GB1561293A

GB1561293A - Methampicillin lysinate and its manufacturing method

Info

Publication number: GB1561293A
Application number: GB3119176A
Authority: GB
Original assignee: Individual
Current assignee: Individual
Priority date: 1976-07-27
Filing date: 1976-07-27
Publication date: 1980-02-20

Description

(54) METHAMPICILLIN LYSINATE AND ITS MANUFACTURING METHOD (71) 1, YOUNG SUL, KIM, a Korean citizen, of Yichon-dong 302-62, Yong San-Ku, Seoul, Korea, do hereby declare the invention, for which I pray that a patent may be granted to me, and the method by which it is to be performed, to be particularly described in and by the following statement:- When penicillin-G was found for the first time, chemical instability of penicillin itself was of great influence on its activity.

Thereafter, the discovery of ampicillin derived and synthesized from 6-amino penicillanic acid improved the weakness with respect to the chemical stability of penicillin-G itself, and enlarged its use as an antibiotic by increasing the activity which was available against only Gram positive bacteria to the activity against not only Gram-positive but also Gram-negative one.

There are several problems on clinical application, for this semisynthetic penicillin has some side effects which penicillin itself has, and also has a low solubility in water.

This solubility in water is the same for ampicillin and methampicillin.

Therefore, it is made strongly acidic, or the pH is made alkaline in order to convert the hydrogen ion of the 2-carboxyl radical which is attached in the penicillanic acid into sodium salt. This free ampicillin and methampicillin, amino or methylene-amino benzyl penicillin, have low solubility in organic solvents.

According to the present invention there is provided a substance, methampicillin lysinate and/or ampicillin methylene lysinate trihydrate of the structure

6 > C 9 fcH h~ve3 I 0:c- N-c-ceoM chemical formula -JW-(tHpXtCII-COO H formula (A) in which M represents hydrogen sodium or potassium, its formula being C1i',,O6N5S, 3H2O.

The invention also includes a pharmaceutical composition comprising or consisting of the above substance.

Methampicillin lysinate is one of the very suitable seraisynthetic penicillin antibiotics which not only makes possible various liquid preparations but also leads to a high absorption rate through the gastrointestine because the solubility of methampicillin lysinate is higher than that of ampicillin or methampicillin in water at 2C"C. This pharmaceutically acceptable substance is a derivative of methylene ampicillin with L-lysine.

So the chemical name of this antibiotic Is D - (-) - 6 - [10 (N - 5' - amino - 5'carboxylpentyl amino methyl) - amino phenyl acetamido] - 3,3 - dimethyl - 7 - oxo - 4thio - 1 - azabicycleheptane - 2 - carboxylic acid trihydrate. This substance is named ampicillin methylene lysinate trihydrate and/ or methampicillin lysinate because L4ysine ;s attached to methylene aminobenzyl penicillin.

In a preferred method for the synthesis of this product, methampicillin lysinate (chemical formula A), the first step is that formaldehyde (D) is reacted with ampicillin (E) to synthesize methylol-ampicillin (C'), which is subsequently converted to methylene ampicillin (C).

As a preliminary step, in order to make this slightly soluble ampicillin more water-soluble it is converted into sodium ampicillinate by the addition of sodium/potassium carbonate or sodium/potassium bicarbonate under reaction conditions in which the pH is 7.0-8.0, at reaction temperature 7--1001C, and at the.

concentration of 0.01 mols ampicillin and 0.01 mole sodium/potassium bicarbonate.

After making ampicillin water soluble, 37 to 40 percent formaldehyde solution, equivalent to Z--10 moles of formaldehyde, is reacted with 1 mole of ampicillin, the concentration influencing the yield.

As a final step L-lysine, an amino acid, is reacted with the intermediate described above, whereby methampicillin lysinate, the last product of this synthesis, is obtained. The entire process may be effected between -50C and 70C.

The following scheme illustrates the preferred method of preparation:

Example.

A suspension of ampicillin (19.50 gm) in water (1,000 ml) was cooled to 5 0C, stirred slowly for 30 minutes to make a homogeneous sludge and then the pH adjusted to 7 to 8 by the addition of 10% sodium bicarbonate solution (51 ml).

A mixture of this solution and formalin (5.8 ml) containing more than 37 percent of formaldehyde was stirred for 1 hour continuously and then was added L-lysine (8.05 gm) while stirring for 1 hour and thereafter this solution was acidified with hydrochloric acid (7.0 ml) to adjust the pH to 2.5 to 3.0, in order to obtain a white crystalline precipitate of methampicillin L-lysinate.

The precipitate was filtered off after the prior resulting mixture was maintained at OOC for 24 hours, washed with dry acetone and then dried below 40 C to yield (54.9 percent) a white powder, M.P. 197 to 19'8 C (decompose).

The properties of this substance, methampicillin L-lysinate are solubility in water, but insolubility in ethanol, and in chloroform.

The solubility in acetic acid is 25 mg per ml, and in dimethyl-formamide 8 mg per millilitre.

The specific rotation is ( )d20 = 240 (C = 0.25), and iRf 0.765 on the thin layer chromatography with silicagel by development in a mixed solvent, i.e. acetic acid 5% and acetone 95% in conventional determination.

WHAT I CLAIM IS:- 1. The substance, methampicillin lysinate or ampicillin methylene lysinate trihydrate of the structure

in which M represents hydrogen, sodium or potassium, its formula being CHa.3Oc,N,S, 3H20.

2. A pharmaceutical composition comprising or consisting of the substance of Claim 1 as a or the active ingredient in association with a carrier.

3. A method of preparing the substance

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. The following scheme illustrates the preferred method of preparation: Example. A suspension of ampicillin (19.50 gm) in water (1,000 ml) was cooled to 5 0C, stirred slowly for 30 minutes to make a homogeneous sludge and then the pH adjusted to 7 to 8 by the addition of 10% sodium bicarbonate solution (51 ml). A mixture of this solution and formalin (5.8 ml) containing more than 37 percent of formaldehyde was stirred for 1 hour continuously and then was added L-lysine (8.05 gm) while stirring for 1 hour and thereafter this solution was acidified with hydrochloric acid (7.0 ml) to adjust the pH to 2.5 to 3.0, in order to obtain a white crystalline precipitate of methampicillin L-lysinate. The precipitate was filtered off after the prior resulting mixture was maintained at OOC for 24 hours, washed with dry acetone and then dried below 40 C to yield (54.9 percent) a white powder, M.P. 197 to 19'8 C (decompose). The properties of this substance, methampicillin L-lysinate are solubility in water, but insolubility in ethanol, and in chloroform. The solubility in acetic acid is 25 mg per ml, and in dimethyl-formamide 8 mg per millilitre. The specific rotation is ( )d20 = 240 (C = 0.25), and iRf 0.765 on the thin layer chromatography with silicagel by development in a mixed solvent, i.e. acetic acid 5% and acetone 95% in conventional determination. WHAT I CLAIM IS:-

1. The substance, methampicillin lysinate or ampicillin methylene lysinate trihydrate of the structure

3. A method of preparing the substance

of Claim 1, wherein a soluble ampicillin conversion is effected by the addition of sodium/ potassium carbonate or sodium/potassium bicarbonate under reaction conditions in which the pH is 7.O.0, at reaction temperature 7-10 C, and at the concentration of 0.01 mole ampicillin and 0.01 mole sodium/potassium bicarbonate to form sodiumlpotassium ampicillinate, which is reacted with 37 to 40% formaldehyde and thereafter L4ysine to synthesize the substance of Claim 1 by the reaction scheme illustrated.

4. A method of preparing the substance of Claim 1 according to the Example.