CH650510A5 - METHOD FOR PRODUCING SEMI-SYNTHETIC PENICILLINES. - Google Patents

Description

25 The present invention relates to a new process for the production of semi-synthetic penicillins of the general

Formula I.

CII-C-NH — f s ..

35

0 (I)

■ N.

GII-

GH-

COOH

is subjected.

in which R stands for H or OH.

40 Semi-synthetic penicillins of the formula (I) are used to a large extent as antibacterial agents thanks to their broad antibacterial activity spectrum and their increased resistance to acids and the enzyme penicillase. They are used in medicine, especially in the treatment of gastrointestinal, lung and urinary tract infections; they are also used as feed additives and chemotherapeutic agents for treating livestock and animal diseases caused by Gram-positive and Gram-negative bacteria.

Some methods are known for the synthesis of semi-synthetic penicillins, the method of acylation of 6-aminopenicillanic acid using suitable acids being predominantly used (FP Doyl, JH Nayler, Advances in Drug Research, Vol. 1, Ed. NJ Harper- Simmonds, Acd. Press, 55 London 1964, p. 21; GV Kaiser, S. Kukolja, Cephalosporins and Penicillins, Ed. EH Flynn, Acad. Pres, New York-London, 1972, p. 76).

In the acylation of 6-aminopenicillanic acid using amino acids, the method of activating the 60 -COOH group in the form of a mixed anhydride with O-monoalkylcarbonic acid is largely used. In this case the -NH2 group is protected by a suitable protective group; the enamine group, which is accessible through the reaction with β-dicarbonyl compounds, has proven to be particularly advantageous 65 [E. Dane, T. Dockner, Angew. Chemie 76 (1974) 342; GB-PS 991586 (1965); A.A.W. Lang et al., J. Chem. Soc. 1971, 1920].

Recently, a new process for the production of amides, peptides, penicillin and cephalosporin derivatives was launched

650 510

carried out by aminolysis of a previously known type of mixed anhydrides, obtainable in the reaction of carboxylic acids with N-chlorocarbonylamides. It has been found that various N-chlorocarbonylamides, e.g. B. N-chlorocarbonyl derivatives of butyrolactam, valerolactam, caprolactam, acetane 5 ilide, N-propylbenzamide, etc., with different reactivity and stability depending on the reaction conditions used. The possibility of using N3-chlorocarbonyl-N8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo (3,2, l) -octan-2-one is of particular interest since it is successful the reaction mixture can be recovered and converted into the chlorocarbonyl derivative.

We have now found that salts of N-protected amino acids of the general formula II

15

H

Y_ /

^ -ÇH-

COOK

HH

(II)

20th

in which R has the above meanings, M represents bait Na, Ri is selected from the group methoxycarbonyl, ethoxycarbonyl, (1-5 C) alkyl- or arylcarbonyl, or an amido group, which are known under the name Dane salts N-chlorocarbonylamides of the general formula in

25th

°

c

II

0

(III)

30th

35

40

in which X is a C1-C6 alkylene group or a group of the formula

-CH0-CH-S-C (CH,), - CH-

2 I I

N 1

[

COCH_

represents, react, wherein a mixed anhydride of general formula IV

S / X

ÇH-C-0-C-N

NH VC

'»

(IV)

50

H5C-C = CH-B1 w in which R and X have the meaning given above, 55 which is formed by selective aminolysis with 6-aminopenicillanic acid of the formula V.

q CH,

60 i,

(V)

derivatives). Thanks to their relatively good stability and the absence of any aggressive smell, they have proven to be exceptionally convenient to handle in technological working conditions, while the latter compounds are highly sensitive and aggressive. N-chlorocarbonyl-pyrrolidine has proven to be the most advantageous, since it reacts quickly with amino acid salts to form a mixed anhydride, which is distinguished from other anhydrides by increased stability in aqueous-organic media.

