Process for the production of estetrol intermediates

• US 11,053,273 B2
• Filed: 06/01/2012
• Issued: 07/06/2021
• Est. Priority Date: 06/01/2011
• Status: Active Grant

• Current Assignee: Mithra Recherche et Developpement SA (Mithra Pharmaceuticals S.A.)
• Original Assignee: Estetra SPRL
• Inventors: Pascal, Jean-Claude
• Primary Examiner(s): Badio, Barbara P
• Application Number:
  US14/122,892
• Publication Number:
  US 20140107091A1
• Time in Patent Office: 3,322 Days
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: C07J 1/0018 substituted in position 17 beta, not substituted in position 17 alfa
• CPC Class Codes: C07J 1/0059 substituted in position 17 by a keto group
• CPC Class Codes: C07J 1/007 the substituent being an OH group free esterified or etherified
• CPC Class Codes: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

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 P¹ is a protecting group selected from R²—Si—R³R⁴ or R¹CO—, R¹ is a group selected from C_1-6alkyl or C_3-6cycloalkyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C_1-4alkyl; R², R³ and R⁴ are each independently a group selected from C_1-6alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C_1-4alkyl; b) halogenation or sulfinylation of the compound of formula (III) to produce a compound of formula (IV); wherein X is halo, or —O—SO—R⁵, and R⁵ is a group selected from C_6-10aryl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from chloro or C_1-4alkyl; 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).

Claims

1. A process for the preparation of a 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 NaBH₄/CeCl₃, LiAlH₄, NaBH₄, NaBH(OAc)₃, and ZnBH₄.

12. The process according to claim 1, wherein the silylating agent is selected from the group consisting of C_1-6alkylsilylchloride, C_1-6alkylsilyltriflate, phenylsilylchloride, phenylsilyltriflate, C_1-6alkylphenylsilylchloride, C_1-6alkylphenylsilyltriflate, each group being optionally substituted by one or more substituents independently selected from fluoro or C_1-4alkyl.

13. The process according to claim 1, wherein the acylating agent is selected from the group consisting of C_2-6alkenylC_1-6alkanoates, C_2-6alkenylC_3-6cycloalkanoates, acyl chlorides and anhydrides.

14. A process for the preparation of estetrol, said process comprising preparing a compound of formula (I) by a process,

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.