Process for the preparation of 17-(3-hydroxypropyl)-17-hydroxysteroids

A technology of hydroxysteroids and hydroxypropyl, which is applied in the production of steroids, organic chemistry, bulk chemicals, etc., and can solve the problems of pure products and yield reduction, propynol instability, difficult separation, etc.

Inactive Publication Date: 2010-06-16
BAYER IP GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] A disadvantage of using prop-1-yn-3 alcohol (propynol) as a functionalized C3 building block is the significant formation of by-products (especially 17-ethynyl steroids) due to its instability to bases
[0011] All in all, the instability of propynyl alcohol can lead to difficulties in the separation of pure products and lower yields

Method used

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  • Process for the preparation of 17-(3-hydroxypropyl)-17-hydroxysteroids
  • Process for the preparation of 17-(3-hydroxypropyl)-17-hydroxysteroids
  • Process for the preparation of 17-(3-hydroxypropyl)-17-hydroxysteroids

Examples

Experimental program
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Effect test

Embodiment 1

[0101] 6β, 7β; 15β, 16β-dimethylene-17α-(3-benzyloxypropynyl)androstane-3β, 5β, 17β-triol (Vb)

[0102] According to GWP1, 100 g (0.303 mol) of 3β, 5β-dihydroxy-6β, 7β; -Alcohol benzyl ether reaction.

[0103] The crude product was recrystallized from 700 ml of toluene. 133 g (0.279 mol) of 6β,7β;15β,16β-dimethylene-17α-(3-benzyloxypropyne)androst-3β,5β,17β-triol were obtained (92% yield of theory).

[0104] [α] D 20 =-70.1° (CHCl 3 , 12.15mg per 1ml solution, T=20°C, d=100mm).

[0105] 1 H-NMR (400MHz, CDCl 3 ): δ=0.37-0.42 (1H, m, H-30exo * ), 0.63(1H, td, J=9.0Hz and 5.1Hz, H-31endo), 0.78(1H, q, J=5.1Hz, H-31endo), 0.82-0.88(1H, m, H-6), 0.85 (3H, s, H-19), 0.91 (3H, s, H-18), 1.13 (1H, tt, J=8.4Hz and 4.3Hz, H-7), 1.15-1.27 (4H, m, H -30exo, H-1, H-9, H-11), 1.39-1.44 (1H, m, H-2α), 1.46-1.54 (3H, m, H-11, H-12β, H-15), 1.57 (1H, dt, J=13.6Hz and 2.9Hz, H-2β), 1.66-1.74 (3H, m, H-12α, H-16, H-8), 1.84 (1H, td, J=14.5Hz and 2.9Hz, H-1β), 1.96-2.01 (1H, m, H-4β)...

Embodiment 2

[0110] 15β,16β-methylene-17α-(3-benzyloxypropynyl)androst-6-ene-3β,5β,17β-triol

[0111] According to GWP1, 100 g (0.317 mol) of 3β, 5β-dihydroxy-15β, 16β-methylene-androst-6-en-17-one was mixed with 50.9 g (0.349 mol) of prop-1-yn-3 -Alcohol benzyl ether reaction.

[0112] The crude product was recrystallized from 700 ml of toluene. 134.5 g (0.291 mol) of 15β,16β-methylene-17α-(3-benzyloxypropynyl)androst-6-ene-3β,5β,17β-triol were obtained (92% theoretical yield) .

[0113] [α] D 20 =-120.3° (CHCl 3 , 12.15mg per 1ml solution, T=20℃, d=100mm)

[0114] 1 H-NMR (400MHz, CDCl 3 ): δ = 0.35-0.42 (1H, m, H-30exo), 0.95 (3H, s, H-18), 0.96 (3H, s, H-19), 1.14 (1H, ddd J = 6.8Hz, 3.7 Hz and 3.5Hz, H-30endo * ), 1.28-1.35 (1H, m, H-11β), 1.38-1.42 (1H, m, H-15), 1.45-1.51 (2H, m, H-1β, H-2), 1.50-1.60 (3H , m, H-12β, H-11α, H-9), 1.60-1.65 (1H, m, H-2), 1.67-1.73 (2H, m, H-16, H-12α), 1.83-1.89 ( 1H, m, H-1α), 1.88-1.97 (3H, m, both H-4, H-14), 2.15-2.19 (1H, m, H-8), 2....

Embodiment 3

[0123] 6β, 7β; 15β, 16β-dimethylene-17α-(3-hydroxypropyl)androstane-3β, 5β, 17β-triol (Ia):

[0124] 100 g (0.210 mol) of 6β, 7β; 15β, 16β-dimethylene-17α-(3-benzyloxypropynyl)androstane-3β, 5β, 17β-triol was reacted according to GWP2 or GWP3, 81.1 g (0.208 mol) of 6β,7β;15β,16β-dimethylene-17α-(3-hydroxypropyl)androstane-3β,5β,17β-triol were obtained (99% yield of theory).

[0125] MS(CI): m / e=389(M-H) + , 373 (M+H-H 2 O) + , 355 (373-H 2 O), 337(355-H 2 O), 319(337-H 2 O).

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Abstract

The present invention relates to a process for the preparation of 17a-(3-hydroxypropyl)- 17ss-hydroxysteroids of the formula (I) starting from 17-ketosteroids of the formula (III) via the intermediates of the formula (V) wherein the radicals R3, R5, R6, R7, R10, R13, R15, R16, R40, R41 and R42 have the meaning indicated in the description.

Description

technical field [0001] The present invention relates to a method for preparing 17α-(3-hydroxypropyl)-17β-hydroxy steroid, the intermediate of the method, the preparation method of the intermediate and the use of these intermediates in the preparation of steroid 21,17-spironolactone, especially DR Uses in spirone. Background technique [0002] 17α-(3-hydroxypropyl)-17β-hydroxy steroid of formula I [0003] [0004] As starting material for the synthesis of pharmacologically active steroid 21,17-carboxylides such as eplerenone (9α,11α-epoxy-7α-methoxy-carbonyl-3-oxo-17α-pregna- 4-ene-21,17-carboxylactone), drospirenone (6β,7β; 15β,16β-dimethylene-3-oxo-17α-pregna-4-ene-21,17-carboxylate ester), spironolactone (7α-acetylthio-3-oxo-17α-pregna-4-ene-21,17-carboxylactone), canrenone (3-oxo-17α-pregna-4, 6-diene-21,17-carboxylactone) and plerenone (6β,7β-methylene-3-oxo-17α-pregna-4-ene-21,17-carboxylactone). [0005] The synthesis of these steroid 21,17-spironolactones is c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J53/00
CPCC07J53/008Y02P20/55C07J71/0005
Inventor C-C·黑泽尔霍夫M·彼得森
Owner BAYER IP GMBH
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