DE2450661A1 - PROCESS FOR PRODUCING 6- / D (-) - ALPHA-AMINOPHENYLACETAMIDO / -PENICILLANIC ACID - Google Patents

Description

MOLLER-BORt ■ GROLHING - DEUFEI. · ALREADY ■ HERTEL

PATENT LAWYERS
BRAUNSCHWEIG · MUNICH · COLOGNE

Dr. W. MOIIer-Bore · Br «un« ctiwelg H. Greening, Dipl.-Ing. ■ Munich Dr. P. Daufal, DIpl.-Chem. ■ Munich Dr. A. Schön, Dipl.-Chem. · Munich Werner Hertel, Dipl.-Phy «. · Cologne

D / S / Sh - K 1130

Munich

2 4th OCT. «71

KRKA tovarna farmacevtskih in kemicnih
izdelkov, NOVO MESTO, Komandanta Staneta 19,

Yugoslavia

Process for the preparation of 6- / D {-) - ££ -aminophtenylacetamido / -penicillanic acid

The invention relates to a new process for the preparation of 6- / D (-) -DC-toinophenylacetamido /.- penicillanic acid of the formula I.

HOO (I.

(D

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The compound of the formula I is "prepared by a process which consists in

a) 6-aminopenicillanic acid of the formula II

HOpC ^ O

H,

(Ii)

with a substituted D-phenylglycine of the formula JJJ

(III)

to condense, being

R _{1 stands} for a 2- (1-carbalkoxy) propenyl group _f a 2- (1 alkylcarbonyl) propenyl group or a hydrogen atom _f

R is an oxycarbethoxy group, an oxyacyl group, a cyanomethylene group, a p-nitrophenyl group, a 2,4,5 * -trichlorophenyl group or a halogen atom and

R ₁ and R2 can together form an oxycarbonyl group,

b) an extraction with a chlorinated inert hydrocarbon is carried out with 1 to 2 carbon atoms and 1 to 3 chlorine atoms, and

c) treatment with a primary or secondary aliphatic Alcohol with 1 to 4 carbon atoms is carried out.

The condensation reaction is preferably carried out in aqueous solutions of aliphatic C ₃ _g-ketones in acetone or methyl isobutyl ketone, within a temperature range of -60 to -30 * ⁰ C. The condensation reaction is conveniently carried out in the presence of an azaheterocyclic organic catalyst

509818/1189

carried out, preferably in the presence of N ^ methylmorpholine or N-ethylpiperidine,

Due to pharmacological requirements which do not allow large amounts of D-phenylglycine in the end product, this would be removed as much as possible. This is effected in such a way that unreacted D-phenylglycine is removed by extraction with chlorinated organic solvents which contain 1 to 2 carbon atoms and 1-3 chlorine atoms, the extraction being preferably carried out with methylene chloride or chloroform. The extraction is most convenient in a fairly acidic one. Medium and carried out within a temperature range of -10 to +10 ⁰ C. The extracted solution is further purified by treatment with primary or secondary aliphatic alcohols containing 1 to 4 carbon atoms, preferably with isopropanol, specifically within a temperature range of 50 to 100 ^° C., working in a slightly acidic medium.

The compound of formula I is a semi-synthetic penicillin, which shows a wide range of antibiotic activity and is resistant to acids and the enzyme penicillase. It is used in medicine mainly for the treatment of gastrointestinal infections, lung infections or urinary tract infections. The compound is known and is described in the literature (cf. KE Price, A, Guorevitch, LC, Cheney; Antimicrob, Agents Chemother., 1966 , 670 etc. ) ,

In general, 6- / D (-} - Qi-aminophenylacetamido / penicillanic acid in the form of a monohydrate of the formula JV

HOOC,

"Ί ¹

(IVl

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and in the form of a trihydrate of the formula V

HOOC>

(V)

obtain.

The anhydrous form of (> - / D ('-) - 0 <»- aminophenylacetamido / * - penicillanic acid was previously produced in such a way that the hydrated forms were prepared according to the formulas IV and V, whereupon these at a temperature between 50 and 80 ⁰ C were dehydrated in organic solvents or in mixtures of organic solvents with water.

