Synthesis of 2,4-pyrimidinediamines
View Patent ↗Disclosed herein are methods for synthesizing 2,4-pyrimidinediamines as well as intermediates used therein.
1. A process for preparing a compound of formula I:
comprising:
a) contacting an acid solvate of a compound of formula II:
with an amide under conditions suitable for forming an amide solvate of the compound of formula II; and
b) contacting the amide solvate with an aqueous base comprising sodium ions under conditions suitable for forming the compound of formula I
wherein the carboxylic acid is R 1 COOH wherein R 1 is —H or a C 1 -C 4 alkyl optionally substituted with up to three halo; and
the amide is R 30 CON(R 2 ) 2 where each R 2 is independently —H or C 1 -C 4 alkyl or both R 2 together with the nitrogen to which they are attached form a 4 to 6 membered aliphatic ring, and R 30 is —H or C 1 -C 4 alkyl; or R 30 and one of the R 2 together with the carbon and nitrogen to which they are attached, respectively, combine to form a 4 to 6-membered aliphatic ring and the other R 2 is independently —H or C 1 -C 4 alkyl.
2. The process of claim 1 , wherein the amide is a N,N-dialkylformamide, N,N-dialkylacetamide, N-alkylpyrrolidinone, or N-alkylpiperidone.
3. The process of claim 2 , wherein the amide is the N,N-dialkylformamide; and
the conditions suitable for forming the amide solvate of the compound of formula II comprise a temperature of between about 20° C. and about 70° C.
4. The process of claim 3 , wherein the amide is N,N-dimethylformamide (DMF);
and the conditions suitable for forming the amide solvate comprise re-slurrying of the acid solvate in the DMF at a temperature of about 50° C.
5. The process of claim 1 , wherein the aqueous base in part b) comprises sodium hydroxide and an alcohol, and the conditions suitable for forming the compound of formula I comprise a temperature of between about 40° C. about 80° C. and a pH of about 8 to about 10.5.
6. The process of claim 5 , wherein the aqueous base in step b) comprises sodium hydroxide (NaOH) and isopropyl alcohol (IPA), and the conditions suitable for forming the compound of formula I comprise a temperature of about 80° C. and a pH of about 9.
7. The process according to claim 1 wherein the compound of formula I is in the form of a hydrate.
8. The process according to claim 7 wherein the hydrate is a hexahydrate.