Simplified procedure for the preparation of darunavir
The present invention relates to an improved process for preparing [(1S,2R)-3-[[(4-aminophenyl)-sulfonyl](2-methyl-propyl)amino]-2-hydroxy-1-(phenylmethyl)-propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester—which compound is also known under its INN as darunavir—by reacting carbonic acid 2,5-dioxo-1-pyrrolidinyl[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester with 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-benzenesulfonamide in ethanol as solvent. Furthermore said process allows for darunavir to be isolated immediately in its ethanolate form, i.e. darunavir monoethanolate, which is the marketed form of darunavir under the tradename Prezista™.
1. A process for preparing darunavir, which process comprises the step of
a) reacting carbonic acid 2,5-dioxo-1-pyrrolidinyl [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester with 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-benzenesulfonamide in ethanol while heating the reaction mixture at a temperature between 30° C. and reflux temperature.
2. The process according to claim 1 wherein step a) is carried out in the absence of an organic base.
3. The process according to claim 2 wherein the molar ratio of carbonic acid 2,5-dioxo-1-pyrrolidinyl [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester and 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-benzenesulfonamide ranges from 0.95 to 1.05.
4. The process according to claim 3 wherein step a) is carried out at a temperature between 30° C. and 70° C.
5. The process according to claim 4 wherein the temperature is between 40° and 60° C.
6. The process according to claim 1 whereby step a) is followed by the following steps:
b) heating till the reaction mixture is homogeneous;
c) cooling the reaction mixture;
d) isolating the precipitated product;
e) crystallizing the thus obtained precipitated product from ethanol; and
f) isolating the crystallized darunavir monoethanolate.
7. The process according to claim 6 wherein the reaction mixture in step b) is cooled to a temperature between 15° C. and −10° C.
8. The process according to claim 6 wherein the crystallization of the obtained precipitated product is performed by suspending the precipitated product in ethanol, heating the resulting mixture until a homogeneous solution is obtained, followed by cooling.
9. The process according to claim 8 wherein the crystallization comprises a temperature cycling procedure.
10. The process according to claim 9 wherein the temperature cycling procedure comprises the steps of:
keeping the crystallization mixture at a temperature between 61° C. and 63° C. for a period of 20 to 40 minutes,
cooling the crystallization mixture to a temperature between 57° C. and 59° C. over a period of 5 to 20 minutes,
keeping the crystallization mixture at a temperature between 57° C. and 59° C. for a period of 20 to 40 minutes.
heating the crystallization mixture to a temperature between 66° C. and 68° C. over a period of 5 to 20 minutes, and
keeping the crystallization mixture at a temperature between 66° C. and 68° C. for a period of 20 to 40 minutes.
11. The process according to claim 8 wherein cooling is done by natural cooling.
12. The process according to claim 8 wherein cooling is done following a linear cooling profile.
13. The process according to claim 11 wherein the crystallization mixture is cooled to a temperature between −5° C. and 25° C. before the darunavir monoethanolate crystals are isolated.
14. A process for preparing darunavir, which process comprises the steps of
a) reacting carbonic acid 2,5-dioxo-1-pyrrolidinyl [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester with 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-benzenesulfonamide in ethanol while heating the reaction mixture at a temperature between 30° C. and reflux temperature;
b) heating till the reaction mixture is homogeneous;
c) cooling the reaction mixture;
d) isolating the precipitated product;
e) crystallizing the thus obtained precipitated product from ethanol; and
f) isolating the crystallized darunavir monoethanolate.
15. The process according to claim 14 wherein the reaction mixture in step b) is cooled to a temperature between 15° C. and −10° C.
16. The process according to claim 15 wherein the crystallization comprises a temperature cycling procedure.
17. The process according to claim 16 wherein the temperature cycling procedure comprises the steps of:
keeping the crystallization mixture at a temperature between 61° C. and 63° C. for a period of 20 to 40 minutes,
cooling the crystallization mixture to a temperature between 57° C. and 59° C. over a period of 5 to 20 minutes,
keeping the crystallization mixture at a temperature between 57° C. and 59° C. for a period of 20 to 40 minutes.
heating the crystallization mixture to a temperature between 66° C. and 68° C. over a period of 5 to 20 minutes, and
keeping the crystallization mixture at a temperature between 66° C. and 68° C. for a period of 20 to 40 minutes.