WO2022156783A1 - Preparation method for imidazopyridine compound and intermediate thereof - Google Patents

Preparation method for imidazopyridine compound and intermediate thereof Download PDF

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WO2022156783A1
WO2022156783A1 PCT/CN2022/073298 CN2022073298W WO2022156783A1 WO 2022156783 A1 WO2022156783 A1 WO 2022156783A1 CN 2022073298 W CN2022073298 W CN 2022073298W WO 2022156783 A1 WO2022156783 A1 WO 2022156783A1
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formula
reaction
intermediate shown
preparation
compound
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PCT/CN2022/073298
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French (fr)
Chinese (zh)
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张学军
李群
臧杨
叶大炳
常少华
李学强
李莉娥
杨俊�
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武汉人福创新药物研发中心有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

Definitions

  • the present invention relates to a preparation method of imidazopyridine compounds and intermediates thereof.
  • P2X receptors are non-selective ATP-gated ion channel receptors, purinergic receptors, that bind to extracellular ATP, mainly from damaged or inflamed tissues.
  • the receptor is widely expressed in the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, endocrine and other systems, and is involved in the regulation of cardiac rhythm and contractility, regulation of vascular tone, regulation of nociception, especially chronic pain, and contraction of the vas deferens during ejaculation , bladder contraction during urination, platelet aggregation, activation of macrophages, apoptosis, and neuron-glial interactions and other physiological processes.
  • P2X receptors include seven homologous receptors: P2X1, P2X2, P2X3, P2X4, P2X5, P2X6 and P2X7, and three heterologous receptors: P2X2/3, P2X4/6, P2X1/5.
  • P2X3 is a subtype of the P2X receptor family and is selectively expressed in dorsal root ganglia, spinal cord, and brain neurons of nerve endings, ie, primary sensory neurons of medium and small diameter.
  • P2X3 and P2X2/3 expressed in primary sensory neurons plays an important role in acute injury, hyperalgesia, and hypersensitivity in rodents.
  • Many studies have shown that the up-regulation of P2X3 receptor expression can lead to the formation of hyperalgesia, which is involved in pain signaling.
  • P2X3 knockout mice exhibited reduced pain responses, and P2X3 receptor antagonists were shown to reduce nociception in models of pain and inflammatory pain.
  • P2X3 is distributed in primary afferent nerves around the airways and is capable of regulating cough.
  • Studies have shown that ATP released from damaged or inflamed tissue in the airway acts on P2X3 receptors in primary neurons, triggering depolarization and action potentials that transmit the impulse to cough, triggering coughing.
  • Preclinical and clinical data strongly demonstrate that P2X3 receptors play an important role in cough reflex hypersensitivity, leading to chronic cough. By antagonizing binding to P2X3 receptors, the hypersensitivity of the cough reflex can be suppressed, thereby suppressing excessive coughing in patients with chronic cough.
  • P2X3 is involved in the afferent pathway that controls the bladder volume reflex, and P2X3 knockout mice have significantly reduced urination frequency and significantly increased bladder capacity.
  • P2X3 antagonists may be potential drugs for the treatment of overactive bladder and other related diseases.
  • P2X3 antagonists can treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension or asthma, so P2X3 antagonists are also expected to become new drugs for the treatment of these diseases.
  • P2X3 antagonists have shown great promise in multiple disease areas, therefore, the development of P2X3 antagonists is of great clinical significance.
  • the invention provides a preparation method of imidazopyridine compounds and an intermediate thereof.
  • the preparation method of the invention has mild conditions, stable process and simple operation, and is suitable for scale-up and industrial production.
  • the present invention provides an intermediate as shown in formula I, formula II or formula III:
  • the R 1 is selected from PG 1 or
  • the R 2 is selected from halogen, carboxyl or
  • the R 2a is selected from C 1 -C 6 alkyl or benzyl
  • the R is selected from methyl or chlorine
  • the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
  • the X is selected from H or Br.
  • the halogen is Br or I, preferably Br.
  • the R 2a is C 1 -C 6 alkyl; preferably, the R 2a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the aforementioned intermediate represented by formula II is selected from any of the following intermediates:
  • the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
  • the R 2 is selected from halogen, carboxyl or
  • Said R 2a has the previously described definition.
  • the present invention also provides a preparation method of the intermediate as shown in formula II-1, which comprises the following steps:
  • Step 1 under the action of a metal amide compound or a metal alkyl compound, the intermediate shown in the formula II-1 is prepared by reacting the intermediate shown in the formula I-3 with the compound shown in 1;
  • the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
  • the R 2 is selected from halogen, carboxyl or
  • Said R 2a has the previously described definition.
  • the amino metal compound is lithium diisopropylamide, lithium bistrimethylsilylamide, potassium bistrimethylsilylamide, sodium bistrimethylsilylamide, preferably It is lithium diisopropylamide or bistrimethylsilylamino.
  • the alkyl metal compound is methyl Grignard reagent, ethyl Grignard reagent, isopropyl Grignard reagent or alkyl lithium compound, preferably methyl lithium or n-butyl lithium .
  • step 1 when the R 2 is halogen, the reaction is carried out under the action of a metal amide compound.
  • step 1 when described R 2 is carboxyl or , the reaction is carried out under the action of a metal amide compound or a metal alkyl compound.
  • the reaction can be carried out in a conventional organic solvent in the art
  • the organic solvent includes but is not limited to diethyl ether, dichloromethane, toluene, 2-methyltetrahydrofuran or tetrahydrofuran, preferably Tetrahydrofuran.
  • the reaction temperature of the reaction is -80 ⁇ 0°C, preferably -10 ⁇ 0°C or -80 ⁇ -60°C.
  • the molar ratio of the compound represented by formula I to the compound represented by formula 1 is 1:1-1:1.6, preferably 1:1-1.2 or 1:1.5 ⁇ 1:1.6, more preferably 1:1.2 or 1:1.5.
  • the reaction time of the reaction is 2-4 hours, preferably 2.5 hours.
  • the reaction described in the step 1 when the reaction is carried out under the action of an alkyl lithium compound, the reaction described in the step 1 further includes a stabilizer, and the stabilizer is N,N,N',N'-tetramethyl Ethylenediamine.
  • the present invention also provides a preparation method of the intermediate shown in formula I, and the preparation method of the intermediate shown in formula I comprises the following steps;
  • Step 2 under the action of an organic base and a condensing agent, the intermediate shown in formula I is prepared by reacting the intermediate shown in formula I-2 with the compound shown in formula 2;
  • the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
  • the reaction temperature of the reaction is 20-25°C.
  • the organic base is selected from N,N-diisopropylethylamine.
  • the condensing agent is 1-propyl phosphoric anhydride.
  • the molar ratio of the intermediate represented by the formula I-2 to the compound represented by the formula 2 is 1:1 to 1:2, preferably 1:1.2.
  • the molar ratio of the intermediate shown in formula I-2 to the compound of the organic base is 1:2 ⁇ 1:4, preferably 1:2.8 ⁇ 1:3.2, more preferably The ground is 1:3.
  • the molar ratio of the intermediate represented by formula I-2 to the condensing agent is 1:1 to 1:2, preferably 1:1.5.
  • the reaction time of the reaction is 14-18 hours, preferably 16 hours.
  • the reaction is carried out in dichloromethane.
  • the preparation method of the intermediate shown in the formula I further includes the preparation method of the intermediate shown in the formula I-2.
  • the preparation method includes the following steps:
  • Step 3 prepare the intermediate shown in formula I-1 by subjecting the compound shown in formula 3 to reduction reaction;
  • Step 4 under the action of inorganic base, prepare the intermediate shown in formula I-2 by hydrolyzing the intermediate shown in formula I-1;
  • the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
  • the reaction further includes hydrogen.
  • the reaction also includes palladium on carbon.
  • the reaction temperature of the reaction is 20-25°C.
  • the pressure of the hydrogen in the reaction is 0.8-1.2 atm, preferably 1 atm.
  • the mass ratio of the palladium carbon to the compound 3 is 1:18 ⁇ 1:22, preferably 1:20.
  • the reaction time of the reaction is 22-26 hours, preferably 24 hours.
  • the inorganic base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide.
  • the reaction temperature of the reaction is 20-25°C.
  • the molar ratio of the intermediate shown in formula I-1 to the inorganic base is 1:1 to 1:4, preferably 1:2.
  • the reaction time of the reaction is 14-18 hours, preferably 16 hours.
  • the reaction is carried out in methanol.
  • the present invention also provides a method for preparing the intermediate shown in formula II-1A, wherein the intermediate shown in formula II-1A is prepared from the intermediate shown in formula II-1, and the The preparation method of the intermediate shown in formula II-1A comprises the following steps;
  • Step 5 under the action of a catalyst and an organic base, the intermediate shown in formula II-1A is obtained by reacting the intermediate shown in formula II-1 with carbon monoxide and the compound shown in formula 4;
  • the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
  • the R 2 is halogen
  • Said R 2a has the previously described definition.
  • the catalyst transition metal catalyst includes palladium metal catalyst, ruthenium metal catalyst, iron metal catalyst, cobalt metal catalyst, nickel metal catalyst, rhodium metal catalyst, preferably palladium metal catalyst metal catalyst;
  • the palladium catalyst comprises tetrakis(triphenylphosphine) palladium, palladium acetate, bistriphenylphosphonium palladium dichloride, 1,1-bis(diphenylphosphonium)ferrocene palladium chloride, [ 1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, 1, 4-bis(diphenylphosphinobutane) palladium dichloride, more preferably, the palladium metal catalyst is 1,1-bis(diphenylphosphonium)ferrocene palladium chloride.
  • the organic base includes but is not limited to triethylamine or N,N-diisopropylethylamine, preferably triethylamine.
  • the reaction is carried out in pressurized carbon monoxide, and the pressure of the carbon monoxide is 40-50 psi, preferably 45 psi.
  • the reaction temperature of the reaction is 55-65°C.
  • the reaction time of the reaction is 22-26 hours, preferably 24 hours.
  • the present invention also provides a method for preparing the intermediate shown in formula II-1A, wherein the intermediate shown in formula II-1A is prepared from the intermediate shown in formula II-1, and the The preparation method of the intermediate shown in formula II-1A comprises the following steps;
  • Step 6 under the action of a base, the intermediate shown in formula II-1A is obtained by reacting the intermediate shown in formula II-1 with the compound shown in formula 5;
  • the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
  • R 2 is carboxyl
  • Said R 2a has the previously described definition.
  • the molar ratio of the intermediate represented by the formula II-1 to the compound represented by the formula 5 is 1:1 to 1:2, preferably 1:1.5.
  • the reaction temperature of the reaction is 20-25°C.
  • the alkali is sodium bicarbonate.
  • step 6 the reaction is carried out in N,N-dimethylformamide.
  • the reaction time is 22-26 hours, preferably 24 hours.
  • the present invention also provides a preparation method of the intermediate shown in formula II-2, and the preparation method of the intermediate shown in formula II-2 comprises the following steps:
  • Step 7 Removing the intermediate protecting group PG 1 shown in formula II-1A to obtain a deprotected product; the deprotected product is reacted with the compound shown in formula 6 under the action of a base, Obtain the intermediate as shown in formula II-2;
  • the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
  • Said R 2a has the previously described definition.
  • the molar ratio of the intermediate represented by the formula II-1A to the compound represented by the formula 6 is 1:1 to 1:2, preferably 1:1.5.
  • step 7 the removal of the intermediate protecting group PG 1 shown in formula II-1A is carried out under the action of hydrochloric acid.
  • step 7 the removal of the intermediate protecting group PG 1 shown in formula II-1A is carried out under the reaction with hydrogen.
  • the reaction temperature of the reaction is 20-25°C.
  • the base includes but is not limited to triethylamine or N,N-diisopropylethylamine, preferably triethylamine.
  • step 7 the deprotection reaction is carried out in 1,4-dioxane.
  • the reaction time of the deprotection group is 2 to 4 hours, preferably 3 hours.
  • step 7 the reaction of the deprotected product with the compound shown in formula 6 is carried out in dichloromethane under the action of a base.
  • the reaction time of the reaction of the deprotected product with the compound shown in formula 6 under the action of a base is 10-14 hours, preferably 12 hours.
  • the present invention also provides a method for preparing the intermediate shown in formula II-3, wherein the intermediate shown in formula II-3 is prepared from the intermediate shown in formula II-2, and the The preparation method of the intermediate shown in formula II-3 comprises the following steps:
  • Step 8 react the intermediate shown in formula II-2 with a bromination reagent to obtain the intermediate shown in formula II-3;
  • R 2a has the definition as previously described.
  • the bromination reagent includes N-bromosuccinimide, dibromohydantoin, pyridine tribromide, liquid copper bromide or liquid bromide, preferably liquid bromine.
  • the molar ratio of the intermediate shown in formula II-2 to the bromination reagent is 1:1 to 1:3, preferably 1:1.2.
  • the reaction is carried out in dichloromethane.
  • the reaction temperature of the reaction is 20-25°C.
  • the reaction time of the reaction is 0.5 to 2 hours, preferably 1 hour.
  • the present invention also provides a method for preparing the intermediate shown in formula III, the intermediate shown in formula III is prepared from the intermediate shown in formula II-3, and the intermediate shown in formula III is prepared
  • the preparation method of the intermediate shown comprises the following steps:
  • Step 9 by reacting the intermediate shown in formula II-3 with the compound shown in formula 7 to obtain the intermediate shown in formula III;
  • Said R 2a has the above-mentioned definition
  • the R3 is selected from methyl or chlorine.
  • the molar ratio of the intermediate represented by the formula II-3 and the compound represented by the formula 7 in the reaction is 1:1 to 1:3, preferably 1:2.
  • the reaction can be carried out in a conventional organic solvent in the art
  • the organic solvent includes but is not limited to acetonitrile, dimethyl sulfoxide, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, n-propanol or n-butanol, preferably acetonitrile.
  • the reaction temperature of the reaction is 110-130°C, preferably 120°C.
  • the reaction time of the reaction is 22-26 hours, preferably 24 hours.
  • the present invention also provides a preparation method of the imidazopyridine compound shown in formula IV, and the preparation method of the imidazopyridine compound shown in formula IV comprises the following steps:
  • Step 10 react the intermediate shown in formula III with methylamine to obtain the compound shown in formula IV;
  • Said R 2a has the above-mentioned definition
  • the R3 is selected from methyl or chlorine.
  • the molar ratio of the intermediate shown in formula III to methylamine is 1:4 to 1:6, preferably 1:5.
  • the reaction temperature of the reaction is 20-25°C.
  • the reaction is carried out in methanol.
  • the reaction time of the reaction is 4 to 6 hours, preferably 5 hours.
  • the present invention also provides a preparation method of the intermediate shown in formula 3, and the preparation method of the intermediate shown in formula 3 comprises the following steps;
  • Step 11 The intermediate shown in formula 3-1 is reacted with Dess-Martin oxidant to obtain the intermediate shown in formula 3-2; the intermediate shown in formula 3-2 is shown in formula 8 The compound is reacted to obtain the intermediate shown in formula 3;
  • the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
  • the molar ratio of the intermediate shown in formula 3-1 to the Dess-Martin oxidant is 1:1.2.
  • the reaction temperature of the intermediate represented by the formula 3-1 and the Dess-Martin oxidant is 20-25°C.
  • the reaction time between the intermediate shown in formula 3-1 and the Dess-Martin oxidant is 1 to 3 hours, preferably 2 hours.
  • step 11 the reaction of the intermediate shown in formula 3-1 with Dess-Martin oxidant is carried out in dichloromethane.
  • the molar ratio of the intermediate shown in formula 3-2 to compound 8 is 1:1 to 1:2, preferably 1:1.1.
  • reaction temperature of the intermediate represented by formula 3-1 and compound 8 is 20-25°C.
  • the reaction time between the intermediate represented by formula 3-1 and compound 8 is 14-18 hours, preferably 16 hours.
  • step 11 the reaction of the intermediate shown in formula 3-1 with Dess-Martin oxidant is carried out in dichloromethane.
  • C 1 -C 6 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbut
  • metal alkyl compound refers to an organic compound in which a metal atom is directly bonded to an alkyl carbon atom to form a bond.
  • the alkyl groups include, but are not limited to, alkyl or cycloalkyl groups, such as C1 - C6 alkyl groups.
  • the metal atoms include, but are not limited to, potassium, sodium, lithium, magnesium, or aluminum.
  • the alkyl metal compounds include but are not limited to Grignard reagents, alkyl lithium compounds.
  • amino metal compound refers to a compound formed by the combination of a metal atom and an amino group through covalent or coordinate bonds
  • amino amino group refers to primary (ie -NH 2 ), secondary (ie -NRH) and tertiary (i.e.
  • the R includes but is not limited to a C 1 -C 6 alkyl, cycloalkyl or silicon group
  • the metal atom includes but is not limited to potassium, sodium, lithium or magnesium
  • the Amino metal compounds include but are not limited to lithium diisopropylamide, lithium bis-trimethylsilyl amide, potassium bis-trimethylsilyl amide, sodium bis-trimethylsilyl amide, sodium amide, potassium amide, Lithium amide.
  • halo or halogen is fluorine, chlorine, bromine and iodine.
  • catalyst refers to any substance or agent that can affect, induce, increase or promote the reactivity or reaction of a compound.
  • transition metal catalyst refers to any metal having an electron in its d orbital, such as a metal selected from Groups 3-12 of the Periodic Table of the Elements or the lanthanides.
  • Catalysts useful in the process of the present invention include atoms, ions, salts or complexes of transition metals from Groups 8-11 of the Periodic Table.
  • Groups 3-12 of the Periodic Table means the Periodic Table groups numbered according to the IUPAC method.
  • transition metals of Groups 8-11 include iron, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver and gold.
  • Such catalysts include but are not limited to CuI, CuCl, CuBr, CuBr2, Cu2Cl2 , Cu2O, Cu, Pd2 ( dba )2 , Pd/C, PdCl2 , Pd(OAc )2 , ( CH3CN ) ) 2 PdCl 2 , Pd[P(C 6 H 5 ) 3 ] 4 , NiCl 2 [P(C 6 H 5 )] 2 and Ni(COD) 2 .
  • R2a -I refers to an iodine reagent containing R2a .
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10-6 (ppm).
  • the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • M molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
  • DIPEA can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
  • TMEDA N,N,N',N'-Tetramethylethylenediamine
  • the synthetic route of the target intermediate A is as follows:
  • reaction solution was slowly poured into a saturated solution of sodium bicarbonate (1 L) and stirred for 0.5 h, and the organic phase was collected after filtration and separation. The organic phase was washed with saturated sodium bicarbonate solution (1L ⁇ 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R)-tert-butyl 2-formylmorpholine-4-carboxylate (A) as a colorless oil. -2) (99 g, 100% yield).
  • reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give (S)-2-(3-methoxy-3-oxoprop-1-en-1-yl)morpholine- tert-Butyl 4-carboxylate (A-3) (75 g, 60.1% yield).
