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Novel method for stereo-selective chemosynthesis of drospirenone

A technology of stereoselectivity and drospirenone, which is applied in the production of organic chemistry, steroids, bulk chemicals, etc., can solve the problems of no innovative synthetic method reported, insufficient stereoselectivity, and low yield

Inactive Publication Date: 2008-05-14
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, the reaction is not stereoselective enough, at Δ 6 -ene isomerized, and a group of 6β, 7β-methylene and 6α, 7α-methylene diastereomers are obtained, the ratio of which is β / α=2 / 1, after a lengthy separation and purification process Although the desired drospirenone can be obtained, the yield is very low
[0008] Regarding the preparation of drospirenone, several methods have been developed afterwards (EP0051143, DE3042136, JP1982122798, US4416985, US4614616, DE2652761, FR2370755, GB1550568, US4129564, DE3626838, Angew.Chem.1983, 913 (5): In recent years, many documents and patents have been reported (WO2006059167, WO2006059168, WO2006061309, WO2007009821, etc.), and the key parts of the synthesis are all focused on the introduction of the 17-position spironolactone ring and the construction of the 6β, 7β-methylene structural unit , the methods were all established by Wiechert R. et al. in the early synthesis of drospirenone, especially for the construction of 6β, 7β-methylene structural units, all of which use the Corey methylation method or Simmons-Smith reaction To achieve, there is no innovative synthetic method report

Method used

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  • Novel method for stereo-selective chemosynthesis of drospirenone
  • Novel method for stereo-selective chemosynthesis of drospirenone
  • Novel method for stereo-selective chemosynthesis of drospirenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1: Preparation of dihydroxy compound 3 (3β, 17β-dihydroxy-15β, 16β-methylene-androstane-5-ene)

[0085]

[0086] Compound 2 (40.0g, 0.1333mol) was dissolved in methanol (700mL) to form a suspension and cooled to 0°C, NaBH was added in batches 4 (5.544g, 0.1467mol) was reacted for 1 hour, and the suspension was clear at this time, and the raw materials were detected by TLC to disappear, so the reaction was stopped. saturated NH 4 Cl aqueous solution (80 mL) was used to quench the reaction, most of the solvent was spin-dried under reduced pressure, the reaction system was poured into a large amount of ice water, the solid was filtered and dried to obtain compound 3 (39.861 g) as a white solid with a reaction yield of 99%.

[0087] Compound 3: Mp 209-211°C; [α] 26 D -55.4 (c 0.37, CHCl 3 );

[0088] 1 H NMR (Py-d 5 , 300MHz) δ5.48(d, J=5.4Hz, 1H), 4.27(d, J=4.5Hz, 1H), 3.87(m, 1H), 1.07(s, 3H), 1.06(s, 3H), 0.30(dd, J=7.2, 13.2Hz, 1H);

[0089] 13 C NM...

Embodiment 2

[0092] Example 2: Preparation of Compound 4 (3β, 17β-bis-TBSyloxy-15β, 16β-methylene-androstane-5-ene)

[0093]

[0094]Compound 3 (13.699g, 0.0454mol) and imidazole (15.40g, 0.227mol) were dissolved in anhydrous DMF (200mL) solvent, and tert-butyldimethylsilyl chloride (20.41g, 0.136mol) was added at room temperature. After stirring and reacting for 5 hours, it was detected by TLC that the reaction was found to be complete, and the reaction was stopped. The reaction system was poured into a large amount of ice water, and a large amount of white solid was precipitated at this time. The solid was collected by filtration and dried to obtain compound 4 (23.812 g) as a white solid with a yield of 99%.

[0095] Compound 4: mp 164-165 °C; [α] 26 D -18.1 (c 1.58, CHCl 3 );

[0096] 1 H NMR (CDCl 3 , 300MHz) δ5.36(d, J=4.8Hz, 1H), 3.95(d, J=4.5Hz, 1H), 3.48(m, 1H), 1.00(s, 3H), 0.91(s, 9H), 0.89(s, 9H), 0.76(s, 3H), 0.17(m, 1H), 0.07(d, J=9.9Hz, 6H), 0.06(s, 6H);

[0097] ...

Embodiment 3

[0101] Example 3: Preparation of Compound 5 (3β, 17β-bisTBSyloxy-15β, 16β-methylene-androstane-5-en-7-one)

[0102]

[0103] Compound 4 (3.642g, 6.872mmol), N-hydroxysuccinimide (NOS, 2.371g, 0.0206mol) were dissolved in acetone (40mL), and sodium dichromate (2.662g, 8.933mmol) was added at room temperature After the reaction was heated to 40°C and stirred for 36 hours, the reaction was stopped, and the reaction was quenched with saturated aqueous sodium sulfite (60 mL), and the reaction system was poured into a large amount of ice water. At this time, a large amount of white solid was precipitated. The solid was filtered, washed with water, dried, and the silica gel H column layer Analysis (petroleum ether: ethyl acetate = 50:1) separated and obtained white solid compound 5 (1.873g), the yield was 50%; recovered raw material 4 (1.743g, 47.9%).

[0104] Compound 5: mp 205-207°C; [α] 27 D -50.3 (c 0.52, CHCl 3 );

[0105] 1 H NMR (CDCl 3 , 300MHz) δ5.71(s, 1H), 3.95(d,...

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Abstract

The invention relates to a new method of stereo selectivity synthesis drospirenone and main intermediate in the synthesizing method; 15 Beta, 16 Beta-methylene dehydroepiandrosterone (3 Beta-hydroxy-15Beta, 16Beta-methylene -androstane -5-ene-17-ketone, 2) are adopted as starting raw material for the methods and the drospirenone is synthesized via fourteen steps. The invention has the advantages of higher yield and good stereo selectivity.

Description

technical field [0001] The present invention relates to the field of pharmaceutical chemical synthesis, specifically, the present invention relates to a stereoselective synthesis of Drospirenone (Drospirenone, 6β, 7β; 15β, 16β-Dimethylene-3-oxo-17α-pregn-4-ene-21, 17-carbolactone) a new method based on 15β, 16β-methylene dehydroepiandrosterone (3β-hydroxyl-15β, 16β-methylene-androstane-5-en-17-one) Starting raw materials, the product drospirenone is synthesized through fourteen steps of reaction. The advantage of this method lies in the novelty of the method, better yield and excellent stereoselectivity. Background technique [0002] Drospirenone, compound 1, is a unique androstane derivative with two methylene structural units and a spironolactone ring structure obtained artificially. It is the structure of the aldosterone antagonist spironolactone (compound 17). It is considered to be an active metabolite of Spirorenone (Compound 18) in vivo. [0003] [0004] Drospi...

Claims

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Application Information

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IPC IPC(8): C07J21/00
CPCY02P20/55
Inventor 李援朝姜标邓刚赵小龙王友富王均良李征
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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