DE3125486A1 - METHOD FOR PRODUCING SEMI-SYNTHETIC PENICILLINES - Google Patents

Description

description

The present invention "relates to a new method for the production of semi-synthetic penicillins of the general formula I.

in which R stands for H or OH.

Semi-synthetic penicillins of formula (I) are made thanks to their broad spectrum of antibacterial activity and their increased resistance to acids and that Enzyme penicillase has been used extensively as an antibacterial agent. They are used in medicine, in particular in the treatment of stomach, intestinal, lung and urinary tract infections; They are also used as feed additives and chemotherapeutic agents for treatment used by livestock and animal diseases caused by Gram-positive and Gram-negative bacteria.

Some methods for the synthesis of semisynthetic penicillins are known, predominantly the method of Acylation of 6-aminopenicillanic acid using suitable acids is used (F.P.-Doyl, J.H. Nayler, Advances in Drug Research, Vol. 1, Ed. N.J. Harper-Simmonds, Acd. Press, London 1964, p. 21; G.V. Kaiser, S. Kukolja, Cephalosporins and Penicillins, Ed. E.H. Flynn, Acad. Press, New York - London, 1972, p. 76).

In the acylation of 6-aminopenicillanic acid by means of amino acids, the method of activating the -COOH group in the form of a mixed anhydride with O-monoalkyl carbonic acid is largely used. , - - in this case the -ΝΗ is f.eachützt group by a f ^r, s own te protecting group; the inhalation group, which is accessible by reaction with β-dicarbonyI compounds, has proven to be particularly advantageous [E. Dane, T. Dockner, Angew. Chemistry £ 6 (1964) 342; GB-PS 991-586 (1965); AAW Lang et al., J. Chem. Soc. 23SIf

Recently, a new process for the preparation of amides, peptides, penicillin and cephalosporin derivatives has been introduced by aminolysis of a previously unknown type of mixed anhydrides, available from the reaction of carboxylic acids with N-chlorocarbonylamides (our earlier application P 31 20 450.3) ' described. It was found that various N-chlorocarbonylamides, e.g. N-chlorocarbonide derivatives of butyrolactam, Valerolactam, Caprolactam, Acetanilide, N-Propylbenzaraid etc., used with different reactivity and stability depending on the particular reaction conditions used will. The possibility of using N'-chlorocarbonyl

N -acetyl .- ?, 7 "dimethyl-6-thia-3» 8-diazabicyclo (3,2,1) -octan-2-one is of particular interest as it is successfully recovered from the reaction mixture and converted to the chlorocarbonyl derivative in accordance with our earlier patent application P J.1 20 451.1 can be transferred. *. -

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

CH-COOM

. (II)

in which R has the above meanings, M stands for K or Na, R ^ from the group methoxycarbonyl, A * thoxycarbonyl,

(1-5 C) alkyl or arylcarbonyl, or an amido group is elected,

which are known as Dane-Snlae,

with N-chlorocarbonylamides of the general formula III

ο / - ^ v

Cl-C-N /

in which X is from the group bis [mono- (1-6 "C) alkyl], bis- (uxmoaryl), Μοηο (1 ~ ί5 G) alkyl odor monory], od (.> r oinem (1-6 G) Alkylddradikal, or a (1 ~ 5 C) alkyl.radikal, which contains a heteroatom from the group K, 0 or S, or a radical of the formula - (CH ₂ ) -CH ^ y ^ CH-, in which Y stands for a (1-5 C) diradical or a (1-4 C) diradical containing a heteroatom selected from N, 0 or S ₁ , while η is an integer from 0 to 3, is selected,

react, with a mixed anhydride of the general formula IV

0 0 s

Il Il /

CH-COCN NH CH ₃ CC = CH-R _{1 O. (IV)}

in which R and X have the above meaning,

is formed, which by selective aminolysis with 6-alainopenicillanic acid of Formula V

HJ * ³

- 8 CH- "~

GH

θ 'GOOH (V)

converted into the 'semi-synthetic penicillin of the formula I. will.

The use of N-chlorocarbonylamides is advanced compared to the use of carbonic acid (O-monoalkyl derivatives), thanks to their relatively good stability and the lack of them any aggressive smell they have proven to be exceptionally favorable for handling in technological working conditions proven, while the latter compounds are highly sensitive and aggressive. N-chlorocarbonyl-pyrrolidine has proven to be the most advantageous, since with amino acid salts it quickly forms a mixed anhydride, which increased compared to other anhydrides Stability in aqueous-organic media distinguishes itself, reacts.

