Process for the production of 19-norpregn-4-en-3,20-dione-17α-ol(gestonorone) and intermediates therefor

Patent metadata

Field	Value
Publication number	US-9562067-B2
Application number	US-201415038299-A
Country	US
Kind code	B2
Filing date	Dec 15, 2014
Priority date	Dec 16, 2013
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

The present invention relates to a new stereoselective process for the synthesis of 17(α)-17-acetyl-17-hydroxy-estr-4-en-3-one of formula (I), as well as to the new intermediates of the process. The 17(α)-17-acetyl-17-hydroxy-estr-4-en-3-one (gestonorone) is an important intermediate in the synthesis of the active ingredients having progestogen activity—such as gestonorone capronate and nomegestroi acetate. Formulas (I), (II) and (III).

First claim

The invention claimed is:

1. A process for the synthesis of (17α)-17-acetyl-17-hydoxy-estr-4-en-3-one of formula (I)

characterized by reacting the compound of formula (II)

with 1.5-10 mol equivalent of methyl lithium in the presence of substituted 1,2-diamino-ethane in an ether or formaldehyde dialkylacetal solvent or a mixture thereof at a temperature between −78° and −10° C., then reacting the protected imine derivative obtained as intermediate with mineral acids or strong organic acids at a temperature between 0° C. and the boiling point of the applied organic solvent.

2. The process according to claim 1 , characterized by synthesizing the compound of formula (II) the following way:
i) reacting the compound of formula (IV)

with 1.5-10 mol equivalent of alkali cyanide in a short-chain aliphatic alcohol solvent in the presence of a mild organic acid, then
ii) reacting the obtained compound of formula (III)

with 2-10 mol equivalent of trimethylchlorosilane in the presence of imidazole in an ether solvent at a temperature between 0 and +40° C.

3. The process according to claim 2 , characterized by carrying out the reaction in step i) in ethanol.

4. The process according to claim 2 , characterized by using potassium cyanide or sodium cyanide as reagent in step i).

5. The process according to claim 2 , characterized by using 2-4 mol excess of cyanide reagent in step i).

6. The process according to claim 2 , characterized by using acetic acid as mild organic acid in step i).

7. The process according to claim 2 , characterized by using 1.5-3 mol excess of acetic acid in step i).

8. The process according to claim 2 , characterized by carrying out the reaction in step ii) at a temperature between 0 and +10° C.

9. The process according to claim 2 , characterized by carrying out the reaction in step ii) in methyl tert-butyl ether or tetrahydrofuran.

10. The process according to claim 2 , characterized by using 2.5-4 mol excess of reagent in step ii).

11. The process according to claim 1 , characterized by using 2.5-5 mol excess of methyl lithium.

12. The process according to claim 1 , characterized by using N,N,N′,N′-tetramethylethylendiamine as substituted 1,2-diamino-ethane.

13. The process according to claim 1 , characterized by carrying out the reaction at a temperature between −40 and −20° C.

14. The process according to claim 1 , characterized by using hydrochloric acid in the transformation of the protected imine obtained as intermediate into the compound of formula (I).

15. The process according to claim 1 , characterized by carrying out the transformation of the protected imine obtained as intermediate into the compound of formula (I) in a mixture of water and tert-butyl methyl ether, or diethoxymethane as solvent.

16. The process according to claim 1 , characterized by carrying out the hydrolysis and acidic rearrangement at a temperature between +5 and +40° C.

17. (17α)-3-methoxy-17-[(trimethylsilyl)-oxy]-estr-2,5(10)-dien-17-carbonitrile of formula (II)

18. A process for the synthesis of (17α)-3-methoxy-17-[(trimethylsilyl)-oxy]-estr-2,5(1.0)-dien-17-carbonitrile of formula (II) of claim 17 characterized by reacting the compound of formula (III)

with 2-10 mol equivalent of trimethylchlorosilane in the presence of imidazole in an ether solvent at a temperature between 0 and +40° C.

19. (17α)-17-hydroxy-3-methoxyestra-2,5(10)-dien-17-carbonitrile of formula (III)

20. A process for the synthesis of (17α)-17-hydroxy-3-methoxyestra-2,5(10)-dien-17-carbonitrile of formula (III) of claim 19 characterized by reacting the compound of formula (IV)

with 1.5-10 mol equivalent of alkali cyanide in a short-chain aliphatic alcohol typo solvent in the presence of a mild organic acid.

Assignees

• Richter Gedeon Nyrt

Inventors

• Csörgei János
• Horváth Anita
• Sánta Csaba
• Mahó Sándor
• Béni Zoltán
• Horváth János

Classifications

• C07J7/006

  by a hydroxy group free esterified or etherified · CPC title

• C07J41/0094

  containing nitrile radicals, including thiocyanide radicals · CPC title

• C07J51/00

  Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00 · CPC title

• C07J1/0081 Primary

  Substituted in position 17 alfa and 17 beta · CPC title

• C07J1/0059 Primary

  substituted in position 17 by a keto group · CPC title