,

NO ₂

), 8.79 (1H, d, J = 8 Hz, -CONH-)

Example 23

7β- [D-5- (pt-butylbenzamido) -5-carboxyvalerylamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4- Carboxylic acid:

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (2-carboxy-4 (or 5) -nitrobenzoyloxy) methyl-3-cepem- 4-carboxylic acid (0.73 g), 5-mercapto-1-methyl-1H-tetrazole (0.12 g) and sodium hydrogencarbonate (0.34 g) are dissolved in water (6 mL) and stirred at 60 ° C. for 30 minutes. . After the completion of the reaction, the product was treated in accordance with Example 11 to obtain 7β- [D-5- (pt-butylbenzamido) -5-carboxyvalerylamido] -3- (1-methyl-1H-tetrazol-5 -Yl) thiomeryl-3-cepem-4-carboxylic acid (0.53 g) was obtained. IR (KBr) and NMR (d ₆ -DMSO) were consistent with those obtained in Example 11.

Example 24

7β- [D-5- (pt-butylbenzamido) -5-carboxyvalerylamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4- Carboxylic acid:

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (2,4 (or 5) -dicarboxybenzoyloxy) methyl-3-cepem-4 -Carboxylic acid (0.73 g), 5-mercapto-1-methyl-1H-tetrazole (0.12 g), and sodium hydrogen carbonate (0.42 g) were dissolved in water (6 ml) and stirred at 60 ° C for 30 minutes. . After completion of the reaction, the treatment according to Example 11 was carried out to obtain 7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvalerylamido] -3- (1-methyl-1H-tetrazol- 5-yl) thiomethyl-3-cepem-4-carboxylic acid (0.52 g) was obtained.

IR (KBr) and NMR (d ₆ -DMSO) were consistent with those obtained in Example 11.

Example 25

7β- (D-5-phthalimido-5-carboxyvalericamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cepem-4- Carboxylic acid:

7β- (D-5-phthalimido-5-carboxy valerylamido) -3- (2-carboxy-4 (or 5) -nitrobenzoyloxy) methyl-3-cepem-4-carboxylic acid (0.70 g ), 5-mercapto-2-methyl-1,3,4-thiadiazole (0.13 g) and sodium hydrogencarbonate (0.34 g) were dissolved in water (6 ml) and stirred at 60 ° C for 30 minutes. After the end of the half-temperature treatment was carried out in accordance with Example 11, 7β- (D-5-phthalimido-5-carboxyvalericamido) -3- (2-methyl-1,3,4-thiadiazole-5 -Yl) thiomethyl-3-cepem-4-carboxylic acid (0.51 g) was obtained.

IR (KBr): 1773 (sh), 1715, 1648 (sh) cm ^-1

NMR (d ₆ -DMSO):

), 8.74(1H, d, J=8Hz, -CONH-)δ 1.53 2.15 (6H,-(CH ₂ ) _2- ), 2.67 (3H, s, -CH ₃ ), 3.45 3.72 (3H, ABq, J = 18 Hz, 2-CH ₂ ), 4.19 4.50 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 4.72 (1H, t, J = 7HZ, -CH-), 5.02 (1H, d, J = 5 Hz, 6-H), 5.61 (1H, dd, J = 5 8 Hz , 7-H), 7.87 (4H, s,

), 8.74 (1H, d, J = 8 Hz, -CONH-)

Example 26

7β- [D-5- (pt-butylbenzamido) -5-carboxyvalericamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3 Sepem-4-carbonic acid:

7β- [D-5- (pt-butylbenzamido) -5-carboxyvalerylamido] -3- (2-carboxy-4 (or 5) -nitrobenzoyloxy) methyl-3-cepem-4- Carbonic acid (0.73 g), 5-mercapto-2-methyl-1,3,4-thiadiazole (9.13 g) and sodium hydrogen carbonate (0.34 g) are dissolved in water (6 ml), and the solution is heated at 60 deg. It stirred for 30 minutes. After the completion of the reaction, the treatment according to Example 11 was carried out to obtain 7β- [D-5- (pt-butylbenzamido) -5-carboxyvalerylamido] -3- (2-methyl-1,3,4- Tiadiazol-5-yl) thiomethyl-3-cepem-3-carboxylic acid (0.55 g) was obtained.

