CS268354B1 - Method of dithiazeme's hydrochloride cleaning - Google Patents

Abstract

δβέβηί refers to the method of StSnl dilthiazamine hydrochloride. significant drug of coronary diseases, crystallization a crude or waste product from a long-aprotic solvents or from a two-component system namely crystallization and long-term aprotic they dissolve by the preferred long-term and aprotic forms solvents aliphatic liquid amides or lactams acids, preferably crystallized solvents are aliphatic alcohols, dialkylothors, ketones, esters aliphatic acids or halogenoaromatics. The aforementioned solution makes it effective elimination of undesirable particles and accompanying substances in the preparation of aubttanca useful for producing a medicament.

Description

The present invention relates to a process for the purification of crude dilthlazem hydrochloride / cis [R] -3-acoxy-2,3-dihydro-5- (2-dimethylaminoethyl) -2- (4-methoxyphenyl) -1,5-benzothiazepine-4 / 5H hydrochloride. of the formula I

CH ₂ -CH ₂ -N / CH _3/2 / 1 /.

which is a significant attraction vaioapaatleká angina, angina pectoris after myocardial infarction and long-term theropeutIkom cardiac ischemia / so-called Ca-antagonist.

Known methods / for example Kugite H. and co-authors! Chem. Pherm. Bull. 18, 2028, 2284/1970 / j Kugite H and co-authors: Chem. Pherm. Bull. 19, 595 (1971)] NSR patent 3 337 176 and longer (prepared hydrochloride dllthlezem contains a smaller amount (esl 0.5%) of compounds of formula II st IV

O-CH _3/11 / x-η; R-CH ₂ CH ₂ N / _CH3 / _2. HC1 / ni / x hj-R-CH ₂ CH ₂ N / CH _3/2 / IV / e XRH web was unknown accompanying substances whose přítomnoet drug is undesirable. Processes commonly used to eliminate impurities from euro hydrochloride, such as crystallization from aliphatic alcohols or precipitation of alcoholic solutions with ether, are relatively inefficient and are often accompanied by significant product losses.

Said shortcomings of the known processes are eliminated by the purification process according to the invention, consisting in the crystallization of euro or other contaminated hydrochloride dllthleze from a long-polar solvent or from a two-component organic solvent, one of the solvents used having long-polar properties. Carboxylic acid amides and lactams, in particular N, N-dimethylformamide, N, Nd imethyl, mid, N-methylcaprolactate, formanide and the like, can be used as dipolar and lactam solvents. Carboxylic acid esters can be used as a crystallization solvent in two-component mixtures. ethyl acetate, n-butyl acetate, n-butyl formate and the like /, aliphatic alcohols and ethers (methanol, ethanol, 2-propanol, 1-butanol, diethyl ether, methyl tert, butyl ether and the like), halogen derivatives of aliphatic or aromatic hydrocarbons (e.g. , 2-dichlorochothane, chlorobenzene and other (and aliphatic ketones (e.g. acetone, non-ethyl ethyl ketone longer). Kryetallzaci can be done in two ways: first elternotlvS ee hydrochloride having dllthlezemu dissolved in dipolar-eprotickém solvent at an elevated temperature of 30 ⁰ EŽ 160 ° C přídevkem suitable eorbentu / not attach ektlvního coal / EA, the solution decolorized by cooling the solution or přídevkem kryetallzečního solvent undergo spontaneous crystallization of the product; in a second alternative, the hydrochloride is dissolved in a rat solvent at an elevated temperature of 30 DEG to 160 DEG C., an epolar-aprotic solvent is added and, after decolorizing the resulting solution by adding an eorbent, the crystallization of the product is induced by cooling the solution to ⁰ DEG to 20 DEG C. distilling off parts of the crystallization solvent.

The advantage of this method of purification of eurolean dllthlezem hydrochloride is the very effective elimination of impurities and accompanying (especially colored) compounds without

CS 268 354 Bl 2 low losses of the Insulated product.

