CS267442B1 - Steroidal derivatives with a 2-propynyloxy group at the 17-position and a process for their preparation - Google Patents

Abstract

The invention relates to steroid derivatives with a propynyloxy group in position 17 and a method for their preparation. The compounds are prepared by reacting propargyl bromide with an alcohol selected from the group consisting of: containing 3-(2-tetrahydropyranyloxy)-1,3,5 (10) estratriene-17β-ο1,3 li -methoxymethoxy-5- , androsten-17β-ol, 3 (i -methoxy-methoxy-5- i androsten-17<Z-ol, 3 fi> -/2-tetrahydropyranyl- * loxy/-5-androsten-17,3 -ol and 17Λ -hydroxy- -4-androsten-4-one in a molar ratio of 5:1 to 1:1 in an organic solvent medium, preferably a mixture of benzene and acetonitrile in a ratio of 2:1, in the presence of a quaternary ammonium salt, preferably tetrabutylammonium sulfate, in a molar ratio of 1:1 to 1:4 to alcohol and in the presence of an aqueous sodium hydroxide solution with a concentration of 10 to 19 mol l”1 for 2 to 48 hours at a temperature of 10 to 70° C. The substances according to the invention serve as direct precursors for the preparation of steroidal dicarbadodecaborane derivatives.

Description

The invention relates to steroidal derivatives with a 2-propinyloxy group in position 17 and to a process for their preparation.

Steroid derivatives with a 2-proplnyloxy group are particularly advantageous as precursors for the preparation of steroidal dlcarbadodecaborane derivatives which can be used as mediators of targeted ¹⁰ B isotope transport into tumor tissues in the treatment of hormone-sensitive tumors by neutron capture therapy (BNCT), as they are low toxicity substances. stable in vivo / Sweet F., Samant BR Synthesis and Application of Isotopically Labeled Compounds; Proceedings of an International Symposium, Kansas City, Mo. USA, June 6-11 1982, WPDuncan and ABSusan (Eds), p. 175 /. Similar derivatives have been used to treat human breast cancer in the BNCT method / Sweet F., Kao M.-S., Williams A., Khachatrian L., Vessels B., Kirsch J .: Proceedings of the 1st International Symposium on Neutron Capture Therapy 1982, RGFairchid and GTBrownell (Eds), BNLab, Upton, NY, USA, p. 323 /. Of this group of substances, only 3- (2-propynyloxy) -1,3,5 (10) -estratien-17-ene has been prepared so far, but only by the reaction of estrone with sodium ethanolate and propargyl bromide in ethanol / Sweet FSSteroids 37, 223 / 1981 /. This method gives only low yields in the case of secondary alicyclic alcohols.

The subject of the invention is the hitherto unprepared novel substances - 2-propynyl ethers with a 2-propinyloxy group in position 17 of the general formula I

HC = C-CH2-O-R (1) where R is 3- (2-tetrahydropyranyloxy) -1,3,5 (10) -estratren-17'-yl, 3,5 / methoxymethoxy-5-androstene -17β-yl, 1,3H-methoxymethoxy-5-androsten-17β-yl, 3β- (2-tetrahydropyranyloxy) -5-androsten-17β-yl or 3-oxo-4 -androsten-17/3-y1 and method for their preparation.

The process according to the invention is based on the fact that propargyl bromide is treated with an alcohol selected from the group consisting of 3- (2-tetrahydropyranyloxy) -1,3,5 / 10 / estratrien-17H-ol, 3Z? -Methoxymethoxy-5- androsen-17 / 5-01, 3/6-methoxymethoxy-5-androsten-17 (X-ol, 3 $ - (2-tetrahydropyranyloxy) -5-androsten-17) -ol or 17α-hydroxy- 4-androsten-3-one in a molar ratio of 5: 1 to 1 = 1 in an organic solvent, preferably a mixture of benzene and acetonitrile in a ratio of 2 = 1, in the presence of quaternary ammonium salts, preferably tetrabutylammonium sulfate, in a molar ratio of 1: 1 to 1 = 4 to a steroid alcohol, and in the presence of an aqueous solution of sodium hydroxide having a concentration of 10 to 19 mol l ^-1 for 2 to 48 hours at a temperature of 10 to 70 ° C.

