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WO2019034094A1 - Procédé de préparation d'un composé alcoolique - Google Patents

Procédé de préparation d'un composé alcoolique Download PDF

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Publication number
WO2019034094A1
WO2019034094A1 PCT/CN2018/100730 CN2018100730W WO2019034094A1 WO 2019034094 A1 WO2019034094 A1 WO 2019034094A1 CN 2018100730 W CN2018100730 W CN 2018100730W WO 2019034094 A1 WO2019034094 A1 WO 2019034094A1
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WO
WIPO (PCT)
Prior art keywords
reaction
formula
compound
organic solvent
combination
Prior art date
Application number
PCT/CN2018/100730
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English (en)
Chinese (zh)
Inventor
刘勇军
王仲清
廖守主
罗忠华
Original Assignee
东莞东阳光药物研发有限公司
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 东莞东阳光药物研发有限公司 filed Critical 东莞东阳光药物研发有限公司
Priority to CN201880052089.2A priority Critical patent/CN111065627B/zh
Publication of WO2019034094A1 publication Critical patent/WO2019034094A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a preparation method of an alcohol compound, and belongs to the technical field of pharmacy.
  • Selexipag is an oral prostacyclin receptor agonist that relaxes smooth muscle wall of blood vessels, dilates blood vessels, reduces pulmonary artery pressure, and is clinically used for the treatment of pulmonary hypertension in adults. As shown below:
  • the present invention provides a process for preparing a compound of the formula (1), which can be easily obtained by subjecting a raw material amine compound and an acid halide compound to an amidation reaction, followed by a reduction reaction, an esterification reaction, and a hydrolysis reaction. product.
  • the invention provides a novel intermediate compound for use in the preparation of a compound of formula (1).
  • the present invention provides a process for preparing a compound of the formula (1), which comprises: hydrolyzing a compound of the formula (2) in an organic solvent under the addition of a base to obtain a compound of the formula (1) ,
  • R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl or phenyl.
  • R 1 is methyl. In some embodiments, R 1 is ethyl.
  • the base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, or at least one of them.
  • the base is sodium hydroxide.
  • the base is potassium hydroxide.
  • the organic solvent is ethanol, methanol, isopropanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran. (THF), 2-methyltetrahydrofuran, or a combination thereof.
  • DMSO dimethyl sulfoxide
  • DMF dimethylacetamide
  • THF tetrahydrofuran
  • 2-methyltetrahydrofuran or a combination thereof.
  • the organic solvent is methanol, ethanol, or a combination thereof to facilitate reaction and processing.
  • the organic solvent is dimethyl sulfoxide, which facilitates reaction and processing.
  • a method for preparing a compound of the formula (1) comprising: hydrolyzing a compound of the formula (2) in an organic solvent under the addition of a base to obtain a formula (1) Compound,
  • R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or phenyl;
  • the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or a hydrate thereof, or a combination thereof;
  • the organic solvent is ethanol, methanol, isopropanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dimethylacetamide (DMAc) ), tetrahydrofuran (THF), 2-methyltetrahydrofuran, or a combination thereof.
  • a method for preparing a compound of the formula (1) comprising: hydrolyzing a compound of the formula (2) in an organic solvent under the addition of a base to obtain a formula (1) Compound,
  • R 1 is a methyl group or an ethyl group
  • the base is sodium hydroxide, potassium hydroxide, or a combination thereof
  • the organic solvent is methanol, ethanol, dimethyl sulfoxide (DMSO), or a combination thereof.
  • the reaction temperature can be controlled to be from 0 ° C to 80 ° C. In some embodiments, in the hydrolysis reaction, the reaction temperature is controlled to room temperature to 80 °C. In some embodiments, in the hydrolysis reaction, the reaction temperature is controlled to be 35 ° C to 70 ° C. In some embodiments, in the hydrolysis reaction, the reaction temperature is controlled to be 40 ° C to 60 ° C to facilitate the product.
  • the compound of the formula (1) obtained by the method provided by the present invention can be directly used in the next reaction, or can be used in the next reaction after purification by washing, crystallization and/or column chromatography.
  • the compound of the formula (2) can be obtained by esterification of a compound represented by the formula (3) with a carboxylate in an organic solvent at a certain temperature:
  • X 1 is chlorine, bromine or iodine
  • R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or phenyl.
  • the carboxylate may be a sodium carboxylate or a potassium carboxylate.
  • the carboxylate is potassium acetate, which facilitates reaction and processing.
  • the carboxylate is sodium acetate.
  • the carboxylate is sodium formate.
  • the carboxylate is potassium formate.
  • the organic solvent may be dimethyl sulfoxide, DMF, DMAc, ethanol, methanol, tetrahydrofuran or a combination thereof.
  • the organic solvent is dimethyl sulfoxide to facilitate the reaction.
  • the reaction temperature may be from room temperature to 120 °C.
