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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

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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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 removal of trace heavy metals
Also, the preparation accumulates large amounts of heavy metal-containing waste which can only be removed by costly and laborious means

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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