KR810001202B1 - Process for preparing semi-synthetic penicillins - Google Patents

Abstract

6-Acylaminopenicillanic acid antibiotics having > 98 % purity was prepd. Thus, 6-Aminopenicillanic acid was treated with a silating agent, R1R2NCOR3 [R1 = H 1-6C alkyl or aralkyl; R2 = tri(1-6C) alkylsylyl or triarylsylyl; R3 = 1-6C alkyl, aralkyl [or R1N=C(OR2)R3[R1 = 1-6C alkyl, aralkyl, tri(1-6C)alkyl sylyl, triarylsylyl and the silayted deriv. I [R4 = H, tri(1-6C) alkylsylyl, triarylsylyl; R5 = tri(1-6C)alkylsylyl, triarylsylyl reacted with an acid chloride or protected acid chloride decompositing the sylyl group to yield the 6-acylaminopenicillanic acid.

Description

Preparation method of semisynthetic penicillin

The present invention relates to a method for preparing a semisynthetic derivative of antibiotic penicillin.

Many recipes have been suggested for preparing semisynthetic derivatives of the antibiotic penicillin, especially for ampicillin.

In general, this method is one that can be easily degraded back to its original state once acylated with 6-amino penicsilane acid or a protected derivative thereof, such as by using acyl halides to introduce the desired acyl group.

One of the better forms of derivatives of protected 6-APA is a mono or bis-silylated intermediate. The silylated intermediates not only prevent the hydrolysis of β-lactams by dissolving the penicillin compound in a neutral solvent, but also readily disintegrate after acylation. It has been widely used for many years.

For example, British Patents 959,853, 964,449 and 1,008,468 describe the use and preparation of silylated 6-APA derivatives in the preparation of antibiotic penicillin.

Practical acylation reactions using silylated intermediates proceed primarily with acid halides of carboxylic acids capable of introducing acyl in the presence of organic bases as hydrogen halide acceptors.

Important bases that have already been used or may be used for this role are amines, in particular secondary or tertiary amines such as trialkylamines, diarykyl aniline, piperidine or pyridine.

In addition, British Patent No. 959,853 also discloses a case where such an acylation reaction is carried out in a tertiary amide solvent.

Acylated antibiotic products obtained by these known methods are disadvantageous, such as being difficult to remove by a small amount of bases or solvents and frequently contaminated even after purification. It is desirable that all pharmaceutical products are manufactured and marketed in high purity. Antibiotics, even when contaminated, are often the cause of unwanted side effects under very small amounts of base.

These side effects are headache, nausea or drowsiness, so it is very important to minimize the amount of contaminants in antibiotics or to reduce the toxicity of such contaminants.

The disadvantages noted above are particularly pronounced when dialkyl aniline is used as the base. Dialkyl aniline and especially dimedyl aniline are widely used commercially available acceptors of hydrogen halides for acylation because the value of Pkb is within a narrow range to maximize the yield of antibiotic products and avoid side effects.

Small amounts of these substances, if incorporated into antibiotic products, are also highly toxic. Small amounts of dimethyl aniline, for example contaminated with antibiotic products, often cause unpleasant side effects as described above.

If we proceed with the silylation of 6-amino penicilanic acid using a silylating agent that can introduce the silyl group or several silyl groups into the 6-APA molecule and produce primary or secondary carboxamide bases, It has been found that the acylation of the silylated intermediates can proceed in the presence of primary or secondary carboxamide bases, which are halogen arc hydrogen acceptors.

Thus, our findings are characterized by the fact that after silylation, no base is added to the reaction mixture, the total number of reaction steps is reduced and the total process is made simpler.

According to this method, the compound obtained in this acylation reaction is high in yield and can be marketed by mass production, and the obtained antibiotic product has much lower contamination by base than in the case of using dimethylaniline, in particular.

Antibiotic products according to the present formulations are much less toxic than their counterparts in conventional methods, and the signs of adverse effects in antibiotic administration are not completely eliminated but are much reduced.

The present invention reacts 6-amino penicsilane acid with a silylating agent in an inert solvent to produce a silylated compound of formula (III), which is then the acid corresponding to the desired 6-acylamino group. A method of dispensing silyl groups and contacting chlorides or protected acid chlorides to produce the desired antibiotic product.

