WO2023126014A1 - Procédé de synthèse d'estrone - Google Patents

Procédé de synthèse d'estrone Download PDF

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Publication number
WO2023126014A1
WO2023126014A1 PCT/CN2023/074486 CN2023074486W WO2023126014A1 WO 2023126014 A1 WO2023126014 A1 WO 2023126014A1 CN 2023074486 W CN2023074486 W CN 2023074486W WO 2023126014 A1 WO2023126014 A1 WO 2023126014A1
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WO
WIPO (PCT)
Prior art keywords
estrone
reaction
weight ratio
synthetic method
add
Prior art date
Application number
PCT/CN2023/074486
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English (en)
Chinese (zh)
Inventor
张峥斌
李纯
尹金玉
张杰锋
刘广源
吴静
吴小芳
Original Assignee
浙江仙居君业药业有限公司
江西君业生物制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江仙居君业药业有限公司, 江西君业生物制药有限公司 filed Critical 浙江仙居君业药业有限公司
Publication of WO2023126014A1 publication Critical patent/WO2023126014A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane

Definitions

  • the invention relates to a preparation method of a steroid compound, in particular to a synthesis method of estrone.
  • Estrone is a natural estrogen in humans and animals, which can maintain the secondary physiological characteristics and normal endocrine system of female individuals. Estrone can be extracted from the urine of pregnant women or pregnant horses, but its content is low and the extraction cost is high.
  • the industry usually uses chemical synthesis.
  • estrone is a synthetic precursor of various estrogens, such as estradiol, estriol, ethinyl estradiol, etc., and is also an important intermediate in the synthesis of 19-norsteroid drugs. Therefore, the chemical synthesis of estrone has been concerned by steroid academia and industry.
  • estrone uses dienes as raw materials, and is synthesized through 7 steps including ketoxime, rearrangement, chlorine purification, cyclization, cyclization hydrolysis, ring opening and bio-fermentation.
  • the production route is long, the source of raw materials is difficult, the synthesis yield is low, and highly toxic substances such as phosphorus oxychloride are used, resulting in a large amount of three wastes, so the total cost of preparing estrone is high.
  • the synthetic route is as follows:
  • the Templteton group reported the synthesis of estrone by using the retro-aldol reaction, using the ring-opened product as a raw material, and undergoing three-step reactions of esterification, dehydrogenation, and aromatization.
  • the yield of each step is not high, and selenium compounds are used in the dehydrogenation reaction, which causes great pollution.
  • a synthetic method for estrone characterized in that: the synthetic method is shown in the following formula
  • the method comprises the following steps:
  • the synthesis method of estrone further includes step 3): adding a recrystallization solvent to the estrone obtained in step 2), heating to reflux for 1-3 hours, cooling to room temperature and continuing to stir for 6 ⁇ 12h, filter, the filter cake is rinsed with recrystallization solvent, and dried to obtain refined estrone.
  • step 1) the weight ratio of described acetic anhydride and 4,9-material is 0.37-2.0, and step 1) described acetyl bromide and 4,9 - The weight ratio of matter is 0.45-2.0.
  • step 1) the weight ratio of said acetic anhydride to 4,9-molecule is 0.4-0.5, and said acetyl bromide in step 1) and 4, The weight ratio of 9-item is 0.6-0.7.
  • the volume-to-weight ratio of the dichloromethane to the 4,9-molecule is 1.5-2.
  • the reaction temperature is 15°C-30°C, and the reaction time is 5-24h. .
  • step 1) lye is added to adjust the pH to 7-8, and the lye is preferably a saturated NaHCO 3 solution.
  • the volume-to-weight ratio of methanol to 4,9-molecule in step 2) is 5-10.
  • the base is KOH, and the weight ratio of base to 4,9-molecule is 0.20-2.0, more preferably 0.4-0.6.
  • the acid is 0.5-2M hydrochloric acid
  • the pH of the system is 5-7, more preferably 6-7.
  • step 2) the volume ratio of water and methanol added is 0.9-2.
  • the synthetic method of described a kind of estrone, further, described recrystallization solvent is ethanol, methanol, acetone or ethyl acetate; 10-15, the volume ratio of the recrystallization solvent for rinsing to the recrystallization solvent for heating and reflux is 0.08-0.16.
  • the synthetic method of a kind of estrone provided by the present invention adopts the cheap 4,9-substance that is supplied in large quantities in the market as the raw material, and can obtain estrone through two steps. Compared with the traditional process, it greatly shortens The reaction steps are simplified, the total reaction yield is high, and harsh conditions such as metal lithium and highly toxic and highly polluting reagents such as phosphorus oxychloride are avoided at the same time, which is beneficial to environmental protection and large-scale production.

