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WO2023083247A1 - Composé intermédiaire de quinoxaline et son procédé de préparation - Google Patents

Composé intermédiaire de quinoxaline et son procédé de préparation Download PDF

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WO2023083247A1
WO2023083247A1 PCT/CN2022/131086 CN2022131086W WO2023083247A1 WO 2023083247 A1 WO2023083247 A1 WO 2023083247A1 CN 2022131086 W CN2022131086 W CN 2022131086W WO 2023083247 A1 WO2023083247 A1 WO 2023083247A1
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combination
compound
alkyl
butyl
halogen
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Jie Liu
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4b Technologies Beijing Co Ltd
4b Technologies Suzhou Ltd
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4b Technologies Beijing Co Ltd
4b Technologies Suzhou Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
    • 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 present application disclosure is related to a drug intermediate synthesis field, particular to an intermediate of quinoxaline and its preparation method.
  • Receptor tyrosine kinase is a multi-group transmembrane protein that acts on receptors for cytokines, growth factors, hormones and other signal molecules.
  • Receptor tyrosine kinases are a larger part of the family of protein tyrosine kinases.
  • WO2018071348A1 discloses a quinoxaline compound as a type III receptor tyrosine kinase inhibitor and a preparation method thereof, wherein the synthesis process of the intermediate is disclosed as follows:
  • This process utilizes intermediate 2-chloro-substituted quinoxaline (25/27) and nucleophile (alcohol or amine) to undergo nucleophilic substitution reaction under alkaline conditions to prepare intermediate (26/28) .
  • the intermediate 25/27 is prepared by reacting 7-chloro-substituted quinoxalinone with phosphoryl chloride, and POCl 3 is used in the reaction process, thereby generating a large amount of phosphorus-containing harmful wastewater.
  • the inventor of this application found that when using 2-position halogen-substituted quinoxaline as a substrate for nucleophilic substitution, on one hand, there is halogen instability, and OH is easily formed during the reaction. On the other hand, serious side reactions and cumbersome separation lead to a decrease in the yield.
  • the present application provides a novel intermediate, its preparation method and its preparation method as a type III receptor tyrosine kinase inhibitor quinoxaline compound.
  • the process of the present application has the following beneficial effects: the method of the present application uses substituted 1, 2-diaminobenzene and glyoxylic acid to prepare 3-hydroxyquinoxaline derivative intermediates, and uses the intermediates to produce nucleophilic substitution reaction raw materials, which solves the problem of using halogens in the prior art.
  • the problem of instability when leaving the group it can reduce the side reaction products, and at the same time avoid the use of phosphoryl chloride as a chlorinating reagent, prevent the production of a large amount of phosphorus-containing harmful waste water during the production process, and can effectively improve the reaction yield, improve environmental friendliness.
  • a method which is comprised by the following steps:
  • reaction process is comprised by the following step: intermediate (A) and compound (B) are reacted in a solvent under alkaline/condensing agent conditions to prepare the compound (I) ,
  • P is selected from a hydroxyl protecting group
  • X is selected from a leaving group
  • R 1 , R 2 and R 3 each independently is selected from hydrogen, (C 1 -C 6 ) alkyl, cyano, nitro, hydroxyl, halogen, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, NR a R b , -OS (O) 2 R a , -SO 2 NR a R b , -NR a COR a , or -NR a SO 2 R a ,
  • W is selected from CR a R b , O, S or NR a ,
  • R a and R b each independently is selected from hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, benzyl, or (C 6 -C 10 ) aryl.
  • X is selected from halogen.
  • X is selected from F, Cl or Br.
  • P is selected from (C 1 -C 6 ) alkylaminosulfonyl, (C 3 -C 6 ) cycloalkylaminosulfonyl, (C 6 -C 10 ) arylaminosulfonyl, (C 1 -C 6 ) alkylphosphoryl, (C 3 -C 6 ) cycloalkylphosphoryl, (C 6 -C 10 ) arylphosphoryl, (C 1 -C 6 ) alkylsulfonyl, (C 3 -C 6 ) cycloalkylsulfonyl or (C 6 -C 10 ) arylsulfonyl, wherein the said alkyl, cycloalkyl, aryl can be optionally substituted with a substituent selected from 0, 1, 2, 3 of the following groups: halogen, hydroxy, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloal
  • P is selected from phenylsulfonyl, phenylaminosulfonyl, phenylphosphoryl, phenylsulfonyl, methylsulfonyl, methylaminosulfonyl, or cyclopropylsulfonyl, wherein, the phenylsulfonyl, phenylamino Sulfonyl, phenylphosphoryl, and phenylsulfonyl groups can be optionally substituted with 0, 1, 2, or 3 selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, hydroxyl, nitro, halogen, cyano, amino, or -SO 3 H.
