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PROCESSES FOR PRODUCTION OF CRYSTALLINE FORM I OF ORLISTAT

IP.com Disclosure Number: IPCOM000172876D
Publication Date: 2008-Jul-17
Document File: 7 page(s) / 466K

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Abstract

The present disclosure provides processes for preparing a crystalline Form I of orlistat, which is tetrahydrolipstatin.

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PROCESSES FOR PRODUCTION OF CRYSTALLINE FORM I OF ORLISTAT

Abstract

The present disclosure provides processes for preparing a crystalline Form I of orlistat, which is tetrahydrolipstatin.

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Orlistat is a useful pancreatic lipase-inhibiting agent and can be used for the prevention and treatment of obesity and hyperlipaemia. Chemically, it isN-formyl-L-leucine [2S-[2alpha(R*), 3 beta]]-1-[(3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester and is known from U.S. Patent No. 4,598,089, in which the product is isolated as a waxy material. It is represented by Formula I.

                                       

Purification of orlistat by chromatographic method using toluene and ethyl acetate has been reported in several references such as U.S. Patent No. 4,983,746; Helv. Chim. Acta., (1987), 70, 1412; J. Org.Chem., (1988), 53, 1218and J. Org. Chem. ,(1993), 58, 7768.

J. Chem, Soc. Perkin. Trans. I, (1998), 17, 2679 reports the use of hexane and ethyl acetate for chromatographic purification of orlistat to obtain the product as an amorphous solid.

Further, U.S. Patent No. 6,156,911; Tetrahedron letters, (1989), 30, 1833; J. Org. Chem., (1991), 56, 4714 and Helv. Chim. Acta., (1987), 70, 1412 disclose a crystalline form of orlistat, obtained by recrystallization with hydrocarbons such as hexane, pentane and heptane, and characterized by melting point and infrared spectroscopy.  For convenience this crystalline form is herein after called as Form I.

U.S. Patent No. 6,156,911 describes a process for preparing the crystalline Form I of orlistat comprising recrystallization with hexane, which results in lower yield  (approximately 76 % or 85%).  Also, this recrystallization process involves heating the solution to reflux temperature.  WO 2005/026140 describes a process for preparing the crystalline Form I of orlistat comprising heating orlistat to melting, and then allowing it to cool.  U.S. Patent No. 6,734,314 describes a process for preparing the crystalline Form I of orlistat comprising dissolving orlistat in hexane and stirring it at 0-5°C for 20 hours, which is a very time consuming process.  Moreover, the methods employed for obtaining crystalline Form I of orlistat in the literature can involve tedious chromatographic techniques, extraction procedures, multi-solvent crystallization at high temperature, or time consuming processes with low yields.  Also, orlistat is thermally labile by nature, therefore there is a need for simple, cost- effective and industrially advantageous process for the preparation and purification of crystalline Form I of orlistat at lower temperatures and free of residual solvents and impurities that overcomes the drawbacks of prior-art processes.

Accordingly, the present discl...