Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes

A technology of oxo and lactone, applied in the field of 6β, can solve the problems of costly, laborious and expensive

Active Publication Date: 2008-07-16
BAYER PHARMA AG
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

The use of transition metal elements in the preparation of pharmaceutical active ingredients often entails the disadvantage of the already expensive remo...

Method used

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  • Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes
  • Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes
  • Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Example 1 6β,7β; 15β,16β-dimethylene-3-oxo-17α-pregnane-5β-ol-21,17-lactone-dichloromethane hemisolvate (IV):

[0097] According to GOP1, 30 g (0.0769 mol) of 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-androstane-3β,5β,17β-triol were reacted.

[0098] During the reaction, the product 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregnane-5β-ol-21,17-lactone accumulated in the form of its dichloromethane hemisolvate . After destruction of excess oxidant and after work-up according to GOP1, 27 g of 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregnane-5β-ol-21,17 were isolated -Lactone-methylene chloride hemisolvate (0.0630 mol) = 82% of theory.

[0099] [α] D 20 =-61° (c=1.0; CHCl 3 ); Melting point = 121°C;

[0100] 1 H-NMR (400MHz, CDCl 3 ): δ = 0.52 (q J = 5.5Hz, 1H, 21α-H [15, 16-methylene bridge]), 0.68-0.78 (m, 2H, 20-H [6, 7-methylene bridge]), 0.89-0.97(m, 1H, 6-H), 0.93(s, 3H, 19-H), 0.99(s, 3H, 18-H), 1.19-1.52(m, 7H), 1.54-1.85(m, 6H), 1.92 (dd J=3.8 and 11.8Hz, 1...

Embodiment 2

[0104] Example 2 6β, 7β; 15β, 16β-dimethylene-3-oxo-17α-pregna-4-ene-21,17-lactone (IIIb):

[0105] According to GOP2, 30 g (0.0769 mol) of 17α-(3-hydroxypropyl)-6β,7β;15β,16β-dimethylene-androstane-3β,5β,17β-triol were reacted. After destroying excess oxidizing agent according to GOP2, the reaction mixture was acidified to pH 1 with 10% sulfuric acid solution and stirred at 25° C. for 30 minutes. After working up according to GOP2, 21.5 g of 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregna-4-ene-21,17-lactone (0.059 mol)= 76.7 Theoretical%.

[0106] [α] D 22 ≈-182°(c=0.5 CHCl 3 ); melting point = 201.3°C; UV(MeOH): ε 265 = 19,000; more important 1 H-NMR data (CDCl 3 ): δ=0.40-0.67(m, 1H, cyclopropyl H), 1.01(s, 3H, 18-H), 1.11(s, 3H, 19-H), 6.04(s, 1H, 4-H) (D. Bittler, H. Hofmeister, H. Laurent, K. Nickisch, R. Nickolson, K. Petzoldt, R. Wiechert; Angew. Chem. Int. Ed. Engl. 1982, 21, 696-697];

[0107] MS (EI, 70eV) m / e=366 (M + ); m / e=338(M + -CO); m / e=351 (M + -CH ...

Embodiment 3

[0108] Example 3 6β, 7β: 15β, 16β-dimethylene-3-oxo-17α-pregna-4-ene-21,17-lactone (IIIb):

[0109]According to GOP3, make 30 g (70, 25 mmol) of 6β,7β:15β,16β-dimethylene-3-oxo-17α-pregnane-5β-ol-21,17-lactone dichloromethane hemisolvent Compound (from Example 1) was reacted to obtain 24.30 g of drospirenone (yield: 94.5%).

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Abstract

This invention relates to processes for the production of 3-oxo-pregnane-21,17-carbolactones of formula (II) as well as 3-oxo-pregn-4-ene-21,17-carbolactones of formula (III) by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes of formula (I). In addition, the invention relates to the dichloromethane hemisolvate of 6ss ,7ss; 15ss,16ss-dimethylene-3-oxo-17a-pregnan-5ss-ol-21,17-carbolactone (IV) as such as well as to a process for the production of drospirenone.

Description

technical field [0001] The present invention relates to a process for the preparation of 3-oxo-pregnane-21,17-lactone and 3-oxo-pregnane-4-ene-21,17-lactone, in particular for the preparation of 3- Methods for oxo-17α-pregnane-21,17-lactone and 3-oxo-17α-pregnane-4-ene-21,17-lactone. Furthermore, the present invention relates to the dichloromethane hemisolvate of 6β,7β;15β,16β-dimethylene-3-oxo-17α-pregnane-5β-ol-21,17-lactone. Background technique [0002] An example of a physiologically active steroid-21,17-lactone is eplerenone (9α,11α-epoxy-7α-methoxycarbonyl-3-oxo-17α-pregna-4-ene-21,17 -lactone), drospirenone (6β,7β; 15β,16β-dimethylene-3-oxo-17α-pregna-4-ene-21,17-lactone), spironolactone (7α-thioxo Acyl (acylthio)-3-oxo-17α-pregna-4-ene-21,17-lactone), canrenone (3-oxo-17α-pregna-4,6-diene-21, 17-lactone) and prorenone (6β,7β-methylene-3-oxo-17α-pregna-4,6-diene-21,17-lactone). [0003] The construction of steroid-21,17-spironolactone can be carried out by using ...

Claims

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Application Information

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IPC IPC(8): C07J53/00
CPCC07J53/008
Inventor C·塞尔兹H·塞巴
Owner BAYER PHARMA AG
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