  • R 1 is selected from cyano
  • R 2 and R 3 is independently selected from H.
  • P is selected from benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl or cyclopropylsulfonyl.
  • W is selected from CH 2 , NH or O.
  • R a and R b are each independently selected from hydrogen, or (C 1 -C 6 ) alkyl.
  • the alkaline is selected from an organic base or an inorganic base
  • the organic base is selected from triethylamine, N, N-diisopropylethylamine, sodium tert-butyl, potassium tert-butyl, sodium ethoxide, sodium methoxide or any combination thereof
  • the inorganic base is selected from NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KHCO 3 , Cs 2 CO 3 or any combination thereof.
  • the solvent is selected from H 2 O, ethanol, methanol, DMSO, THF, DMF, dioxane, chloroform, acetone, carbon tetrachloride, methylene chloride or any combination thereof.
  • the condensing agent is selected from the group consisting of dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) , 4-dimethylaminopyridine (DMAP) or any combination thereof.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • reaction process is comprised by the following step: compound (II) and compound (III) are reacted in a solvent under alkaline/condensing agent conditions to prepare the intermediate A,
  • P is selected from a hydroxyl protecting group
  • X is selected from a leaving group
  • R 1 , R 2 and R 3 each independently is selected from hydrogen, (C 1 -C 6 ) alkyl, cyano, nitro, hydroxyl, halogen, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, NR a R b , -OS (O) 2 R a , -SO 2 NR a R b , -NR a COR a , or -NR a SO 2 R a ,
  • R a and R b each independently is selected from hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, benzyl, or (C 6 -C 10 ) aryl.
  • Y is selected from an active group that can react with OH.
  • X is selected from halogen.
  • X is selected from F, Cl or Br.
  • P is selected from (C 1 -C 6 ) alkylaminosulfonyl, (C 3 -C 6 ) cycloalkylaminosulfonyl, (C 6 -C 10 ) arylaminosulfonyl, (C 1 -C 6 ) alkylphosphoryl, (C 3 -C 6 ) cycloalkylphosphoryl, (C 6 -C 10 ) arylphosphoryl, (C 1 -C 6 ) alkylsulfonyl, (C 3 -C 6 ) cycloalkylsulfonyl or (C 6 -C 10 ) arylsulfonyl, wherein the said alkyl, cycloalkyl, aryl can be optionally substituted with a substituent selected from 0, 1, 2, or 3 of the following groups: halogen, hydroxy, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cyclo
  • P is selected from phenylsulfonyl, phenylaminosulfonyl, phenylphosphoryl, phenylsulfonyl, methylsulfonyl, methylaminosulfonyl, or cyclopropylsulfonyl, wherein, the phenylsulfonyl, phenylamino Sulfonyl, phenylphosphoryl, and phenylsulfonyl groups can be optionally substituted with 0, 1, 2, or 3 selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, hydroxyl, nitro, halogen, cyano, amino, or -SO 3 H.
  • R 1 is selected from cyano
  • R 2 and R 3 is independently selected from H.
  • P is preferably selected from benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl or cyclopropylsulfonyl.
  • R a and R b each independently is selected from hydrogen, or (C 1 -C 6 ) alkyl.
  • Y is selected from halogen (for example, F, Cl, Br) .
  • the alkaline is selected from an organic base or an inorganic base
  • the organic base is selected from triethylamine, N, N-diisopropylethylamine, sodium tert-butyl, potassium tert-butyl, sodium ethoxide, sodium methoxide or any combination thereof
  • the inorganic base is selected from NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KHCO 3 , Cs 2 CO 3 or any combination thereof.
  • the solvent is selected from H 2 O, ethanol, methanol, DMSO, THF, DMF, dioxane, chloroform, acetone, carbon tetrachloride, methylene chloride or any combination thereof.
