WO2022156784A1 - Procédé de préparation d'un composé hétérocyclique, et intermédiaire d'un composé hétérocyclique - Google Patents

Procédé de préparation d'un composé hétérocyclique, et intermédiaire d'un composé hétérocyclique Download PDF

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WO2022156784A1
WO2022156784A1 PCT/CN2022/073299 CN2022073299W WO2022156784A1 WO 2022156784 A1 WO2022156784 A1 WO 2022156784A1 CN 2022073299 W CN2022073299 W CN 2022073299W WO 2022156784 A1 WO2022156784 A1 WO 2022156784A1
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formula
reaction
intermediate shown
preparation
compound
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Chinese (zh)
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张学军
李群
臧杨
蔡立波
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
    • 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
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a preparation method of heterocyclic compounds and their intermediates; in particular, the present invention relates to a preparation method of imidazopyridine compounds and their intermediates.
  • 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 the above 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 a kind of intermediate as shown in formula I or formula II:
  • 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 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.
  • 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;
  • 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 an organic solvent
  • 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 shown in formula I to the compound shown in formula 1 in the reaction is 1:1 ⁇ 1:1.6, preferably 1:1 ⁇ 1.2 or 1:1: 1.5 ⁇ 1:1.6, more preferably 1:1.2 or 1:1.5.
  • the reaction time of the reaction is 2 to 4 hours, preferably 3 hours.
  • the reaction when the reaction is carried out under the action of an alkyl lithium compound, the reaction further includes a stabilizer, and the stabilizer is N,N,N',N'-tetramethylethylenedi amine.
  • 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 N,N-diisopropylethylamine.
  • the condensing agent is 1-propyl phosphoric anhydride.
  • 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 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 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 preparation method of the intermediate shown in formula II-1A, and the preparation method of the intermediate shown in formula II-1A includes 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.
  • 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 method for preparing the intermediate shown in formula II-2, wherein the intermediate shown in formula II-2 is prepared from the intermediate shown in formula II-1A, and the 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.
  • 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 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 previously described definition.
  • 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:
  • the molar ratio of the intermediate shown in formula III to methylamine is 1:4 to 1:6, preferably 1:5.
  • the reaction is carried out in methanol.
  • 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 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.
  • 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.
  • amino metal compound refers to a compound formed by a covalent bond or a coordinate bond between a metal atom and an amino group.
  • amino amino group refers to primary (ie -NH 2 ), secondary (ie -NRH) and tertiary (i.e.
  • 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 lanthanide series.
  • 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 .
  • 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) (100 g, 95% 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:
  • reaction solution was concentrated to dryness under reduced pressure, dichloromethane (600 mL) was added to the residue, the temperature of the reaction solution was adjusted to 0-5 ° C, triethylamine (41.1 g, 406 mmol) was slowly added dropwise, and then methyl chloroformate was added. (19.2 g, 203 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. 400 mL of saturated sodium chloride solution was added to the reaction solution, the layers were separated and the organic phase was collected.
  • the first step Synthesis of (S)-3,5-difluoro-4-(3-(4-(methoxycarbonyl)morpholin-2-yl)propionyl)benzoic acid (C-2)
  • reaction solution was concentrated to dryness under reduced pressure, dichloromethane (70 mL) was added to the residue, the temperature of the reaction solution was adjusted to 0-5 ° C, triethylamine (5.5 g, 54.3 mmol) was slowly added dropwise, and then methyl chloroformate was added. Ester (1.9 g, 23.3 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 target compound 1 is as follows:
  • reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methane) as a yellow solid Methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (1) (7.7 g, 97% yield).

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

Abstract

L'invention concerne un procédé de préparation d'un composé imidazopyridine tel que représenté dans la formule IV, et un intermédiaire de celui-ci tel que représenté dans la formule I ou la formule II. Le composé imidazopyridine tel que représenté dans la formule IV peut antagoniser un récepteur P2X3, et a pour effet la suppression de la toux et l'analgésie.
PCT/CN2022/073299 2021-01-22 2022-01-21 Procédé de préparation d'un composé hétérocyclique, et intermédiaire d'un composé hétérocyclique WO2022156784A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019059A1 (fr) * 1995-11-17 1997-05-29 Sibia Neurosciences, Inc. Nouveaux composes d'aryle substitues utiles comme modulateurs des recepteurs de l'acetylcholine
CN105246888A (zh) * 2013-01-31 2016-01-13 尼奥迈德研究所 咪唑并吡啶化合物及其用途
CN111377917A (zh) * 2018-12-29 2020-07-07 武汉朗来科技发展有限公司 杂环类化合物、中间体、其制备方法及应用
WO2021161109A1 (fr) * 2020-02-14 2021-08-19 Bellus Health Cough Inc. Préparation d'un antagoniste p2x3
WO2021161105A1 (fr) * 2020-02-14 2021-08-19 Bellus Health Cough Inc. Modulateurs de p2x3
CN113549068A (zh) * 2020-04-24 2021-10-26 上海拓界生物医药科技有限公司 一类新型咪唑并吡啶化合物、其制备方法及其在医药上的应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019059A1 (fr) * 1995-11-17 1997-05-29 Sibia Neurosciences, Inc. Nouveaux composes d'aryle substitues utiles comme modulateurs des recepteurs de l'acetylcholine
CN105246888A (zh) * 2013-01-31 2016-01-13 尼奥迈德研究所 咪唑并吡啶化合物及其用途
CN111377917A (zh) * 2018-12-29 2020-07-07 武汉朗来科技发展有限公司 杂环类化合物、中间体、其制备方法及应用
WO2021161109A1 (fr) * 2020-02-14 2021-08-19 Bellus Health Cough Inc. Préparation d'un antagoniste p2x3
WO2021161105A1 (fr) * 2020-02-14 2021-08-19 Bellus Health Cough Inc. Modulateurs de p2x3
CN113549068A (zh) * 2020-04-24 2021-10-26 上海拓界生物医药科技有限公司 一类新型咪唑并吡啶化合物、其制备方法及其在医药上的应用

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