WO2013020460A1 - Procédé de préparation d'atazanavir - Google Patents

Procédé de préparation d'atazanavir Download PDF

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Publication number
WO2013020460A1
WO2013020460A1 PCT/CN2012/079250 CN2012079250W WO2013020460A1 WO 2013020460 A1 WO2013020460 A1 WO 2013020460A1 CN 2012079250 W CN2012079250 W CN 2012079250W WO 2013020460 A1 WO2013020460 A1 WO 2013020460A1
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WO
WIPO (PCT)
Prior art keywords
atazanavir
phenyl
solvent
preparation
monomer
Prior art date
Application number
PCT/CN2012/079250
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English (en)
Chinese (zh)
Inventor
车大庆
朱国良
Original Assignee
浙江九洲药业股份有限公司
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Filing date
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Application filed by 浙江九洲药业股份有限公司 filed Critical 浙江九洲药业股份有限公司
Publication of WO2013020460A1 publication Critical patent/WO2013020460A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom

Definitions

  • the invention belongs to the field of chemical medicine, and particularly relates to a preparation method of atazanavir. Background technique
  • Atazanavir the English name Atazanavir, is an open-chain aza-peptidomimetic compound developed by Bristol-Myers Squibb. It is a novel HIV-1 protease inhibitor with the chemical structure shown in the following formula 1.
  • the product was marketed in the US and Europe on June 20, 2003 and March 2, 2004, respectively.
  • the pharmaceutical ingredient in the marketed dosage form was atazanavir sulfate (trade name: Reyataz).
  • Example 46 is the first disclosure of atazanavir and its preparation method, one of which is a method for preparing atazanavir including the following steps,
  • the compound of formula 2 is treated with the condensing agent 0-(l,2-dihydro-2-oxo-1-pyridyl)-indole, hydrazine, hydrazine, hydrazine, tetramethylphosphonium tetrafluoroborate (TPTU),
  • TPTU tetramethylphosphonium tetrafluoroborate
  • the compound a-(methoxycarbonyl)-(L)-tert-leucine is condensed to obtain the atazanavir monomer of formula 1.
  • the TPTU is very expensive in this method, and it is difficult to obtain an industrial-scale supply, and the separation and extraction steps are complicated and unsuitable for industrial production.
  • the condensing agent may be a carbodiimide such as EDC.
  • Carbodiimides are commonly used activators, but their activation properties are too high for this reaction, resulting in racemization of the amino acids.
  • the patent uses a carbodiimide in combination with a benzotriazole compound, and the benzotriazole compound used is HOBT.
  • HOBT is a dangerous chemical with a high degree of danger.
  • Hazard codes R5 and R11 are very flammable and can cause an explosion due to heating. The transportation is strictly controlled and difficult to obtain, and the method has a large environmental pollution.
  • WO2010146119 discloses a process for using DIC or DCC as a condensing agent alone, without using HOBT, which has improved safety over the above process, but DIC and DCC are still dangerous chemicals, irritating to eyes and skin, The danger of serious eye damage, and DIC is a very toxic chemical.
  • DEPBT is used as a condensing agent, and it is reacted in THF and hydrazine, hydrazine-diisopropylethylamine, and its yield is only 55%.
  • the separation and purification of the product is complicated, and it needs to be separated by a chromatography column, which is not suitable for industrialization. produce.
  • the invention overcomes the defects in the prior art mentioned above, and provides a preparation method of atazanavir which is economical, feasible, safe and environmentally friendly, has high yield, and is easy to separate products.
  • This method will be 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azetane And N-methoxycarbonyl-L-tert-leucine is reacted in the presence of a condensing agent DEPBT to obtain an atazanavir monomer, and the reaction formula is as follows:
  • the atazanavir monomer is prepared by: 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5- Diamino-6-phenyl-2-azahexane is dissolved in an organic solvent, and N-methoxycarbonyl-L-tert-leucine and DEPBT are added, and the reaction is stirred to obtain atazanavir monomer.
  • the organic solvent is a single solvent or a mixed solvent selected from tetrahydrofuran, dichloromethane, chloroform, butanone, triethylamine, N-methylmorpholine or methyl isobutyl ketone.
  • the organic solvent is a mixed solvent selected from the group consisting of dichloromethane, tetrahydrofuran, N-methylmorpholine or triethylamine, more preferably a mixed solvent of dichloromethane and N-methylmorpholine or tetrahydrofuran. Mixed solvent with triethylamine.
  • the reaction is carried out at 20 to 40 ° C, preferably at 28 to 35 ° C.
  • the finished product of atazanavir can be obtained through a post-treatment step.
  • the post-treatment step comprises: adding a base to the reaction solution, concentrating under reduced pressure, adding a crystallization solvent to the residual liquid, and heating and cooling to obtain an atazanavir monomer.
