KR800000100B1 - Process for preparing -carboxy benzyl acetoamido penicillanic salts - Google Patents

Abstract

Title compds. ≮I; M = Na, K, organic amine (H NR3), R = C2-5 alkyl) were prepd. by the reaction of 6-aminopenicillanic acid with anhydride(IV) in organic solvent. Thus, anhydride(IV) was prepd. by the reaction of acylhalide and synthetic intermediate(III) obtained from phenylmalonic acid with N, N' -bistrialkylsilylimidazolidinone (II), and anhydride(IV), R1,R2,R3 are same or not, C1-3 alkyl, R4 - R5R6R7C or C2H5O-, R5,R6R7 are same or not, C1-3 alkyl) was reacted with 6-aminopenicillanic acid in organic solvent to give I.

Description

Method for preparing alpha-carboxybenzyl aceto amido peniclanate

The present invention relates to a method for preparing a compound represented by formula (I) which is a salt of alpha-carboxybenzyl aceto amido peniclanic acid which is a waste nicillin derivative.

In the above formula

이고 R는 탄소수 2-5인 알킬기이다.M is an alkali element, sodium or potassium, or an organic amine

And R is an alkyl group having 2 to 5 carbon atoms.

Conventionally known methods for the preparation of compounds of formula (I) are described in US Pat. Nos. 3,492,291, 3,282,926 and 3,142,673, and the like.

US Pat. No. 3,492,29l discloses monobenzylphenylmalonic acid protecting one carboxy group with benzyl alcohol to protect the carboxy group of phenylmalonic acid as starting material, and the other carboxyl group using thionyl chloride. It was made into an acid chloride and reacted with a sodium salt of 6-aminophenicylanic acid to prepare a sodium salt of alpha- (benzyloxycarbonyl) -benzylphenicillin, and then the salt was again used with palladium charcoal. After removing the ester, which was used to prepare alpha-carboxyphenicillin, alpha-carboxybenzyl acetoamido peniclanate was obtained with the dinathorium salt of peniclanic acid. The yield was as low as 32% and the purity was 58%.

US Pat. No. 3,142,673, on the other hand, reacts the starting material phenylmalonic acid with an excess of thionyl chloride to convert it into two carboxy chlorides, and then reacts with a sodium salt of 6-aminophenicillin to produce benzylphenicillin, an alpha chloride acid chloride. An aqueous solution of caustic soda was treated with alkali and extracted with an organic solvent to prepare a mononathorium salt of alpha-carboxy benzyl penicillin. Since there is no mention of yield and quality at this time, the exact yield or quality was unknown.

In addition, U.S. Patent No. 3,282,926 is also similar to U.S. Patent Nos. 3,492,291 and 3,142,673, described above, in which a carboxy group of phenylmalonic acid is used as an ester, and the other group of carboxy group is prepared as an acid chloride. The reaction was carried out to prepare a dinatorium salt of alpha-carboxy benzylaceto amido peniclanic acid.

U.S. Patent No. 3,647,783 describes a process for preparing derivatives of formula (I) wherein phenylmalonic acid is made of esters to protect one carboxy group, and the other carboxy group is reacted with a salt of 6-aminophenicylanic acid as an acid chloride. Alternatively, phenylmalonic acid was prepared from phenylchloroketene or phenylcarboxy ketene and reacted with a salt of 6-amino penicsilane acid to prepare an alpha-carboxy ester derivative.

Applicant's patent application No. 45 is a method for preparing a salt of alpha-carboxy-3-chienylmethylaceto amidopheniclanic acid, wherein one carboxy group of 3-chienyl malonic acid is protected with a silane or amine salt. The other carboxy group was then made into an acid anhydride and reacted with the amine salt of 6-aminophenicylanic acid to prepare the desired product.

Thus, in order to protect the carboxy group of the starting material phenylmalonic acid, esters or chlorides are used to prepare the other carboxy group with acid chloride, in which case the intermediate must be separated and 6-aminophenic silane acid. When reacted with the salt of benzyl penicillin of mononatorium is produced, and the mononatorium salt was separated to obtain the target of the dinatorium salt, but these methods are yielded in the process of protecting one carboxy group of phenylmalonic acid with a monoester. It is not good and the synthetic intermediates have to be separated, and the manufacturing cost is increased due to the long production reaction time, which has been a cause of raising the production cost.

