CS267443B1 - Steroid derivatives with 2-propyloxy group at the 20-position and a process for their preparation - Google Patents

Abstract

The solution relates to steroid derivatives with a propynyloxy group in position 20 and a method for their preparation. The compounds are prepared by reacting propargyl bromide with an alcohol selected from the group consisting of 3 β -methoxymethoxy-21-nor-5-pregnen-20-ol and 20-hydroxy-21-nor-4-pregnen J -3-one in a molar ratio of 5:1 to 1:1 in an organic solvent environment, 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 the alcohol, and in the presence of an aqueous solution of sodium hydroxide with a concentration of 10 to 19 mol 1-^ for a period of 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 steroid dicarbadocaborane derivatives.

Description

POUZAR VLADIMÍR RNDr.CSc., SCHNEIDEROVÁ LENKA RNDr., DRAŠAR PAVEL RNDr.CSc., STROUF OLDŘICH ing.CSc., HAVEL MIROSLAV ing.CSc., PRAGUE

Steroid derivatives with a 2-propinyloxy group in position 20 and a process for their preparation.

The invention relates to steroidal derivatives with a propinyloxy group in position 20 and to a process for their preparation. Said compounds are prepared by reacting propargyl bromide with an alcohol selected from the group consisting of 3β-methoxymethoxy-21-nor-5pregnen-20-ol and 20-hydroxy-21-nor-4-pregnen-3-one in molar ratio of 5: 1 to 1: 1 in an organic solvent medium, preferably a 2: 1 mixture of benzene and acetonitrile, 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 of aqueous sodium hydroxide solution in a concentration of 10 to 19 mol for 2 to 48 hours at a temperature of 10 to 70 ° C. The compounds according to the invention serve as direct precursors for the preparation of steroidal dicarbadocaborane derivatives.

CS 267443 Bl

The invention relates to steroidal derivatives with a 2-propinyloxy group in position 20 and to a process for their preparation.

Steroid derivatives with a 2-propinyloxy group are extremely advantageous as precursors for the preparation of steroidal dicarbadodecaborane derivatives that 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) because they are substances with low toxicity and stable stability. in vivo / Sweet F., Samant BR Synthesis and Application of Isotopically Labeled Compounds; Proceeding of the International Symposium, Kansas City, Mo. USA, June 6-11 1982, VP Duncan and ABSusan (Eds), p. 175 /. Similar derivatives have been used to treat human breast cancer in BNCT meth'ode / Sweet F., Kao M.-S-, Williams A., Khachatrian L., Vessels B., Kirsch J .; Proceedings of the ist International Symposium on Neutron Capture Therapy 1982, RG Fairchild and G.TBrownell / Eds /, BNLab, Upton, NY, USA. page 323 /. From this group of substances, only 3- (2-propyloxy) -1,3,5 (10) -estratrien-17-ene has been prepared so far, but only the reaction of estrone with sodium ethanolate and proparpropyl bromide in ethanol (Sweet FS Steroids 37,223). 1981 /. This method gives only low yields in the case of primary alcohols.

The present invention relates to novel substances which have not yet been prepared.

H-C5 C-CH2-OR (1) wherein R is 3 (3-methoxymethoxy-21-nor-5-pregnen-20-yl) or 3-oxo-21-nor-5-pregnen-20-yl or 3 -oxo-21-nor-4-pregnen-20-yl and a process 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 3/5-methoxymethoxy-21-nor-5-pregnen-20-ol and 20-hydroxy-21nor-4-pregnen-3- he 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 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 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, as 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.

