Industrial process for the synthesis of ulipristal acetate and its 4′-acetyl analogue

Abstract

The present invention relates to a new process for the synthesis of compounds of formula (I) (wherein the meaning of R is dimethylamino or acetyl group) using the compound of formula (II) (wherein the meaning of R is dimethylamino or 2-methyl-1,3-dioxolan-2-yl group) as starting material, as well as to the intermediate of the process. ##STR00001##

Claims

1. A process for the synthesis of a compound of formula (I) ##STR00009## wherein R in formula (I) is a dimethylamino or an acetyl group, the process comprises a) (1) reacting the compound of formula (II), wherein R in formula (II) is a dimethylamino or a 2-methyl-1,3-dioxolan-2-yl group, ##STR00010## with 2-15 mol equivalent methyllithium in the presence of tetraalkyl ethylenediamine in an ether or a formaldehyde acetal type solvent, or in a mixture thereof, at a temperature of between (78 C.) and (20 C.), (2) reacting the protected imine intermediate obtained from (1) with a mineral or a strong organic acid at a temperature between 0 C. and the boiling point of the organic solvent, (3) acetylating the hydroxyl group in position 17 of the compound of formula (IV) obtained from (2), wherein R in formula (IV) is as described for formula (I), ##STR00011## with acetic anhydride in a halogenated solvent, in the presence of 70% perchloric acid, and at a temperature of between (78 C.) and 0 C., and (4) recrystallizing the compound of formula (I) obtained from (3) from methanol or ethanol; or b) (1) silylating the hydroxyl group in position 5 of the compound of formula (II), wherein R in formula (II) is a dimethylamino or a 2-methyl-1,3-dioxolan-2-yl group, ##STR00012## with chloromethyl silane in the presence of imidazole in a halogenated solvent, tetrahydrofuran or toluene, at room temperature; (2) reacting the compound of formula (III) obtained from (1), wherein R in formula (III) is as described for formula (II), ##STR00013## with 2-15 mol equivalent of methyllithium in the presence of tetraalkyl ethylenediamine in an ether or a formaldehyde acetal type solvent, or in a mixture thereof, at a temperature of between (78 C.) and (20 C.), (3) reacting the protected imine intermediate obtained from (2) with a mineral or a strong organic acid at a temperature between 0 C. and the boiling point of the organic solvent, (4) acetylating the hydroxyl group in position 17 of the compound of formula (IV) obtained from (3), wherein R in formula (IV) is as described for formula (I), ##STR00014## with acetic anhydride in a halogenated solvent, in the presence of 70% perchloric acid, at a temperature of between (78 C.) and 0 C., and (5) recrystallizing the compound of formula (I) obtained from (4), wherein R is a dimethylamino or an acetyl group, from methanol or ethanol.

2. The process of claim 1, wherein the process comprises using an excess of 5-15 mol equivalent of methyllithium in step 1 of process a) or step 2 of process b).

3. The process of claim 1, wherein the tetraalkyl ethylenediamine in step 1 of process a) or step 2 of process b) is tetramethyl ethylenediamine.

4. The process of claim 1, wherein the ratio of tetraalkyl ethylenediamine/methyllithium is 0.5:1-5:1 in step 1 of process a) or step 2 of process b).

5. The process of claim 1, wherein the solvent in step 1 of process a) or step 2 of process b) is diethyl ether, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethoxymethane, or dimethoxymethane.

6. The process of claim 1, wherein the temperature of the reaction in step 1 of process a) or step 2 of process b) is between (50 C.) and (30 C.).

7. The process of claim 1, wherein the mineral or strong organic acid is hydrochloric acid, sulfuric acid, potassium hydrogensulfate, sodium hydrogensulfate, p-toluenesulfonic acid, or perchloric acid.

8. The process of claim 1, wherein the solvent in step 1 of process a) or step 2 of process b) is a solvent miscible with water.

9. The process of claim 1, wherein the temperature in step 2 of process a) or step 3 of process b) is between 20-50 C.

10. The compound of formula (III), wherein R is a 2-methyl-1,3-dioxolan-2-yl group. ##STR00015##

11. The process of claim 5, wherein the solvent in step 1 of process a) or step 2 of process b) is tetrahydrofuran, dimethoxymethane, or diethoxymethane.

