KR790001713B1 - Process for the preparation of -carboxy-3-thienyl methyl acetoamido penicillins - Google Patents

Abstract

Title compds. (I; M = H, alkali metal atom sodium Potassium, H+NR3 (R3 = H, C1-3 alkyl); R =C2-5 lower alkyl) were prepd. Thus, one carboxylic group of II was protected with N, N'-bis-trimethlsilyl imidazolidinone or amine salt to give III (R1 = trimethylsilan, C2-5 t-amine), and then the other carboxylic group was reacted with acyltalide to give (IV; R2 = (R3R4R5), -OC2H5, (R4,R5 = H, C2-5 t-amine) followed by reaction with 6-amino-peni- cillanic acid salt to give I.

Description

Method for preparing alpha-carboxy-3-chienylmethyl acetoamido peniclanate

The present invention relates to a method for preparing penicillin derivative of the following structural formula (I).

NR₃이고, R는 탄소수 2-5인 저급알킬기이다.Wherein M is hydrogen or sodium potassium metal alkali element or organic amine H

NR ₃ and R is a lower alkyl group having 2-5 carbon atoms.

Among the preparation methods for the salts of known alpha-carboxy-3-chienylmethylacetoamidophenylanic acid are described in detail in U.S. Patent 3853849, German Patent 2152821, British Patent 1311454, 1304202 and the like. These methods are generally prepared by protecting one carboxy group of 3-chienyl malonic acid with a suitable substance, and the other carboxy group is made of chloride using thionyl chloride, etc. to proceed with acylation. Either by reacting with aminophenic silane acid, or by making one carboxy group of 3-chienyl malonic acid with chloride under ether, and then reacting the other carboxy group with 6-aminophenic silane directly without protection. .

However, these methods are generally technical difficulties such as the reaction conditions are very demanding in the process of making the monoester to protect one carboxy group of 3-chienyl malonic acid, the reaction time is long, and the intermediates of the monoester must be separated. In addition, in order to separate the disodium salt in the crystallization process, since the solvent conditions or the reaction conditions must be carried out at a high temperature, the purity and yield were poor. In another method, since only one carboxylate is directly reacted with 6-aminophenic silane in chloride, the other carboxyl group becomes unstable, resulting in increased production costs such as manufacturing cost increase due to the complexity of the reaction process due to many technical difficulties in manufacturing. Elevation has been a direct cause.

In the present invention, one of the carboxy groups of the 3-thienyl malonic acid of the structural formula (II) in order to compensate for these disadvantages by protecting with N, N'-bis-trimethylsilyl imidazolidinone or an amine salt III) and the other carboxy group is reacted with an acyl halide to react the acid anhydride compound of formula (IV) with 6-aminophenicylate salt of formula (V) in an organic solvent as an intermediate. Alpha-carboxy-3-chienylmethylacetoamido peniclanic acid, the target compound of formula (I), was prepared.

또는 -OC₂H₅이며 R₃, R₄, R₅은 동일하거나 상이한 것으로서 수소 또는 탄소수가 1-3인 알킬기이다.Wherein M is as defined above, R ₁ is trimethylsilane or tertiary amine having 2-5 carbon atoms and R ₂ is

Or —OC ₂ H ₅ and R ₃ , R ₄ , R ₅ are the same or different and are hydrogen or an alkyl group having 1-3 carbon atoms.

In more detail, the carboxyl group of 3-chienyl malonic acid attracts electrons, so that one carboxy group can more easily ionize protons.

However, the other side of the carboxy group is more difficult to ionize the proton because it has to have two of the same charges very close. The difference between the first and second ionization constants of the dicarboxylic acid depends on the distance between the two carboxyl groups and increases with increasing distance. Here, in the carboxy group protecting group, the protecting group of the present invention, in particular, N, N'-bis-trimethylsilylimidazolidinone or an organic amine, has an excellent protective effect on one carboxyl group of the dicarboxylic acid.

First, the characteristics of N, N'-bis-trimethylsilylimidazolidinone are made in the presence of base when reacting with trimethylchlorosilane in 2-imidazolidinone. The two amide hydrogens of 2-imidazolidinone Since it is weakly acidic, trimethylchlorosilane base is easily reacted, and this compound is substituted with hydrogen of one carboxy group of 3-chienyl malonic acid to become 2-imidazolidinone and carboxy group is easily acylation.

This reaction is because the reactivity of the trimethylsilyl group is weakened so that only the hydrogenation of one carboxy group is substituted.

The protecting group of organic amines is a non-covalent pair of electrons in the nitrogen atom of the amine, which is most important for the reactivity of the amine.

This electron pair explains the basicity of the amine and explains how the amine acts as a nucleophile.

Next, the other carboxy group is made of acyl halide and acid anhydride, and then reacted with 6-aminophenicylanate without separating it, followed by acid hydrolysis in aqueous solution to separate the organic layer. -It acts as an alkali metal salt of ethyl nucleic acid, etc., and disperse | distributes to ethyl acetate, and the objective alpha-carboxy-3- chienyl methyl acetoamido phenysilane acid salt of the present invention is easily obtained in high purity and a high yield in a short time. Can be.

