FI63412B - NOW YOU GOT ATT FRAMSTAELLA CRYSTAL PENISILLINSYROR - Google Patents

Description

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Patent · och registerstyreisen Antokin utiajd och utLskrtfUn publiorad £ υ · υί · υ :) (32) (33) (31) Pyyd «ty Wuolkout — feftrd prlorlttt lU. OU. 73 O6.IO.73 Federal Republic of Germany-Förbunds-republiken Tyskland (DE) P 2318955-1> p 2318955.1 (71) Bayer Aktiengesellschaft, Leverkusen, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Wilfried Schröck, Wuppertal, Wuppertal -Holf Furtwängler, Wuppertal-Elberfeld, Hans Bodo König, Wuppertal-Elberfeld,

Karl Georg Metzger, Wuppertal-Elberfeld, Federal Republic of Germany-Förbundsrepubliken Hyskland (DE) (7U) Oy Kolster Ab (5U) A new way to produce crystalline penicillanic acids

The present invention relates to a new process for the preparation of crystalline penicillinic acids of general formula

O

II

/ \ P * c yCH_ N \ '1 ^

R1-SO2-N N-C-NH-CH-CONH-j-f I

\ - B J-N-y ^ CH- / I 3

O COOH

wherein R 1 is alkyl of 1 to 6 carbon atoms or alkylamino of 1 to 5 carbon atoms, and B is phenyl, hydroxyphenyl or cyclohexadien- (1,4) -1-yl, which, taking into account the asymmetry center C in both in the possible R and S configurations and as mixtures of the resulting diastereomers.

It has already become known that antibacterial agents such as ampicillin (U.S. Patent 2,985,648) have been shown to be very effective in the treatment of infections caused by gram-positive and gram-negative bacteria. However, they are not effective against infections caused by bacteria of the bacterial group Klebsiella-Aerobacter or indole-positive strains of Proteus. Although carbenicillin (U.S. Patents 3,142,673 and 3,282,926) is effective in humans in infections caused by the group of Klebsiella-Aerobacter bacteria, however, it is only effective when administered at a continuous high dose, which is only achieved by infusion.

6- (Of-biureido) -acetamido-penicillanic acids are known from U.S. Patent 3,483,188 and DE Patent 1,959,920; none of these 6- (Of-biureido) -acetamido-penicillanic acids contain any acyl residue in the nitrogen atom of the 5-position biureido residue.

The process according to the invention is characterized in that compounds of the general formula are administered

B-CH-CO-NH-j-f 3 II

NK2 y-N-Y ^ \ CH3

O COOH

* wherein B and C are as defined above, react with compounds of general formula

O

tl

r, -so2n ^^ J ^ n-cow III

wherein W is halogen, in water in the pH range 1-9 at a temperature of 0 to 50 ° C.

The penicillin compounds prepared by the process of the invention are obtained as highly pure, crystalline penicillin acids.

There is no previously known method for producing stable and pure crystalline penicillinic acids. FI patent 56 S39 discloses a process in which the acylation of compounds of the formula II is carried out in a mixture of water and water-miscible solvents. The process according to the application differs from this in that the acylation is carried out in water alone using sparingly water-soluble or insoluble acid chlorides of the formula III, whereby the yields are obtained. This can be considered surprising. Upon acidification of the reaction solution, the penicillinic acids crystallize in pure and stable form.

The penicillin compounds prepared by the process of the invention have the advantage that they do not contain any impurities or organic solvent residues. When using the method according to FI 36835, the organic solvent must be removed under the mildest possible conditions, which is very difficult to carry out completely quantitatively. Because the organic solvents used and the functional groups of the penicillins to be prepared are chemically similar, small amounts of organic solvents remain as impurities in the penicillins. If an attempt is made to remove solvent residues, for example by raising the temperature, the penicillanic acid body decomposes easily.

