Methods for synthesizing molybdopterin precursor Z derivatives

Patent metadata

Field	Value
Publication number	US-9260462-B2
Application number	US-201214000055-A
Country	US
Kind code	B2
Filing date	Feb 17, 2012
Priority date	Feb 18, 2011
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

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.

First claim

What is claimed is:

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 formu

Assignees

• Long Xiangtian
• Dai Danmei
• Brunner Andreas
• Watt Derek Kevin
• Clinch Keith
• Baars Sylvia Myrna
• Dixon Rachel Anne
• Little Gillian Mary
• Landreau Cyrille Abel Sébastien
• Proisy Nicolas Georges Rene
• Alexion Pharma Inc

Inventors

• Long Xiangtian
• Dai Danmei
• Brunner Andreas
• Watt Derek Kevin
• Clinch Keith
• Baars Sylvia Myrna
• Dixon Rachel Anne
• Little Gillian Mary
• Landreau Cyrille Abel Sébastien
• Proisy Nicolas Georges Rene

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D491/147

  the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom · CPC title

• C07F9/65744 Primary

  condensed with carbocyclic or heterocyclic rings or ring systems · CPC title

• C07D491/14

  Ortho-condensed systems · CPC title