NO138851B - PROCEDURE FOR PREPARATION OF 6-AMINOPENICILLANIC ACID - Google Patents

Description

This invention relates to a method for manufacturing

of 6-aminopenicillanic acid of the formula (II),

from a 6-acylamidopenicillanic acid of the general formula (I)

where R"*" means a hydrogen atom or a residual group of an organic carboxylic acid with 1-17 carbon atoms, by a chemical process.

6-aminopenicillanic acid (II) (hereafter referred to as 6-APA) as such does not exhibit any significant biological activity such as anti-

biotic properties, but is an important compound as an initial

material for the production of semi-synthetic penicillins.

An object of the invention is to provide a new chemical

process without the use of an enzymatic process for the production of 6-APA (II), without the content of harmful proteins, from 6-acylamido-

penicillanic acids (I)•

Something has previously been published regarding chemical processes

for the production of 6-APA (II) from 6-acylamidopenicillanic acids (I).

In Chem. Abstract 69, 19145 (1968) and U.S. Patent 3,499,909 are among

otherwise described a method which is characterized by the fact that vessels, boxyl-

the group is protected by converting it to an alkylsilyl ester. This method is considered relatively advantageous, but is not

satisfactory from an industrial point of view.

Furthermore, a method is known for producing an N-monosubstituted iminochloride by reacting an N-substituted acid amide with phosphorus pentachloride [Chemische Berichte, 28, 2367

(1895), ibid., 93, 1231 (1960). In the preparation of a 7-amino-cephalosporanic acid ester [Chem. Abstr. 65, 10596 (1966), Japanese Patent Publication 13,862/66], 7-amino-cephalosporanic acid [Chem. Abstr. , 71, 61403, (1969), ibid., 71, 112959 (1969) and a 6-amino-penicillanic acid ester [J. Med. Chemistry, 13, 607 (1970)], a method characterized by reaction has also been used of an N-monosubstituted iminochloride with an alcohol to form an iminoether, after which the iminoether group is cleaved off by hydrolysis.

As a result of extensive attempts to protect the carboxyl group in the 3-position of penicillins, we have now found a method for protecting the carboxyl group by conversion to a mixed acid anhydride. This is the basis for the present invention.

The present invention thus relates to a method for the production of 6-APA, and it is characterized by

(A) a compound of the general formula (I) or a salt thereof, is reacted with a halogenated compound in the presence of an acid-binding

agent for protecting the carboxyl group in said acyl amino acid by forming a mixed acid anhydride group, the halogenated compound having the formula

4 5

where R is chlorine and R is chlorine, phenyl, alkoxy or alkoxy-substituted alkoxy, where the alkoxy groups contain 1-4 carbon atoms, or R 4 and R 5 together form a C1_3-alkylenedioxy group,

(B) the resulting acyl amino acid having its carboxyl group protected is transferred in a manner known per se to a corresponding

iminohalide by reaction with an iminohalide forming agent under anhydrous conditions at room temperature or lower temperature, e.g. below 0°C,

(C) at a temperature not exceeding -10°C react in a manner known per se the said iminohalide with an alcohol of the formula

R<3->0H (IV)

where R is alkyl with 1 to 12 carbon atoms, aralkyl with 1 to 7 alkyl carbon atoms, cyclohexyl, hydroxyalkyl with 2 to 12 carbon atoms

atoms, alkoxyalkyl of 3 to 13 carbon atoms, monocyclic aryloxyalkyl of 2 to 7 alkyl carbon atoms, monocyclic aralkyl of 3 to 7 alkyl carbon atoms, or hydroxyalkyl of 4 to 7 carbon atoms, to form a corresponding iminoether, and (D) the iminoether is reacted in a manner known per se under acidic conditions with water, a hydroxyl-containing compound or a hydroxyl-containing solvent to form 6-aminopenicillanic acid. Although any of the stated 6-acylamidopenicillanic acids (I) can be used as starting material according to the invention, from a practical point of view it is appropriate to use salts of penicillins obtained by biological methods. Examples of such penicillins include those in which the acyl group is derived, e.g. from aliphatic carboxylic acids such as acetic acid, propionic acid, A 2 -pentenyl carboxylic acid and n-heptyl carboxylic acid; aralkyl carboxylic acids such as p-hydroxyphenylacetic acid and phenylacetic acid; and aryloxyacetic acids. These penicillins are generally employed as a tertiary amine salt, alkali metal salt, alkaline earth metal salt, etc. Examples of compounds of formula III include

Among the compounds of formula III which are used according to the invention are among others PCl^, previously known as a halogenating agent, but not as a protecting group, until we found that these compounds have good properties as a protecting group for carboxylic acids.

