Process for crystallization of reverse transcriptase inhibitor using anti-solvent

A technology of anti-solvent and process, which is applied in the field of crystallization process of reverse transcriptase inhibitors using anti-solvent, which can solve the problems of high viscosity, unevenness, difficulty in mixing and handling, etc.

Inactive Publication Date: 2000-03-01
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Final product slurries are extremely difficult to mix and

Method used

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  • Process for crystallization of reverse transcriptase inhibitor using anti-solvent
  • Process for crystallization of reverse transcriptase inhibitor using anti-solvent
  • Process for crystallization of reverse transcriptase inhibitor using anti-solvent

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0059] Controlled anti-solvent addition crystallization process

[0060] 400 grams of DMP-266 starting material were dissolved in 2.400 liters of ethanol. See Figure 1. The solution was filtered to remove foreign matter. 2.088 liters of deionized (DI) water were added to the solution over a period of 30-60 minutes. To this solution was added 20 grams of DMP-266 seed crystals. The seed layer was allowed to age for 1 hour. The slurry is preferably mixed with an Intermig mixer. If necessary (due to the presence of overgrown crystals or a viscous slurry), the slurry can be wet milled for 15-60 seconds. 1.512 liters of DI water were added to the slurry over a period of 4-6 hours. If necessary (due to the presence of excessively long crystals or a thick slurry), the slurry can be wet milled for 15 to about 60 seconds during the addition. The slurry was allowed to age for 1-3 hours and then cooled to 10°C over 3 hours. The slurry was aged for 2-16 hours until the product conc...

example 2

[0062] Semi-continuous tailings crystallization process

[0063] 400 grams of DMP-266 starting material were dissolved in 2.400 liters of ethanol. See Figure 2. Mix 20 grams of DMP-266 with 0.3 liter of 40% (volume ratio) ethanol aqueous solution to prepare tailing slurry. The dissolved batch and 3.6 liters of DI water were simultaneously added to the above tailings slurry at a constant rate over a period of 6 hours to maintain a constant solvent composition in the crystallizer. It is best to use an Intermig stirrer during crystallization. During this addition, the slurry may be wet milled when the crystal length becomes too long or the slurry becomes too thick. The slurry was aged for 2-16 hours until the product concentration in the supernatant remained constant. The slurry was filtered and a crystalline wet cake was isolated. The wet filter cake was first washed with 1-2 bed volumes of 40% aqueous ethanol solution, and then washed twice with 2 liters of DI water each. ...

example 3-8

[0066] * The sum of solvent and water must be at least 12ml / g. The currently preferred concentration is

[0067] 15ml / g.

[0068] - the method doesn't work.

[0069] ×This method works.

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Abstract

The instant invention describes a method for crystallizing (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one from a solvent and anti-solvent solvent system and producing the crystalline product. The desired final crystal form, Form I, can be produced when using methanol or ethanol. Form II is isolated from 2-propanol and can be converted to the desired crystal form at low drying temperatures, such as between about a temperature of 40 DEG C and 50 DEG C.

Description

Background of the invention [0001] Reverse Transcriptase Inhibitor (RTI), (-)-6-Chloro-4-cyclopropynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazine-2 - Ketone, also known as DMP-266, the synthesis of which is described in US Patent 5,519,021, published May 21, 1996, and the corresponding PCT International Patent Application WO 95 / 20389, published August 3, 1995. In addition, Thompson et al. in Tetrahedron Letters (Tetrahedron Letters) 1995, 36, pp. 937-940, and PCT application WO 96 / 37457 published on November 28, 1996, describe the process of Asymmetric synthesis of enantiomeric benzoxazinones by acetylide addition followed by cyclization. [0002] The compound was first crystallized from a heptane-tetrahydrofuran (THF) solvent system. The crystallization operation requires high temperature (about 90°C) to dissolve the final product. Crystals form during cooling by nucleation. The crystals formed were Form II which converted to the desired Form I when dried under vacu...

Claims

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Application Information

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IPC IPC(8): C12N9/99A61K9/14A61K31/536A61P43/00B01D9/00C07DC07D265/18C12N9/00
CPCC07D265/18A61P31/18A61P43/00
Inventor W·克拉克L·S·克罗克J·L·库库拉二世
Owner SCHERING AG
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