CS202269B1 - Process for preparing hydrochloride of alpha-d-propoxyphenone - Google Patents

Description

COPYRIGHT CERTIFICATE DESCRIPTION OF THE INVENTION CZECHOSLOVAKCASOCIALISTREPUBLIC (19) 202269 dl) (B,)

OFFICE OFFICE

AND DISCOVERIES (61) (23) Show Priority (22) Enrolled 27 06 78 (21) (PV 4210-78) (51) Int. Cl.3C 07 C39 / 16, C 07 C 87/04 (40) Published 30 04 80 (45) Published 30 04 82 (75) MICHALSKÝ JlRl RNDr., OLOMOUC,

Author of the invention STROJIL LADISLAV, TOVAČOV, KUHR IVO RNDr. CSc., HRUBÝ MILAN ing.

FERENC MILAN RNDr., OLOMOUC NEMECEK OLDŘICH dr. DrSc., PRAGUE (54) Method for the production of α-d-propoxyphene hydrochloride

The present invention relates to a process for the preparation of α-d-propoxyphene (1,2-diphenyl-4-dimethylamino-3-methyl-2-propionyloxybutane) hydrochloride by reaction with hydrochloric acid (A. Pohland, HRSullivan, J. Am. Chem. Soc. 75, 4458, 1953; ibid., 77, 3400, 1966; U.S. Pat. No. 2,728,779) .alpha.-d-Propoxyphen is an important analgesic (A. Pohland, HR Sullivan, cited above; RRMiller et al., J. Am Med Med Assoc 213, 6 (996, 1970). Its most common dosage form is hydrochloride and naphthalene-2-sulfonate. It is commonly produced and used in clinical practice by various names.

According to the literature, α-d-propoxyphene hydrochloride is prepared by introducing dry gaseous hydrogen chloride into the solution of the isolated base in ether (A. Pohland, H. R. Sullivan, J. Am. Chem. Soc. 77, 3400, 1955). The presence of the ether in this method is disadvantageous not only in terms of safety at work and in economic terms, but also in that the product of the ether is excreted in the microcrystalline form which retains excess hydrogen chloride, increasing the hygroscopicity of the isolated hydrochloride and complicating drying.

It has now been found that N -d-propoxyphene hydrochloride can be prepared in high yields and in high purity by acidifying base-d-propoxyphene in toluene solutions with hydrogen chloride in alcohols. Since n -d-propoxyphene hydrochloride is well soluble in lower aliphatic alcohols and in mixtures thereof with non-polar solvents, it is necessary to distill off the alcohol together with excess hydrogen chloride from the reaction medium in the form of the azeotropic mixture with toluene. reduced pressures of 40 to 50 ° C. After removing the alcohol and diluting the mixture with anhydrous ethyl acetate, α-d-propoxyphene hydrochloride precipitates out as coarse crystals which are easily and without difficulty sucked off and dried rapidly.

Based on this knowledge, a process for the preparation of the hydrochloride salt of ad-propoxyphenuneutralization of a base of n -d-propoxyphene by the hydrogen chloride according to the invention has been made, based on the base of n -d-propoxyphene in a non-polar organic solvent, e.g. a hydrocarbon, preferably toluene, is treated with a solution of hydrogen chloride in an aliphatic alcohol of 1 to 4 carbon atoms, preferably in ethanol, then an aliphatic alcohol with excess hydrogen chloride is removed in the form of an azeotropic mixture with the non-polar organic solvent used at a pressure of 2600 to 5400 Pa. distillation, 40 to 60% by volume ethyl acetate is added and the crystallization is completed by cooling to below 5 ° C. Furthermore, it has been found that in an ethyl acetate-containing environment, the solubility of the racemic form of the hydrochloride is increased.

