WO2014139087A1 - Procédé de racémisation de l'acide propionique chiral de 2-[(4 6-diméthyl-pyrimidine-2-yl]-3-méthoxy-3,3 biphényle - Google Patents

Procédé de racémisation de l'acide propionique chiral de 2-[(4 6-diméthyl-pyrimidine-2-yl]-3-méthoxy-3,3 biphényle Download PDF

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Publication number
WO2014139087A1
WO2014139087A1 PCT/CN2013/072460 CN2013072460W WO2014139087A1 WO 2014139087 A1 WO2014139087 A1 WO 2014139087A1 CN 2013072460 W CN2013072460 W CN 2013072460W WO 2014139087 A1 WO2014139087 A1 WO 2014139087A1
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Prior art keywords
oxy
methoxy
racemization
solvent
diphenylpropionic acid
Prior art date
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Ceased
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PCT/CN2013/072460
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English (en)
Chinese (zh)
Inventor
张福利
金林勇
萧伟
吴泰志
王振中
郭庆明
张军
章晨峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Pharmaceutical Industry
Jiangsu Kanion Pharmaceutical Co Ltd
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Shanghai Institute of Pharmaceutical Industry
Jiangsu Kanion Pharmaceutical Co Ltd
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Application filed by Shanghai Institute of Pharmaceutical Industry, Jiangsu Kanion Pharmaceutical Co Ltd filed Critical Shanghai Institute of Pharmaceutical Industry
Priority to PCT/CN2013/072460 priority Critical patent/WO2014139087A1/fr
Publication of WO2014139087A1 publication Critical patent/WO2014139087A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom

Definitions

  • the present invention relates to the field of chemistry, and in particular to the optically active chiral compound 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropene
  • the method of racemization of acid is a simple compound of chemistry, and in particular to the optically active chiral compound 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropene
  • Ambrisentan is a selective endothelin receptor antagonist developed by Myogen (Gilead's later acquisition of Myogen) and approved by the US FDA on June 19, 2007 under the trade name Letaris.
  • Clinically suitable for the treatment of pulmonary hypertension (PAH) is (+)-(2S)-2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-methoxy-3, 3-diphenylpropionic acid, the structure of which is shown as I:
  • the racemic form of ambrisentan can be resolved by chiral amine, and the separation of the diastereomers in the solvent can be separated by recrystallization.
  • the salt formed by the (S) configuration and the chiral amine has a smaller solubility from the solution, while the mother liquor is 2-[(4,) containing a large number of (R) configurations and a small (S) configuration.
  • the present invention provides a racemization method in which chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-indolyl-3,3-diphenylpropionic acid is subjected to chiralization.
  • the obtained racemic product can be further resolved to obtain the desired (S) configuration to improve the resolution efficiency of ambrisentan, which is of great significance.
  • Summary of the invention provides a racemization method of chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid.
  • chiral 2-[(4,6-diamidylpyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid is added to the solvent, Racemization above the boiling point of the solvent, post-treatment to give 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-indolyl-3,3-diphenylpropionic acid Racemic product.
  • the solvent in the step 1 is selected from the group consisting of a nitrile solvent, an aromatic hydrocarbon solvent, and an alkane-based solvent.
  • the nitrile solvent is preferably acetonitrile or benzoquinone
  • the aromatic solvent is preferably benzene
  • the alkane solvent is preferably dichloromethane
  • the amide solvent such as DMF is partially racerated at 90 °C.
  • Ester solvents such as ethyl acetate, ether solvents such as t-butyl decyl ether, tetrahydrofuran, dioxane (cycloether), ketone solvents such as acetone, alkane solvents such as n-hexane, water and alcohol solvents Neither sterol nor isopropanol can be used for racemization of the process described herein.
  • the solvent may be a mixture of two or more of acetonitrile, benzoquinone, toluene or dichlorosilane or a mixed solvent of acetonitrile, benzoquinone, toluene or dichlorosilane.
  • amphoteric product of ambrisentan can be precipitated from a solvent because the solubility of the amphoteric racemate is much lower than that of a single configuration of ambrisentan.
  • the racemization process can be carried out at 0 ° C to 200 ° C, more preferably 20 ° C to 110 ° C.
  • the chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-indolyl-3,3-diphenylpropionic acid is (S)-2-[(4,6-Dimercaptopyryl-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid, (R)-2-[(4 ,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid or (S)-2-[(4,6-dimercaptopyrimidine-2 -yl)oxy]-3-indolyl-3,3-diphenylpropionic acid and (R)-2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3- A combination of different ratios of decyloxy-3,3-diphenylpropionic acid.
  • the method for racemization of a chiral 2-[(4,6-diamidinopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid provided by the present invention, Adding 2-[(4,6-dimercaptopyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid with high optical rotation value to a specific solvent, specific
  • the mixture is stirred at a temperature for a period of time to undergo racemization, and after treatment, a racemized product having a lower optical rotation value or an optical rotation value of zero is obtained.
  • the method of the invention has high yield, less waste, and is suitable for industrial production. Moreover, it is easy to operate, and can further improve the separation efficiency, effectively improve the atomic economy, and meet the requirements of green chemistry. detailed description
  • the invention discloses a racemization method of chiral 2-[(4,6-diamidylpyrimidin-2-yl)oxy]-3-decyloxy-3,3-diphenylpropionic acid, in the field
  • the technician can learn from the content of this article 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 and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention.
  • the technique of the present invention is applied.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Ce procédé de racémisation de l'acide propionique chiral de 2-[(4 6-diméthyl-pyrimidine-2-yl]-3-méthoxy-3,3 biphényle consiste à ajouter ledit acide à valeur de rotation optique élevée dans un solvant spécifique, à mélanger le tout à une température spécifique pendant un laps de temps court en vue de sa racémisation de manière à obtenir un produit de racémisation à faible valeur de rotation optique ou à valeur de rotation optique nulle.
PCT/CN2013/072460 2013-03-12 2013-03-12 Procédé de racémisation de l'acide propionique chiral de 2-[(4 6-diméthyl-pyrimidine-2-yl]-3-méthoxy-3,3 biphényle Ceased WO2014139087A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2013/072460 WO2014139087A1 (fr) 2013-03-12 2013-03-12 Procédé de racémisation de l'acide propionique chiral de 2-[(4 6-diméthyl-pyrimidine-2-yl]-3-méthoxy-3,3 biphényle