It has been found that the anhydrous 6 <- / D (-) \ ^ - £ & -aminophenylacetamide / - 'penicillanic acid of the formula I is more stable and, in human therapy, in larger amounts in the blood compared to the hydrated forms according to the formula IV and V is encountered. Therefore, the anhydrous form is becoming more and more important for human therapy.

The process according to the invention leads directly to the pure anhydrous 6- / D (-) - OL -aminophenylacetamido / '- penicillanic acid. It is more economical and simpler than the known processes, since long-term isolation of the hydrated forms is avoided when it is carried out. The process according to the invention gives higher yields compared to the known process. The end product in the pure form contains less than 1% by weight of the undesired D ^ -phenylglycine present in a mixture,

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The following examples illustrate the invention without _f strategy to limit,

example 1

120 g (0.55 moles). 6-rAminopenicillansäure be J _n 200 ml distilling ^ tem water suspended and dissolved in 85 ml of triethylamine at a temperature from 0 to 10 ⁰ C and at a ρίϊτ value of 8 _f. 4 200 ml of acetone are added to the solution, whereupon it is ^{cooled to a temperature of - ^ 15 0} C,

185.2 g (0.65 Moll of the potassium salt of Ντ · / 2 * - (1-carboxyethyl-1-propenyl / -D-phenylglycine are suspended in .1620 ml of acetone, whereupon it is ^{cooled to -57 0} C, then 56.4 ml (0.5 ^s added 5 Moll Äthylchrorcarbonat. The mixture is stirred for a period of 15 minutes at -57 ⁰ C, followed by 0.42 ml N-methylmorpholine are added. stirring is during own time period of 40 minutes continued vird added and the solution of ER-aminopenicillanic acid in one portion. the mixture is kept under stirring for a period of 1 hour at * -45 * C, filtered through Celite and washed twice with 200 ml acetone. the filtrate is washed with 385 * Distillation ml diluted tem water, whereupon the temperature of the filtrate at ⁰ ° C is held for a period of 1 hour, pU value is set using concentrated HCl to 1.35 herabge · ^. the aqueous solution is washed with 1 , 5 1 methylene chloride extracted at 0 ⁰ C, whereupon the aqueous phase is separated , then the addition of dilute ammonia (27 percent by weight) follows until a pH of. 5.1 has been achieved. Then 650 ml of isopropanol are added. The solution is heated to the boiling point, for a period of 30 Me utes at 73 ⁰ C refluxed and cooled to 0 C ^e. The separated product is filtered off and washed twice with 20 ml portions of distilled water and in vacuo

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BATH ORIGINAL

Dried (50 iranHg) at 45 ⁰ C. This gives 103 g (53.2%) of pure anhydrous 6- / D (-) - £ * -Aminophenylacetamido / -penicillansäure. (F 202 -. 204 ⁰ C).

Other features:

Moisture (K. Fischer) 0.3%

D-phenylglycine content 0.5%

Microbiological titration (FDA) 99.5%

Example 2

120 g (0.55 mol) of 6-aminopenicillanic acid are suspended in 20 ml of distilled water and dissolved in 85 ml of triethylamine at a temperature of 0 to + 1O ⁰ C at a pH value of 8.4. 200 ml of acetone are added to the mixture, whereupon it is cooled to a temperature of -15 ° C.

185.2 g (0.65 mol) of the potassium salt of N- / 2- (1-carboxyethyl-ipropenyl) / - D-phenylglycine are suspended in 1620 ml of acetone, followed by cooling to a temperature of -57 ⁰ C. This is followed by the addition of 56.4 ml (0.55 mol) of ethyl chlorocarbonate. The mixture is stirred for a period of 15 minutes at -57 ° C., after which 0.42 ml of N-methylntorpholine are added. Stirring is continued for a further 40 minutes after which the 6-aminopenicillanic acid solution is added in one portion.

