DE2163279A1 - Process for the preparation of alpha-aminobenzylpenicillin - Google Patents

Description

PATENT LAWYERS

DR. O. DKTFTMANN KL SCHIFF DR. A. ν. FONER DIPL. ING. P. STRBHL

MUNICH 80t MARIAHILFPLATZ 2 Sr 8 2163279

DA-4636

Description of the patent application

of the company

E. R. SQUIBB & SONS, INC. Lawrenceville-Princeton Road Princeton, Nevr Jersey 08540, U.S.A.

concerning

Process for the preparation of ai> -aminobenzylpenicillin Priority: December 29, 1970, Japan, No. 45-129635 / 70

The invention relates to a process for the production of various semisynthetic penicillins which have antibiotic activity against a wide variety of gram-positive and gram-negative bacteria. In particular, it relates to a process for the preparation of various oO-aminobenzylpenicillin derivatives, which may optionally have a substituent in the phenyl part, from a Schiff's base of 6-aminopenicillanic acid.

Such penicillins have hitherto been made by converting 6-aminopenicillanic acid produced with reactive derivatives of various organic carboxylic acids (e.g. according to the known

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Japanese patent applications 16277 / T961 and 1336/1967)

The _t i be such processes as the starting material used is 6-aminopenicillanic acid obtained industrially either by direct fermentation ■ or by fermentation and subsequent hydrolysis of penicillin thus obtained. It has also been proposed to win the 6-aminopenicillanic acid in a better way as the corresponding ship ^l's base, instead thereof directly in the free form of a dilute solution, for example, the culture broth or it hydrolysed ~ * terraced liquid (US - Patent 3,288,800).

The invention aims to provide an advantageous process for the preparation of an o £ - -aminobenzylpenicillin derivative with or without one Substituents on the phenyl part directly from a Schiff's base of 6-aminopenicillanic acid available. In this way, a technically advantageous process for production is intended are created by such penicillins.

According to the invention, the above-mentioned aü -aminobenzylpenicillin derivative can be prepared by using a 6-arylideneaminopenicillanic acid having the general formula

R-CH = N-

I \ I - CH,

(I) COOH

wherein R stands for an aryl group with a phenylglycine-N-carboxylic acid anhydride reacted in a substantially anhydrous organic solvent and then with an arylamine brings to implementation. The aryl group expressed by E. can be a monoeyclic or bicyclic carbocyclic aryl group, ζ. Β. Be phenyl or naphthyly. It can be assigned a lower alkoxy, lower alkyl, phenyl, nitro group, or a Halogen atom or the like may be substituted. The phenyl group

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of the hienylglycine-N-carboxylic acid anhydride can be unsubstituted or it can carry a hydroxy or lower alkoxy group or a halogen atom.

The method of the invention can readily be carried out by converting the compound having the general formula (I) given above in a suitable, essentially Brings anhydrous, organic solvent into contact with the JN carboxylic acid anhydride and the arylamine with the reaction mixture inflicts. A wide variety of organic solvents can be used in this reaction, with no particular solvents There are restrictions except that they should not participate in the response. Examples of suitable solvents are di-lower alkyl ketones, e.g. acetone, methyl ethyl ketone, Methyl isobutyl ketone, ethers, e.g. diethyl ether, diisopropyl ether, Tetrahydrofuran, dioxane, halogenated hydrocarbons, preferably with up to four carbon atoms and up to three halogen atoms, especially chlorine, e.g. methylene chloride, chloroform, 1,2-dichloroethane, 1,2-dichloropropane, Esters of lower aliphatic carboxylic acids, e.g. ethyl acetate, butyl acetate, methyl propionate, dimethylformamide, acetonitrile and their mixtures. Of these solvents are the halogenated Hydrocarbons are particularly preferred.

The reaction temperature for the acylation reaction of 6-arylideneaminopenicillanic acid is not critical. However, the reaction is preferably carried out at relatively low temperatures, usually from 10 to IfO ° C, advantageously from -5 to -10 ° C carried out. The reaction time can be varied, mainly depending on the type of 6-arylideneaminopenicillan used acid, the solvent used and the reaction temperature. The reaction time is usually several minutes up to about several hours.

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When carrying out the reaction, the 6-arylideneaminopenicillanic acid with the given formula (I) in the form of their salts, such as the alkali metal salts, e.g. the sodium and potassium salts, the amine salts, e.g. the triethylamine, tributylamine, tert. Butylamiri- and tert. Octylamine salts and the like are used instead of using them in free form. In this case it is advantageous to apply the salt in situ prior to the acylation reaction to be converted into the free form by adding a suitable acid. Examples of suitable acids are Mineral acids, e.g. hydrochloric acid and sulfuric acid, and organic) acids, e.g. dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, Benzenesulfonic acid and p-toluenesulfonic acid. The used Acid can be used as such or dissolved in a suitable solvent.

