KR800000604B1 - Process for preparing parenteral o-formyl cephamandole sodium salt - Google Patents

Abstract

O-Formyl cdphamandole sodium salt was prepd. by esterifying D-(-)-mandelic acid with HCO2H, chlorinating HCO2CHC6H5CO2H, acylating the 7-aminocephemcarboxylic acid with HCO2CHC6H5COCL and converting the acid into sodium salt. Thus, stable parenteral o-formyl cephamandole sodium salt was obtained by mixing the sodium salt with K2CO3, Li2CO3, Na2 Co3,or tris(hydroxymethyl)aminomethane.

Description

Method for preparing 0-formyl sephamandol sodium salt for parenteral use

The present invention is antibiotic antibiotic 7- (D-2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylchiomethyl for the treatment of bacterial infection in warm-blooded animals The present invention relates to a method for producing an antibiotic composition which is stable in an aqueous solution using) -3-cefe-4-carboxylic acid natorium salt as an active substance.

Cephalosporin antibiotic 7- (D-2-hydroxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4- The carboxylic acid (sephamandol) and its pharmacologically possible salts are represented by the following structural formula:

US Patent No. 3,641,021, filed February 8, 1972. This very potent antibiotic is very potent when administered parenterally to warm-blooded animals infected with pathogenic bacteria. However, it was very difficult for these antibiotics to achieve the high purity and dry stability required for pharmaceutical preparations.

Therefore, it has been contemplated to prepare salts and derivatives of these antibiotics which have the same antimicrobial activity as the original antibiotics or provide the original antibiotics under the administration while having stability in high purity and dry condition meeting those requirements. .

7- (D-2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) which is a 0-formyl derivative of the sodium salt of the antibiotic Sodium -3-cefe-4-carboxylic acid (0-formyl sepamandol) was prepared as a high purity stable crystalline compound suitable for parenteral administration. This derivative is represented by the following structural formula and described in US Pat. No. 3,641,021 as an intermediate useful for the preparation of the aforementioned antibiotic.

For convenience of naming, this antibiotic is referred to herein as "0-form antibiotic salt."

7- (D-2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4- made in high purity and stable crystalline form Pharmaceuticals containing sodium carboxylate salts and their alkali metal carbonates, preferably sodium carbonate or tris (hydroxymethyl) aminomethane (tris buffer), are prepared in single dose form for parenteral administration.

The antibiotic preparation of the present invention is prepared as active ingredient 7- (D-2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3- Cefem-4-carboxylic acid sodium salt. Antibiotic salts are obtained in the form of crystalline salts of anhydrides, monohydrates, or dihydrates that are stable for at least one week at 60 ° C in a dry state. This salt is very soluble in water and easily forms a 25% solution at 25 ° C. The water used to dissolve the pharmaceutical composition herein is all sterile tablets.

In the dry state, the crystalline salt is stable, but the dilute aqueous solution has a slightly poor turbidity between pH 7-9, which means that the formic acid ester is hydrolyzed.

When the formic acid ester is hydrolyzed, 7- (D-2-hydroxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid Sodium salt and formic acid are formed, the pH of the solution drops, and at low pH, the antibiotic salt is neutralized, which causes the original antibiotic 7- (D-2-hydroxy-2-phenylacetamido) -3- (1- There is some precipitation of methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid.

It is undesirable to increase the turbidity in the aqueous solution of the 0-formyl antibiotic salts, thus reducing the use of such solutions as pharmaceuticals.

According to the present invention, the crystalline 0-formyl antibiotic salts as anhydrides, monohydrates, and dihydrates are pharmaceutically pure alkali metal carbonates or tris (hydroxymethyl) aminomethane (tris buffer) 0.1 per mole of 0-formyl antibiotic salt. Mix with -1.2 moles. A better ratio is 0.275-1.0 moles of carbonate or Tris buffer per mole of 0-formyl antibiotic salt. Dissolving the sterile combination in sterile purified water is clear and colorless and has zero turbidity for 48 hours at room temperature.

Aqueous solutions of 0-formyl antibiotic salts were prepared at various concentrations and observed after some time had passed at room temperature. The following table shows the elapsed time after mixing the 0-formyl always with water at various concentrations where turbidity, precipitation, or both are observed at room temperature. Turbidity and precipitation would have occurred substantially earlier than the time observed.

In contrast to this, the composition of the 0-formyl antibiotic salt and sodium carbonate did not produce a precipitation clear for much longer. For example, a typical 1% solution of a composition of 0.27 moles of sodium carbonate relative to 1 mole of 0-formyl antibiotic salt had zero turbidity and no precipitation, even when left at room temperature for days to weeks.