The process according to the invention is preferably carried out in such a way that a salt of the amino acid (II) with N-chlorocarbonylamide (HI) in the temperature range from -60 ° to + 10 ° C. in an inert organic water-miscible solvent, optionally in the presence of catalytic amounts an organic base is reacted and then the intermediate mixed anhydride (IV) a selective aminolysis with 6-aminopenicillanic acid (V) in a temperature range from -40 ° to 0 ° C, in a reaction medium containing water and the identical organic water-miscible solvent, which at the reaction of the compound (II) with the compound (IH) defined above is used, is subjected. For reasons of solubility, 6-aminopenicillanic acid is predominantly used in its salt form, in particular as an alkali metal salt, preferably as a Na or K salt, or as a triethylamine salt. The salt should preferably be produced directly from the reaction.

It has been found that acetone and tetrahydrofuran are the most advantageous solvents, but any suitable organic water-miscible solvent which is inert under the reaction conditions can be used.

The organic base which may be used can advantageously be selected from the group pyridine, N-methylmorpholine or N-ethylpiperidine.

The reaction can take from 5 to 30 minutes for the preparation of the intermediate compound (IV) and about 1 hour for the selective aminolysis, in each case with stirring.

The reagents can be used in stoichiometric amounts, but an excess of up to 10% of compound III is more preferred.

The product (I) obtained is isolated and purified from the reaction mixture in a conventional manner, e.g. by adjusting the pH to about 2 by adding a mineral acid and then extracting the organic solvent and the remaining organic components with a suitable water-immiscible solvent, preferably methylene chloride or methyl isobutyl ketone. The aqueous extract is freed of the remaining organic solvent by evaporation, then the pH of the solution is adjusted to 5, the suspension obtained is stirred for 1 to 5 h at a temperature of + 5 ° to + 10 ° C, and finally the product aspirated and washed.

Alternatively, the product can be isolated from the aqueous extract obtained above by precipitation with β-naphthalenesulfonic acid at a temperature of about + 5 ° C and maintaining the pH of the solution at about 1.5 to 2.0. The precipitated penicillin salt is then converted into the penicillin of the general formula (I) by separation with a liquid ion exchanger (ÄmberliteR LA-1) or with triethylamine.

The following examples are intended to illustrate the invention, but in no way limit it.

COOK

is converted into the semi-synthetic penicillin of formula I.

The use of N-chlorocarbonylamides is advanced compared to the use of carbonic acid (0-monoalkyl-

Preparation of 6- [D - (-) - a-aminophenylacetamido] penicillanic acid (ampicillin) trihydrate

65 Example 1

6-aminopenicillanic acid (8.2 g; 38 mmol) is suspended in water (30 ml) and acetone (30 ml) and added dropwise with a 20% NaOH solution (approx

650 510 4

6.2 ml) was added to complete dissolution. The solution is then cooled to a temperature of -30 ° C. by adding liquid nitrogen.

A solution of acetone (65 ml), N-chlorocarbonylpyrrolidin-2-one (6.45 g; 43.7 mmol) and pyridine (50 mg) is stirred 5 at a temperature of -30 ° C with the N- [ l-Methoxycarbo-nylpropen-2-y]] - D - (-) - a-aminopheny] -acetic acid sodium salt (11.6 g; 42.7 mmol) was added. The reaction mixture is stirred for a further 5 min and then introduced into the above solution of 6-aminopenicillanic acid with vigorous stirring and maintaining the temperature of -25 ° C. The reaction mixture is first stirred for 1 h and then for a further 10 to 15 min without cooling, the temperature of the reaction solution being allowed to rise to 0.degree.

While stirring and maintaining the temperature at 0 ° C., a dilute (1: 1) aqueous HCl solution is added dropwise to a constant pH of 2. Cold methylene chloride (150 ml, + 5 ° C.) is then added, and the mixture is stirred for 2 min. The aqueous layer is separated and the residues of the organic solvent are removed by evaporation at reduced pressure (about 20 mbar) and the bath temperature 20 of 10 ° C. The remaining slurry is filtered and the pH of the filtrate is adjusted to 5 by adding a 20% NaOH solution. The suspension obtained is stirred at + 5 ° C for 3 h. The deposited crystals are suction filtered and washed with cold water (10 ml) and acetone (5 ml).