Silylation Reaction The following compound of formula (I) or (II) is used and the compound of formula (III) prepared is reacted with an acid chloride or a protected acid chloride without separation of the intermediate.

Wherein R ⁴ is hydrogen or a tri (C _1-6 ) alkylsilyl group or triarylsilyl group, R ⁵ is a tri (C _1-6 ) alkylsilyl or triallylsilyl group, and R ¹ is a structural formula ( In I) hydrogen or a C _1-6 alkyl or aralkyl group and in formula (II) a C _1-6 alkyl or C _1-6 alkyl or aralkyl or tri (C _1-6 ) alkylsilyl or triarylsilyl group , R ² is a tri (C _1-6 ) alkylsilyl or triarylsilyl group, and R ³ is an amino group substituted with a C _1-6 alkyl or aralkyl group or one or two C _1-6 alkyl groups.

- 페니글라이실 클로라이드의

-아미노그룹은 예를 들면 염산에 의해 보호시킬 수 있다.The acid chloride used is selected according to the nature of the desired 6-acylamino group. If the latter contains a reactive group, it is better to protect it during the reaction of the present invention. D (-)-in making ampicillin

Of pheniglysyl chloride

The amino group can be protected by, for example, hydrochloric acid.

The reactions according to the invention are generally applicable to the preparation of known semisynthetic penicillin antibiotics such as ampicillin, cloxacillin and dicloxacillin, whose properties are well defined in existing literature.

It can be understood that when the silylating agent of general formula (I) or (II) loses the silyl group or the like, the compound of formula (IV) is formed.

R ³ CO.NHR ¹ (Ⅳ)

Wherein R ³ is as described above and R ¹ is hydrogen, C _1-6 alkyl or an aralkyl group.

Of course, R ¹ in formula (IV) is hydrogen if the silylating agent of formula (II) wherein R ¹ is a silyl group is used.

In view of the properties of the silylating agent used in the preparation of the structural formula (III) compound, the structural formula (IV) compound as defined above, which is a residue of the silylating agent, acts as a hydrogen chloride acceptor in the acylation reaction once the silylation reaction occurs.

Therefore, an advantage of the production method of the present invention is that it does not need to be added depending on the reaction solution before the acylation reaction of the base as a hydrogen halide acceptor. It is preferred to produce compounds of formula (IV) wherein R ³ is a lower alkyl (C _1-4 ) group, in particular the silylating agents which produce R ³ is methyl, for example in particular N-trimethyl silylacetamide, N, O-bis-trimethylsilyl acetamide and N-methyl-N-trimethyl-silyl acetamide are preferred.

Particular preference is given to the silylating agent which produces the compound of formula (IV) wherein R ³ is a methyl group and R ¹ is hydrogen, ie acetamide, in particular in view of the non-toxicity of acetamide. When the silylating agent contains an aryl group, monocyclic aryl groups containing 5 to 6 carbon atoms such as phenyl groups are preferable.

The silylation reaction preferably reacts the 6-APA with the silylating agent in a warmed inert solvent for a sufficient time so as to consume enough of the silylation reaction. This reaction generally occurs within two hours.

The amount of silylating agent used depends, of course, on the number of silylating groups possessed by the various silylating agents, but it is generally preferred to use about 1 to 2 equivalents of silylating agent relative to the amount of 6-APA to be silylated.

The silylation reaction is carried out in an inert organic solvent such as halogenated hydrocarbons, aromatic hydrocarbons or ethers such as benzene, toluene, methylene chloride, ethylene chloride, chloroform or tetrahydrofuran.

Methylene chloride is the best solvent.

Once the silylation reaction is performed the solution is cooled to a temperature between + 10 ° C.-30 ° C., e.g., + 5 ° to -25 ° C., more specifically, between + 5 ° and -5 ° C., before adding the acyl halide.

Small amounts of halides are added while maintaining the temperature at or below 0 ° or below.