When a compound of formula III contains two or more chlorine atoms in the molecule, it is not clear whether all

the chlorine atoms take part in the formation of a mixed acid anhydride. When e.g. 0.6 to 0.9 mol of phosphorus trichloride is used for one mol of the compound with formula I, one can e.g. get a very high dividend. On this basis, it is assumed that the reaction takes place according to the following scheme:

When carrying out the present method, a compound of formula (I) or a salt thereof is dissolved or suspended in an inert solvent such as e.g. methylene chloride, chloroform, ethylene chloride, trichlorethylene, tetrahydrofuran, dioxane, diglyme, ethyl acetate, nitromethane or the like, and an acid-binding agent is added. Trialkylamines, N-alkylmorpholines, N-alkylpiperidines, pyridine and homologues thereof, quinoline and homologues thereof, N,N-dialkylarylamines, etc. can be used as acid-binding agents. Among these compounds, N,N-dialkylanilines and 2,6-lutidine are particularly preferred. A compound is then added to the mixture at room temperature or a temperature below 0°C. formula (III) in excess in relation to the amount calculated from the number of chlorine atoms, to form a mixed acid anhydride. It may sometimes be necessary to heat the mixture at a temperature above room temperature, depending on the reaction components used. To the resulting solution of mixed anhydride is added at room temperature or at a temperature below 0°C an imino-halide forming agent in excess based on the number of molar equivalents. As an imino-halide-forming agent, e.g. phosphorus oxychloride (POCl^), phosphorus pentachloride (PCl^), phosphorus tribromide (PBr3), phosgene (COCl,,), oxalyl chloride (COCLCOCl ) and pyrocatechyl phosphorus trichloride (

). Among these for-

bonds are particularly preferred phosphorus pentachloride and phosgene. The optimal conditions for this reaction vary depending on the reagents, solvents and acid-binding agents used. When e.g. methylene chloride, N,N-dimethylaniline and phosphorus pentachloride are used, the reaction is completed within 2 to 3 hours at a temperature of -50 to -20°C.

The resulting iminohalide is reacted with a hydroxyl compound (IV) at a temperature below -10°. As a compound of formula (IV), e.g. methanol, ethanol, propanol, butanol, amyl alcohol, 2-ethylhexyl alcohol, benzyl alcohol, 2-phenethyl alcohol or cyclohexanol are used. Among these alcohols, methanol, n-propanol, n-butanol or isoamyl alcohol are particularly preferred. The compound with formula (IV) is used in an amount of 3 to 20 mol per moles of the compound of formula (I), preferably together with a small amount of a tertiary amine, such as e.g. N,N-dimethylaniline, triethylamine or the like. The formation of iminoethers is complete within 0.5 to 3 hours at a reaction temperature of -60 to -10° when an alcohol (IV) is added dropwise to the reaction mixture, or when a solution of imino chloride is added dropwise to a alcohol (IV), and the iminoether is formed almost quantitatively.

When ice water is added with stirring to the thus obtained solution of iminoether, both hydrolysis of the iminoether and gradual removal of the carboxyl-protecting group occur at the same time, so that a carboxylic acid is formed anew. The reaction mixture is then neutralized with a basic material such as triethylamine, aqueous ammonia, ammonium carbonate, an alkali metal hydrogen carbonate, an alkali metal carbonate, an alkali metal hydroxide or the like, to a pH of about 4.0, i.e. the isoelectric point for 6-APA (II), whereby crystals precipitate. The crystals are collected by filtration and washed with water, aqueous methanol, aqueous ethanol, aqueous acetone or the like, to give impure crystals of 6-APA. Under optimal conditions, crystal plates with 96.5 to 98% purity can be obtained in a yield of approx. 90%, which can be used without further purification as starting material for the production of synthetic penicillins.

As mentioned above, the present invention provides a method for producing 6-aminopenicillanic acid (II) chemically from 6-acylamidopenicillanic acids (I), comprising blocking the carboxyl group in the latter with a new protective group that has not previously been tried, and carrying out a series of reactions through an iminohalide, then iminoethers and finally directly to 6-aminopenicillanic acid (II). With the present method, 6-aminopenicillanic acid (II), which does not contain any proteins, can be obtained with high yield by simple processes from cheap starting materials. These advantages make the method particularly valuable for industry.

The following examples shall serve to further illustrate the invention.

