PROCESS AND INTERMEDIATES FOR THE PRODUCTION OF 17(20)-ENE B-SECO STEROIDS

Abstract

##STR00001##

The invention pertains to a process for producing a compound of formula (11) wherein R.sup.7 and R.sup.8 are each independently selected from H, halogen, alkyl, aryl, or alkylaryl, R.sup.42 is H or a protective group, R.sup.43 is H or R.sup.3, wherein R.sup.3 is a protective group, by contacting a compound of formula (10) with an olefmation reagent, wherein compound of formula (10) comprises a counter acid X.sup.1 when R.sup.42H and R.sup.43H.

Claims

1. A process for producing a compound of formula (11) ##STR00079## wherein R.sup.7 and R.sup.8 are each independently selected from H, halogen, alkyl, aryl, or alkylaryl, R.sup.42 is H or a protective group, R.sup.43 is H or R.sup.3, wherein R.sup.3 is a protective group, by contacting a compound of formula (10) ##STR00080## with an olefination reagent, wherein compound of formula (10) comprises a counter acid X.sup.1 when R.sup.42H and R.sup.43H.

2. Process according to claim further comprising a step of contacting a compound of formula (3) ##STR00081## wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, with a second oxidizing agent to obtain a compound of formula (4) ##STR00082##

3. Process according to claim 2, further comprising the step of contacting a compound of formula (9). ##STR00083## wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, with an first acid capable of forming a pharmaceutically acceptable salt to obtain the compound of formula (10).

4. Process according to claim 2, further comprising: a) converting the compound of formula (4) to a compound of formula (7) ##STR00084## comprising the steps selected from: iv) contacting the compound of formula (4) with a first base and a third protective reagent to form a compound of formula (5) ##STR00085## wherein R.sup.4 is a protective group, and contacting the compound of formula (5) with a third oxidizing agent and optionally with a fourth protective reagent to obtain a compound of formula (6) ##STR00086## wherein R.sup.5 is H or a protective group; and contacting the compound of formula (6) with a fourth oxidizing agent to obtain the compound of formula (7); or v) contacting the compound of formula (4) with a first base and a third oxidizing agent and optionally with a fourth protective reagent to obtain a compound of formula (6), wherein the molar ratio of the third oxidizing agent and the compound of formula (4) is at most 1.5; and contacting a compound of formula (6) with a fourth oxidizing agent to obtain the compound of formula (7); or vi) contacting the compound of formula (4) with a first base and a third oxidizing agent and optionally with a fourth protective reagent to obtain the compound of formula (7), wherein the molar ratio of the third oxidizing agent and the compound of formula (4) is at least 1.5; wherein the process further comprises the steps of: b) contacting the compound of formula (7) with a compound of formula (7a)
NH.sub.2R.sup.6(7a) wherein R.sup.6 is either H or OR.sup.22, wherein R.sup.22 is either H or a protective group, to obtain a compound of formula (8) ##STR00087## and c) contacting the compound of formula (8) with a reducing agent to obtain the compound of formula (9).

5. A process for preparing a compound of formula (12) ##STR00088## wherein R.sup.7 and R.sup.8 are each independently selected from H, halogen, alkyl, cycloalkyl, alkoxy, aryloxy, aryl, or alkylaryl and X is a counter acid, comprising the steps of claim 1, further comprising the conversion of the compound of formula (11) with a second acid capable of forming a pharmaceutically acceptable salt to obtain the compound of formula (12).

6. A process for preparing a compound of formula (4) ##STR00089## wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, comprising the step of contacting a compound of formula (3) ##STR00090## with a second oxidizing agent to obtain the compound of formula (4).

7. (canceled)

8. A compound of formula (5) ##STR00091## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are protective groups.

9. A compound of formula (6) ##STR00092## wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, and R.sup.5 is H or a protective group.

10. A compound of formula (7) ##STR00093## wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups.

11. A compound of formula (8) ##STR00094## wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups and R.sup.6 is either H or OR.sup.22, wherein R.sup.22 is either H or a protective group.

12. A compound of formula (9) ##STR00095## wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups.

13. (canceled)

14. (canceled)

15. (canceled)

Description

EXAMPLE 1

Preparation of (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2-[1,3]dioxolan]-3-ol (compound of formula (1), step a.)