The penicillanic acid backbone also tends to degrade the penicillins formed during isolation by acidifying the reaction solution and extracting the free penicillinic acids with organic solvents. Dissolved penicillinic acids must be precipitated from organic solvents as the sodium salt as quickly as possible in order to avoid decomposition of the penicillinic acids.

It should be emphasized that it is surprising that the new process can be carried out in water at all, since acid halides are known to be easily hydrolyzed.

As is known from penicillin chemistry, Qf-substituted CV-aminomethylpenicillins, such as ampicillin, can be reacted with acyl carbamoylating agents such as benzoyl isocyanate or N-benzoyl-N-methylcarbamoyl chloride in inert organic solvents or methylene or in mixtures of organic solvents such as tetrahydrofuran or dimethylformamide. The use of organic solvents is necessary to achieve better solubility of carbamoylating agents and to prevent water-induced hydrolysis of carbamoylating agents. Before treating the reaction mixtures, the organic solvent must be removed under sparing conditions, which is only very poorly possible quantitatively. Due to the large number of amide bonds in the acyl ureido or acyl biureidopenicillins formed in the reaction, organic solvents such as tetrahydrofuran, ethyl acetate, methylene chloride or dimethylformamide are persistently adhered to, such penicillins are difficult to prepare from such solvents. If another drying step is added to the treatment under difficult conditions, such as at elevated temperature to remove solvent residues, the degree of degradation of the sensitive penicillanic acid core increases. It is further known that penicillins formed in carbamoylation can be isolated by acidifying the solutions and extracting the free penicillinic acids with organic solvents such as ethyl acetate. Dissolved penicillinic acid must be precipitated from the organic solvent as quickly as possible with precipitants such as the sodium salt of sodium methylhexanoate to avoid decomposition of the penicillinic acids in solution.

If 1-chlorocarbonyl-2-oxo-3-mesylimidazolidine and ampicillin are used as starting materials, the reaction procedure can be expressed, for example, by the following scheme: 0 H - (R) CCl @ SC2ff ^ -COCl + t ^ \ cH-CONH —j \ / IJ— N rt, NH S} UH3 Δ 0

COOH

A

H2 ° / NaOH CO, SO ~ N N-CONH-CH-CONH / CH3 (in solution) (j ^) COONa (continued) 5 (continued) 6 341 2 o

II

H2 O / HCl CH2SO-tf ^ N-CONH-CH-CONH / CH, ^ 1, -Ργ * ™; (Crystalline)

The compounds of general formula II used as starting materials in the present invention are known (FI patent 56,839).

The reaction according to the invention is preferably carried out at pH 5-8 or at pH 1.5-3.0.

The bases and acid-binding agents used to maintain a certain pH, for example 5 to 8, are inorganic bases, such as alkali or alkaline earth hydroxides, or inorganic acid-binding agents, such as alkaline earth oxides, alkaline earth carbonates or buffer mixtures, or organic bases. , such as triethylamine, N-methylpiperidine, or sterically hindered secondary amines such as diisopropylamine. The amount of bases used depends on the desired pH.

Reaction temperatures can vary widely. In general, work is carried out at a temperature of 0 to 50 ° C, preferably 0 to 20 ° C. The reaction can be carried out at normal pressure, but also at elevated or reduced pressure. Usually working at normal pressure.

In carrying out the process according to the invention, the reactants can be reacted in an equimolar ratio. However, it may be appropriate to use the second reactant in excess to increase the yield. For example, compounds of general formula II can be used in an excess of 0.1 to 0.3 molar equivalents and thus a slight decomposition of the reactants of general formula III in water can be achieved. Excess compounds of general formula II can be easily removed because they are readily soluble in acidic aqueous solutions. Compounds of general formula III can also be used, e.g. in an excess of 0.1 to 1.0 molar equivalents. In this case, the reactants of the general formula II are better utilized and the hydrolysis of the reactants of the general formula III in water as a side reaction is compensated. Since the reactants of general formula III used in excess are rapidly converted in water to neutral acyl ureas or acylthioureas which can be easily removed, a very pure acid can be prepared.

