Pleuromutilins and process for the preparation of pleuromutilins
A process for the preparation of 14-O—[(N-(3-methyl-2-amino-butyryl-piperidinyl)sulfanyl)acetyl]mutilins of formula feasible for large-scale production of high purity products, and wherein the carbon atom at the piperidine ring attached to the sulphur atom is either in the (S)-configuration or in the (R)-configuration, and a new crystalline form of 14-O—[(N-3-methyl-2-(R)-amino-butyryl-piperidine-3(S)-yl)sulfanyl)acetyl]mutilin-hydrochloride.
1. A process for the preparation of piperidineylsulfanylacetylmutilins of formula
wherein the carbon atom of the piperidine ring attached to the sulphur atom is either in the (S)-configuration or in the (R)-configuration and the 2-amino-3-methyl-butyryl group attached to the piperidine ring is either in the (S)-configuration or in the (R)-configuration, comprising the steps of
a) deprotecting a N-protected piperidineylsulfanylacetylmutilin of formula
and isolating a crystalline compound of formula
wherein the carbon atom of the piperidine ring attached to the sulphur atom is either in the (S)-configuration or in the (R)-configuration, in free form or in the form of an acid addition salt, in crystalline form,
b) acylating said crystalline compound of formula III with either (R)- or (S)-valine protected as an enamine and activated as a carbonic acid mixed anhydride to form a compound of formula
wherein R 1 and R 2 are C 1-4 alkyl, and R 3 is hydrogen or C 1-4 alkyl, and
c) deprotecting the compound of formula IV and isolating the compound of formula I.
2. The process according to claim 1 , wherein the compound of formula I is isolated in form of a pharmaceutically acceptable salt.
3. The process according to claim 1 , wherein the compound of formula I is isolated as a hydrochloride.
4. The process according to claim 1 , wherein said compound of formula III is an addition salt with methanesulfonic acid.
5. The process according to claim 1 , wherein the N-protecting group is a tert.-butoxy-carbonyl group.
6. The process according to claim 1 , wherein said N-protected piperidineylsulfanylacetylmutilin is prepared by reacting a pleuromutilin-22-O-sulfonate (e.g. mesylate, besylate or tosylate) with a N-protected piperidine thiol.
7. The process according to claim 6 , wherein the N-protected piperidineylsulfanylacetyl mutilin is prepared by reacting a pleuromutilin-22-O-sulfonate with a N-protected piperidine thiol wherein the carbon atom of the piperidine ring attached to the sulphur atom is either in the (S)-configuration or in the (R)-configuration.
8. The process according to claim 1 , wherein the isolated compound of formula I is a 3-substituted piperidineylsulfanylacetylmutilin.
9. The process according to claim 1 , wherein said 3-substituted piperidineylsulfanylacetylmutilin is 14-O—[(N-3-methyl-2-(R)-amino-butyryl-piperidine-3(S)-yl)sulfanyl)acetyl-]mutilin hydrochloride.
10. The process according to claim 1 , wherein the crystalline compound of formula III isolated in crystalline form has a diastereomeric excess of the (S)-isomer.
11. The process according to claim 1 , wherein the compound of formula IV is isolated in crystalline form prior to isolating the compound of formula I.
12. The process according to claim 1 , further comprising converting the compound of formula I to a crystalline form using a crystallization process involving seed crystals or that is a recrystallization process.
13. The process according to claim 12 , wherein the compound of formula I in crystalline form has a 3-(S)-diastereomeric excess greater than or equal to 97%.
14. A process for the preparation of piperidineylsulfanylacetylmutilins of formula
wherein the carbon atom of the piperidine ring attached to the sulphur atom is either in the (S)-configuration or in the (R)-configuration and the 2-amino-3-methyl-butyryl group attached to the piperidine ring is either in the (S)-configuration or in the (R)-configuration, comprising the steps of
a) deprotecting a N-protected piperidineylsulfanylacetylmutilin of formula
b) isolating a crystalline compound of formula
wherein the carbon atom of the piperidine ring attached to the sulphur atom is either in the (S)-configuration or in the (R)-configuration, in free form or in the form of an acid addition salt, in crystalline form,
c) acylating said compound of formula III with either (R)- or (S)-valine protected as an enamine and activated as a carbonic acid mixed anhydride to form a compound of formula
wherein R 1 and R 2 are C 1-4 alkyl, and R 3 is hydrogen or C 1-4 alkyl,
d) isolating the compound of formula IV as a crystalline solid, and
e) deprotecting the compound of formula IV and isolating the compound of formula I.
15. The process according to claim 14 , wherein the compound of formula III is isolated in crystalline form so as to have a diastereomeric excess of the (S)-isomer.
16. The process according to claim 14 , further comprising converting the compound of formula I to a crystalline form.
17. The process according to claim 16 , wherein the compound of formula I in crystalline form has a 3-(S)-diastereomeric excess.
18. A process for the preparation of piperidineylsulfanylacetylmutilins of formula
wherein the carbon atom of the piperidine ring attached to the sulphur atom is either in the (S)-configuration or in the (R)-configuration and the 2-amino-3-methyl-butyryl group attached to the piperidine ring is either in the (S)-configuration or in the (R)-configuration, comprising the steps of
a) deprotecting a N-protected piperidineylsulfanylacetylmutilin of formula
b) isolating a crystalline compound having a diastereomeric excess of the (S)-isomer of formula
in free form or in the form of an acid addition salt, in crystalline form,
c) acylating said compound of formula III with either (R)- or (S)-valine protected as an enamine and activated as a carbonic acid mixed anhydride to form a compound of formula
wherein R 1 and R 2 are C 1-4 alkyl, and R 3 is hydrogen or C 1-4 alkyl, and
d) deprotecting the compound of formula IV and isolating the compound of formula I.
19. The process according to claim 18 , further comprising converting the compound of formula IV to a crystalline form prior to forming the compound of formula I.
20. The process according to claim 18 , wherein the compound of formula I is in crystalline form.
21. The process according to claim 18 , wherein the compound of formula I has 3-(S)-diastereomeric excess.