Example 1

To a solution of 3β-methoxymethoxy-21-nor-5-pregnen-20-ol / 0.70 g; 2 mmol (in a mixture of benzene (10 ml) and acetonitrile (5 ml) was added propargyl bromide (0.53 ml); 6 mmol), tetrabutylammonium hydro

CS 267443 B1 gensulfate / 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 provided in vacuo. The residue was chromatographed on an alumina column (60 g). The petroleum ether-benzene ether mixture (9 = 9 = 1) was washed with 0.25 g (32%) of 3/6

-methoxymethoxy-20- (2-propinyloxy) -21-nor-5-pregnene, mp 68-69 ° C (hexane-ether). [α] D - 41.5 ° (c 0.3, chloroform). IR spectrum (carbon tetrachloride) cm ^-1 = 3315, 2120 (CSC-H); 1669 (C-C);

1150, 1106, 1042, 917 (OCH 2 OCH 3) - for C 25 H 38 O 3 (386.6) calculated: 77.68% C, 9.11% H; Found: 77.79% C; 9.28% H.

Example 2

To a solution of 20-hydroxy-21-nor-4-pregnen-3-one / 0.60 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 a silica gel column (50 g), petroleum ether-benzene ether (45 = 45 = 10), eluting with 0.16 g (23%) of 20-2-propinyloxy [21-nor-4-pregnene-3]. -one, mp 106-109 ° C / ether-hexane / [<id 108 ⁰ / c 0.3, chloroform /. IR spectrum (carbon tetrachloride) cm ^-1 = 3315, 2115 (C5C-H); 1677, 1619 / C = C-C '

O/; 1102 / C-0 /. For C 23 H 32 O 2 (304.5) calculated: 81.13% C, 9.47% H; Found: 80.93% C, 9.24% H.

Example 3

The preparation was carried out according to Example 1, except that a mixture of toluene (10 ml) and acetonitrile (5 ml) was used as the solvent, and the reaction mixture was stirred at + 70 ° C for 2 hours with the same result.

Example 4

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

Example 5

The preparation was carried out according to Example 1, except that tetrabutylammonium hydrogen sulfate (0.68 g, 2 mmol) was used as the catalyst, in this yield 0.22 g (28%).

Bl

Example 6

The preparation was 0.17 g q (17%) as a catalyst.

carried out according to Example 1, with the difference that 1 problem of tetrabutylammonium ammonium hydroxide was 1 f t t (0.5 mmol), the yield in this case being 0.13

Example 7

The preparation was carried out according to Example 1, except that propargyl bromide was used in an amount of 0.9 ml (10 mmol), the yield in this case being 0.23 g (30%).

Example 8

The preparation was carried out according to Example 1, except that propargyl bromide was used in an amount of 0.18 ml (2 mmol), the yield in this case being 0.09 g (12%).

Example 9

The preparation was carried out according to Example 1, except that trloctylmethylammonium chloride / 0.04 g was used as catalyst; 1 mmol /. The yield in this case was 0.08 g (10%).

Example 10

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 0.19 g (24%).

Example 11

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 0.23 g (30%).

Example 12

The preparation was carried out according to Example 1, except that cetyl trimethylammonium bromide (0.36 g) was used as catalyst.

mmol /. The yield in this case was 0.08 g (10%).

Example 13

The preparation was carried out according to Example 1, except that benzyl trimethylammonium chloride (0.19 g) was used as the catalyst; 1 mmol /. The yield in this case was 0.09 g (12%).

Example 14

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

Claims (2)

A steroidal derivative with a 2-propynyloxy group in position 20 of general formula I H-C2C-CH2-OR (1) wherein R is selected from the group consisting of 3β-methoxymethoxy-21-nor-5-pregnen-20-yl and 3-oxo-21-nor-4-pregnen-20-yl . 2. A process for the preparation of steroid derivatives having a 2-propinoloxy group in position 20 of general formula 1 according to item 1, characterized in that propargyl bromide is treated with an alcohol selected from the group consisting of 3/3-methoxymethoxy-21-nor-5-pregnene. 20-ol and 20-hydroxy-21-nor-4-pregnen-3-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 quaternary ammonium salts, preferably tetrabutylammonium sulphate, in a molar ratio of 1: 1 to 1 = 4 to alcohol, and in the presence of an aqueous sodium hydroxide solution having a concentration of 10 to 19 mol l ^-1 for 2 to 48 hours at a temperature of 10 to 70 ° C.