WO2019129309A1 - Procédé de préparation d'un intermédiaire de dexaméthasone - Google Patents

Procédé de préparation d'un intermédiaire de dexaméthasone Download PDF

Info

Publication number
WO2019129309A1
WO2019129309A1 PCT/CN2019/076373 CN2019076373W WO2019129309A1 WO 2019129309 A1 WO2019129309 A1 WO 2019129309A1 CN 2019076373 W CN2019076373 W CN 2019076373W WO 2019129309 A1 WO2019129309 A1 WO 2019129309A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
compound
dexamethasone intermediate
dexamethasone
preparing
Prior art date
Application number
PCT/CN2019/076373
Other languages
English (en)
Chinese (zh)
Inventor
杨坤
于传云
周健柳
Original Assignee
广西万德药业有限公司
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 广西万德药业有限公司 filed Critical 广西万德药业有限公司
Publication of WO2019129309A1 publication Critical patent/WO2019129309A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals

Definitions

  • the invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of a dexamethasone intermediate.
  • Steroidal drugs are a widely used drug in clinical practice; dexamethasone, alias Desamethasone, and dexamethasone acetate, mainly used for allergic and autoimmune inflammatory diseases, severe bronchial asthma, dermatitis and other allergic diseases. Etc., widely used in medicine, market economy benefits.
  • the substrate is directly reacted with acetone cyanohydrin in an inorganic weak base salt system, and the yield of the cyanidation reaction is low, about 83%, because the 5-CN impurity compound IV is produced during the reaction. More than 14%, resulting in low yield and increased cost. Therefore, it is especially important to control the formation of impurity compound IV during the reaction.
  • the structural formula is as follows:
  • the object of the present invention is to provide a preparation method of a high yield and high purity dexamethasone intermediate, and the specific technical scheme is as follows:
  • a method for preparing a dexamethasone intermediate comprises the following reaction steps:
  • rings A and B represent the following groups:
  • R3 is an ether or an ester residue, and when R3 is an ether residue, R3 is a C1-C2 hydrocarbon group, a C6-C8 aryl group; and when R3 represents an ester residue, it is -COR3;
  • n 2 or 3;
  • R9 is ⁇ -OH or H
  • the cyanation reaction uses Compound I as a raw material, and cyanidation reaction with a cyano compound in a buffer salt system to obtain a compound II;
  • the transposition reaction is a dexamethasone intermediate obtained by transposing a compound II in a weakly basic inorganic salt aqueous solution to obtain a compound III.
  • the cyanation reaction is carried out by adding an organic solvent 1 to a buffer salt system, adding a compound I, stirring uniformly, adding a cyano compound, and monitoring the reaction completely by TLC.
  • the compound II is obtained by water analysis, vacuum filtration, and drying.
  • the transposition reaction is carried out by sequentially adding an organic solvent 2, a compound II in a weakly basic inorganic salt aqueous solution, stirring uniformly, and the heat preservation reaction is completed, and the TLC monitoring reaction is complete. After that, water and water were added to adjust the pH of the reaction system to 6.9-7.2, and the dexamethasone intermediate, Compound III, was obtained by filtration, rinsing and drying.
  • the buffer salt is one of borax-sodium carbonate, boric acid-potassium chloride, borax-boric acid.
  • the cyano compound is one of sodium cyanide, potassium cyanide or acetone cyanohydrin.
  • the organic solvent 1 is methanol, ethanol, or a mixed solvent of methanol, ethanol and tetrahydrofuran.
  • the organic solvent 2 is one of water-soluble solvents such as methanol, ethanol, and acetone.
  • the weakly basic inorganic salt is one of sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate.
  • the molar ratio of the compound I to the cyano compound is 1: (3-5).
  • the cyanation reaction is carried out under the conditions of 15-25 ° C for 15-25 h, preferably at 25-30 ° C.
  • the molar ratio of the compound II to the inorganic salt is 1: (0.18-0.3); and the condition of the transposition reaction is 10 at 50-50 ° C. -15h, preferably the reaction temperature is 25-30 °C.
  • the invention has the following advantages:
  • the present invention synthesizes 17 ⁇ -CN by a buffer salt system, and then synthesizes 17 ⁇ -CN by transposition reaction, thereby effectively controlling the generation of 5-CN impurities during the reaction, and improving the reaction yield and purity. reduce manufacturing cost;