  • the third step synthesis of (S)-2-(3-methoxy-3-oxypropyl) morpholine-4-carboxylic acid tert-butyl ester (A-4)
  • the fourth step the synthesis of (S)-3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionic acid (A-5)
  • Step 5 Synthesis of (S)-2-(3-(methoxy(methyl)amino)-3-oxypropyl)morpholine-4-carboxylic acid tert-butyl ester (A)
  • the synthetic route of the target intermediate B is as follows:
  • the synthetic route of the target intermediate B is as follows:
  • the synthetic route of the target intermediate B is as follows:
  • reaction solution was concentrated to dryness under reduced pressure, dichloromethane (820 mL) was added to the residue, the temperature of the reaction solution was adjusted to 0-5 ° C, triethylamine (48.1 g, 475 mmol) was slowly added dropwise, and then methyl chloroformate was added. (26.9 g, 285 mmol). Adjust the reaction temperature to 20-25 °C, the reaction solution was stirred at 20-25 °C for 12h, TLC showed that the reaction was complete.
  • the first step Synthesis of (S)-2,3,5-trifluoro-4-(3-(4-(methoxycarbonyl)morpholin-2-yl)propionyl)benzoic acid (C-2)
  • reaction solution was concentrated to dryness under reduced pressure, dichloromethane (72 mL) was added to the residue, the temperature of the reaction solution was adjusted to 0-5 ° C, triethylamine (6.87 g, 67.9 mmol) was slowly added dropwise, and then methyl chloroformate was added. Ester (2.36 g, 29.1 mmol). The reaction temperature was adjusted to 20-25 °C, and the reaction solution was stirred at 20-25 °C for 12 h.
  • the synthetic route of the target intermediate E is as follows:
  • the synthetic route of target compound 1 is as follows:
  • reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid (S)-2-((2-(2,3,6-trifluoro-4-(methylcarbamoyl)phenyl)-7 - Methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (1) (7.7 g, 97% yield).
  • the synthetic route of target compound 2 is as follows:
  • reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid (S)-2-((2-(2,3,6-trifluoro-4-(methylcarbamoyl)phenyl)-7 -chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (2) (27 g, 90% yield).

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Abstract

The present invention provides a preparation method for an imidazopyridine compound as represented by formula IV and an intermediate as represented by formula I, formula II, or formula III. The imidazopyridine compound as represented by formula IV can antagonize a P2X3 receptor, and has the effects of suppressing cough and analgesia.

Description

咪唑并吡啶类化合物的制备方法及其中间体Preparation method of imidazopyridine compounds and intermediates thereof
优先权信息priority information
本申请请求2021年01月22日向中国国家知识产权局提交的、专利申请号为202110090342.7的专利申请的优先权和权益，并且通过参照将其全文并入此处。This application claims the priority and rights of patent application No. 202110090342.7 filed with the State Intellectual Property Office of China on January 22, 2021, and is hereby incorporated by reference in its entirety.
技术领域technical field
本发明涉及咪唑并吡啶类化合物的制备方法及其中间体。The present invention relates to a preparation method of imidazopyridine compounds and intermediates thereof.
背景技术Background technique
P2X受体是一种非选择性的ATP门控离子通道受体，即嘌呤能受体，可与胞外的ATP结合，这些ATP主要来源于受损或发炎的组织。该受体广泛表达在神经、免疫、心血管、骨骼、胃肠、呼吸、内分泌等系统，并参与心律和收缩力调节、血管张力的调节、伤害感受尤其是慢性疼痛的调节、射精时输精管收缩、排尿期间膀胱的收缩、血小板的聚集、巨噬细胞的激活、细胞凋亡以及神经元-神经胶质相互作用等多种生理过程。上述P2X受体包括七种同源性受体：P2X1、P2X2、P2X3、P2X4、P2X5、P2X6和P2X7，三种异源性受体：P2X2/3、P2X4/6、P2X1/5。P2X receptors are non-selective ATP-gated ion channel receptors, purinergic receptors, that bind to extracellular ATP, mainly from damaged or inflamed tissues. The receptor is widely expressed in the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, endocrine and other systems, and is involved in the regulation of cardiac rhythm and contractility, regulation of vascular tone, regulation of nociception, especially chronic pain, and contraction of the vas deferens during ejaculation , bladder contraction during urination, platelet aggregation, activation of macrophages, apoptosis, and neuron-glial interactions and other physiological processes. The above P2X receptors include seven homologous receptors: P2X1, P2X2, P2X3, P2X4, P2X5, P2X6 and P2X7, and three heterologous receptors: P2X2/3, P2X4/6, P2X1/5.
P2X3是P2X受体家族的一个亚型，选择性地表达在神经末梢的背根神经节、脊髓和脑神经元中，即中小直径的初级感觉神经元中。P2X3 is a subtype of the P2X receptor family and is selectively expressed in dorsal root ganglia, spinal cord, and brain neurons of nerve endings, ie, primary sensory neurons of medium and small diameter.
大量研究表明，在初级感觉神经元中表达的P2X3和P2X2/3的激活对啮齿类动物的急性损伤、痛觉过敏和超敏反应起重要作用。许多研究表明，P2X3受体表达上调可导致痛觉过敏形成，参与疼痛的信号传递。P2X3基因敲除小鼠表现出疼痛反应减轻，在疼痛和炎性疼痛模型中，P2X3受体拮抗剂显示出减轻伤害感受的作用。Numerous studies have shown that activation of P2X3 and P2X2/3 expressed in primary sensory neurons plays an important role in acute injury, hyperalgesia, and hypersensitivity in rodents. Many studies have shown that the up-regulation of P2X3 receptor expression can lead to the formation of hyperalgesia, which is involved in pain signaling. P2X3 knockout mice exhibited reduced pain responses, and P2X3 receptor antagonists were shown to reduce nociception in models of pain and inflammatory pain.
P2X3分布于气道周围的初级传入神经中，能够调节咳嗽。研究表明，气道受损或发炎的组织释放的ATP作用于初级神经元的P2X3受体，触发去极化和动作电位，这些电位传递引起咳嗽冲动，引发咳嗽。临床前和临床数据有力地证明了P2X3受体在咳嗽反射超敏反应中起重要作用，从而导致慢性咳嗽。通过拮抗与P2X3受体结合，可以抑制咳嗽反射的超敏反应，从而抑制慢性咳嗽患者的过度咳嗽。P2X3 is distributed in primary afferent nerves around the airways and is capable of regulating cough. Studies have shown that ATP released from damaged or inflamed tissue in the airway acts on P2X3 receptors in primary neurons, triggering depolarization and action potentials that transmit the impulse to cough, triggering coughing. Preclinical and clinical data strongly demonstrate that P2X3 receptors play an important role in cough reflex hypersensitivity, leading to chronic cough. By antagonizing binding to P2X3 receptors, the hypersensitivity of the cough reflex can be suppressed, thereby suppressing excessive coughing in patients with chronic cough.
据报道，P2X3涉及控制膀胱容量反射的传入通路，P2X3基因敲除小鼠的排尿频率显著降低、膀胱容量显著增加。因此，抑制P2X3受体拮抗剂与P2X3受体结合具有治疗储尿和排尿障碍的病症，如膀胱过度活动症的作用。因此，P2X3拮抗剂可能是治疗膀胱过动症等相关疾病的潜在药物。It has been reported that P2X3 is involved in the afferent pathway that controls the bladder volume reflex, and P2X3 knockout mice have significantly reduced urination frequency and significantly increased bladder capacity. Thus, inhibiting the binding of P2X3 receptor antagonists to P2X3 receptors has utility in the treatment of disorders of urinary storage and voiding disorders, such as overactive bladder. Therefore, P2X3 antagonists may be potential drugs for the treatment of overactive bladder and other related diseases.
另外，有研究表明P2X3拮抗剂可以治疗慢性阻塞性肺病，肺纤维化，肺动脉高压或者是哮喘，因此P2X3拮抗剂也有望成为治疗上述疾病的新药物。In addition, studies have shown that P2X3 antagonists can treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension or asthma, so P2X3 antagonists are also expected to become new drugs for the treatment of these diseases.
P2X3拮抗剂在多个疾病领域显示出巨大前景，因此，开发P2X3拮抗剂对于临床具有重要意义。P2X3 antagonists have shown great promise in multiple disease areas, therefore, the development of P2X3 antagonists is of great clinical significance.
发明内容SUMMARY OF THE INVENTION
本发明提供了一种咪唑并吡啶类化合物的制备方法及其中间体。本发明的制备方法条件温和，工艺稳定，操作简单，适合放大以及工业化生产。The invention provides a preparation method of imidazopyridine compounds and an intermediate thereof. The preparation method of the invention has mild conditions, stable process and simple operation, and is suitable for scale-up and industrial production.
本发明提供了一种如式I、式II或式III所示的中间体：The present invention provides an intermediate as shown in formula I, formula II or formula III:
Figure PCTCN2022073298-appb-000001
Figure PCTCN2022073298-appb-000001
其中，in,
所述R 1选自PG 1或
Figure PCTCN2022073298-appb-000002
The R 1 is selected from PG 1 or
Figure PCTCN2022073298-appb-000002
所述R 2选自卤素、羧基或
Figure PCTCN2022073298-appb-000003
The R 2 is selected from halogen, carboxyl or
Figure PCTCN2022073298-appb-000003
所述R 2a选自C 1-C 6烷基或苄基； The R 2a is selected from C 1 -C 6 alkyl or benzyl;
所述R 3选自甲基或氯； The R is selected from methyl or chlorine;
所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
所述X选自H或Br。The X is selected from H or Br.
在本发明的一优选实施方案中，当R 2为卤素时，所述卤素为Br或I，较佳地为Br。 In a preferred embodiment of the present invention, when R 2 is halogen, the halogen is Br or I, preferably Br.
在本发明的一优选实施方案中，所述R 2a为C 1-C 6烷基；较佳地，所述R 2a为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a preferred embodiment of the present invention, the R 2a is C 1 -C 6 alkyl; preferably, the R 2a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在本发明的一优选实施方案中，如前文所述的如式II所示的中间体选自下列任一中间体：In a preferred embodiment of the present invention, the aforementioned intermediate represented by formula II is selected from any of the following intermediates:
Figure PCTCN2022073298-appb-000004
Figure PCTCN2022073298-appb-000004
其中，in,
所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
所述R 2选自卤素、羧基或
Figure PCTCN2022073298-appb-000005
The R 2 is selected from halogen, carboxyl or
Figure PCTCN2022073298-appb-000005
所述R 2a具有前文所述的定义。 Said R 2a has the previously described definition.
本发明还提供了一种如式II-1所示的中间体的制备方法，其包括以下步骤：The present invention also provides a preparation method of the intermediate as shown in formula II-1, which comprises the following steps:
步骤1：在氨基金属化合物或烷基金属化合物的作用下，通过将如式I-3所示的中间体与如1所示的化合物进行反应制备如式II-1所示的中间体；Step 1: under the action of a metal amide compound or a metal alkyl compound, the intermediate shown in the formula II-1 is prepared by reacting the intermediate shown in the formula I-3 with the compound shown in 1;
Figure PCTCN2022073298-appb-000006
Figure PCTCN2022073298-appb-000006
其中，in,
所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
所述R 2选自卤素、羧基或
Figure PCTCN2022073298-appb-000007
The R 2 is selected from halogen, carboxyl or
Figure PCTCN2022073298-appb-000007
所述R 2a具有前文所述的定义。 Said R 2a has the previously described definition.
所述的步骤1中，所述氨基金属化合物为二异丙基氨基锂、双三甲基硅基氨基锂、双三甲基硅基氨基钾、双三甲基硅基氨基钠，较佳地为二异丙基氨基锂或双三甲基硅基氨基。In the step 1, the amino metal compound is lithium diisopropylamide, lithium bistrimethylsilylamide, potassium bistrimethylsilylamide, sodium bistrimethylsilylamide, preferably It is lithium diisopropylamide or bistrimethylsilylamino.
所述的步骤1中，所述烷基金属化合物为甲基格氏试剂、乙基格氏试剂、异丙基格氏试剂或烷基锂化合物，较佳地为甲基锂或正丁基锂。In the described step 1, the alkyl metal compound is methyl Grignard reagent, ethyl Grignard reagent, isopropyl Grignard reagent or alkyl lithium compound, preferably methyl lithium or n-butyl lithium .
所述的步骤1中，当所述的R 2为卤素时，所述反应在氨基金属化合物的作用下进行。 In the step 1, when the R 2 is halogen, the reaction is carried out under the action of a metal amide compound.
所述的步骤1中，当所述的R 2为羧基或
Figure PCTCN2022073298-appb-000008
时，所述反应在氨基金属化合物或烷基金属化合物作用下进行。 In described step 1, when described R 2 is carboxyl or
Figure PCTCN2022073298-appb-000008
, the reaction is carried out under the action of a metal amide compound or a metal alkyl compound.
所述的步骤1中，所述的反应可以在本领域常规的有机溶剂中进行，所述有机溶剂包括但不限于乙醚、二氯甲烷、甲苯、2-甲基四氢呋喃或四氢呋喃，较佳地为四氢呋喃。In the step 1, the reaction can be carried out in a conventional organic solvent in the art, the organic solvent includes but is not limited to diethyl ether, dichloromethane, toluene, 2-methyltetrahydrofuran or tetrahydrofuran, preferably Tetrahydrofuran.
所述的步骤1中，所述反应的反应温度为-80～0℃，较佳地为-10～0℃或者-80～-60℃。In the step 1, the reaction temperature of the reaction is -80～0°C, preferably -10～0°C or -80～-60°C.
所述的步骤1中，所述的如式I所示的化合物与如式1所示的化合物的摩尔比为1:1～1:1.6，较佳地为1:1～1.2或者1:1.5～1:1.6，更佳地为1:1.2或1:1.5。In the step 1, the molar ratio of the compound represented by formula I to the compound represented by formula 1 is 1:1-1:1.6, preferably 1:1-1.2 or 1:1.5 ~1:1.6, more preferably 1:1.2 or 1:1.5.
所述的步骤1中，所述反应的反应时间为2～4小时，较佳地为2.5小时。In the step 1, the reaction time of the reaction is 2-4 hours, preferably 2.5 hours.
所述的步骤1中，当所述反应在烷基锂化合物作用下进行时，步骤1所述的反应还包括稳定剂，所述稳定剂为N,N,N',N'-四甲基乙二胺。In the step 1, when the reaction is carried out under the action of an alkyl lithium compound, the reaction described in the step 1 further includes a stabilizer, and the stabilizer is N,N,N',N'-tetramethyl Ethylenediamine.
本发明还提供了一种如式I所示的中间体的制备方法，所述的如式I所示的中间体的制备方法包括以下步骤；The present invention also provides a preparation method of the intermediate shown in formula I, and the preparation method of the intermediate shown in formula I comprises the following steps;
步骤2：在有机碱和缩合剂作用下，通过将如式I-2所示的中间体与如式2所示的化合物进行反应制备如式I所示的中间体；Step 2: under the action of an organic base and a condensing agent, the intermediate shown in formula I is prepared by reacting the intermediate shown in formula I-2 with the compound shown in formula 2;
Figure PCTCN2022073298-appb-000009
Figure PCTCN2022073298-appb-000009
其中，所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基。 Wherein, the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
所述的步骤2中，所述反应的反应温度为20～25℃。In the step 2, the reaction temperature of the reaction is 20-25°C.
所述的步骤2中，所述有机碱选自N,N-二异丙基乙胺。In the step 2, the organic base is selected from N,N-diisopropylethylamine.
所述的步骤2中，所述缩合剂为1-丙基磷酸酐。In the step 2, the condensing agent is 1-propyl phosphoric anhydride.
所述的步骤2中，所述如式I-2所示的中间体与如式2所示的化合物的摩尔比为1:1～1:2，较佳地为1:1.2。In the step 2, the molar ratio of the intermediate represented by the formula I-2 to the compound represented by the formula 2 is 1:1 to 1:2, preferably 1:1.2.
所述的步骤2中，所述如式I-2所示的中间体与有机碱的化合物的摩尔比为1:2～1:4，较佳地为1:2.8～1:3.2，更佳地为1:3。In the step 2, the molar ratio of the intermediate shown in formula I-2 to the compound of the organic base is 1:2～1:4, preferably 1:2.8～1:3.2, more preferably The ground is 1:3.
所述的步骤2中，所述如式I-2所示的中间体与缩合剂的摩尔比为1:1～1:2，较佳地为1:1.5。In the step 2, the molar ratio of the intermediate represented by formula I-2 to the condensing agent is 1:1 to 1:2, preferably 1:1.5.
所述的步骤2中，所述反应的反应时间为14～18小时，较佳地为16小时。In the step 2, the reaction time of the reaction is 14-18 hours, preferably 16 hours.
所述的步骤2中，所述反应在二氯甲烷中进行。In the step 2, the reaction is carried out in dichloromethane.
根据本发明的实施例，所述的如式I所示的中间体的制备方法还包括如式I-2所示中间体的制备方法，所述的如式I-2所示的中间体的制备方法包括以下步骤：According to an embodiment of the present invention, the preparation method of the intermediate shown in the formula I further includes the preparation method of the intermediate shown in the formula I-2. The preparation method includes the following steps:
步骤3：通过将如式3所示的化合物进行还原反应制备如式I-1所示的中间体；Step 3: prepare the intermediate shown in formula I-1 by subjecting the compound shown in formula 3 to reduction reaction;
Figure PCTCN2022073298-appb-000010
Figure PCTCN2022073298-appb-000010
步骤4：在无机碱的作用下，通过将如式I-1所示的中间体水解制备如式I-2所示的中间体；Step 4: under the action of inorganic base, prepare the intermediate shown in formula I-2 by hydrolyzing the intermediate shown in formula I-1;
Figure PCTCN2022073298-appb-000011
Figure PCTCN2022073298-appb-000011
其中，所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基。 Wherein, the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
所述的步骤3中，所述反应还包括氢气。In the step 3, the reaction further includes hydrogen.
所述的步骤3中，所述反应还包括钯碳。In the step 3, the reaction also includes palladium on carbon.
所述的步骤3中，所述反应的反应温度为20～25℃。In the step 3, the reaction temperature of the reaction is 20-25°C.
所述的步骤3中，所述反应中氢气的压力为0.8～1.2个大气压，较佳地为1个大气压。In the step 3, the pressure of the hydrogen in the reaction is 0.8-1.2 atm, preferably 1 atm.
所述的步骤3中，所述钯碳与化合物3的质量比为1:18～1:22，较佳地为1:20。In the step 3, the mass ratio of the palladium carbon to the compound 3 is 1:18～1:22, preferably 1:20.
所述的步骤3中，所述反应的反应时间为22～26小时，较佳地为24小时。In the step 3, the reaction time of the reaction is 22-26 hours, preferably 24 hours.
所述的步骤4中，所述无机碱选自氢氧化锂、氢氧化钠或氢氧化钾，较佳地为氢氧化锂。In the step 4, the inorganic base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide.
所述的步骤4中，所述反应的反应温度为20～25℃。In the step 4, the reaction temperature of the reaction is 20-25°C.
所述的步骤4中，所述如式I-1所示的中间体与无机碱的摩尔比为1:1～1:4，较佳地为1:2。In the step 4, the molar ratio of the intermediate shown in formula I-1 to the inorganic base is 1:1 to 1:4, preferably 1:2.