  • the condensing agent is selected from the group consisting of dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) , 4-dimethylaminopyridine (DMAP) or any combination thereof.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • P is selected from a hydroxyl protecting group
  • X is selected from a leaving group
  • R 1 , R 2 and R 3 each independently is selected from hydrogen, (C 1 -C 6 ) alkyl, cyano, nitro, hydroxyl, halogen, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, NR a R b , -OS (O) 2 R a , -SO 2 NR a R b , -NR a COR a , or -NR a SO 2 R a ,
  • W is selected froms CR a R b , O, S or NR a ,
  • R a and R b are each independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, benzyl, or (C 6 -C 10 ) aryl.
  • Y is selected from an active group that can react with OH
  • step (I) includes: compound (II) and compound (III) are reacted in a solvent under alkaline/condensing agent conditions to prepare the intermediate A,
  • step (II) includes: intermediate (A) and compound (B) are reacted in a solvent under alkaline/condensing agent conditions to prepare the compound (I) .
  • X is selected from halogen.
  • X is selected from F, Cl or Br.
  • Y is selected from halogen (for example, F, Cl, Br) .
  • P is selected from (C 1 -C 6 ) alkylaminosulfonyl, (C 3 -C 6 ) cycloalkylaminosulfonyl, (C 6 -C 10 ) arylaminosulfonyl, (C 1 -C 6 ) alkylphosphoryl, (C 3 -C 6 ) cycloalkylphosphoryl, (C 6 -C 10 ) arylphosphoryl, (C 1 -C 6 ) alkylsulfonyl, (C 3 -C 6 ) cycloalkylsulfonyl or (C 6 -C 10 ) arylsulfonyl, wherein the said alkyl, cycloalkyl, aryl can be optionally substituted with a substituent selected from 0, 1, 2, or 3 of the following groups: halogen, hydroxy, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cyclo
  • P is selected from phenylsulfonyl, phenylaminosulfonyl, phenylphosphoryl, phenylsulfonyl, methylsulfonyl, methylaminosulfonyl, or cyclopropylsulfonyl, wherein, the phenylsulfonyl, phenylamino Sulfonyl, phenylphosphoryl, and phenylsulfonyl groups can be optionally substituted with 0, 1, 2, or 3 selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, hydroxyl, nitro, halogen, cyano, amino, or -SO 3 H.
  • R 1 is selected from cyano
  • R 2 and R 3 are each independently selected from H.
  • P is selected from benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl or cyclopropylsulfonyl.
  • W is selected from CH 2 , NH or O.
  • R a and R b each independently is selected from hydrogen, or (C 1 -C 6 ) alkyl.
  • Y is selected from halogen (for example, F, Cl, Br) .
  • the alkaline in step (I) is selected from an organic base or an inorganic base
  • the organic base is selected from triethylamine, N, N-diisopropylethylamine, sodium tert-butyl, potassium tert-butyl, sodium ethoxide, sodium methoxide or any combination thereof
  • the inorganic base is selected from NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KHCO 3 , Cs 2 CO 3 or any combination thereof.
  • the solvent in step (I) is selected from H2O, ethanol, methanol, DMSO, THF, DMF, dioxane, chloroform, acetone, carbon tetrachloride, methylene chloride or any combination thereof.
  • the condensing agent in step (I) is selected from the group consisting of dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) , 4- dimethylaminopyridine (DMAP) or any combination thereof.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
  • DMAP 4- dimethylaminopyridine
  • the alkaline in step (II) is selected from an organic base or an inorganic base
  • the organic base is selected from triethylamine, N, N-diisopropylethylamine, sodium tert-butyl, potassium tert-butyl, sodium ethoxide, sodium methoxide or any combination thereof
  • the inorganic base is selected from NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KHCO 3 , Cs 2 CO 3 or any combination thereof.
  • the solvent in step (I) is selected from H 2 O, ethanol, methanol, DMSO, THF, DMF, dioxane, chloroform, acetone, carbon tetrachloride, methylene chloride or any combination thereof.
