RU2395488C1 - Method of producing pharmaceutically acceptable dec-glaucine salts - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method involves reaction of a pharmaceutically acceptable glaucine salt with water at 200-300°C in sealed conditions (subcritical water medium). Possible ratio of the glaucine salt to water (pts. wt) is equal to 1:1-1000, and primarily 1: 10-150.

EFFECT: design of an improved method of producing pharmaceutically acceptable salts of 1-[2-(N-methylaminoethyl)]-3,4,6,7-tetramethoxyphenanthrene (dec-glaucine) of formula I

.

3 cl, 1 ex

Description

The invention relates to methods for producing phenanthrene alkaloids, namely to the preparation of pharmaceutically acceptable salts (chlorides, bromides, phosphates, citrates, etc.) of 1- [2- (N-methylaminoethyl)] - 3,4,6,7-tetramethoxyphenanthrene, that is, salts of des-glaucine (secoglaucine), formula I

exhibiting antitussive activity.

A known method of producing benzyl des-glaucine, from boldine, by acting on it with benzyl chloride in DMF medium (US patent No. 5594033, С07С 213/02, 1997).

The disadvantage of this method is the length of the process and the need to use an organic solvent and catalyst.

The closest to the implementation is a method of producing a trifluoroacetyl derivative of des-glaucine (I) 1- [2- (N-methyl-N-trifluoroacetylaminoethyl)] - 3,4,6,7-tetramethoxyphenanthrene, (JLCastro et al., J. Org.Chem., 1987, 52, 3579-3584), the action of glaucin with trifluoroacetic anhydride in pyridine in an argon atmosphere. Subsequent hydrolysis can be obtained des-glaucine.

The disadvantage of this method is the need to use highly toxic reagents, inert atmosphere and sophisticated equipment.

The technical result is to simplify the process due to the absence of the need to use toxic organic reagents, inert atmosphere and sophisticated equipment.

The technical result is achieved by the fact that glaucine isomerized with water under sealed conditions at a temperature of 200-300 ° C, that is, in subcritical water (at a temperature above 100 ° C). The components can be taken in a ratio of 1: 1-1000 parts, preferably 1: 10-150 parts, respectively

The invention has an inventive step, since it is not known to carry out isomerization, including the conversion of glaucine to des-glaucine (isomeric form), in subcritical water.

The following is an example of producing des-glaucine hydrochloride (secoglaucine).

Example.

A solution of 0.3 g (0.001 mol) of glaucine hydrochloride in 6 ml (0.33 mol) of water is heated in a 10 cm ³ reactor for 2 hours at a temperature of 250 ° C. The warm solution is filtered off from mechanical impurities. The crystalline precipitate formed after cooling is filtered off and washed. The yield of green crystals is 53% (0.16 g). Mp 136-137 ° C.

¹ H NMR spectrum (CDCl ₃ , δ, ppm): 3.53 (m, 4H, 2CH ₂ ), 3.82 (s, 12H, 6CH ₃ ), 4.80 (d, 3H, 3CH ₂ ), 6.80-7.30 (6H, arom). 9.53 (q, 2H, NH ₂ )

IR spectrum, cm ^-1 : 1150, 1590, 1600.

Found,%: C 77.10, H 5.79. Gross formula C ₂₁ H ₂₆ O ₄ N. Calculated,%: C 76.98, H 6.1

Similar results are obtained using the ratios of glaucine: water 1: 1, 1:10, 1: 150, 1: 1000 parts and a temperature of 200 ° C and 300 ° C.

Claims (3)

1. The method of obtaining pharmaceutically acceptable salts of 1- [2- (N-methylaminoethyl)] - 3,4,6,7-tetramethoxyphenanthrene (des-glaucine) of the formula I

consisting in the fact that a pharmaceutically acceptable salt of glaucine is introduced into interaction with water at a temperature of 200-300 ° C in sealed conditions. 2. The method according to claim 1, characterized in that the glaucine salt is introduced into interaction with water in the ratio of parts of the corresponding components 1: 1-1000. 3. The method according to claim 1, characterized in that the glaucine salt is introduced into interaction with water in the ratio of parts of the corresponding components 1: 10-150.