The reaction mixture is treated by adjusting the pH of the mixture to 1-4 with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with readily water-soluble organic acids such as oxalic acid or citric acid, whereby the penicillins of general formula I are crystallized from the aqueous phase. and dried.

Example 1

sK <R) S

CH, SO-N N-CONH-CH-CONH - ^ ^ / ^ 3 ^ Λ U O COOH. H 2 O 204 parts by weight of ampicillin trihydrate were suspended in 3000 volumes of water and adjusted to pH 8.5 with 2N sodium hydroxide while cooling the solution and adding ice cubes, whereby the ampicillin dissolved. 123 parts by weight of 1-chlorocarbonyl-2-oxo-3-mesylimidazolidine were added portionwise with stirring over 15 minutes, maintaining the pH with sodium hydroxide at 7-8, and stirred for a further 3 hours, at which time the pH 7 In order to preserve -8, it was no longer necessary to add sodium hydroxide, and a clear solution had formed. By the dropwise addition of 1N hydrochloric acid, the pH was adjusted to 2.0 within 1 hour with vigorous stirring, whereby penicillinic acid crystallized. Stirring was continued for 30 min under ice-cooling, 163412 was suction filtered, reslurried in 6000 volumes of water, stirred vigorously for 15 min, suction filtered again and the operation was repeated once more. The strongly aqueous crystal cake thus obtained was comminuted, and dried with stirring and pounding in a mortar for 24 hours under a fan. The product was placed in a vacuum oven containing 12 hours, but no significant weight loss was observed.

Yield: 254 parts by weight = 90.5% of theory (microscopically small needles) of D-O '- [' (2-oxo-3-mesylimidazolidin-1-yl) carbonylamino] benzylpenicillinic acid monohydrate.

Β-lactam content (iodometrically): 94% β-lactam content (enzymatically): 100% β-lactam content did not change when the product was stored for 2 months at room temperature.

Water content according to Fischer: 3.6% = 1.1 moles.

Penicillin content (uniform main product) 97.5% of dry matter (according to analytical Craig distribution).

Analysis: Calculated (1.1 moles of H 2 O): C 45.1 H 4.9 N 12.5 S11.5 Found: C 44.3 H4.4 N 12.1 S 22.5 IR spectrum 3700 - 2800, 3355 , 3320, 3063, 3025, 2978, 2930, 1770, 1720, 1668, 1517, 1389, 1354, 1253, 1210, 1168, 1130, 973 and 764 cm -1 (KBr) NMR spectrum (in CD 3 OD) ' t = 2.4 - 2.8 (5H), 4.4 (1H), 4.5 (2H), 5.7 (1H), 6.0 - 6.4 (4H), 6.7 (3H), 8.5 (3H) and 8.6 ppm (3H).

Example 2 / CCk (RI / S \ / CH3 CH -, - SO_-N N-CO-NH-CH-CO-NH - f

3 2 w A A-A

II O COOH * H 2 ° 2.5 parts by weight of D-Of-amino-1,4-cyclohexadienyl (1) -methylpenicillin were suspended in 50 parts by volume of water, brought into solution by adding just the required amount of 2N sodium β 6341 2 hydroxide, and finally 1-chlorocarbonyl-2-oxo-3-methylsulfonylimidazolidine (1.6 parts by weight) was added under ice / water cooling and maintaining the pH of the mixture at 7 by adding 2N sodium hydroxide. After no more sodium hydroxide was consumed, the reaction mixture was slowly acidified with 1N hydrochloric acid (30 min, pH 2). The free acid precipitated D-Of - [* (2-oxo-3-methylsulfonylimidazolidin-1-yl) carbonylamino] -1,4-cyclohexanedienyl-1-methylpenicillin was suction filtered, washed with water and dried in air or in a desiccator. It was observed under a microscope that penicillin was in crystalline form (as needles).