Yield: 9.55 g (62%) ampicillin trihydrate wet content «12.9%

[aß = + 291 ° (c = 0.5; HzO)

Microb. Content: 97.5 (calculated on dry substance) 30 IR spectrum and thin layer chromatography correspond to the standard.

Example 2

Methyl isobutyl ketone (30 ml) is added to an aqueous solution of ampicillin hydrochloride, which was obtained after extraction with methylene chloride according to the procedure described in Example 1, and then a solution is added with stirring at a temperature of + 5 ° C of β-naphthalene-sulfonic acid sodium salt (15 g) in water (150 ml) over the course of 40 for 15 min. The suspension obtained is stirred for a further 1 to 2 hours while maintaining the temperature at + 5 ° C. The crystals of the ampicillin-β-naphthalene sulfonate which have separated out are filtered off with suction and washed with methyl isobutyl ketone (10 ml). 45

The moist product is added in portions with intensive stirring at + 25 ° C for 30 to 40 min in a mixture of water (150 ml), methyl isobutyl ketone (50 ml) and liquid ion exchanger AmberliteR LA-1 (10 ml). After the addition of ampicillin-β-naphthalenesulfonate, the pH 50 of the solution or the mixture is adjusted to 5.0 to 5.5. After stirring for two hours, the ampicillin trihydrate is filtered off and washed with methyl isobutyl ketone (10 ml) and then with acetone (5 ml).

Yield: 10.2 g (66.2%) of the product as in Example 1. 55

Example 3

Triethylamine (3.84 g; 38 mmol) is added to a suspension of 6-aminopenicillanic acid (8.2 g, 38 mmol) in water (30 ml) and acetone (30 ml) and the mixture is stirred at + 10 ° C stirred to 60 to complete dissolution. The clear solution is cooled to −30 ° C. by adding liquid nitrogen, after which it is mixed with a suspension of the mixed anhydride obtained according to the instructions in Example 1.

The reaction mixture is stirred for 1 hour at a temperature of 65-25 ° C. and finally worked up by the process described in Example 1.

Yield: 11.1 g (72.2%) of the product as in Example 1.

Example 4

A solution of acetone (100 ml), N3-chlorocarbonyl-N8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo [3,2, l] octan-2-one (12.3 g, 44 mmol) and N-methylmorpholine (50 mg), cooled to -40 ° C. with liquid nitrogen, is stirred vigorously with N- (l-methoxycarbonylpropen-2-yl) -D - (-) - a-amino-phenyl- potassium acetate salt (12.4 g; 43 mmol) are added, the reaction mixture is stirred for 10 min and then the 6-aminopenicillanic acid solution obtained according to Example 3 is added.

The reaction mixture is stirred for 1 h at -25 ° C and finally worked up according to the procedure described in Example 1.

Yield: 8.47 g (55%) of a product whose quality corresponds to that obtained in Example 1.

Example 5

A suspension of 6-aminopenicillanic acid (8.2 g; 38 mmol) in water (30 ml) is added dropwise with a 20% KOH solution (approx. 10 ml) at + 10 ° C., and the resulting solution is diluted with acetone (30 ml). The solution is cooled to -25 ° C by adding liquid nitrogen.

A solution of acetone (65 ml), N-chlorocarbonylpyrrolidin-2-one (6.45 g; 43.7 mmol) and N-methylmorpholine (40 mg), cooled to -60 ° C with liquid nitrogen, is cooled with N- (1-Methoxycarbonylpropen-2-yl) -D - (-) - a-aminophenyl-acetic acid, potassium salt (11.62 g; 40.5 mmol) is added, and the reaction mixture is stirred for 5 min. The suspension is then introduced into the above 6-aminopenicillanic acid solution and the reaction solution is stirred for 1 h at -25 ° C.

