Method for the production of d-threo-2-phenyl-2-piperidine-2-yl acetates

• US 20060135777A1
• Filed: 01/27/2004
• Published: 06/22/2006
• Est. Priority Date: 02/05/2003
• Status: Abandoned Application

• Current Assignee: Siegfried Ltd. (Siegfried Holding AG)
• Original Assignee: Siegfried Ltd. (Siegfried Holding AG)
• Inventors: Trafelet, Huldreich, Wollenweber, Markus
• Application Number:
  US10/544,791
• Publication Number:
  US 20060135777A1
• Time in Patent Office: Days
• US Class Current: 546/238
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Disclosed is a method for producing d-threo-[R(R*,R*)]-2-phenyl-2-piperidine-2-yl acetate and the acid addition salts thereof by converting d-threo-[R(R*,R*)]-2-phenyl-2-piperidine-2-yl ethanoic acid or an acid addition salt thereof into the corresponding d-threo-[R(R*,R*)]-2-phenyl-2-piperidine-2-yl ethanoic acid halide, producing the desired d-threo-[R(R*,R*)]-2-phenyl-2-piperidine-2-yl-acetate or an acid addition salt thereof by means of esterification, and optionally recrystallizing the obtained product. The invention also relates to methods for producing pure threo-2-phenyl-2-piperidine-2-yl acetamide or the starting material for producing d-threo-[R(R*,R*)]-2-phenyl-2-piperidine-2-yl ethanoic acid.

Claims

1. Method of preparing d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetates and their acid addition salts compromising the steps of converting d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetic acid or an acid addition salt into the corresponding d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetic acid halide and preparing the d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate or an acid addition salt through esterification and optionally crystallizing the obtained product.

2. The method, according to claim 1, wherein, said d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetic acid halide is d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetic acid chloride.

3. The method, according to claim 1, wherein said d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate is a (C_1-4)-alkylester.

4. The method, according to claim 1 or 2, wherein the said d-threo-[R(R*,R*)]2-Phenyl-2-piperidine-2-yl-acetic acid hydrochloride is chlorinated with thionylchloride in an inert solvent, and in the presence of a catalytically active aprotic solvent, and, that the obtained acid chloride on reaction with absolute alcohol, is transformed into the d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate by splitting off hydrogen halides.

5. The method, according to claim 4, wherein the halogenation is carried out at a temperature below 90°

C.

7. The method, according to claim 1, wherein the d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetic acid is prepared from d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate amide through hydrolysis with a suitable acid.

8. Method of preparation of pure d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate-amide or the starting material for the preparation of corresponding carboxylic acid, as in claim 7, wherein a racemic mixture of 2-phenyl-2-piperidine-2-yl-acetate amide is converted at first, with (+)-O,O-dibenzoyl-D-tartaric acid in a suitable solvent, preferably in isopropanol, said d-threo-[R(R*,R*)]2-Phenyl-2-piperidine-2-yl-acetate-amide-dibenzoyl-D-tartrate thus formed crystallizes at a temperature between 25-40°

C. and is optionally purified, through recrystallization and subsequently through alkali treatment, and is converted into d-threo-[R(R*,R*)]2-Phenyl-2-piperidine-2-yl-acetate-amide.

9. The method according to claim 8, wherein the recrystallization of the separated d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate amide-dibenzoyl-D-tartrate is caused by heating up to 70°

C., until complete dissolution of the compound in the solvent, and subsequently cooling down slowly to 25°

C., whereby d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate-amide-dibenzoyl-D-tartrate crystallizes out.

10. The method as in claim 8, wherein d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate-amide is treated with a 30% aqueous solution of sodium hydroxide at room temperature and subsequently cooled down to 2-10°

C., so that d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetateamide crystallizes out.

11. Method of preparation of threo-2-phenyl-2-piperidine-2-yl-acetate amide or the starting product for the method, as per claim 8, wherein the said method comprises the treatment of a erythro/threo-mixture of 2-phenyl-2-piperidine-2-yl-acetate amide with a base.

12. The method, according to claim 11 wherein the erythro/threo 2-phenyl-2-piperidine-2-yl-acetate amide on being heated with a 20% aqueous sodium hydroxide solution to a temperature of 100°

C. for approximately 60 minutes, produces a mixture containing approximately 85% of the threo-compound.

13. Method of preparing d-threo-methylphenidate-hydrochloride comprising (1.) reacting erythro/threo 2-phenyl-2-piperidine-2-yl-acetate amide with a base, to produce a threo enriched mixture, (2.) converting the racemic mixture of 2-phenyl-2-piperidine-2-yl-acetate amide, with(+)-O,O-dibenzoyl-D-tartaric acid in a suitable solvent, separately the formed d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate amide-dibenzoyl-D-tartrate from the mixture and optionally purifying through crystallization, subsequently treating the d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate-amide-dibenzoyl-D-tartrate is with alkali and isolating the d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate-amide, (3.) hydrolyzing the d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetate amide, according to claim 7 with a suitable acid, whereby d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetic acid is obtained, (4.) converting the obtained d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-acetic acid is into the corresponding d-threo-[R(R*,R*)]2-phenyl-2-piperidine-2-yl-chlorideacetate, and subsequently preparing, d-threo-methylphenidate-hydrochloride through esterification with methanol and (5.) recrystallizing the obtained product from hydrochloric acid.

6. A purification method of d-threo-methylphenidate-hydrochloride wherein d-threo-methylphenidate-hydrochloride is crystallized out, by dissolving it in water heated at a temperature of 80°

C., cooling down said solution to room temperature and introducing gaseous hydrogen chloride of at the concentration in the range of 12 weight % to 20 weight %, and filtering out the obtained pure d-threo-methylphenidate-hydrochloride as a precipitate.