Pharmaceutical process and intermediates
The present disclosure provides for processes and intermediates in the large-scale manufacture of the compound of formula (I) or hydrates thereof.
1. A process for preparing a compound of formula (I) or hydrate thereof:
comprising:
a) contacting an amide solvate of the compound of formula (II):
with an amine to form an amine salt of the compound of formula (II); and
b) contacting the amine salt with a reagent comprising sodium ions to form the compound of formula (I) or hydrate thereof.
2. The process according to claim 1 , wherein the compound of formula (I) is in the form of a hexahydrate.
3. A process for preparing a compound of formula (VI):
comprising contacting a compound of formula (VII):
with a compound of formula (VIII):
in the presence of a tetra-alkylammonium salt,
wherein:
R 3 and R 4 are each independently C 1-6 alkyl; and
X is halogen;
to form a compound of formula (VI).
4. A process for preparing a compound of formula (I) or hydrate thereof comprising:
(a) contacting a compound of formula (VI):
wherein R 3 and R 4 are each independently C 1-6 alkyl;
with acetic acid and water to form the compound of formula (V):
(b) contacting the compound of formula (V) with an amide to form an amide solvate of the compound of formula (II):
(c) contacting the amide solvate of the compound of formula (II) with an amine to form an amine salt of the compound of formula (II); and
(d) contacting the amine salt of the compound of formula (II) with a reagent comprising sodium ions to form the compound of formula (I) or hydrate thereof.
5. The process according to claim 4 , wherein the compound of formula (I) is in the form of a hexahydrate.
6. The process according to claim 1 , wherein the amide component of the amide solvate is N,N-dimethylformamide (DMF).
7. The process according to claim 1 , wherein the amine component of the amine salt of the compound of formula (II) is N(R 40 ) 3 , where each R 40 is independently —H or C 1-12 alkyl, or two R 40 groups together with the nitrogen to which they are attached form a 4 to 6-membered heterocyclic ring and the remaining R 40 is —H or C 1-12 alkyl.
8. The process according to claim 1 , wherein the amine component of the amine salt of the compound of formula (II) is triethylamine.
9. The process according to claim 1 , wherein the reagent comprising sodium ions is sodium 2-ethylhexanoate.
10. The process according to any claim 2 , wherein the amide component of the amide solvate is N,N-dimethylformamide (DMF).
11. The process according to claim 2 , wherein the amine component of the amine salt of the compound of formula (II) is N(R 40 ) 3 , where each R 40 is independently —H or C 1-12 alkyl, or two R 40 groups together with the nitrogen to which they are attached form a 4 to 6-membered heterocyclic ring and the remaining R 40 is —H or C 1-12 alkyl.
12. The process according to claim 2 , wherein the amine component of the amine salt of the compound of formula (II) is triethylamine.
13. The process according to claim 2 , wherein the reagent comprising sodium ions is sodium 2-ethylhexanoate.
14. The process according to any claim 7 , wherein the amide component of the amide solvate is N,N-dimethylformamide (DMF).
15. The process according to claim 7 , wherein the amine component of the amine salt of the compound of formula (II) is N(R 40 ) 3 , where each R 40 is independently —H or C 1-12 alkyl, or two R 40 groups together with the nitrogen to which they are attached form a 4 to 6-membered heterocyclic ring and the remaining R 40 is —H or C 1-12 alkyl.
16. The process according to claim 7 , wherein the amine component of the amine salt of the compound of formula (II) is triethylamine.
17. The process according to claim 7 , wherein the reagent comprising sodium ions is sodium 2-ethylhexanoate.