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Details for Patent: 5,965,729

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Details for Patent: 5,965,729

Title: Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent
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.
Inventor(s): Clarke; William (Iselin, NJ), Kukura, II; Joseph L. (Metuchen, NJ)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Filing Date:Jan 20, 1998
Application Number:09/008,824
Claims:1. 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.

2. The process as recited in claim 1 wherein the solvent is defined as (C.sub.1 -C.sub.6)-alcohol.

3. The process as recited in claim 2 wherein the anti-solvent is defined as water.

4. The process as recited in claim 1 wherein the temperature during the anti-solvent addition (Step 3) is about 20.degree. C. to about 25.degree. C.

5. The process as recited in claim 1 wherein the temperature used during the drying of the washed wetcake (Step 12) is about 40.degree. C. to about 60.degree. C.

6. The process as recited in claim 3 wherein the solvent volume to anti-solvent volume ratio used is about 30% to about 50%.

7. The process as recited in claim 6 wherein the (C.sub.1 -C.sub.6)-alcohol is selected from methanol, ethanol and 2-propanol.

8. The process as recited in claim 7 wherein the (C.sub.1 -C.sub.6)-alcohol is 2-propanol.

9. The process as recited in claim 8 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm of about a 30% to about a 40% ethanol to water solvent to anti-solvent volume to volume ratio.

10. The process as recited in claim 6 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm of about 40% to about 50% methanol to water solvent to anti-solvent volume to volume ratio.

11. The process as recited in claim 6 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm of about 25% to about 35% 2-propanol to water solvent to anti-solvent volume to volume ratio.

12. The process as recited in claim 10 wherein the total solvent system volume per gram of compound is about 15 ml/gm of about 30% 2-propanol to water solvent to anti-solvent volume to volume ratio.

13. 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.

14. The process as recited in claim 13 wherein solvent is defined as acetonitrile, dimethyl acetamide, dimethyl formamide or alcohol.

15. The process as recited in claim 14 wherein the anti-solvent is defined as water.

16. The process as recited in claim 15 wherein the alcohol solvent is defined as (C.sub.1 -C.sub.6)-alcohol.

17. The process as recited in claim 13 wherein the temperature of the solution during the compound-solvent solution/anti-solvent addition (Step 2) is about 5.degree. C. to about 20.degree. C.

18. The process as recited in claim 13 wherein the temperature used during the drying of the washed wetcake (Step 7) is about 40.degree. C. to about 60.degree. C.

19. The process as recited in claim 16 wherein the alcohol to anti-solvent volume to volume ratio used is about 30% to about 50%.

20. The process as recited in claim 19 wherein the alcohol solvent is selected from methanol, ethanol and 2-propanol.

21. The process as recited in claim 20 wherein the solvent is 2-propanol.

22. The process as recited in claim 20 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm of about a 30% to about a 40% ethanol to water solvent to anti-solvent volume to volume ratio.

23. The process as recited in claim 20 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm of about 40% to about 50% methanol to water solvent to anti-solvent volume to volume ratio.

24. The process as recited in claim 21 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm of about 25% to about 35% 2-propanol to water solvent to anti-solvent volume to volume ratio.

25. The process as recited in claim 23 wherein the total solvent system volume per gram of compound is about 15 ml/gm of about 30% 2-propanol to water solvent to anti-solvent volume to volume ratio.
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