12. The process of claim 7, wherein the mineral or strong organic acid is sulfuric acid.

13. The process of claim 8, wherein the solvent miscible with water is methanol, ethanol, or tetrahydrofuran.

14. The process of claim 13, wherein the solvent miscible with water is methanol.

15. The process of claim 9, wherein the temperature in step 2 of process a) or step 3 of process b) is from 20 to 25 C.

16. The process of 1, wherein the halogenated solvent is dichloromethane.

17. The process of claim 1, wherein the temperature of step 1 of process a) or step 2 of process b) is between (45 C.) and (40 C.).

18. The process of claim 1, wherein R of the compound of formula (I) is a dimethylamino group.

19. The process of claim 1, wherein R of the compound of formula (I) is an acetyl group.

20. The process of claim 9, wherein the temperature in step 2 of process a) or step 3 of process b) is from 25 to 50 C.

Description

EXAMPLES

Example 1

Synthesis of 11-[4-(N,N-dimethylamino)-phenyl]-17-hydroxy-19-norpregna-4,9-dien-3,20-dione

(1) 8.0 g (14.5 mM) of 11-[4-(N,N-dimethylamino)-phenyl]-3,3-ethylenedioxy-5-hydroxy-17-[(trimethylsilyl)oxy]-5-estr-9-en-17-carbonitrile was dissolved in 130 ml of tetrahydrofuran and the solution was cooled to 50 C. First 60 ml (180 mM) of methyllithium 3.0 M solution in diethoxymethane, then 27 ml (180 mM) of tetramethyl ethylenediamine were added dropwise at such a rate to keep the reaction temperature below 45 C. The reaction mixture was stirred at a temperature between 45-(40) C. for 3 hours, then 70 ml of water was added dropwise very carefully to the reaction mixture while the temperature was allowed to rise to +20 C. After stirring for 5 min the phases were separated, the organic phase was washed with 20 ml of water, then it was concentrated at reduced pressure. 80 ml of methanol and 110 ml of 1N sulfuric acid solution were added to the residue and the homogeneous solution was stirred at 40 C. for 3 hours. This acidic solution was poured into a solution of 5.8 g of sodium carbonate in 720 ml of water, then the precipitated material was filtered off and washed with water until neutral pH. The obtained 5.2 g of crude product was recrystallized from a mixture of ethanol and water to yield 4.4 g (70%) of the title compound.

(2) Melting point: 188-190 C.

(3) .sup.1H NMR (500 MHz, CDCl.sub.3) : 6.95-7.01 (m, 2H), 6.58-6.70 (m, 2H), 5.76 (s, 1H), 4.36 (m, 1H), 3.12 (s, 1H), 2.91 (s, 6H), 2.71-2.78 (m, 1H), 2.64 (m, 1H), 2.59 (dd, J=8.3, 4.4 Hz, 2H), 2.47-2.54 (m, 1H), 2.29-2.46 (m, 4H), 2.26 (s, 3H), 1.97-2.07 (m, 3H), 1.84-1.95 (m, 1H), 1.69-1.80 (m, 1H), 1.60-1.69 (m, 1H), 1.47-1.58 (m, 1H), 1.42 (qd, J=12.0, 6.1 Hz, 1H), 0.46 (s, 3H) ppm

(4) .sup.13C NMR (125 MHz, CDCl.sub.3) : 211.7, 199.7, 156.8, 148.5, 146.1, 131.9, 129.1, 127.4, 122.7, 112.7, 89.6, 49.9, 48.7, 40.6, 39.3, 38.1, 36.9, 35.9, 33.2, 31.0, 28.0, 27.9, 25.8, 24.3, 16.9 ppm

Example 2

Synthesis of 11-[4-(N,N-dimethylamino)-phenyl]-17-hydroxy-19-norpregna-4,9-dien-3,20-dione

