Process for the production of 21-methoxy-11-beta-phenyl-19-nor-pregna-4,9-diene-3,20-dione derivatives

Abstract

The present invention relates to a process for the synthesis of compounds of formula (I), ##STR00001##
wherein the meaning of R is dimethylamino or acetyl group, using the compound of formula (III) or (IV), wherein the meaning of R is dimethylamino or 2-methyl-1,3-dioxan-2-yl group, as starting material and methoxymethyl lithium as reagent. ##STR00002##

Claims

1. Process for the synthesis of compound of formula (I) ##STR00017## wherein the meaning of R is dimethylamino or acetyl group, characterized by a) reacting the compound of formula (III) or (IV), ##STR00018## wherein the meaning of R is dimethylamino or 2-methyl-1,3-dioxolan-2-yl group, with methoxymethyl lithium, b) removing the protective groups of the so obtained intermediate, and c) acylating the hydroxyl group in position 17 of the so obtained compound of formula (II) ##STR00019##

2. The process according to claim 1, characterized by synthesizing the methoxymethyl lithium reagent the following way: a) an isolated or a condensed ring aromatic hydrocarbon is dissolved in an ether type solvent, b) lithium metal is added to the so obtained solution under inert atmosphere, c) the mixture is stirred at 0-20 C. until lithium is dissolved, d) the mixture is cooled to (78)-(40) C. and methoxymethyl chloride is added.

3. The process according to claim 2, characterized by using naphthalene or biphenyl as an isolated or a condensed ring aromatic hydrocarbon.

4. The process according to claim 2, characterized by using tetrahydrofuran as an ether type solvent.

5. The process according to claim 2, characterized by carrying out the reaction of step c) of claim 2 at a temperature between 5-10 C.

6. The process according to claim 2, characterized by carrying out the reaction of step d) of claim 2 at a temperature of 55 C.

7. The process according to claim 1 characterized by removing the protective groups by acid hydrolysis and dehydration.

8. The process according to claim 1, characterized by synthesizing the methoxymethyl lithium reagent in situ.

9. The process according to claim 1, wherein R and R are dimethylamino.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) ##STR00009## ##STR00010##

(2) The present invention relates to a new process (Figure 3.) for the synthesis of 21-methoxy-pregnane derivatives of formula (I)

(3) ##STR00011##
wherein the meaning of R is dimethylamino or acetyl group, to the synthesis of the methoxymethyl lithium reagent used in the process,
as well as to the intermediate of formula (III), wherein the meaning of R is 2-methyl-1,3-dioxolan-2-yl group.

(4) ##STR00012##

(5) The advantage of the process of our invention is that it has less steps as the known ones described earlier, it is industrially realizable, safe and economical.

(6) According to the process of our invention the hydroxyl group in position 5 of compound of formula (IV),

(7) ##STR00013##
wherein the meaning of R is 2-methyl-1,3-dioxolan-2-yl group, and synthesized according to method described in patent application No. WO2009001148, is silylated with chloro-trimethylsilane in the presence of imidazole in a halogenated solvent or tetrahydrofuran or toluene, preferably in dichloromethane, at room temperature to yield the compound of formula (III), wherein the meaning of R is as described above.

