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Preparation method for dienogest

A technology for dienogest and compound, which is applied in the field of compound preparation and achieves the effects of strong alkalinity, less side reactions and improved yield

Inactive Publication Date: 2012-10-10
HAISCO PHARMA GRP INC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problem with this reaction is that when 17-cyanomethyl is introduced, the route of 17-epoxidation and potassium cyanide ring opening still uses highly toxic potassium cyanide

Method used

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  • Preparation method for dienogest
  • Preparation method for dienogest
  • Preparation method for dienogest

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] In this embodiment, the R base is And n=2.

[0045] (1) Preparation of formula 12 compound

[0046] In a 1L round bottom flask, add 500 mL of cyclohexane, 163 g of triethyl orthoformate (183 mL, 1.10 mol), 96.2 g of ethylene glycol (86.3 mL, 1.55 mol) and 0.9 g of p-toluenesulfonic acid (4.70 mmol), and stir Reflux reaction, fractional distillation of ethanol-cyclohexane azeotrope at normal pressure, additional cyclohexane to keep the volume of the reaction solution basically constant. After completion of the reaction, 5g of potassium carbonate was added to the system, and under reduced pressure distillation, the fraction above 130°C was collected under 10mmHg, which was a colorless oily liquid to obtain 85g of active ester (chemical name: 2,2'-(1,2-ethylene Dioxy)-bis-1,3-dioxolane, hereinafter referred to as active ester), the yield is about 80%, ρ=1.03g / mL.

[0047] In a 3L round bottom flask, under nitrogen protection, add 151g of estro-4,9-diene-3,17-dione, add...

Embodiment 2

[0056] The base R is And n=2.

[0057] (1) Preparation of formula 12 compound

[0058] With embodiment 1.

[0059] (2) Preparation of formula 14 compound

[0060] In a 500mL single-necked bottle, add 15g of the compound of formula 12, 150mL of isopropyl ether, stir to dissolve, add 13mL of acetonitrile, protect with nitrogen, and add 48mL of tetrahydrofuran solution of lithium hexamethyldisilazide dropwise at an external temperature of -20 to 0°C (the content of lithium hexamethyldisilazide is 2mol / L), react at the same temperature for 3 hours after dropping, add 60mL of water, adjust the pH to about 2 with 1N hydrochloric acid, extract three times with ethyl acetate, and combine the acetic acid The ethyl ester phase was washed with saturated brine, dried, and concentrated under reduced pressure to obtain a brown solid. Recrystallization with ethyl acetate gave 15 g of a light yellow solid with a yield of 88.2% and a purity of 99.3% by HPLC.

[0061] (3) Refining of form...

Embodiment 3

[0064] The base R is wherein R' is a methyl group.

[0065] (1) Preparation of formula 12 compound

[0066] In a 1L round bottom flask, add 540mL of anhydrous methanol and 50g of estro-4,9-diene-3,17-dione, stir, and under the protection of nitrogen, add 120mL of 20% hydrochloric acid / methanol dropwise, and continue After reacting for three hours, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution, part of the solvent was distilled off, and a white solid was precipitated. After suction filtration, the filter cake was recrystallized from ethyl acetate to obtain 54 g of white solid, with a yield of about 97%.

[0067] (2) Preparation of formula 14 compound

[0068] In a 500mL single-necked bottle, add 15g of the compound of formula 12, 150mL of isopropyl ether, stir to dissolve, add 13mL of acetonitrile, nitrogen protection, and at an external temperature of -40~-80°C, add dropwise 95mL of lithium hexamethyldisilazide tetrahydrofuran solution ...

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Abstract

The invention relates to the field of compound preparation. The invention discloses a preparation method for dienogest to solve the problems of low product yield and using highly toxic reactant in the dienogest preparation methods of prior art. A non-nucleophilic alkyl amino base acts as a catalyst. Estra-4,9-diene-3,17-dione protected by 3-carbonyl is reacted with acetonitrile in an organic solvent. The dienogest is obtained after removing the protecting group. The method of the invention has high yield and simple operation, and is environmental friendly.

Description

technical field [0001] The invention belongs to the field of compound preparation, and in particular relates to a method for preparing dienogest. Background technique [0002] Dienogest is a powerful progestin, which has dual properties of 19-nortestosterone derivatives and progesterone derivatives, and has unique pharmacodynamic and pharmacokinetic properties. Its structural formula is as follows: [0003] [0004] The compound of dienogest and ethinyl estradiol was launched in Germany in 1995 as an oral contraceptive. It has high and reliable effects, low bleeding and other adverse reactions, and is quite well tolerated. It has become the best-selling compound in the German market Oral contraceptives. The compound tablet of dienogest and estradiol valerate was launched in 2002 by Schering AG of Germany, and it is the first continuous hormone replacement drug used to treat postmenopausal women with remarkable effect. [0005] In the prior art, some preparation methods ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00
CPCY02P20/55
Inventor 王俊民郑伟吴勇袁辛娅许战锋
Owner HAISCO PHARMA GRP INC
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