Manufactured with a composition other than weak alkali metal carbonates (e.g., sodium citrate, monobasic sodium phosphate, dibasic sodium phosphate) .Unexpectedly, over time only with 0-formyl antibiotic salt There was turbidity and precipitation that was seen in the solution.

Solutions containing only 0-formyl antibiotic salts may lead to turbidity and precipitation within 4-72 hours at room temperature, whereas solutions containing 0-formyl antibiotic salts and mixtures of sodium carbonate or potassium carbonate and tris (hydroxymethyl) aminomethane The concentration solution was stable for several days. Alkali metal carbonates that can be used include potassium carbonate, lithium carbonate, and preferably sodium carbonate.

Hydrolysis was observed when a combination of 0-formyl antibiotic salts and sodium carbonates in different amounts and a combination of tris (hydroxymethyl) aminomethane (THAM) were used as the solution. Hydrolysis of the 0-formyl antibiotic salts was investigated by Varian T-60 and HA spectrometer. For each mole of 0-formyl antibiotic salt, 0.90 mole, 0.60 mole, and 0.275 mole of sodium carbonate are dissolved in an appropriate amount of water or D ₂ O and immediately tested with a 10-25% solution. The hydrolyzed% is calculated from the peak intensity. As a function of time, formyl protons disappeared at δ8.2 and formyl-pronone at δ8.5.

The occurrence of hydrolysis when THAM was added was caused by the disappearance of α-phenyl methine protons of 0-formyl antibiotics and salts and the hydrolysis product 7- (D-2-hydroxy-2-phenylacetamido) -3- ( Α-phenyl methine protons of 1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid natorium salt resulted.

The results of this hydrolysis observation are as follows.

The 0-formyl group hydrolyzes rapidly and then very slowly. The initial rapid rate is proportional to the amount of sodium carbonate or THAM present in the solution.

When 0.28 times mole of sodium carbonate is present with the 0-formyl antibiotic salt, about 30% decomposes rapidly within 5 minutes and then more slowly. When only the 0-formyl antibiotic salt is present in the aqueous solution, it is slowly hydrolyzed but shows that the slope of the hydrolysis curve is about 10% hydrolyzed after 24 hours.

Although the degree of hydrolysis of the combination containing sodium carbonate or THAM is increased, the solution of the combination has no clouding or accumulation of precipitates at room temperature for days to weeks.

Dry combinations of crystalline 0-formyl antibiotic salts containing 0.275 times molar sodium carbonate (i.e., about 5-6% by weight) are better than higher concentrations of sodium carbonate because they contain small amounts of sodium. This is because parenteral administration of natrium, such as heart patients, should be avoided.

The combination of the invention is best prepared in a single dose for parenteral use. For example, a dry sterile combination is filled into ampoules or rubber stopper vials containing 250 mg, 500 mg and 1,000 mg of 0-formyl antibiotic salt. In use, for example, 1 ml of water is added to an ampoule to give a colorless transparent antibiotic solution for intramuscular injection. Clinically more importantly, a single dose of the combination may be dissolved in water and placed in a hypodermic syringe and added to a large volume of standard intravenous solution.

When the combination of the present invention is diluted in such a large amount of intravenous injectable solution, turbidity begins to occur there. In contrast, dilution of an aqueous solution of concentrated 0-formyl antibiotic salt in such intravenous injectable solution results in indescribably turbidity.

Standard intravenous infusions containing this combination are used clinically, for example 5% glucose U.S.P and physiological saline (0.9% NaCl solution) U.S.P., electrolyte solutions in 5% glucose and the like.

The active ingredient 0-formyl antibiotic salt in the combination of the present invention can be prepared in crystalline form by the following method.

0-formylmandelic acid is prepared by heating D (-) mandelic acid with excess 98% formic acid to formyl the -OH group. This 0-formyl derivative is then heated with an excess of thionyl chloride to produce D-(-) 0-formylmandeloin chloride. Then it was used for the acylation of 7-amino-3- (1-methyl-1H-tetrazol-5-ylchiomethyl) -3-cefe-4-carboxylic acid to give 7- (D-2-formyloxy-2 -Phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid is prepared.

Acylation first dissolves the acid of the 7-amino-3-cepem nucleus in an inert solvent such as ethyl acetate to react with a silylating agent such as monosilylacetamide. The silylated 7-amino-3-cepem nucleus in solution was acylated with 0-formyl mandeloyl chloride at 20-25 ° C. and the reaction mixture was treated with water to obtain 7- (D-2-formyloxy-2-phenyl. Acetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid.

