Novel method for synthesizing didrogesterone, and compound

A synthesis method and compound technology, which is applied in the production of steroids, organic chemistry, bulk chemicals, etc., can solve the problems of synthetic dydrogesterone, etc., and achieve the effect of easy-to-obtain raw materials and simple and mild reaction conditions

Pending Publication Date: 2022-01-04
SUZHOU LANXITE BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis method of dydrogesterone, which has wide sources of starting materials, good economy, mild reaction conditions and is suitable for industrial production, still needs to be further explored.
[0011] 21-Hydroxy-20-methyl-4-pregnene-3-one (CAS No. 60966-36-1; referred to as BA, also known as bisbutanol) is a commonly used steroid drug starting material, the market source It is widely used and economical, and is often used in the synthesis of many steroid hormone drugs, such as progesterone, hydrocortisone and bile acid products, but there is no report on the synthesis of dydrogesterone using dindenol as a raw material

Method used

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  • Novel method for synthesizing didrogesterone, and compound
  • Novel method for synthesizing didrogesterone, and compound
  • Novel method for synthesizing didrogesterone, and compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] N 2 Under protection, bisnaniline BA (500 g, 1.513 mol) and triethylamine (229.6 g, 2.269 mol) were dissolved in 3LDCM, and the temperature was lowered to 0-5°C. Under stirring, chloroacetyl (130.6 g, 1.664 mol) was added dropwise to the above reaction solution, and the temperature was controlled not to exceed 10°C. After the dropwise addition, stir for 1 h, and add 1 L of ice water to quench. After static liquid separation, the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 541 g of white solid compound i, HPLC=97%, yield 96%.

Embodiment 2

[0057] Dissolve BA (300 g, 0.908 mol) and 4-dimethylaminopyridine (166.3 g, 1.361 mol) in 2.4 LDCM and lower the temperature to 5-10°C. N 2Under protection, acetic anhydride (102.1 g, 0.953 mol) was added dropwise to the above reaction solution, and the temperature was controlled not to exceed 10°C. After the dropwise addition, stir for 3 h, then add 500 ml of ice water to quench. Static liquid separation, organic phase with saturated NaHCO 3 Washed with aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 331 g of white solid compound i, HPLC=99%, yield 97.8%.

[0058] The obtained compound i: 1 HNMR (400MHz, CDCl 3 )δ5.73(s, 1H), δ4.06-4.09(q, 1H), 3.75-3.79(q, 1H), 2.24-2.45(m, 4H), 2.05(s, 3H), 2.0-2.04( m, 2H), 1.34-1.86(m, 9H), 1.12-1.24(m, 6H), 0.91-1.05(m, 6H), 0.74(s, 3H)

[0059] Synthesis of compound ii series

Embodiment 3

[0061] Under stirring, add 4L of anhydrous toluene, 389g of compound i (1.044mol), 866g of ethylene glycol and 10g of p-toluenesulfonic acid monohydrate into a 10L reactor with a reflux separator, heat to 120°C to reflux and separate water . After stirring for 3 h, TLC detected that the starting material disappeared. Cool down to room temperature, add 2 L of water and stir for 30 min, then separate the layers, and wash the organic phase twice with 1 L of water. The organic phase was concentrated under reduced pressure to obtain the crude compound ii. The obtained crude product was added into 500ml of methanol, refluxed, lowered in temperature, slurried and filtered to obtain 343g of white solid compound ii, HPLC=96%, yield 80%.

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Abstract

The invention provides a novel synthesis method of didrogesterone. According to the novel synthesis method, dinorhydrin is used as a starting material, and didrogesterone is obtained through the steps of double bond construction, illumination overturning configuration and the like. The method has the advantages of easily available raw materials and mild reaction conditions, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, in particular to a new synthesis method of dydrogesterone and related intermediate compounds. Background technique [0002] Dydrogesterone (Dydrogesterone) is a synthetic progesterone, which has a similar molecular structure to endogenous progesterone and has a strong affinity. It can be used to treat diseases caused by insufficient endogenous progesterone, such as dysmenorrhea, intrauterine Membranesis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, and infertility caused by corpus luteum insufficiency are the current comparative Ideal progestogen drug. [0003] At present, there are many synthetic routes of dydrogesterone, such as: [0004] Reference patent: 79 (1960) RECUEIL771, applicant institution: N.V.Philips-Duphar), with photosterol as the starting...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J7/00C07J5/00C07J71/00
CPCC07J7/002C07J5/0015C07J71/0026Y02P20/55
Inventor 王飞袁海涛
Owner SUZHOU LANXITE BIOTECH
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