WO2021012671A1 - Procédé de préparation de progestérone hautement efficace et faiblement polluant - Google Patents

Procédé de préparation de progestérone hautement efficace et faiblement polluant Download PDF

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Publication number
WO2021012671A1
WO2021012671A1 PCT/CN2020/076496 CN2020076496W WO2021012671A1 WO 2021012671 A1 WO2021012671 A1 WO 2021012671A1 CN 2020076496 W CN2020076496 W CN 2020076496W WO 2021012671 A1 WO2021012671 A1 WO 2021012671A1
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WIPO (PCT)
Prior art keywords
weight
reaction
substrate
hydroxy
progesterone
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PCT/CN2020/076496
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English (en)
Chinese (zh)
Inventor
邵振平
王友富
王荣
王炳乾
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浙江神洲药业有限公司
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Publication of WO2021012671A1 publication Critical patent/WO2021012671A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16

Definitions

  • the invention relates to the technical field of preparation and processing of steroid hormone medicines, in particular to a preparation method of progesterone medicine with high efficiency and low pollution.
  • Progesterone also known as progesterone, is a natural progesterone secreted by the corpus luteum of the ovary and is necessary to maintain pregnancy. Progesterone was first isolated and extracted from pregnant urine in 1934, and its structure was determined to be 4-en-3-one pregnane. Progesterone plays an important role in the secretion and transformation of the endometrium, the process of decidualization, the maintenance of the sexual cycle and the maintenance of pregnancy. It can also be used as the main component of female steroid oral contraceptives. It has a wide range of clinical uses.
  • progesterone is also adrenal cortex hormone, male
  • the prodrugs of hormones and estrogen, whose structure is modified, can synthesize many steroid hormone drugs, so the research on progesterone also promotes the development of these fields.
  • the existing progesterone preparation processes are mainly as follows: 1) The currently widely used process is reported in Chinese Patent CN102060901 and "National API Process Compendium", through the chromic anhydride oxidation degradation product of Diosgenin, Pregnocta-5, 16-diene-20-keto-3-ol acetate (dienol ketone acetate) undergoes a three-step reaction of catalytic hydrogenation, alkaline hydrolysis and Wörner’s oxidation to obtain progesterone.
  • the main limitations of this route see below
  • the shortage of yam saponin resources and the large oxidation pollution of chromic anhydride have caused the price of raw materials to rise sharply. Catalytic hydrogenation and Wöhren's oxidation reactions are more difficult to control, and more impurities are prone to be produced and purification is difficult. All these have led to higher and higher production costs of this route,
  • Patent CN103524588 reported that 4-androstenedione was used as a starting material to synthesize progesterone through five-step reactions of hydroxycyanation, dehydration, protection, hydrogenation, and addition hydrolysis. This route (specifically as follows) has long steps and low total yield.
  • the purpose of the present invention is to solve the limitations of high raw material cost, long reaction route, difficult purification, low total yield, and large pollution in the production process in the prior preparation process of progesterone, and to promote the large-scale industrial production of progesterone.
  • the present invention provides a new method for preparing progesterone with high efficiency, simplicity and low pollution.
  • the method uses 21-hydroxy-20-methylpregn-4-en-3-one as starting material and uses TEMPO-NaClO reagent to oxidize Progesterone is prepared through enamination and copper-catalyzed oxidative degradation.
  • the synthetic route of the method is as follows:
  • R 1 and R 2 represent an alkyl group with any carbon number between 1-10, an alkyl group containing N, O atoms,
  • Oxidation reaction step Dissolve 21-hydroxy-20-methylpregna-4-en-3-one as a substrate in an organic solvent, then add oxidation catalyst and buffer in sequence, and then dropwise add sodium hypochlorite aqueous solution. After the reaction is completed under stirring at low temperature of 10 ⁇ 10°C, add sodium thiosulfate aqueous solution to quench the reaction for 2 ⁇ 10 minutes, stand for layering, wash the organic layer until neutral, concentrate, filter, and dry to obtain 20-formyl pregnant Ster-4-en-3-one;
  • step 2) Enamination reaction step: Dissolve the 20-formylpregn-4-en-3-one obtained in step 1) in a solvent, add a secondary organic amine or enamine formed therefrom and an acid catalyst, After the stirring reaction is completed at a heating temperature of 30 to 70°C, the temperature is lowered to -20 to 15°C and filtered to obtain pregna-4-en-3-one-22-enamine;