The 0-formyl antibiotic acid can be converted to crystalline sodium salt by treatment with the sodium salt of the organic acid in the presence of an organic solvent.

The crystalline salt is precipitated by cooling the acetone solution, adding a nuclear tablet, filtering it, recrystallization, or vacuum drying overnight at 40 ° C. to produce a crystalline salt suitable for medical use.

Sodium salts of organic solvents and organic acids include: methanol: sodium acetate, isopropanol / acetone: sodium 2-ethylhexanoate, dimethylformamide / acetonitrile: sodium 2-ethylhexanoate, acetone anhydrous: Nathium 2-ethylhexanoate,

The crystalline sodium salt is dried and then passed through a screen to even out the crystallinity. The selected 0-formyl antibiotic salts are then mixed with alkali metal carbonate or Tris buffer in a mixer to obtain the raw 0-formyl antibiotic salt-carbonate or Tris buffer combination.

Then, in a single dose to administer the drug substance, place it in a glass ampoule or rubber stopper vial.

Preferred single dose formulations are alkali metal carbonates containing 5.0-6.0% (by weight) of sodium carbonate relative to the active 0-formyl antibiotic salt. For example, a single combination of doses might be:

Although the above-mentioned ratio of sodium carbonate is good, to contain more than 6% in order to prevent turbidity when diluted in the intravenous solution can be used as a suitable combination. In clinical practice, however, it is sometimes desirable to minimize the amount of natrium, thus avoiding excess sodium carbonate.

A good combination of 0-formyl antibiotic salt and sodium carbonate, when dissolved in water, has an initial pH of 8.9 and rapidly drops to pH 6.5-7.0. The pH value is then left as it is for several hours.

Dry 0-formyl antibiotic salts provide a buffer environment when in lean aqueous solution, preventing the 0-formyl groups from hydrolysis to become cloudy. Thus, when diluted in intravenous solution, the original antibiotic acid 7- (D-2-hydroxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5- The monomethyl -3-cefem-4-carboxylic acid is the result of hydrolysis and remains in solution.

Although the 0-formyl ester group can be hydrolyzed from the 0-formyl antibiotic salt to provide the antibiotics described in US Pat. No. 3,641,021, the 0-formyl antibiotic salt itself inhibits the growth of microorganisms extensively even when tested in vivo. do. To present the results of this examination in a table and conduct. Table I shows the different Gram-positive and minimum inhibitory concentrations (MIC) for 0-formyl antibiotic salts and negative grams and fungi.

MIC values were obtained according to standard agar batch dilution. Further testing reveals that the 0-formyl antibiotic salt inhibits the growth of selected isolates. Table II shows the MIC values of the 0-formyl antibiotic salts for various isolated pathogens to Klebsiella pneumoniae. In Table IV. E. coli MIC values are shown.

O-formyl antibiotic salts are also effective in inhibiting the development of penicillin-resistant staphylococci. For example, the MIC for methicillin-resistant Staphylococcus aureus 3130 is 0.13 mcg / ml.

In view of the tendency to hydrolyze 0-formyl esters, some of the antimicrobial activity seen in vivo and in vivo experiments is due to the chemical and enzymatic hydrolysis of the 0-formyl esters in the side chains of the 0-formyl antibiotic salts. Possibility attributable to-(D-2-hydroxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid natorium salt There is this. This possibility is demonstrated by the formation of hydrolysis products during the chromatography of 0-formyl antibiotic salts. 7- (D-2-hydroxy-2-phenylacetamido) -3-cephem antibiotics appear in spots very close to the positions shown in the chromatogram. Likewise, blood was collected at several time intervals after injection of 0-formyl antibiotic salt into mice and chromatographed. Amido) -3-cepem antibiotics were found to be significant. The antimicrobial activity of the 0-formyl antibiotic salts is 7- (D-2-hydroxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem- Whether represented by 4-carboxylic acids or not, their 0-formyl derivatives are the only ones that can be obtained as pure and stable crystalline compounds that can be used in single dose combinations. Thus, 0-formyl antibiotic salts can be used in place of conventional antibiotics.

This antibiotic is administered intramuscularly in sterile aqueous solution or dissolved intravenously in standard intravenous injections.

When administered to humans or warm-blooded animals, the effective dose is 50-1000 mg / kg. Single dose combinations are antibiotic formulations readily applicable in the present invention as described above.