  • the condensing agent in step (I) is selected from the group consisting of dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) , 4-dimethylaminopyridine (DMAP) or any combination thereof.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • P is selected from a hydroxyl protecting group
  • X is selected from a leaving group
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, (C 1 -C 6 ) alkyl, cyano, nitro, hydroxyl, halogen, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, NR a R b , -OS (O) 2 R a , -SO 2 NR a R b , -NR a COR a , or -NR a SO 2 R a ,
  • W is selected from CR a R b , O, S or NR a ,
  • T is selected from CH or N
  • R 4 and R 5 are independently selected from hydrogen, (C 1 -C 6 ) alkyl, cyano, nitro, hydroxyl, halogen, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, NR a R b , -OS (O) 2 R a , -SO 2 NR a R b , -NR a COR a , or -NR a SO 2 R a ,
  • R a and R b each independently is selected from hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, benzyl, or (C 6 -C 10 ) aryl,
  • n and m are independently selected from 0, 1, or 2
  • step (II) is comprised by the following step: intermediate (A) and compound (B) are reacted in a solvent under alkaline/condensing agent conditions to prepare compound (I) ,
  • step (III) is comprised by the following step: compound (I) and compound (IV) are reacted in a solvent under alkaline conditions to prepare the compound (V) .
  • X is selected from halogen.
  • X is selected from F, Cl or Br.
  • P is selected from (C 1 -C 6 ) alkylaminosulfonyl, (C 3 -C 6 ) cycloalkylaminosulfonyl, (C 6 -C 10 ) arylaminosulfonyl, (C 1 -C 6 ) alkylphosphoryl, (C 3 -C 6 ) cycloalkylphosphoryl, (C 6 -C 10 ) arylphosphoryl, (C 1 -C 6 ) alkylsulfonyl, (C 3 -C 6 ) cycloalkylsulfonyl or (C 6 -C 10 ) arylsulfonyl, wherein the said alkyl, cycloalkyl, aryl can be optionally substituted with a substituent selected from 0, 1, 2, or 3 of the following groups: halogen, hydroxy, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cyclo
  • P is selected from phenylsulfonyl, phenylaminosulfonyl, phenylphosphoryl, phenylsulfonyl, methylsulfonyl, methylaminosulfonyl, or cyclopropylsulfonyl, wherein, the phenylsulfonyl, phenylamino Sulfonyl, phenylphosphoryl, and phenylsulfonyl groups can be optionally substituted with 0, 1, 2, or 3 selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, hydroxyl, nitro, halogen, cyano, amino, or -SO 3 H.
  • R 1 is selected from cyano
  • R 2 and R 3 are each independently selected from H.
  • P is preferably selected from benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl or cyclopropylsulfonyl.
  • W is selected from CH 2 , NH or O.
  • R a and R b are each independently selected from hydrogen or (C 1 -C 6 ) alkyl.
  • the alkaline in step (II) is selected from an organic base or an inorganic base
  • the organic base is selected from triethylamine, N, N-diisopropylethylamine, sodium tert-butyl, potassium tert-butyl, sodium ethoxide, sodium methoxide or any combination thereof
  • the inorganic base is selected from NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KHCO 3 , Cs 2 CO 3 or any combination thereof.
  • the solvent in step (II) is selected from H 2 O, ethanol, methanol, DMSO, THF, DMF, dioxane, chloroform, acetone, carbon tetrachloride, methylene chloride or any combination thereof.
  • the condensing agent in step (II) is selected from the group consisting of dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) , 4-dimethylaminopyridine (DMAP) or any combination thereof.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • the alkaline in step (II) is selected from an organic base or an inorganic base
  • the organic base is selected from triethylamine, N, N-diisopropylethylamine, sodium tert-butyl, potassium tert-butyl, sodium ethoxide, sodium methoxide or any combination thereof
  • the inorganic base is selected from NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KHCO 3 , Cs 2 CO 3 or any combination thereof.
  • the solvent in step (II) is selected from H 2 O, ethanol, methanol, DMSO, THF, DMF, dioxane, chloroform, acetone, carbon tetrachloride, methylene chloride or any combination thereof.
  • an intermediate A which is selected from the following structure:
  • P is selected from a hydrogen or hydroxyl protecting group
  • X is selected from a leaving group
  • R 2 and R 3 are each independently selected from hydrogen, (C 1 -C 6 ) alkyl, cyano, nitro, hydroxyl, halogen, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, NR a R b , -OS (O) 2 R a , -SO 2 NR a R b , -NR a COR a , or -NR a SO 2 R a ,
  • R a and R b each independently is selected from hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, benzyl, or (C 6 -C 10 ) aryl.