Example 1

7.8 g of a dry fine powder of technical grade benzylpenicillin potassium (95% purity) was added to 30 ml of non-alcoholic methylene chloride containing 5.6 ml of N,N-dimethylaniliri, and the mixture was cooled to 0°C. A liquid mixture of 2.2 g of phosphorus trichloride and 5 ml was added dropwise to the stirred mixture

methylene chloride. After the addition, the mixture was further stirred for 20 to 30 minutes while being cooled in ice. Meanwhile, almost all of the potassium salt of penicillin, which was the starting material, disappeared, and various crystals of potassium chloride were de-

sat. While the mixture was cooled at a temperature below -60°C

and was vigorously stirred, 4.5 g of phosphorus pentachloride which had been finely ground just before the addition was added at once, and the powder which stuck to the inlet was washed down with a small amount of methylene chloride. As the reaction was accompanied by moderate heat generation, care was taken so that the temperature did not rise above

-30°C. After stirring at -50 to -30°C for approx. 2 hours, was mixed

none again cooled to a temperature below -60°C. To the force-

A mixed solution of 1 ml of N,N-dimethylaniline and 30 ml of n-butanol was added dropwise to the stirred mixture. As heat was developed at the beginning of the addition, the dripping rate of the solution was controlled so that the temperature was kept below

-40°C. After completion of the addition, the mixture was stirred at -50 to -40°C for approx. 2 hours, and then the cooling bath was removed while stirring was continued until the temperature of the reaction mixture rose to -15 to -10°C. The mixture was then whole-

ease in 30 ml of ice water. The reactor was washed with 10 ml of ice-cooled 60% methanol, and the washing liquids were added to the reaction mixture in ice-

water. The combined mixture was vigorously stirred, while it was de-

cooled in ice, whereupon the pH value of the mixture began to decrease. After approx. 10 to 20 minutes, ammonium carbonate was added in small por-

tions to gradually raise the pH value" At a pH of approx. 3 be-

favor crystals to be precipitated. The pH was finally adjusted to 4.0 and the solution was kept overnight in a refrigerator. The crystals were collected, washed several times with cold 60%

methanol, then with acetone and dried. 3.8 g (88% yield) was obtained

change) of crystal plates with a melting point of 190 - 191°C (split-

ning). Thin layer chromatogram and infrared absorption spectrum

for the product showed agreement with what was obtained for a standard sample. The purity was found to be 97.3% by the hydroxylamine method and alkali titration.

Phenoxymethylpenicillin potassium (98% purity) was used

instead of benzylpenicillin potassium to give the same results.

Example 2

The procedure according to example 1 was repeated below

the same reaction conditions, except that 0.7 to 0.8 mol of

each chlorinated phosphorus compound listed in the following table was used per moles of penicillin-potassium instead of phosphorus trichloride. 6-APA (II) was obtained in yields from 84 to 89% as shown in the table.

Phenoxymethylpenicillin potassium was used instead of benzylpenicillin potassium to give equivalent results.

Example 3

The procedure according to example 1 was repeated under the same reaction conditions, except that 1.3 to 1.5 mol of the chlorinated phosphorus compound indicated in the following table was used per moles of penicillin-potassium instead of phosphorus trichloride. 6-APA (II) was obtained in a yield of 90% as shown in the table.

Claims (1)

Process for the production of 6-aminopenicillanic acid, characterized in that (A) an acylamino acid with the formula where R is hydrogen or a residual group of an organic carboxylic acid with 1 to 17 carbon atoms, or a salt thereof, is reacted with a halogenated compound in the presence of an acid-binding agent to protect the carboxyl group of said acyl amino acid by forming a mixed acid anhydride group, the halogenated compound has the formula where R 4 is chlorine and R <5> is chlorine, phenyl, alkoxy or alkoxy-substituted alkoxy, where the alkoxy groups contain 1-4 carbon-4 5 atoms, or R and R together form a C^_3~alkylenedioxy group, (B) the resulting acylamino acid having its carboxyl group protected is transferred in a manner known per se to a corresponding iminohalide by reaction with an iminohalide-forming agent under anhydrous conditions at room temperature or lower temperature, e.g. below 0°C, (C) at a temperature not exceeding -10°C is reacted in a manner known per se with said iminohalide with an alcohol of the formula where R 3 is alkyl of 1 to 12 carbon atoms, aralkyl of 1 to 7 alkyl carbon atoms, cyclohexyl, hydroxyalkyl of 2 to 12 carbon atoms, alkoxyalkyl of 3 to 13 carbon atoms, monocyclic aryloxyalkyl of 2 to 7 alkyl carbon atoms, monocyclic aralkyl of 3 to 7 alkyl carbon atoms or 4 to 7 carbon hydroxyalkylalkyl, to form a corresponding iminoether, »and (D) the iminoether is reacted in a manner known per se under acidic conditions with water, a hydroxyl-containing compound or a hydroxyl- containing solvent to form 6-aminopenicillanic acid.