Hereinafter, the method of the present invention will be described in detail by way of examples.

Example 1

Add 13.76 grams of 2-imidazolidinone to 100 milliliters of methylene chloride, add 3 milliliters of triethylamine, and add 39 milliliters of trimethylchlorosilane, and reflux for 3 hours to obtain N, N'-bis-trimethylsilyl imide. Obtain dazolidinone.

While stirring the reaction, the temperature was kept at room temperature, 22.32 grams of 3-chienyl malonic acid was added, and the mixture was refluxed for 2 hours. Then, 14.7 grams of pibaryl chloride was added while maintaining the temperature at -10 ° C, and the reaction was carried out at 0--5 ° C for 1 hour. This results in acid anhydrides.

21.6 grams of 6-aminophenicylanic acid is added to 80 ml of isopropanol and 20 ml of distilled water, the temperature is kept between -5 and -10 ° C, 18.8 ml of triethylamine is added and stirred until complete solution is obtained. This solution is added to the acid anhydride solution prepared above at -30 ~ -25 ℃ for 30 minutes, and reacted at -15 ~ -20 ℃ for two hours, 50 ml of distilled water is added and adjusted to pH 1.0 with 1: 1 hydrochloric acid.

The organic layer was separated, dehydrated with magnesium sulfate, 43 milliliters of sodium 2-ethylhexanoate (43% methyl isobutyl ketone solution) was added thereto, stirred for 1 hour, dispersed in 200 milliliters of ethyl acetate, stirred for 2 hours, and left at 0 ° C. for 4 hours. Filtration and drying at 40 ° C yielded 33 grams (80%) of the desired product.

에서 1,615㎝^-1, 1,400㎝^-1, 1,300㎝^-1, 1,250㎝^-1, 760㎝^-1특히 1,770㎝^-1(β-락람) 1,695㎝^-1(아미드)의 특징적인 피크를 찾을 수 있었다.The compound had S content of 14.8%, 101-104% by chemical analysis and 95-98% by iodine assay.

In ^{1,615㎝ -1, 1,400㎝ -1, 1,300㎝ -1} , 1,250㎝ -1, 760㎝ -1 was found particularly characteristic peaks of 1,770㎝ ^-1 (β- rakram) 1,695㎝ ^-1 (amide) .

Example 2

9.3 grams of 3-chienylmalonic acid is added to 100 milliliters of methylene chloride, and 8.0 grams of triethylamine are added to give a clear solution.

To this, 6.4 milliliters of pivalyl chloride was added, and the temperature was adjusted to -5-0 占 폚 and allowed to react for 1 hour.

30 milliliters of isopropanol was added to 8.6 grams of 6-amino penicsilane acid, 7.5 milliliters of distilled water was added, and 7.5 milliliters of triethylamine was added by stirring the temperature to −10 ° C. to obtain a clear solution.

This solution is added to an acid anhydride solution at -25 占 폚 for 20 minutes and reacted at -25 ~ -30 占 폚 for 2 hours.

After adding 50 milliliters of distilled water to the reaction solution, the pH was adjusted to 1.0 with 1: 1 hydrochloric acid and stirred to separate the organic and water layers.

The organic layer was dehydrated with magnesium sulfate, 34 milliliters of sodium 2-ethylhexanoate (43% methyl isobutyl ketone solution) was added thereto, stirred for 15 minutes, dispersed in 250 milliliters of ethyl acetate, stirred for 2 hours, and stirred at 0 DEG C for 4 hours. Leave it.

은 1,775㎝^-1(β-락탐), 1,695㎝^-1(아미도) 1,615㎝^-1, 1,400㎝^-1, 1,300㎝^-1, 1,250㎝^-1, 760㎝^-1등에서 특징적인 피크를 찾을 수 있었다.Filtration yielded 13.1 grams (76.6%) of the desired compound. The compound was almost white crystalline powder, 102-106% by chemical analysis. The content of S was 15.0% and 94-98% by iodine analysis titration.

It is 1,775㎝ ^-1 (β- lactam), 1,695㎝ ^{-1 (amido) 1,615㎝ -1, 1,400㎝ -1, 1,300㎝} -1, 1,250㎝ -1, to find the characteristic peaks, etc. 760㎝ ^-1 there was.

Claims (1)

As described above in the text, one of the carboxy groups of 3-thienyl malonic acid of the following structural formula (II) is protected by using N, N'-bis-trimethylsilylimidazolidinone or an amine salt to give a compound of formula (III) The other carboxy group is reacted with an acyl halide to make an intermediate of the acid anhydride of formula (IV) and reacted with 6-aminophenicylanate in an organic solvent to alpha-carboxy- of the target formula (I) of the present invention. Method for preparing 3-chienylmethylacetoamidophenylanate.

Wherein M is hydrogen or an alkyl potassium metallic element sodium potassium or an organic amine H

NR ₃ and R is a lower alkyl group having 2-5 carbon atoms. R ₁ is trimethylsilane or tertiary amine having 2 to 5 carbon atoms, R ₂ is

Or —OC ₂ H ₅ , wherein R ₃ , R ₄ , R ₅ are the same or different and are hydrogen or an alkyl group having 1-3 carbon atoms.