KR790001045B1 - Process for the conversion of 6-aminopenicillanic acid(6-apa) into 7-aminodesacetokyciphalos poranic acid(7-adca) - Google Patents

Abstract

6 - aminopenicillanic acid(6-APA) was converted to 7 - aminodesacetoxycephalosporanic acid (7-ADCA) by reaction of 1 mole ofα- halobenzylpenicillin (S) - sulphoxide with 2 moles of 3-trimethylsilyl - 2 - oxaz didinone(TMSO) at 60 - 12≰C in acetonitrile soln. in the presence of a tertiary organic base p - tolu - ene sulphonate and thiourea, then the solvent evaporated, diluted with water and adjusted to pH 4.2 to isolate 7-ADCA.

Description

Method of converting 6-aminophenicylanic acid to 7-aminodesacetoxy cephalosporanic acid

The present invention relates to a method for converting 6-aminophenicylaninic acid (6-APA) to 7-aminodesacetoxy cephalosporanic acid (7-ADCA).

Converting 6-APA to 7-ADCA, as shown in Scheme I, acylates 6-APA and oxidizes sulfur atoms to form α-chlorobenzyl penicillin- (S) -sulfoxide, which produces Tooth expansion causes ring expansion, which removes the protecting group to produce 7-ADCA.

In this method, both 6-APA and epi-6-APA can be used for the C-6 alpha-chlorobenzyl penicillin- (S) -sulfoxide epimer. That is, the commercially available 7-ADCA can be obtained using β-6-APA and α-6-APA.

It is known that 7-chloroacetaminocephalosporanic acid is deacylated by itself as urea and becomes 7-aminocephalosporanic acid (7-ACA). This type of reaction with chloroacetamide has been generalized by Masaki et al. Similarly, it has been anticipated that 6-APA can be produced from chloromethylphenicillin. (E.H. Flyn cephalosporins and penicillins, chemistry and biology; Journal, New York 1972, p. 69).

Deacylating to prepare 6-APA- (S) -sulfoxide involves reacting the corresponding α-chlorobenzyl penicillin with 3-trimethylsilyl-2-oxazolidinone (TMSO) to silylate the carboxyl and amide groups. Perform. Subsequently, it is reacted with thiourea in acetonitrile to obtain the surprisingly unexpected 7-ADCA.

The ring expansion of penicillin- (S) -sulfoxide is characterized by the presence of acid anhydrides in the presence of sulfonic acid (Morin et al., US Pat. No. 3,275,626; Chlorosilanes in the presence of organic bases (Spain 388733; UK Pat. 35797/70); under the same conditions, trimethyl chlorosilane (British Patent No. 763104); and sulfulic acid (Spain 388964, US Patent Application No. 16926/70).

Scheme 1

Spanish Patent No. 411867 (US Patent Application No. 443849) also describes that 3-methylsilyl-2-oxazolidinone (TMSO) acts under a basic catalyst as a strong silylating agent. In other words, α-chlorobenzylphenicillin- (S) -sulfoxide acts as a strong silylation inhibitor against nucleophilic groups that provide carboxylate ions in the presence of a tertiary organic base. On the other hand, silylated amide requires heating of the reaction mixture.

In addition, through silylation, TMSO absorbs intermediate sulfonic acids prepared according to the mechanism claimed by Morin et al. (J. Am. Chem. Soc., 85, 1896, 1963) and reacts thiourea in the presence of tertiary base tosylate. Pseudoiourea intermediate represented by Scheme I is produced. This is related to the reaction product, Phenyldoschiohidantoin and 7-ADCA tosylate.

Acylation with TMSO is carried out in the presence of a tertiary base as described in Spanish Patent No. 411867. Subsequent addition of P-toluene sulfonic acid is necessary to prevent the base from destroying the Pseudoiourea compound. It was observed that tosylate catalyzes the formation of tooth nuclei.

According to Scheme 1, a convenient method for the purposes of the present invention is to form the acid form of α-chlorobenzyl penicillin- (S) -sulfoxide in acetonitrile with at least 2 moles of TMSO and a small amount of triethylamine tosyl per mole of penicillin. Rate, for example reflux heating in the presence of up to 0.1 mole triethyl aminetosylate for 30-60 minutes and again add 1 mole of tertiary base tosylate and 1-1.2 mole of thiourea.

Alternatively, one mole of tertiary organic base is added to a one molar solution in the form of penicillin- (S) -sulfoxide acid to prepare the corresponding salt and at least two moles of TMSO are added at room temperature with stirring. The base released after 15-30 minutes is neutralized by heating to reflux for 60-120 minutes with anhydrous P-toluene sulfonic acid and thiourea. In either case, separating 7-ADCA hydrolyzes the silyl ester by concentrating the solution and diluting with water. Phenylshudohydantoin is removed by filtration and pH is adjusted to precipitate 7-ADCA as a precipitate.

Suitable tosylates for the present invention include P-toluene sulfonates of triethylamine, quinolein, and picoline, which are reacted in an organic solvent having no hydroxyl group, such as benzene, toluene, chloroform, dimethylformamide, and dimethylacetamide. Do this. Other good solvents as well as acetonitrile include dimethylacetamide and mixtures with other solvents thereof.