  • X is halogen
  • X is selected from F, Cl or Br.
  • P is selected from (C 1 -C 6 ) alkylaminosulfonyl, (C 3 -C 6 ) cycloalkylaminosulfonyl, (C 6 -C 10 ) arylaminosulfonyl, (C 1 -C 6 ) alkylphosphoryl, (C 3 -C 6 ) cycloalkylphosphoryl, (C 6 -C 10 ) arylphosphoryl, (C 1 -C 6 ) alkylsulfonyl, (C 3 -C 6 ) cycloalkylsulfonyl or (C 6 -C 10 ) arylsulfonyl, wherein the said alkyl, cycloalkyl, aryl can be optionally substituted with a substituent selected from 0, 1, 2, 3 of the following groups: halogen, hydroxy, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloal
  • P is selected from phenylsulfonyl, phenylaminosulfonyl, phenylphosphoryl, phenylsulfonyl, methylsulfonyl, methylaminosulfonyl, or cyclopropylsulfonyl, wherein, the phenylsulfonyl, phenylamino Sulfonyl, phenylphosphoryl, and phenylsulfonyl groups can be optionally substituted with 0, 1, 2, or 3 selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, hydroxyl, nitro, halogen, cyano, amino, or -SO 3 H.
  • R 2 and R 3 is independently selected from H.
  • P is selected from benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl or cyclopropylsulfonyl.
  • R a and R b are independently selected from hydrogen or (C 1 -C 6 ) alkyl.
  • P is selected from a hydrogen or hydroxyl protecting group
  • X is selected from a leaving group
  • Y is selected from an active group that can react with OH
  • R 1 and R 2 each independently is selected from hydrogen, (C 1 -C 6 ) alkyl, cyano, nitro, hydroxyl, halogen, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, NR a R b , -OS (O) 2 R a , -SO 2 NR a R b , -NR a COR a , or -NR a SO 2 R a ,
  • R a and R b each independently is selected from hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, benzyl, or (C 6 -C 10 ) aryl.
  • reaction process in step (I) is comprised by the following steps: compound (I) and compound (II) are reacted in a solvent under alkaline/condensing agent conditions to prepare the intermediate A.
  • X is halogen
  • X is selected from F, Cl or Br.
  • Y is selected from halogen (for example, F, Cl, Br) .
  • P is selected from (C 1 -C 6 ) alkylaminosulfonyl, (C 3 -C 6 ) cycloalkylaminosulfonyl, (C 6 -C 10 ) arylaminosulfonyl, (C 1 -C 6 ) alkylphosphoryl, (C 3 -C 6 ) cycloalkylphosphoryl, (C 6 -C 10 ) arylphosphoryl, (C 1 -C 6 ) alkylsulfonyl, (C 3 -C 6 ) cycloalkylsulfonyl or (C 6 -C 10 ) arylsulfonyl, wherein the said alkyl, cycloalkyl, aryl can be optionally substituted with a substituent selected from 0, 1, 2, or 3 of the following groups: halogen, hydroxy, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cyclo
  • P is selected from phenylsulfonyl, phenylaminosulfonyl, phenylphosphoryl, phenylsulfonyl, methylsulfonyl, methylaminosulfonyl, or cyclopropylsulfonyl, wherein, the phenylsulfonyl, phenylamino Sulfonyl, phenylphosphoryl, and phenylsulfonyl groups can be optionally substituted with 0, 1, 2, or 3 selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, hydroxyl, nitro, halogen, cyano, amino, or -SO 3 H.
  • R 2 and R 3 is independently selected from H.
  • P is selected from benzenesulfonyl, p-toluenesulfonyl, methylsulfonyl or cyclopropylsulfonyl.
  • R a and R b are independently selected from hydrogen or (C 1 -C 6 ) alkyl.
  • the alkaline condition is selected from an organic base or an inorganic base
  • the organic base is selected from triethylamine, N, N- diisopropylethylamine, sodium tert-butyl, potassium tert-butyl, sodium ethoxide, sodium methoxide or any combination thereof
  • the inorganic base is selected from NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KHCO 3 , Cs 2 CO 3 or any combination thereof.
  • the solvent is selected from H 2 O, ethanol, methanol, DMSO, THF, DMF, dioxane, chloroform, acetone, carbon tetrachloride, methylene chloride or any combination thereof.
