DE2053214A1 - Process for 6-(d(-)-alpha-amino-phenylacet- - amido)-penicillanic acid - Google Patents

Abstract

6-APA is acylated with D(-)alpha-aminophenylacetic acid protected by reaction with a beta-keto ester, a beta-dicarboxylic acid or O-nitrophenylsulphenyl chloride in an organic solvent at pH 8-10 at 20-80 degrees C. As the product hydrolysed in aq. acetone pref. at pH 2-3.5, evapd., the residue extd. with an organic solvent, pref. BuOAc and the title product (I) isolated. (I) is a broad spectrum anti-biotic and is produced by a simple procedure without isolation of intermediates.

Description

PROCESS FOR THE PREPARATION OF 6- [D - @ (-) α-AMINOPHENYL-AZETAMIDO] -PENICILIC ACID The present invention relates to a method for producing semi-synthetic Penicillins, in particular a process for the production of aminophenylazetamido] -penicillanic acid, which has a broad spectrum of antimicrobial activity and during treatment diseases caused by both gram-positive and gram-negative microorganisms are caused, is used.

BS are processes for the preparation of nophenylazetamido] -penicillanic acid of the following formula known, for example a process for the preparation of 6- [D - (-) α-aminophenylazetamido] -penicillanic acid, which consists in that the sodium salt of D (-) α-aminophenylacetic acid with β-dicarbonyl compounds, for example acetyl acetone, or with ß-keto esters, for example ethyl acetoacetate, boils in methanol. The sodium salt of N-substituted D (-) α-aminophenylacetic acid obtained is treated in anhydrous acetone with alkyl chlorocarbonate in the presence of catalytic amounts of some bases (N, N-dimethylbenzylamine, methylmorpholine, etc.), and then aqueous acetone solution of 6-aminopenicillanic acid / salt is added. After completion of the acylation, the acetone is distilled off and the remaining reaction mass is treated with hydrochloric acid at a pH of 2.0 in the presence of methyl isobutyl ketone. The aminophenylazetamido] penicillanic acid, which contains 80-85 percent pure anhydrous penicillin with a yield of 66-72 percent by weight of theory, is then separated from the aqueous solution at a pH of 6-6.4. (British Patent No. 991586).

A disadvantage of the process mentioned is the complexity of the Technology, due to the additional stage for the preparation of the sodium salt of the α-aminophenylacetic acid, as well as the implementation of the hydrolysis under unfavorable -gen conditions in heterogeneous medium using @ethylisobutylketone as an additional solvent.

Processes are also known by which the α-aminophenylacetic acid with o-nitrophenylsulfenyl thiocyanate in 50% dioxane at a pH of 7.0, then with the obtained α-N- (nitrophenylsulphenyl) -phenylglycine the 6-aminopenicillanic acid acylated.

The N-o-mitrophenyl derivative of 6- [D (-) α-aminophenylazetamido] -penicillanic acid formed is disconnected.

Then the said product is subjected to hydrolysis in one aqueous or water-based organic solvents (aqueous acetone, aqueous Dioxane, aqueous ethanol) in the presence of nucleophilic reagents, iodides, fluorines, Hyposulfite and other sodium salts, at a pH of 2-7. The target product formed is separated and identified by paper chromatography (Hollands patent No. 6500537; Japanese Patent Publication No. 42-11073; Patent of the Czechos @ owakei No. 124836).

The process mentioned provides for a previous separation of the N-substituted Product, the 6- [D (-) α-aminophenylazetamido] -penicillanic acid, then the @urchf @@@ ung before hydrolysis, which complicates the technology of the process.

The aim of the present invention is to avoid the above @disadvantages.

In accordance with the stated goal, the task posed, by changing the technological operations, the technology of the To simplify the process.

This object has been achieved by the fact that in the process for production of 6- [D (-) - α-aminophenylazetamido] -penicillanic acid by acylation of 6-aminopenicillanic acid with the N-substituted D (-) - α-aminophenylacetic acid, Hydrolysis of the N-substituted 6- [D (-) α-aminophenylazetamido] -penicillanic acid obtained and subsequent separation of the target product, 6-aminopenicillanic acid, according to the invention with N-substituted D (-) - α-aminophenylacetic acid, they are transformed by reaction of D (-) - α-aminophenylacetic acid with ß-keto esters, ß-dicarbonyl compounds or o-nitrophenylsulfenyl chloride in an organic or aqueous-organic Solvent with gradual addition of alkali until a pH value is achieved of 8-10 at a temperature of 20-80 ° C forms, acylated that after acylation obtained N-substituted 6- [D (-) - α-aminophenylazetamido] penicillanic acid subjected to a hydrolysis in aqueous acetone, after which the acetone is distilled off, treated the remaining reaction mass with an organic solvent and then separating the target product.