The inventive method is carried out in such a way that a salt of the amino acid (II) with N-chlorocarbonylamide (III) in the Temperature range from -60 ° C to + 10 ° C, in an inert organic water-miscible solvent, if necessary is reacted in the presence of catalytic amounts of an organic base and then the intermediate mixed anhydride (IV) a selective aminolysis with 6-aminopenicillanic acid (V) in a temperature range from -40 C to 0 C, in a reaction medium which is water and the identical organic water-miscible solvent used in the above defined reaction of the compound (II) with the compound (III) was used, is subjected. For solubility reasons 6-aminopenicillanic acid is predominantly in its salt form, in particular as an Na or K salt, or as a triethylamine salt is used. The salt should preferably be prepared immediately prior to the reaction.

It was found that acetone and tetrahydrofuran are the The most advantageous solvents are, but any one can be used Use suitable organic, water-miscible solvents which are inert under the reaction conditions.

The organic base used, if any, can be advantageous from the group consisting of pyridine, N-methylmorpholine or N-ethylpiperidine to get voted·

The reaction can occur in the production of the intermediate compound 5 to 3> 0 minutes and for selective ainolysis about Take 1 hour, each time stirring.

The reagents can be used in stoichimetric amounts, an excess of up to 10% of the compound III however, it is more often preferred.

The resulting product (I) is isolated from the reaction mixture in the usual way and purified, 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 solvent containing V / water immiscible solvents, preferably methylene chloride or methyl isobutyl ketone. The aqueous extract is removed by evaporation from the residual organic solvent, then the pH of the solution is adjusted to 5, the suspension obtained is stirred for 1 to 5 hours at a temperature of + 5 ° to + 10 ⁰ C and finally, the product is Aspirated and * washed.

Alternatively, the product can be obtained from the aqueous extract obtained above by precipitation with ß-naphthalenesulfonic acid at a Temperature of about + 5 ° C and maintenance of the pH value of the solution at about 1.5 to 2.0 can be isolated. The precipitated one Penicillin salζ is then converted into the penicillin of the general formula (I) by separation with a liquid ion exchanger (Amberlite LA-1) or with triethylamine convicted.

The invention is illustrated by the following examples, however, in no way be restricted.

- .10 -

Preparation of 6- [D - (-) - a-Aminophfc'nylacetamido3-penicillanic acid (ampicillin) trihydrate

example 1

6-Aininoperiicillanäure (8.2 g; 38 mmol) is suspended in water (30 ml) and acetone (30 ml) and with stirring at +10 ⁰ C dropwise with a 20% HaOH solution (about 6.2 ml) postponed until complete dissolution. The solution is then cooled to a temperature of -3O C by adding liquid nitrogen.

A solution of acetone (65 ml), N-chlorocarbonylp "yiTolidin - 2-one gj 4-3 »7 mmol) and pyridine (50 mg) is added with stirring

the ri- [1-methoxycarbonylpropen-2-yl] -D - (-) - a-aminophenyl-acetic acid sodium salt (11.6 gj 42.7 mmol) was added at a temperature of -30 ° C. The reaction mixture is stirred in for 5 minutes and then. entered into the above .solution of 6-aminopenicillanic acid while stirring vigorously and maintaining the temperature of -25 C. The reaction mixture is first stirred for 1 hour and then for a further 10 to 15 minutes without cooling, the temperature of the reaction solution being allowed to rise to ^{0 ° C.}

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

Yield: 9.55 6 (62%) ampicillin trihydrate wet content: 12.9 %

Ca] Jp = + 291 ° (c >>0.5; H ₃ O)

Microb. Content: 97.5 (calculated on the dry matter) IR spectrum and thin film chronographs correspond to this Default..

Methyl isobutyl ketone (30 ml) is added to an aqueous solution of ampicillin hydroxyl chloride, which was obtained after extraction with methylene chloride according to the procedure described in Example 1, and then a solution of β- NaphthaIensulfonsäurenatriumsalz (I5 g) i ⁿ water (15Ο ml) i ^ Laxife added 15 minutes * the resulting suspension is stirred for a further 1 to 2 hours while maintaining the temperature at +5 ^0C. The precipitated crystals of the ampicillin-ß-naphthalene sulfonate are filtered off with suction and washed with methyl isobutyl ketone (10 ml). ·

Bas moist product vrird portionwise with vigorous stirring at +25 ⁰ C for 30 to 40 minutes in a mixture of water (150 ml), methyl isobutyl ketone (50 ml) and liquid ion exchanger Amberlite LA.-1 (10 ml). After ampicillin-β-naphthalene sulfonate has been added, the pH of the solution or the mixture is adjusted to 5.0 to 5.5. To

The ampicillin trihydrate is filtered off with suction and stirred for 2 hours 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 Example ^

A suspension of 6-aminopenicillanic acid (8.2 g, J8 mmol) in water (30 ml) and acetone (30 ml) is treated with triethylamine (3j84 · g >> 38 mmol) and the mixture is heated at +10 ⁰ C up to complete dissolution stirred. The clear solution

is cooled to -30 ° C by adding liquid nitrogen, after which a suspension of the mixed anhydride obtained according to the instructions of Example 1 is added will.