IR (KBr): 1780, 1728, 1644 cm ^-1

NMR (d ₆ -DMSO):

), 5.05(1H, d, J=5HZ 6-H), 5.65(1H, dd, J =5 8Hz 7-H), 7.44 7.80(4H,

), 8.42(1H, d, J=8Hz,

), 8.80(1H, d, J=8Hz, -CONH-)δ 1.28 (9H, s, -C (CH ₃ ) ₃ ), 1.74 2.23 (6H,-(CH ₂ ) ₃ ), -2.66 (3H, s, -CH ₃ ), 3.50 3.75 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 4.20 4.50 (2H, ABq, J = 13 Hz, 3 = CH ₂ ), 4.39 (1H,

), 5.05 (1H, d, J = 5HZ 6-H), 5.65 (1H, dd, J = 5 8 Hz 7-H), 7.44 7.80 (4H,

), 8.42 (1H, d, J = 8 Hz,

), 8.80 (1H, d, J = 8 Hz, -CONH-)

Example 27

Sodium salt of 7β- (D-mandelylamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl 3-cefe-4-carboxylic acid:

7β- (D-mandelirylamido) -3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid (0.46 g), 5-mercapto-1-methyl-1H-tetrazole ( 0.12 g) and sodium hydrogencarbonate (0.25 g) were dissolved in water (5 mL) and stirred at 60 ° C for 1 hour. After the step, the mixture was subjected to XAD-2-column chromatography, separated by water, followed by water-methanol and a mixed solvent, and eluted. The desired fraction was concentrated and lyophilized to obtain 7β- (D-mandelyl amido)-. Sodium 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid (0.31 g) was obtained.

IR (KBr): 1761, 1675, 1604 cm ^-1

NMR (D ₂ O):

), 4.02 4.29(2H, ABq, J=13Hz, 3-CH₂), 4.97(1H, d, J =5Hz, 6-H), 5.18(1H, s,

), 5.51(1H, d, J=5Hz, 7-H), 7.37(5H, s,

)δ 3.25 3.68 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 3.95 (3H, s,

), 4.02 4.29 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 4.97 (1H, d, J = 5 Hz, 6-H), 5.18 (1H, s,

), 5.51 (1H, d, J = 5 Hz, 7-H), 7.37 (5H, s,

)

Example 28

7β- (2-thienylacetamido) -3- (1-pyridylmethyl) -3-cepem-4-carboxylic acid betaine:

7β- (2-thienylacetamido) -3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid (0.50 g), sodium bicarbonate (0.17 g), potassium iodide (0.40 g) And pyridine (0.21 g) were dissolved in water (5 ml), and after adjusting to pH 6.5, the mixture was stirred at 60 ° C for 1 and a half hours. After air cooling, the mixture was eluted with XAD-2 column chromatography, eluted with water and then with a mixed solvent of water and methanol, and the desired fraction was concentrated and lyophilized to obtain 7β- (2-thienylacetamido) -3-. (1 pyridylmethyl) -3-cepem-4-carboxylic acid betaine (0.23 g) was obtained.

IR (KBr): 1763, 1698, 1617cm ^-1

NMR (D ₂ O):

), 8.15 8.62 9.04(5H,

)δ 3.17 3.67 (2H, ABq, J = 17 Hz, 2-CH ₂ ), 3.88 (2H, s, -CH ₂ CO-), 5.19 (1H, d, J = 5 Hz, 6-H), 5.41 5.67 (2H , ABq, J = 14 Hz, 3-CH ₂ ), 5.75 (1H, d, J = 5 Hz, 7-H), 7.01 7.28 (3H,

), 8.15 8.62 9.04 (5H,

)

Example 29

According to Example 25, the following compounds were synthesized.

(1) 7β- (D-5-phthalimido-5-carboxyvalerylamido) -3-2- [2-hydroxyethylthio) -1,3,4-thiadiazol-5-yl] Thiomethyl-3-cepem-4-carboxylic acid

IR (KBr): 3325, 1780, 1715, 1645, 1530cm ^-1

NMR (d ₆ -DMSO):

δ 1.30 to 2.40 (m, 6H), 3.20 to 3.80 (m, 6H), 4.27 (AB pattern, 2H, J = 12cps), 4.65 (t, 1H, J = 9cps), 4.96 (d, 1H, J = 5 cps), 5.55 (q, 1H, J = 5 8 cps), 7.87 (s, 4H), 8.70 (d, 1H, J = 8 cps) ppm

