Preparation method of compound dienogest

A technology for dienogest and compound, which is applied in the field of compound preparation, can solve the problems of high price, low yield, unsuitability for industrialized large-scale production and the like, and achieves the effects of cheap raw materials and high yield

Inactive Publication Date: 2013-03-13
ZHEJIANG XIANJU PHARMA
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  • Abstract
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Problems solved by technology

[0009] In this reaction scheme, compound (4) is obtained by hydrolysis with oxalic acid. In the post-treatment washing process, the number of washings is large, and it is unstable to acid and alkali, and the yield is low; after obtaining the crude product of dienogest, a column layer is required. According to the analysis, the whole process route is longer, after the trial experiment, the overall yield is less than 18%, it is not easy to realize industrialized production
[0012] In this reaction scheme, using triethyl orthoformate and propylene glycol as raw materials, under the catalysis of p-toluenesulfonic acid, the ketone group at the 3-position is protected in the form of ketal, which can make the compound (2) resistant to strong alkali, Improve the 17-position epoxidation efficiency; epoxidation to obtain formula (3), and cyanide ring opening to obtain formula (4), but trimethylsulfonium iodide is expensive, the epoxidation yield is low, and potassium cyanide is highly toxic , not suitable for industrialized mass production

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  • Preparation method of compound dienogest
  • Preparation method of compound dienogest

Examples

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preparation example Construction

[0041] The preparation method of compound dienogest of the present invention comprises the following steps:

[0042] The first step is to prepare 17α-cyanomethyl-17β-hydroxyl-5(10), 9(11)-estradiene-3,17-dione-3,3-ethylene ketal (formula 2 );

[0043] Put tetrahydrofuran into the reaction bottle, lower the temperature to below -40°C, add n-butyllithium solution, dropwise add the mixed solution of acetonitrile and tetrahydrofuran, stir for 15 minutes, then add the raw materials estra-5(10), 9(11 )-diene-3,17-dione-3,3-ethylene ketal (Formula 1) and tetrahydrofuran mixed solution, the temperature is controlled between -80 ~ -20 ° C, preferably -50 ~ -30 ℃, stirred for 0.5 hours, after the reaction was complete, water was added dropwise to terminate the reaction, the organic layer was separated, washed with water, dehydrated and concentrated to obtain compound formula (2), with a purity of more than 96%;

[0044] The second step is to prepare 17α-cyanomethyl-17β-hydroxyl-13β-me...

Embodiment 1

[0053] Example 1: Preparation of 17α-cyanomethyl-17β-hydroxyl-5(10), 9(11)-estradiene-3,17-dione-3,3-ethylene ketal (Formula 2 )

[0054] Add 450ml of tetrahydrofuran into a 3L four-neck flask, cool down to below -50°C, slowly add 525ml of n-butyllithium solution, the reaction is exothermic, stir to adjust the temperature between -80~-20°C, add dropwise 300ml of tetrahydrofuran and 130ml of acetonitrile mixed solution, after dropping, stir for 15 minutes; dissolve 148g of estro-5(10), 9(11)-diene-3,17-dione-3,3-ethylene with 900ml of dry tetrahydrofuran Base ketal (Formula 1), dropwise into the reaction bottle between -80~-20°C, after dropping, stir for 0.5 hours, adjust the temperature below -40°C, add 400ml of water dropwise, stir for 1 hour, stand still Separate the layers and collect the organic phase. The organic phase was washed twice with 800 ml of water, dehydrated, and concentrated to dryness under reduced pressure at 40°C to obtain an oily substance (compound formul...

Embodiment 2

[0055] Example 2: Preparation of crude 17α-cyanomethyl-17β-hydroxyl-13β-methylstan-4,9-dien-3-one (Formula 3)

[0056] With 17α-cyanomethyl-17β-hydroxyl-5(10), 9(11)-estradiene-3,17-dione-3,3-ethylene ketal (formula 2) according to Add 200ml of methanol to a 1000ml reaction bottle of 48g of formula (1), stir to dissolve, add 10ml of hydrochloric acid at room temperature, stir for 1.5 hours, concentrate to a small volume at 40°C, water analysis, filter, and wash with water to obtain 48g of a yellow solid , which is the crude product of dienogest with a purity (HPLC) of 70%.

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Abstract

The invention discloses a preparation method of compound dienogest, comprising the following steps of: reacting a compound steroidal estrogens-5(10),9(11)-diene-3,17-diketone-3,3-ethylidene ketal serving as a raw material with cyanmethyl lithium obtained by reacting acetonitrile with n-butyl lithium at the reaction temperature of -50 DEG C to -35 DEG C; thus obtaining a compound 17alpha-cyanmethyl-17beta-hydroxy-5(10),9(11)-steroidal estrogens diene-3,17-diketone-3,3-ethylidene ketal; carrying out deprotection transposition to obtain 17alpha-cyanmethyl-17beta-hydroxy-13beta-methylsterane-4,9-diketone-3-ketone; and refining to obtain a dienogest high-quality product. The preparation method disclosed by the invention has the advantages of very simple route, novelty, easily available and cheap raw materials, low cost, no-toxic or low-toxic raw materials, short synthetic route, moderate conditions, easiness for operation, stability for amplification and high yield, and can be suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of the compound dienogest. Background technique [0002] Dienogest is a mixed progestogen. In 1995, the compound preparation of dienogest and ethinyl estradiol (2mg+0.03mg) was launched in Germany as a contraceptive, and in Australia in 2007 under the trade name Valette. It has the pharmacological characteristics of synthetic and mixed progestogens and the dual properties of 19-nortestosterone derivatives, and at the same time has high progestogenic activity, and its endocrine pharmacological properties are very ideal, free of estrogen, anti-estrogenic and androgenic Activity, anti-gonadotropin effect is also very weak, but also has a certain anti-androgen activity. [0003] As early as the 1970s, many scholars have studied the synthesis of dienogest. So far, there are many synthetic literatures of dienogest, and there are mainly the following synthetic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00
Inventor 李爱文徐顺广
Owner ZHEJIANG XIANJU PHARMA
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