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Method for synthesizing dydrogesterone

A technology of dydrogesterone and a synthesis method is applied in the field of production technology of steroid drugs, and can solve the problems of environmental pollution, hidden safety hazards, three wastes discharge and the like

Inactive Publication Date: 2021-05-18
江苏诺维尔医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Disadvantages: This route uses progesterone as the starting material, and the final product is obtained through nine-step linear synthesis. Serious emissions of three wastes and environmental pollution; in addition, the sixth step of catalytic hydrogenation reduction requires the use of high-pressure hydrogen, which poses a major safety hazard
[0013] In summary, the existing synthetic methods of dydrogesterone all have obvious deficiencies and need to be improved

Method used

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  • Method for synthesizing dydrogesterone
  • Method for synthesizing dydrogesterone
  • Method for synthesizing dydrogesterone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 35.8 g of pregnenolone acetate (Ib), 28.4 g of dibromohydantoin and 3.28 g of azobisisobutyronitrile to 1 L of petroleum ether (60-90° C.), heat the mixture under reflux for 0.5 to 1 hour, and cool to After room temperature, filter and wash with chloroform (3X100mL). After combining the filtrates, the solvent was recovered by distillation under reduced pressure. Add 200 mL of 2,4,6-collidine to the distillation residue, heat at 140°C for 15 minutes under nitrogen protection, and cool to room temperature. Add 100mL of petroleum ether, wash with water three times (3×100mL), then wash with 2N sulfuric acid three times (3×100mL), finally wash with 5% sodium carbonate, wash with water, combine the organic phases, and dry over anhydrous sodium sulfate. After filtration, the residue after distilling off the solvent was recrystallized with methanol / acetone (v / v=150mL / 10mL) to obtain 26.7 g of IIb (75%, purity 99.8%).

Embodiment 2

[0026] NBS, N-bromoacetamide, bromochlorohydantoin, N-chlorosuccinimide (NCS), dichlorohydantoin (DCDMH), trichloroisocyanuric acid, N-iodosuccinyl Imine (NIS), diiodohydantoin (DIDMH) instead of dibromohydantoin, others are the same as in Example 1, and the productive rate of compound IIb is respectively 76%, 60%, 66%, 70%, 55%, 61 %, 58%, 59%.

Embodiment 3

[0028] Use azobisisoheptanonitrile, di-tert-butyl azodicarboxylate, diisophenylpropyl azodicarboxylate, di-tert-butoxy azide, tert-butanol peroxide (TBHP), tert-butyl peroxyether (DTBP), benzoyl peroxide (BPO), dicumyl peroxide (DCP), dilauroyl peroxide (DLP), tert-butyl peroxy acetate (TBPA), m-chloroperbenzoic acid (mCPBA) Instead of AIBN, the others were the same as in Example 1, and the yields of compound IIb were 70%, 68%, 72%, 50%, 52%, 65%, 53%, 49%, 55%, and 43%, respectively.

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Abstract

The invention relates to a method for synthesizing a steroid drug dydrogesterone (CAS: 152-62-5). The method comprises the following steps: starting from pregnenolone, carrying out allylic halogenation and elimination to obtain a Pregna-5, 7-dien-3-ol-20-one intermediate; carrying out illumination isomerization to obtain a key intermediate 9 beta, 10 alpha-Pregna-5, 7-dien-3-ol-20-one; then carrying out Oppenauer oxidation (Oppenauer oxidation) to obtain 7-Dehydro-9beta, 10 alpha-progesterone, and finally, carrying out olefin shift isomerization under the action of acid to obtain the final product 6-Dehydro-9beta, 10 alpha-progesterone (a crude drug of dydrogesterone). The method is economical in steps and comprises four conversion steps; the total yield is as high as 16.4%; the raw materials are cheap and easy to obtain, the whole process route is green and safe, the bulk drugs are high in quality, the purity can reach 99.5% or above, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the production process of steroid medicine, in particular to a synthesis method of steroid medicine dydrogesterone. Background technique [0002] Dydrogesterone, also known as dehydroprogesterone, 6-dehydroreverse progesterone, procyclidine hydrochloride, piperidine hydrochloride; English name Dydrogesterone, 9β,10α-Pregna-4,6-diene-3 ,20-dione; CAS No. 152-62-5. It is an oral progestogen that induces the endometrium to enter a fully secretory phase, thereby preventing endometrial hyperplasia and cancer risk caused by estrogen. Dydrogesterone can be used to treat diseases caused by insufficient endogenous progesterone levels in women, such as: infertility caused by insufficient progesterone hormone levels in the body, threatened or habitual abortion caused by progesterone deficiency, dysmenorrhea, Endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, etc. Accor...

Claims

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Application Information

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IPC IPC(8): C07J7/00C07J31/00A61P15/00A61P15/08A61P5/34
CPCC07J7/002C07J31/006A61P15/00A61P15/08A61P5/34
Inventor 郑婷芬
Owner 江苏诺维尔医药科技有限公司
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