After the acylation reaction, the preparation of the eC -aminobenzylpenicillin derivative can be carried out expediently carried out from the reaction mixture by adding the arylamine to the reaction mixture will. Suitable arylamines for this reaction are unsubstituted and substituted arylamines, in which the aryl group is an unsubstituted or substituted monocyclic or bicyclic carbocyclic aryl group .der . type mentioned above, e.g. aniline, toluidine, ™ Anisidine, oC -naphthylamine, ß-naphthylamine, p-nitroaniline, p-chloroaniline and the same.

After the reaction has ended, the desired oC -aminobenzylpenicillin can be separated off from the reaction mixture by conventional methods. For example, after the reaction has ended, the crude penicillin which precipitates out of the reaction mixture can be separated off by filtration and dissolved in dilute hydrochloric acid. The resulting solution is then filtered to remove insoluble impurities and the filtrate is made weakly alkaline and washed with a water-immiscible solvent such as methylene chloride. The aqueous layer becomes

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Again made weakly acidic and concentrated at low temperature. The precipitated crystalline substance can through Filtration can be separated, whereby pure penicillin is obtained »Alternatively, the desired pure product, if a solvent which is immiscible with water is used as the solvent for the reaction, in such a way that that dilute hydrochloric acid is added to the reaction mixture with stirring, without the crude desired formed in situ Product is separated off by filtration. Then will the aqueous layer separated and treated in the same manner as indicated above.

The invention is illustrated in the examples. example 1

150 ml of 1,2-dichloroethane are added to 15 g of the tertiary octylamine salt of 6-benzylideneaminop'enicillanic acid and the mixture obtained is cooled ^{to 1 to 3 ° C.} 6.26 g of diethyl ether containing 1.26 g of hydrogen chloride are then added dropwise with stirring over a period of 15 minutes. 8.0 g of D-phenylglycine-N-carboxylic acid anhydride are added to the resulting mixture. The mixture is stirred for 30 minutes. A solution of 5.5 g of 06-naphthylamine in 20 ml of 1,2-dichloroethane is then added dropwise to the reaction mixture over a period of 10 minutes. After completion of the dropwise addition, stirring is continued for one hour, as a result of which amorphous penicillin is deposited. 100 ml of η-hexane are added to the mixture. It is filtered off to recover the ampicillin. The solid obtained in this way is washed with a mixture of 1,2-dichloroethane-n-hexane (1: 1) and dried in a vacuum desiccator. The product is identified as ampicillin by the infrared spectrum (5.62 u. (Ss-lactam), 5.9Zf η (amide-I)) and by the nuclear magnetic resonance spectrum (solvent: heavy water-trichloroacetic acid). To the cupid

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phen ampicillin, IQO ml of water are added and the pH of the mixture obtained is adjusted to 2.0 with 18% hydrochloric acid. The mixture is then stirred for 30 minutes. After the removal of insoluble substances by filtration, 15 ml of methylene chloride are added to the filtrate and the pH of the aqueous layer is adjusted to 78 with a 2Q aqueous sodium hydroxide solution. The mixture is then stirred for 30 minutes . After a small amount of insoluble substances has been removed by filtration, the aqueous layer is separated from the filtrate, adjusted to a pH of 1.5 with hydrochloric acid and then concentrated under reduced pressure. The crystalline substance which separates out is separated off by filtration, washed with a small amount of cold water and dried. In this way 10 g (73%) of B-o & aminobenzylpenicillin trihydrate are obtained. The antibacterial activity value for this substance is 865 / ig / mg

According to a procedure which can also be used, water and hydrochloric acid are added to the reaction mixture obtained after addition of the c6-naphthylamine in 1,2-dichloroethane, without the precipitate being separated off by filtration. This is how the raw ampicillin is dissolved. The aqueous layer is separated xmä. treated in the above manner. In this way 10gD-06-aminobenzylpenicillin trihydrate are obtained.

Example 2

The reaction and the work-up of the reaction mixture are carried out in the same way as in Example 1, with the exception that instead of the oC -naphthylamine 4 »1 g of p-toluidine is used» In this way D- oC -aminobenzylpenicillin trihydrate is obtained.

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Example 5

The reaction and work-up are carried out in the same way as in Example 1, with the exception that 6.5 g of 2-phenylaniline are used instead of the oO -naphthylamine. In this way, D-co -aminobenzylpenicillin trihydrate is obtained. -

Example 4

The reaction and the work-up are carried out in the same V / eise as in Example 1, with the exception that instead of the tertiary octylamine salt of 6-benzylidene aminopenicillanic acid 16.8 g of the tertiary octylamine salt of 6-06 -naphthylideneaminopenicillanic acid be used. In this way, D-06 aminobenzylpenicillin trihydrate is obtained.