(5) 25.0 g (40.1 mM) of 11-[4-(N,N-dimethylamino)-phenyl]-3,3-ethylenedioxy-5,17-bis[(trimethylsilyl)oxy]-5-estr-9-en-17-carbonitrile was dissolved in 500 ml of dimethoxymethane and the solution was cooled to 50 C. First 66.7 ml (200 mM) of methyllithium 3.0 M solution in diethoxymethane, then 30 ml (200 mM) of tetramethyl ethylenediamine were added dropwise at such a rate to keep the reaction temperature below 40 C. The reaction mixture was stirred at a temperature between 45-(35) C. for 3 hours, then 210 ml of water was added dropwise very carefully to the reaction mixture while the temperature was allowed to rise to +20 C. After stirring for 5 min the phases were separated, the organic phase was washed with 50 ml of water, then it was concentrated at reduced pressure. 220 ml of methanol and 300 ml of 1N sulfuric acid solution were added to the residue and the homogeneous solution was stirred at 40 C. for 3 hours. This acidic solution was poured into a solution of 16 g of sodium carbonate in 2 l of water, then the precipitated material was filtered off and washed with water until neutral pH. The obtained 14.7 g of crude product was recrystallized from a mixture of ethanol and water to yield 12.3 g (70.7%) of the title compound.

(6) Melting point: 188-190 C.

(7) .sup.1H NMR (500 MHz, CDCl.sub.3) : 6.95-7.01 (m, 2H), 6.58-6.70 (m, 2H), 5.76 (s, 1H), 4.36 (m, 1H), 3.12 (s, 1H), 2.91 (s, 6H), 2.71-2.78 (m, 1H), 2.64 (m, 1H), 2.59 (dd, J=8.3, 4.4 Hz, 2H), 2.47-2.54 (m, 1H), 2.29-2.46 (m, 4H), 2.26 (s, 3H), 1.97-2.07 (m, 3H), 1.84-1.95 (m, 1H), 1.69-1.80 (m, 1H), 1.60-1.69 (m, 1H), 1.47-1.58 (m, 1H), 1.42 (qd, J=12.0, 6.1 Hz, 1H), 0.46 (s, 3H) ppm

(8) .sup.13C NMR (125 MHz, CDCl.sub.3) : 211.7, 199.7, 156.8, 148.5, 146.1, 131.9, 129.1, 127.4, 122.7, 112.7, 89.6, 49.9, 48.7, 40.6, 39.3, 38.1, 36.9, 35.9, 33.2, 31.0, 28.0, 27.9, 25.8, 24.3, 16.9 ppm

Example 3

Synthesis of 3,3-ethylenedioxy-11-[4-(2-methyl-1,3-dioxolan-2-yl)-phenyl]-5,17-bis[(trimethylsilyl)oxy]-5-estr-9-en-17-carbonitrile

(9) 25.0 g (41.68 mM) of 3,3-ethylenedioxy-11-[4-(2-methyl-1,3-dioxolan-2-yl)-phenyl]-5-hydroxy-17-[(trimethylsilyl)oxy]-5-estr-9-en-17-carbonitrile (Example 25 of WO2001/74840) was dissolved in 125 ml of dichloromethane, 5 g of imidazole and then 8.4 ml of chlorotrimethylsilane were added dropwise to the solution at 20 C. The reaction mixture was stirred at 20-25 C. for 1 hour, then it was diluted with 70 ml of dichloromethane and 70 ml of water. After vigorous stirring for 10 min the phases were separated, the organic phase was washed with 250 ml of water, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from methanol to yield 22.2 g (80.0%) of the title compound.

(10) Melting point: 134-135 C.

(11) .sup.1H NMR (800 MHz, CDCl.sub.3) : 7.34 (m, 2H), 7.16 (m, 2H), 4.33 (m, 1H), 3.99-4.05 (m, 2H), 3.96 (m, 1H), 3.88-3.94 (m, 1H), 3.83-3.88 (m, 1H), 3.77-3.83 (m, 2H), 3.73-3.77 (m, 1H), 2.37-2.46 (m, 1H), 2.24-2.35 (m, 3H), 2.21 (dd, J=14.4, 2.6 Hz, 1H), 2.12-2.18 (m, 1H), 2.04 (m, 1H), 2.08 (dd J=14.4, 0.9 Hz, 1H) 1.97 (ddd, J=14.8, 9.1, 5.5 Hz, 1H), 1.75-1.88 (m, 2H), 1.65-1.73 (m, 4H), 1.64 (s, 3H), 1.47-1.57 (m, 1H), 1.34 (m, 1H), 1.20 (td, J=12.8, 4.0 Hz, 1H), 0.48 (s, 3H), 0.26 (s, 9H), 0.18 (s, 9H) ppm