[0273] ##STR00069##

[0274] A reactor was charged with 100 g (1.0 eq.) dehydroepiandrosteron (DHEA), 800.0 ml (8.0 vol) toluene, 43 g (3.6 eq.) ethylene glycol and 500 mg camphor-12-sulfonic acid. The reaction mixture was heated to approximately 111 C. and ethylene glycol was removed. Half of the volume of the reaction mixture was separated by distillation and allowed to cool to ambient temperature. To this solution 400 ml (4.0 vol) of hexane were charged and mixed for 2 hours. The solids were isolated by filtration, washed four times each with 100 ml (1.0 vol) of hexane and dried under vacuum at 50 C. to afford 119 g of compound of formula (1) with 100% yield.

EXAMPLE 2

Preparation of tert-butyl (((3S,8R,9S,10R,13S,14S)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2-1,3dioxolan]-3-yl)oxy)dimethylsilane (compound of formula (2), step b

[0275] ##STR00070##

[0276] A reactor was charged with 100.7 g (1.0 eq.) compound of formula (1), 24.74 g (1.4 eq.) imidazole, 11.1 g (0.3 eq.) 4-(dimethylamino)-pyridin (4-DMAP) and 504 ml (5.0 vol) dichloromethane (DCM). The reaction mixture was mixed until a complete solution was obtained. Subsequently the reaction mixture was cooled to 10 C. and 57 g (1.25 eq.) tert-butyldimethylsilyl chloride (TBDMS-Cl) slowly charged while maintaining the temperature below 15 C. The reaction contents were then allowed to warm to ambient temperature. Thereafter, the reaction mixture was diluted with 1,510 ml (15 vol) methyl-tert-butylether (MTBE) and extracted with 805.6 ml (8.0 vol) H.sub.2O. After phase separation the organic phase was washed with a solution of 503.5 ml (5.0 vol) H.sub.2O and 15.91 g (0.25 eq.) citric acid monohydrate, 201.4 ml (2.0 vol) aqueous solution of sodium bicarbonate (NaHCO.sub.3 aq. solution), 201.4 ml (2.0 vol) aqueous solution of sodium chloride (brine), dried over sodium sulphate, separated by filtration, rinsed with methyl-tert-butylether (MTBE) and concentrated to dryness under vaccum at 45 C. to afford 137.8 g of compound of formula (2) with 100% yield.

EXAMPLE 3

Preparation of (3S,5S,8R,9S,10R,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-17,2-[1,3]dioxolan]-6-ol (compound of formula (3), step c.)

[0277] ##STR00071##

[0278] A reactor was charged with a solution of 136.6 g (1.0 eq.) compound of formula (2) in 683 ml (5.0 vol) tetrahydrofuran (THF) anhydrous. The solution was cooled to 30 C., slowly charged with 336 ml (1.1 eq.) borane (BH.sub.3) in tetrahydrofuran (THF) and mixed at ambient temperature until complete conversion, monitored by chromatography, was achieved. Thereafter, the reaction mixture was quenched by drop wise addition of 1,319 ml (9.7 vol) H.sub.2O and 183.10 g (6.0 eq.) of sodium perborate (NaBO.sub.3) and mixed at ambient temperature until complete conversion to compound of formula (3) was achieved, which took approximately 10 hours. Subsequently 2,732 ml (10 vol) methyl-tert-butylether (MTBE) and 1,366 ml (10 vol) H.sub.2O were charged to the reactor and mixed. Any remaining excess solids where removed from the present bi-phasic mixture by filtration and the remaining bi-phasic mixture was rinsed with 800 ml (5.9 vol) H.sub.2O. Subsequent to phase separation the aqueous phase was extracted with 1,000 ml (7 vol) methyl-tert-butylether (MTBE) and the combined organic phases washed with 273.2 ml (2 vol) brine. Subsequently the separated organic phase was dried over sodium sulphate. Thereafter the organic phase was filtered and concentrated in vacuum at 45 C. The obtained material was dissolved twice with a minimal amount of ethyl acetate (EtOAc) and concentrated to complete dryness to afford 136 g of compound of formula (3) with 96% yield.

EXAMPLE 4

Preparation of (3S,5S,8R,9S,10R,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethyltetradecahydrospiro[cyclopenta[a]phenanthrene-17,2-[1,3]dioxolan]-6(1H)-one (compound of formula (4), step d.)