(8) ##STR00014##

(9) In the next step the methoxymethyl lithium reagent is synthesized. A condensed or conjugated aromatic hydrocarbon in given case substituted with alkyl groups, for example naphthalene, alklylnaphthalene, anthracene, 4,4-di-tertbutyl-biphenyl, preferably biphenyl, is dissolved in an ether, aliphatic or aromatic hydrocarbon or formaldehyde dialkylacetal type solvent, for example tetrahydrofuran, methyltetrahydrofuran, diethyl ether, diisopropyl ether, methyl-tertbutyl ether, toluene, dimethoxyethane, diethoxyethane, preferably tetrahydrofuran, and lithium metal is added to the so obtained solution under inert atmosphere. The reaction mixture is vigorously stirred for 0.5-5 hours, preferably for 3 hours, until the lithium is dissolved at 0-20 C., preferably at 5-10 C. Then the solution is cooled to (78)-(40) C., preferably to 55 C., and methoxymethyl chloride in itself or in a solution of any of the above mentioned solvents is added to the mixture in such a rate as to keep the reaction temperature between (78)-(30) C., preferably between (55)-(40) C. The solution of compound of formula (III) or (IV) is added to the so obtained solution at a temperature between (78)-(30) C., preferably between (55)-(50) C. The reaction mixture is stirred at a temperature between (78)-(30) C., preferably between (48)-(52) C. for 0.5-3 hours, preferably for 2 hours.

(10) Then water is added to the reaction mixture in such a rate as to keep the reaction temperature below 0 C., preferably at 10 C. After the addition of water the reaction mixture is vigorously stirred for 10-120 min, preferably for 30 min, while the temperature is allowed to rise to 10-15 C. After settling the phases are separated, the solution containing the protected intermediate is treated with a strong acid, for example hydrochloric acid, sulphuric acid, p-toluenesulphonic acid, perchloric acid, methanesulphonic acid, phosphoric acid, potassium hydrogensulphate, preferably sodium hydrogensulphate, to yield the solution of the compound of formula (II), from which the compound of formula (II),

(11) ##STR00015##
wherein the meaning of R is dimethylamino or acetyl group, is isolated in a suitable way. The obtained product in given case is purified by chromatography. The hydroxyl group in position 17 is acetylated according to the method described in patent application No. WO2009001148 to yield the final product of formula (I),

(12) ##STR00016##
wherein the meaning of R is as described above.

EXAMPLES

(13) The invention is illustrated by the following not limiting examples.

Example 1

Synthesis of 11-[(4-dimethylamino)phenyl]17-hydroxy-21-methoxy-19-norpregna-4,9-dien-3,20-dione :

(14) 146.8 g (0.95 M) of biphenyl was dissolved in 920 ml of tetrahydrofuran, the so obtained solution was cooled to 0 C. and 6.0 g (0.84 M) of lithium metal granulate was added under argon atmosphere to the solution. The reaction mixture was vigorously stirred for 3 hours, until the lithium was dissolved at 5-10 C. Then the black solution was cooled to 55 C. During this time 34.6 ml (0.45 M) of methoxymethyl chloride was dissolved in 140 ml of toluene and the so obtained solution was added (about 20 min) to the reaction mixture while keeping the temperature between (55)-(40) C. The so obtained solution of the methoxymethyl lithium reagent was cooled to 55 C. 20.0 g (32.1 mM) of 11-[4-(dimethylamino)phenyl]-3,3-ethylenedioxy-5, 17-bisz-[(trimethylsilyl)oxy]-estr-9-en-17-carbonitrile (Example 5 of WO2009001148) was dissolved in 60 ml of toluene and this solution was added over a period of about 10 min to the methoxymethyl lithium reagent while keeping the temperature of the reaction mixture between (55)-(50) C. Then the reaction mixture was stirred at (52)-(48) C. for 2 hours. After this 240 ml of water was added over a period of about 10 min, the reaction mixture became colourless and warmed to 10 C. After addition of water the reaction mixture was vigorously stirred for 30 min while its temperature was allowed to warm to 10-15 C. The inert atmosphere was kept until the end of the work-up. Stirring was stopped, and after 20 min settling the phases were separated. 150 ml of water was added to the upper organic phase containing the steroid and the mixture was stirred for 5 min, after 20 min settling the phases were separated. Then a 15-20 C. solution of 35 g of sodium hydrogensulphate in 500 ml of water was added over a period of 5-10 min to the upper organic phase containing the steroid. During the hydrolysis the temperature of the reaction mixture was kept at 15-20 C. After 2 hours stirring was stopped, and after settling the phases were separated, the upper organic phase was washed with 2100 ml of about 10v/v % sulphuric acid, and the water phases were combined. The combined water phases containing the steroid were extracted with 2100 ml of cyclohexane. Then the water phase was added to a solution of 83.73 g of sodium carbonate in 3 L of water over a period of 10-15 min. The precipitated crystals were filtered off after 30 min stirring, washed several times with water until neutral pH. The product was dried at 40 C. in vacuum oven until constant weight to yield 14.5 g (97.44%) of the title compound.