  • Oxidative degradation reaction step dissolve the pregna-4-en-3-one-22-enamine obtained in step 2) in an organic solvent, add a copper catalyst, and pass in an oxygen-containing mixed gas for oxidation reaction. After the reaction thin layer chromatography analysis under low temperature stirring at -10 to 10°C shows that the conversion of the raw materials is complete, an acid aqueous solution is added, the organic layer is washed, and then washed with water to neutrality, concentrated, filtered, and dried to obtain the product progesterone.
  • the organic solvent described in step 1 is at least one of dichloromethane, dichloroethane, toluene, methyl tert-butyl ether, ethyl acetate, chlorobenzene and chloroform, and its volumetric amount is the substrate 21.
  • -Hydroxy-20-methylpregna-4-en-3-one is 2 to 5 times the weight;
  • the oxidation catalyst is 4-hydroxy-TEMPO or TEMPO, and its weight is the substrate 21-hydroxy-20- 0.01 to 0.03 times the weight of methylpregnancy-4-en-3-one;
  • the weight of the buffer is as much as the weight of the substrate 21-hydroxy-20-methylpregn-4-en-3-one 0.05-0.1 times the amount of potassium bromide, 0.05-0.1 times the amount of sodium bicarbonate and 0.5-1.5 times the amount of water, the volume of the sodium hypochlorite aqueous solution is the substrate 21-hydroxy-20-methylpregna-
  • the weight of 4-en-3-one is 2 to 5 times, and the mass concentration is 5 to 15%;
  • the volumetric dosage of the sodium thiosulfate aqueous solution is the substrate 21-hydroxy-20-methylpregna-4-ene
  • the weight of -3-ketone is 1 to 3 times, and the mass concentration is 5 to
  • the solvent in step 2 is DMF (dimethylformamide), acetonitrile, DMSO (dimethyl sulfoxide), DMAC (dimethylacetamide), DMI (1,3-dimethyl-2- At least one of imidazolinone) and toluene, the volume dosage of which is 0.5-10 times the weight of the substrate 20-formylpregna-4-en-3-one; the organic secondary amine may be formed from it Enamines are ethyleneimine, azacyclobutane, pyrrolidine, piperidine, morpholine, cycloheximine, cycloheptaimine, octamethine imine, cyclononimine, cyclodecimine One kind, there are some other heterocyclic secondary amines or secondary amines with large groups, or the dehydration condensate of the above secondary amines with cyclopentanone, cyclohexanone, cycloheptanone, cyclooct
  • the organic solvent in step 3 is DMF, (dimethylformamide), acetonitrile, DMSO (dimethylsulfoxide), DMAC (dimethylacetamide), DMI (1,3-dimethyl- At least one of 2-imidazolinone), dichloromethane, dichloroethane, toluene, methyl tert-butyl ether, ethyl acetate, chlorobenzene, and chloroform, and the volumetric amount is the substrate pregna-4-ene
  • the weight of -3-keto-22-enamine is 2-10 times;
  • the copper catalyst refers to one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, and the weight amount is the bottom 0.001-0.05 times the weight of pregnost-4-en-3-one-22-enamine;
  • the oxygen-containing mixed gas is a mixed gas with an oxygen volume concentration of 5-100%, and the remaining gas is nitrogen and helium One of
  • the 4-hydroxy-TEMPO is 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxy
  • the TEMPO is 2,2,6,6-tetramethyl Piperidine-1-oxy.
  • the preparation method of the present invention has a mild and safe reaction, and is easy to control and operate;
  • the preparation method of the present invention is simple and convenient to purify, and the total mass yield is higher than 75%;
  • the reagents used in the preparation method of the present invention have little environmental pollution, especially without using chromium-containing highly polluting reagents, such as sodium hypochlorite aqueous solution, which conforms to the industrial development trend of green chemistry and has good economic and social benefits.
  • the residual solid obtained is crystallized with acetone, filtered and dried to obtain 7.8 G progesterone, the obtained progesterone has a melting point of 130.1-131.1°C, an HPLC content of 99.5%, and a total mass yield of 81.5%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de progestérone hautement efficace et faiblement polluant se rapportant au domaine technique de la préparation et du traitement de médicaments à base d'hormones stéroïdes. Le procédé utilise de la 21-hydroxy-20-méthylprégna-4-én-3-one en tant que produit de départ, oxyde celui-ci en un aldéhyde à l'aide d'un réactif TEMPO-NaClO, et soumet l'aldéhyde à une énamination et à une dégradation d'oxydation catalytique du cuivre pour préparer de la progestérone. Le procédé de préparation de la progestérone selon la présente invention présente les avantages suivants : les matières premières et les réactifs sont peu coûteux et facilement disponibles, apportant une compétitivité de marché extrêmement élevée en termes d'investissement d'équipement et de coût de production ; la réaction est modérée et sûre et elle est facile à contrôler et à réaliser ; le rendement de la réaction est élevé et la purification est simple et pratique ; les réactifs utilisés engendrent une faible pollution environnementale et, en particulier, des réactifs hautement polluants contenant du chrome ne sont pas utilisés, ce qui correspond à la tendance au développement de la chimie verte et présente donc de bons avantages économiques et sociaux.
PCT/CN2020/076496 2019-07-21 2020-02-24 Procédé de préparation de progestérone hautement efficace et faiblement polluant WO2021012671A1 (fr)