所述的步骤4中，所述反应的反应时间为14～18小时，较佳地为16小时。In the step 4, the reaction time of the reaction is 14-18 hours, preferably 16 hours.
所述的步骤4中，所述反应在甲醇中进行。In the step 4, the reaction is carried out in methanol.
本发明还提供了一种如式II-1A所示的中间体的制备方法，所述的如式II-1A所示的中间体由如式II-1所示的中间体制备得到，所述的如式II-1A所示的中间体的制备方法包括以下步骤；The present invention also provides a method for preparing the intermediate shown in formula II-1A, wherein the intermediate shown in formula II-1A is prepared from the intermediate shown in formula II-1, and the The preparation method of the intermediate shown in formula II-1A comprises the following steps;
步骤5：在催化剂和有机碱的作用下，通过将如式II-1所示的中间体与一氧化碳和式4所示的化合物进行反应得到如式II-1A所示的中间体；Step 5: under the action of a catalyst and an organic base, the intermediate shown in formula II-1A is obtained by reacting the intermediate shown in formula II-1 with carbon monoxide and the compound shown in formula 4;
Figure PCTCN2022073298-appb-000012
Figure PCTCN2022073298-appb-000012
其中，in,
所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
所述R 2为卤素； The R 2 is halogen;
所述R 2a具有前文所述的定义。 Said R 2a has the previously described definition.
所述的步骤5中，所述的催化剂过渡金属催化剂，所述过渡金属催化剂包括钯金属催化剂、钌金属催化剂、铁金属催化剂、钴金属催化剂、镍金属催化剂、铑金属催化剂，较佳地为钯金属催化剂；In the step 5, the catalyst transition metal catalyst, the transition metal catalyst includes palladium metal catalyst, ruthenium metal catalyst, iron metal catalyst, cobalt metal catalyst, nickel metal catalyst, rhodium metal catalyst, preferably palladium metal catalyst metal catalyst;
较佳地，所述钯催化剂包括四(三苯基膦)钯、醋酸钯、双三苯基磷二氯化钯、1,1-双(二苯基磷)二茂铁氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、三(二亚苄基丙酮)二钯、双(二亚芐基丙酮)钯、1,4-双(二苯基膦丁烷)二氯化钯，更佳地所述钯金属催化剂为1,1-双(二苯基磷)二茂铁氯化钯。Preferably, the palladium catalyst comprises tetrakis(triphenylphosphine) palladium, palladium acetate, bistriphenylphosphonium palladium dichloride, 1,1-bis(diphenylphosphonium)ferrocene palladium chloride, [ 1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, 1, 4-bis(diphenylphosphinobutane) palladium dichloride, more preferably, the palladium metal catalyst is 1,1-bis(diphenylphosphonium)ferrocene palladium chloride.
所述的步骤5中，所述有机碱包括但不限于三乙胺或N,N-二异丙基乙胺，较佳地为三乙胺。In the step 5, the organic base includes but is not limited to triethylamine or N,N-diisopropylethylamine, preferably triethylamine.
所述的步骤5中，所述反应在加压的一氧化碳中进行，所述一氧化碳的压力为40～50psi，较佳地为45psi。In the step 5, the reaction is carried out in pressurized carbon monoxide, and the pressure of the carbon monoxide is 40-50 psi, preferably 45 psi.
所述的步骤5中，所述反应的反应温度为55-65℃。In the step 5, the reaction temperature of the reaction is 55-65°C.
所述的步骤5中，所述反应的反应时间为22～26小时，较佳地为24小时。In the step 5, the reaction time of the reaction is 22-26 hours, preferably 24 hours.
本发明还提供了一种如式II-1A所示的中间体的制备方法，所述的如式II-1A所示的中间体由如式II-1所示的中间体制备得到，所述的如式II-1A所示的中间体的制备方法包括以下步骤；The present invention also provides a method for preparing the intermediate shown in formula II-1A, wherein the intermediate shown in formula II-1A is prepared from the intermediate shown in formula II-1, and the The preparation method of the intermediate shown in formula II-1A comprises the following steps;
步骤6：在碱的作用下，通过将如式II-1所示的中间体与式5所示的化合物进行反应得到如式II-1A所示的中间体；Step 6: under the action of a base, the intermediate shown in formula II-1A is obtained by reacting the intermediate shown in formula II-1 with the compound shown in formula 5;
Figure PCTCN2022073298-appb-000013
Figure PCTCN2022073298-appb-000013
其中，in,
所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
所述R 2为羧基； Described R 2 is carboxyl;
所述R 2a具有前文所述的定义。 Said R 2a has the previously described definition.
所述的步骤6中，所述如式II-1所示的中间体与如式5所示的化合物的摩尔比为1:1～1:2，较佳地为1:1.5。In the step 6, the molar ratio of the intermediate represented by the formula II-1 to the compound represented by the formula 5 is 1:1 to 1:2, preferably 1:1.5.
所述的步骤6中，所述反应的反应温度为20～25℃。In the step 6, the reaction temperature of the reaction is 20-25°C.
所述的步骤6中，所述碱为碳酸氢钠。In the described step 6, the alkali is sodium bicarbonate.
所述的步骤6中，所述反应在N,N-二甲基甲酰胺中进行。In the step 6, the reaction is carried out in N,N-dimethylformamide.
所述的步骤6中，所述的反应时间为22～26小时，较佳地为24小时。In the step 6, the reaction time is 22-26 hours, preferably 24 hours.
本发明还提供了一种如式II-2所示的中间体的制备方法，所述的如式II-2所示的中间体的制备方法包括以下步骤：The present invention also provides a preparation method of the intermediate shown in formula II-2, and the preparation method of the intermediate shown in formula II-2 comprises the following steps:
步骤7：脱去如式II-1A所示的中间体保护基PG 1，得到脱保护基的产物；所述脱保护基的产物在碱的作用下与如式6所示的化合物进行反应，得到如式II-2所示的中间体； Step 7: Removing the intermediate protecting group PG 1 shown in formula II-1A to obtain a deprotected product; the deprotected product is reacted with the compound shown in formula 6 under the action of a base, Obtain the intermediate as shown in formula II-2;
Figure PCTCN2022073298-appb-000014
Figure PCTCN2022073298-appb-000014
其中，in,
所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
所述R 2a具有前文所述的定义。 Said R 2a has the previously described definition.
所述的步骤7中，所述如式II-1A所示的中间体与如式6所示的化合物的摩尔比为1:1～1:2，较佳地为1:1.5。In the step 7, the molar ratio of the intermediate represented by the formula II-1A to the compound represented by the formula 6 is 1:1 to 1:2, preferably 1:1.5.
所述的步骤7中，所述脱去如式II-1A所示的中间体保护基PG 1在盐酸的作用下进行。 In the step 7, the removal of the intermediate protecting group PG 1 shown in formula II-1A is carried out under the action of hydrochloric acid.
所述的步骤7中，所述脱去如式II-1A所示的中间体保护基PG 1在与氢气的反应下进行。 In the step 7, the removal of the intermediate protecting group PG 1 shown in formula II-1A is carried out under the reaction with hydrogen.
所述的步骤7中，所述反应的反应温度为20～25℃。In the step 7, the reaction temperature of the reaction is 20-25°C.
所述的步骤7中，所述的碱包括但不限于三乙胺或N,N-二异丙基乙胺，较佳地为三乙胺。In the step 7, the base includes but is not limited to triethylamine or N,N-diisopropylethylamine, preferably triethylamine.
所述的步骤7中，所述的脱保护基的反应在1,4-二氧六环中进行。In the step 7, the deprotection reaction is carried out in 1,4-dioxane.
所述的步骤7中，所述的脱保护基的反应时间为2～4小时，较佳地为3小时。In the step 7, the reaction time of the deprotection group is 2 to 4 hours, preferably 3 hours.
所述的步骤7中，所述的脱保护基的产物在碱的作用下与如式6所示的化合物的反应在二氯甲烷中进行。In the step 7, the reaction of the deprotected product with the compound shown in formula 6 is carried out in dichloromethane under the action of a base.
所述的步骤7中，所述的脱保护基的产物在碱的作用下与如式6所示的化合物的反应的反应时间为10～14小时，较佳地为12小时。In the step 7, the reaction time of the reaction of the deprotected product with the compound shown in formula 6 under the action of a base is 10-14 hours, preferably 12 hours.
本发明还提供了一种如式II-3所示的中间体的制备方法，所述的如式II-3所示的中间体由如式II-2所示的中间体制备得到，所述的如式II-3所示的中间体的制备方法包括以下步骤：The present invention also provides a method for preparing the intermediate shown in formula II-3, wherein the intermediate shown in formula II-3 is prepared from the intermediate shown in formula II-2, and the The preparation method of the intermediate shown in formula II-3 comprises the following steps:
步骤8：将如式II-2所示的中间体与溴化试剂反应，得到如式II-3所示的中间体；Step 8: react the intermediate shown in formula II-2 with a bromination reagent to obtain the intermediate shown in formula II-3;
Figure PCTCN2022073298-appb-000015
Figure PCTCN2022073298-appb-000015
其中，R 2a具有如前文所述的定义。 wherein R 2a has the definition as previously described.
所述的步骤8中，所述的溴化试剂包括N-溴代丁二酰亚胺、二溴海因、三溴化吡啶、液溴化铜或液溴，较佳地为液溴。In the step 8, the bromination reagent includes N-bromosuccinimide, dibromohydantoin, pyridine tribromide, liquid copper bromide or liquid bromide, preferably liquid bromine.
所述的步骤8中，所述如式II-2所示的中间体与溴化试剂的摩尔比为1:1～1:3，较佳地为1:1.2。In the step 8, the molar ratio of the intermediate shown in formula II-2 to the bromination reagent is 1:1 to 1:3, preferably 1:1.2.
所述的步骤8中，所述的反应在二氯甲烷中进行。In the step 8, the reaction is carried out in dichloromethane.
所述的步骤8中，所述反应的反应温度为20～25℃。In the step 8, the reaction temperature of the reaction is 20-25°C.
所述的步骤8中，所述反应的反应时间为0.5～2小时，较佳地为1小时。In the step 8, the reaction time of the reaction is 0.5 to 2 hours, preferably 1 hour.
本发明还提供了一种如式III所示的中间体的制备方法，所述的如式III所示的中间体由如式II-3所示的中间体制备得到，所述的如式III所示的中间体的制备方法包括以下步骤：The present invention also provides a method for preparing the intermediate shown in formula III, the intermediate shown in formula III is prepared from the intermediate shown in formula II-3, and the intermediate shown in formula III is prepared The preparation method of the intermediate shown comprises the following steps:
步骤9：通过将如式II-3所示的中间体与如式7所示的化合物进行反应得到如式III所示的中间体；Step 9: by reacting the intermediate shown in formula II-3 with the compound shown in formula 7 to obtain the intermediate shown in formula III;
Figure PCTCN2022073298-appb-000016
Figure PCTCN2022073298-appb-000016
其中，in,
所述R 2a具有前文所述的定义； Said R 2a has the above-mentioned definition;
所述R 3选自甲基或氯。 The R3 is selected from methyl or chlorine.
所述的步骤9中，所述反应中如式II-3所示的中间体与所述如式7所示的化合物摩尔比为1:1～1:3，较佳地为1:2。In the step 9, the molar ratio of the intermediate represented by the formula II-3 and the compound represented by the formula 7 in the reaction is 1:1 to 1:3, preferably 1:2.
所述的步骤9中，所述的反应可以在本领域常规的有机溶剂中进行，所述有机溶剂包括但 不限于乙腈、二甲基亚砜、乙醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、1,4-二氧六环、正丙醇或正丁醇，较佳地为乙腈。In the step 9, the reaction can be carried out in a conventional organic solvent in the art, the organic solvent includes but is not limited to acetonitrile, dimethyl sulfoxide, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, n-propanol or n-butanol, preferably acetonitrile.
所述的步骤9中，所述反应的反应温度为110～130℃，较佳地为120℃。In the step 9, the reaction temperature of the reaction is 110-130°C, preferably 120°C.
所述的步骤9中，所述反应的反应时间为22～26小时，较佳地为24小时。In the step 9, the reaction time of the reaction is 22-26 hours, preferably 24 hours.
本发明还提供了一种如式IV所示的咪唑并吡啶化合物的制备方法，所述的如式IV所示的咪唑并吡啶化合物的制备方法包括以下步骤：The present invention also provides a preparation method of the imidazopyridine compound shown in formula IV, and the preparation method of the imidazopyridine compound shown in formula IV comprises the following steps:
步骤10：将如式III所示的中间体与甲胺进行反应，得到如式IV所示的化合物；Step 10: react the intermediate shown in formula III with methylamine to obtain the compound shown in formula IV;
Figure PCTCN2022073298-appb-000017
Figure PCTCN2022073298-appb-000017
其中，in,
所述R 2a具有前文所述的定义； Said R 2a has the above-mentioned definition;
所述R 3选自甲基或氯。 The R3 is selected from methyl or chlorine.
所述的步骤10中，所述如式III所示的中间体与甲胺的摩尔比为1:4～1:6，较佳地为1:5。In the step 10, the molar ratio of the intermediate shown in formula III to methylamine is 1:4 to 1:6, preferably 1:5.
所述的步骤10中，所述反应的反应温度为20～25℃。In the step 10, the reaction temperature of the reaction is 20-25°C.
所述的步骤10中，所述反应在甲醇中进行。In the step 10, the reaction is carried out in methanol.
所述的步骤10中，所属反应的反应时间为4～6小时，较佳地为5小时。In the step 10, the reaction time of the reaction is 4 to 6 hours, preferably 5 hours.
本发明还提供了一种如式3所示的中间体的制备方法，所述的如式3的中间体的制备方法包括以下步骤；The present invention also provides a preparation method of the intermediate shown in formula 3, and the preparation method of the intermediate shown in formula 3 comprises the following steps;
步骤11：将如式3-1所示的中间体与戴斯-马丁氧化剂反应，得到如式3-2所示的中间体；将如式3-2所示的中间体与式8所示的化合物进行反应，得到如式3所示的中间体；Step 11: The intermediate shown in formula 3-1 is reacted with Dess-Martin oxidant to obtain the intermediate shown in formula 3-2; the intermediate shown in formula 3-2 is shown in formula 8 The compound is reacted to obtain the intermediate shown in formula 3;
Figure PCTCN2022073298-appb-000018
Figure PCTCN2022073298-appb-000018
其中，in,
所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基。 The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
所述的步骤11中，所述如式3-1所示的中间体与戴斯-马丁氧化剂的摩尔比为1:1.2。In the step 11, the molar ratio of the intermediate shown in formula 3-1 to the Dess-Martin oxidant is 1:1.2.
所述的步骤11中，所述如式3-1所示的中间体与戴斯-马丁氧化剂的反应温度为20-25℃。In the step 11, the reaction temperature of the intermediate represented by the formula 3-1 and the Dess-Martin oxidant is 20-25°C.
所述的步骤11中，所述如式3-1所示的中间体与戴斯-马丁氧化剂的反应时间为1～3小时，较佳地为2小时。In the step 11, the reaction time between the intermediate shown in formula 3-1 and the Dess-Martin oxidant is 1 to 3 hours, preferably 2 hours.
所述的步骤11中，所述如式3-1所示的中间体与戴斯-马丁氧化剂反应在二氯甲烷中进行。In the step 11, the reaction of the intermediate shown in formula 3-1 with Dess-Martin oxidant is carried out in dichloromethane.
所述的步骤11中，所述如式3-2所示的中间体与化合物8的摩尔比为1:1～1:2，较佳地为1:1.1。In the step 11, the molar ratio of the intermediate shown in formula 3-2 to compound 8 is 1:1 to 1:2, preferably 1:1.1.
所述的步骤11中，所述如式3-1所示的中间体与化合物8的反应温度为20-25℃。In the step 11, the reaction temperature of the intermediate represented by formula 3-1 and compound 8 is 20-25°C.
所述的步骤11中，所述如式3-1所示的中间体与化合物8的反应时间为14～18小时，较佳地为16小时。In the step 11, the reaction time between the intermediate represented by formula 3-1 and compound 8 is 14-18 hours, preferably 16 hours.
所述的步骤11中，所述如式3-1所示的中间体与戴斯-马丁氧化剂反应在二氯甲烷中进行。In the step 11, the reaction of the intermediate shown in formula 3-1 with Dess-Martin oxidant is carried out in dichloromethane.
术语和定义Terms and Definitions
除非另有说明，用于本发明申请，包括本申请说明书和权利要求书中记载的术语和定义如下。Unless otherwise specified, terms and definitions used in the present application, including the description and claims of this application, are as follows.
本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，
Figure PCTCN2022073298-appb-000019
用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。 Those skilled in the art can understand that, according to the convention used in the art, in the structural formula of the present application,
Figure PCTCN2022073298-appb-000019
Used to delineate a chemical bond, which is the point at which a moiety or substituent is attached to a core or backbone structure.
术语“C 1-C 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。 The term "C 1 -C 6 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, the group has 1, 2 or 3 carbon atoms (" C1 -C3 alkyl"), eg methyl, ethyl, n-propyl or isopropyl.
术语“烷基金属化合物”，是指金属原子与烷基碳原子直接相连成键而形成的有机化合物。所述烷基包括但不限于烷基或环烷基，例如C 1-C 6烷基。所述金属原子包括但不限于钾、钠、锂、镁或铝。所述烷基金属化合物包括但不限于格氏试剂、烷基锂化合物。 The term "metal alkyl compound" refers to an organic compound in which a metal atom is directly bonded to an alkyl carbon atom to form a bond. The alkyl groups include, but are not limited to, alkyl or cycloalkyl groups, such as C1 - C6 alkyl groups. The metal atoms include, but are not limited to, potassium, sodium, lithium, magnesium, or aluminum. The alkyl metal compounds include but are not limited to Grignard reagents, alkyl lithium compounds.
术语“氨基金属化合物”，是指金属原子与氨基基团通过共价键或配位键结合形成的化合物，所述“氨基”氨基是指伯(即–NH 2)、仲(即–NRH)和叔(即–NRR)胺，所述R包括但不限于 C 1-C 6的烷基、环烷基或硅基，所述金属原子包括但不限于钾、钠、锂或镁，所述氨基金属化合物包括但不限于二异丙基氨基锂、双三甲基硅基胺基锂、双三甲基硅基胺基钾、双三甲基硅基胺基钠、氨基钠、氨基钾、氨基锂。 The term "amino metal compound" refers to a compound formed by the combination of a metal atom and an amino group through covalent or coordinate bonds, and the "amino" amino group refers to primary (ie -NH 2 ), secondary (ie -NRH) and tertiary (i.e. -NRR) amines, the R includes but is not limited to a C 1 -C 6 alkyl, cycloalkyl or silicon group, the metal atom includes but is not limited to potassium, sodium, lithium or magnesium, the Amino metal compounds include but are not limited to lithium diisopropylamide, lithium bis-trimethylsilyl amide, potassium bis-trimethylsilyl amide, sodium bis-trimethylsilyl amide, sodium amide, potassium amide, Lithium amide.
术语“卤代基”或“卤素”为氟、氯、溴和碘。The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.