The mixture is stirred for a period of 1 hour at -45 ° C., filtered through Celite and washed twice with 200 ml of acetone. The filtrate is diluted with 385 ml of distilled water, 'whereupon during a period of 1 hour, the temperature of the filtrate to 0 ⁰ C. The pH is lowered to 1.35 using concentrated HCl. The aqueous solution is extracted with 1.5 1 of methylene chloride at ⁰ ° C. The aqueous phase is separated off, followed by the addition of dilute ammonia (27% strength by weight) until a pH of

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BATH ORIGINAL

5, T has been reached. Then 650 ml of n-propanol are added. The solution is heated to the boiling point tie, while held a period of 30 minutes at 73 ^e C under reflux and cooled to 0 ⁰ C. The separated product is filtered off and washed twice with 20 ml portions of distilled water and dried in vacuo (50 mmHg) at 45 ° C. 85 g (43.8%) of the pure anhydrous 6 "- / D - (-) --aminophenylacetamido / penicillanic acid (melting point 202 to 204 ° C.) are obtained.

Other features:

Humidity (X. Fischer) 0 8 %

D-phenylglycine content O 7%

Microbiological titration (FDA) 99 9%

Example 3

120 g (0.55 mol) of 6-aminopenicillanic acid are suspended in 200 ml of distilled water and dissolved in 85 ml of triethylamine at a temperature of 0 to +10 ⁰ C and at a pH value of 8.4. 200 ml of acetone are added to the solution, whereupon it is cooled to a temperature of -15 ° C.

185.2 g (0.65 mol) of the potassium salt of N- / 2- (1-carboxyethyl-1-propenyl / -D-phenylglycine are added in 1620 ml of acetone is then cooled to -57 ⁰ C. Then, the addition of 56.4 ml (0.55 mol) Äthylchlorcarbonat. The mixture is stirred for one. period of 15 minutes at -57 ⁰ C, followed by 0.42 ml N-methylmorpholine are added. The stirring is further for a period of 40 minutes, after which the solution of 6-aminopenicillanic acid is added in one portion.

The mixture is for a period of 1 hour at -45 ° C stirred, filtered through gelite and washed twice with 200 ml of acetone. The filtrate is diluted with 385 ml of distilled water,

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followed by maintaining the temperature of the filtrate at 0 ⁰ C for a period of 1 hour. The pH is lowered to 1.35 using concentrated HCl. The aqueous solution is extracted with 1.5 1 of methylene chloride at ⁰ ° C. The aqueous phase is separated off, whereupon dilute ammonia (27 percent by weight) is added until a pH of 5.1 has been reached. Then 700 ml of ethanol are added. The solution is heated to boiling and refluxed for a period of 30 minutes at 73 ⁰ C and then cooled to 0 ⁰ C. The precipitated product is filtered off and washed twice with 20 ml portions of distilled water and dried in vacuo (50 mmHg) at 45 ° C. 98 g (50.5%) of the pure anhydrous 6- / D (-) - & -aminophenylacetamido / -penicillanic acid (mp 202-2o4 ° C.) are obtained.

Other features:

Moisture (K. Fischer) "1.0%

D-phenylglycine content 0.5%

Microbiological titration (FDA) 99.7%

Example 4

120 g (0, '55 mol) of 6-aminopenicillanic acid are suspended in 200 ml of distilled water and dissolved in 85 ml of triethylamine at a temperature of 0 to +10 ⁰ C and at a pH value of 8.4. 200 ml of acetone are added to the solution, whereupon it is cooled to a temperature of -15 ° C.

185.2 g (0.65 mol) of the potassium salt of N- / 2- (1-carboxyethyl-ipropenyl) / -D-phenylglycine are suspended in 1620 ml of acetone is then cooled to -57 ⁰ C. Then 56.4 ml (0.55 mol) of ethyl chlorocarbonate are added. The mixture is stirred for a period of 15 minutes at -57 ⁰ C, followed by 0.42 ml N-methylmorpholine are added. Stirring is continued for a further 40 "minutes,

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whereupon the addition of the solution of G'-alinopenicillanic acid in one serving.