The work-up of the reaction mixture and the isolation of the ampicillin trihydrate are carried out according to the method explained in Example 1.

Yield: 11.2 g (72.7%) of the product

Wet content: 13.3%

[ocjo = + 288 ° (c = 0.5; H20)

Microb. Content: 96.3% (calculated on dry matter)

IR spectrum and thin layer chromatography correspond to the standard.

Example 6

6-Aminopenicillanic acid (8.2 g; 38 mmol) is suspended in water (30 ml) and tetrahydrofuran (30 ml) and triethylamine (3.84 g; 38 mmol) is added at 0 ° C. The suspension obtained is stirred until the 6-aminopenicillanic acid has completely dissolved (about 10 min).

A solution of tetrahydrofuran (50 ml) and N-chlorocarbonylpyrrolidin-2-one (6.45 g; 43.7 mmol) is dissolved at 0 ° C. with N- (l-methoxycarbonylpropen-2-yl) -D - (-) a-aminophenyl-acetic acid sodium salt (11.6 g; 42.7 mmol) was added, and the reaction mixture was stirred at 0 ° C. for 15 min. The mixture is then introduced into the above 6-aminopenicillanic acid solution, and the reaction mixture is stirred at 0 ° C. for 30 minutes. Finally, the reaction mixture is worked up in the manner explained in Example 2 and the ampicillin trihydrate is isolated.

Yield: 7.9 g (51.5%) of the ampicillin trihydrate

Example 7

A solution of tetrahydrofuran (50 ml) and N-chlorocarbonylpyrrolidin-2-one (6.45 g; 43.7 mmol) is mixed with the N- (l-ethoxycarbonylpropen-2-yl) -D - (-) - a aminophenyl acetic acid sodium salt (11.41 g; 40 mmol) was added at a temperature of -15 ° C, and the suspension was stirred vigorously for 10 min. The mixture is then introduced into a solution of 6-aminopenicillanic acid obtained according to Example 6 and cooled to −15 ° C.

The reaction mixture was stirred at -15 ° C for 1 h. Finally, the reaction mixture is worked up and the ampicillin trihydriate isolated in the manner explained in Example 1.

Yield: 10 g (65.3%) of the ampicillin trihydrate.

5

Preparation of the 6- [D - (-) - a-amino-p-hydroxyphenyIacetamido] penicillanic acid (amoxicillin) trihydrate

Example 8

A solution of acetone (65, ml), N-chlorocarbonylpyrrolidinio 2-one (6.4 g, 43.6 mmol) and N-methylmorpholine (40 mg) is stirred with a temperature of -40 ° C with N- (l-Meth-oxycarbonylpropen-2-yl) -D - (-) - a-amino-p-hydroxyphenyl-acetic acid potassium salt (12.3 g; 40.5 mmol) is added, and the reaction mixture is 5 min at a temperature of -30 ° to î5-35 ° C stirred. The resulting suspension is then introduced into the 6-aminopenicillanic acid solution prepared according to the method described in Example 5. The reaction solution is stirred for 1 h at -25 ° C and worked up in the manner explained in Example 1. 2o

Yield: 10 g (62.6%) of the amoxicillin trihydrate. Wet content: 13.2%.

[aß = + 293 ° (c = 0.2; H20)

Microb. Content: 98.3% (calculated on dry substance) IR spectrum and thin layer chromatography correspond to 25 the standard.

Example 9

A solution of tetrahydrofuran (50 ml) and N-chlorocarbonyl pyrrolidin-2-one (6.4 g; 43.6 mmol) is stirred with 30-10 ° C with N- (l-ethoxycarbonylpropen-2-yl) -D - (-) - a-amino-p-hydoxyphenyl-acetic acid sodium salt (12 g; 40 mmol) are added, and the reaction mixture is stirred for 30 min. Then the reaction mixture is combined with the 6-aminopenicillanic acid solution prepared according to Example 6 and cooled to 10 ° C. The reaction mixture is stirred for 45 min, then

650 510

it is worked up in the manner explained in Example 1 and the product is isolated.