The therapeutic dose depends on the nature and extent of the infection, the condition of the patient, and the conditions of the treatment responses. Intramuscular administration may be administered four times and intravenous administration may be administered throughout the day over a much longer time period.

TABLE I

The numbers and letters following the name of the microorganism refer to the species of the test microorganism.

TABLE II

Letters and numbers mean special species.

Table III shows the minimum effective concentrations of clinically isolated proteus species.

TABLE III

TABLE IV

The following example illustrates the determination of a 0-formyl antibiotic salt and a process for preparing a composition containing it as an active substance.

Example 1

A process for preparing a salt of 7- (D-2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid sodium.

21.6 kg (17.8 L) of 98% formic acid is added to 1.14 kg (7.5 M) of D-(-)-mandelic acid and the reaction mixture is heated at 70 ° C. for 4 hours. The excess formic acid was evaporated in vacuo, the residual syrup was dissolved in 6.1 liters of benzene, washed twice with 6.1 liters of water, dried with a spoon of sulfuric acid and filtered. The filtrate was washed with 1.5 liters of benzene, combined with the filtrate and evaporated in vacuo. (-) Mandelic formic acid ether is obtained as a syrup. Crystallization with cyclohexane gives a melting point of 55-58 ° C.

The ether obtained above is mixed at about 70 ° C. with 2.9 kg (about 1.75 L) of thionyl chloride.

Excession of thionyl chloride is evaporated off and the remaining green solution is vacuum distilled to distill the 0-formyl mandeloyl chloride at 127-130 ° C (15mm) or 108-112 ° C (7mm).

Specific optical intensity [α] ²⁵ _D -175 ℃

Elemental Analysis of C ₉ H ₇ ClO ₃

Found: C, 54.42; H, 3.55; Cl, 17.85

Calculated: C, 54.17; H, 3. 48; Cl, 17.95

851.1 g (2.59 M) of 7-amino-3- (1-methyl-1H-tetrazol-5-ylchiomethyl) -3-cepem-4-carboxylic acid and 1336 g of mono-trimethyl-silyl acetamide in 13 l of ethyl acetate (10.37M) was added and stirred at 50 ° C until a clear solution was obtained, and the solution was cooled to 20 ° C to give 514 g (2.59M) of 0-formyl mandeloyl chloride. Apply under ice-cooling at a rate that can be maintained. After completion of the dropwise addition of mandelloyl chloride, the mixture is stirred at approximately room temperature for 1.5 hours, diluted with 5 liters of water, and stirred for 10 minutes. The organic solvent layer was separated, washed twice, combined with washed water, extracted with 1.5 L of ethyl acetate, combined with the washed organic layer, dried over magnesium sulfate, and filtered. Evaporation under vacuum at 25 ° C. water bath led to 7- (D-2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4- Carboxylic acid is obtained as a yellow foam.

The product was dissolved in 5 liters of acetone and mixed with a solution of 430 g (2.59 M) of sodium 2-ethylhexanoate in 5.4 liters of acetone. A core tablet was added and stirred for 1.5 hours in an ice bath. 7- (D-2-formyloxy-2 -Phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid sodium salt precipitated in crystalline form, which was filtered and washed with 5 L of acetone to form crystalline salt It was dried overnight in a vacuum oven at 40 ℃. This yields 1,060 g (80%) of product with a melting point of about 182-184 ° C.

In the later reaction, acetone: isopropanol (1: 1) is used instead of acetone to give 85% of the product.

Example 2

A process for the preparation of a combination of sodium carbonate-0-formyl antibiotic salts in a single dose combination.

60 kg of 1 kg of 7- (D-2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid sodium salt Pass 100 mesh sieves (US screen size) and mix with 54 g sodium carbonate and a stainless steel mixer.

The mixed mixture is added to the vial in a single dose.

Example 3

A process for preparing a combination of tris (hydroxymethyl) aminomethane-0-formyl antibiotic salts.

60 kg of 1 kg of 7- (D-2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid Pass through a mesh sieve (US screen size) and mix with 237 g of Tris (hydroxymethyl) aminomethane in a mixer. Tris buffer is passed through 50 mesh sieves before mixing. The mixed dry mixture is added to the sterile vial as needed in a single dose.

Claims (1)

Dry 7- (D-2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid sodium salt ( A method for preparing a dry parenteral 0-formyl cephamandol sodium salt, characterized by mixing a 0-formyl sephamandol sodium salt with alkali metal carbonate or tris (hydroxymethyl) aminomethane.