In the reaction of D (-) - α-aminopnenyl acetic acid with ß-keto esters or ß-dicarbonyl compounds, the process can expediently be carried out in an alcoholic medium under gradual Adding alcoholic caustic potash solution to one pH of 8-8.5 and at a temperature of 75-80 ° C which leads to D (-) α-aminophenylacetic acid with the o @ nitrophenylsulfenyl chloride one expediently the process in aqueous acetone with the gradual addition of aqueous Caustic soda solution until a pH value of 9-10 is achieved.

@an expediently leads to the hydrolysis of the N-substituted 6- [D (-) - α-aminophenylazetamido] -penicillanic acid at a pH of 2-3.5.

As an organic solvent is used for the treatment of the after the acetone has been distilled off, preferably Butyl acetate.

The method according to the invention is carried out as follows: D (-) - α-aminophenylacetic acid is used with ß-keto esters, e.g. azo acetic acid ethyl ester, or with o-nitrophenylsulfenyl chloride. In the implementation of D (-) - α-aminophenylacetic acid with ß-ketoesters or ß-dicarbonyl compounds, the process is expediently carried out in alkoho @@ schem medium with gradual addition of alcoholic caustic potash solution up to Ores with a pH of 8-8.5 at a temperature of 75-80 ° C.

The formed @ -salt of N- (1-methyl-2-ethoxycarbonylvinyl) -D (-) - α-aminophenyl acetic acid crystallized out after partial evaporation of alcohol.

In the implementation of the D (-) - α-aminophenylacetic acid with the o-Nitrophenylsulfenyl chloride in aqueous acetone leads to the process under gradual Add aqueous caustic soda solution until a pH value of 9-10 is achieved. The solution is then filtered, diluted with water, washed with ethyl acetate and acidified the aqueous layer to a pH of 4.0, the deposited N-o-nitrophenylsulfenyl-D (-) - α-aminophenylacetic acid Crystallized with cooling.

illit the obtained N-substituted derivative of aminophenylacetic acid 6-aminopenicillanic acid is acylated.

The acylation is carried out using the mixed anhydride method from the R salt of N- (1-methyl-2-ethoxy @ arbonylvinyl) -D (-) - α-aminophenylacetic acid or the N-o- @ itrophenylsulfenyl-D (-) - α-aminophenylacetic acid and the alkyl chloroformate evaluate formed in wassiem acetone in the presence of N, N-dimethylbenzylamine carried out.

When using N-o-nitrophenylsulfenyl-D - (-) - α - aminophenyl acetic acid if equimolecular amounts of triethylamine are added to the reaction solution, the process is carried out by adding an aqueous acetone solution to the mixed anhydride formed of the 6-aminopenicillanic acid salt of triethylamine, stirs the aelic during 1-1.5 hours after which hydrochloric acid up to Achieving a pH value of 2.0-3.5 for hydrolysis of the N-substituted 6- [D (-) - α-aminophenylazetamido] - penicillanic acid formed is added. After the hydrolysis has ended, the acetone is distilled off, the residue treated with butyl acetate, from the aqueous solution at a pH of 5.0-5.6 the target product is separated.

The yield of the target product is against 67 percent by weight, the Basic material content 90-97 percent by weight.

6- [D (-) - α-aminophenylazetamido] -penicillanic acid is used for parenteral use obtained in the form of the sodium salt.

To do this, the 6- [D (-) - α-aminophenylazetamido] -penicillanic acid is dissolved in aqueous caustic soda solution at a pH of 8-9 on below Filtration through bacterial filters and lyophilization.

The proposed method makes it possible, the technology Simplify the process because it eliminates the need for the sodium salt to prepare the D (-) - α-aminophenyl acetic acid, what with significant Loss of D (-) - α-aminophenylacetic acid is connected. It is omitted Necessity to o-nitrophenyl @@@ - fenylthiocyanate and dioxane (according to the known Method) to be used in the method according to the invention by cheaper Reagents, o-nitrophenylsulfenyl chloride and Aze @@ are replaced.

The hydrolysis by the process according to the invention is less favorable Conditions, namely carried out in homogeneous aqueous acetone medium.