术语“催化剂”是指可以影响，诱导，增加或促进化合物反应性或反应的任何物质或试剂。The term "catalyst" refers to any substance or agent that can affect, induce, increase or promote the reactivity or reaction of a compound.
术语“过渡金属催化剂”是指在其d轨道上具有电子的任何金属，例如选自元素周期表的3-12族或镧系元素的金属。可用于本发明方法的催化剂包括来自周期表第8-11族的过渡金属的原子，离子，盐或配合物。“元素周期表的3-12族”是指根据IUPAC方法编号的周期表族。因此，第8-11族的过渡金属包括铁、钌、钴、铑、铱、镍、钯、铂、铜，银和金。这种催化剂包括不限于CuI、CuCl、CuBr、CuBr 2、Cu 2Cl 2、Cu 2O、Cu、Pd 2(dba) 2、Pd/C、PdCl 2、Pd(OAc) 2、(CH 3CN) 2PdCl 2、Pd[P(C 6H 5) 3] 4、NiCl 2[P(C 6H 5)] 2和Ni(COD) 2。 The term "transition metal catalyst" refers to any metal having an electron in its d orbital, such as a metal selected from Groups 3-12 of the Periodic Table of the Elements or the lanthanides. Catalysts useful in the process of the present invention include atoms, ions, salts or complexes of transition metals from Groups 8-11 of the Periodic Table. "Groups 3-12 of the Periodic Table" means the Periodic Table groups numbered according to the IUPAC method. Thus, transition metals of Groups 8-11 include iron, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver and gold. Such catalysts include but are not limited to CuI, CuCl, CuBr, CuBr2, Cu2Cl2 , Cu2O, Cu, Pd2 ( dba )2 , Pd/C, PdCl2 , Pd(OAc )2 , ( CH3CN ) ) 2 PdCl 2 , Pd[P(C 6 H 5 ) 3 ] 4 , NiCl 2 [P(C 6 H 5 )] 2 and Ni(COD) 2 .
术语“R 2a-I”，是指含有R 2a的碘试剂。 The term " R2a -I" refers to an iodine reagent containing R2a .
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
具体实施方式Detailed ways
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The solution of the present invention will be explained below with reference to the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. If no specific technique or condition is indicated in the examples, the technique or condition described in the literature in the field or the product specification is used. The reagents or instruments used without the manufacturer's indication are conventional products that can be obtained from the market.
如无特别说明，本发明的化合物均是通过核磁共振(NMR)和/或质谱(MS)来确定其结构的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。 Unless otherwise specified, the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are 10-6 (ppm). The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
本发明的缩写定义如下：Abbreviations of the present invention are defined as follows:
M：摩尔浓度，如1M盐酸表示1mol/L盐酸溶液M: molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
DIPEA：也可写为DIEA，二异丙基乙胺，亦即N,N-二异丙基乙胺DIPEA: can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
DMF：N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide
DCM：二氯甲烷DCM: dichloromethane
Et 3N：三乙胺 Et 3 N: triethylamine
Dess-Martin：戴斯-马丁氧化剂Dess-Martin: Dess-Martin Oxidizer
T 3P：1-丙基磷酸酐 T 3 P: 1-propyl phosphoric anhydride
LDA：二异丙基氨基锂LDA: lithium diisopropylamide
n-BuLi：正丁基锂n-BuLi: n-butyllithium
TMEDA：N,N,N',N'-四甲基乙二胺TMEDA: N,N,N',N'-Tetramethylethylenediamine
NaHCO 3：碳酸氢钠 NaHCO 3 : sodium bicarbonate
THF：四氢呋喃THF: Tetrahydrofuran
Pd(dppf)Cl 2：1,1-双(二苯基磷)二茂铁氯化钯 Pd(dppf)Cl 2 : 1,1-bis(diphenylphosphonium)ferrocene palladium chloride
LC-MS：液质联用色谱LC-MS: Liquid chromatography-mass spectrometry
TLC：薄层色谱TLC: Thin Layer Chromatography
制备1：中间体(S)-2-(3-(甲氧基(甲基)氨基)-3-氧丙基)吗啉-4-羧酸叔丁酯(A)的制备Preparation 1: Preparation of intermediate (S)-tert-butyl 2-(3-(methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylate (A)
Figure PCTCN2022073298-appb-000020
Figure PCTCN2022073298-appb-000020
目标中间体A的合成路线如下所示：The synthetic route of the target intermediate A is as follows:
Figure PCTCN2022073298-appb-000021
Figure PCTCN2022073298-appb-000021
第一步：(R)-2-甲酰基吗啉-4-羧酸叔丁酯(A-2)的合成The first step: Synthesis of (R)-2-formylmorpholine-4-carboxylic acid tert-butyl ester (A-2)
Figure PCTCN2022073298-appb-000022
Figure PCTCN2022073298-appb-000022
在2L三口瓶中加入(R)-2-羟甲基吗啉-4-甲酸叔丁酯(A-1)(100g,460mmol)、二氯甲烷(1L)。调节反应温度至0-5℃,缓慢分批加入戴斯-马丁氧化剂(234g,552mmol)同时将反应温度维持在0-5℃,反应继续在0-5℃下搅拌0.5h。将反应温度调节至20-25℃并且继续搅拌2h, TLC显示原料反应完全。将反应液缓慢倒入饱和溶液碳酸氢钠(1L)中并且搅拌0.5h，过滤、分液后收集有机相。有机相用饱和碳酸氢钠溶液(1L×2)洗涤，经过无水硫酸钠干燥并且减压下浓缩得到无色油状(R)-2-甲酰基吗啉-4-羧酸叔丁酯(A-2)(99g,产率100％)。In a 2L three-necked flask, (R)-2-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (A-1) (100 g, 460 mmol) and dichloromethane (1 L) were added. The reaction temperature was adjusted to 0-5°C, Dess-Martin oxidant (234 g, 552 mmol) was slowly added in batches while maintaining the reaction temperature at 0-5°C, and the reaction was continued to stir at 0-5°C for 0.5 h. The reaction temperature was adjusted to 20-25 °C and stirring was continued for 2 h, TLC showed that the starting material was fully reacted. The reaction solution was slowly poured into a saturated solution of sodium bicarbonate (1 L) and stirred for 0.5 h, and the organic phase was collected after filtration and separation. The organic phase was washed with saturated sodium bicarbonate solution (1L×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R)-tert-butyl 2-formylmorpholine-4-carboxylate (A) as a colorless oil. -2) (99 g, 100% yield).
第二步：(S)-2-(3-甲氧基-3-氧代丙-1-烯-1-基)吗啉-4-羧酸叔丁酯(A-3)的合成The second step: Synthesis of (S)-2-(3-methoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylic acid tert-butyl ester (A-3)
Figure PCTCN2022073298-appb-000023
Figure PCTCN2022073298-appb-000023
在2L三口瓶中加入(R)-2-甲酰基吗啉-4-羧酸叔丁酯(A-2)(99g,460mmol)、二氯甲烷(1L)。调节反应温度至20-25℃,缓慢分批加入甲氧甲酰基亚甲基三苯基膦(154g,460mmol)同时将反应温度维持在20-25℃,反应继续在20-25℃下搅拌16h，TLC显示原料反应完全。反应液在减压下浓缩干，残余物经过硅胶柱色谱纯化得到无色油状(S)-2-(3-甲氧基-3-氧代丙-1-烯-1-基)吗啉-4-羧酸叔丁酯(A-3)(75g,产率60.1％)。In a 2L three-necked flask, (R)-2-formylmorpholine-4-carboxylic acid tert-butyl ester (A-2) (99 g, 460 mmol) and dichloromethane (1 L) were added. Adjust the reaction temperature to 20-25°C, slowly add methoxyformylmethylene triphenylphosphine (154 g, 460 mmol) in batches while maintaining the reaction temperature at 20-25°C, and continue to stir the reaction at 20-25°C for 16h , TLC showed that the reaction of the starting material was complete. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give (S)-2-(3-methoxy-3-oxoprop-1-en-1-yl)morpholine- tert-Butyl 4-carboxylate (A-3) (75 g, 60.1% yield).
1H NMR(400MHz,Chloroform-d)δ6.83(ddd,J＝15.9,4.2,1.0Hz,0.76H),6.16–6.07(m,1H),5.87(dt,J＝11.8,1.2Hz,0.24H),4.18–3.80(m,4H),3.74(s,1.0Hz,3H),3.64–3.53(m,1H),3.05–2.85(m,1H),2.75–2.55(m,1H),1.47(t,J＝1.6Hz,9H). 1 H NMR (400MHz, Chloroform-d) δ 6.83 (ddd, J=15.9, 4.2, 1.0Hz, 0.76H), 6.16-6.07 (m, 1H), 5.87 (dt, J=11.8, 1.2Hz, 0.24 H), 4.18–3.80 (m, 4H), 3.74 (s, 1.0Hz, 3H), 3.64–3.53 (m, 1H), 3.05–2.85 (m, 1H), 2.75–2.55 (m, 1H), 1.47 (t,J=1.6Hz,9H).
第三步：(S)-2-(3-甲氧基-3-氧丙基)吗啉-4-羧酸叔丁酯(A-4)的合成The third step: synthesis of (S)-2-(3-methoxy-3-oxypropyl) morpholine-4-carboxylic acid tert-butyl ester (A-4)
Figure PCTCN2022073298-appb-000024
Figure PCTCN2022073298-appb-000024
在2L单口瓶中加入(S)-2-(3-甲氧基-3-氧代丙-1-烯-1-基)吗啉-4-羧酸叔丁酯(A-3)(75g,276mmol)、甲醇(750mL)，反应体系置换氮气3次，加入Pd/C(3.75g),反应体系用氢气置换3次，调节反应温度至20-25℃并在1atm氢气氛围下搅拌24h,TLC显示原料反应完全。反应体系置换氮气3次，过滤得到(S)-2-(3-甲氧基-3-氧丙基)吗啉-4-羧酸叔丁酯(A-4)(76g,产率100％)的甲醇溶液直接用于下一步。Add (S)-2-(3-methoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate tert-butyl ester (A-3) (75g) into a 2L single-neck bottle , 276mmol), methanol (750mL), the reaction system was replaced with nitrogen 3 times, Pd/C (3.75g) was added, the reaction system was replaced with hydrogen 3 times, the reaction temperature was adjusted to 20-25 ℃ and stirred for 24h under 1atm hydrogen atmosphere, TLC showed complete reaction of starting material. The reaction system was replaced with nitrogen three times, and filtered to obtain (S)-2-(3-methoxy-3-oxopropyl)morpholine-4-carboxylate tert-butyl ester (A-4) (76g, yield 100%) ) in methanol was used directly in the next step.
1H NMR(400MHz,Chloroform-d)δ3.90–3.65(m,3H),3.59(s,3H),3.44–3.33(m,1H),3.33–3.22(m,1H),2.83(t,J＝13.2Hz,1H),2.50(t,J＝22.0Hz,1H),2.45–2.24(m,2H),1.78–1.61(m,2H),1.40–1.36(m,9H)。 1 H NMR (400MHz, Chloroform-d)δ3.90-3.65(m,3H), 3.59(s,3H), 3.44-3.33(m,1H), 3.33-3.22(m,1H), 2.83(t, J=13.2Hz, 1H), 2.50 (t, J=22.0Hz, 1H), 2.45–2.24 (m, 2H), 1.78–1.61 (m, 2H), 1.40–1.36 (m, 9H).
第四步：(S)-3-(4-(叔丁氧基羰基)吗啉-2-基)丙酸(A-5)的合成The fourth step: the synthesis of (S)-3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionic acid (A-5)
Figure PCTCN2022073298-appb-000025
Figure PCTCN2022073298-appb-000025
在2L三口瓶中加入(S)-2-(3-甲氧基-3-氧丙基)吗啉-4-羧酸叔丁酯(A-4)(76g，278mmol)的甲醇(750mL)溶液，加入75mL水，调节反应温度至20-25℃,缓慢加入一水合氢氧化锂(23.3g,556mmol)同时保持反应温度在20-25℃，反应继续在20-25℃下搅拌16h。减压下浓缩干甲醇,加入400mL水，水相用乙酸乙酯(200mL×2)洗涤，收集水相，调节水相温度至0-5℃,搅拌下用4M盐酸水溶液调节pH至4-5，用二氯甲烷(400mL×3)萃取水相，合并有机相用无水硫酸钠干燥并在减压下浓缩得到无色油状(S)-3-(4-(叔丁氧基羰基)吗啉-2-基)丙酸(A-5)(72g,产率99.8％)。In a 2L three-necked flask, add (S)-2-(3-methoxy-3-oxopropyl)morpholine-4-carboxylate tert-butyl ester (A-4) (76g, 278mmol) in methanol (750mL) solution, add 75 mL of water, adjust the reaction temperature to 20-25 °C, slowly add lithium hydroxide monohydrate (23.3 g, 556 mmol) while keeping the reaction temperature at 20-25 °C, and continue to stir the reaction at 20-25 °C for 16h. Concentrate dry methanol under reduced pressure, add 400 mL of water, wash the aqueous phase with ethyl acetate (200 mL×2), collect the aqueous phase, adjust the temperature of the aqueous phase to 0-5 °C, and adjust the pH to 4-5 with 4M aqueous hydrochloric acid under stirring , the aqueous phase was extracted with dichloromethane (400 mL×3), the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S)-3-(4-(tert-butoxycarbonyl)-(S)-3-(4-(tert-butoxycarbonyl)) as a colorless oil. olin-2-yl)propionic acid (A-5) (72 g, 99.8% yield).
1H NMR(400MHz,Chloroform-d)δ3.97–3.69(m,3H),3.46(td,J＝11.7,2.8Hz,1H),3.41–3.32(m,1H),2.97-2.81(m,1H),2.67–2.38(m,J＝21.0,16.7,9.5Hz,3H),1.76(qd,J＝9.9,8.6,6.1Hz,2H),1.44(s,9H). 1 H NMR(400MHz, Chloroform-d)δ3.97-3.69(m,3H),3.46(td,J=11.7,2.8Hz,1H),3.41-3.32(m,1H),2.97-2.81(m, 1H), 2.67–2.38 (m, J=21.0, 16.7, 9.5Hz, 3H), 1.76 (qd, J=9.9, 8.6, 6.1Hz, 2H), 1.44 (s, 9H).
第五步：(S)-2-(3-(甲氧基(甲基)氨基)-3-氧丙基)吗啉-4-羧酸叔丁酯(A)的合成Step 5: Synthesis of (S)-2-(3-(methoxy(methyl)amino)-3-oxypropyl)morpholine-4-carboxylic acid tert-butyl ester (A)
Figure PCTCN2022073298-appb-000026
Figure PCTCN2022073298-appb-000026
在2L三口瓶中加入(S)-3-(4-(叔丁氧基羰基)吗啉-2-基)丙酸(A-5)(72g,278mmol)、N,O-二甲基羟胺盐酸盐(32.5g,333mmol)和二氯甲烷(720mL)，将反应温度调节至0-5℃。向反应液中缓慢滴加DIEA(108g,833mmol)、1-丙基磷酸酐(50％的DMF溶液，265g，417mmol)。调节反应内温至20-25℃并且搅拌16h。将500mL饱和NaHCO 3溶液缓慢滴加至反应液中，分液并收集有机相。有机相用500mL饱和碳酸氢钠溶液洗涤并在减压下浓缩干。向残留物中加入360mL乙酸乙酯,用饱和的氯化铵洗涤(300mL×3)，有机相在减压下浓缩干得到无色油状(S)-2-(3-(甲氧基(甲基)氨基)-3-氧丙基)吗啉-4-羧酸叔丁酯(A)(71g,产率85％)。 In a 2L three-necked flask, add (S)-3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionic acid (A-5) (72g, 278mmol), N,O-dimethylhydroxylamine The hydrochloride salt (32.5 g, 333 mmol) and dichloromethane (720 mL), and the reaction temperature was adjusted to 0-5 °C. DIEA (108 g, 833 mmol) and 1-propylphosphoric anhydride (50% solution in DMF, 265 g, 417 mmol) were slowly added dropwise to the reaction solution. The internal temperature of the reaction was adjusted to 20-25 °C and stirred for 16 h. 500 mL of saturated NaHCO 3 solution was slowly added dropwise to the reaction solution, the layers were separated and the organic phase was collected. The organic phase was washed with 500 mL of saturated sodium bicarbonate solution and concentrated to dryness under reduced pressure. To the residue was added 360 mL of ethyl acetate, washed with saturated ammonium chloride (300 mL×3), and the organic phase was concentrated to dryness under reduced pressure to obtain (S)-2-(3-(methoxy(methyl)) as a colorless oil. (A) (71 g, 85% yield).
1H NMR(400MHz,Chloroform-d)δ3.96–3.74(m,3H),3.67(s,3H),3.46(td,J＝11.7,2.9Hz,1H),3.36(td,J＝7.9,6.8,4.2Hz,1H),3.16(s,3H),2.98–2.83(m,1H),2.55(dd,J＝13.8,6.6Hz,3H),1.87–1.70(m,2H),1.44(s,9H)。 1 H NMR (400MHz, Chloroform-d) δ3.96-3.74 (m, 3H), 3.67 (s, 3H), 3.46 (td, J=11.7, 2.9Hz, 1H), 3.36 (td, J=7.9, 6.8,4.2Hz,1H),3.16(s,3H),2.98-2.83(m,1H),2.55(dd,J=13.8,6.6Hz,3H),1.87-1.70(m,2H),1.44(s , 9H).
制备2：中间体(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸叔丁酯(B) 的制备Preparation 2: Intermediate (S)-tert-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid Preparation of Butyl Ester (B)
Figure PCTCN2022073298-appb-000027
Figure PCTCN2022073298-appb-000027
目标中间体B的合成路线如下所示：The synthetic route of the target intermediate B is as follows:
Figure PCTCN2022073298-appb-000028
Figure PCTCN2022073298-appb-000028
第一步：(S)-2-(3-(4-溴-2,3,6-三氟苯基)-3-氧丙基)吗啉-4-羧酸叔丁酯(B-1)的合成The first step: (S)-2-(3-(4-bromo-2,3,6-trifluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-1 )Synthesis
Figure PCTCN2022073298-appb-000029
Figure PCTCN2022073298-appb-000029
在氮气氛围下，向2L三口瓶中加入2,3,5-三氟溴苯(74.3g,352mmol)、无水四氢呋喃(710mL),调节反应温度至-10～0℃,缓慢滴加二异丙基氨基锂(176mL,352mmol,2mol/L的四氢呋喃溶液)同时维持反应温度在-10～0℃，反应液继续搅拌1h后,缓慢向溶液中滴加(S)-2-(3-(甲氧基(甲基)氨基)-3-氧丙基)吗啉-4-羧酸叔丁酯(A)(71g,235mmol)的四氢呋喃(140mL)溶液,反应继续在-10～0℃搅拌2h，TLC显示反应完全。向反应液中缓慢滴加饱和氯化铵溶液(500mL)，反应液升至室温，加入500mL乙酸乙酯稀释，分液并且用500mL乙酸乙酯萃取水相，合并有机相用饱和氯化铵(1L)洗涤，收集的有机相经无水硫酸钠干燥、减压浓缩，最后通过硅胶柱色谱(乙酸乙酯:石油醚＝1:5)纯化得到白色固体(S)-2-(3-(4-溴-2,3,6-三氟苯基)-3-氧丙基)吗啉-4-羧酸叔丁酯(B-1)(91g,产率86％)。Under a nitrogen atmosphere, 2,3,5-trifluorobromobenzene (74.3g, 352mmol) and anhydrous tetrahydrofuran (710mL) were added to a 2L three-necked flask, the reaction temperature was adjusted to -10～0°C, and diiso was slowly added dropwise. Lithium propylamide (176 mL, 352 mmol, 2 mol/L tetrahydrofuran solution) while maintaining the reaction temperature at -10 ~ 0 ° C, the reaction solution was stirred for 1 h, and (S)-2-(3-() was slowly added dropwise to the solution. Methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylate tert-butyl ester (A) (71g, 235mmol) in tetrahydrofuran (140mL) solution, the reaction continued to stir at -10～0℃ 2h, TLC showed that the reaction was complete. Saturated ammonium chloride solution (500 mL) was slowly added dropwise to the reaction solution, the reaction solution was warmed to room temperature, 500 mL of ethyl acetate was added to dilute, the layers were separated and the aqueous phase was extracted with 500 mL of ethyl acetate, and the organic phases were combined with saturated ammonium chloride ( 1L) was washed, the collected organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5) to obtain a white solid (S)-2-(3-( 4-Bromo-2,3,6-trifluorophenyl)-3-oxopropyl)morpholine-4-carboxylate tert-butyl ester (B-1) (91 g, 86% yield).