(15) Overall impurities: 7.15% according to HPLC

(16) .sup.1H NMR (DMSO-d.sub.6, 500 MHz) : 6.94-7.06 (m, 2H), 6.62 (s, 2H), 5.66 (s, 1H), 5.37 (s, 1H), 4.51 (d, J=18.4 Hz, 1H), 4.30-4.39 (m, 1H), 4.21 (d, J=18.4 Hz, 1H), 3.26 (s, 3H), 2.82 (s, 6H), 2.75 (dt, J=14.9, 5.1 Hz, 1H), 2.39-2.66 (m, 6H), 2.28-2.38 (m, 1H), 2.07-2.26 (m, 2H), 1.89-2.06 (m, 3H), 1.63-1.75 (m, 1H), 1.32-1.51 (m, 2H), 1.20-1.30 (m, 2H), 0.19 ppm (s, 3H)

(17) .sup.13C NMR (CDCl.sub.3, 125 MHz) : 208.8, 197.9, 156.5, 148.2, 146.5, 132.0, 128.1, 127.2, 121.9, 112.5, 88.6, 75.4, 58.3, 50.0, 47.0, 40.1, 38.7, 37.9, 36.5, 36.3, 32.9, 30.3, 27.7, 25.2, 23.4, 15.8 ppm

Example 2

Synthesis of 11-[(4-dimethylamino)phenyl]-17-hydroxy-21-methoxy-19-norpregna-4,9-dien-3,20-dione :

(18) 121.8 g (0.95 M) of naphthalene was dissolved in 920 ml of tetrahydrofuran, the so obtained solution was cooled to 0 C. and 6.0 g (0.84 M) of lithium metal cutted into small pieces was added under argon atmosphere to the solution. The reaction mixture was stirred at 5-10 C. until the lithium was dissolved. Then the black solution was cooled to 55 C. and a solution of 34.6 ml (0.45 M) of chloromethyl methyl ether in 140 ml of toluene was added to the reaction mixture while keeping the temperature below 40 C. The so obtained solution was cooled to 55 C. and a solution of 20.0 g (32.1 mM) of 11-[4-(dimethylamino)phenyl]-3,3-ethylenedioxy-5, 17-bisz-[(trimethylsilyl)oxy]-estr-9-en-17-carbonitrile in 60 ml of toluene was added while keeping the temperature of the reaction mixture below 50 C. Then the reaction mixture was stirred at 50 C. for 3 hours. After this 240 ml of water was added and the reaction mixture was allowed to warm to 20 C. After stirring for 10 min the phases were separated. 500 ml of 0.3 M sulphuric acid was added to the upper organic phase and the mixture was stirred for 2 hours at 20 C. The phases were separated, the upper organic phase was washed with 2100 ml of 10% sulphuric acid, and the water phases were combined. The combined water phases were extracted with 2100 ml of cyclohexane. Then the water phase was added to 3 L of 0.3 M sodium carbonate solution. The precipitated crystals were filtered off, washed with water and dried to yield 14.5 g (97.4%) of the title compound.

