Processes for preparing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine
The present invention is related to processes for preparing 4-chloro-7H-pyrollo[2,3,-d]pyrimidine, and related synthetic intermediate compounds. 4-Chloro-7H-pyrrolo[2,3,-d]pyrimidine is an intermediate for preparing chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines, which are useful as inhibitors of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases.
1. A process for preparing a compound of Formula XIa:
wherein the process comprises:
treating a compound of Formula F-1:
with acid in a solvent at reflux temperature, to form the compound of Formula XIa above.
2. The process according to claim 1 , wherein the acid is aqueous concentrated hydrochloric acid.
3. The process according to claim 1 , wherein the solvent is tetrahydrofuran.
4. A process for preparing a compound of Formula XIa:
wherein the process comprises:
(1) reacting a compound of Formula F-2:
with one or more equivalents of a Wittig-type reagent selected from (methoxymethyl)triphenylphosphonium chloride and diethyl methoxymethylphosphonate in the presence of a solvent and a base, to form a compound of Formula F-1:
and
(2) treating the compound of Formula F-1 above with acid in a solvent at reflux temperature, to form the compound of Formula XIa above.
5. The process according to claim 4 , wherein the Wittig-type reagent is (methoxymethyl)triphenylphosphonium chloride.
6. The process according to claim 4 , wherein the Wittig-type reagent is diethyl methoxymethyl phosphonate.
7. The process according to claim 4 , wherein the base is selected from the group consisting of sodium hydride, sodium ethoxide, sodium hydroxide, potassium carbonate and sodium carbonate.
8. The process according to claim 4 , wherein the base is an alkali metal tert-butoxide.
9. The process according to claim 8 , wherein the alkali metal tert-butoxide is potassium tert-butoxide or sodium tert-butoxide.
10. A process for preparing a compound of Formula XIa:
wherein the process comprises:
(1) reacting a compound of Formula F-3:
with two or more equivalents of ammonia in the presence of an organic solvent, to form a compound of Formula F-2:
(2) reacting the compound of Formula F-2 above with one or more equivalents of a Wittig-type reagent selected from (methoxymethyl)triphenylphosphonium chloride and diethyl methoxymethylphosphonate in the presence of a solvent and a base, to form a compound of Formula F-1:
and
(3) treating the compound of Formula F-1 above with acid in a solvent at reflux temperature, to form the compound of Formula XIa above.
11. The process according to claim 10 , wherein the solvent is methanol.
12. The process according to claim 10 , wherein the solvent is toluene.
13. A process for preparing a compound of Formula XIa:
wherein the process comprises:
(1) reacting a compound of Formula F-4:
with two or more equivalents of phosphorous oxychloride in the presence of N,N-dimethylformamide, to form a compound of Formula F-3:
(2) reacting the compound of Formula F-3 above with two or more equivalents of ammonia in the presence of an organic solvent, to form a compound of Formula F-2:
(3) reacting the compound of Formula F-2 above with one or more equivalents of a Wittig-type reagent selected from (methoxymethyl)triphenylphosphonium chloride and diethyl methoxymethylphosphonate in the presence of a solvent and a base, to form a compound of Formula F-1:
and
(4) treating the compound of Formula F-1 above with acid in a solvent at reflux temperature, to form the compound of Formula XIa above.