The mixture is stirred for a period of 1 hour at -45 ⁰ C, filtered through Celite and washed twice with 200 ml acetone. The filtrate is diluted with 335 ml of distilled water, whereupon the temperature of the filtrate is kept at 0 ⁰ C for a period of 1 hour. The pH is reduced to 1.35 by adding concentrated HCl. The aqueous solution is extracted with 1.5 1 methylene chloride at 0 ^{° C.} The aqueous phase is separated off, followed by the addition of dilute ammonia (27% by weight iq) until a pH of 5.1 has been reached. Then 600 ml of methanol are added. The solution is heated to boiling point for a time. span of 30 minutes at 73 ° C refluxed and cooled to 0 ⁰ C. The deposited product is filtered off, washed twice with 20 ml portions of distilled water and dried in vacuo (50 mmHg) at 45.degree. 80 g (41.3%) are obtained. the pure, anhydrous 6- / D (-) -Ci -aminophenylacetamido / '- penicillan acid (P. 202-204 * ⁰ C).

Other features:

Moisture (K. Fischer) 0.8%

D-phenylglycine content 0.9%

Microbiological titration (FDA) 98.3%

Example 5

120 g (0.55 mol) of 6-aminopenicillanic acid are suspended in 200 ml of distilled water and dissolved in 85 ml of triethylamine at a temperature of 0 to +10 ⁰ C and at a pH value of 8.4. The solution is added 200 ml of acetone, whereupon it is cooled to a C temperature of -15 ⁰ C.

185.2 g (0.65 mol) of the potassium salt of N- / 2- (1-carboxyethyl-i ^ propenyl) / - D'-phenylglycine are suspended in 1620 ml of acetone,

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what is cooled to -57 ^0C. Then 56.4 ml (O ₇ 55 mol) of ethyl chlorocarbonate are added. The mixture is maintained at -57 ⁰ C under stirring during a period of 15 minutes, followed by the addition of 0.42 ml of N-methylmorpholine followed. Stirring is continued for an additional 40 minutes. Then the solution of 6 ^ aminopenicillanic acid is added in one portion.

The mixture is rested for a period of 1 hour at -45 ^ ⁰ C., filtered through celite and washed twice with 200 ml acetone. The filtrate is diluted with 385 ml of distilled water, whereupon the temperature of the filtrate is kept at ⁰ ° C. for a period of 1 hour. The pH is lowered to 1.35 with concentrated HCl. The aqueous solution is extracted with 1.5 1 of chloroform at ⁰ ° C. The aqueous phase is separated off, followed by the addition of dilute ammonia (27 percent by weight) until a pH of 5.1 has been reached. Then 650 ml of isopropanol are added. The solution is heated to the boiling point, for a period of 3 0 min at 73 ⁰ C refluxed and cooled to 0 ⁰ C. The separated product is filtered off, washed twice with 20 ml portions of distilled water and dried ^{at 45 ° C. in vacuo (50 mmHg).} This gives 105 g (54.5%) of pure anhydrous 6- / D (-) - ^ - AminophenylacetamidoZ-penicillansaure (F. 202-204 ⁰ C).

Other features:

Moisture (K. Fischer) 1.2%

D-phenylglycine content 0.5%

Microbiological titration (FDA) 98.7%

Example 6

120 g (0.55 mol) of 6-aminopenicillanic acid are suspended in 200 ml of distilled water and dissolved in 85 ml of triethylamine at a temperature of 0 to 10 ^° C. and a pH of 8.4,

5 09818/1189

200 ml of acetone are added to the solution, whereupon a Temperature of -15 ° C is cooled,

185.2 g (0.65 mol) of the potassium salt of N- / 2- (1R-car boxy äthy 1-1-propenyl / iD ~ phenylglycine are suspended in 1620 ml of acetone and cooled to -57 ⁰ C. Then, 56 , 4 ml (0.55 Moll Äthylchlorcarbonat added. The mixture is stirred for a time ^ span of 15 minutes at -57 ⁰ C, followed by 0.42 ml N-methylmorpholine are added. stirring is continued for 40 minutes Zeitrspanne , whereupon the solution of 6-aminopenicillanic acid is added in one portion,

