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

Abstract

The present invention relates to a new stereoselective process for the synthesis of 17()-17-acetyl-17-hydroxy-estr-4-en-3-one of formula (I), as well as to the new intermediates of the process. The 17()-17-acetyl-17-hydroxy-estr-4-en-3-one (gestonorone) is an important intermediate in the synthesis of the active ingredients having progestogen activitysuch as gestonorone capronate and nomegestroi acetate. Formulas (I), (II) and (III). ##STR00001##

Claims

1. A process for the synthesis of (17)-17-acetyl-17-hydoxy-estr-4-en-3-one of formula (I) ##STR00003## characterized by reacting the compound of formula (II) ##STR00004## 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) ##STR00005## 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) ##STR00006## 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. (17)-3-methoxy-17-[(trimethylsilyl)-oxy]-estr-2,5(10)-dien-17-carbonitrile of formula (II) ##STR00007##

18. A process for the synthesis of (17)-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) ##STR00008## 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. (17)-17-hydroxy-3-methoxyestra-2,5(10)-dien-17-carbonitrile of formula (III) ##STR00009##

20. A process for the synthesis of (17)-17-hydroxy-3-methoxyestra-2,5(10)-dien-17-carbonitrile of formula (III) of claim 19 characterized by reacting the compound of formula (IV) ##STR00010## 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.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a flowchart showing the synthesis of gestonorone starting from estron-3-alkyl ether as disclosed in U.S. Pat. No. 3,381,003.

(2) FIG. 2 is a flowchart showing the synthesis of 17-cyano-17-hydroxy-3-methoxy-estra-2,5(10)-diene starting from 3-methoxy-estra-2,5(10)-dien-17-one with acetone cyanohydrin as disclosed in U.S. Pat. No. 3,423,435.

(3) FIG. 3 is a flowchart showing the synthesis of 17-hydroxy-pregnane derivatives as disclosed in U.S. Pat. No. 3,764,615.

(4) FIG. 4 is a flowchart showing the synthesis of estr-4-en-3-on-17-cyanohydrine from estr-4-en-3,17-dione as shown in Journal of Central South University of Technology (English Edition) (2004), 11(3), 300-303.

(5) FIG. 5 is a flowchart showing the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

(6) The process of our invention (FIG. 5.) is described in detail hereunder.

(7) The synthesis of compound (III) from compound (IV) is carried out the following way:

(8) Short-chain aliphatic alcohols, preferably methanol or ethanol are used as solvent.

(9) Alkali cyanides, preferably potassium or sodium cyanides are used as reagents, the molar ratio is selected between 1.5-10, preferably between 2-4 mol, and a mild organic acid, preferably acetic acid is used as further reagent for liberating hydrogen cyanide, the molar ratio is selected between 1.3-8, preferably between 1.5-3 mol.

(10) The temperature of the reaction is kept between +20-+63 C., preferably the temperature program described in Example 1 is kept.

(11) The synthesis of compound (II) from compound (III) is carried out the following way:

(12) Ethers, for example diethyl ether, tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, preferably methyl tert-butyl ether or tetrahydrofuran are used as solvent.

(13) Trimethyl chlorosilane is used as reagent in the presence of imidazole, the molar excess of the reagent is between 2-10 mol, preferably 2.5-4 mol.

(14) The temperature of the reaction is kept between 0-+40 C., preferably between 0-+10 C.

(15) The synthesis of compound (I) from compound (II) is carried out the following way:

(16) Ethers or formaldehyde dialkylacetals, for example diethyl ether, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethoxymethane, dimethoxymethane, preferably methyl tert-butyl ether, tetrahydrofuran or diethoxymethane are used as solvent.

(17) The excess of methyl lithium reagent can be 1.5-10 mol equivalent, preferably 2.5-5 mol equivalent.

(18) The stability of methyl lithium oligomers can be reduced with substituted 1,2-diamino-ethanes, preferably with N,N,N,N-tetramethylethylendiamine.

(19) The temperature of the reaction is kept between 78 and 10 C., preferably between 40 and 20 C.