(2) 7β- (D-5-phthalimido-5-carboxyvalericamido) -3- (2-carbamoylmethylthio-1,3,4-thiadiazol-5-yl) thiomethyl -3-cefe-4-carboxylic acid:

IR (KBr): cm ^-1 3430, 3340, 1776, 1717, 1680, 1535

NMR (d ₆ -DMSO):

δ 1.30-2.40 (m, 6H), 3.57 (br, 2H), 4.40 (s, 2H), 4.32 (AB pattern, 2H, J = 12cps), 4.70 (t, 1H, J = 8.0cps), 5.0 ( d, 1H, J = 5cps), 5.5 (q, 1H, J = 5.8cps), 7.20 (br, 1H), 7.60 (br, 1H), 7,86 (S, 4H), 8.74 (d, 1H, J = 5cps) ppm

Example 30

7β- (2-thienylacetamido) -3- (1-methyl-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid:

7β- (2-thienylacetamido) -3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid (0.50 g), 5-mercapto-1-methyl-1H-tetrazole ( 0.12 g) and sodium hydrogencarbonate (0.25 g) were dissolved in two (5 mL), and the mixture was stirred at 60 ° C for 1 and a half hours. After the reaction was completed, the reaction was carried out in accordance with Example 11 to obtain 7β- (2-thienylacetamido) -3- (1-methyl-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid ( 0.37 g) was obtained.

IR (KBr): 1776, 1734, 1672 cm ^-1

NMR (d ₆ -DMSO):

), 4.21 4.37(2H, ABq, J=13Hz, 3-CH₂), 5.03(1H, d, J=5Hz, 6-H), 5.66(1H, dd, J=5 8Hz, 7-H), 6.90 7.29(3H,

), 9.10(1H, d, J=8Hz, -CONH-)δ 3.56 3.78 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 3.73 (2H, s, -CH ₂ CO-), 3.92 (3H, s,

), 4.21 4.37 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 5.03 (1H, d, J = 5 Hz, 6-H), 5.66 (1H, dd, J = 5 8 Hz, 7-H), 6.90 7.29 (3H,

), 9.10 (1H, d, J = 8 Hz, -CONH-)

Example 31

(1) A mixture of 300 ml of dichloromethane and 100 ml of triethylamine 27 ml diAPthylaniline was cooled to 10 ° C., and 7- [D-5- (phthalimido) adipineamido] -3- ( 50 g of 1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid was added and dissolved, followed by addition of 36 ml of dichlorodimethylsilane. At this time, internal temperature rose to 27 degreeC. After stirring at this temperature for 30 minutes, the internal temperature was cooled to -35 ° C and 32.4 g of phosphorus pentachloride was added. It stirred at -25 degreeC for 40 minutes, and also cooled to -35 degreeC, and added 20 g of thioacetamidos. After 40 minutes of stirring at -20 to -25 ° C, the mixture was cooled to -30 ° C and 200 ml of methanol was slowly added dropwise.

At the same temperature, 17 ml of sulfur monochloride was slowly added dropwise. After stirring for 20 minutes, 200 ml of water was added thereto, and then the pH was adjusted to 3.2 with 40% aqueous potassium carbonate solution. After stirring for 60 minutes, the precipitated crystals were filtered off and washed with water and acetone.

The crude crystal thus obtained was suspended in 230 ml of 10% hydrochloric acid, and stirred at 30 ° C for 1 hour. The insolubles were filtered, cooled to 5 to 10 ° C., stirred with potassium carbonate for 1 hour as pH 3.3, the precipitated crystals were filtered off, washed with water and acetone, dried over phosphorus pentoxide and 7-amino-3- 17.0 g of (1-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid was obtained.

IR (KBr): 1795cm ^-1

NMR (in D ₂ O + NaHCO ₃ ):

δ 3.6 and 3.98 (ABq, J = 18 Hz, 2-CH ₂ ), 4,21 (s, tetrazole-CH ₃ ), 5.21 (d, J = 4.5 Hz, 6-H), 5.60 (d, J = 4.5 Hz, 7-H)

(2) 2.8 g of chlorine gas was introduced over 100 minutes while cooling and stirring 3.3 g of diketene to 160 ml of methylene chloride to maintain the internal temperature at -25 to -35 ° C, and then the mixed solution was added at 30 ° C in the same degree of silver. Stirred for minutes. Separately, 10.0 g of 7-amino-3- (1-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid and 7.9 g of dibutylamine were dissolved in 60 ml of methylene chloride, It cooled, and the said reaction solution was dripped here over 30 minutes, stirring and cooling so that liquid temperature might be -10--20 degreeC, and then this mixed liquid was stirred for 40 minutes at the same temperature. When the reaction solution was observed by thin layer chromatography, 7- (4-chloro-3-oxobutyrylamido) -3- (1-methyltetrazol-5-yl) thiomethyl-3-cepem-4- The presence of carboxylic acid was confirmed.

