Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
2001-10-19
2003-10-28
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
Reexamination Certificate
active
06639071
ABSTRACT:
BACKGROUND OF THE INVENTION
The synthesis of the reverse transcriptase inhibitor (RTI), (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H3,1-benzoxazin-2-one, also known as DMP-266 has been described in U.S. Pat. No. 5,519,021 issued on May 21, 1996 and the corresponding PCT International Patent Application WO 95/20389, which published on Aug. 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 937-940, as well as the PCT publication, WO 96/37457, which published on Nov. 28, 1996.
The compound was previously crystallized from a heptanetetrahydrofuran (THF) solvent system. The crystallization procedure required the use of high temperatures (about 90° C.) to dissolve the final product. Crystals formed by nucleation during the cooling process. The crystals which were produced were Form II and are converted to the desired Form I while drying under vacuum at 90° C. This crystallization provided minimal purification and produced material with inconsistent physical properties. The final product slurry was extremely difficult to mix and handle due to its high viscosity and heterogeneous nature.
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 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, as low at 40° C.
SUMMARY OF THE INVENTION
A process for the crystallization of a compound of the structural formula
comprising the use of a solvent to effect the dissolution of the compound followed by the addition of an anti-solvent to initiate the crystallization.
REFERENCES:
patent: 4518597 (1985-05-01), Narr et al.
patent: 5519021 (1996-05-01), Young et al.
patent: 5633405 (1997-05-01), Thompson et al.
patent: 5663467 (1997-09-01), Thompson et al.
patent: 0 169 618 (1986-01-01), None
patent: 0 582 455 (1994-01-01), None
patent: WO 95/20389 (1995-08-01), None
patent: WO 98/45278 (1995-10-01), None
patent: WO 96/37457 (1996-11-01), None
patent: WO 98/04535 (1998-02-01), None
patent: WO 98/14436 (1998-04-01), None
patent: WO 99/64405 (1999-12-01), None
T. L. Threifall, “Analysis of Organic Polymorphs”, Analyst, vol. 120, pp. 2435-2460 (Oct. 1995).
D. Giron, “Thermal Analysis and calorimetric methods in the characterization of polymorphs and solvates”, Thermochimica Acta, vol. 248, pp. 1-59 (1995).
A. S. Thompson et al., “Use of an Ephedrine Alkoxide to Mediate Enantioselective Addition of an Acetylide to a Prochiral Ketone: Assymmetric Synthesis of the Reverse Transcriptase Inhibitor L-743,726”, Tetrahedron Letters, vol. 36, No. 49, pp. 8937-8940 (1995).
Crocker Louis S.
Kukura, II Joseph L.
Stelmach Christine
Thompson Andrew S.
Young Steven D.
Camara Valerie J.
Merck & Co. , Inc.
Raymond Richard L.
Walton Kenneth R.
Winokur Melvin
LandOfFree
Crystal Forms of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Crystal Forms of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Crystal Forms of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3112451