(20) The protected imine obtained as intermediate is transformed into the final product of formula (I) with mineral acids or strong organic acids, for example with hydrochloric acid, sulfuric acid, potassium hydrogensulfate, sodium hydrogensulfate, p-toluenesulfonic acid, perchloric acid, preferably with hydrochloric acid.

(21) During the hydrolysis alcohols or ethers, preferably methanol, ethanol or methyl tert-butyl ether, diethoxymethane, tetrahydrofuran are used as solvent.

(22) The hydrolysis is carried out at a temperature between 0 C. and the boiling point of the applied solvent, preferably between +5 and +40 C.

(23) The process of our invention is illustrated by the following not limiting examples.

Example 1

Synthesis of (17)-hydroxy-3-methoxyestra-2,5(10)-dien-17-carbonitrile

(24) Under inert atmosphere 50.0 g of 3-methoxyestra-2,5(10)-dien-17-one was suspended in 500 ml of ethanol and 34.25 g of potassium cyanide and 0.15 g of 2,6-ditert-butyl-4-methyl-phenol were added while stirring. After 10 minutes stirring 20.0 ml of acetic acid was added dropwise over a period of 10 minutes. The reaction mixture was warmed from 30-35 C. to 58-63 C., stirred at this temperature for 1 h, then cooled to 20-25 C. and stirred for 16 h. 50 ml of water was added to the reaction mixture and the slurry was stirred for 1 h. The precipitated crystals were filtered off, suspended with 5150 ml of water, and washed with 2100 ml of water. The wet crystals were stirred under inert atmosphere with 300 ml of ion-exchanged water for 15 minutes, filtered off and washed with 2100 ml of water. The wet crystals were washed with 75 ml of cold ethanol and 350 ml of methyl tert-butyl ether.

(25) Yield: 53.0 g (96.9%)

(26) Purity (HPLC): 97.49%

(27) .sup.1H NMR (DMSO-d6, 500 MHz) : 6.26 (s, 1H), 4.64 (t, J=3.3 Hz, 1H), 3.45 (s, 3H), 2.70-2.87 (m, 1H), 2.49-2.63 (m, 2H), 2.37-2.49 (m, 1H), 2.22-2.34 (m, 1H), 1.97-2.08 (m, 1H), 1.76-1.96 (m, 3H), 1.61-1.75 (m, 4H), 1.51-1.60 (m, 1H), 1.37-1.47 (m, 1H), 1.24-1.36 (m, 2H), 1.11-1.25 (m, 2H), 0.83 (s, 3H)

(28) .sup.13C NMR (DMSO-d6, 125 MHz) : 151.8, 127.3, 124.3, 121.8, 90.4, 76.5, 53.4, 48.9, 46.6, 44.3, 38.7, 37.4, 33.6, 29.8, 27.8, 26.9, 24.6, 22.9, 16.2

Example 2

Synthesis of (17)-3-methoxy-17-[(trimethylsilyl)-oxy]-2,5(10)-dien-17-carbonitrile

(29) Under inert atmosphere to a stirred mixture of 53.0 g of (17)-17-hydroxy-3-methoxyestra-2,5(10)-dien-17-carbonitrile, 0.15 g of 2,6-ditert-butyl-4-methyl-phenol and 900 of methyl tert-butyl ether a solution of 36.0 g of imidazole in 100 ml of tetrahydrofuran was added. The reaction mixture was cooled to 0-5 C. and 60.0 ml of trimethylchlorosilane was added dropwise at such a rate to keep the temperature below 5 C. After stirring for 2 h 50 ml of water was added to the reaction mixture and after 10 minutes stirring the organic phase was separated and washed with 350 ml of water. The organic phase was dried over 7.5 g of MgSO4, filtered and the filtered drying agent was washed with 225 ml of methyl tert-butyl ether. The filtrate was concentrated to half volume, and 3300 ml of methyl tert-butyl ether was distilled off at 30-35 C. The solution was diluted to 600 nil and used in the next step.