4.64 g of thiourea was added to this reaction liquid to dissolve it, and the internal temperature was gradually raised to 17-19 degreeC, and this mixed liquid was stirred at this temperature, and crystal | crystallization precipitated. This crystal was filtered off with suction, washed with 30 ml of methylene chloride and dried to yield 12.6 g of 2- (2-imino-4-thiazolin-4-yl) acetamido compound.

mp 176-180 ° C (decomposition)

IR (cm ^-1 KBr): 1762, 1662

NMR (δ value W in d ₆ -DMSO):

3.39 (s, CH ₂ CO), 3.55 and 3.77 (ABq, J = 18 Hz, 2-CH ₂ ), 3.90 (s, tetrazol 1-CH ₃ ), 4.21 and 4.36 (ABq, J = 14 Hz, 3-CH ₂ ), 5.03 (d, J = 5 Hz, 6-H), 5.66 (dd, J = 9 and 5 Hz, 7-H), 6.23 (s, thiazole 5-H), 6.2-7.1 (m, NH ₂ ), 8.85 (d, J = 6 Hz, CONH).

Example 32

7β-amino-3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid (7.33 g) was suspended in water (48 mL), and 2N-sodium hydroxide (19.5 mL) at 0-3 ° C. Was added little by little so that PH did not exceed 8.5, and then sodium hydrogencarbonate (3.65 g) was added, followed by dissolving the solution of D-α-sulfophenylacetyl chloride (5.0 g) in ethyl acetate (8.8 mL). It is dripped at 5 degreeC for 1 hour, and after completion | finish of dripping, it reacts at 0-5 degreeC for 20 minutes. After adjusting the reaction liquid to pH 5.5, liquid-separated, the water layer was taken out, this aqueous solution was degassed, and after confirming that it was pH 5.5-6.5, ethanol (800 mL) was added to this aqueous solution (about 80 mL) for 1 hour, After stirring for 30 minutes thereafter, the mixture was cooled to 5 ° C. or lower, and the precipitated crystals were filtered out. The crystals were washed sequentially with ethanol-water (10: 1) and ethanol, and then dried, and then 7β- (D-α- Sulfophenylacetamido) -3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid trisodium salt (11.6 g) was obtained.

IR (KBr): 3350, 1768, 1735, 1670, 1610 cm ^-1

NMR (D ₂ O):

δ 3.44 (2H, ABq, J = 18 Hz), 5.00 (2H, ABq, J = 13 Hz), 5.06 (1H, d, J = 5 Hz), 5.08 (1H, s), 5.67 (1H, d, J = 5 Hz ), 7.3 to 7.9 (m, 9H).

Example 33

7β- (D-α-sulfenphenylacetamido) -3-hydroxymethyl-3-cepem-4-carboxylic acid disodium salt (940 mg), glutaric anhydride (580 mg), triethylamine (404 Mg) was dissolved in dimethylformamide (10 ml) and stirred at room temperature for 2 hours. Dimethylformamide was distilled off, a small amount of water was added to make an aqueous solution, desalted with IR-120 (H), the desalted solution was adjusted to pH 6.0 with 1N sodium hydroxide solution, and lyophilized. It was dissolved in water again, and purified by XAD-2 column chromatography, and 7β- (D-α-sulfophenylacetamido) -3- (4-carboxybutythyloxy) methyl 3-sefe-4-carboxylic acid tri Sodium was obtained.

IR (KBr): 1760, 1675, 1620cm ^-1

), 5.08(1H, d, 6-H), 5.75(1H, d, 7-H), 7.47(5H, m).NMR (D ₂ O): δ 1.65 to 2.60 (6H, m), 3.41 (2H, q, 2-CH ₂ ), 4.83 (2H, d, 3-CH ₂ ), 5.0 (1H,

), 5.08 (1H, d, 6-H), 5.75 (1H, d, 7-H), 7.47 (5H, m).