The present invention uses N, N'-bistri alkylsilyl imidazolidinone represented by Structural Formula (II) for special protection of one carboxy group of phenylmalonic acid in order to solve this disadvantage, and the synthetic intermediate Without separating the compound represented by the structural formula (III), reacted with an acyl halide to form an acid anhydride represented by the structural formula (IV), and reacted with 6-aminophenic silane acid in an organic solvent to obtain the structural formula ( I) alpha-carboxybenzylaceto amido peniclanate was prepared.

In the above formula

R ₁ , R ₂ , and R ₃ are the same alkyl group or different alkyl groups, each having 1 to 3 carbon atoms.

또는 C₂H₅O-이며 R₅,R₆,R₇은 동일하거나 상이한 것으로서 수소 또는 탄소수가 1-3인 알킬기 이다.R ₄ is

Or C ₂ H ₅ O— and R ₅ , R ₆ , R ₇ are the same or different and are hydrogen or an alkyl group having 1-3 carbon atoms.

In more detail, the carboxyl group of phenylmalonic acid is preferably protected by protecting one carboxy group of phenylmalonic acid with N, N'-bistrialkylsilyl imidazolidinone of the formula (II). It is easy to pull so that one carboxy group can easily ionize protons. On the other hand, the carboxy group on the other side becomes more difficult to ionize protons because they must have two equal charges very close together. The difference between one carboxylic acid and the second carboxylic acid ionization constant of dicarboxylic acid of phenylmalonic acid depends on the distance between the two carboxyl groups and increases with increasing distance.

The chemical properties of N, N'-bistrialkylsilyl imidazolidinone used in the present invention are prepared by reacting 2-imidazolinone in the presence of trialkylchlorosilane and base. Hydrogen is weakly acidic, so trialkylchlorosilane reacts easily in the presence of a base.

This compound is substituted with hydrogen of one carboxy group of phenylmalonic acid so that the carboxy group can be easily silized and protected to give structural formula (III), and 2-imidazolidinone is removed.

This reaction is because the reactivity of the trialkylsilyl group is weakened to cause a substitution reaction with hydrogen of one carboxy group. The other carboxy group is reacted with an acyl halide to form an acid anhydride structural formula (IV), without being separated and reacted with 6-aminophenic silane acid to hydrolyze the acid in an aqueous solution to separate the organic layer, and to control the organic layer moisture. By dispersing in ethyl acetate by acting as an alkali metal salt, the target product of the present invention was obtained in high purity and high yield within a short time.

The method of the present invention will be described in detail with reference to the following Examples.

Example 1

Ethylphenyl Acetate Manufacture

When 68 milliliters of concentrated sulfuric acid is added to 153 milliliters of ethyl alcohol, the temperature of the reactant is increased. Add 75 grams of benzylcide to reflux for 8 hours, cool, and add 350 ml of distilled water.

The organic layer is separated, the aqueous layer is extracted with 75 ml of ether, combined with the organic layer, and dehydrated with magnesium sulfate for 30 minutes.

After filtration, the ether solution was removed under reduced pressure and distilled under reduced pressure (116-118 ° C./20 mm) to obtain 90 grams (85.6%) of ester.

This compound was a colorless liquid, and as a result of analysis, bp was 225-229 degreeC (mainly 228 degreeC).

Example 2

Dimethylphenyl malonic acid

When 11.5 grams of metallic sodium is added to 250 ml of ethyl alcohol, the reaction is exothermic and the temperature is increased.

Cool the temperature to 60 ° C, add 73 grams of dimethyl oxalate, and add 87.5 grams of pure ethyl phenyl acetate to precipitate within 4-7 minutes. This precipitate is dispersed in 400 milliliters of ether and filtered to yield ethylphenyl acetate.

The precipitate is added to a diluted sulfuric acid solution (14.5 ml of concentrated sulfuric acid and 250 ml of distilled water) and stirred to separate the organic and aqueous layers.

The aqueous layer was extracted three times with 50 ml of ether, the ether and the organic layer were combined, the water was dehydrated with magnesium sulfate, the ether was removed under low pressure and the impurities were removed under high pressure and the temperature was maintained at 175 ° C for 6-7 hours. Decarbonyl reaction.

Distillation of the contents under reduced pressure (165-166 ° C./15 mm) yielded 95 grams (75.4%) of ethylphenylmalonic acid.