The mixture is stirred for 1 hour at -45 ° C., filtered through Celite and washed twice with 200 ml of acetone. The filtrate is diluted with 38 5 ml of distilled water, whereupon the temperature of the filtrate is increased over a period of 1 hour is kept at 0 ^° C. The pH is reduced to 1.35 using concentrated HCl. The aqueous solution is ^{extracted with 1.5 l of methylene chloride at 0 °} C. The aqueous phase is separated off, whereupon dilute ammonia (2nd 7 weight percent) was added so long has been reached until a pH value of ^ 5.1. Then 650 ml Jsopropanol are added. The solution is heated to reflux temperature. The Iso'-propanol is distilled off, followed by cooling to 0 ⁰ C The precipitated product is filtered off and washed twice with 20 ml portions of distilled water and dried in vacuo (50 mmHg) at 4 "5 ° C. This gives 105 g (54.2%) of the pure, anhydrous 6 - / D (-) - (/> W \ minophenyla cetamido / penicillanic acid (F. - 204 ⁰ C),

Other features:

Moisture (K, Fischer) 1.5%

D-phenylglycine content 0.6%

Microbiological titration 97.9%

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Example 7

120 g (0.55 mol) of 6-aminopenicillanic acid are suspended in 200 ml of distilled water and dissolved in 85 ml of triethylamine at a temperature of 0 to 10 ^° C. and at a pH of 8.4. 200 ml of acetone are added to the solution, whereupon it is cooled to a temperature of -15 ° C.

185.2 g (0.65 mol) of the potassium salt of N- / 2- (1-carboxyethyl-1-propenyl) / - D-phenylglycine are suspended in 1620 ml of acetone, whereupon the mixture is cooled to -57 ° C. Then 56.4 ml (0.55 mol) of ethyl chlorocarbonate are added. The mixture is stirred for a period of 15 minutes at -57 ⁰ C, followed by 0.8 ml of N-ethylpiperidine is added. Stirring is continued for a further 40 minutes, after which the 6-aminopenicillanic acid solution is added in one portion.

The mixture is stirred for a period of 1 hour at -45 ⁰ C, filtered through celite and washed twice with 200 ml acetone. The filtrate is diluted with 385 ml of distilled water, whereupon the temperature of the filtrate is kept .for 0 ⁰ C for a period of 1 hour. The pH is lowered to 1.35 using concentrated HCl. The aqueous solution is extracted with 1.5 1 of methylene chloride at ⁰ ° C. The aqueous phase is separated off, followed by the addition of dilute ammonia (27 percent by weight) until a pH of 5.1 has been reached. Then 650 ml of isopropanol are added. The solution is heated to reflux temperature. The isopropanol is then cooled to 0 ⁰ C is distilled off. The precipitated product is filtered off and washed twice with 20 ml portions of distilled water and dried in vacuo (50 mmHg) at 45 ° C. This gives 83 g {42.8%) of the pure, anhydrous 6- / D (-) - Ctf Aminophenylacetamid ^ -penicillansäure (F. 202-204 ⁰ C).

509818/1 1 89

Other features:

Moisture (K. Fischer) 0.5%

D-phenylglycine content 0.5%

Microbiological titration 98.3%

Example 8

120 g (0.55 mol) of 6-aminopenicillanic acid are suspended in 200 ml of distilled water and dissolved in 85 ml of triethylamine at a temperature of 0 to 10 ^° C. and a pH of 8.4. 200 ml of acetone are added to the solution, whereupon it is cooled to a temperature of -15 ° C.

176.2 g (0.65 mol) of the potassium salt of N- / 2- (1-acetyl-1-propenyl) / -D-phenylglycine are suspended in 1620 ml of acetone, whereupon the mixture is cooled to -57 ° C. Then 56.4 ml (0.55 mol). Ethyl chlorocarbonate added. The mixture is stirred for 15 minutes at -57 ° C, followed by the addition of 0.42 ml N-methylmorpholine follows. The stirring is continued for a period of time continued for a further 40 minutes, whereupon the solution of the 6-aminopenicillanic acid is added in one portion.