The hydrolysis of N-o-nitrophenylsulfenyl-6- [D (-) - α-aminophenylazetamido] -penicillanic acid their separation immediately in aqueous acetone, dat after the acylation the 6-aminopenicillanic acid is obtained, thereby enhancing the technology the process is significantly simplified.

In order to better understand the present invention, the following The following examples of the experience of the process for the preparation of 6- [D (-) - α-aminophenylazetamido] -penicillanic acid cited.

Example 1. A suspension, which is 0.94 kg of D (-) - α-aminophenylacetic acid, to 5.1 1 from ethyl alcohol u @@ to 0.793 1 from acetoacetic acid ethyl ester, the mixture is heated to a temperature of 70-75 ° C. and added in small portions under rounds 4.14 1 alcoholic 1.5 N caustic potash solution @ei a pH value of 8-8.5. Then distilled one from 4.4-4.7 1 ethyl alcohol. After the end of the crystallization, the @ ie @ hit filtered off and up to a moisture content of not more than 0.5 Weight percent getrock @ e @.

@an receives 1.5 kg of aalium derivative of @ - (1-methyl-2-ät @ oxykarbonylvingl) - @ (-) - α-aminophenylacetic acid (80 percent by weight of theory), [α] D 270 ° (C 0.5; @tOH), m.p. 228-233 ° C. 1, @ @@ @es received @ aliumd @@ iva @ N- (1-methzl-2-ethoxycarbonylvinyl) -D (-) - α-aminophenylacetic acid one mixed with 15 l of acetone, cooled to a temperature of -7 to -8 ° C and gives with stirring rapidly 0.387 l of methyl chloroformate and 0.189 l of 1% strength acetone solution of N, N-dimethylbenzylamine to. The leaction mass obtained is stirred at a Temperature from -7 to -8 ° C for 30-35 minutes. At the same time you prepare one Solution (pH 8.0-8.7) of 1.030 kg of 6-aminopenicillanic acid, 6.6 l of water, 0.685 l of triethylamine and 0.6 1 acetone and cools to a temperature of -7 to -8 ° C.

The resulting solution of the 6-aminopenizällansäuresalzes is poured the abovementioned reaction mass is added and stirring is continued for 1.5 hours.

When the acylation has ended, 1.44 is added to the reaction mass 1 add 20% hydrochloric acid solution until a pH value of 3.0-3.4 has been achieved and stir continued for 1 hour. The acetone is then distilled under a residual pressure of 30-40 torr, the residue treated with butyl acetate, separated at pH from 2.0 the aqueous layer gives off 20% aqueous caustic soda solution up to Achieve a pH of 5.0-5.5 too.

The target product which has separated out is filtered off and washed with water and dried at a temperature of 25 ° C-30 ° C. @an receives 1.235 kg of 6- [D (-) - α-aminophenylaze @@ penicillanic acid (67 percent by weight of theory) with a salary of base material from 96-97 percent by weight, αD 284 ° (C 0.25; H2O).

Example 2. A bus pension made up of l5.1 0 from aminophinyl acetic acid, 84 ml of ethyl alcohol and 10.3 ml of acetyl acetone are heated at a temperature of 70-75 ° C and gives 67 ml of alcoholic in small portions while stirring 1.5N caustic potash solution up to a pH value of 8-8.5, after which 70-75 ml of ethyl alcohol be distilled. After the end of the crystallization, the repetition occurs filtered off. 20.3 g of potassium derivative (75 percent by weight of theory), αD, are obtained 256 ° (C 1; H2O), m.p. 117-12O00. The process is also carried out analogously to Example 1. The yield of target product is 30 percent by weight of theory, the content of Base material 75 percent by weight.

Example 3. To a solution of 27.2 g of D (-) - α-aminophenylacetic acid in 180 ml of 1N caustic soda diluted with 160 ml of acetone is added in stages 37.8 g of o- @ itrophenylsulfenyl chloride and 2N caustic soda solution up to a pH value from 9.0 to 10.0 too. After the completion of the reaction, the solution is triple Volume of water diluted, washed with ethyl acetate and the aqueous layer acidified with 10% sulfuric acid until the pH value is 4.0. The eliminated N-o-Nitrophenylsulfenyl-D (-) α-aminophenylacetic acid crystallizes in the Cooling down.