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2013/072460 WO2014139087A1 (fr) 2013-03-12 2013-03-12 Procédé de racémisation de l'acide propionique chiral de 2-[(4 6-diméthyl-pyrimidine-2-yl]-3-méthoxy-3,3 biphényle

Publications (1)

Publication Number Publication Date
WO2014139087A1 true WO2014139087A1 (fr) 2014-09-18

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PCT/CN2013/072460 Ceased WO2014139087A1 (fr) 2013-03-12 2013-03-12 Procédé de racémisation de l'acide propionique chiral de 2-[(4 6-diméthyl-pyrimidine-2-yl]-3-méthoxy-3,3 biphényle

Country Status (1)

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WO (1) WO2014139087A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011004402A2 (fr) * 2009-07-10 2011-01-13 Cadila Healthcare Limited Procédé amélioré de préparation d'ambrisentan et nouveaux intermédiaires associés
CN103012281A (zh) * 2011-09-22 2013-04-03 江苏康缘药业股份有限公司 一种手性2-[(4,6-二甲基嘧啶-2-基)氧基]-3-甲氧基-3,3-二苯基丙酸的消旋化方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011004402A2 (fr) * 2009-07-10 2011-01-13 Cadila Healthcare Limited Procédé amélioré de préparation d'ambrisentan et nouveaux intermédiaires associés
CN103012281A (zh) * 2011-09-22 2013-04-03 江苏康缘药业股份有限公司 一种手性2-[(4,6-二甲基嘧啶-2-基)氧基]-3-甲氧基-3,3-二苯基丙酸的消旋化方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DOUSA, M. ET AL.: "Rapid determination of ambrisentan enantiomers by enantioselective liquid chromatography using cellulose-based chiral stationary phase in reverse phase mode", JOURNAL OF SEPARATION SCIENCE, vol. 35, no. 7, 2012, pages 798 - 803 *
LIU, AIXIA ET AL.: "Improved Synthesis of Ambrisentan", CHEMICAL WORLD, vol. 2, 2011, pages 99 - 102 *
ZHOU, FUGANG ET AL.: "Synthesis of Ambrisentan", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 41, no. 1, 2010, pages 1 - 3 *

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