In the following examples, the method of diluting the hydrochloride dilthlezem according to the invention is only illustrated, the scope of the invention being not limited in any way by the above-mentioned embodiments.

Example 1

In 120 ml of formamide, preheated to 120 DEG C., 50 g of euroic dilthlezem hydrochloride / e. decolorized by adding 4.0 g active carbon, and the resulting clear, nearly colorless solution aa otálého under stirring is cooled to 10 ⁰ EŽ 20 ° C. The crystallized white product is filtered off, washed with 30 ml of ethanol and the mixture is obtained, 40 g of pure hydrochloride hydrochloride (and a circulation of defined impurities XI-0.05% and ΙΙΙ-Ο, ΟΟ X), which after roryetallzacl from 150 ml of ethanol. / for detachment of captured formamide heating / for eubetence in the jaw required for the production of dosage forms. The mother liquors after kryetallzecl can be used repeatedly to dilute further portions of euro hydrochloride dllthlazem.

Example 2

To the dark brown zkalenému solution resulting rozpultlním 1.0 kg odpedního hydrochlorides dllthlazemu / e content defined nečletot 11-1,4% and 111-0,8% / 4.0 in 1 N Ndinethylformemidu temperature of 100 ⁰ C 110 EŽ ee add 60 g of charcoal ektlvniho e emia resulting from heat zflltruje Preem Huot filter) zíokaný clear solution olabí ocher zbervený what ochledí not the temperature of 50 ⁰ ° C 60 EŽ e stirring silylating agents diluted with 5.0 1 ethyl octene. Epontene kryetallzecl hydrochloride dllthiosome occurs in a homogeneous solution for 10 minutes | The crystallizing solution was cooled to 20 DEG C. and, after 3 hours of melting, the crystallized product was removed, washed with 0.1 ml of ethyl acetate and washed. Crystallization of ee gave 920 g of dilthlezem hydrochloride (e circulating defined impurities 11-0.10% and 111-0.05%), corresponding to a yield of 94%. Recrystallization of the purified product from 4.0 L of ethanol gives the eubetence useful in making the mold. Ethyl acetate is recovered from inert liquors after crystallization of the depleted hydrochloride dilthlezem in a yield of 91% by distillation at atmospheric pressure and N, N-dimethylformamide in a yield of 89% by distillation from a reduced pressure of 6 to 10 kPa.

Example 3

To 5.0 l of an ocher of colored methane liquors, 200 ml of .beta.-.beta.-dimethylecetem. E. The thickened yellow-brown solution is dehydrated by adding 12 g of ectopic charcoal, the resulting clear colorless solution is cooled to 10 DEG C. with constant stirring and, after seeding with a product cap, allowed to crystallize spontaneously for 5 hours! The precipitated dilute hydrochloride is removed, washed with ethanol or leopropyl alcohol and dried. Ee 105 g of hydrochloride hydrochloride (with a content of deficient impurities of 11-0.02% by 111-0.00%) are obtained, which can be used directly for the production of dosage forms.

Claims (8)

OBJECT OF THE INVENTION 1. A process for purifying dllthlezem hydrochloride, characterized in that! provided that the crude or waste product o crystallizes from a long-solvent solvent or from a two-component solvent system, namely a crystallization and a full-strength solvent. 2. The process according to item 1, characterized in that the amide or N-alkylamide or N, N-alkylamide of alphoteric acids is used as the polar solvent. 3. The process according to claim 1, characterized in that elbow or N-alkyllacta of aliphatic acids is used as the long-acting solvent. 4. The process according to item 1, characterized in that the erythatic acid ether is used as the crystallization solvent ee. 5. The process of claim 1, wherein the crystallizing solvent is an aliphatic alcohol. 6. The process according to item 1, characterized in that all crystalline solvent is used as the crystallization solvent. 7. The process according to item 1, characterized in that an aliphatic or chromatic halide is used as the coating solvent. 8. The process of claim 1, wherein the crystallization solvent is an alkaline ketone.