KR810000636B1 - Process for preparing cephalosporin compound - Google Patents

Abstract

Title compds.(I; X = organic group) were prepd. by substitution of R' with H of II(R1 = acyl). Thus, 6.15 g 7-[D-5-phthalimido-5-carboxyvalerylamido -3-(2-carboxybenzoyloxy)methyl-3-cephem-4-carboxylic acid was suspended in dichloromethane and reacted with N,N-dimethylaniline and dimethyldichlorosilane at 20-25≰C for 30 min. The obtained product was reacted with 4.20 g phosphorus pentachloride at -25±2≰C for 30 min to give 3.43 g 7β-amino-3-(2-carboxybenzoyloxy)methyl-3-cephem-4-carboxylic acid.

Description

Preparation of Cephalosporin Compound

This invention relates to the manufacturing method of the compound represented by following General formula (I) as a division of 1976 patent application 686.

In the above formula,

X represents an organic group.

That is, the production method of the present invention represented by the above-mentioned formula (Ⅰ), characterized by Sikkim introducing the compound R ¹ is hydrogen by cutting acyl group indicated by R ¹ in the compound represented by the following general formula (Ⅱ) compound It is about.

In the above formula

R ¹ is an acyl group,

X is as described above.

The raw material compound and the target compound of the method of the present invention may be in the form of a free acid or a free salt, but the compound of the general formula (I) and the compound of the general formula (II) also include a light oil of such salt. The compounds of interest of the present invention are novel compounds not described in the literature and are sometimes important as intermediates of cephalosporin antibiotics.

According to the method of the present invention, the compound of the general formula (II) to be used as a raw material compound is a novel compound not described in the literature, and is prepared by reacting the compound of the general formula (III) with the compound of the general formula (IV) Can be.

In the above formula,

R ³ is an acyl group or hydrogen,

X is as described above.

As mentioned above, the compounds of the general formula (III) also include the case of salts.

The 3-hydroxymethyl body represented by the general formula (III) is generally enzymatically removed the 3-acetyl group of the cephalosporin having a 3-acetoxymethyl group, or in the culture of cephalosporin C. Although only obtained by separating from living organisms, 7- (D-5-aminoadinepinamido) -3-hydroxymethyl-3-cepem-4-carboxylic acid (deacetyl cephalosporin C, DCPC) has recently been fermented. It is possible to produce a high unit by cultivation (Nature 246 154 (1973), Patent Publication No. 491 1974), together with Josephalosporin C, attention as a raw material to induce more antibacterial cephalosporin compounds It came to be.

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

However, acylating 3-hydroxymethyl groups of 3-hydroxyethyl bodies such as cephalosporadesinic acid has not been easy until now. For example, henigen (E. van Heyningen J. Med. Chem., 8 , 22 (1965), Advan. Drug. Res. 4,28 (1968)) is a zero-acylation reaction of cephalosporadesin acid. It is only possible following the use of a large excess of alloyl chloride (yield 32% to 57%), but it has been reported that no acetylation or lactone ring formation occurs as ketene, an aliphatic chloride, anhydrous acetic acid.

In addition, kukolja (J.Med. Chem. 13,114 (1970), reported a method for 0-acylating a G3-hydroxymethyl-2-cefecem to synthesize 0-acyloxymethylcephalosporin, and then isomerize to 3-cefeceme, US Patent No. 3,532,694 and Belgian Patent No. 719-711 protect the method of 0-acylation after protecting 4-carboxyl groups of cephalosporadesin acid with an ester or the like to prevent lactonation. No. 42792 1972 discloses a method for zero-acylating cephalosporadesinic acid with azolide. However, these methods are low in yield, laborious in operation, and cannot be said to be industrially advantageous methods such as using expensive reagents.

In other words, for example, the esterification reaction of cephalosporadesin cannot be achieved by preferential transesterification or lactonation of double bonds. Only a diazo compound such as diazomethane, diazoethane, diphenyl diazomethane, phenyl diazomethane, etc., although it is possible to introduce 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, and the product during the reaction, and the reaction time becomes longer, resulting in lowered yield (AB Taylor J. chem Soc 7020 (1965)] Preferred are derivatives that are more likely to cause substitution reactions than acetoxy groups.