After recrystallization from the aqueous alcohol, 29.5 is obtained g (54.3 percent by weight of theory), melting point 141-143 ° C. (decomposition), αD -155 ° # (c 0.5; @tOH).

To a solution of 10.8 g of ethyl C @ loroformate in 197 ml of acetone, which has cooled to a temperature of -8 ° C., 2.95 ml of 1% strength acetone solution are added of N, N-dimethylbenzylamine and a solution of 29.5 g of N-o-nitrophenylsulfenyl-D (-) - α-aminophenylacetic acid in 150 nl of acetone containing 13.5 g of triethylamine. The mixture is stirred during 15 minutes at a temperature of -8 ° C. A solution of 22 g of 6-aminopenicillanic acid is then added in 124 ml of water, 124 ml of acetone and 14.7 triethylamine and stir for 1 hour continue until the temperature rises to 0 ° C.

Then add 20% hydrochloric acid solution until a pH value is achieved from 2.0 to, lets stand for 8-10 hours at a temperature of 5-6 ° C. After At the end of the hydrolysis, the acetone is distilled off and washed with Butylaze @@ t aqueous solution 20% aqueous ethynatron solution until a pH value is achieved of 5.0-5.5 are added, the precipitated product is filtered off and washed with water and dried at a temperature of 25-30 ° C.

@an receives 6- [D (-) - α-aminophenylazetamido] -penicillanic acid in a yield of 30 percent by weight of theory.

Example 4. 62.6 g of 6 - [D (-) - α -aminophenylazetamido] penicillic acid, Eliminate analogously @ example 1, it is suspended in 243 ml of water at a temperature from 1-5 ° C and gradually increases to one temperature while stirring intensively Caustic soda solution cooled from 1-5 ° C until a pH value of 8.5 is achieved.

The solution is filtered off and then passed through a sterile filter a temperature of 1-5 °. The sterile solution obtained is filled into bottles which are used at a temperature of -45-50 ° C for 4-5 stalls and afterwards after ... etaode aer sublimation drying for 21 hours (of which 17 hours without heating and for the last 4 hours at a temperature of 40 ° C) will. The preparation obtained is hermetically sealed.

The yield of the preparation is 72.6 percent by weight with one content of base material of 95.8 percent by weight.

Claims (5)

PAT @@@@@ SPEECH: 1. Process for the preparation of 6- [D (-) - α-aminophanylazetamido] penicillic acid by acylation of 6-aminopenicillanic acid with N-substituted D (-) - α-aminophenylacetic acid, Hydrolysis of the N-substituted 6- [D (-) - α-aminophenylazetamido] -penicillanic acid obtained and subsequent separation of the target product, ie g e k e n n n z e i c h n e t that 6-aminopenicillanic acid with the N-substituted D (-) - α- Aminophenylacetic acid, which is produced by reacting D (-) - α-aminophenylacetic acid obtained with ß-ketoesters, ß -dicarbonyl compounds or o-nitrophenylsulfenyl chloride in an organic or aqueous-organic solvent under gradual To @ a @ e from @@ kali until a pH value of 8-10 is reached at one temperature from 20-80 ° C @ zyl @ ert, the @ -substituted 6- [D (-) α obtained after the acylation -Aminophenylazetamido] -penicillanic acid subjected to a hydrolyte @@ in aqueous acetone, then the acetone is distilled off, the remaining reaction mass with an organic Treated solvent and then separates the target product from. 2. The method of claim 1, d a d u r c h g e -k e n n z e i c h n e t that the D (-) - α-Ami @@@@@@ acetic acid with ß-ketoesters or ß-dicarbonyl compounds in alkaline medium with gradual addition of alcoholic caustic potash solution up to Achieving a pH of 8-8.5 at a temperature of 75-80 ° C. 3. The method according to claim 1, d a d u r c h .s e -k e n n z e i c h n e t that the D (-) - α-aminophenyl acetic acid with the o-nitrophenylsulfenyl chloride in aqueous acetone solution with the gradual addition of aqueous caustic soda solution until a pH value of 9-10 is achieved. 4. The method according to claim 1-3, a a d u r c g g e -k e n n z e i c h n c t that the hydrolysis of the @ -substituted 6- [D (-) - α-aminophenylazetamido] -p @@ i cillanic acid at a pH of 2-3.5. 5. The method according to claim 1-4, d a d u r c h g e ;; e ri n z e i c n n e t that one can use as an organic solvent for the treatment of the after Distilling off the acetone, butyl acetate behind the reaction solution, ends.