The mixture is stirred for a period of 1 hour at -45 ⁰ C, filtered through celite and washed twice with 200 ml portions of acetone. The filtrate is diluted with 385 ml of distilled water, whereupon the temperature of the filtrate is kept at 0 ⁰ C for a period of 1 hour. The pH is lowered to 1.35 using concentrated HCl. The aqueous solution is extracted with 1.5 1 methylene chloride at 0 ^{° C.} The aqueous phase is separated off. Then dilute ammonia (27 percent by weight) is added until a pH of 5.1 has been reached. Then 650 ml of isopropanol are added. The solution is heated to reflux temperature. Is cool - the isopropanol followed to 0 ⁰ C abge ^ is distilled off. The precipitated product is filtered off, twice with

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20 ml portions of distilled water and washed in vacuo (50 mmHg). dried at 45 ⁰ C, to give 88 g (45.4%) of pure anhydrous 6- / D (T -) .- <# - Aminophenylacetamidoy-penicillanic acid (F, 202 - 2Q4 ° C),

Other properties;

Moisture (K, Fischer). 3 _f 15%

D-phenylglycine content 0.8%

Microbiological titration 98 _f . 5%

Example 9

120 g (0.55 moles). 6VAminopenicillansäure be £ n 200 ml of distilled water was suspended and dissolved in 8 5 ml of triethylamine at a temperature of 0 to 3O ⁰ C and at a pH value of 8.4. 200 ml of acetone are added to the solution, whereupon it is cooled ^{to a temperature of -3 5 ° C.}

185.2 g (0.65 mol) of the potassium salt of M / 2- (IrpropenyDV-p-phenylglycine are suspended in 1620 ml of acetone is then cooled to -57 ⁰ C. Then, 78, 3 ml (0, 55 mole) of trimethylacetyl chloride was added. the mixture is stirred for a period of 15 minutes at -57 ⁰ C, followed by the addition of 0.42 ml of N-methylmorpholine followed connects. the stirring is continued for a time machining of a further 40 minutes, after which the Solution of 6-aminopenicillanic acid is added in one portion.

The mixture is .gerührt over a period of 3 hour at -45 ⁰ C, filtered through celite and washed twice with 200 ml of acetone The filtrate is diluted with 385 ml of distilled water, after which over a period of 1 hour, the temperature of the filtrate at O ⁰ C is held. The pH is lowered to 1.35 using concentrated PCI. The aqueous solution is treated with 1.5 l of methylene chloride at Q ⁰ C

5 0 98 18/1189

extracted. The aqueous phase is separated off, followed by the addition of dilute ammonia (27 percent by weight) until a pH of 5.1 is established. Then 650 ml of isopropanol are added. The solution is heated to reflux temperature. The isopropanol is distilled off, whereupon the mixture is cooled to 0 ° C. The precipitated product is filtered off, washed twice with 20 ml portions of distilled water and dried in vacuo (50 mmHg) at 45 ° C., 80 g (41.2%) of the pure, anhydrous 6- / D (<-1 * Oi t-amino- "phenvlacetamidoZ-penicillanic acid (F, 202 to 204 ⁰ Cl,

Other features:

Humidity (K. Fischer) 0.95%

D-phenylglycine content. 0.5%

Microbiological titration 99.3%

Example 10

120 g (0.55 mol) of 6-aminopenicillanic acid are suspended in 200 ml of distilled water and 85 ml of triethylamine in gerlöst at a temperature from 0 to 10 ⁰ C and at a pH value of 8.4 at. 200 ml of acetone are added to the solution, whereupon it is ^{cooled to a temperature of - ^ 15 0} C,

1.15,0 g (0.65 mol) of 4-phenyloxazolidin ^ 2,5-dione in 1620 ml of acetone, s \ ispendiert, is then cooled to -57 ⁰ C, then 56.4 ml (0.55 mol) Xthylchlorcarbonat added. The mixture is stirred at -57 ° C. for a period of 15 minutes, followed by the addition of 0.4 2 ml of H-rMethylmorphol.in. Stirring is continued for a further 40 minutes, after which the 6 ^ aminopenicillic acid solution is added in one portion.