  • the compound of formula (2) can be prepared by esterification of a compound of formula (3) with a carboxylate in an organic solvent at a temperature:
  • X 1 is chlorine, bromine or iodine
  • R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or phenyl
  • the carboxylate may be a carboxylic acid a sodium salt or a potassium salt
  • the organic solvent may be dimethyl sulfoxide, DMF, DMAc, ethanol, methanol, tetrahydrofuran or a combination thereof; the reaction temperature is from room temperature to 120 °C.
  • the reaction temperature is from 40 ° C to 120 ° C. In the above esterification reaction, in some embodiments, the reaction temperature is from 60 ° C to 100 ° C, which is advantageous for reaction control and progress.
  • the compound of formula (2) is prepared by esterification of a compound of formula (3) with a carboxylate in an organic solvent at a temperature:
  • X 1 is chlorine or bromine
  • R 1 is hydrogen or methyl
  • the carboxylate is potassium acetate
  • the organic solvent is dimethyl sulfoxide
  • the reaction temperature is from 60 ° C to 100 ° C.
  • the compound of formula (2) is prepared by esterification of a compound of formula (3) with a carboxylate in an organic solvent at a temperature:
  • X 1 is chlorine, R 1 is methyl; the carboxylate is potassium acetate; the organic solvent is dimethyl sulfoxide; and the reaction temperature is from 60 ° C to 100 ° C.
  • the compound of the formula (2) prepared according to the method of the present invention can be directly used in the next reaction, or can be used in the next reaction after purification by washing, crystallization and/or column chromatography.
  • the compound represented by the formula (3) can be produced by a reduction reaction of a compound represented by the formula (4) under a reducing agent and a Lewis acid in an organic solvent at a certain temperature:
  • X 1 is chlorine, bromine or iodine.
  • the reducing agent may be lithium aluminum hydride, sodium borohydride or potassium borohydride, or a combination thereof.
  • the Lewis acid may be aluminum trichloride, zinc chloride, iron chloride, cobalt chloride, or a combination thereof. In some embodiments, the Lewis acid is aluminum trichloride, facilitating the reaction to proceed and the product.
  • the organic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, methyl tert-butyl ether or ethylene glycol dimethyl ether, or a combination thereof.
  • the organic solvent for the reduction reaction is tetrahydrofuran or 2-methyltetrahydrofuran or a combination thereof to facilitate the reaction and the product.
  • the reaction temperature of the reduction reaction may be from -25 ° C to 50 ° C. In some embodiments, the reaction temperature of the reduction reaction is from -25 °C to 40 °C. In some embodiments, the reaction temperature of the reduction reaction is from -25 °C to 30 °C. In some embodiments, the reaction temperature of the reduction reaction is from -20 °C to 40 °C. In some embodiments, the reaction temperature of the reduction reaction is from -20 °C to 30 °C. In some embodiments, the reaction temperature of the reduction reaction is from 0 °C to 30 °C. In some embodiments, the reaction temperature of the reduction reaction is from -20 °C to 5 °C.
  • the compound of the formula (3) is prepared by a reduction reaction of a compound of the formula (4) by adding a reducing agent and a Lewis acid in an organic solvent at a certain temperature:
  • the X 1 is chlorine, bromine or iodine;
  • the reducing agent is lithium tetrahydrogen aluminum, sodium borohydride or potassium borohydride, or a combination thereof;
  • the Lewis acid may be aluminum trichloride, zinc chloride, Iron chloride, cobalt chloride, or a combination thereof;
  • the organic solvent for the reaction is tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, methyl tert-butyl ether or ethylene glycol dimethyl ether, or a combination thereof; reaction temperature It is -25 ° C - 50 ° C.
  • the compound of the formula (3) is prepared by a reduction reaction of a compound of the formula (4) by adding a reducing agent and a Lewis acid in an organic solvent at a certain temperature:
  • the X 1 is chlorine or bromine;
  • the reducing agent is sodium borohydride or potassium borohydride, or a combination thereof;
  • the Lewis acid is aluminum trichloride, zinc chloride or ferric chloride, or a combination thereof;
  • the organic solvent for the reaction is tetrahydrofuran, 2-methyltetrahydrofuran or a combination thereof; the reaction temperature is -25 ° C to 30 ° C.
  • the compound of the formula (3) obtained by the method of the present invention can be directly used in the next reaction, or can be used in the next reaction after purification by washing, crystallization, and/or column chromatography.
  • the compound represented by the formula (4) can be produced by subjecting the compound represented by the formula (5) and the compound of the formula (01) to an amidation reaction at a certain temperature under an alkali condition in an organic solvent:
  • X 1 is chlorine, bromine or iodine; and X is chlorine, bromine or iodine.
  • the organic solvent may be toluene, xylene, THF, 2-methyltetrahydrofuran, DMF, DMAc, ethylene glycol dimethyl ether (DME), or a combination thereof.
  • the organic solvent in the amidation reaction, is toluene, DMF, ethylene glycol dimethyl ether (DME), or a combination thereof.