Example 5

A solution of 10.5 g of 6-benzylideneaminopenicillanic acid in 150 ml of 1,2-dichloropropane is cooled to 1 to 3 ° C. and 9, Hg of D-phenylglycine-N-carboxylic acid anhydride is added while stirring. 30 minutes after the addition is complete, a solution of 3> 5 g of aniline in 20 ml of 1,2-dichloropropane is added dropwise over a period of 1 + 5 minutes. After the dropwise addition has ended, the mixture is stirred for a further 30 minutes. 100 ml of v / water are added to the reaction mixture and the pH of the aqueous layer is adjusted to 2.0 with hydrochloric acid. The mixture is then stirred for an additional 30 minutes. The aqueous layer is separated and filtered to remove insolubles. 15 ml of methylene chloride are added to the filtrate. The mixture obtained is treated with alkali and acid as in Example 1, whereby D-oC-aminobenzylpenicillin trihydrate is obtained.

Example 6

To 16 g of the tertiary octylamine salt of 6-anisylideneaminopeni-

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15> 0 ml of methylene chloride are added to cillanic acid and the resulting mixture is cooled to 1 to 3 ° C. 6.26 g of isopropyl ether containing 1.26 g of hydrogen chloride are then added dropwise over a period of 10 minutes with stirring. When the dropwise addition is complete, 8.0 g of D-phenylglycine-N-carboxylic acid anhydride are added and the mixture is stirred for a further J> 0 minutes. A solution of 6.75 g of 4-chloro- oO- naphthylamine in 20 ml of methylene chloride is added dropwise to the reaction mixture over a period of 40 minutes. Then, the resulting mixture is treated in the same manner as in Example 1, whereby D-oC-aminobenzylpenicillin trihydrate is obtained.

Example 7

The reaction and the work-up are carried out in the same way as in Example 6, with the exception that a solution of 5-95 g of p-toluenesulfonic acid in 20 ml of methylene chloride is used instead of the solution of hydrogen chloride in isopropyl ether. In this way D- oO -aminobenzylpenicillin trihydrate is obtained.

Example 8

The reaction and the work-up are carried out in the same way as in Example 1, with the exception that instead of the D-phenylglycine-N-carboxylic acid anhydride 7, h S DL-p-hydroxyphenylglycine-N-carboxylic acid anhydride, dissolved in 30 ml of tetrahydrofuran, is used will. In this way, 8.8 g (62%) of DL- cC -amino-p-hydroxybenzylpenicillin trihydrate are obtained.

The reaction is carried out in the same way as indicated above, with the exception that optically active p-hydroxyphenyl ~ glycine-N-carboxylic acid anhydride is used, whereby optically active oC-amino-p-hydroxybenzylpenicillin is obtained.

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Example 9

The reaction and the work-up are carried out in the same way as in Example 1, with the exception that 9-5 g DL ~ p-chlorophenyl ~ glycine-N-carboxylic anhydride are used instead of the D-phenylglycine-N-carboxylic acid anhydride. In this way DL- oC -amino-p-chlorobenzylpenicillin is obtained.

Example TO

The reaction and the work-up are carried out in the same manner as in Example 1, with the exception that instead of the D-phenylglycine-N-carboxylic acid anhydride 9 | 3 S DL-p-methoxyphenylglycine-N-carboxylic acid anhydride be used. In this way, DL-oC -amino-p-methoxybenzylpenicillin is obtained.

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Claims (1)

Claims , A process for the preparation of oil- aminobenzylpenicillin, characterized in that a 6-arylideneaminopenicillanic acid with the general formula R-CH = N wherein R is an unsubstituted or substituted aryl group stands in a substantially anhydrous organic solvent with a phenylglycine-N-carboxylic acid anhydride, which can optionally have a substituent in the phenyl part, implemented and then brought to implementation with an arylamine. 2. The method according to claim 1, characterized in that there is a 6-arylidenearainopenicillanic acid used, in which the substituent R is optionally with a lower alkoxy, lower alkyl, phenyl, or Nitro group or a halogen atom substituted, monocyclifc see or bicyclic carbocyclic aryl group is that the Phenyl group of the phenylglycine-N ~ carboxylic acid anhydride, if necessary is substituted by a hydroxy or lower alkoxy group or a halogen atom, and that the aryl group des Arylamines, one optionally with a lower alkoxy, lower alkyl, phenyl or nitro group or a halogen atom substituted, monoeyclic or bicyclic carbocyclic aryl group. 3. Method according to claim 1 or 2, characterized in that g e k e η η draws that one is called 6-arylideneaminopenicillanic acid 6-benzylidene aminopenicillanic acid, 6-anisylideneamine penicillanic acid -11- 2 0 9 8 3 2/1208 acid or 6- o6 -naphthylideneaminopenicillanic acid and used as arylamine naphthylamine, toluidine, aniline, phenylaniline or chloronaphthylamine / f. Method according to one of claims 1 to 3? through this characterized in that one is called 6-arylideneaminopenicillanic acid 6-benzylidene aminopenicillanic acid is used. 5 · method according to one of claims 1 to l + _} thereby characterized in that the arylamine used is oO - naphthylamine, 6 · Method according to one of Claims 1 to 5> through this characterized in that one is used as a solvent uses a halogenated hydrocarbon. 7. The method according to any one of claims 1 to 6, characterized characterized in that the reaction temperature is 0 to 10 ° C. 209832/1208