  • the condensing agent in step (II) is selected from the group consisting of dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) , 4-dimethylaminopyridine (DMAP) or any combination thereof.
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • Figure 8 NMR spectrum of intermediate SM3-3 (Cyclosulfonyl-7-chloro-8-cyano-quinoxalin-2-yl ester)
  • Step (I) The main raw material SM1-1 (1.0 g) and 40 mL of methanol was added into an Erlenmeyer flask, stir until dissolved, and set aside. Add 4.5eq of glyoxylic acid monohydrate, 10mL methanol, stir to dissolve in a four-necked flask, cool to 15°C, drop the methanol solution of the main raw material, keep the reaction temperature and stir for 2h after dripping, take a sample for HPLC detection.
  • Step (II) Add 10mL of acetonitrile, 1.0g of SM1-2 prepared in step (I) , and 1.2eq of p-toluenesulfonyl chloride into a four-necked flask, cool to 2°C, add 3.0eq of triethylamine dropwise and react for 2h. Sampling and monitoring by HPLC. After the reaction is completed, filter and collect the filter cake, obtain intermediate SM1-3 after vacuum drying. The yield is 79.24%, the HPLC purity is 100%, and the NMR spectrum is shown in Figure 2, and the obtained intermediate SM1-3 is used directly in next step.
  • Step (III) Add 0.5g of intermediate SM1-3 of step (II) into a four-necked flask, then add 5mL of acetonitrile, cool to 2°C, drop 1.2eq of triethylamine, and then dropwise add 1.0eq of morpholine, gradually warm up to room temperature, react for 12h, take samples and check by HPLC. After the reaction is completed, add 15mL purified water drop wisely, then concentrate to 15mL under reduced pressure, filter and collect the filter cake. After the filter cake is vacuum-dried, add 5mL ethyl acetate, heat up to 80°Cand stir.
  • Step (I) Add the main raw material SM2-1 (1.0 g) and 40 mL of methanol into an Erlenmeyer flask, stir until dissolved, and set aside. Add 4.5 eq of glyoxylic acid monohydrate and 10 mL of methanol to a four-necked flask, stir to dissolve, cool to 15°C, drop the methanol solution of the main raw material, keep it warm and stir for 2 hours after dripping, take a sample for HPLC detection, and filter after the reaction is completed. The filter cake was rinsed with pre-cooled 10 mL methanol, and after vacuum drying, the intermediate 6-chloro-3-hydroxyquinoxaline (SM2-2) was obtained. The yield was 74.0%and the HPLC purity was 40.5% (NMR spectroscopy) . The NMR spectrum is shown as Figure 4.
  • Step (II) Add 10mL of acetonitrile, 1.0g of 6-chloro-3-hydroxyquinoxaline (SM2-2) , and 1.2eq of p-toluenesulfonyl chloride into a four-necked flask. Then add 3.0eq of triethylamine, react for 2h, sample and monitor by HPLC. After the reaction is completed, filter and collect filter cake, and vacuum-dry to obtain intermediate SM2-3. The yield was 52.9%and HPLC purity was 100%. The NMR spectrum is shown as Figure 5.
  • Step (III) Add the intermediate SM2-3 (0.5g) of step (II) into a four-necked flask, then add 5 mL of acetonitrile, cool to 2°C, drop in 1.2 eq of triethylamine, and then drop in 1.0 eq of morpholine. Gradually warm up to room temperature, react for 12 hours, sample and check by HPLC. After the reaction is completed, add 15 mL of purified water drop wisely, concentrate to 15 mL under reduced pressure, filter and collect the filter cake.
  • Step (I) Add SM3-1 (1.0 g) and 40 mL of methanol to an Erlenmeyer flask, stir until dissolved, and set aside. Add 4.5 eq of glyoxylic acid monohydrate and 10 mL of methanol into a four-neck flask, stir to dissolve, cool to 15°C, drop the methanol solution of the main raw material, keep it warm and stir for 2 hours after dripping, sample for HPLC detection, and filter after completion of the reaction. The filter cake is rinsed with pre-cooled 10 mL methanol, and after vacuum drying, the intermediate 5-cyano 6-chloro-3-hydroxyquinoxaline (SM3-2) is obtained. The yield was 91%and the HPLC purity was 98.7%.