Once all acyl halides have been added, it is desirable to maintain the temperature relatively rapidly during the acylation reaction, typically for 30 minutes to 3 hours, for example for 2 hours. The degree of acylation can be controlled by measuring the amount of starting material remaining by thin layer chromatography.

In general, in the acylation step, it is preferable to use a chemical equivalent of acyl halide, i.e., 1 equivalent or less, usually 1.0 equivalent, relative to the amount of silylated 6-APA.

The compound remaining in the silylation reaction is preferably present in an amount of 1 to 2 equivalents relative to the equivalent of silylated 6-APA.

After the completion of the acylation reaction confirms that all of the starting materials present are consumed, the resulting solution is treated with compounds containing active hydrogens such as water, acidic or alkaline water, alcohols or phenols, and then the silyl groups present in the penicillin reaction product. Remove it. Water is preferred as the releasing agent used for this purpose.

Penicillin antibiotics such point coins the reaction mixture is diluted with a base as in the case of ampicillin set the _P H or clock fact Lin and D. clock fact form a salt thereof in an organic solvent as in the case of the lean or by precipitation and the precipitation It was recovered and dried in a conventional manner. If it is desired to form salts of penicillin antibiotics, a suitable base is added to form a salt, for example an alkali metal alkanoate such as sodium 2-ethyl hexanoate.

The preparation according to the invention particularly produces ampicillin, ie 6- (D-2-amino-2-phenylacetamido) -2,2-dimethylphenam-3-carboxylic acid, in the form of a hydrate (eg trihydrate) or anhydride. Applicable to

-카복시벤질 페니실린 에스텔류, 옥사실린, 플루오토클록사실란과 메타실린이 있다.Other semisynthetic penicillin antibiotics that can be prepared according to the methods of the present invention include clockxacillin, dicloxacillin,

Carboxybenzyl penicillin esters, oxacillin, fluorotoxaxasilane and methacillin.

The present invention will now be described in more detail by the following examples, which do not limit the invention.

In the examples, the properties and purity of the final product are determined by standard test methods, including photometric, spectroscopic, acidic, and biological tests. The spectroscopic analysis used for ampicillin analysis is described on page 30 of the British Pharmacopoeia (1973, HMSO), and the biological test methods used are described in Appendix 102 to 104 of the British Pharmacopoeia (1973, HMSO). The pH measurement method used for the analysis of cloxacillin and dicloxacillin is described on page 81 of the British Pharmacopoeia (1973, HMSO).

Moisture content analysis for clocksacillin and dicloxacillin is examined by Karl Fischer analysis, and in the case of ampicillin trihydrate, the weight loss is determined by the above method or by heating to anhydrous compound.

The purity of the ampicillin product is determined after measuring the water (hydrate) content of the resulting impicillin product.

In the examples, the specific lightness of ampicillin trihydrate was measured in water (C = 0.25%), and the specific lightness of coloxacillin and dicoloxacillin was measured in water (C = 1.0%), in this case at all 20 ° C. do.

The specific lightness of ampicillin anhydride is [α] ²⁰ _D = 280 ° to + 300 ° (C = 0.25 in water) and the specific light intensity of coloxacillin as sodium salt monohydrate is [α] ²⁰ _D = + 156 ° + 146 ° (C = 1 in water) is described in British Pharmacopoeia (1973, HMSO). The specific light intensity of dicoloxacillin is described in the Merck index (8th edition) as [α] ²⁴ _D = + 134 ° (C = 0.4 in water).

Example 1

[Preparation of 6- (D-2-ami-2-phenylacetamido) -2,2-dimethylphenam-3-carboxylic acid trihydrate using N-trimethylsilinacetamido as a silylating agent.]

52.5 g (0.400 mole) of N-trimethylsilyl acetamide are added to the suspension of 43.2 g (0.200 mole) of 6-APA suspended in 350 ml of methylene chloride with stirring. The mixture is allowed to warm to 40 ° C. for 120 minutes before cooling to −25 ° C. and many acetamides precipitate out during cooling. 43.3 g (0.200 mol, purity 95.0%) of D (-)-α-phenylglycyl-chloride hydrochloride was then added at -25 ° C and the temperature was gradually -5 over a total of 90 minutes after starting to add acid chloride hydrochloride Increase to ° C.

