The present invention is related to a simple and efficient process for the preparation of tofacitinib citrate 1, a Pfizer molecule approved for the treatment of rheumatoid arthritis. The process relies upon an improved process for the preparation of a key intermediate (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methylamine as tartarate salt 3 and its simple and impurity-free conversion to tofacitinib citrate 1. The current invention is aimed at addressing process development issues related to quality and yields. The disclosed process is capable of delivering much higher yield compared to the prior state-of-the-art process and is able to yield very highly pure compound.

Donepezil, a cholinesterase inhibitor with good central nervous system penetration, has been crystallized as a tertiary amine salt with a disordered oxalate anion to give the title compound, (R,S)-1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidinium hydrogen oxalate trihydrate, C24H30NO3+.C2HO4-.3H2O. The indanone and piperidine ring planes are inclined at an angle of 33.4 (1) degrees. A comparison is made with the piperidinium cation bound in acetylcholinesterase in the solid state. The methylene units bridging the indanone-piperidine-benzyl groups determine the molecular shape and conformational features. The structure is stabilized mainly by O-H...O and N-H...O hydrogen bonds, with water molecules mediating interactions between oxalate anions and donepezilium cations.

Polymorphs have a tendency to undergo solution-mediated transformation from one form to another during crystallization. Various in situ techniques explored for understanding the crystallization process include, Raman spectroscopy, near-infrared spectroscopy (NIR), and focused beam reflectance measurement (FBRM). Both Raman and NIR techniques are used for polymorphic identification. FBRM has gained much popularity as an ideal technique for studying and improving particle size. The crystallization process can be improved using FBRM by studying the meta-stable zone, temperature of crystallization, and primary and secondary nucleation. This FBRM technique offers a quick and time-saving approach along with insight on the particle size of the product. The same technique can be used during scale up to understand and monitor crystallization processes. This report describes a different application of FBRM, which involves monitoring the changes in chord length distribution as a result of polymorphic transformation associated with temperature during crystallization. Needle-shaped Form III of acitretin undergoes solvent-mediated transformation to cube-shaped Form II. This polymorphic transformation is monitored by monitoring the chord length distribution.

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Synthesis of 3,5-Lutidine by Catalytic Transfer Hydrogenation via 1,2, 5,6-Tetrahydropyridine.-Substituted pyridines, e.g. 3,5-lutidine (II), which can be used as starting material for the synthesis of anti-ulcer drug omeprazole, are prepared from the corresponding tetrahydropyridines (I) by a novel catalytic transfer-hydrogenation procedure. -(SATHE, D. G.; KULKARNI, V. M.; Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 33 (1994) 10, 986-987; Dep. Chem. Technol., Univ. Bombay, Bombay 400 019, India; EN)