Example 34

7β- (D-α-sulfophenylacetamido) -3-hydroxymethyl-3-cepem-4-carboxylic acid disodium salt (470 mg), succinic anhydride (250 mg), triethylamine (200 mg) Was dissolved in dimethylformamido (3 ml) and stirred at room temperature for 2 hours. After the reaction, a small amount of water was added, and dimethylformamide was distilled off under reduced pressure. Water was added to dissolve and purified by XAD-2 column chromatography, 7β- (D-α-sulfophenylacetamido) -3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid Sodium salt was obtained.

IR (KBr): 1765, 1685, 1600cm ^-1

), 5.21(1H, d, 6-H), 5.91(1H, d, 7-H), 7.78(5H, m,

).NMR (D ₂ O): δ 2.62 (4H, s, -CO (CH ₂ ) ₂ CO-), 3.38 (2H, q, 2-CH ₂ ), 4.95 (2H, 3-CH ₂ ), 5.10 (1H , s,

), 5.21 (1H, d, 6-H), 5.91 (1H, d, 7-H), 7.78 (5H, m,

).

Example 35

Diketene (0.20 mL) dichloromethane (1 mL) solution was cooled to -30 ° C, and 1.5 mol chlorine-tetrachloride carbon solution (2.0 g) was added dropwise for 10 minutes while stirring, and -25 to -35 for 30 minutes. It stirred at ° C. Separately, 7β-amino-3-2-carboxy-6 (or 3) -nitrobenzoyloxy methyl-3-cepem-4-carboxylic acid (0.90 g) and triethylamine (0.84 g) were added to dichloromethane (5 mL). It melt | dissolved, it cooled at -5-10 degreeC, and the said reaction solution was dripped at -20--30 degreeC over 15 minutes, Then, this mixed liquid was stirred at the same temperature for 45 minutes. Next, the reaction solution was distilled off under reduced pressure, ethyl acetate (25 mL), tetrahydrofuran (5 mL) and 10% aqueous phosphoric acid solution (20 mL) were added to the residue, followed by vigorous stirring. The organic layer was washed with saturated brine (15 mL), dehydrated with sodium sulfate, concentrated under reduced pressure, and ether (20 mL) was added to obtain a powder. The powder was filtered off, washed with ether (10 mL), and dried under reduced pressure on phosphorus pentoxide to give 7β- (4-chloro-3-oxobutylamido) -3- [2-carboxy-6 (or 3)- Nitrobenzoyloxy) methyl-3-cepem-4-carboxylic acid (0.70 g) was obtained.

), 9.04(1H, d, J=8Hz, -CONH-)NMR (d ₆ -DMSO): δ 3.4 to 3.8 (2H, 2-CH ₂ ), 3.54 (2H, s, -COCH ₂ CO-), 4.52 (2H, s, ClCH _2- ), 4.94 5.52 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 5.04 (1H, d, J = 5 Hz, 6-H), 5.68 (1H, dd, J = 5 8 Hz, 7-H), 7.7 to 8.5 (3H, m ,

), 9.04 (1H, d, J = 8 Hz, -CONH-)

Example 36

7β-phenylacetyl-3-hydroxymethyl-3-cepem-4-carboxylic acid triethylamine salt (4.5 g) was dissolved in dichloromethane (50 mL), and succinic anhydride (1.5 g) was added thereto for 5 hours at room temperature. Stirred. The solvent was distilled off under reduced pressure, water and ethyl acetate were added to pH 2.0 with phosphoric acid. The ethyl acetate layer was dehydrated, concentrated, and the precipitated crystals were filtered out (2.9 g), and further concentrated and left to be added with ether to obtain crystals (1.6 g).

The crystals were recrystallized from ethyl acetate to obtain 7β-phenylacetamido-3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid.

mp 86-89 °

IR (KBr): 1800, 1735, 1692, 1660 cm ^-1

), 9.02(1H, d, J=9Hz, -CONH-)NMR (d ₆ -DMSO): δ 2.48 (4H,-(CH ₂ ) _2- ), 3.51 (4H, 2-CH ₂ , -CH ₂ CO-), 4.69 5.02 (2H, ABq, J = 13 Hz), 5.00 (1H, d, J = 5 Hz, 6-H), 5.63 (1H, dd, J = 5 9 Hz, 7-H), 7.23 (5H,

), 9.02 (1H, d, J = 9 Hz, -CONH-)