  • reaction of the invention has good stability, is easy to operate, and is suitable for large-scale production.
  • Fig. 1 is a liquid phase diagram of an intermediate of dexamethasone prepared by the transposition reaction of Example 1 of the present invention, that is, Compound III.
  • a method for preparing a dexamethasone intermediate comprises the following reaction steps:
  • rings A and B represent the following groups:
  • R3 is an ether or an ester residue, and when R3 is an ether residue, R3 is a C1-C2 hydrocarbon group, a C6-C8 aryl group; and when R3 represents an ester residue, it is -COR3;
  • n 2 or 3;
  • R9 is ⁇ -OH or H
  • the cyanation reaction uses Compound I as a raw material, and cyanidation reaction with a cyano compound in a buffer salt system to obtain a compound II;
  • the transposition reaction is a dexamethasone intermediate obtained by transposing a compound II in a weakly basic inorganic salt aqueous solution to obtain a compound III.
  • the cyanation reaction is carried out by adding an organic solvent 1 to a buffer salt system, adding a compound I, stirring uniformly, adding a cyano compound, and monitoring the reaction completely by TLC, and crystallization, vacuum filtration, and drying to obtain a compound II. .
  • the transposition reaction is to sequentially add the organic solvent 2, the compound II in the inorganic weak base solution, stir evenly, and the heat preservation reaction is completed.
  • the water is analyzed by adding water and water, and the pH of the reaction system is adjusted to 6.9-7.2, and the filtration is carried out.
  • the dexamethasone intermediate, that is, the compound III, is obtained by rinsing and drying.
  • the buffer salt is one of borax-sodium carbonate, boric acid-potassium chloride, borax-boric acid.
  • the cyano compound is one of sodium cyanide, potassium cyanide or acetone cyanohydrin.
  • the organic solvent 1 is methanol, ethanol, or a mixed solvent thereof with tetrahydrofuran.
  • the organic solvent 2 is one of water-soluble solvents such as methanol, ethanol, and acetone.
  • the weakly basic inorganic salt is one of sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate.
  • the molar ratio of the compound I to the cyano compound is 1: (3-5).
  • the conditions for the cyanation reaction are 15-25 h at 15-50 °C.
  • the conditions of the transposition reaction are 10-15 h at 15-50 °C.
  • the filter cake was rinsed with ice acetone and dried at 40 ° C to obtain 49.4 g of the desired product. Yield: 96.0%, purity 98.5%.
  • the wet cake of the filter cake was added with 100 ml of acetone, and the mixture was stirred at 40 ° C for 0.5 h, and 25 ml of water was added dropwise. Filtration at 25 ° C, the filter cake was rinsed with ice acetone, and the solid was dried at 40 ° C to obtain 20.45 g of the desired product. Yield: 85.2%, purity 98.2%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Toxicology (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'un intermédiaire de dexaméthasone, se rapportant au domaine de la synthèse de principes actifs pharmaceutiques. Le composé I dans un système de sel tampon subit une réaction de cyanure pour synthétiser 17α-CN, et ledit produit subit une réaction de transposition et de réarrangement dans une solution saline faiblement alcaline inorganique pour synthétiser du 17β-CN, c'est-à-dire le composé III. La présente invention utilise un système de sel tampon, par comparaison aux techniques classiques, pour la synthèse de 17α-CN et la réaction de transposition ultérieure pour la synthèse de 17β-CN qui commande de manière efficace la génération d'impuretés de 5-CN pendant les réactions, ce qui permet d'améliorer le rendement et la pureté de la réaction et de réduire le coût de production. La présente invention est appropriée pour une mise à l'échelle industrielle.
PCT/CN2019/076373 2017-12-29 2019-02-27 Procédé de préparation d'un intermédiaire de dexaméthasone WO2019129309A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711483575.3A CN108033990A (zh) 2017-12-29 2017-12-29 地塞米松中间体的制备方法
CN201711483575.3 2017-12-29

Publications (1)

Publication Number Publication Date
WO2019129309A1 true WO2019129309A1 (fr) 2019-07-04

Family

ID=62099058

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/076373 WO2019129309A1 (fr) 2017-12-29 2019-02-27 Procédé de préparation d'un intermédiaire de dexaméthasone

Country Status (2)