  • the NMR spectrum is shown in Figure 7
  • Step (II) Add 10mL of acetonitrile, 1.0g of intermediate SM3-2 prepared in Step 1, 1.05eq of cyclopropanesulfonyl chloride into a four-necked flask, cool to 2°C, drop 3.0eq of triethylamine, and react 2h, sample and monitor by HPLC. After the reaction is completed, filter and collect the filter cake, obtain intermediate SM3-3 after vacuum drying. The yield was 69.04%, the HPLC purity was 83%, and the NMR spectroscopy is shown in FIG. 8.
  • Step (II) Add 1.0g of intermediate SM3-3 prepared in step (II) into a four-necked flask, then add 5mL of acetonitrile, cool to 2°C, drop 1.2eq of triethylamine, and then drop 1.0eq of morpholine. Gradually warm to room temperature, react for 12h, sample and check by HPLC. After the reaction is completed, add 15mL purified water drop wisely, concentrate to 15mL under reduced pressure, filter and collect the filter cake.
  • Step (I) Refers to the patent WO2018071348A1 specification or the steps of Example 1 and Example 2 of the present application to synthesize intermediate SM3-2;
  • Step (I) Add 10mL of acetonitrile, 1.0g of intermediate SM3-2 prepared in step (I) of Example 3, 1.2eq of p-toluenesulfonyl chloride into a four-necked flask, reduce the temperature to 2°C, and then add 3.0eq of three Ethylamine, react for 2h, sample and monitor by HPLC.
  • Step (I) Add 10mL of acetonitrile, 1.0g SM4-2, 1.2eq p-toluenesulfonyl chloride into a four-necked flask, cool to 2°C, add 3.0eq triethylamine drop wisely, react for 2h, sample and monitor by HPLC. After the reaction is completed, filter and collect the filter cake, obtain intermediate SM4-3 after vacuum drying. The yield was 60.95%, the HPLC purity was 99.99%, and the NMR spectroscopy is shown in FIG. 11.
  • Step (II) Add 0.5 g of intermediate SM4-3 into a four-neck flask, then add 5 mL of acetonitrile, cool to 2°C, drop 1.2 eq of triethylamine, and then drop 1.0 eq of morpholine, and gradually warm to room temperature to react 12h, sample and check by HPLC. After the reaction is completed, add 15mL purified water drop wisely, concentrate to 15mL under reduced pressure, filter and collect the filter cake.
  • Step (I) Add 10 mL of acetonitrile, 1.0 g of intermediate SM3-2 prepared in step (I) of Example 3, 4.5 mL of phosphorous oxychloride, 0.05 eq DMF into a four-necked flask, warm up to 100°C,
  • Step (II) Add 0.45g of SM3-3'’ from step (I) to a four-necked flask, then add 5mL of acetonitrile, 3.0eq of potassium carbonate, and 5.0eq of morpholine drop wisely, increase the temperature to 90°C, react for 4h, and sample for HPLC detection. After the reaction is completed, filter and collect the filtrate. The filtrate is spin-dried and then added 2x5mL ethyl acetate to condensate, then 20ml ethyl acetate is added for recrystallization. After filtration, 1mL ethyl acetate is used to rinse the filter cake, and the product SM3-4 of 0.36 g is obtained after vacuum drying. The yield was 65.25%, and the HPLC purity was 99.34%.
  • Example 2 It can be seen from the results of Example 2 and Comparative Example 1 that the synthesis method of the present application avoids the use of phosphorus oxychloride, avoids the risk of violent heat generation, gas release, and product degradation into raw materials in post-processing, and at the same time obtains a higher yield.

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Abstract

L'invention concerne un composé intermédiaire de quinoxaline de formule A, l'utilisation dans la préparation d'intermédiaires et de médicaments en vrac de celui-ci, et un procédé de synthèse. Le procédé évite des étapes de séparation et de purification encombrantes, réduit les coûts, améliore le rendement de la réaction, évite l'utilisation de POCl3 dans l'état de la technique, évite la génération d'une grande quantité d'eaux usées nocives, et est plus approprié pour une production industrielle.
PCT/CN2022/131086 2021-11-11 2022-11-10 Composé intermédiaire de quinoxaline et son procédé de préparation Ceased WO2023083247A1 (fr)

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