Yield 2.5 parts by weight (65% of theory) β-lactam content: 92.3%

Analysis: Calculated (as monohydrate): C 45.0 H 5.2 N 12.5 S 11.4 Found: C 44.9 H 5.3 N 12.4 S 11.2 NMR spectrum (in CD iOD): Z = 4.05 (1H), 4.25 (2H), 4.4 (2H), 4.95 (1H), 5.6 (1H), 6.05 (4H), 6.65 (3H), 7.25 (4H) and 8.2-8.5 ppm (6H).

IR spectrum (in Nujol; carbonyl region): 1780, 1735, 1670 and 1530 cm-1.

Example 3 (R) SN / CH3 CH -SO - N N-CO-NH-CH-CO-NH -, - / / V_ „\ —j i. 3

O COOH

V

OH

2.5 parts by weight of D-PT-amino-p-hydroxy-benzyl-penicillin trihydrate were reacted with 1.3 parts by weight of 1-chlorocarbonyl-2-oxo-3-methylsulfonylimidazolidine as described in Example 2 to give D-O - ['(2-Oxor-3-methylsulfonyl-imidazolidin-1-yl) -carbonyl-amino] -N-hydroxy-benzylpenicillin in 60% yield. It was found under a microscope that penicillin was in crystalline form 9,63412 (as needles).

Β-lactam content: 94%.

Analysis: Calculated (as dihydrate): C 42.6 H 4.9 N 11.8 S 10.8 Found: C 42.9 H 4.5 N 11.9 S 11.0 NMR spectrum (in CD 3 OD): t = 2.5 - 2.8 (2H), 3.0 - 3.3 (2H), 4.3 - 4.6 (3H), 5.35 (1H), 5.9 - 6.3 (4 H), 6.65 (3 H) and 8.3 - 8.6 ppm (6 H).

IR spectrum (in Nujol; carbonyl region): 1780, 1735, 1670 and 1525 cm-1.

Example 4

(R) s .✓CH

CH, -SO, - N N-CO-NH-CH-CO-NH- f J. Ho0 ^ X 0Xv ^ "CH3

LsJJ COOH

204 parts by weight of ampicillin trihydrate were suspended in 2400 parts by volume of ice water. Under external cooling and with good stirring, 51 parts by weight of triethylamine, the highly water-soluble triethylamine salt of ampicillin, were prepared at 0 to 5 ° C. The pH of the solution was 8.5. Within 30 minutes, 116 parts by weight of 1-chlorocarbonyl-2-oxo-3-mesylimidazolidine were added portionwise at 0 to 5 ° C. The pH was maintained at 7-8 by the addition of triethylamine. The mixture was stirred for a further 5 hours at 0-5 ° C and pH 7-8. With dilute hydrochloric acid (1: 1), the pH was adjusted to 2 under ice-cooling. Stirred for 30 min. The crystallized penicillinic acid was separated by centrifugation, the resulting wet product was slurried in 5,000 volumes of distilled water and stirred for 30 min at room temperature. Penicillinic acid was centrifuged again. The slurry was repeated until the mother liquor was chloride free. The product was dried at 20-25 ° C in a stream of air until a constant weight was reached.

Yield: D-O '- [(2-oxo-3-mesylimidazolidin-1-yl) carbonylamino] benzyl penicillanic acid monohydrate 245 to 255 parts by weight, i.e. 87.5 to 91% of theory.

Β-lactam content (iodometrically): 91% β-lactam content (enzymatically): 90% 6341 2 10

Example 5 (Compound formula same as in Example 4).