The inventors of the present invention have conducted various studies 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) in a high yield. I) found that substitution reaction occurred very easily by nucleophilic compound. Until now, the 0-acylation of cephalosporadesinic acid, which has been difficult, has been achieved in good yield by cheap compound (IV), and compound (I) derived from compound (II) thus synthesized is 3-acetoxy Compared with methyl cephalosporins, substitution reaction with nucleophilic compounds proceeds rapidly.

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

Thus, R ₃ includes hydrogen or phenylacetyl, phenoxyacetyl, 5-amino-5-carboxybutyryl and its amino or carboxyl groups, but the phenylsilin and cephalosporin derivatives or Aliphatic carboxylic acid acyl groups such as formyl, acetyl, propionoyl, hexanoyl, butanoyl, heptanoyl, octanoyl, cyclopentanoyl, phenylacetyl, 2-thienylacetyl, Tetrazolylthioacetyl, tetrazolylacetyl, cyanoacetyl, phenoxyacetyl, acetoacetyl, 4-methylthio-3-oxobutyryl, 4-carbamoylmethylthio-3-oxobutyryl, α-phenoxypropy O'Neill, α-phenoxybutycoyl, 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-pyridylthioacetyl Mono-substituted aliphatic carboxylic acid acyl groups such as 2- (3-sidone) acetyl, 1-pyrazolylacetyl, 2-furylacetyl, 6- (2'-oxo-3'-methylpyridazinyl) thioacetyl, α-carboxyphenylacetyl, α-aminophenylacetyl, mandelyl, α-sulfophenylacetyl, α-sulfo- (p-aminophenyl) acetyl, phenylglasyl, 1-cyclohexenyl glycyl, tenenyl glycyl , Aromatic acyl groups such as di-substituted aliphatic carboxylic acid acyl groups such as furyl glycyl, cyclohexanedienyl glycyl, α- (β-methylsulfonylethoxycarbonyl) -aminophenylacetyl, benzoyl and p-nitrobenzoyl And heterocyclic acyl groups such as 5-methyl-3-phenyl-4-isoxazolylcarbonyl and 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl. Moreover, functional groups, such as an amino group or a (and) carboxyl group, in these acyl groups are also included. For example, as the protecting group of the amino group, for example, phthaloyl, benzoyl p-nitrobenzoyl, toluoyl, naphthoyl, p-tert-butylbenzoyl, p-tert-butylbenzenesulfonyl, phenylacetyl, benzenesulfonyl, Aromatic acyl groups such as phenoxyacetyl, toluenesulfonyl, chlorobenzoyl, acetyl, valeryl, caprylyl, n-decanoyl, acryloyl, pivaloyl, camphorsulfonyl, methanesulfonyl, chloroacetyl, etc. Esterified carboxyl groups such as aliphatic acyl groups, ethoxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, methylcarbamoyl, phenylcarbamoyl, Carbamoyl groups, such as naphthyl carbamoyl, or the same thiwa carbamoyl group, etc. are used. Moreover, as a protecting group of the organic residue heavy group carboxyl group represented by said R <^3> , and the 4th position carboxyl group of a cefe ring, for example, methyl, ethyl, tert- butyl, tert-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl , Benzhydryl, 1-indanyl, phenacyl, phenyl, p-nitrophenyl, methoxymethyl, aoxymethyl, benzyloxymethyl, acetoxymethyl, pivaloyloxymethyl, β-methylsulfonylethyl, methyl Silyl groups such as thiomethyl, trityl, β, β, β-trichloroethyl, trimethylsilyl, dimethylsilyl and the like.

Moreover, these carboxyl groups are alkali metals, such as lithium, sodium, potassium, magnesium, and alkaline-earth metals, such as calcium, for example, various amines, such as multicyclohexylamine, triethylamine, pyridine, and tributylamine, and an inorganic salt. Even if it becomes an organic salt, it can use.