  • the base comprises: an aqueous solution of sodium hydroxide, sodium hydrogencarbonate or sodium carbonate.
  • the crystallization solvent includes a mixed solution of water and methanol, ethanol, isopropanol or a ketone solvent, preferably a mixed solution of ethanol and water.
  • the post-treatment step is: adding a base to the reaction solution, stirring, standing layering, washing the organic layer with water, adding ethanol, concentrating under reduced pressure, adding ethanol and water to the residual liquid, heating to 60 °C, slowly reduce the temperature to about 0 ° C, stir, suction filtration, baking, to obtain solid atazanavir monomer.
  • the compound of the formula 2 is 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2 - azahexane from the compound of formula 3 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxyl -5(S)-2,5-bis[(tert-butoxycarbonyl)amino]-6-phenyl-2-azane was obtained by deprotection reaction in an organic solvent.
  • the protecting group is a tert-butoxycarbonyl group on the amino group.
  • the 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-nitrogen The heterohexane can be prepared by: 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-di[(tert-butoxycarbonyl) Amino] -6-phenyl-2-azahexane is mixed with an organic solvent, and the reaction is kept warm after heating, then the temperature is lowered, the alkali is added, the layer is allowed to stand, and the organic layer is concentrated to obtain 1-[4 - (Pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azanium solid.
  • the organic solvent is selected from a mixed solvent of one or more of tetrahydrofuran, chloroform, methyl ethyl ketone, dichloromethane or methyl isobutyl ketone.
  • the acid includes sulfuric acid, hydrochloric acid, hydrogen chloride, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.
  • the base may be an inorganic base such as an aqueous solution of sodium hydroxide, sodium hydrogencarbonate or sodium carbonate, or an organic base such as pyridine, N-methylmorpholine, triethylamine or diethylamine.
  • inorganic base such as an aqueous solution of sodium hydroxide, sodium hydrogencarbonate or sodium carbonate
  • organic base such as pyridine, N-methylmorpholine, triethylamine or diethylamine.
  • the atazanavir monomer can be reacted with concentrated sulfuric acid to prepare atazanavir sulfate, and the preparation method comprises the following steps: dissolving the atazanavir monomer in an organic solvent, adding a concentrated sulfuric acid solution, incubating the reaction, and cooling the temperature to 0 ⁇ 5 ° C, stirring to get atazanavir sulfate.
  • the organic solvent is acetone, methyl tert-butyl ether, dichloromethane or isopropanol.
  • the invention adopts DEPBT as a condensing agent for synthesizing atazanavir monomer, and has the following advantages over the prior art synthesis process of atazanavir: (1) the price of DEPBT is low, and the reaction requires no other auxiliary materials, and the reaction condition is mild. The equipment and operation requirements are relatively low, and can be carried out at 20 ⁇ 40 °C, which effectively reduces the cost; (2) DEPBT has good safety and produces less pollutants. Environmentally friendly; (3) Operating the cartridge, does not require activation of the carboxylic acid; (4) High product yield, easy to separate and purify, suitable for industrial production. detailed description
  • the invention discloses a preparation method of atazanavir, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method of the present invention has been described by the preferred embodiments, and it is obvious that the method and application described herein can be modified or appropriately modified and combined without departing from the scope of the present invention. Invention technology.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne le domaine des médicaments chimiques. L'invention concerne un procédé de préparation d'Atazanavir, avec une équation réactionnelle telle que représentée dans la figure (I). La présente invention utilise le DEPBT comme agent de condensation; le 1-[4-(pyridine-2-yl)-phényl]-4(S)-hydroxy-5(S)-2, 5-diamino-6- phényl-2-azahexane est mis à réagir avec de la N-méthoxycarbonyl-L-leucine tertiaire dans un solvant organique pour donner l'Atazanavir. L'agent de condensation normalement utilisé dans la réaction dans la littérature existante est le TPTU, une combinaison de composés carbo diimines et de composés benzotriazoles, ou seulement les composés carbo diimines. Cependant, les composés sont coûteux, toxiques et lourdement polluants. La présente invention utilise le DEPBT bon marché, sans danger et écologique comme agent de condensation, et fournit un procédé de préparation d'Atazanavir économiquement réalisable, sans danger et écologique avec un haut rendement et une séparation aisée du produit.
PCT/CN2012/079250 2011-08-05 2012-07-27 Procédé de préparation d'atazanavir WO2013020460A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110223998.8 2011-08-05
CN201110223998.8A CN102911113B (zh) 2011-08-05 2011-08-05 一种阿扎那韦的制备方法