The reaction mixture is stirred for 1 hour at a temperature of -25 ° C. and finally according to that explained in Example 1 Process worked up.

Yield: 11.1 g (72.2%) of the product as in Example 1. Example 4

• ζ ο

A solution of acetone (100 ml), N -chlorocarbonyl-N -acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo [3,2, ioctan-2-one (12.3 g, 44 mmol) and N-methyl imorpholine (50 mg), with liquid nitrogen cooled to -40 ° C, with vigorous stirring with N- (1 -Methoxycarbony lpropen-2-yl) -D - (-) - ^ aminophenylacetic acid potassium salt (12.4 g; 43 mmol) are added, the reaction mixture is stirred for 10 minutes and then with the 6-aminopenicillanic acid solution obtained according to Example 3 is added. ·

The reaction mixture is stirred for 1 hour at -25 ° C and finally worked up according to the method explained 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 stirred at + 10 ° C with a 20 ^ KOH solution (about 10 ml) added dropwise and the resulting solution is diluted with acetone (30 ml). The solution is brought to -25 ° C by adding liquid nitrogen cooled down.

A solution of acetone (65 ml), N-chlorocarbonylpyrrolidin-2-one (6.45 g; 43.7 mmol) and N-methyl imorpholine (40 mg), with liquid Nitrogen cooled to -60 ° C, N- (1-methoxy-

carbonylpropen-2-yl) -D - (-) ^ jaminophenyl-esetic acid potassium salt (11.62 g; 40.5 mmol) are added and the reaction mixture is Stirred for 5 minutes. The suspension is then introduced into the above 6-aminopenicillanic acid solution and the reaction. solution is stirred at -25 ° C. for 1 hour.

The work-up of the reaction mixture and the isolation of the ampicillin trihydrate are explained in accordance with that described in Example 1 Procedure carried out.

Yield: 11.2 g (72.7 %) of the product, wet content: 13.3 %

G? Y ² _D ³ = + 288 ° (c = 0.5; H ₂ O)

Microb. Content: 96.3 % (calculated on the 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 at 0 C with Triethylamine (3.84 g; 38 mmol) was added. The suspension obtained is until the 6-aminopenicillanic acid has completely dissolved (about 10 minutes) stirred.

A solution of tetrahydrofuran (50 ml) and N-chlorocarbonylpyrrolidin-2-one (6.45 g; 43.7 mmol) is treated at 0 ° C with N- (1-methoxycarbonylpropen-2-yl) -D - (-) - ₀ (^ aminophenyl-acetic acid sodium salt (11.6 g; 42.7 mmol) are added and the reaction mixture is stirred for 15 minutes at 0 ° C. The mixture is then added to the above 6-aminopenicillanic acid solution and the reaction mixture becomes Stirred for 30 minutes at 0 C. 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- (1-ethoxycarbonylpropen-2-yl) -D - (-) - rJj- 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 minutes. 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 is stirred for 1 hour at -15 ° C. Finally the reaction mixture is worked up in the manner explained in Example 1 and the ampicillin trihydrate is isolated.

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

Preparation of the 6-Cb - (-) - ^ amino-p-hydroxyphenylacetamidoj -penicillanic acid (amoxicillin) trihydrate

Example 8

A solution of acetone (65 ml), N-chlorocarbonylpyrrolidin-2-one (6.4 g, 43.6 mmol) and N-methylmorpholine (40 mg) is taken under Stirring at a temperature of -40 ° C with N- (1-methoxycarbonylpropen-2-yl) -D - (-) • ^ • amino-p-hydroxyphenylacetic acid potassium salt (12.3 g; 40.5 mmol) are added and the reaction mixture is stirred at a temperature of -30 ° to -35 ° C. for 5 minutes. The resulting suspension is then poured into the 6-aminopenicillanic acid solution prepared according to the method described in Example 5 registered. The reaction solution is stirred at -25 ° C. for one hour and then adjusted to that explained in Example 1 Way worked up.

