Pharmaceutical intermediate

Inventors

HALUSZCZUK, Adam • POGODA, Dorota

Assignees

Zaklady Farmaceutyczne Polpharma SA

Abstract

This invention relates to 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate and a process for the preparation of 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate comprising treating 4-(4-fluorobenzylamino)-1-methylpiperidine with water.The invention also relates to a process for the preparation of pimavanserin comprising reacting 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate with 1-isobutoxy-4-(isocyanatomethyl)benzene; to a process for the preparation of a pimavanserin acid addition salt comprising reacting 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate with 1-isobutoxy-4-(isocyanatomethyl)benzene and converting pimavanserin into a pimavanserin acid addition salt, pimavanserin and pimavanserin acid addition salts obtainable by the process, and to the use of 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate for preparing pimavanserin or an acid addition salt thereof.

Core Innovation

The disclosed subject matter relates to crystalline 4-(4-fluorobenzylamino)-1-methylpiperidine trihydrate, described as a solid monohydrate/three-water hydrate form. The document also addresses its use to synthesize pimavanserin and pimavanserin acid addition salts, with improved purity and stability compared with prior art forms of the corresponding amine intermediate.

Prior art provides 4-(4-fluorobenzylamino)-1-methylpiperidine as an oily amine with suboptimal purity, attributed to unreacted starting materials and under/over-reduced impurities that are difficult to remove from the oily form. The problem being solved is the removal of such impurities and the improvement of purity and stability using an alternative crystalline intermediate form.

The invention converts 4-(4-fluorobenzylamino)-1-methylpiperidine to the trihydrate by treating the amine with water, optionally using water/alcohol, water/organic solvent, or aqueous inorganic salt solutions. The resulting trihydrate is described as a white crystalline product with improved stability and purity, and with reduced/avoided distillation and base-free handling requirements.

The document provides characterization of the trihydrate, including XRPD peaks, IR bands, melting point in the range of about 37–42°C, and DSC method, and it states a monoclinic space group P21/n with water content in the asymmetric unit. Example results report near-quantitative conversion and greater than 99% GC purity for trihydrate prepared from anhydrous amine batches, and purification of commercial/crude material to greater than 99% GC purity.

Claims Coverage

The provided independent claims cover 2 inventive features: the crystalline compound itself and a process for preparing that trihydrate. The inventive features explicitly emphasized in the claim set are the specific trihydrate identity and aqueous treatment that yields the trihydrate.

Overall, the claim coverage centers on the crystalline trihydrate of 4-(4-fluorobenzylamino)-1-methylpiperidine and on an aqueous treatment process that forms and allows precipitation/isolation of the trihydrate.

Stated Advantages

Documented Applications