[0279] ##STR00072##

[0280] A reactor was charged with a solution of 27.9 g (1.0 eq.) compound of formula (3) in 83.7 ml (3 vol) ethyl acetate (EtOAc), 167.4 ml (6 vol) dimethyl sulfoxide (DMSO) and 33.6 g (2.0 eq.) 2-iodobenzoic acid (IBX). The reaction mixture was mixed at ambient temperature until completion of the reaction, which was monitored by chromatography. Subsequently the reaction mixture was extracted with 558 ml (20 vol) methyl-tert-butylether (MTBE) and 279 ml (10 vol) H.sub.2O. The contents were separated by filtration and the obtained cake washed with 50 ml (1.8 vol) methyl-tert-butylether (MTBE). The liquid phases where collected and the aqueous phase removed. Thereafter, the organic phase was washed two times each with 239.5 ml (5 vol) aqueous sodium bicarbonate (NaHCO.sub.3 aq.) and one time with 55.8 ml (2 vol) brine. Subsequently, the organic phase was dried over sodium sulphate, separated by filtration and concentrated to dryness under vacuum at 60 C. to afford 26.1 g compound of formula (4) with 83% yield.

EXAMPLE 5

Preparation of tert-butyl(((3S,5S,8R,9S,10R,13S,14S)-10,13-dimethyl-6-((trimethylsilyl)oxy)-1,2,3,4,5,8,9,10,11,12,13,14,15,16-tetradecahydrospiro-[cyclopenta[a]phenanthrene-17,2-[1,3]dioxolan]-3-yl)oxy)dimethylsilane (compound of formula (5), step e.1))

[0281] ##STR00073##

[0282] A reactor was charged with 47.6 g (1.0 eq.) of compound of formula (4) and 238 ml (5 vol) tetrahydrofuran (THF) anhydrous. The mixture was cooled to 70 C., slowly charged with 77.14 ml (1.5 eq.) lithium diisopropylamide (LDA) and mixed for 3 hours at 70 C. While keeping the temperature in the range of 70 C. to 65 C. 15.61 ml (1.2 eq.) trimethylsilyl chloride (TMS-Cl) were slowly added to the reaction mixture. Upon completion of the dosing the reaction mixture was allowed to warm to ambient temperature during a period lasting for approximately 10 hours. Thereafter, the reaction mixture was quenched with 952 ml (20 vol) aqueous sodium bicarbonate (NaHCO.sub.3 aq.) and extracted with 952 ml (20 vol) methyl-tert-butylether (MTBE). Subsequently, the organic phase was washed with 95.2 ml (2 vol) brine and dried over sodium sulphate. Thereafter the organic phase was filtered, rinsed with 100 ml (2.1 vol) methyl-tert-butylether (MTBE) and concentrated to dryness under vacuum at 30-35 C. to afford 55.2 g compound of formula (5) with 100% yield.

EXAMPLE 6

Preparation of (3S,5S,8R,9S,10R,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-7-hydroxy-10,13-dimethyltetradecahydrospiro[cyclopenta[a]phenanthrene-17,2-1,3dioxolan]-6(1H)-one (compound of formula (6), step e.1))

[0283] ##STR00074##

[0284] A reactor was charged with 54.0 g (1.0 eq.) of compound of formula (5) in 270 ml (5 vol) dichloromethane (DCM) and allowed to cool to 20 C. While keeping the temperature below 0 C., 26 g (1.15 eq.) meta-Chloroperoxybenzoic acid (mCPBA) were slowly charged to the reaction mixture and further mixed at a temperature of 0 C. until completion of the reaction, which was monitored by chromatography. Thereafter 120 ml (2.2 vol) aqueous sodium bicarbonate (NaHCO.sub.3 aq.) were charged to the mixture to adjust the pH to 7-8 at while keeping the temperature at 10 C. 1,080 ml (20 vol) methyl-tert-butylether (MTBE) were charged to the reaction mixture followed by an extraction which was performed with 270 ml (5 vol) H.sub.2O. The phases were separated and the organic phase washed with 270 ml (5 vol) aqueous sodium bicarbonate (NaHCO.sub.3 aq.), 270 ml (5 vol) brine. Thereafter the organic phase was dried over sodium sulphate, filtered, rinsed with 100 ml (2 vol) methyl-tert-butylether (MTBE) and concentrated to dryness under vacuum at 30 C. to afford 55 g of compound of formula (6) with 100% yield.

EXAMPLE 7

Preparation of (1,2R,5S)-5((tert-butyldimethylsilyl)oxy)-2-((3aS,4R,5S,7aS)-4-formyl-7a-methyloctahydrospiro[indene-1,2-[1,3]dioxolan]-5-yl)-2-methylcyclohexane-1-carboxylic acid (compound of formula (7), step f.)

