Methods for synthesizing molybdopterin precursor Z derivatives
View Patent ↗Provided herein are synthetic methods for preparing a compound of formula (I): Also provided herein are synthetic methods for preparing a compound of formula (XIII): The disclosure also provides useful intermediates, derivatives, prodrugs, and pharmaceutically acceptable salts, solvates and hydrates of the formula (I) and formula (XIII) compounds. These compounds are useful for treating diseases associated with molybdenum cofactor deficiency.
1. A process for preparing a compound of formula (I):
or a pharmaceutically acceptable salt thereof, the process comprising:
(a) reacting a compound of formula (II):
wherein:
each R 1 is independently H or a protecting group,
with a compound of formula (III):
to produce a compound of formula (IV):
(b) selectively protecting the compound of formula (IV) to prepare a compound of formula (V):
(c) phosphorylating the compound of formula (V) to prepare a compound of formula (VI):
(d) oxidizing the compound of formula (VI) to prepare a compound of formula (VII):
and (e) deprotecting the compound of formula (VII) to prepare the compound of formula (I).
2. The process of claim 1 , wherein the pharmaceutically acceptable salt is an HCl salt.
3. The process of claim 1 , wherein the compound of formula (II) is:
4. The process of claim 1 , wherein the compound of formula (III) is a protected or unprotected galactose, mannose, glucose, or gulose.
5. The process of claim 1 , wherein the compound of formula (III) is:
6. The process of claim 1 , wherein two adjacent R 1 groups come together to form an isopropylidine acetal or benzylidine acetal moiety.
7. The process of claim 1 , wherein step (a) comprises reacting the compound of formula (II) and the compound of formula (III) in the presence of a hydrazine.
8. The process of claim 7 , wherein the hydrazine is selected from the group consisting of phenylhydrazines and alkylhydrazines.
9. The process of claim 8 , wherein the hydrazine is phenylhydrazine.
10. The process of claim 1 , wherein the phosphorylation of step (c) comprises reacting the compound of formula (V) with a P(V) phosphorylating agent.
11. The process of claim 10 , wherein the P(V) phosphorylating agent is selected from the group consisting of: POCl 3 ; H 3 PO 4 ; PO(OBn) x Cl 3-x ; Cl 3 CCH 2 OP(O)Cl 2 ; and (BnO) 2 P(O)OP(O)(OBn) 2 .
12. The process of claim 10 , wherein the P(V) phosphorylating agent is POCl 3 .
13. The process of claim 1 , wherein the phosphorylation of step (c) comprises reacting the compound of formula (V) with a P(III) phosphitylating agent.
14. The process of claim 13 , wherein the P(III) phosphitylating agent is selected from the group consisting of: P(OCH 2 CH 2 CN) 2 Cl; P(OCH 2 CH 2 CN)(NPr 2 -i)Cl; and cyanoethyl-O—P[N(i-Pr) 2 )] 2 .
15. The process of claim 13 , wherein step (c) further comprises oxidizing the resulting phosphite to prepare the phosphate of compound (VI).
16. The process of claim 1 , wherein step (d) comprises reacting the compound of formula (VI) with an oxidizing agent selected from the group consisting of: RuO 4 ; Dess-Martin; DMSO/triflic anhydride; and PDC.
17. The process of claim 1 , wherein the deprotection of the compound of formula (VII) is performed under anaerobic conditions.
18. The process of claim 1 , wherein the compound of formula (IV) is:
19. The process of claim 1 , wherein the compound of formula (V) is:
20. The process of claim 1 , wherein the compound formula (VI) is:
21. The process of claim 1 , wherein the compound of formula (VII) is:
22. The process of claim 1 , wherein the process further comprises formulating the compound of formula (I) as a pharmaceutical composition.
23. A compound of formula (IV):
or a pharmaceutically acceptable salt form thereof, wherein:
each R 1 is independently H or a protecting group.
24. A compound of formula (V):
or a pharmaceutically acceptable salt form thereof, wherein:
each R 1 is independently H or a protecting group.
25. A compound of formula (VI):
or a pharmaceutically acceptable salt form thereof, wherein:
each R 1 is independently H or a protecting group, and at least R 1 is a protecting group.
26. A compound of formula (VII):
or a pharmaceutically acceptable salt form thereof, wherein:
each R 1 is independently H or a protecting group; and at least one R 1 is a protecting group.
27. A process for preparing a compound of formula (XIII):
or a pharmaceutically acceptable salt form thereof, the process comprising:
(a) reacting a compound of formula (II):
with a compound of formula (III):
to produce a compound of formula (IV):
wherein:
each R 1 is independently H or a protecting group;
(b) selectively protecting the compound of formula (IV) to prepare a compound of formula (V):
(c) phosphorylating the compound of formula (V) to prepare a compound of formula (VI):
(d) oxidizing the compound of formula (VI) to prepare a compound of formula (XIV):
and (e) deprotecting the compound of formula (XIV) to prepare the compound of formula (XIII).
28. The process of claim 27 , wherein the pharmaceutically acceptable salt is an HCl salt.
29. The process of claim 27 , wherein the compound of formula (II) is:
30. The process of claim 27 , wherein the compound of formula (III) is a protected or unprotected galactose, mannose, glucose, or gulose.
31. The process of claim 27 , wherein the compound of formula (III) is:
32. The process of claim 27 , wherein two adjacent R 1 groups come together to form an isopropylidine acetal or benzylidine acetal moiety.
33. The process of claim 27 , wherein step (a) comprises reacting the compound of formula (II) and the compound of formula (III) in the presence of a hydrazine.
34. The process of claim 33 , wherein the hydrazine is selected from the group consisting of phenylhydrazines and alkylhdrazines.
35. The process of claim 34 , wherein the hydrazine is phenylhydrazine.
36. The process of claim 27 , wherein the phosphorylation of step (c) comprises reacting the compound of formula (V) with a P(V) phosphorylating agent.
37. The process of claim 36 , wherein the P(V) phosphorylating agent is selected from the group consisting of: POCl 3 ; H 3 PO 4 ; PO(OBn) x Cl 3-x ; Cl 3 CCH 2 OP(O)Cl 2 ; and (BnO) 2 P(O)OP(O)(OBn) 2 .
38. The process of claim 37 , wherein the P(V) phosphorylating agent is POCl 3 .
39. The process of claim 27 , wherein the phosphorylation of step (c) comprises reacting the compound of formula (V) with a P(III) phosphitylating agent.
40. The process of claim 39 , wherein the P(III) phosphitylating agent is selected from the group consisting of: P(OCH 2 CH 2 CN) 2 Cl; P(OCH 2 CH 2 CN)(NPr 2 -i)Cl; and cyanoethyl-O—P[N(i-Pr) 2 )] 2 .
41. The process of claim 39 , wherein step (c) further comprises oxidizing the resulting phosphite to prepare the phosphate of compound (VI).
42. The process of claim 27 , wherein step (d) comprises reacting the compound of formula (VI) with an oxidizing agent selected from the group consisting of: Ru 04 ; Dess-Martin; DMSO/triflic anhydride; and PDC.
43. The process of claim 27 , wherein the deprotection of the compound of formula (XIV) is performed under anaerobic conditions.
44. The process of claim 27 , wherein the compound of formula (IV) is:
45. The process of claim 27 , wherein the compound of formula (V) is:
46. The process of claim 27 , wherein the compound formula (VI) is:
47. The process of claim 27 , wherein the compound of formula (XIV) is:
48. The process of claim 27 , wherein the process further comprises formulating the compound of formula (XIII) as a pharmaceutical composition.