Example 3

Synthesis of 11-[(4-dimethylamino)phenyl]-17-hydroxy-21-methoxy-19-norpregna-4,9-dien-3,20-dione :

(19) 146.8 g (0.95 M) of biphenyl was dissolved in 920 ml of tetrahydrofuran, the so obtained solution was cooled to 0 C. and 6.0 g (0.84 M) of lithium metal cutted into small pieces was added under argon atmosphere to the solution. The reaction mixture was stirred at 5-10 C. until the lithium was dissolved. Then the black solution was cooled to 55 C. and a solution of 34.6 ml (0.45 M) of chloromethyl methyl ether in 140 ml of toluene was added to the reaction mixture while keeping the temperature below 40 C. The so obtained solution was cooled to 55 C. and a solution of 16.6 g (30.1 mM) of 11-[4-(dimethylamino)phenyl]-3,3-ethylenedioxy-5-hydroxy-17-[(trimethylsilyl)oxy]-estr-9-en-17-carbonitrile in 120 ml of tetrahydrofuran was added while keeping the temperature of the reaction mixture below 50 C. Then the reaction mixture was stirred at 50 C. for 3 hours. After this 240 ml of water was added and the reaction mixture was allowed to warm to 20 C. After stirring for 10 min the phases were separated. 500 ml of 0.3 M sulphuric acid was added to the upper organic phase and the mixture was stirred for 2 hours at 20 C. The phases were separated, the upper organic phase was washed with 2100 ml of 10% sulphuric acid, and the water phases were combined. The combined water phases were extracted with 2100 ml of cyclohexane. Then the water phase was added to 3 L of 0.3 M sodium carbonate solution. The precipitated crystals were filtered off, washed with water and dried to yield 13.3 g (95.2%) of the title compound.

Example 4

Synthesis of 11-(4-acetylphenyl)-17-hydroxy-21-methoxy-19-norpregna-4,9-dien-3,20-dione :

(20) 146.8 g (0.952 M) of biphenyl was dissolved in 920 ml of tetrahydrofuran, the so obtained solution was cooled to 0 C. and 6.0 g (0.84 M) of lithium metal cutted into small pieces was added under argon atmosphere to the solution. The reaction mixture was stirred at 5-10 C. until the lithium was dissolved. Then the black solution was cooled to 55 C. and a solution of 34.6 ml (0.452 M) of chloromethyl methyl ether in 140 ml of toluene was added to the reaction mixture while keeping the temperature below 40 C. The so obtained solution was cooled to 55 C. and a solution of 21.0 g (31.5 mM) of 3,3-ethylendioxy-11-[4-(2-methyl-1,3-dioxolan-2-yl)phenyl]-5,17-bisz-[(trimethylsilyl)oxy]-estr-9-en-17-carbonitrile in 80 ml of toluene was added while keeping the temperature of the reaction mixture below 50 C. Then the reaction mixture was stirred at 50 C. for 3 hours. After this 240 ml of water was added and the reaction mixture was allowed to warm to 20 C. After stirring for 10 min the phases were separated. 500 ml of 5% sulphuric acid was added to the upper organic phase and the mixture was stirred for 2 hours at 20 C. The phases were separated, and the water phase was extracted with 2100 ml of toluene. The combined organic phases were washed with 3100 ml of water and 1100 ml of brine, dried over anhydrous sodium sulphate and concentrated. The residue was crystallized from methanol in order to remove considerable amount of biphenyl (about 115 g). The methanolic mother liquor was concentrated (about 48 g) and purified by column chromatography using 500 g of silicagel and a 95:5 mixture of dichloromethane and acetone. The fractions containing the product were concentrated and the residue was crystallized from acetone to yield 11.87 g (81.4%) of the title compound.

