Process for the production of estetrol intermediates
The present invention relates to a process for the preparation of a compound of formula (I) comprising the steps of a) reacting a compound of formula (II) with a silylating or an acylating agent to produce compound of formula (III), wherein P 1 is a protecting group selected from R 2 —Si—R 3 R 4 or R 1 CO—, R 1 is a group selected from C 1-6 alkyl or C 3-6 cycloalkyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl; R 2 , R 3 and R 4 are each independently a group selected from C 1-6 alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl; b) halogenation or sulfinylation of the compound of formula (III) to produce a compound of formula (IV); wherein X is halo, or —O—SO—R 5 , and R 5 is a group selected from C 6-10 aryl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from chloro or C 1-4 alkyl; c) dehalogenation or desulfinylation of the compound of formula (IV) to produce compound of formula (V); and d) reacting the compound of formula (V) with a reducing agent to produce compound of formula (I).
1. A process for the preparation of a compound of formula (I)
comprising the steps of
a) reacting a compound of formula (II) with a silylating agent to produce a compound of formula (III), wherein P 1 is R 2 —Si—R 3 R 4 ; R 2 , R 3 and R 4 are each independently a group selected from C 1-6 alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl;
b) halogenation or sulfinylation of the compound of formula (III) to produce a compound of formula (IV); wherein X is halo, or —SO—R 5 , and R 5 is a group selected from C 6-10 aryl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from chloro or C 1-4 alkyl;
wherein the halogenation or sulfinylation is performed by directly reacting the compound of formula (III) with a halogenation or sulfinylation reagent;
c) direct dehalogenation or desulfinylation of the compound of formula (IV) to produce compound of formula (V); and
d) reacting the compound of formula (V) with a reducing agent to produce compound of formula (I).
2. The process according to claim 1 , wherein step (b) is a sulfinylation and the sulfinylation is performed by reacting the compound of formula (III) with a base and with a sulfinylation reagent.
3. The process according to claim 1 wherein step (b) is a sulfinylation and a sulfinylation reagent is methyl 2-pyridinesulfinate, methyl benzenesulfinate, methyl 4-methyl-benzenesulfinate, methyl 4-chloro-benzene sulfinate.
4. The process according to claim 2 , wherein the base used in the sulfinylation step is selected from the group consisting of potassium hydride, potassium terbutylate, sodium hydride, sodium terbutylate and a mixture thereof.
5. The process according to claim 1 , wherein step (b) is a halogenation and the halogenation is performed by reacting the compound of formula (III) with a halogenating reagent.
6. The process according to claim 1 wherein step (b) is a bromination and a brominating reagent is selected from the group consisting of copper(II) bromide, bromine, and pyridinium bromide perbromide.
7. The process according to claim 1 , wherein the desulfinylation step is carried out with heat, or optionally in the presence of cupric sulfate.
8. The process according to claim 1 , wherein the dehalogenation step is performed in the presence of a base.
9. The process according to claim 8 , wherein the base is selected from the group consisting of imidazole, collidine, 2,6-lutidine, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene.
10. The process according to claim 1 , wherein step (d) is performed using a reducing agent selected from the group consisting of metal hydride compounds.
11. The process according to claim 1 , wherein step (d) is performed using a reducing agent selected from the group consisting of NaBH 4 /CeCl 3 , LiAlH 4 , NaBH 4 , NaBH(OAc) 3 , and ZnBH 4 .
12. The process according to claim 1 , wherein the silylating agent is selected from the group consisting of C 1-6 alkylsilylchloride, C 1-6 alkylsilyltriflate, phenylsilylchloride, phenylsilyltriflate, C 1-6 alkylphenylsilylchloride, C 1-6 alkylphenylsilyltriflate, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl.
13. The process according to claim 1 , wherein the acylating agent is selected from the group consisting of C 2-6 alkenylC 1-6 alkanoates, C 2-6 alkenylC 3-6 cycloalkanoates, acyl chlorides and anhydrides.
14. A process for the preparation of estetrol, said process comprising preparing a compound of formula (I) by a process,
the process comprising the steps of:
a) reacting a compound of formula (II) with a silylating agent to produce a compound of formula (III), wherein P 1 is R 2 —Si—R 3 R 4 ; R 2 , R 3 and R 4 are each independently a group selected from C 1-6 alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C 1-4 alkyl;
b) halogenation or sulfinylation of the compound of formula (III) to produce a compound of formula (IV); wherein X is halo, or —SO—R 5 , and R 5 is a group selected from C 6-10 aryl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from chloro or C 1-4 alkyl;
wherein the halogenation or sulfinylation is performed by directly reacting the compound of formula (III) with an halogenation or sulfinylation reagent;
c) direct dehalogenation or desulfinylation of the compound of formula (IV) to produce compound of formula (V); and
d) reacting the compound of formula (V) with a reducing agent to produce compound of formula (I);
and further reacting compound of formula (I) to produce estetrol.
15. The process according to claim 14 , wherein step (b) is a sulfinylation and the sulfinylation is performed by reacting the compound of formula (III) with a base and with a sulfinylation reagent.
16. The process according to claim 14 wherein step (b) is a sulfinylation and a sulfinylation reagent is methyl 2-pyridinesulfinate, methyl benzenesulfinate, 4-methyl-benzenesulfinate, methyl 4-chloro-benzene sulfinate.
17. The process according to claim 15 , wherein the base used in the sulfinylation step is selected from the group consisting of potassium hydride, potassium terbutylate, sodium hydride, sodium terbutylate and a mixture thereof.
18. The process according to claim 14 , wherein step (b) is a halogenation and the halogenation is performed by reacting the compound of formula (III) with a halogenating reagent.
19. The process according to claim 14 wherein step (b) is a bromination and a brominating reagent is selected from the group consisting of copper(II) bromide, bromine, and pyridinium bromide perbromide.