204 parts by weight of ampicillin trihydrate were suspended in 2400 parts by volume of ice water. With external cooling and good stirring at 0 to 5 ° C, a 10% sodium hydroxide solution (20 parts by weight of sodium hydroxide) was prepared, the sodium salt solution being adjusted to pH 8.5. Within 30 minutes, 116 parts by weight of 1-chlorocarbonyl-2-oxo-3-mesylimidazolidine were added portionwise at 0 to 5 ° C. The pH was maintained between 7 and 8 by the addition of triethylamine. The mixture was stirred for a further 5 hours at 0-5 ° C and pH 7-8. With dilute hydrochloric acid (1: 1), the pH of the ice-cold solution was adjusted to 2. Stirred for 30 min. The crystallized peniclinic acid was separated by centrifugation. The resulting wet product was slurried in 5,000 volumes of distilled water and stirred for 30 min at room temperature, and centrifuged again. The slurry and centrifugation were repeated until the mother liquor was free of chloride. The product was dried at 20-25 ° C in a stream of air until a constant weight was reached.

The yield of D-C '- [' (2-oxo-3-mesylimidazolidin-1-yl) carbonylamine] benzylpenicillinic acid monohydrate was 235 to 250 parts by weight, i.e. 84 to 89.5% of theory.

Example 6 (compound of the same formula as in Example 4) 204 parts by weight of ampicillin trihydrate were suspended in 2400 parts by volume of ice water. With external cooling and good stirring, a highly water-soluble triethylamine salt of ampicillin was prepared by adding 51 parts by weight of triethylamine to 51 parts by weight. The pH of the solution was 8.5. within half an hour was added to 116 parts by weight of 1-chlorocarbonyl-2-oxo-3-mesyl-imidazolidine portions at 0 - 5 ° C. The pH was maintained at 7-8 by the addition of 10% sodium hydroxide.

The mixture was stirred for a further 5 hours at 0-5 ° C and pH 7-8. Dilute hydrochloric acid (1: 1) brought the pH to 2 under ice-cooling. Stirred for 30 min. The crystallized penicillinic acid was separated by centrifugation. The resulting wet product was slurried in 5,000 volumes of distilled water and stirred for 30 minutes at room temperature. Centrifugation and slurry were repeated until the mother liquor was chloride free.

11 6341 2

The product was dried at 20-25 ° C in a stream of air until a constant weight was reached.

The yield of D-ex '- [(2-oxo-3-mesylimidazolidin-1-yl) carbonylamino] -7-benzylpenicillinic acid monohydrate was 230-240 parts by weight, i.e. 82-85.5% of theory.

Example 7

O

CH3NH-SO2-N N-CONH-CH-CONH-1-f '-' (R) 3

u COOH

4.03 parts by weight of ambicillin trihydrate were reacted with 2.42 parts by weight of 1-chlorocarbonyl-2-oxo-3-methylaminosulfonylimidazolidine as described in Example 1 to give D-O -3-methylaminosulfonyl (imidazolidin-1-yl) carbonylamino / benzylpenicillin free acid in 65% yield.

NMR spectrum (in CD 3 OD):% = 2.3 - 2.8 (5H), 4.4 (1H), 4.55 (2H), 5.8 (1H), 6.5 (4H), 7.25 (3H), 8.45 (3H) and 8.5 ppm (3H).

Claims (2)

Claim: A process for the preparation of crystalline penicillinic acids of the general formula H 0 / t * / S ^ CH3 R1-SO2-lf and ^ -C-NH-p-CONH - - ^ 1 B <r N * 3 COOH in which is alkyl of 1 to 6 carbon atoms or alkylamino / of 1 to 5 carbon atoms, and B is phenyl, hydroxyphenyl or cyclohexadien- (1,4) -1-yl, which, taking into account both possible centers of asymmetry, In the R and S configurations and as mixtures of the resulting diastereomers, characterized in that the compounds of the general formula B-CH-CO-NH-S CH3 II qu 0 COOH * wherein B and C are as defined above, react with compounds of general formula O R 111 where W is halogen in water at pH 1-9 at 0-50 ° C.