(21) .sup.1H NMR (800 MHz, CDCl.sub.3) : 7.84-7.90 (m, 2H), 7.25-7.28 (m, 2H), 5.79 (s, 1H), 4.49 (m, 1H), 4.43 (m, 1H), 4.27 (m, 1H), 3.45 (s, 3H), 2.71-2.75 (m, 1H), 2.59-2.65 (m, 3H), 2.57 (s, 3H), 2.53-2.57 (m, 1H), 2.54 (s, 1H), 2.43 (ddd, J=16.3, 11.6, 5.9 Hz, 1H), 2.35 (dt, J=16.3, 5.5 Hz, 1H), 2.24-2.30 (m, 1H), 2.18 (s, 6H), 2.05-2.10 (m, 2H), 1.84-1.91 (m, 1H), 1.61 (ddd, J=15.2, 9.3, 6.2 Hz, 1H), 1.50-1.57 (m, 1H), 1.38 (qd, J=11.7, 6.4 Hz, 1H), 0.34 (s, 3H)

(22) .sup.13C NMR (201 MHz, CDCl.sub.3) : 208.2, 199.2, 197.5, 156.2, 150.3, 144.2, 134.9, 129.8, 128.7, 127.0, 123.2, 89.6, 77.0, 59.3, 49.8, 48.3, 40.4, 38.2, 36.7, 36.6, 33.5, 30.9, 30.9, 27.8, 26.5, 25.7, 23.9, 16.3

Example 5

Synthesis of 11-(4-acetylphenyl)-17-hydroxy-21-methoxy-19-norpregna-4,9-dien-3,20-dione :

(23) 146.8 g (0.952 M) of biphenyl was dissolved in 920 ml of tetrahydrofuran, the so obtained solution was cooled to 0 C. and 6.0 g (0.84 M) of lithium metal cutted into small pieces was added under argon atmosphere to the solution. The reaction mixture was stirred at 5-10 C. until the lithium was dissolved. Then the black solution was cooled to 55 C. and a solution of 34.6 ml (0.452 M) of chloromethyl methyl ether in 140 ml of toluene was added to the reaction mixture while keeping the temperature below 40 C. The so obtained solution was cooled to 55 C. and a solution of 17.8 g (30.0 mM) of 3,3-ethylendioxy-11-[4-(2-methyl-1,3-dioxolan-2-yl)phenyl]-5-hydroxy-17-[(trimethylsilyl)oxy]-estr-9-en-17-carbonitrile in 80 ml of toluene was added while keeping the temperature of the reaction mixture below 50 C. Then the reaction mixture was stirred at 50 C. for 3 hours. After this 240 ml of water was added and the reaction mixture was allowed to warm to 20 C. After stirring for 10 min the phases were separated. 500 ml of 5% sulphuric acid was added to the upper organic phase and the mixture was stirred for 2 hours at 20 C. The phases were separated, and the water phase was extracted with 2100 ml of toluene. The combined organic phases were washed with 3100 ml of water and 1100 ml of brine, dried over anhydrous sodium sulphate and concentrated. The residue was crystallized from methanol in order to remove considerable amount of biphenyl (about 115 g). The methanolic mother liquor was concentrated (about 48 g) and purified by column chromatography using 500 g of silicagel and a 95:5 mixture of dichloromethane and acetone. The fractions containing the product were concentrated and the residue was crystallized from acetone to yield 10.5 g (75.7%) of the title compound.

Example 6

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

(24) 25 g (41.68 mM) of 3,3-ethylendioxy-11-[4-(2-methyl-1,3-dioxolan-2-yl)phenyl]-5-hydroxy-17-[(trimethylsilyl)oxy]-estr-9-en-17-carbonitrile (Example 25 of WO174840) was dissolved in 125 ml of dichloromethane and 5 g of imidazole was added to the solution. 8.4 ml of chlorotrimethylsilane was added dropwise to the so obtained solution at 20 C. The reaction mixture was stirred at 20-25 C. for 1 hour, then diluted with 70 ml of dichloromethane and 70 ml of water was added. After vigorously stirring for 10 min the phases were separated, the organic phase was washed with 250 ml of water, dried over anhydrous sodium sulphate and concentrated. The residue was crystallized from methanol to yield 22.2 g (80.0%) of the title compound.