Country Link
CN (1) CN108033990A (fr)
WO (1) WO2019129309A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108033990A (zh) * 2017-12-29 2018-05-15 广西万德药业有限公司 地塞米松中间体的制备方法
CN109734762B (zh) * 2018-12-05 2020-04-17 郑良彬 一锅法合成16-β甲基甾体化合物的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991008218A1 (fr) * 1989-11-27 1991-06-13 Schering Corporation Procede de deshydratation d'intermediaires de corticosteroides
CN108033990A (zh) * 2017-12-29 2018-05-15 广西万德药业有限公司 地塞米松中间体的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103641878B (zh) * 2013-11-22 2016-01-06 湖南新合新生物医药有限公司 倍他米松中间体或其类似物的制备方法
CN103910775A (zh) * 2014-03-31 2014-07-09 仙居县圃瑞药业有限公司 17α-羟基黄体酮的合成方法
CN105017377B (zh) * 2015-07-06 2018-02-16 湖南新合新生物医药有限公司 肾上腺皮质激素药物中间体的制备方法
CN105399791B (zh) * 2015-10-27 2017-03-29 江苏远大仙乐药业有限公司 一种倍他米松中间体的制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991008218A1 (fr) * 1989-11-27 1991-06-13 Schering Corporation Procede de deshydratation d'intermediaires de corticosteroides
CN108033990A (zh) * 2017-12-29 2018-05-15 广西万德药业有限公司 地塞米松中间体的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ERCOLI: "An improved method of preparing testosterone, dihydrotestosterone, and some of their esters", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 75, no. 3, 31 December 1953 (1953-12-31), pages 650 - 653, XP002415619, ISSN: 0002-7863, DOI: 10.1021/ja01099a040 *
MEYER ET AL.: "Glucosides and aglucons. XIII. Methyl ester of 3(beta)-aceto- xy-16-etiocholenic acid from gitoxigenin", HELVETICA CHIMICA ACTA, 31 December 1946 (1946-12-31) *

Also Published As

Publication number Publication date
CN108033990A (zh) 2018-05-15

Similar Documents

Publication Publication Date Title
JP2019510128A (ja) スガマデクスの調製のための改善されたプロセス
CN106256824B (zh) 一种高纯度德拉沙星葡甲胺盐的制备方法
EP2462098B1 (fr) Procédé de préparation de dérivés d'acides de 1-(2-halobiphényl-4-yl)-cyclopropane carboxylique
CN103570696B (zh) 一种阿西替尼中间体的制备方法以及在制备阿西替尼中的应用
WO2019129309A1 (fr) Procédé de préparation d'un intermédiaire de dexaméthasone
WO2017096996A1 (fr) Procédé de préparation de cobimetinib
US10538507B2 (en) Preparation process for high-purity dabigatran etexilate
EP2921473B1 (fr) Composé 1-cyano-1-(7-méthoxy-1-naphtyl) méthanol ester et procédé de préparation et utilisation correspondants
WO2023174449A1 (fr) Procédé de préparation de n-(3-chloro-4-(2-pyridylméthoxy)phényl)-2-cyanoacétamide
WO2018010651A1 (fr) Procédé de fabrication d'acide obéticholique et de ses intermédiaires
CN110790809B (zh) 一种醋酸阿比特龙的制备方法
CN107266304B (zh) 天然产物Salvianolic Acid F的新合成方法
WO2018121050A1 (fr) Procédé de préparation d'ester méthylique d'acide 3-cyano-4-hydroxybenzoïque
WO2018121051A1 (fr) Méthode de préparation de 3-cyano-4-isopropoxybenzoate de méthyle
CN108047296B (zh) 一种倍他米松中间体的制备方法
JP6670744B2 (ja) ヒオデオキシコール酸ナトリウム（ＮａＨＤＣ）の多形形態およびその調製方法
CN111454315B (zh) 一种雄甾-16-烯-3β-醇的合成方法
CN104803846B (zh) 制备双[4-(6-丙烯酰氧己基)苯基]环己烷-1,4-二羧酸酯的方法
JPH07503008A (ja) ３−アシルエストラトリエンおよびアシルベンゼンの製造方法
JPS63258487A (ja) １７α−エチニル−１７β−ヒドロキシ−１８−メチル−４，１５−エストラジエン−３−オンの製造方法、及びこの方法の中間生成物
CN108203455B (zh) 一种双氢非那雄胺碘化物脱碘制备非那雄胺的方法
WO2015184798A1 (fr) Procédé de préparation de phényl glycine à substitution n
CN109942659B (zh) 倍他米松中间体的合成方法
WO2018168899A1 (fr) Procédé de production d'un dérivé de benzimidazole
JP3773064B2 (ja) フェノキシアルキルカルボン酸誘導体の製造法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19733932

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19733932

Country of ref document: EP

Kind code of ref document: A1