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

³ = + 293 ° (c = 0.2; H ₂ O)

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

Example 9

A solution of tetrahydrofuran (50 ml) and N-chlorocarbonylpyrrolidin-2-one (6.4 g; 43.6 mmol) is stirred at -10 ° C with N- (1-ethoxycarbonylpropen-2-yl) -D- (-) - ^ amino-p-hydroxyphenyl-acetic acid sodium salt (12 g; 40 mmol) are added and the reaction mixture is stirred for 30 minutes. Then the reaction mixture combined with the 6-aminopenicillanic acid solution prepared according to Example 6 and cooled to -10.degree. That The reaction mixture is stirred for 45 minutes, then it is worked up in the manner explained in Example 1 and that 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 at -20 ° C with N-ethylpiperidine (0.2 ml) and, after stirring for 5 minutes, with N- (1-ethoxycarbonylpropen-2-yl) -D ~ (-) - £ -aminop-hydroxyphenyl-acetic acid sodium salt (12 g; 40 mmol) mixed. The reaction mixture is stirred for 10 minutes and then to the 6-aminopenicillanic acid solution prepared according to Example 6 and cooled to -20 ° C. The received The reaction mixture is stirred for 40 minutes and according to the example 1 worked up.

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

- 16 Example 11

"5 ft

A solution of acetone (70 ml) and N -acetyl -Chlorcarbonyl-N-7, 7-d1 inethyl-G-thia-3,8-diazabicyclo [3,? ■, 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- (1-ethoxycarbonylpropen-2-yl) -D - (-) - ^ - amino-p-hydroxyphenyl-acetic acid sodium salt (12 g; 40 mmol) was added. The reaction mixture is stirred for 10 minutes, combined with the 6-aminopenicillanic acid solution obtained according to Example 3 and cooled to -10 ° C. and stirred for a further hour.

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.

Evaporation of the solvent from the organic extract

by means of and the crystallization of the residue, the N -acetyl-7,7-dimethyl-6-thia-3,8-diazabicyclo £ 3,2,1-octan-2-one isolated.

Claims (5)

PATENTANWÄLTE O i C. Ό Lt Ö U SCHIFF v. FÜNER STREHL SCHÜBEL-HOPF EBBINGHAUS FINCK MARIAHILFPLATZ 2 Λ 3, MÖNCHEN 9O POST ADDRESS: POST BOX BB O1 6O1D-BOOO MPNCHEN 85. ■ SO PROFESSIONAL REPRESENTATIVE BEFORE THE EUROPEAN PATENT OFFICE • KARL LUDWIO SCHIFF (19G1-1Ö78) DIPL. CHEM. DR. ALEXANDER V. FÜNER - DIPL. ING. PETER STREHL DIPL. CHEM. DR. URSULA SCHÜBEL-HOPF OIPL. INQ. DIETER ESBINGHAUS DR. ING. DIETER FINCK SOUR PLIVA farmaceutska, kemijska, prehrambena i kozmeticka industrija TELEFON (189) 489OM TELEX B-Sa b65 AURO D TELEGRAMME & UROMARCPA1 MUNICH June 29, 1981 DEA-22091 METHOD FOR MANUFACTURING HALF-CLAIMS 1) Method of making semi-synthetic Penicillins of the general formula I (D in which R stands for H or OH, characterized that salts of N-protected amino acids of the general formula II —CH-COOH in which R has the above meanings, M stands for K or Na, R, from the group methoxycarbonyl, ethoxycarbonyl, (1-5 C) alkyl or arylcarbonyl, or an amido group is selected, with N-chlorocarbonyl amides of the general Formula III -. ci-c- δ. ■ (in) in which X is selected from the group bis [mono- (1-6 C) alkylJ, bis- (monoaryl), mono (1-5 C) alkyl or monoaryl, or a (1-6 C) alkyl diradical, or a (1- 5 C) alkyl radical which contains a hetero atom from the group N, 0 or S, or a radical of the formula - (CH ₂ ) -CH ^- Cy ^ CH-, in which Y is a (1-5 C) diradical or a (1-4 C) diradical containing a heteroatom selected from N, 0 or S, while η is an integer from 0 to 3, is selected in a mixed anhydride of the general formula IV 0 0 CH-COCN
NlI \
H ₅ CC = CH-R ₁ δ. _(IV) in which R and X have the above meaning, are converted, which is a selective aminolysis with 6-aminopenicillanic acid of the formula V COOH is subject. 2) Method according to claim 1, characterized that 6-aminopenicillanic acid is used in the form of its water-soluble salt will. 3) Method according to claim 2, characterized that the water-soluble salt of 6-aminopenicillanic acid from its Na, K or Triethylamine salts is chosen. 4) Method according to one of the preceding claims, characterized in that the reaction of the compound (II) defined in claim 1 with the compound (ill) defined in claim 1, at a temperature in the range from -60 ° C to + 10 ° C in an organic water-miscible solvent, optionally in the presence of an organic base. 5) Method according to claims 1, 2 or 3 »thereby characterized in that selective aminolysis the compound (IV) defined in claim 1 with the compound (V) defined in claim 1 at a temperature in the range of -40 ° C to ^{0 0} C in a reaction medium which is water and the identical inert organic water-miscible solvent contains, which is used in the reaction of the compound (II) with the compound (III) is carried out.