1H NMR(400MHz,Chloroform-d)δ7.22–7.15(m,1H),3.85–3.78(m,3H),3.44(td,J＝11.7,2.8Hz,1H),3.36(ddt,J＝12.8,10.2,3.1Hz,1H),3.07–2.80(m,3H),2.68–2.54(s,1H),1.92(dtd,J＝14.5,7.3,3.7Hz,1H),1.81(tq,J＝14.0,8.0,6.8Hz,1H),1.45(s,9H). 1 H NMR (400MHz, Chloroform-d) δ 7.22-7.15 (m, 1H), 3.85-3.78 (m, 3H), 3.44 (td, J=11.7, 2.8Hz, 1H), 3.36 (ddt, J= 12.8, 10.2, 3.1Hz, 1H), 3.07–2.80 (m, 3H), 2.68–2.54 (s, 1H), 1.92 (dtd, J=14.5, 7.3, 3.7Hz, 1H), 1.81 (tq, J= 14.0,8.0,6.8Hz,1H),1.45(s,9H).
LC-MS,M/Z:352.1[M+H] + LC-MS, M/Z: 352.1[M+H] +
第二步：(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸叔丁酯(B)的合成The second step: (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl Synthesis of Ester (B)
Figure PCTCN2022073298-appb-000030
Figure PCTCN2022073298-appb-000030
将(S)-2-(3-(4-溴-2,3,6-三氟苯基)-3-氧丙基)吗啉-4-羧酸叔丁酯(B-1)(91.0g，201mmol)溶解在甲醇(1L)中，加入三乙胺(60g，603mmol)和1,1-双(二苯基磷)二茂铁氯化钯(5.90g，8.05mmol)，抽真空，氮气置换三次，一氧化碳置换三次，然后在一氧化碳(45psi)条件下，55-65℃反应24小时。TLC显示反应完全，将反应液浓缩干，然后加入水(1L)，用柠檬酸调至中性，然后用乙酸乙酯(800mL×2)萃取，有机相合并，用无水硫酸钠干燥，过滤，浓缩得到棕色油状化合物(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸叔丁酯(B)(82g，产率93.5％)。(S)-tert-butyl 2-(3-(4-bromo-2,3,6-trifluorophenyl)-3-oxopropyl)morpholine-4-carboxylate (B-1) (91.0 g, 201 mmol) was dissolved in methanol (1 L), triethylamine (60 g, 603 mmol) and 1,1-bis(diphenylphosphonium)ferrocene palladium chloride (5.90 g, 8.05 mmol) were added, vacuum was applied, The nitrogen was replaced three times, and the carbon monoxide was replaced three times, and then the reaction was carried out at 55-65° C. for 24 hours under the condition of carbon monoxide (45 psi). TLC showed that the reaction was complete, the reaction solution was concentrated to dryness, then added with water (1L), adjusted to neutrality with citric acid, then extracted with ethyl acetate (800mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered , concentrated to give a brown oily compound (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-Butyl ester (B) (82 g, 93.5% yield).
1H NMR(400MHz,Chloroform-d)δ7.52–7.27(m,1H),3.98(s,3H),3.85–3.82(m,3H)，3.46–3.38(m,2H)，3.05–2.90(m,2H)，2.90–2.77(m,1H)，2.75–2.51(m,1H)，1.96–1.82(m,2H)，1.47(s,9H). 1 H NMR (400MHz, Chloroform-d) δ7.52-7.27(m,1H), 3.98(s,3H), 3.85-3.82(m,3H), 3.46-3.38(m,2H), 3.05-2.90( m, 2H), 2.90–2.77 (m, 1H), 2.75–2.51 (m, 1H), 1.96–1.82 (m, 2H), 1.47 (s, 9H).
LC-MS,M/Z:332.2[M+H] +。 LC-MS, M/Z: 332.2 [M+H] + .
制备3：中间体(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸叔丁酯(B)的制备Preparation 3: Intermediate (S)-tert-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid Preparation of Butyl Ester (B)
Figure PCTCN2022073298-appb-000031
Figure PCTCN2022073298-appb-000031
目标中间体B的合成路线如下所示：The synthetic route of the target intermediate B is as follows:
Figure PCTCN2022073298-appb-000032
Figure PCTCN2022073298-appb-000032
第一步：(S)-2-(3-(4-溴-2,3,6-三氟苯基)-3-氧丙基)吗啉-4-羧酸叔丁酯(B-2)的合成The first step: (S)-2-(3-(4-bromo-2,3,6-trifluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-2 )Synthesis
Figure PCTCN2022073298-appb-000033
Figure PCTCN2022073298-appb-000033
在氮气氛围下，向500mL三口瓶中加入2,3,5-三氟溴苯(10.5g,50mmol)、无水四氢呋喃(100mL),调节反应温度至-80～-60℃,缓慢滴加二异丙基氨基锂(25mL,50mmol,2mol/L的四氢呋喃溶液)同时维持反应温度在-80～-60℃，反应液继续搅拌1h后,缓慢向溶液中滴加 (S)-2-(3-(甲氧基(甲基)氨基)-3-氧丙基)吗啉-4-羧酸叔丁酯(A)(10g,33mmol)的四氢呋喃(20mL)溶液,继续在-80～-60℃搅拌2h，TLC显示反应完全。向反应液中缓慢滴加饱和氯化铵溶液(100mL)，反应液升至室温，加入100mL乙酸乙酯稀释，分液并且用100mL乙酸乙酯萃取水相，合并有机相用饱和氯化铵(200mL)洗涤，收集的有机相经无水硫酸钠干燥、减压浓缩，最后通过硅胶柱色谱(乙酸乙酯:石油醚＝1:5)纯化得到白色固体(S)-2-(3-(4-溴-2,3,6-三氟苯基)-3-氧丙基)吗啉-4-羧酸叔丁酯(B-2)(9.3g,产率62％)。Under a nitrogen atmosphere, 2,3,5-trifluorobromobenzene (10.5g, 50mmol) and anhydrous tetrahydrofuran (100mL) were added to a 500mL three-necked flask, the reaction temperature was adjusted to -80～-60°C, and two Lithium isopropylamide (25 mL, 50 mmol, 2 mol/L tetrahydrofuran solution) while maintaining the reaction temperature at -80 to -60 °C, the reaction solution was stirred for 1 h, and (S)-2-(3) was slowly added dropwise to the solution. -(Methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylate tert-butyl ester (A) (10 g, 33 mmol) in tetrahydrofuran (20 mL), continue at -80～-60 It was stirred at °C for 2 h, and TLC showed that the reaction was complete. Saturated ammonium chloride solution (100 mL) was slowly added dropwise to the reaction solution, the reaction solution was warmed to room temperature, diluted with 100 mL of ethyl acetate, separated and the aqueous phase was extracted with 100 mL of ethyl acetate, and the organic phases were combined with saturated ammonium chloride ( 200 mL) was washed, the collected organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5) to obtain a white solid (S)-2-(3-( 4-Bromo-2,3,6-trifluorophenyl)-3-oxopropyl)morpholine-4-carboxylate tert-butyl ester (B-2) (9.3 g, 62% yield).
LC-MS,M/Z:352.1[M+H] + LC-MS, M/Z: 352.1[M+H] +
第二步：(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸叔丁酯(B)的合成The second step: (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl Synthesis of Ester (B)
Figure PCTCN2022073298-appb-000034
Figure PCTCN2022073298-appb-000034
将(S)-2-(3-(4-溴-2,3,6-三氟苯基)-3-氧丙基)吗啉-4-羧酸叔丁酯(B-2)(9.3g，20.5mmol)溶解在甲醇(93mL)中，加入三乙胺(6.12g，61.5mmol)和1,1-双(二苯基磷)二茂铁氯化钯(0.6g，0.82mmol)，抽真空，氮气置换三次，一氧化碳置换三次，然后在一氧化碳(45psi)条件下，55-65℃反应24小时。TLC显示反应完全，将反应液浓缩干，然后加入水(100mL)，用柠檬酸调至中性，然后用乙酸乙酯(100mL×2)萃取，有机相合并，用无水硫酸钠干燥，过滤，浓缩得到棕色油状化合物(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸叔丁酯(B)(8g，产率91％)。(S)-tert-butyl 2-(3-(4-bromo-2,3,6-trifluorophenyl)-3-oxopropyl)morpholine-4-carboxylate (B-2) (9.3 g, 20.5 mmol) was dissolved in methanol (93 mL), triethylamine (6.12 g, 61.5 mmol) and 1,1-bis(diphenylphosphonium)ferrocene palladium chloride (0.6 g, 0.82 mmol) were added, Evacuate, replace with nitrogen three times, replace with carbon monoxide three times, and then react at 55-65° C. for 24 hours under the condition of carbon monoxide (45 psi). TLC showed that the reaction was complete, the reaction solution was concentrated to dryness, then added with water (100 mL), adjusted to neutrality with citric acid, then extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. , concentrated to give a brown oily compound (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-Butyl ester (B) (8 g, 91% yield).
LC-MS,M/Z:332.2[M+H] +。 LC-MS, M/Z: 332.2 [M+H] + .
制备4：中间体(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸叔丁酯(B)的制备Preparation 4: Intermediate (S)-tert-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid Preparation of Butyl Ester (B)
Figure PCTCN2022073298-appb-000035
Figure PCTCN2022073298-appb-000035
目标中间体B的合成路线如下所示：The synthetic route of the target intermediate B is as follows:
Figure PCTCN2022073298-appb-000036
Figure PCTCN2022073298-appb-000036
第一步：(S)-4-(3-(4-(叔丁氧基羰基)吗啉-2-基)丙酰基)-2,3,5-三氟苯甲酸(B-3)的合成The first step: (S)-4-(3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionyl)-2,3,5-trifluorobenzoic acid (B-3) synthesis
Figure PCTCN2022073298-appb-000037
Figure PCTCN2022073298-appb-000037
在氮气氛围下，向250mL三口瓶中加入2,3,5-三氟苯甲酸(7.0g,40mmol)、TMEDA(10.2g,88mmol)、无水四氢呋喃(100mL),调节反应温度至-10～0℃,缓慢滴加正丁基锂(35.2mL,88mmol,2.5mol/L的正己烷溶液)同时维持反应温度在-10～0℃，反应液继续搅拌0.5h后,缓慢向溶液中滴加(S)-2-(3-(甲氧基(甲基)氨基)-3-氧丙基)吗啉-4-羧酸叔丁酯(A)(10g,33mmol)的四氢呋喃(20mL)溶液,继续在-10～0℃搅拌2h，TLC显示反应完全。向反应液中缓慢滴加水(100mL)，反应液升至室温，用1M盐酸水溶液调节水相pH至4-5，加入100mL乙酸乙酯稀释，分液并且用100mL乙酸乙酯萃取水相，合并有机相，收集的有机相经无水硫酸钠干燥、减压浓缩，得到白色固体(S)-4-(3-(4-(叔丁氧基羰基)吗啉-2-基)丙酰基)-2,3,5-三氟苯甲酸(B-3)(7.6g,产率55％)。Under nitrogen atmosphere, 2,3,5-trifluorobenzoic acid (7.0g, 40mmol), TMEDA (10.2g, 88mmol), anhydrous tetrahydrofuran (100mL) were added to a 250mL three-necked flask, and the reaction temperature was adjusted to -10～ 0°C, slowly add n-butyllithium (35.2mL, 88mmol, 2.5mol/L n-hexane solution) dropwise while maintaining the reaction temperature at -10～0°C, after the reaction solution continues to stir for 0.5h, slowly add dropwise to the solution A solution of (S)-tert-butyl 2-(3-(methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylate (A) (10 g, 33 mmol) in tetrahydrofuran (20 mL) , Continue to stir at -10 ~ 0 ℃ for 2h, TLC shows that the reaction is complete. Water (100 mL) was slowly added dropwise to the reaction solution, the reaction solution was warmed to room temperature, the pH of the aqueous phase was adjusted to 4-5 with 1M aqueous hydrochloric acid, diluted with 100 mL of ethyl acetate, separated and the aqueous phase was extracted with 100 mL of ethyl acetate, combined The organic phase, the collected organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a white solid (S)-4-(3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionyl) -2,3,5-Trifluorobenzoic acid (B-3) (7.6 g, 55% yield).
LC-MS,M/Z:318.1[M+H] + LC-MS, M/Z: 318.1[M+H] +
第二步：(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸叔丁酯(B)的合成The second step: (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl Synthesis of Ester (B)
Figure PCTCN2022073298-appb-000038
Figure PCTCN2022073298-appb-000038
将(S)-4-(3-(4-(叔丁氧基羰基)吗啉-2-基)丙酰基)-2,3,5-三氟苯甲酸(B-3)(7.6g，18.2mmol)溶解在N,N-二甲基甲酰胺(76mL)中，加入碳酸氢钠(3.06g，36.4mmol)和碘甲烷(3.87g，27.3mmol)，反应在20-25℃反应24小时。TLC显示反应完全，向反应液中加入水(100mL)，然后用乙酸乙酯(100mL×2)萃取，合并有机相，用饱和的碳酸氢钠溶液(300mL×2)以及饱和的氯化钠溶液(300mL)洗涤,无水硫酸钠干燥，过滤，浓缩得到棕色油状化合物(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸叔丁酯(B)(7.2g，产率91％)。(S)-4-(3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionyl)-2,3,5-trifluorobenzoic acid (B-3) (7.6 g, 18.2 mmol) was dissolved in N,N-dimethylformamide (76 mL), sodium bicarbonate (3.06 g, 36.4 mmol) and methyl iodide (3.87 g, 27.3 mmol) were added, and the reaction was carried out at 20-25 ° C for 24 hours . TLC showed that the reaction was complete, water (100 mL) was added to the reaction solution, then extracted with ethyl acetate (100 mL×2), the organic phases were combined, and saturated sodium bicarbonate solution (300 mL×2) and saturated sodium chloride solution were used. (300 mL) washed, dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oily compound (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)benzene) (B) (7.2 g, 91% yield).
LC-MS,M/Z:332.2[M+H] +。 LC-MS, M/Z: 332.2 [M+H] + .
制备5：中间体(S)-2-(3-(4-(叔丁氧羰基)-2,3,6-三氟苯基)-3-氧丙基)吗啉-4-羧酸叔丁酯(B-Bu)的制备Preparation 5: Intermediate (S)-tert-2-(3-(4-(tert-butoxycarbonyl)-2,3,6-trifluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid Preparation of Butyl Ester (B-Bu)
Figure PCTCN2022073298-appb-000039
Figure PCTCN2022073298-appb-000039
目标中间体B-Bu的合成路线如下所示：The synthetic route of the target intermediate B-Bu is shown below:
Figure PCTCN2022073298-appb-000040
Figure PCTCN2022073298-appb-000040
第一步：(S)-2-(3-(4-(叔丁氧羰基)-2,3,6-三氟苯基)-3-氧丙基)吗啉-4-羧酸叔丁酯(B-Bu)的合成The first step: (S)-2-(3-(4-(tert-butoxycarbonyl)-2,3,6-trifluorophenyl)-3-oxypropyl)morpholine-4-carboxylic acid tert-butyl Synthesis of Esters (B-Bu)
Figure PCTCN2022073298-appb-000041
Figure PCTCN2022073298-appb-000041
在氮气氛围下，向250mL三口瓶中加入2,3,5-三氟苯甲酸叔丁酯(11.5g,49.5mmol)、无水四氢呋喃(100mL),调节反应温度至-10～0℃,缓慢滴加二异丙基氨基锂(24.8mL,49.5mmol,2mol/L的正己烷溶液)同时维持反应温度在-10～0℃，反应液继续搅拌1h后,缓慢向溶液中滴加(S)-2-(3-(甲氧基(甲基)氨基)-3-氧丙基)吗啉-4-羧酸叔丁酯(A)(10g,33mmol)的四氢呋喃(20mL)溶液,继续在-10～0℃搅拌3h，TLC显示反应完全。向反应液中缓慢滴加饱和氯化铵溶液(100mL)，反应液升至室温，加入100mL乙酸乙酯稀释，分液并且用100mL乙酸乙酯萃取水相，合并有机相用饱和氯化铵(200mL)洗涤，收集的有机相经无水硫酸钠干燥、减压浓缩，最后通过硅胶柱色谱(乙酸乙酯:石油醚＝1:5)纯化得到白色固体(S)-2-(3-(4-(叔丁氧羰基)-2,3,6-三氟苯基)-3-氧丙基)吗啉-4-羧酸叔丁酯(B-Bu)(9.2g,产率59％)。Under nitrogen atmosphere, add tert-butyl 2,3,5-trifluorobenzoate (11.5g, 49.5mmol) and anhydrous tetrahydrofuran (100mL) to a 250mL three-necked flask, adjust the reaction temperature to -10～0°C, slowly Lithium diisopropylamide (24.8mL, 49.5mmol, 2mol/L n-hexane solution) was added dropwise while maintaining the reaction temperature at -10～0°C. After the reaction solution was stirred for 1h, (S) was slowly added dropwise to the solution. - A solution of tert-butyl 2-(3-(methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylate (A) (10 g, 33 mmol) in tetrahydrofuran (20 mL), continued in -10 ~ 0 ℃ stirred for 3h, TLC showed that the reaction was complete. Saturated ammonium chloride solution (100 mL) was slowly added dropwise to the reaction solution, the reaction solution was warmed to room temperature, diluted with 100 mL of ethyl acetate, separated and the aqueous phase was extracted with 100 mL of ethyl acetate, and the organic phases were combined with saturated ammonium chloride ( 200 mL) was washed, the collected organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5) to obtain a white solid (S)-2-(3-( 4-(tert-Butoxycarbonyl)-2,3,6-trifluorophenyl)-3-oxopropyl)morpholine-4-carboxylate tert-butyl ester (B-Bu) (9.2 g, 59% yield) ).
