KR910005418B1 - Process for preparing clindamycin-2-phosphate - Google Patents

Abstract

A process for preparing clindamycin-2-phosphate of formula (I) comprises (a) reacting 3,4-O-arylidene-clindamycin-HCl with bis- (2,2,2-trichloroethyl)-phosphoro chloridate in the presence of a tert. amine at O deg.C for 10 hrs., and acid hydrolyzing of the resulting cpd. with Zn powder. Pref. the tert. amine is triethylamine, pyridine, tripropylamine, tributylamine, triisopropylamine, dimethylaniline or N-methylpiperidine, and the acid is formic acid, propionic acid, d-HCl, d.H2SO4 or 80% HAc. (I) may be used as an antibiotic in the treatment of respiratory infection.

Description

Method for preparing clindamycin-2-phosphate

The present invention provides a phosphate compound of formula (II) by reacting 3,4-O-arylidene-clindamycin hydrochloride represented by formula (I) with bis (2,2,2-ethyl trichloride) -phosphorochlorate. The present invention relates to a method for preparing 7 (S) -chloro-7-deoxy-lincomycin-2-phosphate (Clindamycin-2-phosphate) of formula (III) by synthesizing the hydrolyzate.

Clindamycin-2-phosphate is an antibiotic that has excellent therapeutic effect on infections of the respiratory system. It has almost the same antibiotic activity as clindamycin hydrochloride and is widely used as an injection because of its high solubility in water at neutral pH.

As a general method for the preparation of clindamycin-2-phosphate, clindamycin free bases protected with cisdiol at positions 3 and 4 are reacted with a phosphorylating agent (phosphoryl chloride) at a low temperature of -40 ° C. or lower in the presence of a base. 4-O-arylidene-clindamycin-2-phosphochloridate was prepared, and then hydrolyzed to obtain 3,4-O-arylidene-clindamycin-2-phosphate, which was then acidified at 100 ° C. U.S. Patent No. 3,487,068, which decomposes to remove the protecting group and purifies with ion exchange resin to obtain clindamycin-2-phosphate.

However, this method requires that the reaction be carried out at a low temperature of -40 ° C. or lower during the phosphorylation reaction, and the side reaction proceeds according to the temperature change, thereby producing unnecessary side reactions, as well as difficult reaction conditions. The separate reaction and the protecting group removal reaction had disadvantages such as complex separation of the product.

Therefore, the present inventors have solved the problems of the conventional manufacturing method by using bis (2,2,2-ethyl trichloride) -phosphochloridate as a phosphorylating agent, and a method for producing clindamycin-2-phosphate with high yield. Developed to complete the present invention.

That is, the present invention uses a cisdiol-protected 3,4-O-arylidene-clidamycin hydrochloride (formula (I)) described in US Pat. Nos. 3,655,885 and 3,580,904 as a starting material and A novel phosphate compound, an intermediate of clindamycin-2-phosphate, was reacted at 0 ° C. in the presence of a base using bis (2,2,2-ethyl trichloride) -phosphochloridate instead of phosphoryl chloride. )), And then the phosphate compound is mildly acid hydrolyzed using zinc powder to remove the protecting group of cisdiol, while hydrolyzing the phosphate ester group to remove clindamycin-2-phosphate as a target compound in a small amount of other phosphate impurities. After obtaining together with this, it is purified by using an anion exchange resin to obtain pure crystals of clindamycin-2-phosphate.

As described above, the present invention can carry out the phosphorylation reaction as the first step under mild conditions and obtain a phosphate compound as an intermediate of clindamycin-2-phosphate in high yield, and the acid hydrolysis reaction as the second step is also conventional. It can be carried out in milder conditions than the method, and since the reaction of removing the cisdiol protecting group and the hydrolysis of the phosphate ester group are simultaneously performed, clindamycin-2-phosphate can be obtained in a high yield by a simple manufacturing process.

In the present invention, bases used in the phosphorylation reaction include pyridine, triethylamine, tripropylamine, tributylamine, triisopropylamine, dimethyl aniline, diethyl aniline and N-methyl piperi of tertiary amines. Formic acid, propionic acid, diluted hydrochloric acid, diluted sulfuric acid, 80% acetic acid and the like are used for the acid hydrolysis reaction. In the purification of clindamycin-2-phosphate, anion exchange resins such as DEAE-cellulose and DOWEX-1 × 2 are used.

