Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent
AssigneeMerck & Co., Inc.
InventorsWilliam Clarke, Joseph L. Kukura, II
Life of this patent
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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-ben zoxazin-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.degree. C. and 50.degree. C.
Claims25
A process for the crystallization of a compound of the structural formula ##STR5## comprising the steps of:
- (1) dissolving the compound in a solvent in a ratio of about 3.0 ml to about 10.0 ml of solvent to 1 gram of the compound;
- (2) filtering the solution of the compound to remove any particulate matter;
- (3) adding the anti-solvent to the stirring solution at room temperature over a period of about 30 minutes to about an hour to reach the saturation point of the solution containing the compound;
- (4) adding to the solution a solid seed charge of the compound in the amount of about 2 to about 10 percent by weight to form a slurry;
- (5) milling the slurry to reduce the thickness of the slurry;
- (6) adding the remaining water to reach the desired solvent composition of about 30% to about 50% and milling the slurry as needed during the addition;
- (7) slowly cooling the slurry to about 5.degree. C. to about 20.degree. C.;
- (8) aging for about 2 to about 16 hours until the supernatant concentration reaches equilibrium;
- (9) milling the slurry, as needed, to reduce the thickness of the slurry;
- (10) filtering the milled slurry to isolate a wet cake of the crystalline compound;
- (11) washing the wetcake once with about 1 to about 2 bed volumes of the final crystallization solvent composition and then twice with water using about 5-10 ml water per gram of compound;
- and
- (12) drying the washed wetcake at about 40.degree. C. to about 90.degree. C. under vacuum for about 1 hour to about 3 days, or until the loss on dryness is less than 0.5 weight percent.
A process for the crystallization of a compound of the structural formula ##STR6## comprising the steps of:
- (1) mixing about 10% to about 20% by weight of the final amount of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one in the desired v/v ratio of solvent to anti-solvent at about 20.degree. C. to form the heel;
- (2) adding the solution of solvent and (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one, and anti-solvent to the heel simultaneously at constant rates over about 6 hours maintaining the v/v ratio of solvent to anti-solvent;
- (3) milling the slurry during the addition to reduce the thickness of the slurry;
- (4) cooling the slurry to about 10.degree. C. over about 3 hours and aging slurry until the supernatant concentration reaches equilibrium;
- (5) filtering the milled slurry to isolate a wet cake of the crystalline compound;
- (6) washing the wetcake once with about 1 to about 2 bed volumes of the final crystallization solvent composition and then twice with water using about 5 ml to about 10 ml water per gram of compound;
- and
- (7) drying the washed wetcake at about 40.degree. C. to about 90.degree. C. under vacuum for about 1 hour to about 3 days, or until the loss on dryness is less then 0.5 weight percent.
Dependencies are inferred from the claim text.