(12) .sup.13C NMR (200 MHz, CDCl.sub.3) : 145.9, 140.3, 136.2, 132.6, 126.9, 125.1, 120.9, 108.8, 108.4, 78.8, 73.5, 64.5, 64.5, 64.4, 63.4, 50.1, 49.0, 47.2, 38.9, 38.6, 38.6, 38.5, 35.6, 34.9, 27.4, 24.6, 24.5, 23.5, 17.0, 2.6, 1.1 ppm

Example 4

Synthesis of 11-(4-acetylphenyl)-17-hydroxy-19-norpregna-4,9-dien-3,20-dion

(13) 10.0 g (15.0 mM) of 3,3-ethylenedioxy-11-[4-(2-methyl-1,3-dioxolan-2-yl)-phenyl]-5,17-bis[(trimethylsilyl)oxy]-5-estr-9-en-17-carbonitrile was dissolved in 150 ml of dimethoxymethane and the solution was cooled to 50 C. First 50 ml (150 mM) of methyllithium 3.0 M solution in diethoxymethane, then 22.5 ml (150 mM) of tetramethyl ethylenediamine were added dropwise at such a rate to keep the reaction temperature below 45 C. The reaction mixture was stirred at a temperature between 45-(40) C. for 5 hours, then 70 ml of water was added dropwise very carefully to the reaction mixture while the temperature was allowed to rise to +20 C. After stirring for 5 min the phases were separated, the organic phase was washed with 20 ml of water, then it was concentrated at reduced pressure. 150 ml of tetrahydrofuran and 50 ml of 10% hydrochloric acid solution were added to the residue and the mixture was stirred for 1 hour, then 100 ml of dichloromethane was added and the mixture was cooled to 10 C. It was neutralized with 14 ml of 25% ammonia solution and after 5 min stirring the phases were separated. The organic phase was washed with water until neutral pH, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from a acetone to yield 5.13 g (79.0%) of the title compound.

(14) .sup.1H NMR (500 MHz, CDCl.sub.3) : 7.80-7.93 (m, 2H), 7.20-7.30 (m, 2H), 5.79 (s, 1H), 4.48 (m, 1H), 3.22 (br. s., 1H), 2.72 (dt, J=15.2, 5.5 Hz, 1H), 2.59-2.67 (m, 3H), 2.57 (s, 3H), 2.52 (dd, J=13.3, 7.9 Hz, 2H), 2.39-2.47 (m, 1H), 2.30-2.38 (m, 1H), 2.20-2.30 (m, 4H), 1.99-2.14 (m, 4H), 1.88-1.98 (m, 1H), 1.76-1.88 (m, 1H), 1.66 (ddd, J=15.1, 9.4, 6.1 Hz, 1H), 1.55 (dq, J=12.8, 9.0 Hz, 1H), 1.34-1.49 (m, 1H), 0.40 (s, 3H) ppm

(15) .sup.13C NMR (125 MHz, CDCl.sub.3) : 211.5, 199.2, 197.5, 156.1, 150.5, 144.1, 135.0, 129.9, 128.7, 127.1, 123.3, 89.4, 49.6, 48.6, 40.4, 38.2, 36.7, 36.2, 33.2, 31.0, 28.0, 27.8, 26.5, 25.8, 24.2, 16.8 ppm

Example 5

Synthesis of 17-acetoxy-11-[(4-(N,N-dimethylamino)-phenyl]-19-norpregna-4,9-dien-3,20-dione

(16) 12.0 g (27.7 mM) of 11-[4-(N,N-dimethylamino)-phenyl]-17-hydroxy-19-norpregna-4,9-dien-3,20-dione was dissolved in 72 ml of dichloromethane and 38 ml (402 mM) of acetic anhydride was added. The reaction mixture was cooled to 25 (20) C. and 5.2 ml (60.6 mM) of 70% perchloric acid was added dropwise over a period of 15-20 min. The reaction mixture was stirred at a temperature between 25 (20) C. for 30 min, then it was poured into a cooled (0-(5) C.) mixture of 64 ml of 25% aqueous ammonia and 100 ml of water. The obtained mixture was diluted with 70 ml of dichloromethane and stirred at 20-25 C. for 30 min. The phases were separated, the organic phase was washed with 250 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was recrystallized form methanol to yield 11.2 g (85%) of title compound.