The mixture is at for a period of 1 hour Stirred -45 ° C, filtered through Celite and twice with 200 ml

50981 8/1 189

Washed portions of acetone. The filtrate is diluted with 38 5 ml of distilled water, whereupon the temperature of the filtrate is kept at 0 ⁰ C for a period of 1 hour. The pH is lowered to 1.35 using concentrated HCl. The aqueous solution is extracted with 1.5 l of methylene chloride at 0 ^° C., whereupon the aqueous phase is separated off. Then dilute ammonia (27 percent by weight) is added until a pH of 5.1 has been reached. Then 650 ml of isopropanol are added. The solution is heated to reflux temperature. The isopropanol is distilled off. It is then cooled to 0 ° C. The deposited product is filtered off, washed twice with 20 ml portions of distilled water and dried in vacuo (50 mmHg) at 4 5 ° C., 93 g (48.0%) of the pure, anhydrous 6- / D (-) - > ^ - AminophenylacetamidoZ-penicillanic acid (M.p. 202 to 204 ⁰ C).

Other features:

Moisture (K. Fischer) 0.43%

D-phenylglycine content 0.5%

Microbiological titration 98.3%

Example 11

At 2O ⁰ C 100 g (0.46 mol) of 6-aminopenicillanic acid are dissolved in a mixture of 120 ml of distilled water, 120 ml of acetone and 90 ml of a 15% aqueous solution of HCl. The solution is diluted with 1100 ml of acetone and cooled ^{to -3 0 0 C.} The solution thus prepared is added over a period of 30 minutes at a temperature of -30 ⁰ C 110 g (0.53 mol) D-Phenylglycylchloridhydrochlorid and an aqueous ammonia solution (weight percent 27) to adjust the pH value of the reaction mixture within of the range from 1.8 to 2. The mixture is stirred for a period of 30 minutes at -25 ° C, then filtered, diluted with 200 ml of distilled water and extracted with 1500 ml Methylenchlordd at 0 ^Q C. The aqueous phase is separated off, whereupon the addition of ammonia (27 percent by weight) occurs

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a temperature of 0 ° C until a pH value of 5.1 is set. 500 ml of isopropanol are then added. It is stirred for 30 minutes at reflux temperature. The reaction mixture is cooled to ^{0 ° C.} The precipitated product is filtered off, washed twice with 20 ml portions of distilled water and dried in vacuo (50 mmHg) at 4 5 ⁰ C. This gives 140 g (8 6.7%) of pure anhydrous 6- / D (-) - '-AminophenylacetamidoZ-penicillanic acid (F. 202-204 ⁰ C).

Other features:

Moisture (K. Fischer) 0.8%

D-phenylglycine content 0.5%

Microbiological titration 98.5%

Example 12

At 0 ^° C., 60 g (0.28 mol) of 6-aminopenicillanic acid are suspended in 100 ml of distilled water and in 43 ml of triethylamine. dissolved. The solution is diluted with 100 ml of acetone and cooled to -15 ⁰ C.

The solution of 6-aminopenicillanic acid prepared in this way is in a portion of the suspension of 92.6 g (0.34 mol) of the potassium salt of N- / 2- (1-acetyl-i-propenyl) / - D-phenylglycine, 10 ml of acetone, 28.2 ml of methyl carbonate and 0.4 ml of N-methylpiperidine were added. The whole mixture is stirred for a period of 1 hour at a temperature of -47 ⁰ C and filtered over 18 g Celite. The residue on the filter is two times! washed with 100 ml portions of acetone. The filtrate is diluted with 192 ml of distilled water. At ⁰ ° C., the pH * value is kept at 1.2 using concentrated HCl. The solution is extracted with 75 g ml of methylene chloride. The aqueous phase is separated off, whereupon the pH ^ value is obtained at 5.5 using ammonia (27 percent by weight). The solution is in a vacuum (50 mmHg) for a period of 2 hours;