Example 37

In Example 40, the reaction was carried out using phthalic anhydride (2.2 g) instead of succinic anhydride to obtain 7β-phenylacetamido-3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid. .

mp 128-129 degreeC (ethyl acetate-ether)

IR (KBr): 1788, 1731, 1695, 1662 cm ^-1

), 7.62(4H,

), 9.07(1H, d, J=8Hz, -CONH-)NMR (d ₆ -DMSO): δ 3.53 (2H, s, -CH ₂ CO-), 3.61 (2H, 2-CH ₂ ), 4.90 5.27 (2H, ABq, J = 13 Hz, 3-CH ₂ ), 5.088 (1H, d, J = 5 Hz, 6-H), 5.68 (1H, dd, J = 5 8 Hz, 7-H), 7.25 (5H,

), 7.62 (4H,

), 9.07 (1H, d, J = 8 Hz, -CONH-)

Example 38

7β-amino-3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid (660 mg) was suspended in dichloromethane (7 mL), and N, N-dimethylacetamide (0.7 mL). Was added, and ice-cooled stirring (1H-tetrazol-1-yl) acetyl chloride (294 mg) was dissolved in dichloromethane (2 mL) and added.

The mixture was stirred at room temperature for 1 hour, poured into an aqueous sodium hydrogen carbonate solution, separated, and the aqueous layer was taken. The aqueous layer was washed with dichloromethane, acidified with phosphoric acid, extracted with ethyl acetate, and extracted with aqueous sodium hydrogen carbonate solution. Transfer to a water layer, purify this solution by hanging on Sephadex LH-20 column chromatography, and classify 주 of the main product to lyophilize to obtain 7β- {2- (1H-tetrazol-1-yl) acetamido}. 3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid sodium salt was obtained.

IR (KBr): 1765, 1620cm ^-1

NMR (D ₂ O): δ 2.60 (4H, m,-(CH ₂ ) _2- ), 3.44 3.74 (2H, ABq, J = 17 Hz, 2-CH ₂ ), 5.20 (1H, d, J = 5 Hz, 6-H), 5.59 (2H, s, NCH ₂ CO-), 5.76 (1H, d, J = 5 Hz, 7-H), 9.33 (1H, s, tetrazole)

Example 39

7β- (2-thienylacetamido) -3- [2-carboxy-6 (or 3) nitrobenzoyloxy] methyl-3-cepem-4-carboxylic acid (2.65 g), acetylacetone (2.42 g), Sodium bicarbonate (1.22 g) was dissolved in 50% acetone water (40 ml) and stirred at 60 ° C for 1 hour. The reaction solution was returned to room temperature, and most of the acetone was distilled off under reduced pressure, and an aqueous 5% phosphoric acid solution and ethyl acetate were added. The ethyl acetate layer was washed with saturated brine (20 mL), dehydrated (magnesium sulfate), and concentrated under reduced pressure to add ether to obtain a powder. This powder was suspended in water (3 mL), dissolved by adding sodium hydrogen carbonate, and developed on water by hanging on Sephadex LH-20 column chromatography. The desired fractions were combined and lyophilized to yield sodium 7β- (2-thienylacetamido) -3- (2-acetyl-3-oxo) butyl-3-cefe-4-carboxylic acid. This was dissolved in water (10 mL), and 10% aqueous phosphoric acid solution (2 mL) and ethyl acetate (20 mL) were added thereto. The ethyl acetate layer was washed with water, dehydrated (magnesium sulfate) and concentrated under reduced pressure, and ether was added to give a powder. The powder was filtered off, washed with ether, and then dried on phosphorus pentoxide to obtain 7β- (2-thienylacetamido) -3- (2-acetyl-3-oxo) butyl-3-sefe-4-car Main acid (1.26 g) was obtained.

IR (KBr): 1765, 1718 cm ^-1

), 5.01(1H, d, J=5Hz, 6-H), 5.58(1H, dd, J=5 8Hz, 7-H), 6.92 7.30(3H,

), 9.04(1H, d, J=8Hz. -CONH).NM (d ₆ -DMSO): δ 2.13 2.18 (6H, s, (COCH ₃ ) ₂ ), 2.6 to 3.1 (2H, m, 3-CH ₃ ), 3.31 3.36 (2H, ABq, 2-CH ₂ , 3.75 (2H, s, -CH ₂ CO-), 4.14 (1H,

), 5.01 (1H, d, J = 5 Hz, 6-H), 5.58 (1H, dd, J = 5 8 Hz, 7-H), 6.92 7.30 (3H,

), 9.04 (1H, doublet, J = 8 Hz. -CONH).