This compound was a colorless liquid, and elemental analysis showed C 66.7% and O: 0.28%.

Example 3

Phenylmalonic acid

Add 46.1 grams of potassium hydroxide to 43.5 grams of diethylphenyl malonic acid and slowly raise the temperature to allow potassium hydroxide to melt and visualize precipitation. The reaction is exothermic and the temperature rises.

20 ml of ethanol are added to allow the reaction to proceed completely and to cool the reaction to room temperature. 80 milliliters of distilled water was added to the precipitate, and after complete dissolution, the pH was adjusted to 1.0 with 1: 1 hydrochloric acid and the aqueous layer was extracted three times with 50 milliliters of ether.

When the ether layers were combined and dehydrated with magnesium sulfate, the ether was removed under low temperature and reduced pressure to obtain a pale yellow precipitate. The precipitate was dispersed in benzene to obtain 25 grams (75%) of phenylmalonic acid.

This compound was nearly white crystal and had melting point of 151-153 ℃. Purity was 97-99% by chemical analysis. Elemental analysis showed C: 60.5% O: 34.5%.

Example 4

Preparation of salts of alpha-carboxy benzylaceto amido peniclanic acid

To 200 milliliters of methylene chloride, add 5.5 grams of 2-imidazolidinone and 3 milliliters of toricylamine, add 16.9 milliliters of trimethylchloro-silane, and reflux for 4 hours.

After cooling, 21.6 grams of phenylmalonic acid was refluxed for 4 hours, and after cooling to -20 -25 ° C, 14.5 milliliters of pivalyl chloride was added and reacted at 0?

50 milliliters of isopropanol and 20 milliliters of distilled water are added to 21.6 grams of 6-aminophenicsilane acid, and 16.7 milliliters of triethylamine is completely dissolved at a temperature of -10-5 占 폚.

The temperature of the 6-aminophenic silane acid solution was adjusted to -20 ° C and dropped into the acid anhydride solution for 20 minutes. The temperature is kept at -25--30 ° C and reacted for 2 hours.

L00 ml of distilled water was added and the pH was adjusted to 1.0 with 1: 1 hydrochloric acid. After stirring, the organic layer was separated. The organic layer was washed with distilled water, dehydrated with magnesium sulfate, and then 2-ethyl hexanoate was added to the filtrate. Stir for 15 minutes and disperse in 350 milliliters of ethyl acetate. Then, the mixture is stirred for 2 hours and left at 0 ° C for 4 hours to obtain good crystals. Filtration and drying at 40 ° C. yield 31.5 grams (74.6%) of the desired product.

은+178-182°였으며 화학적 분석으로 101-105%였고, 요오드법 분석으로 94-97%였으며 S함량은 6.7%였으며,

에서는 1,775㎝^-1(β-락탐)1,655(아미드) 1,600㎝^-1, 1,500㎝^-1,1,450㎝^-1, 1,370㎝^-1, 1,300㎝^-1, 1,230㎝^-1, 1,100㎝^-1등에서 특징적인 피크를 찾을수 있었다.This compound is a white crystalline powder

Silver was + 178-182 °, 101-105% by chemical analysis, 94-97% by iodine method analysis, S content was 6.7%.

The features, etc. 1,775㎝ ^-1 (β- lactam), 1655 ^{(amide) 1,600㎝ -1, 1,500㎝ -1, 1,450㎝} -1, 1,370㎝ -1, 1,300㎝ -1, 1,230㎝ -1, 1,100㎝ -1 I could find the peak.

Claims (1)

As described above in the text, one carboxy group of phenylmalonic acid is protected using N, N'-bistrialkylsilyl imidazolidinone of the formula (II) to form a compound of formula (III), and the other carboxy group is Reaction with an acyl halide to form an acid anhydride of formula (IV) and reaction with 6-aminophenic silane in an organic solvent to prepare a salt of alpha-carboxy benzylaceto amido penicilanic acid of formula (I) .

In the above formula M is an alkali element, sodium or potassium, or an organic amine

R is an alkyl group having 2 to 5 carbon atoms, R ₁ R ₂ R ₃ is the same alkyl group or a different alkyl group, and is an alkyl group having 1-3 carbon atoms. R ₄ is

Or C ₂ H5O, R ₅ , R ₆ and R ₇ are the same or different and are hydrogen or an alkyl group having 1-3 carbon atoms.