The present invention is explained in more detail in the following examples.

Example 1

20 g of 3,4-O-anisylidene-7 (S) -chloro-7-deoxy-rincomycin hydrochloride was dissolved in 200 ml of distilled water, and then stirred with 2N sodium hydroxide until the pH in the aqueous solution reached 11 while stirring. After slowly adding, the aqueous solution was extracted with 50 ml of ethyl acetate. The organic layer was separated, washed twice with distilled water, dried over sodium sulfate and distilled under reduced pressure to obtain a foamy white crystal, 3,4-O-anisylidene-7 (S) -chloro-7-deoxy-rincomycin free base. 17.8 g was obtained.

Yield: 95%

Melting Point: 67-68 ℃

Example 2

15 g (27.6 mmole) of 3,4-O-anisylidene-7 (S) -chloro-7-deoxy-rincomycin free base was dissolved in 150 ml of dried pyridine, the temperature was adjusted to 0 ° C. and 12.6 g ( 1.2 equivalents of 33.1 mmole of bis (2,2,2-ethyl trichloride) phosphorochlorate were added and then reacted under nitrogen for 10 hours. After the reaction was completed, a small amount of methanol was added, distilled under reduced pressure to remove pyridine, 200 ml of ethyl acetate and 100 ml of distilled water were added to the residue, followed by stirring for 30 minutes. The organic layer was separated, washed twice with saturated brine, and then sodium sulfate The resulting mixture was dried under reduced pressure and distilled under reduced pressure to obtain a yellow oily residue having a high viscosity.

This was purified by column chromatography packed with 600 g of silica gel to remove impurities to obtain 3,4-O-anisylidene-7 (S) -chloro-7-deoxy-rincomycin-2-bis (2) as white crystals. 21 g of 2,2-ethyl trichloride) phosphate were obtained.

Yield: 87%

Melting Point: 180-182 ℃

NMR (CDCl ₃ , δ); 0.8-1.8 (11H, m), 1.8-2.1 (4H, m), 2.2 (3H, S), 2.4 (3H, S), 3.8 (3H, S), 3.9-4.9 (7H, m), 4.7 ( 2H, S), 4.8 (2H, S), 5.5 (1H, d), 6.2 (1H, S), 6.7 (4H, AB _q ), 7.3 (4H, AB _q ), 7.6 (1H, br.d) .

IR (KBr, Cm ⁻¹ ); 3200, 2800, 1650, 1490, 1260-1300

Example 3

22.7 g of zinc in 20 g (22.7 mmol) of 3,4-O-anisylidene-7 (S) -chloro-7-deoxy-rincomycin-2-bis (2,2,2-ethyl trichloride) phosphate After the flour was added, 200 ml of 80% acetic acid was added again and reacted with stirring at 50 ° C. for 1 hour. After completion of the reaction, the residue was distilled under reduced pressure by adding 30 ml of water, and the residue was diluted again with 200 ml of water, 10 ml of ammonium hydroxide was added thereto, and the aqueous solution was washed twice with 50 ml of chloroform.

Distillation under reduced pressure at 30 ℃ or less to obtain a pale yellow crystals containing impurities.

The crystal compound was purified again with DOWEX-1 × 2 anion exchange resin to obtain 7 g of pure white crystals of 7 (S) -chloro-7-deoxy-rincomycin-2-phosphate.

Yield: 61%

Melting Point: 175-178 ℃ (Decomposition)

Claims (5)

The 3,4-O-arylidene-clindamycin hydrochloride represented by Structural Formula (I) was phosphorylated with bis (2,2,2-ethyltrichloride) -phosphorochlorate in the presence of a base of tertiary amines. A method for producing clindamycin-2-phosphate represented by formula (III), wherein the compound of formula (II) is prepared, and then the compound of formula (II) is subjected to acid hydrolysis using zinc powder.

The method of claim 1, wherein the base of the tertiary amines is triethylamine, pyridine, tripropylamine, tributylamine, triisopropylamine, dimethylaniline, N-methylpiperidine. The method of claim 1 wherein the phosphorylation reaction is conducted at 0 ° C. for 10 hours. The method of claim 1, wherein formic acid, propionic acid, diluted hydrochloric acid, diluted sulfuric acid, 80% acetic acid, and the like are used in the acid hydrolysis reaction. A compound represented by the following structural formula.