Claims (2)

2-α-propoxyphene, so that the α-d-propoxyphene hydrochloride has a high degree of optical purity. Further, it has been found that satisfactory .alpha.-d-propoxyphene hydrochloride can be prepared as described above by acidification of the ethanolic solution of hydrogen chloride-treated toluene solutions of the crude .alpha., .Beta.-diphenyl-4-dimethylamino-3-methyl. -2-butanol with propionic acid angydride and thus shorten the synthesis of n -d-propoxyphene hydrochloride by one step, i.e. iso-bibase N -d-propoxyphene. Quite analogously to the preparation of α-d-propoxyphene hydrochloride, it is also possible to synthesize isomeric α-1-propoxyphenol hydrochloride after acylation of α-1,2-diphenyl-4-dimethylamino-3-methyl-2-butanol hydrochloride with propionic anhydride. The technical progress achieved by the method of the invention depends on shortening the technological process, increasing the yields and quality of the product, saving material, energy and living work and increasing occupational safety. EXAMPLES EXAMPLE 1 20.0 g of α-d-propoxyphene base of satisfactory quality are dissolved in 200 ml of toluene, filtered and the filtrate is acidified with 12 ml with stirring. hydrogen chloride in ethanol. The mixture was heated to 40 ° C and the azeotropic mixture of ethanol and toluene (20 to 40 mL) was distilled off under reduced pressure from 2600 to 5400 Pase. Once the hydrochloride crystallization begins; the distillation was stopped and 80 ml of anhydrous ethyl acetate was added to the crystalline suspension. The mixture was stirred for 1 hour at 40 ° C, then cooled to 0 ° C and stirred at this temperature A process for the preparation of ad-propyloxyphenol hydrochloride by neutralizing a base with ad-propoxyphenol hydrochloride, characterized in that a solution of hydrogen chloride in an aliphatic hydrocarbon is used in the non-polar organic solvent, e.g. with 1 to 4 carbon atoms, preferably in ethanol, then, under a pressure of 2600 to 5400 Pa, the aliphatic alcohol is removed in the form of the azeotropic mixture with the non-polar organic solvent used for 5 hours. The product is sucked off sharply, washed with 20 ml of ethyl acetate and dried at 80 ° C to constant weight. Yield 19.5-20.2g (88.0-91.2% of theory), m.p. 164-166 ° C (capillary). EXAMPLE 2 40 g of d-camphorsulfonate ad-1,2-diphenyl-4 are gradually introduced into a three-necked flask equipped with a stirrer, separator, reflux condenser and thermometer. -dimethylamino-3-methyl-2-butanol (prepared according to No. 193 315), 200 ml of toluene, 24 ml of propyne anhydride and 10 ml of triethylamine. The mixture is heated to a gentle boil and kept under reflux for 24 hours after formation of a clear solution (about 30 minutes). Thereafter, 400 ml of cold water was added to the reaction mixture with vigorous water cooling, and 70 ml of dilute aqueous ammonia (1: 1) was added dropwise with stirring over 30 minutes. The mixture is further stirred for 1 hour, the phases are separated and the toluene layer containing the α-d-propoxyphene base is washed 3 times with 100 ml of water. The washed solution is dried over 5 g of sodium bisulfate, stirred with 2 g of activated carbon and filtered. The clear yellowish filtrate was carefully acidified with 15 mL of 25% HCl in ethanol to pH 1 with stirring and the mixture was heated to 40-50 ° C and 20 to 40 mL of ethanol / toluene was distilled off under reduced 2600 to 5400 Pase. After crystallization was started, 80 ml of ethyl acetate was added to the mixture, the crystalline suspension was slowly cooled to 0 ° C and stirred at this temperature for 5 hours. The process for isolating and drying the crystalline α-d-propoxyphene hydrochloride is the same as in the previous example. Yield: 23.5 to 24.5 g (81.0 to 84.5% of theory based on α-d-1,2-diphenyl-4-dimethylamino-3-methyl-2-butanol d-camphorsulfonate). M.p. 163-166 ° C (capillary), (α) 2θ = -I- 54.5 ° (C 1.0; water). With hydrogen chloride, when crystallization begins, distillation is discontinued, 40-60% by volume ethyl acetate is added and the crystallization is completed by cooling to below 5 ° C. 2. Process according to claim 1, characterized in that the starting product of the .alpha.-d-propoxyphene used in the dried toluene solution after acylation of d-camphorsulfonate is 1,2-diphenyl-4-dimethylamino-3-methyl-2. butanol with propionic anhydride and after alkalizing the reaction mixture.