450 ml of water is added, followed by precipitation of ampicillin trihydrate by adjusting _P H to 4.5 with dilute ammonia water.

After stirring for 60 minutes at +10 ° C / +15 ° C, the mixture was filtered and washed with 2 x 75 ml of water and 3 x 125 ml of acetone and the solid material was dried at +35 ° C / +40 ° C.

Yield: 84.0 ± 1.0%

Specific light intensity: + 296 ° ± 1 ° (256 ° ± 1 ° for hydrate)

Spectroscopic analysis: 99.0 ± 0.5% (Ampicillin purity as hydrate is 85.7% ± 0.5%)

Moisture Content: 13.4-14.0%

Example 2

[Preparation of 6- (D-2-amino-2-phenylacetamido) -2,2-dimethylphenam-3-carboxylic acid trihydrate using N, O-bis-trimethylsilyl acetamide as a silylating agent.]

48.9 ml (0.200 mole) of N, O-bis-trimethyl-silylacetamide is added to the suspension of 43.2 g (0.200 mole) of aminophenic silane acid suspended in 350 ml of methylene chloride. The mixture is allowed to warm to + 40 ° C. over 120 minutes, then cooled to −25 ° C. and 43.3 g (0.200 mole, purity 95.0%) of D (−)-α-phenyl-glycyl chloride hydrochloride are added followed by the next step. Is carried out as described in Example 1.

Yield: 80.0% Spectroscopy: 98.7%

Specific luminance: + 296 ° Moisture content: 13.9%

Example 3

[6- [3- (2-chlorophenyl) -5-methyl-4-isoxazolecarboxamido] using N-trimethylsilyl acetamide as the silylating agent] -2,2-dimethylphenam-3-carboxylate (Cloxacillin) Preparation of Sodium Monohydrate]

52.5 g (0.400 mole) of N-trimethylacetamide are added to the suspension of 43.2 g (0.200 mole) of 6-aminophenicylanic acid suspended in 350 ml of methylene chloride.

The mixture is allowed to warm to + 40 ° C. over 120 minutes, then cooled to −25 ° C., while acetamide precipitates during cooling.

51.2 g (0.200 mole) of 3- (2-chlorophenyl) -5-methylisoxazolyl-4-carbonylchloride is added and the temperature is allowed to warm to 60 ° C. over a total of 60 minutes below the beginning of addition of the acid chloride. .

175 ml of methyl isobutyl ketone and 300 ml of water are then added, the separated layer is separated, the water layer is discarded, the organic layer is washed again with 300 ml of water and the water layer is discarded.

The organic layer is treated with anhydrous sodium for 30 minutes, after which the dehydrating agent is filtered off and washed with 175 ml of methyl isobutyl ketone and combined with the main organic layer. Thereafter, a solution of 1N sodium 2-ethylhexanoate dissolved in 200 ml of methyl isobutyl ketone is added to the combined organic layers to precipitate the sodium salt monohydrate of coloxacillin.

After stirring for 60 minutes, the crystalline white solid was filtered off, washed with 3 × 150 ml of acetone and dried in a vacuum oven at + 35 ° C./40° C.

Yield: 84.6% Specific Luminance: 163 °

Acidity Analysis: 98.8% (Sodium Salt Monohydrate) Water Content: 3.9%

Example 4

6- [3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolecarboxamido] -2,2-dimethylphenam-3-carboxyl using N-trimethylsilyl acetamide as a silicide Preparation of Latex (Dicloxacillin) Sodium Monohydrate 52.5 g (0.400 mole) of N-trimethyl silylacetamide was suspended in a suspension of 43.2 g (0.200 mole) of 6-aminophenicylic acid suspended in 350 ml of methylene chloride. And add.

The mixture is allowed to warm to + 40 ° C. over 120 minutes and then cooled to −25 ° C. while acetamide is precipitated during cooling.

