Process for preparation of nitrogen mustard derivatives
The present invention provides a process for the production of compound (III) or a deprotected product thereof: comprising reacting compound (II) with chloroacetic acid, in the presence of a reducing agent; wherein PG is a protecting group and R is OH in a suitably protected form or (A). The invention further provides intermediate compounds formed in the process of the invention, and processes for the production of intermediate compounds.
1. A process for the production of compound (III):
comprising reacting compound (II)
with chloroacetic acid, in the presence of a reducing agent and a chloroacetate salt buffering agent;
wherein PG is a protecting group and R is OH in a suitably protected form or
2. The process of claim 1 , wherein the reducing agent is selected from the group consisting of borane, a borane-Lewis base complex, a borohydride, a metal hydride, and H 2 in the presence of a metal catalyst.
3. The process of claim 2 , wherein the reducing agent is BH 3 or borane dimethylsulfide.
4. The process of claim 1 , wherein PG is selected from the group consisting of methyl oxycarbonyl, ethyl oxycarbonyl, 9-fluorenylmethyl oxycarbonyl, t-butyl oxycarbonyl, benzyl oxycarbonyl, p-methoxybenzyl oxycarbonyl, 1-adamantyl oxycarbonyl, p-bromobenzyl oxycarbonyl, trifluoroacetyl, chloroacetyl, phenylacetyl, benzacetyl, p-toluenesulfonyl, 2-nitrobenzenesulfonyl, t-butylsulfonyl, 2- or 4-nitrobenzenesulfonyl, 2,4-dinitrobenzenesulfonyl, and 2-naphthalenesulfonyl.
5. The process of claim 4 , where PG is t-butyl oxycarbonyl.
6. The process of claim 1 , which is performed at a temperature in the range of from 3 to 50° C.
7. The process of claim 1 , wherein the molar ratio of chloroacetic acid:the chloroacetate salt is from 2:1 to 5:1.
8. The process of claim 1 , wherein the molar ratio of chloroacetic acid:the chloroacetate salt is from 1:7 to 1:20.
9. The process of claim 1 , wherein R is
10. The process of claim 1 , further comprising a step of forming a salt of compound (III).
11. The process of claim 1 , further comprising a step of producing compound (II), comprising reacting compound (VI):
with a reducing agent,
wherein PG is as defined for compound (II) and R is OH in a suitably protected form or
12. The process as claimed in claim 11 , wherein the reducing agent used to produce compound (II) from compound (VI) in the step recited in claim 11 is hydrogen and a catalyst.
13. The process of claim 11 , wherein R is
and further comprising a step of producing compound (VI) by reacting compound (IV):
with compound (V):
wherein PG is as defined for compound (II).
14. The process of claim 1 , further comprising deprotecting compound (III) to produce compound (I), or a salt thereof:
wherein R is OH optionally in a suitably protected form or
15. The process as claimed in claim 14 , wherein compound (I) is compound (Ib), or a salt thereof:
16. The process of claim 14 , wherein compound (I) is produced from the deprotection step and further comprising a step of forming a salt of compound (I).
17. The process of claim 16 , wherein the salt of compound (I) is:
18. A process for the production of compound (VIb):
comprising reacting compound (IV):
with compound (V):
wherein PG is a protecting group.
19. A compound having the following structure:
wherein Y is NH 2 or NO 2 , and PG is a protecting group.
20. The compound of claim 19 , wherein PG is t-butyl oxycarbonyl.
21. The process of claim 1 , which is performed at a temperature in the range of from 4 to 45° C.
22. The process of claim 1 , which is performed at a temperature in the range of from 5 to 40° C.
23. The process of claim 1 , wherein the chloroacetate salt is sodium chloroacetate.
24. The process of claim 12 , wherein the catalyst is Pd/C.
25. The process of claim 1 , further comprising a step of forming a hydrochloride salt of compound (III).
26. The process of claim 14 , wherein compound (I) is produced from the deprotection step and further comprising a step of forming a hydrochloride salt of compound (I).