LC-MS,M/Z:374.1[M+H] +。 LC-MS, M/Z: 374.1 [M+H] + .
制备6：中间体(2S)-2-(2-溴-3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C)的制备Preparation 6: Intermediate (2S)-2-(2-bromo-3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4 - Preparation of methyl carboxylate (C)
Figure PCTCN2022073298-appb-000042
Figure PCTCN2022073298-appb-000042
目标中间体C的合成路线如下所示：The synthetic route of the target intermediate C is shown below:
Figure PCTCN2022073298-appb-000043
Figure PCTCN2022073298-appb-000043
第一步：(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C-1)的合成The first step: (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylate methyl ester Synthesis of (C-1)
Figure PCTCN2022073298-appb-000044
Figure PCTCN2022073298-appb-000044
在氮气氛围下，向2L三口瓶中加入(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸叔丁酯(B)(82g,190mmol)和1,4-二氧六环(200mL),调节反应温度至20-25℃。缓慢向溶液中加入盐酸的1,4-二氧六环溶液(143mL,4mol/L)，保持反应温度在20-25℃，反应继续搅拌3h,LC-MS显示反应完全。反应液在减压下浓缩干，向残留物中加入二氯甲烷(820mL),调节反应液温度至0-5℃，缓慢滴加三乙胺(48.1g,475mmol)，然后加入氯甲酸甲酯(26.9g,285mmol)。调节反应温度至20-25℃,反应液在20-25℃搅拌12h,TLC显示反应完全。向反应液中加入400mL饱和氯化钠溶液，分液并收集有机相，有机相用1L饱和氯化铵洗涤，有机相浓缩干得到棕色油状(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C-1)(71g,产率96％)。Under nitrogen atmosphere, add (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine to a 2L three-necked flask - 4-Carboxylic acid tert-butyl ester (B) (82 g, 190 mmol) and 1,4-dioxane (200 mL), adjust the reaction temperature to 20-25 °C. A solution of hydrochloric acid in 1,4-dioxane (143 mL, 4 mol/L) was slowly added to the solution, the reaction temperature was kept at 20-25 °C, and the reaction continued to be stirred for 3 h. LC-MS showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, dichloromethane (820 mL) was added to the residue, the temperature of the reaction solution was adjusted to 0-5 ° C, triethylamine (48.1 g, 475 mmol) was slowly added dropwise, and then methyl chloroformate was added. (26.9 g, 285 mmol). Adjust the reaction temperature to 20-25 ℃, the reaction solution was stirred at 20-25 ℃ for 12h, TLC showed that the reaction was complete. 400 mL of saturated sodium chloride solution was added to the reaction solution, the organic phase was separated and collected, the organic phase was washed with 1 L of saturated ammonium chloride, and the organic phase was concentrated to dryness to obtain (S)-2-(3-oxo-3- (2,3,6-Trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylate (C-1) (71 g, 96% yield).
LC-MS,M/Z:390.1[M+H] + LC-MS, M/Z: 390.1[M+H] +
第二步：(2S)-2-(2-溴-3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C)的合成The second step: (2S)-2-(2-bromo-3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4- Synthesis of Methyl Carboxylic Acid (C)
Figure PCTCN2022073298-appb-000045
Figure PCTCN2022073298-appb-000045
向2L三口烧瓶中加入(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲 酯(C-1)(71g,182mmol)，二氯甲烷(710mL)和33％的溴化氢醋酸溶液(2.24g,9.12mmol)。调节反应温度至20-25℃,向反应液中缓慢滴入液溴(35g,219mmol)，反应在20-25℃下继续搅拌1h,TLC显示反应完全。向反应体系中加入300mL饱和亚硫酸氢钠溶液，以及800mL饱和碳酸氢钠溶液。分液并收集有机相，有机相用800mL饱和碳酸氢钠溶液洗涤，收集的有机相经无水硫酸钠干燥、减压浓缩，最后通过硅胶柱色谱(乙酸乙酯:石油醚＝1:3)纯化得到棕色油状(2S)-2-(2-溴-3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C)(76g,产率89％)。Add (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid to a 2L three-necked flask Methyl ester (C-1) (71 g, 182 mmol), dichloromethane (710 mL) and a 33% solution of hydrobromide in acetic acid (2.24 g, 9.12 mmol). The reaction temperature was adjusted to 20-25°C, and liquid bromine (35 g, 219 mmol) was slowly added dropwise to the reaction solution. The reaction was stirred at 20-25°C for 1 h, and TLC showed that the reaction was complete. 300 mL of saturated sodium hydrogen sulfite solution and 800 mL of saturated sodium hydrogen carbonate solution were added to the reaction system. The organic phase was separated and collected, the organic phase was washed with 800 mL of saturated sodium bicarbonate solution, the collected organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally passed through silica gel column chromatography (ethyl acetate:petroleum ether=1:3) Purification gave (2S)-2-(2-bromo-3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4- as a brown oil Methyl carboxylate (C) (76 g, 89% yield).
1H NMR(400MHz,Chloroform-d)δ7.51(ddd,J＝9.3,4.7,2.2Hz,1H),5.16–5.11(m,1H),3.97–3.83(d,J＝0.7Hz,6H),3.71(s,3H),3.69–3.36(m,2H),2.98–2.95(m,1H),2.76–2.68(m,1H),2.59–2.29(m,1H),2.24–2.07(m,1H). 1 H NMR (400MHz, Chloroform-d) δ7.51 (ddd, J=9.3, 4.7, 2.2Hz, 1H), 5.16-5.11 (m, 1H), 3.97-3.83 (d, J=0.7Hz, 6H) ,3.71(s,3H),3.69–3.36(m,2H),2.98–2.95(m,1H),2.76–2.68(m,1H),2.59–2.29(m,1H),2.24–2.07(m, 1H).
LC-MS,M/Z:468.0[M+H] +。 LC-MS, M/Z: 468.0 [M+H] + .
制备7：中间体(2S)-2-(2-溴-3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C)的制备Preparation 7: Intermediate (2S)-2-(2-bromo-3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4 - Preparation of methyl carboxylate (C)
Figure PCTCN2022073298-appb-000046
Figure PCTCN2022073298-appb-000046
目标中间体C的合成路线如下所示：The synthetic route of the target intermediate C is shown below:
Figure PCTCN2022073298-appb-000047
Figure PCTCN2022073298-appb-000047
第一步：(S)-2,3,5-三氟-4-(3-(4-(甲氧基羰基)吗啉-2-基)丙酰基)苯甲酸(C-2)的合成The first step: Synthesis of (S)-2,3,5-trifluoro-4-(3-(4-(methoxycarbonyl)morpholin-2-yl)propionyl)benzoic acid (C-2)
Figure PCTCN2022073298-appb-000048
Figure PCTCN2022073298-appb-000048
在氮气氛围下，向250mL三口瓶中加入(S)-2-(3-(4-(叔丁氧羰基)-2,3,6-三氟苯基)-3-氧丙 基)吗啉-4-羧酸叔丁酯(B-Bu)(9.2g,19.4mmol)和1,4-二氧六环(20mL),调节反应温度至20-25℃。缓慢向溶液中加入盐酸的1,4-二氧六环溶液(20.0mL,4mol/L)，保持反应温度在20-25℃，反应继续搅拌15h。反应液在减压下浓缩干，向残留物中加入二氯甲烷(72mL),调节反应液温度至0-5℃，缓慢滴加三乙胺(6.87g,67.9mmol)，然后加入氯甲酸甲酯(2.36g,29.1mmol)。调节反应温度至20-25℃,反应液在20-25℃搅拌12h。向反应液中加入100mL水，用5M的盐酸溶液调节水相的pH至4-5，分液并收集有机相，水相用二氯甲烷萃取(100mL×2)，合并的有机相浓缩干得到白色固体(S)-2,3,5-三氟-4-(3-(4-(甲氧基羰基)吗啉-2-基)丙酰基)苯甲酸(C-2)(6.0g,产率83％)。Under nitrogen atmosphere, add (S)-2-(3-(4-(tert-butoxycarbonyl)-2,3,6-trifluorophenyl)-3-oxopropyl)morpholine to a 250 mL three-necked flask -4-Carboxylic acid tert-butyl ester (B-Bu) (9.2 g, 19.4 mmol) and 1,4-dioxane (20 mL), adjust the reaction temperature to 20-25 °C. A solution of hydrochloric acid in 1,4-dioxane (20.0 mL, 4 mol/L) was slowly added to the solution, and the reaction temperature was kept at 20-25 °C, and the reaction continued to be stirred for 15 h. The reaction solution was concentrated to dryness under reduced pressure, dichloromethane (72 mL) was added to the residue, the temperature of the reaction solution was adjusted to 0-5 ° C, triethylamine (6.87 g, 67.9 mmol) was slowly added dropwise, and then methyl chloroformate was added. Ester (2.36 g, 29.1 mmol). The reaction temperature was adjusted to 20-25 °C, and the reaction solution was stirred at 20-25 °C for 12 h. 100 mL of water was added to the reaction solution, the pH of the aqueous phase was adjusted to 4-5 with 5M hydrochloric acid solution, the organic phase was separated and collected, the aqueous phase was extracted with dichloromethane (100 mL×2), and the combined organic phases were concentrated to dryness to obtain White solid (S)-2,3,5-trifluoro-4-(3-(4-(methoxycarbonyl)morpholin-2-yl)propionyl)benzoic acid (C-2) (6.0 g, yield 83%).
LC-MS,M/Z:376.1[M+H] + LC-MS, M/Z: 376.1[M+H] +
第二步：(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C-1)的合成The second step: (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylate methyl ester Synthesis of (C-1)
Figure PCTCN2022073298-appb-000049
Figure PCTCN2022073298-appb-000049
将(S)-2,3,5-三氟-4-(3-(4-(甲氧基羰基)吗啉-2-基)丙酰基)苯甲酸(C-2)(6.0g，16.0mmol)溶解在N,N-二甲基甲酰胺(60mL)中，碳酸氢钠(2.69g，32.0mmol)和碘甲烷(3.40g，24mmol)，反应在20-25℃反应24小时。TLC显示反应完全，向反应液中加入水(100mL)，然后用乙酸乙酯(100mL×2)萃取，有机相合并，饱和的碳酸氢钠溶液(300mL×2)以及饱和的氯化钠溶液(300mL)洗涤,无水硫酸钠干燥，过滤，浓缩得到白色油状化合物(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C-1)(4.67g，产率75％)。(S)-2,3,5-trifluoro-4-(3-(4-(methoxycarbonyl)morpholin-2-yl)propionyl)benzoic acid (C-2) (6.0 g, 16.0 mmol) was dissolved in N,N-dimethylformamide (60 mL), sodium bicarbonate (2.69 g, 32.0 mmol) and methyl iodide (3.40 g, 24 mmol), and the reaction was carried out at 20-25 °C for 24 hours. TLC showed that the reaction was complete, water (100 mL) was added to the reaction solution, then extracted with ethyl acetate (100 mL×2), the organic phases were combined, saturated sodium bicarbonate solution (300 mL×2) and saturated sodium chloride solution ( 300 mL) was washed, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white oily compound (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl) ) propyl) morpholine-4-carboxylic acid methyl ester (C-1) (4.67 g, 75% yield).
LC-MS,M/Z:390.1[M+H] + LC-MS, M/Z: 390.1[M+H] +
第三步：(2S)-2-(2-溴-3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C)的合成The third step: (2S)-2-(2-bromo-3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4- Synthesis of Methyl Carboxylic Acid (C)
Figure PCTCN2022073298-appb-000050
Figure PCTCN2022073298-appb-000050
向100mL三口烧瓶中加入(S)-2-(3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C-1)(4.67g,12.0mmol)、二氯甲烷(50mL)和33％的溴化氢醋酸溶液(0.15g,0.61mmol)。调节反应温度至20-25℃,向反应液中缓慢滴入液溴(2.3g,14.4mmol)，反应在20-25℃下继续搅拌1h,TLC显示反应完全。向反应体系中加入30mL饱和亚硫酸氢钠溶液，以及50mL饱和碳酸氢钠溶液。分液并收集有机相，有机相用50mL饱和碳酸氢钠溶液洗涤，收 集的有机相经无水硫酸钠干燥、减压浓缩，最后通过硅胶柱色谱(乙酸乙酯:石油醚＝1:3)纯化得到棕色油状(2S)-2-(2-溴-3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C)(5.3g,产率95％)。Add (S)-2-(3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid to a 100mL three-necked flask Methyl ester (C-1) (4.67 g, 12.0 mmol), dichloromethane (50 mL) and a 33% solution of hydrobromide in acetic acid (0.15 g, 0.61 mmol). The reaction temperature was adjusted to 20-25°C, and liquid bromine (2.3 g, 14.4 mmol) was slowly added dropwise to the reaction solution. The reaction was stirred at 20-25°C for 1 h, and TLC showed that the reaction was complete. 30 mL of saturated sodium hydrogen sulfite solution and 50 mL of saturated sodium hydrogen carbonate solution were added to the reaction system. The organic phase was separated and collected, the organic phase was washed with 50 mL of saturated sodium bicarbonate solution, the collected organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally passed through silica gel column chromatography (ethyl acetate:petroleum ether=1:3) Purification gave (2S)-2-(2-bromo-3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4- as a brown oil Methyl carboxylate (C) (5.3 g, 95% yield).
LC-MS,M/Z:468.0[M+H] +。 LC-MS, M/Z: 468.0 [M+H] + .
制备8：中间体(S)-2-((2-(2,3,6-三氟代-4-(甲氧羰基)苯基)-7-甲基咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(D)的制备Preparation 8: Intermediate (S)-2-((2-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)-7-methylimidazo[1,2-a] Preparation of pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (D)
Figure PCTCN2022073298-appb-000051
Figure PCTCN2022073298-appb-000051
目标中间体D的合成路线如下所示：The synthetic route of the target intermediate D is shown below:
Figure PCTCN2022073298-appb-000052
Figure PCTCN2022073298-appb-000052
第一步：(S)-2-((2-(2,3,6-三氟代-4-(甲氧羰基)苯基)-7-甲基咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(D)的合成The first step: (S)-2-((2-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)-7-methylimidazo[1,2-a]pyridine Synthesis of -3-yl)methyl)morpholine-4-carboxylic acid methyl ester (D)
Figure PCTCN2022073298-appb-000053
Figure PCTCN2022073298-appb-000053
向350mL反应瓶中加入(2S)-2-(2-溴-3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C)(15g,31.4mmol)、2-氨基-4-甲基吡啶(6.93g，62.8mmol)和乙腈(150mL),将反应瓶封闭，调节反应温度为120℃并搅拌24h，冷却至室温下过滤，滤液在减压下浓缩干，最后通过硅胶柱色谱(乙酸乙酯:石油醚＝1:1)纯化得到黄色固体(S)-2-((2-(2,3,6-三氟代-4-(甲氧羰基)苯基)-7-甲基咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(D)(8g,产率52％)To a 350 mL reaction flask was added (2S)-2-(2-bromo-3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine- Methyl 4-carboxylate (C) (15 g, 31.4 mmol), 2-amino-4-methylpyridine (6.93 g, 62.8 mmol) and acetonitrile (150 mL), the reaction flask was closed, and the reaction temperature was adjusted to 120° C. and Stirred for 24 h, cooled to room temperature and filtered, the filtrate was concentrated to dryness under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain yellow solid (S)-2-((2-(2 ,3,6-Trifluoro-4-(methoxycarbonyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (D) (8 g, 52% yield)
LC-MS,M/Z:478.2[M+H] +。 LC-MS, M/Z: 478.2 [M+H] + .
制备9：中间体(S)-2-((2-(2,3,6-三氟代-4-(甲氧羰基)苯基)-7-氯咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(E)的制备Preparation 9: Intermediate (S)-2-((2-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)-7-chloroimidazo[1,2-a]pyridine Preparation of -3-yl)methyl)morpholine-4-carboxylic acid methyl ester (E)
Figure PCTCN2022073298-appb-000054
Figure PCTCN2022073298-appb-000054
目标中间体E的合成路线如下所示：The synthetic route of the target intermediate E is as follows:
Figure PCTCN2022073298-appb-000055
Figure PCTCN2022073298-appb-000055
第一步：(S)-2-((2-(2,3,6-三氟代-4-(甲氧羰基)苯基)-7-氯咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(E)的合成The first step: (S)-2-((2-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)-7-chloroimidazo[1,2-a]pyridine- Synthesis of 3-yl)methyl)morpholine-4-carboxylic acid methyl ester (E)
Figure PCTCN2022073298-appb-000056
Figure PCTCN2022073298-appb-000056
向1L反应瓶中加入(2S)-2-(2-溴-3-氧代-3-(2,3,6-三氟-4-(甲氧羰基)苯基)丙基)吗啉-4-羧酸甲酯(C)(60g,128mmol)、2-氨基-4-氯吡啶(32.9g，256mmol)和乙腈(600mL)。反应瓶在120℃下搅拌24h，冷却至室温下过滤，滤液在减压下浓缩干，最后通过硅胶柱色谱(乙酸乙酯:石油醚＝1:1)纯化得到黄色固体(S)-2-((2-(2,3,6-三氟代-4-(甲氧羰基)苯基)-7-氯咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(E)(30g,产率47％)。To a 1L reaction flask was added (2S)-2-(2-bromo-3-oxo-3-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine- Methyl 4-carboxylate (C) (60 g, 128 mmol), 2-amino-4-chloropyridine (32.9 g, 256 mmol) and acetonitrile (600 mL). The reaction flask was stirred at 120°C for 24h, cooled to room temperature and filtered, the filtrate was concentrated to dryness under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain a yellow solid (S)-2- ((2-(2,3,6-Trifluoro-4-(methoxycarbonyl)phenyl)-7-chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine- Methyl 4-carboxylate (E) (30 g, 47% yield).
LC-MS,M/Z:498.1[M+H] +。 LC-MS, M/Z: 498.1 [M+H] + .