Said method of preparation of the listed substances is economically advantageous, since it allows the isolation of unreacted alcohols and their reuse despite the lower conversion. The purity of the prepared substances can advantageously be verified using high-quality liquid chromatography.

CS 267442 Bl

Example 1

To a solution of 3- (2-tetrahydropyranyloxy) -1,3,5 (10) estratrien-17 (0-ol) (0.71 g; 2 mmol (in a mixture of benzene (10 ml) and acetonitrile (5 ml) was added propargyl bromide (0.53 ml); 6 mmol), tetrabutylammonium hydrogen sulfate (0.34 g; 1 mmol) and 19M aqueous sodium hydroxide solution (0.5 ml). The reaction mixture was stirred at room temperature for 10 h, then diluted with ether (100 mL) and washed with water (100 mL). The aqueous phase was extracted with ether (3 x 50 ml), the combined organic phases were washed with water and filtered through a column of silica gel (10 g) overlaid with anhydrous sodium sulphate. The column was washed with ether and the solvents were evaporated in vacuo. The residue was chromatographed on an alumina column (60 g). 0.25 g (32%) of oily 17β- (2-propynyloxy) -3- (2-tetrahydropyranyloxy) -1,3,5 / 10 were washed with petroleum ether-benzene-ether (49:49: 2). / estratriene. IR spectrum / carbon tetrachloride / cm ^-1 ; 3315, 2115 (C = CH); 1608, 1575, 1499 (aromatic system).

For C26H34O3 (394.6) calculated; 79.15% C, 8.69% H; found;

78.85% C. 8.52% H.

Example 2

To a solution of 3H-methoxymethoxy-5-androsten-17β-ol (0.67 g); 2 mmol (in a mixture of benzene (10 ml) and acetonitrile (5 ml) was added propargyl bromide (0.53 ml); 6 mmol /. tetrabutylammonium hydrogen sulfate / 0.34 g; 1 mmol / a 19 M aqueous sodium hydroxide solution (0.5 ml). The reaction mixture was stirred at room temperature for 10 h, then diluted with ether (100 mL) and washed with water (100 mL). The aqueous phase was extracted with ether (3 x 50 ml), the combined organic phases were washed with water and filtered through a column of silica gel (10 g) overlaid with anhydrous sodium sulphate. The column was washed with ether and the solvents were evaporated in vacuo. The residue was chromatographed on a silica gel column (50 g). The benzene-ether mixture (95 = 5) eluted with 0.12 g (16%) of 3'-methoxymethoxy-17β- (2-propynyloxy) -5-androstene, mp 74-77 ° C (hexane), IXJd-51 ⁰ (c 0.3, chloroform). IR spectrum / carbon tetrachloride / cm ^-1 ; 3315. 2120 / CS

C-H /; 1668 (C, C); 1146, 1100, 1040, 913 (OCH 2 OCH 3). For C26H36O3 (372.6) calculated; 77.38% C, 9.74% H; Found: 77.52% C, 9.94% H.

Example 3

To a solution of 3β-methoxymethoxy-5-androstene-17β-ol / 0.67 g; 2 mmol (in a mixture of benzene (10 ml) and acetonitrile (5 ml) was added propargyl bromide (0.53 ml); 6 mmol /. tetrabutylammonium hydrogen sulfate (0.34 g; 1 mmol) and 19 M aqueous sodium hydroxide solution (0.5 ml). The reaction mixture was stirred at room temperature for 10 hours, then diluted with ether (100 ml) and washed with water (100 ml). The aqueous phase was extracted with ether (3 x 50 ml), the combined organic phases were washed with water and filtered through a column of silica gel (10 g) overlaid with anhydrous sodium sulphate, washed with ether and the solvents evaporated in vacuo. (50 g) The benzene ether mixture (95 = 5) eluted with 0.12 g (16%) of 3 (3-roethoxymethoxy-17β) - (2-propynyloxy) of 5-androstene, mp 101-104 ° C. hexane /, [<< Jd - 72 ⁰ / c 0.3,