58.1 g (0.200 mole) of 3- (2,6-dichlorophenyl) -5-methylisoxazolyl-4-carbonylchloride was added at -25 ° C and 0 ° C over a total of 60 minutes since the acid chloride was added. Increase the temperature with. 175 ml of methyl isobutyl ketone and 300 ml of water are added and the separated layer is separated. Discard the aqueous layer, wash the organic layer again with 300 ml of water, and discard the aqueous layer again.

The organic layer was treated with anhydrous sodium sulfate for 30 minutes, after which the dehydrating agent was filtered off, 175 ml of methyl isobutyl ketone and 300 ml of water were added and the separated layer was separated. Discard the aqueous layer, wash the organic layer again with 300 ml of water, and discard the aqueous layer again.

The organic layer is treated with anhydrous sodium sulfate for 30 minutes, after which the dehydrating agent is filtered off and washed with 175 ml of methyl isobutyl ketone and the wash is combined with the main organic layer.

To a combined organic layer of sodium salt monohydrate of dicholoxacillin was added a solution of 1N sodium 2-ethyl hexanoate dissolved in 200 ml of isobutyl ketone and precipitated.

After stirring for 60 minutes, the crystalline white solid was filtered, washed with 3 x 150 ml of acetone and dried in a vacuum oven at +35 ° C / +40 ° C.

Yield: 81.8% Specific Luminance: 139 °

Acidity analysis: 98.6% (as sodium salt monohydrate) Moisture content: 3.8%

Example 5

[Preparation of 6- (D-2-amino-2-phenylacetamido) -2,2-dimethylphenam-3-carboxylic acid trihydrate using N-trimethylsilyl acetamide as a silylating agent]

43.2 g (0.20 mole) of 6-amino penicsilane acid, 350 ml of methylene chloride and 52.5 g (0.40 mole) of N-trimethylsilylacetamide mixture are heated and refluxed for 2 hours.

The temperature of the mixture is then lowered to -5 ° C and 43.2 g (0.2 mol, purity 95%) of D-(-)-alpha -phenylglycyl chloride hydrochloride is added while maintaining below 0 ° C.

The temperature is reduced to 0 ° C from 0 ° C to + 10 ° C for an hour and a half and 450 ml of water is added. Ampicillin trihydrate was added with ammonia water to lower the _P H to 4.5 to precipitate and the crystalline product was filtered off, washed with water and acetone and dried.

Yield: 82.7% Specific Luminance: + 296 °

Spectroscopic Analysis: 99.0% Moisture Content: 13.4%

Biological test: 97.9%

Example 6

[Preparation of 6- (D-2-amino-2-phenylacetamido) -2,2-dimethylphenam-3-carboxylic acid trihydrate using N-methyl-N-trimethylsilylacetamide as a silylating agent]

58.1 g (0.40 mole) of N-methyl-N-trimethylsilyl acetamide are added to a suspension of 43.2 g (0.7 mole) of 6-aminophenicylic acid suspended in 350 ml of methylene chloride with stirring.

The mixture is heated at 40 ° C. for 120 minutes and then cooled to −25 ° C.

The subsequent method is carried out as described in Example 1.

Yield: 79.3% Spectroscopy: 97.6%

Specific Luminance: + 292 ° Moisture Content: 13.7%

Claims (1)

The 6-aminophenic silane acid is reacted with a silylating agent of the following structural formula (I) or (II) in an inert solvent to produce a silylated compound of the following structural formula (III), after which the desired 6-acyl is not isolated from the intermediate. A method of preparing a 6-acylamino-phenicylic acid antibiotic product by decomposing the silyl group by contact with an acid chloride or protected acid chloride corresponding to an amino group.

Wherein R ¹ is hydrogen or C _1-6 alkyl or aralkyl group in formula (I) or C _1-6 alkyl or aralkyl or tri (C _1-6 ) alkyl silyl or triaryl in formula (II) Is a silyl group, R ² is a tri (C _1-6 ) alkylsilyl or triarylsilyl group, R ³ is an amino substituted with a C _1-6 alkyl or aralkyl group or one or two C _1-6 alkyl groups And R ⁴ is hydrogen or a tri (C _1-6 ) alkylsilyl group or triarylsilyl group, and R ⁵ is a tri (C _1-6 ) alkylsilyl group or triarylsilyl group.