实施例1：(S)-2-((2-(2,3,6-三氟代-4-(甲基氨基甲酰基)苯基)-7-甲基咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(1)的制备Example 1: (S)-2-((2-(2,3,6-trifluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a Preparation of ]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (1)
Figure PCTCN2022073298-appb-000057
Figure PCTCN2022073298-appb-000057
目标化合物1的合成路线如下所示：The synthetic route of target compound 1 is as follows:
Figure PCTCN2022073298-appb-000058
Figure PCTCN2022073298-appb-000058
第一步：(S)-2-((2-(2,3,6-三氟代-4-(甲基氨基甲酰基)苯基)-7-甲基咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯的制备(1)的合成The first step: (S)-2-((2-(2,3,6-trifluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a Preparation of ]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (1) Synthesis
Figure PCTCN2022073298-appb-000059
Figure PCTCN2022073298-appb-000059
向100mL反应瓶中加入(S)-2-((2-(2,3,6-三氟代-4-(甲氧羰基)苯基)-7-甲基咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(D)(8g,16.7mmol)、甲醇(16mL)。向反应液中加入33％甲胺的甲醇溶液(7.8g，83mmol)，调节反应温度至20-25℃并且搅拌5h。TLC显示反应结束。反应液减压浓缩干，用硅胶柱色谱纯化得到黄色固体(S)-2-((2-(2,3,6-三氟代-4-(甲基氨基甲酰基)苯基)-7-甲基咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(1)(7.7g,产率97％)。To a 100 mL reaction flask, add (S)-2-((2-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)-7-methylimidazo[1,2-a] ]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (D) (8 g, 16.7 mmol), methanol (16 mL). 33% methylamine in methanol (7.8 g, 83 mmol) was added to the reaction solution, the reaction temperature was adjusted to 20-25 °C and stirred for 5 h. TLC showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid (S)-2-((2-(2,3,6-trifluoro-4-(methylcarbamoyl)phenyl)-7 - Methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (1) (7.7 g, 97% yield).
1H NMR(400MHz,Chloroform-d)δ8.13(d,J＝7.1Hz,1H),7.62(ddd,J＝9.6,5.6,2.1Hz,1H),7.32(dt,J＝2.0,1.1Hz,1H),7.00(s,1H),6.64(dd,J＝7.1,1.7Hz,1H),3.95–3.68(m,3H),3.62(s,3H),3.54–3.47(m,1H),3.37–3.27(m,1H),3.02(d,J＝4.8,0.9Hz,3H),3.00–2.78(m,3H),2.55(dd,J＝13.0,10.6Hz,1H),2.37(d,J＝1.1Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ8.13 (d, J=7.1Hz, 1H), 7.62 (ddd, J=9.6, 5.6, 2.1Hz, 1H), 7.32 (dt, J=2.0, 1.1Hz) ,1H),7.00(s,1H),6.64(dd,J=7.1,1.7Hz,1H),3.95–3.68(m,3H),3.62(s,3H),3.54–3.47(m,1H), 3.37–3.27 (m, 1H), 3.02 (d, J=4.8, 0.9Hz, 3H), 3.00–2.78 (m, 3H), 2.55 (dd, J=13.0, 10.6Hz, 1H), 2.37 (d, J=1.1Hz, 3H).
LC-MS,M/Z:477.2[M+H] +。 LC-MS, M/Z: 477.2 [M+H] + .
实施例2：(S)-2-((2-(2,3,6-三氟代-4-(甲基氨基甲酰基)苯基)-7-氯咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(2)的制备Example 2: (S)-2-((2-(2,3,6-trifluoro-4-(methylcarbamoyl)phenyl)-7-chloroimidazo[1,2-a] Preparation of pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (2)
Figure PCTCN2022073298-appb-000060
Figure PCTCN2022073298-appb-000060
目标化合物2的合成路线如下所示：The synthetic route of target compound 2 is as follows:
Figure PCTCN2022073298-appb-000061
Figure PCTCN2022073298-appb-000061
第一步：(S)-2-((2-(2,3,6-三氟代-4-(甲基氨基甲酰基)苯基)-7-氯咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(2)的合成The first step: (S)-2-((2-(2,3,6-trifluoro-4-(methylcarbamoyl)phenyl)-7-chloroimidazo[1,2-a] Synthesis of Pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (2)
Figure PCTCN2022073298-appb-000062
Figure PCTCN2022073298-appb-000062
向100mL反应瓶中加入(S)-2-((2-(2,3,6-三氟代-4-(甲氧羰基)苯基)-7-氯咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(E)(30g,60.3mmol)、甲醇(60mL)。向反应液中加入33％的甲胺甲醇溶液(28.4g，301mmol)，调节反应温度至20-25℃并且搅拌5h。TLC显示反应结束。反应液减压浓缩干，用硅胶柱色谱纯化得到黄色固体(S)-2-((2-(2,3,6-三氟代-4-(甲基氨基甲酰基)苯基)-7-氯咪唑并[1,2-a]吡啶-3-基)甲基)吗啉-4-甲酸甲酯(2)(27g,产率90％)。To a 100 mL reaction flask, add (S)-2-((2-(2,3,6-trifluoro-4-(methoxycarbonyl)phenyl)-7-chloroimidazo[1,2-a] Pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (E) (30 g, 60.3 mmol), methanol (60 mL). 33% methylamine methanol solution (28.4 g, 301 mmol) was added to the reaction solution, the reaction temperature was adjusted to 20-25 °C and stirred for 5 h. TLC showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid (S)-2-((2-(2,3,6-trifluoro-4-(methylcarbamoyl)phenyl)-7 -chloroimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (2) (27 g, 90% yield).
1H NMR(400MHz,Chloroform-d)δ8.27(d,J＝7.4Hz,1H),7.69(ddd,J＝9.6,5.6,2.1Hz,1H),7.60(dd,J＝2.1,0.8Hz,1H),6.81(m,4.1Hz,2H),4.04–3.73(m,3H),3.67(s,3H),3.60–3.50(m,1H),3.35(t,J＝11.7Hz,1H),3.06(dd,J＝4.9,1.0Hz,3H),3.02–2.81(m,3H),2.60(t,J＝11.8Hz,1H).1H NMR (400MHz, Chloroform-d) δ8.27 (d, J=7.4Hz, 1H), 7.69 (ddd, J=9.6, 5.6, 2.1Hz, 1H), 7.60 (dd, J=2.1, 0.8Hz, 1H), 6.81(m, 4.1Hz, 2H), 4.04-3.73(m, 3H), 3.67(s, 3H), 3.60-3.50(m, 1H), 3.35(t, J=11.7Hz, 1H), 3.06(dd,J=4.9,1.0Hz,3H),3.02-2.81(m,3H),2.60(t,J=11.8Hz,1H).
LC-MS,M/Z:497.2[M+H] +。 LC-MS, M/Z: 497.2 [M+H] + .

Claims (37)

  1. 一种如式I、式II或式III所示的中间体：An intermediate as shown in formula I, formula II or formula III:
    Figure PCTCN2022073298-appb-100001
    Figure PCTCN2022073298-appb-100001
    其中，in,
    所述R 1选自PG 1或
    Figure PCTCN2022073298-appb-100002
    The R 1 is selected from PG 1 or
    Figure PCTCN2022073298-appb-100002
    所述R 2选自卤素、羧基或
    Figure PCTCN2022073298-appb-100003
    The R 2 is selected from halogen, carboxyl or
    Figure PCTCN2022073298-appb-100003
    所述R 2a选自C 1-C 6烷基或苄基； The R 2a is selected from C 1 -C 6 alkyl or benzyl;
    所述R 3选自甲基或氯； The R is selected from methyl or chlorine;
    所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
    所述X选自H或Br。The X is selected from H or Br.
  2. 根据权利要求1所述的如式II所示的中间体，其特征在于，The intermediate shown in formula II according to claim 1, wherein,
    当R 2为卤素时，所述卤素为Br或I； When R 2 is halogen, the halogen is Br or I;
    和/或，所述R 2a为C 1-C 6烷基。 And/or, said R 2a is C 1 -C 6 alkyl.
  3. 根据权利要求1所述的如式II所示的中间体，其特征在于，The intermediate shown in formula II according to claim 1, wherein,
    当R 2为卤素时，所述卤素为Br； When R 2 is halogen, the halogen is Br;
    和/或，所述R 2a为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 And/or, the R 2a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  4. 根据权利要求1-3任一项所述的中间体，其特征在于，所述如式II所示的中间体选自下列任一中间体：The intermediate according to any one of claims 1-3, wherein the intermediate shown in formula II is selected from any of the following intermediates:
    Figure PCTCN2022073298-appb-100004
    Figure PCTCN2022073298-appb-100004
    其中，in,
    所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
    所述R 2选自卤素、羧基或
    Figure PCTCN2022073298-appb-100005
    The R 2 is selected from halogen, carboxyl or
    Figure PCTCN2022073298-appb-100005
    所述R 2a具有权利要求1-3任一项所述的定义。 Said R 2a has the definition of any one of claims 1-3.
  5. 一种如权利要求4所述中间体中如式II-1所示的中间体的制备方法，其包括以下步骤：A kind of preparation method of the intermediate as shown in formula II-1 in the intermediate as claimed in claim 4, it comprises the following steps:
    步骤1：在氨基金属化合物或烷基金属化合物的作用下，通过将如式I所示的中间体与如1所示的化合物进行反应制备如式II-1所示的中间体；Step 1: under the action of metal amide compound or metal alkyl compound, by reacting the intermediate shown in formula I with the compound shown in 1 to prepare the intermediate shown in formula II-1;
    Figure PCTCN2022073298-appb-100006
    Figure PCTCN2022073298-appb-100006
    其中，in,
    所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
    所述R 2选自卤素、羧基或
    Figure PCTCN2022073298-appb-100007
    The R 2 is selected from halogen, carboxyl or
    Figure PCTCN2022073298-appb-100007
    所述R 2a具有权利要求1-3任一项所述的定义。 Said R 2a has the definition of any one of claims 1-3.
  6. 一种如权利要求1所述中间体中如式I所示的中间体的制备方法，其包括以下步骤：A kind of preparation method of the intermediate shown in formula I in the intermediate as claimed in claim 1, it comprises the following steps:
    步骤2：在有机碱和缩合剂作用下，通过将如式I-2所示的中间体与如式2所示的化合物进行反应制备如式I所示的中间体；Step 2: under the action of an organic base and a condensing agent, the intermediate shown in formula I is prepared by reacting the intermediate shown in formula I-2 with the compound shown in formula 2;
    Figure PCTCN2022073298-appb-100008
    Figure PCTCN2022073298-appb-100008
    其中，所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基。 Wherein, the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
  7. 根据权利要求6所述的如式I所示的中间体的制备方法，其特征在于，所述的如式I所示的中间体的制备方法还包括如式I-2所示中间体的制备方法，所述的如式I-2所示的中间体的制备方法包括以下步骤：The preparation method of the intermediate shown in formula I according to claim 6, wherein the preparation method of the intermediate shown in formula I further comprises the preparation of the intermediate shown in formula I-2 Method, the preparation method of described intermediate as shown in formula I-2 comprises the following steps:
    步骤3：通过将如式3所示的化合物进行还原反应制备如式I-1所示的中间体；Step 3: prepare the intermediate shown in formula I-1 by subjecting the compound shown in formula 3 to reduction reaction;
    Figure PCTCN2022073298-appb-100009
    Figure PCTCN2022073298-appb-100009
    步骤4：在无机碱的作用下，通过将如式I-1所示的中间体水解制备如式I-2所示的中间体；Step 4: under the action of inorganic base, prepare the intermediate shown in formula I-2 by hydrolyzing the intermediate shown in formula I-1;
    Figure PCTCN2022073298-appb-100010
    Figure PCTCN2022073298-appb-100010
    其中，所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基。 Wherein, the PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
  8. 一种如权利要求4所述中间体中如式II-1A所示的中间体的制备方法，其特征在于，所述的如式II-1A所示的中间体由如式II-1所示的中间体制备得到，所述的如式II-1A所示的中间体的制备方法包括以下步骤：A preparation method of an intermediate shown in formula II-1A in the intermediate according to claim 4, wherein the intermediate shown in formula II-1A is represented by formula II-1 The intermediate is prepared, and the preparation method of the intermediate shown in the formula II-1A comprises the following steps:
    步骤5：在催化剂和有机碱的作用下，通过将如式II-1所示的中间体与一氧化碳和式4所示的化合物进行反应得到如式II-1A所示的中间体；Step 5: under the action of a catalyst and an organic base, the intermediate shown in formula II-1A is obtained by reacting the intermediate shown in formula II-1 with carbon monoxide and the compound shown in formula 4;
    Figure PCTCN2022073298-appb-100011
    Figure PCTCN2022073298-appb-100011
    其中，in,
    所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
    所述R 2为卤素； The R 2 is halogen;
    所述R 2a具有权利要求1-3任一项所述的定义。 Said R 2a has the definition of any one of claims 1-3.
  9. 一种如权利要求4所述中间体中如式II-1A所示的中间体的制备方法，其特征在于，所述的如式II-1A所示的中间体由如式II-1所示的中间体制备得到，所述的如式II-1A所示的中间体的制备方法包括以下步骤：A preparation method of an intermediate shown in formula II-1A in the intermediate according to claim 4, wherein the intermediate shown in formula II-1A is represented by formula II-1 The intermediate is prepared, and the preparation method of the intermediate shown in the formula II-1A comprises the following steps:
    步骤6：在碱的作用下，通过将如式II-1所示的中间体与式5所示的化合物进行反应得到如式II-1A所示的中间体；Step 6: under the action of a base, the intermediate shown in formula II-1A is obtained by reacting the intermediate shown in formula II-1 with the compound shown in formula 5;
    Figure PCTCN2022073298-appb-100012
    Figure PCTCN2022073298-appb-100012
    其中，in,
    所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
    所述R 2为羧基； Described R 2 is carboxyl;
    所述R 2a具有权利要求1-3任一项所述的定义。 Said R 2a has the definition of any one of claims 1-3.
  10. 一种如权利要求4所述中间体中如式II-2所示的中间体的制备方法，其特征在于，所述的如式II-2所示的中间体由如式II-1A所示的中间体制备得到，所述的如式II-2所示的中间体的制备方法包括以下步骤：A preparation method of the intermediate shown in the formula II-2 in the intermediate as claimed in claim 4, wherein the intermediate shown in the formula II-2 is represented by the formula II-1A The intermediate is prepared, and the preparation method of the intermediate shown in the formula II-2 comprises the following steps:
    步骤7：脱去如式II-1A所示的中间体保护基PG 1，得到脱保护基的产物；所述脱保护基的产物在碱的作用下与如式6所示的化合物进行反应，得到如式II-2所示的中间体； Step 7: Removing the intermediate protecting group PG 1 shown in formula II-1A to obtain a deprotected product; the deprotected product is reacted with a compound shown in formula 6 under the action of a base, Obtain the intermediate as shown in formula II-2;
    Figure PCTCN2022073298-appb-100013
    Figure PCTCN2022073298-appb-100013
    其中，in,
    所述PG 1选自叔丁氧基羰基、苄氧基羰基或苄基； The PG 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
    所述R 2a具有权利要求1-3任一项所述的定义。 Said R 2a has the definition of any one of claims 1-3.
  11. 一种如权利要求4所述中间体中如式II-3所示的中间体的制备方法，其特征在于，所述的如式II-3所示的中间体由如式II-2所示的中间体制备得到，所述的如式II-3所示的中间体的制备方法包括以下步骤：A preparation method of the intermediate shown in the formula II-3 in the intermediate as claimed in claim 4, wherein the intermediate shown in the formula II-3 is composed of the intermediate shown in the formula II-2 The intermediate is prepared, and the preparation method of the intermediate shown in the formula II-3 comprises the following steps:
    步骤8：将如式II-2所示的中间体与溴化试剂反应，得到如式II-3所示的中间体；Step 8: react the intermediate shown in formula II-2 with a bromination reagent to obtain the intermediate shown in formula II-3;
    Figure PCTCN2022073298-appb-100014
    Figure PCTCN2022073298-appb-100014
    其中，R 2a具有如权利要求1-3任一项所述的定义。 wherein R 2a has the definition as claimed in any one of claims 1-3.
  12. 一种如权利要求1所述中间体中如式III所示的中间体的制备方法，其特征在于，所述的如式III所示的中间体由如式II-3所示的中间体制备得到，所述的如式III所示的中间体的制备方法包括以下步骤：A method for preparing the intermediate shown in the formula III in the intermediate as claimed in claim 1, wherein the intermediate shown in the formula III is prepared from the intermediate shown in the formula II-3 Obtain, the preparation method of described intermediate as shown in formula III comprises the following steps:
    步骤9：通过将如式II-3所示的中间体与如式7所示的化合物进行反应得到如式III所示的中间体；Step 9: by reacting the intermediate shown in formula II-3 with the compound shown in formula 7 to obtain the intermediate shown in formula III;
    Figure PCTCN2022073298-appb-100015
    Figure PCTCN2022073298-appb-100015
    其中，in,
    所述R 2a具有权利要求1-3任一项所述的定义； The R 2a has the definition of any one of claims 1-3;
    所述R 3选自甲基或氯。 The R3 is selected from methyl or chlorine.
  13. 一种如式IV所示的咪唑并吡啶化合物的制备方法，其包括以下步骤：A kind of preparation method of imidazopyridine compound as shown in formula IV, it comprises the following steps:
    步骤10：将如式III所示的中间体与甲胺进行反应，得到如式IV所示的化合物；Step 10: react the intermediate shown in formula III with methylamine to obtain the compound shown in formula IV;
    Figure PCTCN2022073298-appb-100016
    Figure PCTCN2022073298-appb-100016
    其中，in,
    所述R 2a具有权利要求1-3任一项所述的定义； The R 2a has the definition of any one of claims 1-3;
    所述R 3选自甲基或氯。 The R3 is selected from methyl or chlorine.
  14. 根据权利要求5所述的如式II-1所示的中间体的制备方法，其特征在于，所述步骤1中，The preparation method of the intermediate shown in formula II-1 according to claim 5, is characterized in that, in described step 1,
    所述氨基金属化合物为二异丙基氨基锂、双三甲基硅基胺基锂、双三甲基硅基胺基钾、双三甲基硅基胺基钠；The amino metal compound is lithium diisopropylamide, lithium bis-trimethylsilyl amide, potassium bis-trimethyl silyl amide, and sodium bis-trimethyl silyl amide;
    所述烷基金属化合物为甲基格氏试剂、乙基格氏试剂、异丙基格氏试剂、烷基锂化合物；The alkyl metal compounds are methyl Grignard reagents, ethyl Grignard reagents, isopropyl Grignard reagents, and alkyl lithium compounds;
    当所述的R 2为卤素时，所述反应在氨基金属化合物的作用下进行； When the R 2 is halogen, the reaction is carried out under the action of a metal amide compound;
    当所述的R 2为羧基或
    Figure PCTCN2022073298-appb-100017
    时，所述反应在氨基金属化合物或烷基金属化合物作用下进行；     When the R 2 is carboxyl or
    Figure PCTCN2022073298-appb-100017
    , the reaction is carried out under the action of a metal amide compound or a metal alkyl compound;
    所述反应的反应温度为-80～0℃；The reaction temperature of the reaction is -80～0°C;
    所述反应中如式I所示的中间体与如式1所示的化合物的摩尔比为1:1～1:1.6；In the reaction, the molar ratio of the intermediate shown in formula I to the compound shown in formula 1 is 1:1 to 1:1.6;
    所述反应在有机溶剂中进行，所述有机溶剂包括乙醚、二氯甲烷、甲苯、2-甲基四氢呋 喃或四氢呋喃；Described reaction is carried out in organic solvent, described organic solvent comprises ether, dichloromethane, toluene, 2-methyltetrahydrofuran or tetrahydrofuran;
    所述反应的反应时间为2～4小时；The reaction time of the reaction is 2 to 4 hours;
    当所述有机金属化合物为烷基锂化合物时，所述反应还包括稳定剂，所述稳定剂为N,N,N',N'-四甲基乙二胺。When the organometallic compound is an alkyl lithium compound, the reaction further includes a stabilizer, and the stabilizer is N,N,N',N'-tetramethylethylenediamine.