Landscapes

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

Abstract

L'invention concerne un procédé de synthèse d'estrone. Le procédé comprend les étapes suivantes consistant à : 1) réaliser une réaction d'aromatisation, mélanger uniformément estra-4,9-diène-3,17-dione, de l'anhydride acétique et du dichlorométhane qui servent de matières premières, ajouter du bromure d'acétyle, puis faire réagir sous protection d'azote, la température de réaction étant de 0 à 50 °C, le temps de réaction étant de 1 à 24 h, après achèvement de la réaction, ajouter une lessive pour réguler le pH à 7 à 9, stratifier et concentrer une phase organique pour obtenir un produit estérifié ; et 2) réaliser une réaction d'hydrolyse, ajouter du méthanol pour disperser le produit estérifié, ajouter un alcali, poursuivre la réaction, la température de réaction étant de 0 à 50 °C, le temps de réaction étant de 1 à 24 h, après achèvement de la réaction, ajouter de l'acide à neutraliser, ajouter de l'eau à du diluant, et filtrer pour obtenir de l'estrone.
PCT/CN2023/074486 2021-12-29 2023-02-04 Procédé de synthèse d'estrone WO2023126014A1 (fr)

Applications Claiming Priority (2)

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CN202111629438.2 2021-12-29
CN202111629438.2A CN114315942B (zh) 2021-12-29 2021-12-29 一种雌酚酮的合成方法

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WO2023126014A1 true WO2023126014A1 (fr) 2023-07-06

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WO (1) WO2023126014A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114315942B (zh) * 2021-12-29 2023-10-17 浙江仙居君业药业有限公司 一种雌酚酮的合成方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3117142A (en) * 1961-03-01 1964-01-07 Roussel Uclaf Novel preparation of estradiol and estrone
CN102603840A (zh) * 2012-02-13 2012-07-25 上海共拓医药化工有限公司 一种17α-雌二醇及其中间体的制备方法
CN102675393A (zh) * 2012-04-09 2012-09-19 浙江仙琚制药股份有限公司 制备19-去甲-4-雄烯二酮的方法
CN105001293A (zh) * 2015-06-10 2015-10-28 浙江仙居君业药业有限公司 雌酚酮的制备方法
CN112225773A (zh) * 2020-11-12 2021-01-15 湖南新合新生物医药有限公司 一种醋酸乌利司他原料药杂质的制备方法
CN114315942A (zh) * 2021-12-29 2022-04-12 浙江仙居君业药业有限公司 一种雌酚酮的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000309599A (ja) * 1999-04-13 2000-11-07 Kyowa Hakko Kogyo Co Ltd エストラ−１，３，５（１０），１６−テトラエン誘導体
US10385093B2 (en) * 2012-12-10 2019-08-20 Northeastern University Estrogen receptor imaging agents
CN107602650B (zh) * 2017-10-16 2019-10-15 中国科学院上海有机化学研究所 一种雌酚酮的合成方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3117142A (en) * 1961-03-01 1964-01-07 Roussel Uclaf Novel preparation of estradiol and estrone
CN102603840A (zh) * 2012-02-13 2012-07-25 上海共拓医药化工有限公司 一种17α-雌二醇及其中间体的制备方法
CN102675393A (zh) * 2012-04-09 2012-09-19 浙江仙琚制药股份有限公司 制备19-去甲-4-雄烯二酮的方法
CN105001293A (zh) * 2015-06-10 2015-10-28 浙江仙居君业药业有限公司 雌酚酮的制备方法
CN112225773A (zh) * 2020-11-12 2021-01-15 湖南新合新生物医药有限公司 一种醋酸乌利司他原料药杂质的制备方法
CN114315942A (zh) * 2021-12-29 2022-04-12 浙江仙居君业药业有限公司 一种雌酚酮的合成方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ADAM HENDRICKS J.; HANSON ROBERT N.; AMOLINS MICHAEL; MIHELCIC JOHN M.; BLAGG BRIAN S.: "Synthesis and preliminary evaluation steroidal antiestrogen–geldanamycin conjug", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 23, no. 12, 4 April 2013 (2013-04-04), Amsterdam NL , pages 3635 - 3639, XP028543376, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2013.03.116 *
POUZAR VLADIMÍR, ČERNÝ IVAN, DRAŠAR PAVEL, HAVEL MIROSLAV: "New method of preparation of cardioglycoside hemisuccinates", COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, vol. 51, no. 9, 1 September 1986 (1986-09-01), pages 2019 - 2028, XP093075728, ISSN: 0010-0765, DOI: 10.1135/cccc19862019 *

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CN114315942B (zh) 2023-10-17

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