와 5∼6원환을 형성할 수 있는 탄소쇄이며, 그 탄소쇄의 중간에 이중결합, 산소 혹은 황을 갖고 있어도 좋고, 또 그 탄소 상에 적당한 치환기를 갖고 있어도 좋다. 이와 같은 탄소쇄 상의 치환기로서는, 카르복실기, 할로겐, 니트로기, 예를 들면 메틸, 에틸, 프로필, 메틸렌, 에틸렌 등의 아랄킬기, 페닐, 톨릴 등의 아릴기, 또한 이들이 치환한 히드록시기 혹은 메르캅토기(예를 들면, 메톡시, p-클로로페닐티오 등)등이 사용된다. 이들의 치환기가 2이상인 경우에는 탄소쇄와 함께 환을 형성하고 있어도 좋다. 따라서, 화합물(Ⅳ)의 구체적인 예로서는, 무수 말레인산, 무수 호박산, 두수 프탈산, 무수 글루타르산, 무수 디글리코올산, 무수 티오디글리코올산, p-클로로 페닐호박산 무수물, 메틸렌 호박산 무수물, 3-니트로 무수 프탈산, 무수 트리멜리트산 등이 포함된다.In addition, the organic residue represented by X in compound (IV) is normally

And a carbon chain capable of forming a 5-6 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. As such a substituent on the carbon chain, a carboxyl group, a halogen, a nitro group, for example, an aralkyl group such as methyl, ethyl, propyl, methylene or ethylene, an aryl group such as phenyl or tolyl, and a hydroxy group or mercapto group substituted with these ( For example, methoxy, p-chlorophenylthio, etc.) are used. When these substituents are two or more, you may form the ring with a carbon chain. Therefore, as a specific example of compound (IV), maleic anhydride, succinic anhydride, dianhydride phthalic acid, glutaric anhydride, diglycolic anhydride, thiodiglycolic acid anhydride, p-chloro phenyl succinic anhydride, methylene succinic anhydride, 3-nitro anhydride Phthalic acid, trimellitic anhydride and the like.

Generally, the reaction of compound (III) with compound (IV), which is frequently used in the presence of a suitable inert solvent, is, for example, dichloromethane, chloroform, dichloroethane, ethyl acetate, acetonitrile, acetone, tetrahydro Furan, 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 (IV). However, even if compound (IV) is used excessively in consideration of shortening of reaction time, decomposition of compound (IV), and the like. good. The reaction is generally performed 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 in the case of using an alkyl metal salt as the starting material (III), the reaction is carried out by adding an equimolar amount of triethylamine hydrochloride or the like, followed by salt exchange. You can also Moreover, when raw material (III) has an unprotected amino group, it acylates by an acyl group simultaneously with the acylation of the hydroxy group of a 3rd position on this reaction condition.

The compound (II) thus obtained may be in a free form, but may be, for example, an alkali metal salt such as sodium or potassium, or an organic amine salt such as triethylamine or trimethylamine, and is provided for the cleavage reaction of the acyl group at the seventh position. .

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, et al., 35079/1975, US Pat. No. 3,632,578 and the like) to cleave the acyl group at the seventh position to induce a compound wherein R ¹ is hydrogen to prepare the target compound (I) of the present invention There is a number.

The cephalosporin compound (I) thus obtained can be isolated and purified by known means, for example, solvent extraction, liquid conversion, conversion, distillation, crystallization, recrystallization, chromatography, etc., in a free state or as a salt thereof, Alternatively, although various esters are used as antimicrobial substances themselves, they are also useful as raw material compounds for producing more powerful antimicrobial substances.

For example, the cephalosporin compound (I) is reacted with 4-halogeno-3-oxobutylylhalogenide to form 4-halogeno-3-oxobutyrylamide, followed by reacting thiourea, 7- [2- (2-imino-4-thiazolin-4-yl) acetamide], and the compound obtained by reacting this compound with a nucleophilic reagent is somewhat different depending on the kind of the third substituent. , Which shows excellent antimicrobial properties, for example, the third position is a 1-methyltetrazol-5-yl-thiomethyl group, and the like is patent useful, and about 1/5 the amount of cefazoline can be expected to have almost equal effects. Can be.