CS 267442 B1 chloroform / - IR spectrum Tetrachloromethane Z cm 3315, 2115 ZC = C-HZ; 1668 ZC ^ C-HZ; 1149, 1106, 1045, 918 Z0CH _{2 0CH 3} Z. Pro

C24H36O3 Z372.6Z calculated-- 77.38% C, 9.74% H; found- · 77.51% C. 9.87% H.

Example 4

To a solution of 3/3 -Z2-tetrahydropyranyloxyZ-5-androsten-17/5-ol ZO, 67 g; 2 mmolZ in a mixture of benzene Z10 mlZ and acetonitrile Z5 mlZ was added propargyl bromide ZO, 53 ml; 6 mmolZ, tetrabutylammonium hydrogen sulfate Z.34 g; 1 mmol Z and 19 M aqueous sodium hydroxide solution Z0.5 ml Z. The reaction mixture was stirred at room temperature for 10 h, then diluted with ether Z100 ml Z and washed with water Z100 ml Z. The aqueous phase was extracted with ether Z3 x 50 ml Z, the combined organic phases were washed with water and filtered through a column of silica gel Z10 gZ overlaid with anhydrous sodium sulphate. The column was washed with ether and the solvents were evaporated in vacuo. The residue was chromatographed on a silica gel column Z50 g; alkalized by standing in an atmosphere of ammonia 24 hZ. 0.18 g of Z22% / 17/3-Z2-propinyloxyZ-3/5-Z2-tetrahydropyranyloxyZ-5-androstene, m.p. 114 DEG-116 DEG C., was washed with petroleum ether-benzene ether. [</. Id ~ 59 ⁰ Zc 0.3, chloroformZ. IR spectrum ZtetrachlormethanZ cm “ ¹ ·· 3315, 2120 ZCS C-HZ; 1668 ZC »CZ; 1134, 1094, 1033 ZC-DZ- Calculated for C27H40003 Z412.6Z; 78.60% C, 9.77% H; found 78.81% C. 9.85% H.

Example 5

To a solution of 17,5-hydroxy-4-androsten-3-one Z0.58 g; 2 mmolZ in a mixture of benzene Z10 mlZ and acetonitrile Z5 mlZ was added propargyl bromide Z0.53 ml; 6 mmolZ, tetrabutylammonium hydrogen sulfate Z.34 g; 1 mmol Z and 19 M aqueous sodium hydroxide solution Z0.5 ml Z. The reaction mixture was stirred at room temperature for 10 h, then diluted with ether Z100 ml Z and washed with water Z100 ml Z. The aqueous phase was extracted with ether Z3 x 50 mlZ, combined the organic phases were washed with water and filtered through a column of silica gel Z10 gZ overlaid with anhydrous sodium sulphate. The column was washed with ether and the solvents were evaporated in vacuo. The residue was chromatographed on a Z50 gZ silica gel column. 0.13 g of crude product was washed with a mixture of petroleum ether-benzene-ether Z1O: 2O; 1Z, which was further purified by chromatography on two preparative silica gel plates Z200 x 200 x 0.7 mm2 in the system benzene-ether Z9 = 1Z. Was obtained 0.11 g of Z 16% / absolute 17/5-Z2-prop LNY loxyZ-4-androstene-3-one, mp 95-97 ⁰ from hexane-etherZ [O <id + 60 ° C Zc 0.1 chloroformZ. IR spectrum of tetrachloromethane Z cm ^-1 ; 3315, 2120 / Cz

C-HZ; 1677, 1620 (C = CC-O). For C2zH ₃ oO ₃ Z326,5 Z calculated:

80.94% C, 9.26 £ H; found: 81.03% C, 9.41 £ H.

