Crystalline dipeptides useful in the synthesis of elamipretide
Disclosed are crystalline forms of L-Lys(Boc)-Phe-NH 2 and Boc-D-Arg-DMT. The crystalline forms may be used in the synthesis of elamipretide.
1. A crystalline form of a compound according to formula II:
2. A method of making a compound of formula II:
comprising:
(a) combining an HCl salt represented by formula I, and a mixture of CH 3 OH and H 2 O, thereby forming a suspension comprising the compound of Formula II; wherein the compound of formula I is:
3. The method of claim 2 , further comprising:
(b) heating the suspension, thereby forming a solution.
4. The method of claim 3 , wherein the suspension is heated to about 45° C. to about 50° C.
5. The method of claim 3 , further comprising:
(c) adding an aqueous solution of Na 2 CO 3 to the solution formed in (b), thereby forming a second suspension.
6. The method of claim 5 , wherein about 1.2 equivalents of Na 2 CO 3 is added relative to the amount of the compound of formula I.
7. The method of claim 5 , further comprising:
(d) stirring the second suspension.
8. The method of claim 7 , wherein the second suspension is heated to about 45° C. while being stirred.
9. The method of claim 8 , wherein the second suspension is stirred at about 45° C. for about one hour.
10. The method of claim 8 , further comprising:
(e) cooling the second suspension to about 15° C.
11. The method of claim 10 , wherein the second suspension is stirred at about 15° C. for about one hour.
12. The method of claim 10 , further comprising:
(f) isolating from the second suspension the compound of formula II in solid form.
13. The method of claim 12 , wherein (f) comprises filtering the second suspension, and collecting the solid form of the compound of formula II.
14. The method of claim 13 , further comprising:
(g) drying the compound of formula II, thereby forming a dried compound of formula II.
15. The method of claim 14 , wherein the dried compound of formula II has a purity of 99.4% as measured by HPLC.
16. The method of claim 14 , wherein the dried compound of formula II is crystalline.
17. A method of making a compound of formula II:
comprising:
(a) adding an aqueous solution of Na 2 CO 3 to a solution comprising an HCl salt represented by formula I and a mixture of CH 3 OH and H 2 O; wherein the HCl salt of formula I is:
thereby forming a suspension comprising the compound of Formula II.
18. The method of claim 17 , wherein about 1.2 equivalents of Na 2 CO 3 is added relative to the amount of the compound of formula I.
19. The method of claim 17 , further comprising:
(b) isolating from the suspension the compound of formula II in solid form, wherein the solid form of formula II has a purity of 99.4% as measured by HPLC.