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Olanzapine form I Disclosure Number: IPCOM000125182D
Publication Date: 2005-May-23
Document File: 3 page(s) / 81K

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The Prior Art Database


An improved method for the preparation of Olanzapine form I

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Olanzapine of formula I is first described in EP454436. The synthetic route described in this patent is based on the reaction of the benzodiazepine of formula II with methylpiperazine (III). The reaction is described in aprotic solvents such as toluene, dimethylsulfoxide or dimethylformamide. The product obtained is not pure and a crystallisation is needed to afford the desired quality and polymorphic form. The crystalline form obtained with this method is not reproducible.

Other methods have been published to obtain polymorphic form I in a consistent way but they involve the use of dichloromethane.

There is a need for an improved method for preparing Olanzapine Form I characterised by:


  1. the use of any alcohol as reaction solvent, preferably tert-butanol or 1-butanol
  2. the use of a phase transfer catalyst, preferably benzyltriethylammonium

to obtain Olanzapine crude, and


  1. dissolution of the crude in acetic acid solution and purification with a not chlorinated solvent.
  2. Addition of the Olanzapine acetate to a sodium bicarbonate solution previously seeded
  3. high yield

to obtain Olanzapine form I

Summary of the method

1.      The present method describes the reaction of the benzodiazepine II, with an excess of III, in an alcohol as a solvent. This reaction had always been described in aprotic high boiling solvents or mixtures thereof. It has surprisingly been found that the reaction rate is high in alcohols. The preferred solvent is tert-butanol.

2.      The presence of a phase transfer catalyst increases substantially the reaction rate. The preferred catalyst is benzyltriethylammonium chloride, and the percentages around 10% w/w respect the benzodiazepine. This percentage is not limiting.

3.      Another improvement of this method is the low level of impurities in the final product (single impurity <0.1%), due to the purification of the Olanzapine through the acetate. This purification has already been published, but not using isopropyl acetate as the purifying solvent. The advantage in the use of isopropyl acetate is that it is a Class 3 solvent, instead of the previously used dichloromethane (class 2) and performs very good as a purifying agent.

4.      The precipitation of the olanzapine Form I is performed by addition of the Olanzapine acetate to a previously seeded sodium bicarbonate solution. This is to ensure that the seeding is efficient, and the pH is easily controlled.

5.      The Crude as well as the purification give high...