(30) Dry substance content: 58.9 g (90.4%)

(31) Water content: 0.09 g/100 ml

(32) Purity (HPLC): 96.53%

(33) .sup.1H NMR (CD.sub.2Cl.sub.2, 500 MHz) : 4.65 (t, J=3.3 Hz, 1H), 3.50-3.57 (m, 3H), 2.80-2.95 (m, 1H), 2.56-2.69 (m, 2H), 2.45-2.55 (m, 1H), 2.33-2.41 (m, 1H), 2.09 (br. s., 1H), 2.01 (ddd, J=14.8, 9.2, 5.6 Hz, 1H), 1.95 (dd, J=13.3, 2.8 Hz, 1H), 1.90 (dd, J=6.4, 0.7 Hz, 1H), 1.76-1.84 (m, 1H), 1.60-1.76 (m, 4H), 1.49-1.55 (m, 1H) 1.33-1.44 (m, 2H), 1.20-1.32 (m, 2H), 0.92 (s, 3H), 0.25 (s, 9H)

(34) .sup.13C NMR (CD.sub.2Cl.sub.2, 125 MHz) : 153.1, 128.1, 125.4, 121.6, 91.0, 79.4, 54.2, 51.0, 47.6, 45.3, 40.0, 39.5, 34.6, 31.0, 30.8, 28.8, 27.9, 25.8, 24.0, 16.7, 1.3

Example 3

Synthesis of (17)-17-acetyl-17-hydoxy-estr-4-en-3one

(35) The stirred solution of (17)-3-methoxy-17-[(trimethysilyl)-oxy]-estr-2,5(10)-dien-17-carbonitrile in 600 ml of methyl tert-butyl ether was cooled to 40 C., then 80 ml of N,N,N,N-tetramethylethylendiamine and 180 ml of methyl lithium solution (3M in diethoxymethane) were added at such a rate to keep the temperature below 30 C. The reaction mixture was stirred at this temperature for 1 h, then poured into 1000 ml of 4N hydrochloric acid solution cooled to 15-(10) C. with intensive cooling. The reaction mixture was stirred at 20-25 C. for 16 h, then the pH of the solution was adjusted to 4-5 by the addition of about 800 ml of 3M sodium acetate. The volatile organic components were distilled off and the residue was stirred at 20-25 C. for 1 h. The precipitated crude product was filtered off, suspended with 5500 ml of water, washed with 100 ml of cold methanol, and dried in vacuum oven.

(36) Yield: 32.42 g (67.1%)

(37) Purity (HPLC): 89.66%

(38) Under inert atmosphere 32.42 g of crude product was added to 97 ml of methanol at 60 C., after a clear solution was obtained the mixture was cooled to 20-25 C. 16.2 ml of water was added to the stirred slurry over a period of 2-3 minutes, then it was cooled to 0-5 C. After stirring for 1 h, the crystals were filtered off, suspended with a mixture of 11.2 ml of water and 67.1 ml of methanol, then dried in vacuum oven.

(39) Yield: 25.67 g (79.2%)

(40) Purity (HPLC): 98.47%

(41) .sup.1HNMR (CDCl.sub.3, 800 MHz) : 5.82-5.85 (m, 1H), 2.85 (s, 1H), 2.69 (ddd, J=14.9, 11.5, 3.1 Hz, 1H), 2.47-2.51 (m, 1H), 2.39-2.43 (m, 1H), 2.28 (s, 3H), 2.23-2.31 (m, 3H), 2.06-2.11 (m, 1H), 1.89-1.93 (m, 1H), 1.81-1.88 (m, 2H), 1.72-1.80 (m, 2H), 1.61 (ddd, J=15.2, 9.2, 6.3 Hz, 1H), 1.52-1.58 (m, 1H), 1.35-1.44 (m, 3H), 1.22-1.29 (m, 1H), 1.12-1.18 (m, 1H), 0.90 (dtd, J=12.0, 10.6, 4.2 Hz, 1H), 0.78 (s, 3H)

(42) .sup.13C NMR (CDCl.sub.3, 201 MHz) : 211.6, 199.9, 166.4, 124.6, 89.8, 49.2, 49.0, 48.4, 42.4, 40.2, 36.5, 35.5, 33.5, 31.1, 30.0, 27.9, 26.6, 25.9, 23.8, 15.5