Example 6

The preparation was carried out according to Example 1, except that a mixture of toluene Z10 ml2 and acetonitrile Z5 ml2 was used as solvent, and the reaction mixture was stirred at + 70 ° C for 2 h with the same result.

CS 267442 Bl

Example 7

The preparation was carried out according to Example 1, except that the reaction mixture was stirred at + 10 ° C for 48 h with the same result.

Example 8

The preparation was carried out according to Example 1, except that tetrabutylammonium hydrogen sulfate in an amount of 0.68 g (2 mmol) was used as the catalyst, the yield in this case being 0.24 g (30%).

Example 9

The preparation was carried out according to Example 1, except that tetrabutylammonium hydrogen sulfate (0.17 g, 0.5 mmol) was used as the catalyst, in this yield 0.13 g (16%).

Example 10

The preparation was carried out according to Example 1, except that propargyl bromide was used in an amount of 0.9 ml (10 mmol) and the yield in this case was 0.24 g (30%).

Example 11

The preparation was carried out according to Example 1, except that propargyl bromide was used in an amount of 0.18 ml (2 mmol) and the yield in this case was 0.11 g (14%).

Example 12

The preparation was carried out according to Example 1, except that trioctylmethylammonium chloride (0.40 g) was used as catalyst. 1 mmol /. The yield in this case was 0.06 g (8%).

Example 13 The preparation was carried out according to Example 1, except that tetrabutylammonium bromide (0.32 g) was used as catalyst. 1 mmol /. The yield in this case was 0.20 g (25%).

Example 14

The preparation was carried out according to Example 1, except that tetrabutylammonium iodide / 0.37 g was used as catalyst; 1 mmol /. The yield in this case was 0.21 g (27%).

Example 15

The preparation was carried out according to Example 1, except that acetyltrimethylammonium bromide / 0.36 g was used as catalyst. 2 mmol /. The yield in this case was 0.09 g (11%).

CS 267442 Bl

Example 16

The preparation was carried out according to Example 1, except that benzyltrimethylaroonium chloride / 0.19 g was used as catalyst. 1 mmol /. The yield in this case was 0.09 g (11%).

Example 17

The preparation was carried out according to Example 1, except that a 10 M aqueous sodium hydroxide solution was used. The yield in this case was 0.10 g (13%).

Claims (3)

Steroid derivatives with a 2-propinyloxy group in position 17 of general formula I H-Cs C -CH2-O-R (1), wherein R is selected from the group consisting of 3- (2-tetrahydropyranyloxy) -1,3,5 (10) estratren-17β-yl, 3 H -methoxymethoxy -5-androsten-17β-yl 1,3,3-methoxymethoxy-5-androsten-17β-yl, 3β- / 2-tetrahydropyranyloxy 7-5-androsten-17β-yl and 3-oxo-4-androsten-1753-yl. 2. A process for the preparation of sterol derivatives having a 2-propinyloxy group in position 17 of general formula I according to item 1, characterized in that the propargyl bromide is treated with an alcohol selected from the group consisting of 3- (2-tetrahydropyranyloxy) -1,3,5 / 10 / estratrlen-17 / 3-01, 3/3-methoxymethoxy-5-androsten-17β-ol, 3- (3-methoxymethoxy-5-androsten-17β-ol, 3β- (2-tetrahydropyranyloxy) -5-androsten-17β-ol and 17β-hydroxy-4-androsten-4-one in a molar ratio of 5 = 1 to 1: 1 in an organic solvent medium, preferably a mixture of benzene and acetonitride in a ratio of 2 = 1, in the presence of a quaternary ammonium salt, preferably tetrabutylammonium sulfate, in a molar ratio of 1: 1 to 1 = 4 to alcohol, and in the presence of an aqueous solution of sodium hydroxide with a concentration of 10 to 10 mol l ^-1 for 2 to 48 hours at a temperature of 10