All attempts to isolate the intermediate compound identified in Scheme (1) failed because the rate of conversion to 7-ADCA was much faster than that of the intermediate. (Possible intermediates include α-pseudoureabenzylphenicillin- (S) -sulfoxide and 7 (α-pseudoiourea-phenylacetamido) desacetoxycephalosporanic acid. Reaction of desacetoxycephalosporanic acid silyl ester with thiourea did not confirm the presence of an intermediate, 7-ADCA was isolated, and the rate of conversion or deacylation was previously determined. N of the amide increases with 2 moles of TMSO relative to 1 mole of cephalosporin, and the same is true for α-bromophenyl acetate as α-chlorophenyl acetate in acylating 6-APA. The result was obtained.

Example 1

The pH of a solution of 0.1 mol (40.57 g) of the sodium salt of α-chlorobenzyl penicillin- (S) -sulfoxide is adjusted to 2, extracted with methylene chloride, dried over anhydrous sodium thorium sulfate, and evaporated under reduced pressure. Dissolve the residue in 250 ml of acetonitrile.

To the solution, 3-trimethylsilyl-2-oxazolidinone (TMSO, 38.2 0.28 mol and 0.02 mol of triethylamine P-toluenesulfonate (8.468 g) are added, stirred for 15 minutes, and stirred for 120 minutes while refluxing. 0.1 mol of dimethylaniline P-toluene sulfonate (29.3 g) and 0.12 mol of thiourea (9.13 g) are then added and heating is continued for 60 minutes, after which the mixture is concentrated under reduced pressure and 100 ml of water is added to the residue. Adjust to pH 8.5 in the presence of methylene chloride and filter the phenyl-Schirochiohidatoin and drain the water layer Adjust to pH 4.2 and filter the mixture again to give 7-ADCA (14.9 g) in 70% yield. Check by spectrum.

Melting Point: 232-42 (d), [α] ²⁰ _D = 105.0 ° (C = 1% 0.5N HCl)

[Example 2]

The pH of an aqueous solution of 0.1 mol (38.87 g) of α-chlorobenzyl desacetoxy cephalosporin natorium salt is adjusted to 1.5 and the solution is extracted with 100 ml of chloroform. 0.12 mol (18.4 ml) of TMSO and 0.01 mol (1.4 ml) of triethylamine are added and stirred at room temperature for 15 minutes. Then, 150 ml of dimethylacetamide and 9.13 g of thiourea are added, heated to reflux for 60 minutes, cooled, and 100 ml of water is made acidic with hydrochloric acid. The solution is poured off the organic layer under filtration and the aqueous layer is extracted with chloroform. The aqueous layer was treated as in Example 1, the precipitate was filtered, washed with water, washed with acetone and dried to give 7-ADCA (16 g) 75%.

Melting Point: 230-42 (d), [α] ²⁰ _D = + 104.8 ° (0.5N HCl)

Example 3

In the same manner as in Example 1, 7-ADCA was obtained in a similar yield using α-bromobenzyl penicillin- (S) -sulfoxide (0.1 mol, 45.0 g) instead of the α-chloride derivative.

It is confirmed by IR spectrum, melting point, and optical activity.

Example 4

Epi-7-ADCA was obtained in similar yields using epi-α-chlorobenzyl penicillin- (S) -sulfoxide in the same manner as in Example 1 in place of the α-chloride derivative.

[α] ²⁰ _D = + 203.6 ° (C = 1%, 0.5NHCl), Melting point: 238-42 (d)

Example 5

In the same manner as in Example 1, using 0.1 mole α-chlorobenzyl penicillin- (S) -sulfoxide acid form, instead of acetonitrile, dimethylformamide and P-tolupox sulfonate instead of α-picolin P-tolupox Sulfonate is applied to obtain 7-ADCA in similar yield.

Example 6

In the same manner as in Example 1, half-chloroform was applied in place of acetonitrile using α-chlorophenyl penicillin, followed by half acetonitrile in place of dimethylaniline P-tolupox sulfonate, yielding 7-ADCA in a similar yield. Get

Example 7

In the same manner as in Example 1, using γ-picoline P-toluenesulfonate in place of 0.1 mole of α-chlorophenyl penicillin and 1.2-dimethoxyethane instead of acetonitrile and dimethylaniline P-toluene sulfonate in a similar yield 7 Obtain ADCA.

Claims (1)

A method for converting 6-aminophenicylanin acid (6-APA) to 7-aminodesacetoxy cephalosporanic acid (7-ADCA), wherein 1 mole of α-halobenzylphenicillin- (S) -sulfoxide Was reacted in acetonitrile with at least 2 moles of 3-trimethylsilyl-2-oxazolidinone (TMSO) at 60-120 ° C. in the presence of a tertiary freebase P-tolupox sulfonate and thiourea, and then the solvent was evaporated off. After diluting the residue with water and adjusting the pH to 4.2 to isolate 7-aminodes acetoxy cephalosporanoic acid (7-ADCA).