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CN201910658197.0A CN110437295A (zh) 2019-07-21 2019-07-21 一种高效低污染的黄体酮制备方法
CN201910658197.0 2019-07-21

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Publication number Priority date Publication date Assignee Title
CN110437295A (zh) * 2019-07-21 2019-11-12 浙江神洲药业有限公司 一种高效低污染的黄体酮制备方法
CN112390841B (zh) * 2020-05-25 2021-09-28 浙江神洲药业有限公司 一种黄体酮的纯化方法

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US3661942A (en) * 1969-09-08 1972-05-09 Upjohn Co Novel chemical process
US4257949A (en) * 1979-10-22 1981-03-24 The Upjohn Company Bisnoraldehyde-22-enamine process
CN1137800A (zh) * 1993-12-17 1996-12-11 厄普约翰公司 双降醇至双降醛的转化
CN104109183A (zh) * 2014-07-04 2014-10-22 湖北葛店人福药业有限责任公司 一种合成黄体酮的新工艺
CN106589037A (zh) * 2016-12-22 2017-04-26 浙江仙琚制药股份有限公司 制备黄体酮及其衍生物的方法
CN110437295A (zh) * 2019-07-21 2019-11-12 浙江神洲药业有限公司 一种高效低污染的黄体酮制备方法

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US2601287A (en) * 1949-08-18 1952-06-24 Upjohn Co Partial synthesis of progesterone
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US3661942A (en) * 1969-09-08 1972-05-09 Upjohn Co Novel chemical process
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CN1137800A (zh) * 1993-12-17 1996-12-11 厄普约翰公司 双降醇至双降醛的转化
CN104109183A (zh) * 2014-07-04 2014-10-22 湖北葛店人福药业有限责任公司 一种合成黄体酮的新工艺
CN106589037A (zh) * 2016-12-22 2017-04-26 浙江仙琚制药股份有限公司 制备黄体酮及其衍生物的方法
CN110437295A (zh) * 2019-07-21 2019-11-12 浙江神洲药业有限公司 一种高效低污染的黄体酮制备方法

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