  15. 根据权利要求5所述的如式II-1所示的中间体的制备方法，其特征在于，所述步骤1中，The preparation method of the intermediate shown in formula II-1 according to claim 5, is characterized in that, in described step 1,
    所述氨基金属化合物为二异丙基氨基锂或双三甲基硅基胺基锂；The amino metal compound is lithium diisopropylamide or lithium bistrimethylsilylamide;
    所述烷基金属化合物为甲基锂或正丁基锂；Described alkyl metal compound is methyl lithium or n-butyl lithium;
    当所述的R 2为卤素时，所述反应在氨基金属化合物的作用下进行； When the R 2 is halogen, the reaction is carried out under the action of a metal amide compound;
    当所述的R 2为羧基或
    Figure PCTCN2022073298-appb-100018
    时，所述反应在氨基金属化合物或烷基金属化合物作用下进行；     When the R 2 is carboxyl or
    Figure PCTCN2022073298-appb-100018
    , the reaction is carried out under the action of a metal amide compound or a metal alkyl compound;
    所述反应的反应温度为-10～0℃或者-80～-60℃；The reaction temperature of the reaction is -10～0℃ or -80～-60℃;
    所述反应中如式I所示的中间体与如式1所示的化合物的摩尔比为1:1～1.2或者1:1.5～1:1.6；In the reaction, the molar ratio of the intermediate shown in formula I to the compound shown in formula 1 is 1:1-1.2 or 1:1.5-1:1.6;
    所述反应在有机溶剂中进行，所述有机溶剂为四氢呋喃；The reaction is carried out in an organic solvent, and the organic solvent is tetrahydrofuran;
    所述反应的反应时间为2～4小时。The reaction time of the reaction is 2 to 4 hours.
  16. 根据权利要求5所述的如式II-1所示的中间体的制备方法，其特征在于，所述步骤1中，所述反应中如式I所示的中间体与如式1所示的化合物的摩尔比为1:1.2或1:1.5。The method for preparing the intermediate shown in formula II-1 according to claim 5, wherein in the step 1, the intermediate shown in the formula I and the intermediate shown in the formula 1 in the reaction The molar ratio of the compounds was 1:1.2 or 1:1.5.
  17. 根据权利要求6所述的如式I所示的中间体的制备方法，其特征在于，所述步骤2中，The preparation method of the intermediate shown in formula I according to claim 6, is characterized in that, in described step 2,
    所述如式I-2所示的中间体与如式2所示的化合物的摩尔比为1:1～1:2；The molar ratio of the intermediate shown in formula I-2 to the compound shown in formula 2 is 1:1 to 1:2;
    所述如式I-2所示的中间体与有机碱的化合物的摩尔比为1:2～1:4；The molar ratio of the intermediate shown in formula I-2 to the compound of the organic base is 1:2 to 1:4;
    所述如式I-2所示的中间体与缩合剂的摩尔比为1:1～1:2；The molar ratio of the intermediate shown in formula I-2 to the condensing agent is 1:1 to 1:2;
    所述有机碱为N,N-二异丙基乙胺；The organic base is N,N-diisopropylethylamine;
    所述反应的反应温度为20～25℃；The reaction temperature of the reaction is 20～25 ℃;
    所述缩合剂为1-丙基磷酸酐；Described condensing agent is 1-propyl phosphoric anhydride;
    所述反应在二氯甲烷中进行；The reaction is carried out in dichloromethane;
    所述反应的反应时间为14～18小时。The reaction time of the reaction is 14-18 hours.
  18. 根据权利要求6所述的如式I所示的中间体的制备方法，其特征在于，所述步骤2中，The preparation method of the intermediate shown in formula I according to claim 6, is characterized in that, in described step 2,
    所述如式I-2所示的中间体与如式2所示的化合物的摩尔比为1:1.2；The molar ratio of the intermediate shown in formula 1-2 to the compound shown in formula 2 is 1:1.2;
    所述如式I-2所示的中间体与有机碱的化合物的摩尔比为1:2.8～1:3.2；The molar ratio of the intermediate shown in formula I-2 to the compound of the organic base is 1:2.8～1:3.2;
    所述如式I-2所示的中间体与缩合剂的摩尔比为1:1.5；The mol ratio of the intermediate shown in formula I-2 and the condensing agent is 1:1.5;
    所述反应的反应时间为16小时。The reaction time for the reaction was 16 hours.
  19. 根据权利要求6所述的如式I所示的中间体的制备方法，其特征在于，所述步骤2中，所述如式I-2所示的中间体与有机碱的化合物的摩尔比为1:3。The preparation method of the intermediate shown in the formula I according to claim 6, is characterized in that, in the step 2, the molar ratio of the intermediate shown in the formula I-2 to the compound of the organic base is: 1:3.
  20. 根据权利要求7所述的如式I所示的中间体的制备方法，其特征在于，所述步骤3中，The preparation method of the intermediate shown in formula I according to claim 7, is characterized in that, in described step 3,
    所述反应还包括氢气；The reaction also includes hydrogen;
    所述反应还包括钯碳；Described reaction also includes palladium carbon;
    所述反应的反应温度为20～25℃；The reaction temperature of the reaction is 20～25 ℃;
    所述反应中氢气的压力为0.8～1.2个大气压；The pressure of hydrogen in the reaction is 0.8 to 1.2 atmospheres;
    所述钯碳与化合物3的质量比为1:18～1:22；The mass ratio of described palladium carbon and compound 3 is 1:18～1:22;
    所述反应的反应时间为22～26小时。The reaction time of the reaction is 22 to 26 hours.
  21. 根据权利要求7所述的如式I所示的中间体的制备方法，其特征在于，所述步骤3中，The preparation method of the intermediate shown in formula I according to claim 7, is characterized in that, in described step 3,
    所述反应中氢气的压力为1个大气压；The pressure of hydrogen in the reaction is 1 atmosphere;
    所述钯碳与化合物3的质量比为1:20；The mass ratio of described palladium carbon and compound 3 is 1:20;
    所述反应的反应时间为24小时。The reaction time for the reaction was 24 hours.
  22. 根据权利要求7所述的如式I所示的中间体的制备方法，其特征在于，所述步骤4中，The preparation method of the intermediate shown in formula I according to claim 7, is characterized in that, in described step 4,
    所述无机碱选自氢氧化锂、氢氧化钠或氢氧化钾；The inorganic base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide;
    所述反应的反应温度为20～25℃；The reaction temperature of the reaction is 20～25 ℃;
    所述如式I-1所示的中间体与无机碱的摩尔比为1:1～1:4；The molar ratio of the intermediate shown in formula I-1 to the inorganic base is 1:1 to 1:4;
    所述反应在甲醇中进行；The reaction is carried out in methanol;
    所述反应的反应时间为14～18小时。The reaction time of the reaction is 14-18 hours.
  23. 根据权利要求7所述的如式I所示的中间体的制备方法，其特征在于，所述步骤4中，The preparation method of the intermediate shown in formula I according to claim 7, is characterized in that, in described step 4,
    所述无机碱选自氢氧化锂；The inorganic base is selected from lithium hydroxide;
    所述如式I-1所示的中间体与无机碱的摩尔比为1:2；The mol ratio of the intermediate shown in the formula I-1 to the inorganic base is 1:2;
    所述反应的反应时间为16小时。The reaction time for the reaction was 16 hours.
  24. 根据权利要求8所述的如式II-1A所示的中间体的制备方法，其特征在于，所述步骤5中，The preparation method of the intermediate shown in formula II-1A according to claim 8, is characterized in that, in described step 5,
    所述催化剂为过渡金属催化剂，所述过渡金属催化剂包括钯金属催化剂、钌金属催化剂、铁金属催化剂、钴金属催化剂、镍金属催化剂、铑金属催化剂；The catalyst is a transition metal catalyst, and the transition metal catalyst includes a palladium metal catalyst, a ruthenium metal catalyst, an iron metal catalyst, a cobalt metal catalyst, a nickel metal catalyst, and a rhodium metal catalyst;
    所述有机碱为三乙胺或N,N-二异丙基乙胺；The organic base is triethylamine or N,N-diisopropylethylamine;
    所述反应在加压的一氧化碳中进行，所述一氧化碳的压力为40～50psi；The reaction is carried out in pressurized carbon monoxide, and the pressure of the carbon monoxide is 40-50 psi;
    所述反应的反应温度为55～65℃；The reaction temperature of the reaction is 55～65 ℃;
    所述反应的反应时间为22～26小时。The reaction time of the reaction is 22 to 26 hours.
  25. 根据权利要求8所述的如式II-1A所示的中间体的制备方法，其特征在于，所述步骤5中，The preparation method of the intermediate shown in formula II-1A according to claim 8, is characterized in that, in described step 5,
    所述催化剂为过渡金属催化剂，所述过渡金属催化剂为钯金属催化剂；The catalyst is a transition metal catalyst, and the transition metal catalyst is a palladium metal catalyst;
    所述有机碱为三乙胺；Described organic base is triethylamine;
    所述反应在加压的一氧化碳中进行，所述一氧化碳的压力为45psi；The reaction was carried out in pressurized carbon monoxide at a pressure of 45 psi;
    所述反应的反应温度为55～65℃；The reaction temperature of the reaction is 55～65 ℃;
    所述反应的反应时间为24小时。The reaction time for the reaction was 24 hours.
  26. 根据权利要求25所述的如式II-1A所示的中间体的制备方法，其特征在于，所述钯金属催化剂为四(三苯基膦)钯、醋酸钯、双三苯基磷二氯化钯、1,1-双(二苯基磷)二茂铁氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、三(二亚苄基丙酮)二钯、双(二亚芐基丙酮)钯、1,4-双(二苯基膦丁烷)二氯化钯。The preparation method of the intermediate shown in formula II-1A according to claim 25, wherein the palladium metal catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, bistriphenylphosphorus dichloride Palladium, 1,1-bis(diphenylphosphonium)ferrocene palladium chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, trichloromethane (dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, 1,4-bis(diphenylphosphinobutane)palladium dichloride.
  27. 根据权利要求25所述的如式II-1A所示的中间体的制备方法，其特征在于，所述钯金属催化剂为1,1-双(二苯基磷)二茂铁氯化钯。The method for preparing the intermediate represented by formula II-1A according to claim 25, wherein the palladium metal catalyst is 1,1-bis(diphenylphosphorus)ferrocene palladium chloride.
  28. 根据权利要求9所述的如式II-1A所示的中间体的制备方法，其特征在于，所述步骤6中，The preparation method of the intermediate shown in formula II-1A according to claim 9, is characterized in that, in described step 6,
    所述如式II-1A所示的中间体与如式5所示的化合物的摩尔比为1:1～1:2；The molar ratio of the intermediate shown in formula II-1A to the compound shown in formula 5 is 1:1 to 1:2;
    所述反应的反应温度为20～25℃；The reaction temperature of the reaction is 20～25 ℃;
    所述碱为碳酸氢钠；Described alkali is sodium bicarbonate;
    所述反应在N,N-二甲基甲酰胺中进行；The reaction is carried out in N,N-dimethylformamide;
    所述反应的反应时间为22～26小时。The reaction time of the reaction is 22 to 26 hours.
  29. 根据权利要求9所述的如式II-1A所示的中间体的制备方法，其特征在于，所述步骤6中，The preparation method of the intermediate shown in formula II-1A according to claim 9, is characterized in that, in described step 6,
    所述如式II-1A所示的中间体与如式5所示的化合物的摩尔比为1:1.5；The molar ratio of the intermediate shown in formula II-1A to the compound shown in formula 5 is 1:1.5;
    所述反应的反应时间为24小时。The reaction time for the reaction was 24 hours.
  30. 根据权利要求10所述的如式II-2所示的中间体的制备方法，其特征在于，所述步骤7中，The preparation method of the intermediate shown in formula II-2 according to claim 10, is characterized in that, in described step 7,
    所述如式II-1A所示的中间体与如式6所示的化合物的摩尔比为1:1～1:2；The molar ratio of the intermediate shown in formula II-1A to the compound shown in formula 6 is 1:1 to 1:2;
    所述脱去如式II-1A所示的中间体保护基PG 1在盐酸的作用下进行； The removal of the intermediate protecting group PG 1 shown in formula II-1A is carried out under the action of hydrochloric acid;
    所述脱去如式II-1A所示的中间体保护基PG 1在与氢气的反应下进行； The removal of the intermediate protecting group PG 1 shown in formula II-1A is carried out under the reaction with hydrogen;
    所述反应的反应温度为20～25℃；The reaction temperature of the reaction is 20～25 ℃;
    所述碱为三乙胺或N,N-二异丙基乙胺；The base is triethylamine or N,N-diisopropylethylamine;
    所述的脱保护基的反应在1,4-二氧六环中进行；The reaction of the deprotection group is carried out in 1,4-dioxane;
    所述的脱保护基的反应时间为2～4小时；The reaction time of described deprotection group is 2～4 hours;
    所述的脱保护基的产物在碱的作用下与如式6所示的化合物的反应在二氯甲烷中进行；The reaction of the product of the deprotected group with the compound shown in formula 6 is carried out in dichloromethane under the action of a base;
    所述的脱保护基的产物在碱的作用下与如式6所示的化合物的反应的反应时间为10～14小时。The reaction time of the reaction of the deprotected product with the compound shown in formula 6 under the action of a base is 10-14 hours.
  31. 根据权利要求10所述的如式II-2所示的中间体的制备方法，其特征在于，所述步骤7中，The preparation method of the intermediate shown in formula II-2 according to claim 10, is characterized in that, in described step 7,
    所述如式II-1A所示的中间体与如式6所示的化合物的摩尔比为1:1.5；The molar ratio of the intermediate shown in formula II-1A to the compound shown in formula 6 is 1:1.5;
    所述碱为三乙胺；Described base is triethylamine;
    所述的脱保护基的反应时间为3小时；The reaction times of described deprotection group is 3 hours;
    所述的脱保护基的产物在碱的作用下与如式6所示的化合物的反应的反应时间为12小时。The reaction time of the reaction of the deprotected product with the compound shown in formula 6 under the action of a base is 12 hours.
  32. 根据权利要求11所述的如式II-3所示的中间体的制备方法，其特征在于，所述步骤8中，The preparation method of the intermediate shown in formula II-3 according to claim 11, is characterized in that, in described step 8,
    所述溴化试剂为N-溴代丁二酰亚胺、二溴海因、三溴化吡啶、溴化铜或液溴；Described bromination reagent is N-bromosuccinimide, dibromohydantoin, pyridine tribromide, copper bromide or liquid bromine;
    所述如式II-2所示的中间体与溴化试剂的摩尔比为1:1～1:3；The molar ratio of the intermediate shown in formula II-2 to the bromination reagent is 1:1 to 1:3;
    所述反应在二氯甲烷中进行；The reaction is carried out in dichloromethane;
    所述反应的反应温度为20～25℃；The reaction temperature of the reaction is 20～25 ℃;
    所述反应的反应时间为0.5～2小时。The reaction time of the reaction is 0.5 to 2 hours.
  33. 根据权利要求11所述的如式II-3所示的中间体的制备方法，其特征在于，所述步骤8中，The preparation method of the intermediate shown in formula II-3 according to claim 11, is characterized in that, in described step 8,
    所述溴化试剂为液溴；Described bromination reagent is liquid bromine;
    所述如式II-2所示的中间体与溴化试剂的摩尔比为1:1.2；The mol ratio of the intermediate shown in the formula II-2 to the bromination reagent is 1:1.2;
    所述反应的反应时间为1小时。The reaction time for the reaction was 1 hour.
  34. 根据权利要求12所述的如式III所示的中间体的制备方法，其特征在于，所述步骤9中，The preparation method of the intermediate shown in formula III according to claim 12, is characterized in that, in described step 9,
    所述反应中如式II-3所示的中间体与所述如式7所示的化合物摩尔比为1:1～1:3；In the reaction, the molar ratio of the intermediate shown in formula II-3 to the compound shown in formula 7 is 1:1 to 1:3;
    所述反应在有机溶剂中进行，所述有机溶剂包括乙腈、二甲基亚砜、乙醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、1,4-二氧六环、正丙醇或正丁醇；The reaction is carried out in an organic solvent including acetonitrile, dimethyl sulfoxide, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, n-propanol or n-butanol;
    所述反应的反应温度为110～130℃；The reaction temperature of the reaction is 110～130 ℃;
    所述反应的反应时间为22～26小时。The reaction time of the reaction is 22 to 26 hours.
  35. 根据权利要求12所述的如式III所示的中间体的制备方法，其特征在于，所述步骤9中，The preparation method of the intermediate shown in formula III according to claim 12, is characterized in that, in described step 9,
    所述反应中如式II-3所示的中间体与所述如式7所示的化合物摩尔比为1:2；In the reaction, the mol ratio of the intermediate shown in formula II-3 to the compound shown in formula 7 is 1:2;
    所述反应在有机溶剂中进行，所述有机溶剂为乙腈；The reaction is carried out in an organic solvent, and the organic solvent is acetonitrile;
    所述反应的反应温度为120℃；The reaction temperature of the reaction is 120°C;
    所述反应的反应时间为24小时。The reaction time for the reaction was 24 hours.
  36. 根据权利要求13所述的如式IV所示的化合物的制备方法，其特征在于，所述步骤10中，The method for preparing the compound of formula IV according to claim 13, wherein in the step 10,
    所述如式III所示的中间体与甲胺的摩尔比为1:4～1:6；The molar ratio of the intermediate shown in formula III to methylamine is 1:4 to 1:6;
    所述反应的反应温度为20～25℃；The reaction temperature of the reaction is 20～25 ℃;
    所述反应在甲醇中进行；The reaction is carried out in methanol;
    所述反应的反应时间为4～6小时。The reaction time of the reaction is 4 to 6 hours.
  37. 根据权利要求13所述的如式IV所示的化合物的制备方法，其特征在于，所述步骤10中，The method for preparing the compound of formula IV according to claim 13, wherein in the step 10,
    所述如式III所示的中间体与甲胺的摩尔比为1:5；The mol ratio of the intermediate shown in formula III and methylamine is 1:5;
    所述反应的反应时间为5小时。The reaction time for the reaction was 5 hours.
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CN105246888A (en) * 2013-01-31 2016-01-13 尼奥迈德研究所 Imidazopyridine compounds and uses thereof
CN111377917A (en) * 2018-12-29 2020-07-07 武汉朗来科技发展有限公司 Heterocyclic compound, intermediate, preparation method and application thereof
WO2021161105A1 (en) * 2020-02-14 2021-08-19 Bellus Health Cough Inc. P2x3 modulators
WO2021161109A1 (en) * 2020-02-14 2021-08-19 Bellus Health Cough Inc. Preparation of a p2x3 antagonist
CN113549068A (en) * 2020-04-24 2021-10-26 上海拓界生物医药科技有限公司 Novel imidazopyridine compound, preparation method and medical application thereof
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CN111377917A (en) * 2018-12-29 2020-07-07 武汉朗来科技发展有限公司 Heterocyclic compound, intermediate, preparation method and application thereof
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