Example 40

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- [2-carboxy-6 (or 3) -nitrobenzoyloxy] methyl-3-cepem-4 -Carboxylic acid (0.73 g) acetyl acetone (0.50 g) and sodium hydrogencarbonate (0.34 g) were dissolved in 50% acetone water (8 ml), and the mixture was stirred at 60 ° C for 1 hour.

After the completion of the reaction, the mixture was treated in accordance with Example 53, and 7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- (2-acetyl-3-oxy) Butyl-3-cepem-4-carboxylic acid (0.29 g) was obtained.

IR (KBr): 1767, 1721, 1655, 1635 cm ^-1

), 4.99(1H, d, J =5Hz, 6-H ), 5.57(1H, dd, J=5 8Hz, 7-H), 7.34 7.83(4H,

), 8.40(1H, d, J=8Hz,

), 8.77(1H, d, J=18Hz, -CONH-)NMR (d ₆ -DMSO): δ 1.30 (9H, s, -C (CH ₃ ) ₂ ), 1.76 2.25 (H,-(CH ₂ ) _3- ), 2.6-3.1 (2H, m, 3-CH ₂ ), 3.2 to 3.6 (2H, 2-CH ₂ ), 4.13 (1H, -CH (COCH ₃ ) ₂ , 4.37 (1H,

), 4.99 (1H, d, J = 5 Hz, 6-H), 5.57 (1H, dd, J = 5 8 Hz, 7-H), 7.34 7.83 (4H,

), 8.40 (1H, d, J = 8 Hz,

), 8.77 (1H, d, J = 18 Hz, -CONH-)

Example 41

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3,2-carboxy-6- (or 3) -nitrobenzoyloxy methyl-3-cepem-4- Carbonic acid (0.73 g), pyrrole (0.20 g) and sodium hydrogencarbonate (0.25 g) were dissolved in 50% acetone water (14 ml) and stirred at 60 ° C for 1 hour. The reaction solution was cooled to room temperature, and most of the acetone was distilled off under reduced pressure, and 5% aqueous phosphoric acid solution (15 mL) and ethyl acetate (30 mL) were added thereto.

The ethyl acetate layer was washed with saturated brine (20 mL), dehydrated (magnesium sulfate), and concentrated under reduced pressure, followed by addition of erre to obtain a powder. This powder was suspended in water (3 mL), dissolved by adding sodium hydrogencarbonate (0.17 g), suspended in Sephadex LH-20 (250 mL) column chromatography, and developed with water. The desired fractions were collected and lyophilized to yield 7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- (2-pyrrolyl) methyl-3-cepem 4-sodium carboxylate (0.29 g) was obtained.

IR (KBr): 1760, 1600㎝ ^-1

), 7.80(1H, 피롤 -1-H)NMR (D ₂ O): δ 1.23 (9H, s, -C (CH ₃ ) ₃ ), 1.86 2.42 (5 6H,-(CH ₂ ) _3- ), 2.86 3.25 (2H, ABq, J = 18 Hz, 2 -CH ₂ ), 3.42 3.73 (2H, ABq, J = 15 Hz, 3-CH ₂ ), 4.51 (1H, -CH-), 4,96 (1H, d, J = 5 Hz, 6-H), 5.61 ( 1H, d, J = 5 Hz, 7-H), 5.93 (1H, pyrrole-3-H), 6.07 (1H, pyrrole-4-H), 6.77 (1H, pyrrole 5-H), 7.38 7.76 (4H,

), 7.80 (1H, pyrrole-1-H)

Example 42

7β- [D- (5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- [2-carboxy-6 (or 3) -nitrobenzoyloxy] methyl-3-cepem- 4-carboxylic acid (0.73 g), N-methylpyrrole (0.24 g) and sodium hydrogencarbonate (0.25 g) were dissolved in 50% acetone water (14 mL) and stirred at 60 ° C. for 1 hour. In the same manner as in Example 57, 7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- (N-methylpyrrole-2-yl) methyl-3- Cefem-4-disodium carbonate (0.21 g) was obtained.