(25) .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)

(26) .sup.13C NMR (201 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

Example 7

Synthesis of 17-acetoxy-11-[(4-dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-dien-3,20-dione (CDB-4124)

(27) 21 ml (222 mM) of acetic anhydride was cooled to (25)-(20) C. and 2.8 ml (33 mM) of 70% perchloric acid was added while keeping the temperature below 15 C. A solution of 7 g (15.1 mM) of 11-[(4-dimethylamino)phenyl]-17-hydroxy-21-methoxy-19-norpregna-4,9-dien-3,20-dione in 32 ml of dichloromethane was added to the acylating mixture at (25)-(20) C. After the addition was finished the reaction mixture was stirred at (25)-(20) C. for 30 min, then it was added to a cooled mixture0-(5) C.of 35 ml of 25% aqueous ammonia and 55 ml of water. The so obtained mixture was diluted with 30 ml of dichloromethane, and stirred at 20-25 C. for 30 min. The phases were separated, the organic phase was washed with 225 ml of water, then dried over sodium sulphate, filtered and concentrated. The obtained crude product (7.5 g) was purified by column chromatography using a 1:1 mixture of cyclohexane and ethyl acetate. The fractions containing the product were concentrated and the residue was crystallized from methanol to yield 4.9 g (64%) of the title compound.

(28) Melting point: 201-204 C.

(29) NMR: .sup.1H NMR (500 MHz, CDCl.sub.3 (TMS), (ppm)): 0.40 (3H, s, 18-CH.sub.3); 2.10 (3H, s. OCOCH.sub.3); 2.90 (6H, s, NCH.sub.3); 3.41 (3H, s, OCH.sub.3); 4.09 (1H, d, H.sub.x-21); 4.38 (1H, m, H-11); 4.29 (1H, d, H.sub.y-21); 5.77 (1H, br, H-4); 6.62 (2H, m, H-3 & H-5); 6.96 (2H, m, H-2 & H-6)

(30) .sup.13C NMR (125 MHz, CDCl.sub.3 (IMS), (ppm)): 15.6 (C-18); 21.1 (OCOCH.sub.3); (39.3 (C-11); 40.6 (NCH.sub.3); 59.4 (OCH.sub.3); 76.0 (C-21); 93.9 (C-17); 112.8 (C-3 & C-5); 123.0 (C-4); 127.3 (C-2 & C-6); 129.4 (C-10); 131.3 (C-1); 145.5 (C-9); 148.7 (C-4); 156.4 (C-5); 170.7 (OCOCH.sub.3); 199.4 (C-3); 202.7 (C-20)

Example 8

Synthesis of 17-acetoxy-11-(4-acetylphenyl)-21-methoxy-19-norpregna-4,9-dien-3,20-dione (CDB-4239):

(31) 25 ml (264 mM) of acetic anhydride was cooled to (25)-(20) C. and 3.4 ml (40 mM) of 70% perchloric acid was added while keeping the temperature below 15 C. A solution of 8.5 g (18.4 mM) of 11-(4-acetylphenyl)-17-hydroxy-21-methoxy-19-norpregna-4,9-dien-3,20-dione in 90 ml of dichloromethane was added to the acylating mixture at (25)-(20) C. After the addition was finished the reaction mixture was stirred at (25)-(20) C. for 30 min, then it was added to a cooled mixture0-(5) C.of 42 ml of 25% aqueous ammonia and 70 ml of water. The reaction mixture was stirred at 20-25 C. for 30 min, then the phases were separated, the organic phase was washed with 230 ml of water, dried over sodium sulphate, filtered and concentrated in vacuum. The obtained crude product (8.5 g) was purified by column chromatography using a 1:1 mixture of cyclohexane and ethyl acetate. The fractions containing the product were concentrated and the residue was crystallized from methanol to yield 6.8 g (73%) of the title compound.

(32) Melting point: 110-116 C.