  • the base may be 1,8-diazabicycloundec-7-ene (DBU), triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP). ), N-methylmorpholine (NMM), potassium carbonate, sodium carbonate or a combination thereof.
  • the base in the amidation reaction, is 1,8-diazabicycloundec-7-ene (DBU), triethylamine, diisopropylethylamine, 4-di Methylaminopyridine (DMAP), N-methylmorpholine (NMM) or a combination thereof.
  • the base in the amidation reaction, is 1,8-diazabicycloundec-7-ene (DBU), triethylamine, diisopropylethylamine, 4-di Methylaminopyridine (DMAP), N-methylmorpholine (NMM) or a combination thereof.
  • DBU 1,8-diazabicycloundec-7-ene
  • DMAP 4-di Methylaminopyridine
  • NMM N-methylmorpholine
  • the reaction temperature may be from room temperature to 100 °C.
  • the compound of the formula (4) is prepared by amidating a compound of the formula (5) and a compound of the formula (01) in an organic solvent under a base condition at a certain temperature.
  • X 1 is chlorine, bromine or iodine; the X is chlorine, bromine or iodine; the organic solvent may be toluene, THF, 2-methyltetrahydrofuran, DMF, DMAc, ethylene glycol dimethyl ether ( DME), or a combination thereof; the base may be 1,8-diazabicycloundec-7-ene (DBU), triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), potassium carbonate, sodium carbonate or a combination thereof; the reaction temperature is from room temperature to 100 °C.
  • DBU 1,8-diazabicycloundec-7-ene
  • DMAP diisopropylethylamine
  • NMM N-methylmorpholine
  • the reaction temperature is from room temperature to 100 °C.
  • the compound of the formula (4) is prepared by amidating a compound of the formula (5) and a compound of the formula (01) in an organic solvent under a base condition at a certain temperature.
  • X 1 is chlorine or bromine
  • X is chlorine or bromine
  • the organic solvent is toluene, xylene or a combination thereof
  • the base is 1,8-diazabicycloundec-7 -ene (DBU); the temperature of the reaction is from room temperature to 100 °C.
  • the compound of the formula (4) obtained by the method of the present invention can be directly used in the next reaction, or can be used in the next reaction after purification by washing, crystallization, and/or column chromatography.
  • the invention provides novel intermediate compounds which can be used in the preparation of compounds of formula (1).
  • R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl or phenyl.
  • the compound of formula (2) has the structure:
  • X 1 is chlorine, bromine or iodine. In some embodiments, X 1 is chlorine or bromine. In some embodiments, X 1 is chlorine.
  • the compound of formula (4) has the structure:
  • the invention provides a method for preparing the compound of the formula (1), which is cheap and easy to obtain, has high yield, mild reaction condition, simple operation and convenient industrial production, and is also provided for preparing the formula (1).
  • a novel intermediate compound of the compound, which is easy to prepare, can simplify the process for preparing the compound represented by the formula (1), and can be used in industrial production.
  • reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
  • room temperature refers to an ambient temperature of 15 ° C to 38 ° C or 20 ° C to 35 ° C or 20 ° C to 30 ° C.
  • X is chlorine
  • X 1 is chlorine
  • R 1 is a methyl group.
  • the target product is prepared by the method of the following examples.
  • the compound of the formula (5) can be produced by a known method such as the method in the patent application CN106316967.
  • the organic layer was washed twice with 30 mL of water, and the organic layer was concentrated to give 6 g of crude material,
  • the compound represented by the formula (4) has a yield of 88.2% and a purity of 97.96%.
  • the obtained crude product can be subjected to silica gel column chromatography, and the mixture of ethyl acetate and petroleum ether in a volume ratio of 1:9 is used as an eluent, and can also be directly used in the next step.
  • the obtained crude product can be directly used for the next reaction, or can be subjected to silica gel column chromatography, and a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10 is used as an eluent.
  • reaction vessel To the reaction vessel were added 12 g of the compound of the formula (4), 110 mL of tetrahydrofuran and 2.9 g of sodium borohydride, and the mixture was cooled to -15 ° C with stirring, and 5.3 g of aluminum trichloride was added thereto, and stirring was continued at -15 ° C for 24 hours, and the reaction was completed.
  • the reaction was quenched by adding 10 mL of water, and then a mixture of 6.5 g of sodium hydroxide and 40 mL of water was added, and then stirred at room temperature for 0.5 h, and the mixture was allowed to stand for separation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation d'un composé alcoolique, comprenant les étapes consistant à soumettre des matières premières, à savoir un composé amine et un composé halogénure d'acide, à une réaction d'amidation, à une réaction de réduction, à une réaction d'estérification et/ou à une réaction d'hydrolyse pour obtenir le produit cible.
PCT/CN2018/100730 2017-08-17 2018-08-16 Procédé de préparation d'un composé alcoolique WO2019034094A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880052089.2A CN111065627B (zh) 2017-08-17 2018-08-16 一种醇化合物的制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710705973 2017-08-17
CN201710705973.9 2017-08-17