Publications (1)

Publication Number Publication Date
WO2013020460A1 true WO2013020460A1 (fr) 2013-02-14

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CN (1) CN102911113B (fr)
WO (1) WO2013020460A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104356054A (zh) * 2014-09-30 2015-02-18 东北制药集团股份有限公司 一种制备阿扎那韦单体的新方法
CN113603634A (zh) * 2021-08-06 2021-11-05 江苏八巨药业有限公司 一种阿扎那韦中间体的制备方法

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104098509B (zh) * 2013-04-15 2018-04-10 上海迪赛诺化学制药有限公司 一种制备a型阿扎那韦硫酸盐的方法
CN104163787A (zh) * 2014-08-08 2014-11-26 山东威智医药工业有限公司 阿扎那韦及其硫酸盐的制备方法
CN105503705B (zh) * 2014-09-22 2019-06-25 浙江九洲药业股份有限公司 一种阿扎那韦相关物质及其制备方法
CN106588755B (zh) * 2016-12-23 2019-09-13 东北制药集团股份有限公司 一种制备抗艾滋病药物阿扎那韦单体的方法
CN107540603B (zh) * 2017-03-29 2018-09-21 南宁信肽生物技术有限责任公司 阿扎那韦的合成方法
CN107245052A (zh) * 2017-06-21 2017-10-13 连云港杰瑞药业有限公司 一种阿扎那韦制备方法

Citations (2)

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CN1980666A (zh) * 2004-05-04 2007-06-13 布里斯托尔-迈尔斯斯奎布公司 制备阿扎那韦硫酸氢盐的方法和新的形式
CN101039954A (zh) * 2004-10-12 2007-09-19 弗·哈夫曼-拉罗切有限公司 固相肽合成

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US7834043B2 (en) * 2003-12-11 2010-11-16 Abbott Laboratories HIV protease inhibiting compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1980666A (zh) * 2004-05-04 2007-06-13 布里斯托尔-迈尔斯斯奎布公司 制备阿扎那韦硫酸氢盐的方法和新的形式
CN101039954A (zh) * 2004-10-12 2007-09-19 弗·哈夫曼-拉罗切有限公司 固相肽合成

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104356054A (zh) * 2014-09-30 2015-02-18 东北制药集团股份有限公司 一种制备阿扎那韦单体的新方法
CN104356054B (zh) * 2014-09-30 2017-04-19 东北制药集团股份有限公司 一种制备阿扎那韦单体的方法
CN113603634A (zh) * 2021-08-06 2021-11-05 江苏八巨药业有限公司 一种阿扎那韦中间体的制备方法

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CN102911113B (zh) 2015-08-19
CN102911113A (zh) 2013-02-06

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