IR (KBr): 1757, 1597㎝ ^-1

)NMR (D ₂ O): δ 1.21 (9H, s, -C (CH ₃ ) ₃ ), 1.87 2.45 (6H,-(CH ₂ ) _3- ), 2.97 3.07 (2H, ABq, J = 18 Hz, 2- CH ₂ ), 3.46 (3H, s, N-CH ₃ ), 3.51 3.87 (2H, ABq, J = 15 Hz, 3-CH ₂ ), 4.51 (1H, -CH-), 4.91 (1H, d, J = 5 Hz, 6-H), 5.58 (1H, d, J = 5 Hz, 7-H), 5.86 (1H, pyrrole-3-H), 5.99 (1H, pyrrole-4H), 6.61 (1H, pyrrole-5- H), 7.39 7.79 (4H,

)

Example 43

7β- (D-5-phthalimido-5-carboxyvaleramido) -3-2-carboxy-6 (or 3) -nitrobenzoyloxymethyl-3-cepem-4-carboxylic acid (0.70 g), indole (0.35 g) and sodium hydrogencarbonate (0.25 g) were dissolved in 50% acetone water (14 ml) and stirred at 60 ° C for 45 minutes. After completion of the reaction, the mixture was treated in accordance with Example 57, and 7β- (D-5-phthalimido-5-carboxyvaleramido) -3- (3-indolyl) methyl-3-cepem-4-carboxylic acid di Nitrile (0.22 g) was obtained.

This product was the same as the IR spectrum obtained in Example 59.

Example 44

7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- [2-carboxy-6 (or 3) -nitrobenzoyloxy) methyl-3-cepem-4 -Carboxylic acid (0.73 g), sodium azide (0.26 g), and sodium hydrogencarbonate (0.25 g) were dissolved in water (7 mL) and stirred at 60 ° C for 40 minutes. The reaction mixture was returned to room temperature, 10% aqueous phosphate (10 mL) was added, extraction was performed with ethyl acetate (30 mL), and the ethyl acetate layer was washed with saturated brine (20 mL), dehydrated (magnesium sulfate), and depressurized. After concentration, ether was added to give a powder. This powder was suspended in water (3 ml), and sodium hydrogencarbonate (0.17 g) was added and dissolved. This was suspended in Sephadex LH-20 (250 mL) column chromatography and developed with water.

Collect the desired fractions and freeze-dried to obtain 7β- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido) -3-azidomethyl-3-cepem-4-carbon Disodium acid (0.36 g) was obtained.

IR (KBr): 2100, 1766, 1606 cm ^-1

)NMR (D ₂ O): δ 1.32 (9H, s, -C (CH ₃ ) ₃ ), 1.92 2.48 (6H,-(CH ₂ ) _3- ), 3.05 3.53 (2H, ABq, J = 18 Hz, 2- CH), 4.03 4.20 (2H, ABq. J = 13 Hz. 3-CH ₂ ), 4.52 (1H, -CH-), 5.08 (1H, d, J = 5 Hz, 6-H), 5.68 (1H, d, J = 5 Hz, 7-H), 7.56 7.86 (4H,

)

Example 45

5-mercapto-2-methyl-1,3,4-thiadiazole (79 mg), sodium bicarbonate (50 mg) and 7β- [2- (1H-tetrazol-1-yl) acetamido] 3- (3-carboxypropionyloxy) methyl-3-cepem-4-carboxylic acid disodium salt (243 mg) was dissolved in phosphate complete layer 3 having a pH of 6.4, and heated at 60 ° C for 1 hour. The reaction solution was cooled, concentrated under reduced pressure, purified by hanging on Sephadex LH-20 column chromatography, and the fractions of the main product were collected and lyophilized to obtain 7β- {2- (1H-tetrazol-1-yl. ) Acetamido} -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid sodium salt was obtained.

NMR (within D ₂ O): 2.78 (3H, s, -CH ₃ ), 3.60 (2H, ABq, J = 18 Hz, 2-CH ₂ ), 4.25 (2H, ABq, J = 13 Hz, 3-CH ₃ ) , 5.12 (1H, d, J = 4.5 Hz, 6-H), 5.58 (2H, s, -CH ₂ OC-), 5.70 (1H, d, J = 4.5 Hz, 7-H), 9.15 (1H, s, tetrazol-H).

Claims (1)

A method for preparing the following general formula (I) and cephalosporin compound, characterized by reacting the following general formula (II) compound with a nucleophilic compound.

Where R ¹ represents hydrogen or an acyl group, R ² represents a residue of a nucleophilic compound, X represents an organic residue.