[0285] ##STR00075##

[0286] A reactor was charged with a solution of 62.7 g (1.0 eq.) compound of formula (6) in 376 ml (6 vol) methanol followed by charging of 56 g (2 eq.) sodium periodate (NalO.sub.4). The reaction mixture was mixed at ambient temperature until completion of the reaction which was monitored by chromatography and lasted for a period of approximately 10 hours. Thereafter the reaction mixture was charged with 3,000 ml (48 vol) methyl-tert-butylether (MTBE) and extracted with 4,000 ml (64 vol) H.sub.2O. Subsequently the separated organic phase was washed with 125.4 ml (2 vol) brine, dried over 100 g, filtered, and concentrated to dryness under vacuum to afford 55.7 g of compound of formula (7) with 86% yield.

EXAMPLE 8

Preparation of (3aS,4R,5S,7aS)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyloctahydro-1H-inden-1-one 4-methylbenzenesulfonate (compound of formula (10), step g-i.)

[0287] ##STR00076##

[0288] A solution of 5.0 g (1.0 eq.) compound of formula (7) in 15.0 ml (3 vol) tetrahydrofuran (THF) and 0.61 ml (1.1eq.) 50% aqueous hydroxylamine (NH.sub.2OH 50% aq.) were mixed over a period of approximately 10 hours and subsequently charged into 80.8 ml (8 eq.) of a freshly prepared THF solution of 1M aluminium hydride (AlH.sub.3). The reaction mixture was heated to 60 C. and mixed for 8 hours, then cooled to ambient temperature and charged with 16.2 g (5 eq.) of sodium sulfate decahydrate (Na.sub.2SO.sub.4.10H.sub.2O) followed by mixing lasting 2 hours. Thereafter the reaction mixture was filtered, the obtained cake washed three times each with 20 ml (4 vol) tetrahydrofuran (THF) and three times each with 20 ml (4 vol) methanol. The filtrates were concentrated and the solvent exchanged with ethanol until 20-30 ml solution remained. Subsequently 2 g (1.05 eq.) of p-toluenesulfonic acid (p-TSA) monohydrate were charged to the reactor and mixed for 2 hours at 45 C. The mixture was cooled to ambient temperature and charged into 300 ml (60 vol) methyl-tert-butylether (MTBE) at vigorous mixing. The precipitates were separated by filtration, washed three times each with 20 ml (4 vol) methyl-tert-butylether (MTBE) and dried under vacuum at ambient temperature to afford 5 g of compound of formula (10) with 100% yield.

Example 9

Preparation of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymeth)-4-methylcyclohexan-1-ol (compound of formula (11), step j.)

[0289] ##STR00077##

[0290] A reactor was charged with 5.0 g (1.0 eq.) compound of formula (10) in 50.5 ml (5 eq.) potassium tert.-butoxide (KOt-Bu) (1M/THF) and the reaction mixture mixed for 20 minutes at ambient temperature. 14.4 g (4.0 eq.) of Ph.sub.3P.sup.+MeBr.sup. were added and the reaction mixture mixed at a temperature of 45-50 C. until complete conversion which took approximately 2 hours, and was monitored by chromatography. Subsequently the reaction mixture was cooled to 0 C., charged with 20 ml (4 vol) H.sub.2O, evaporated and chased twice each with 20 mil (4 vol) tetrahydrofuran (THF). The residue was suspended in 100 ml (20 vol) dichloromethane (DCM), separated by filtration and concentrated. The crude compound of formula (11) was purified via silica gel column eluted with 9:1:0.2 DCM/EtOH/7M NH.sub.3:MeOH to afford 1.4 g compound of formula (11), 95% pure by HPLC. Thereafter, 40 ml of dichloromethane (DCM) were charged to compound of formula (11) and mixed at ambient temperature for approximately 10 hours. Subsequently compound of formula (11) was isolated by filtration, washed twice each with 10 ml dichloromethane (DCM) and dried under vacuum to afford 1.2 g of compound of formula (11), 99.2% pure by HPLC.

EXAMPLE 10

Preparation of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol acetate (compound of formula (12), step k.)

[0291] ##STR00078##

[0292] A reactor was charged with 1.0 g (1 eq.) compound of formula (11), 10 ml (10 vol) MeOH and 0.2 g (1.1 eq.) of AcOH, concentrated in a vacuum and triturated with 20.0 ml (20 vol) CAN. The solids were separated by filtration and dried under vacuum to afford 1.18 g compound of formula (12), 100% yield.

[0293] All examples for steps a. to i. according to the invention result in a high yield (greater or equal to 86%), step j. according to the invention results in a yield of at least 40% in combination with a high purity (>80%) for each of the steps a. to j.