5 0 9 8 18/1189

τ- 38 τ-

the evaporated at 40 to 50 ^{0 C.} The residue is cooled ^{to 0 ° C.} The deposited product is filtered off, twice with. 10 ml portions of distilled water washed and then dried in vacuo (50 mmHgl at 50 ⁰ C dried to give 80 g (78.5%) of the trihydrate of 6- / D (-) -.% -Aminophenylacetamido / Tpenicillansäure (F, 200 up to 202 ⁰ CL,

Other properties;

Moisture (K, Fischer) .12.8%. - -

There is practically no D-phenylglycine content

Microbiological test .99.3%

Example 13

At 0 ⁰ C 120 g (0.55 mol) of 6-aminopenicillanic acid j_ _n 200 ml of distilled water was suspended and dissolved in 85 ml of triethylamine. The solution is diluted with 200 ml of acetone and cooled to -15 ⁰ C.

The solution of ÖT-aminopenicillanic acid prepared in this way is in one portion of a suspension of 90 g (0.67 mol) of N- / 2- (i-carboxyethyl ^ l-propenyliV-D ^ -phenylglycine cyanomethyl ester, 1620 ml of acetone The residue, 56.4 ml (0.55 Moll £ chlorocarbonate thy! and 0.4 ml of N-methylmorpholine was added. The whole mixture is stirred for a period of 1 hour at -45 ⁰ C and filtered over 36 g Gelite. to the filter is washed twice with 200 ml portions of acetone. The filtrate is then diluted with 385 ml of distilled water. ^{The pH is maintained at 1.35 using concentrated HCl at 0} ° C. The solution is extracted with 1500 ml of methylene chloride The aqueous phase is separated and the pH is maintained at 5.1 using an ammonia solution (27% by weight), then 650 ml of isopropanol are added and the solution is refluxed with stirring for 30 minutes, followed by them to O ⁰ C is cooled,

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* - 19 -

The deposited product is filtered off and washed twice with 20 ml portions of distilled water and then dried at 45 ° C. in vacuo (50 mmHg). This gives 98.5 g (51.0%) of pure anhydrous 6- / D (-) -OO -AminophenylacetamidoyVpenicillansäure (F, 202-204 ⁰ C).

Other features:

Moisture (K, Fischer). 0 _f 9%

D-phenylglycine content '0.5%

Microbiological test 99.4%

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Claims (8)

2A50661 claims 1. Process for the preparation of 6- / D (-) -Oi- aminophenylacetamido / penicillanic acid of the formula I. (D characterized in that a) 6-aminopenicillanic acid of the formula II HOOC (II) with a substituted D-phenylglycine of the general formula III (III) is condensed, wherein R ^ for a 2- (1-carbalkoxy) propenyl group, a 2- (1-alkylcarbonyl) propenyl group or represents a hydrogen atom, R _{2 represents} an oxycarbethoxy group, an oxyacyl group, a cyanomethylene group, a p-nitrophenyl group, a 2,4,5-trichlorophenyl group or a halogen atom, and 50981 8/1189 R ₁ and 1 * 2 can together form an oxycarbonyl group, ■ b) an extraction with a chlorinated hydrocarbon with 1 to 2 carbon atoms and 1 to 3 chlorine atoms is carried out and c) treatment with a primary or secondary aliphatic Alcohol with 1 to 4 carbon atoms is carried out. 2. The method according to claim 1, characterized in that the condensation temperature is maintained at a value of -60 to -30 ⁰ C. 3. The method according to claim 1, characterized in that the condensation in an aqueous solution of an aliphatic ketone is carried out with 3 to 6 carbon atoms. 4. The method according to claim 1, characterized in that the extraction ^{temperature between -10 and +10 0} C is kept. 5. The method according to claim 1, characterized in that the The pH of the extraction is kept between 0.5 and 3. 6. The method according to claim 1, characterized in that the treatment is carried out at a temperature between 50 and 100 ^° C. 7. The method according to claim 1, characterized in that the treatment is carried out in a slightly acidic medium. 8. The method according to any one of the preceding claims, characterized in that pure anhydrous 6- / D (-) - i £ ~ aminophenylacetamido / penicillanic acid will be produced. 50981 8/1189