Publications (1)

Publication Number Publication Date
WO2019034094A1 true WO2019034094A1 (fr) 2019-02-21

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279047A (zh) * 2015-05-13 2017-01-04 上海适济生物科技有限公司 一种前列环素受体激动剂的制备方法
CN106316967A (zh) * 2016-08-19 2017-01-11 上海艾康睿医药科技有限公司 西里帕格中间体及西里帕格的制备方法
WO2017029594A1 (fr) * 2015-08-17 2017-02-23 Dr. Reddy's Laboratories Limited Procédés de préparation de selexipag et de sa forme amorphe
WO2017042828A2 (fr) * 2015-09-10 2017-03-16 Megafine Pharma (P) Ltd. Procédé de préparation de sélexipag et intermédiaires de ce dernier
WO2017060827A1 (fr) * 2015-10-07 2017-04-13 Lupin Limited Procédé amélioré pour la préparation de sélexipag ou de ses sels pharmaceutiquement acceptables

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102014112747A1 (de) * 2014-09-04 2016-03-10 Eberhard Karls Universität Tübingen Medizinische Fakultät Verwendung eines Quinoxalinderivats in einem bildgebenden Verfahren

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279047A (zh) * 2015-05-13 2017-01-04 上海适济生物科技有限公司 一种前列环素受体激动剂的制备方法
WO2017029594A1 (fr) * 2015-08-17 2017-02-23 Dr. Reddy's Laboratories Limited Procédés de préparation de selexipag et de sa forme amorphe
WO2017042828A2 (fr) * 2015-09-10 2017-03-16 Megafine Pharma (P) Ltd. Procédé de préparation de sélexipag et intermédiaires de ce dernier
WO2017060827A1 (fr) * 2015-10-07 2017-04-13 Lupin Limited Procédé amélioré pour la préparation de sélexipag ou de ses sels pharmaceutiquement acceptables
CN106316967A (zh) * 2016-08-19 2017-01-11 上海艾康睿医药科技有限公司 西里帕格中间体及西里帕格的制备方法

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CN111065627A (zh) 2020-04-24

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