Warner-lambert Company

Godecke Aktiengesellschaft

Godecke Akt.

The Procter Gamble Company

Wolfram Geibel

Wolfgang Dieter Herrmann

Gerhard Satzinger

Johannes Hartenstein

Joachim Witzke

Otto Richard Goettel

The instant invention concerns a novel process for the preparation of 1-aminomethyl-1-cyclohexaneacetic acid (gabapentin), a known compound useful for treating certain cerebral diseases such as epilepsy and dizziness.

Process for the preparation of 1-aminomethyl-1-cyclohexaneacetic acid

A new catalytic process for the isomerization of asocainol isomers at the 6-position which provides an inexpensive, rapid, and simple method for large scale production of the (R,R) isomer of (R,S) asocainol is asocainol. The (R,R) isomer of (R,S) asocainol is treated with small amounts of a salt and an oxidizing agent at an elevated temperature. The compounds and their pharmaceutically acceptable salts are useful as potent antiarrhythmic agents and local anesthetics.

Process for the isomerization of asocainol

The present invention provides a process for the preparation of 4-hydroxy-3-(heterocyclocarbamoyl)-2H-1,2-benzothiazine-1,1-dioxides of the general formula: ##STR1## wherein R.sub.1 is a hydrogen atom or a methyl radical, R.sub.2 is a nitrogen-containing heterocyclic radical and R.sub.3 is a hydrogen or halogen atom or a methyl radical, and of the alkali metal, alkaline earth metal and amine salts thereof, by the reaction of an amine-substituted, nitrogen-containing heterocyclic compound with a halo-acetyl halide, reaction of the intermediate thus obtained with sodium benzoic acid sulphimide, ring expansion of the benzoisothiazole ring to give a benzothiazine ring and, in case R.sub.2 is to be an isoxazolyl radical, reverse rearrangement of the oxadiazole-ring formed by ring expansion to the isoxazolyl ring, wherein (in a one-pot reaction A) the reaction of an amine-substituted, nitrogen-containing heterocyclic compound with a halo-acetyl halide is carried out, without the addition of a base, in boiling ethyl acetate, the intermediate formed is, without isolation, reacted with sodium benzoic acid sulphimide and the reaction product isolated, whereafter, in a one-pot reaction B, the reaction product from the one-pot reaction A is reacted in a dipolar aprotonic solvent under an atmosphere of a protection gas with a strongly basic alkali-alkohole and thereafter with so much acid that about 2 equivalents of base remained unneutralized in the reaction solution and, if desired, the benzothiazine ring is N-methylated in the usual manner and the product obtained is, if desired, converted in known manner into an alkali metal, alkaline earth metal or amine salt.

Process for the preparation of

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Hunfeld, Germany

Wolfram Geibel