Example 1

Dichloromethane (75 ml) with 7- [D-5-phthalimido-5-carboxyvaleryl amido] -3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid (6.15 g) Suspension was added, and triethylamine (4.20 ml) was added and dissolved at 10 degrees C or less, and then N, N-dimethylaniline (10.0 ml) and dimethyldichlorosilane (4.40 ml) were added, and it stirred at 20-25 degreeC for 30 minutes. did. Then, the mixture was cooled at -30 ° C, phosphorus pentachloride (4.20g) was added, the reaction was carried out at -25 ± 2 ° C for 30 minutes, and methanol (25 ml) was added dropwise at -20 ° C or lower, and 20 minutes at -15 to -10 ° C. After the reaction, water (50 ml) was added at -15 to -10 ° C and vigorously stirred for 5 minutes. Next, the reaction solution was separated, the water layer was taken, the aqueous solution was washed with dichloromethane ethyl acetate, and the precipitated crystals were filtered out with a 40% aqueous solution of 40% carbonate and filtered. The crystals were filtered off, and the crystals were water. After sequential washing with 50% water-methanol and acetone, it was dried and 7β-amino-3- (2-carboxybenzoyloxy) methyl-3-cepem-4-carboxylic acid (3.43 g) was obtained.

IR (KBr): 3170, 1798, 1730, 1700, 1615 cm ^-1

NMR (D ₂ O + NaOD): 3.55 (2H, ABq, J = 18Hz) 4.6 ~ 5.6 (4H, m), 7.30 ~ 7.90 (4H, m)

Example 2

Deacetylcephalosporin C (13.7 g) is suspended in dimethylformamido (70 ml), concentrated hydrochloric acid (2.4 ml) is added to dissolve, triethylamine (29 ml) and N-carboethoxyphthalamide ( 8.5 g) was added, and it stirred at 30 degreeC for 50 minutes. Then, succinic anhydride (3.0 g) was added, it stirred for 30 minutes, Furthermore, succinic anhydride (0.6 g) was added, and it stirred for 1 hour.

The mixture was cooled to saturated brine (200 ml), acidified with phosphoric acid, and extracted three times with ethyl acetate. The extract was back extracted with water (150 ml) in which sodium hydrogen carbonate (8 g) was dissolved. The water layer was adjusted to pH 1.7 with phosphoric acid, extracted with a mixture of tetrahydrofuran-dichloromethane (1: 4), dried over magnesium sulfate, filtered and triethylamine (18 ml) was added and concentrated to dryness. Dichloromethane (200 ml), triethylamine (6 ml) and dimethylaniline (30 ml) were added to the residue, followed by addition of dimethylchlorosilane (21 ml), stirring for 30 minutes, cooling to -30 ° C, and phosphorus pentachloride (20 g). The mixture was stirred for 30 minutes at -30 ° C, methanol (63 ml) was added and stirred for 30 minutes, then water (120 ml) was added, the pH was adjusted to 3.0, and after cooling with ice, the precipitated crystals were filtered out to obtain 7-amino-3. -(3-carboxypropionyloxy) methyl-3-cepem-4-carnic acid (5.4 g) was obtained.

IR (KBr): 1802, 1735, 1720 (Shoulder) cm ^-1

Example 3

7β- [D-5- (pt-butylbenzamido) -5-carboxyvalerylamido] -3- [2-carboxy-6 (or 3) -nitrobenzoyloxy] methyl-3-cepem-4- Dichloromethane (60 ml) was added to carnic acid (7.26 g), and dimethylaniline (3.78 ml) and triethamine (4.20 ml) were added and dissolved under ice-cooling. Next, dimethyl chlorosilane (3.87 g) was added, and it stirred at 7-15 degreeC for 1 hour and a half. Then, it cooled to -30 degreeC, dimethylaniline (1.26 ml) and phosphorus pentachloride (4.17g) were added, and it stirred at -30--20 degreeC for 2 hours. Next, it cooled to -45 degreeC, and methanol (30 ml) was dripped at 15 minutes. After dripping, it stirred at -10-8 degreeC for 40 minutes, and water (20 ml) was dripped for 10 minutes. Subsequently, when the pH was adjusted to 3.4 with the concentrated ammonia water, almost white slurry precipitated. After 45 minutes of ice cooling, the mixture was filtered and washed sequentially with water, methanol and ether. Drying under reduced pressure over phosphorus pentachloride gave 7β-amino-3- [2-carboxy-6 (or 3) -nitrobenzoyloxy] methyl-3-cepem-4-carboxylic acid (2.93 g).

IR (KBr): 1787, 1734, 1614, 1535, 1350 cm ^-1

Claims (1)

A process for producing a cephalosporin compound represented by the following general formula (I), wherein the acyl group at the seventh position of the compound represented by the following formula (II) is cleaved to induce a compound wherein R ¹ is hydrogen.

In the above formula, R ¹ is an acyl group, X is an organic group.