Crystallization of (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D
Disclosed are methods of purifying the compound (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D 3 to obtain the compound in crystalline form. The methods typically include the steps of dissolving a product containing the compound in a solvent comprising hexane and 2-propanol, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of crystals, and recovering the crystals. Certain diol precursors formed during the synthesis of the compound and its diasteromers also may be obtained in crystalline form using ethyl acetate as a solvent.
1. (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D 3 having the formula
in crystalline form.
2. A crystalline form of (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D 3 having molecular packing arrangement defined by space group C2 and unit cell dimensions a=27.03 Å b==6.47 Å c=17.41 Å α=90°, β=103.35° and γ=90°.
3. A three dimensional structure for (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D 3 as defined by the molecular packing arrangement set forth in claim 2 .
4. A method of purifying (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D 3 , comprising the steps of:
(a) preparing a solvent comprising hexane;
(b) adding a product containing (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D 3 to be purified to said hexane to form a suspension of the product in the hexane;
(c) adding 2-propanol dropwise to the suspension to form a mixture of the product in the hexane and 2-propanol;
(d) heating the mixture to dissolve the product containing (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D 3 to be purified in said mixture;
(e) cooling said mixture and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D 3 crystals; and
(f) separating the (20R,22R)-2-methylene-19-nor-22-methyl-1α,25-dihydroxyvitamin D 3 crystals from the mixture.
5. The method of claim 4 including the further step of allowing said mixture and dissolved product to cool to ambient temperature prior to cooling below ambient temperature.
6. The method of claim 4 wherein the step of separating comprises filtering the mixture and precipitate to obtain the crystals.
7. The method of claim 4 including a further step (g) comprising repeating steps (a) through (f) using the recovered crystals from step (f) as the product of step (b).
8. The method of claim 4 wherein said mixture comprises about 15% 2-propanol and about 85% hexane, by volume.
9. A compound having the formula
in crystalline form, wherein the wavy line at carbon 22 indicates the methyl group attached to carbon 22 may be in its R or S orientation.
10. (8S,20R,22S)-Des-A,B-22-methyl-cholestan-8,25-diol having the formula
in crystalline form.
11. A crystalline form of (8S,20R,22S)-Des-A,B-22-methyl-cholestan-8,25-diol having molecular packaging arrangement defined by space group C2 and unit cell dimensions a=26.39 Å b=6.08 Å c=12.68 Å α=90°, β=118.38° and γ=90°.
12. A three dimensional structure for (8S,20R,22S)-Des-A,B-22-methyl-cholestan-8,25-diol as defined by the molecular packaging arrangement set forth in claim 11 .
13. A method of purifying (8S,20R,22S)-Des-A,B-22-methyl-cholestan-8,25-diol comprising the steps of:
(a) preparing a solvent comprising ethyl acetate;
(b) dissolving a product containing (8S,20R,22S)-Des-A,B-22-methyl-cholestan-8,25-diol to be purified in said solvent;
(c) cooling said solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of (8S,20R,22S)-Des-A,B-22-methyl-cholestan-8,25-diol crystals; and
(d) separating the (8S,20R,22S)-Des-A,B-22-methyl-cholestan-8,25-diol crystals from the solvent.
14. The method of claim 13 including the further step of allowing said solvent and dissolved product to cool to ambient temperature prior to cooling below ambient temperature.
15. The method of claim 13 wherein said solvent comprises 100% ethyl acetate, by volume.
16. The method of claim 13 wherein the step of separating comprises filtering the solvent and precipitate to obtain the crystals.
17. The method of claim 13 including a further step (e) comprising repeating steps (a) through (d) using the recovered crystals from step (d) as the product of step (b).
18. (8S,20R,22R)-Des-A,B-22-methyl-cholestan-8,25-diol having the formula
in crystalline form.
19. A crystalline form of (8S,20R,22R)-Des-A,B-22-methyl-cholestan-8,25-diol having molecular packaging arrangement defined by space group P2(1) and unit cell dimensions a=11.39 Å b=16.53 Å c=11.45 Å α=90°, β=119.26° and γ=90°.
20. A three dimensional structure for (8S,20R,22R)-Des-A,B-22-methyl-cholestan-8,25-diol as defined by the molecular packaging arrangement set forth in claim 19 .
21. A method of purifying (8S,20R,22R)-Des-A,B-22-methyl-cholestan-8,25-diol comprising the steps of:
(a) preparing a solvent comprising ethyl acetate;
(b) dissolving a product containing (8S,20R,22R)-Des-A,B-22-methyl-cholestan-8,25-diol to be purified in said solvent;
(c) cooling said solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of (8S,20R,22R)-Des-A,B-22-methyl-cholestan-8,25-diol crystals; and
(d) separating the (8S,20R,22R)-Des-A,B-22-methyl-cholestan-8,25-diol crystals from the solvent.
22. The method of claim 21 including the further step of allowing said solvent and dissolved product to cool to ambient temperature prior to cooling below ambient temperature.
23. The method of claim 21 wherein the step of separating comprises filtering the solvent and precipitate to obtain the crystals.
24. The method of claim 21 including a further step (e) comprising repeating steps (a) through (d) using the recovered crystals from step (d) as the product of step (b).
25. The method of claim 21 wherein said solvent comprises 100% ethyl acetate, by volume.
26. (8S,20S,22R)-Des-A,B-22-methyl-cholestan-8,25-diol having the formula
in crystalline form.
27. A crystalline form of (8S,20S,22R)-Des-A,B-22-methyl-cholestan-8,25-diol having molecular packaging arrangement defined by space group P2(1) and unit cell dimensions a=9.68 Å b=19.15 Å c=9.68 Å α=90°, β=91.27° and γ=90°.
28. A three dimensional structure for (8S,20S,22R)-Des-A,B-22-methyl-cholestan-8,25-diol as defined by the molecular packaging arrangement set forth in claim 27 .
29. A method of purifying (8S,20S,22R)-Des-A,B-22-methyl-cholestan-8,25-diol comprising the steps of:
(a) preparing a solvent comprising ethyl acetate;
(b) dissolving a product containing (8S,20S,22R)-Des-A,B-22-methyl-cholestan-8,25-diol to be purified in said solvent;
(c) cooling said solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of (8S,20S,22R)-Des-A,B-22-methyl-cholestan-8,25-diol crystals; and
(d) separating the (8S,20S,22R)-Des-A,B-22-methyl-cholestan-8,25-diol crystals from the solvent.
30. The method of claim 29 including the further step of allowing said solvent and dissolved product to cool to ambient temperature prior to cooling below ambient temperature.
31. The method of claim 29 wherein the step of separating comprises filtering the solvent and precipitate to obtain the crystals.
32. The method of claim 29 including a further step (e) comprising repeating steps (a) through (d) using the recovered crystals from step (d) as the product of step (b).
33. The method of claim 29 wherein said solvent comprises 100% ethyl acetate, by volume.