(17) Melting point: 184-186 C.

(18) .sup.1H NMR (CDCl.sub.3, 500 MHz) : 6.95-7.01 (m, 2H), 6.61-6.69 (m, 2H), 5.78 (s, 1H), 4.39 (d, J=7.3 Hz, 1H), 2.91 (s, 6H), 2.84-2.90 (m, 1H), 2.78 (ddd, J=15.0, 5.6, 5.3 Hz, 1H), 2.56-2.63 (m, 3H), 2.48-2.56 (m, 1H), 2.42-2.48 (m, 1H), 2.30-2.41 (m, 2H), 2.20 (d, J=13.2 Hz, 1H), 2.13 (s, 3H), 2.10 (s, 3H), 2.05 (dq, J=12.7, 4.4 Hz, 1H), 1.92-2.02 (m, 1H), 1.74-1.88 (m, 2H), 1.46-1.57 (m, 1H), 1.32-1.42 (m, 1H), 0.36 (s, 3H) ppm

(19) .sup.13C NMR (CDCl.sub.3, 125 MHz) : 203.8, 199.5, 170.6, 156.5, 145.6, 129.3, 127.3, 122.9, 112.8, 96.2, 50.9, 47.0, 40.6, 39.3, 38.3, 36.8, 36.7, 31.0, 30.2, 27.8, 26.8, 25.8, 24.2, 21.2, 15.6 ppm

Example 6

Synthesis of 17-acetoxy-11-(4-acetyl-phenyl)-19-norpregna-4,9-dien-3,20-dione

(20) 5.0 g (11.6 mM) of 11-(4-acetylphenyl)-17-hydroxy-19-norpregna-4,9-dien-3,20-dion was dissolved in 50 ml of dichloromethane and 17 ml (180 mM) of acetic anhydride was added. The reaction mixture was cooled to 25-(20) C. and 2.3 ml (38.2 mM) of 70% perchloric acid was added dropwise over a period of 15-20 min. The reaction mixture was stirred at a temperature between 25-(20) C. for 30 min, then it was poured into a cooled (0-(5) C.) mixture of 30 ml of 25% aqueous ammonia and 50 ml of water. The obtained mixture was diluted with 50 ml of dichloromethane and stirred at 20-25 C. for 30 min. The phases were separated, the organic phase was washed with 250 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was recrystallized form methanol to yield 4.56 g (83%) of title compound.

(21) Melting point: 249-252 C.

(22) .sup.1H NMR (CDCl.sub.3, 500 MHz) : 7.84-7.90 (m, 2H), 7.24-7.28 (m, 2H), 5.81 (s, 1H), 4.50 (d, J=7.6 Hz, 1H), 2.81-2.93 (m, 1H), 2.67-2.79 (m, 2H), 2.63 (dd, J=8.1, 3.4 Hz, 2H), 2.57 (s, 3H), 2.41-2.55 (m, 2H), 2.32-2.41 (m, 1H), 2.20-2.32 (m, 2H), 2.14 (s, 3H), 2.08-2.12 (m, 1H), 2.05-2.09 (m, 1H), 1.99 (td, J=12.3, 6.6 Hz, 1H), 1.76-1.91 (m, 2H), 1.47-1.62 (m, 1H), 1.29-1.45 (m, 1H), 0.30 (s, 3H) ppm

(23) .sup.13C NMR (CDCl.sub.3, 125 Mhz) : 203.6, 199.0, 197.4, 170.4, 155.8, 150.1, 143.4, 135.1, 130.1, 128.8, 127.0, 123.5, 95.7, 50.6, 47.0, 40.4, 38.4, 37.0, 36.7, 31.0, 30.3, 27.8, 27.0, 26.5, 25.8, 24.1, 21.2, 15.6 ppm