Yield: 11.2 g (70.5%) of the amoxicillin trihydrate, the quality of which corresponds to that obtained in Example 8.

Example 10

A solution of tetrahydrofuran (65 ml) and N-chlorocarbonylpyrrolidin-2-one (6.4 g; 43.6 mmol) is added at -20 ° C with N-ethylpiperidine (0.2 ml) and, after 5 min has been stirred, mixed with N- (l-ethoxycarbonylpropen-2-yl) -D - (-) - a-amino-p-hydroxyphenyl-acetic acid sodium salt (12 g; 40 mmol). The reaction mixture is stirred for 10 min and then added to the 6-aminopenicillanic acid solution prepared according to Example 6 and cooled to −20 ° C. The reaction mixture obtained is stirred for 40 min and worked up according to Example 1.

Yield: 11.5 g (72.2%) of the amoxicillin trihydrate, the quality of which corresponds to that obtained in Example 8.

Example 11

A solution of acetone (70 ml) and N3-chlorocarbonyl-N8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo [3,2,1] octan-2-one (12.3 g; 44 mmol) is mixed with pyridine (0.1 ml) at a temperature of -10 ° C and with vigorous stirring, and then N- (l-ethoxycarbonylpropen-2-yl) -D - (-) - a-amino -p-hydroxyphenyl acetic acid sodium salt (12 g; 40 mmol) added. The reaction mixture is stirred for 10 min, combined with the 6-amino-penicillanic acid solution obtained according to Example 3 and cooled to −10 ° C. and stirring is continued for 1 h.

The reaction mixture is cooled and finally worked up in the manner explained in Example 1.

Yield: 9.9 g (62.4%) of the amoxicillin trihydrate

The N8-acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo [3,2,1] octan-2-one is isolated from the organic extract by evaporation of the solvent and crystallization of the residue.

M

Claims (5)

650 510 1. Process for the preparation of semi-synthetic penicillins of the general formula I CGOH in which R is H or OH, characterized in that salts of N-protected amino acids of the general formula II R CH-COOM ira (II) in which R has the above meanings, M represents K or Na, Rj is selected from the group methoxycarbonyl, ethoxycarbonyl, (1-5 C) alkyl- or arylcarbonyl, or an amido group, with N-chlorocarbonylamides of the general formula ni 0 Cl-C-1 X ^ J n (Iii) C. tf 0 in which X is a Q-Q alkylene group or a group of the formula -CH0-CH-S-C (CH_) 0-CH-2 | 3 2 | N 1 I. COCH3 represents, in a mixed anhydride of the general formula IV 0 0 CH-C-O-C-N \ (IV) H3C-C = CH-i? 1 G rt o in which R and X have the meaning given above, which is a selective aminolysis with 6-aminopenicillanic acid of the formula V (V) OüOH 2. The method according to claim 1, characterized in that the 6-aminopenicillanic acid is used in the form of its water-soluble salt. 2nd PATENT CLAIMS 3. The method according to claim 2, characterized in that 5 the water-soluble salt of 6-aminopenicillanic acid from them Na, K or triethylamine salts is selected. 4. The method according to any one of the preceding claims, characterized in that the reaction of the compound (II), defined in claim 1, with the compound (III), defined in Claim 10, at a temperature in the range of -60 ° to + 10 ° C in an organic water-miscible solvent, optionally in the presence of an organic base. 5. The method according to claims 1, 2 or 3, characterized in that the selective aminolysis of the compound (IV), defined in claim 1, with the compound (V) defined in claim 1, at a temperature in the range of -40 ° to 0 ° C in a reaction medium containing water and the identical inert organic water-miscible solvent, which at 20 ches the reaction of the compound (II) with the compound (III) is carried out.