WO2022111683A1 - Composé d'azabicyclooctane substitué, son procédé de préparation, et intermédiaire et son procédé de préparation - Google Patents

Composé d'azabicyclooctane substitué, son procédé de préparation, et intermédiaire et son procédé de préparation Download PDF

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WO2022111683A1
WO2022111683A1 PCT/CN2021/133949 CN2021133949W WO2022111683A1 WO 2022111683 A1 WO2022111683 A1 WO 2022111683A1 CN 2021133949 W CN2021133949 W CN 2021133949W WO 2022111683 A1 WO2022111683 A1 WO 2022111683A1
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acid
compound
formula
preparation
hydrogen
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PCT/CN2021/133949
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Chinese (zh)
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曾振亚
张江波
贾淼
吴波
蔡训志
张兴松
李雪健
冯一骁
马有红
高清富
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN202180079164.6A priority Critical patent/CN116635392A/zh
Publication of WO2022111683A1 publication Critical patent/WO2022111683A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • 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
    • 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
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the field of organic chemical synthesis, in particular to a substituted azabicyclo[3.2.1]octane compound, an intermediate thereof and a preparation method thereof.
  • Orexin is a hunger-regulating signal secreted by the hypothalamus, named for its strong orexinic effect.
  • Orexin A (Orexin A) and orexin B (Orexin B) are a kind of neuropeptides, both act on G protein-coupled receptors orexin receptor OX1R and orexin receptor OX2R.
  • Orexin A and orexin B act on G protein-coupled receptors orexin receptor OX1R and orexin receptor OX2R.
  • the binding ability of OX1R to orexin A was stronger than that of orexin B, while the binding ability of OX2R to orexin A and orexin B was comparable.
  • dogs with narcolepsy are due to mutations in the gene that expresses OX2R, which leads to OX2R dysfunction.
  • the object of the present invention is to provide a substituted azabicyclo[3.2.1]octane compound, a preparation method thereof, an intermediate thereof and a preparation method of the intermediate, the azabicyclo[3.2.1]octane compound can be used for Preparation of orexin receptor antagonists.
  • a first aspect of the present invention provides a compound of formula (I) or a salt thereof:
  • Ring A is a benzene ring, a pyridine ring or a naphthalene ring;
  • (R a ) n represents that the hydrogen on the ring A is substituted by n R a , and each R a is the same or different, and is independently hydrogen, halogen, C 1- 3 alkyl or C 1-3 alkoxy;
  • R 1 , R 2 are each independently C 1-3 alkyl
  • n 0, 1 or 2.
  • n is 0 or 1.
  • R a is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R a is hydrogen
  • R 1 and R 2 are each independently methyl, ethyl, propyl or isopropyl.
  • R 1 is isopropyl
  • R 2 is methyl
  • ring A is a benzene ring.
  • the compound of formula (I) has the following structure:
  • the salt is a salt formed by the compound of formula (I) and an acid.
  • the acid is an inorganic acid.
  • the inorganic acid is hydrochloric acid.
  • a second aspect of the present invention provides a preparation method of a compound of formula (I), comprising the steps:
  • ring A is a benzene ring, a pyridine ring or a naphthalene ring;
  • R a represents that the hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • R 1 and R 2 are each independently C 1-3 alkyl
  • n 0, 1 or 2;
  • n is 0 or 1.
  • R a is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 1 and R 2 are each independently methyl, ethyl, propyl or isopropyl.
  • R 1 is isopropyl
  • R 2 is methyl
  • ring A is a benzene ring.
  • the molar ratio of the compounds of formula a, formula b and formula c is (1-2):1:1.
  • the mixture comprising the compound of formula (I) further comprises the isomer represented by formula (II),
  • Rings A, R a , n, R 1 and R 2 are as defined in the above specification.
  • the isomer represented by formula (II) is the following structure:
  • the compound of formula a is prepared by a method comprising the following steps:
  • R 1 is a C 1-3 alkyl group.
  • R 1 is methyl, ethyl, propyl or isopropyl.
  • the temperature of the reaction is -20°C to 50°C, preferably 0°C to 30°C, more preferably 5°C to 25°C.
  • step (1) the reaction time is greater than 0.5 hour.
  • step (1) in the mixture comprising the compound of formula (I), the molar ratio of the compound of formula (I) to the compound of formula (II) is greater than 1:1, preferably (1.5-2 ):1.
  • step (1) the compound of formula a participates in the reaction in the form of an unpurified reaction solution.
  • step (1) the compound of formula b participates in the reaction in the form of a reaction solution after reacting with hydrochloric acid.
  • step (1) the compound of formula c participates in the reaction in the form of a mixed solution with hydrochloric acid.
  • step (1) the reaction is carried out in a system with a pH value of 1 to 5, preferably in a system with a pH value of 3 to 4.
  • reaction of step (1) is carried out in a system containing a pH adjuster.
  • the pH adjusting agent is selected from: sodium acetate, sodium hydroxide, a combination of sodium acetate and sodium hydroxide.
  • step (2) the acid addition treatment is treatment with an acid-containing solution.
  • the acid-containing solution is a solution containing an acid and a solvent selected from the group consisting of: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1 ,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof .
  • a solvent selected from the group consisting of: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1 ,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonit
  • the acid is selected from organic acids and inorganic acids, wherein the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid; the organic acid is selected from: acetic acid, propionic acid, isobutyl acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and Methanesulfonic acid.
  • the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid
  • the organic acid is selected from: acetic acid, propionic acid, isobutyl acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric
  • the acid concentration is 0.1 mol/L to 10 mol/L, preferably 0.5 mol/L to 5 mol/L.
  • the acid is hydrochloric acid.
  • the acid-containing solution is a solution composed of hydrochloric acid and ethyl acetate.
  • the treatment (or "free") in the step (3) refers to treating the salt of the compound of formula (I) obtained in the step (2) with a solution containing a base selected from: Triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5, 4,0]-7-undecene (DBU), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, or a combination thereof.
  • a base selected from: Triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide,
  • the treatment (or "free") in the step (3) refers to treating the salt of the compound of formula (I) obtained in the step (2) with a solution containing sodium hydroxide.
  • the preparation method of the mixture comprising the compound of formula (I) comprises the steps:
  • reaction solution 1a containing the compound of formula a;
  • the first solvent is selected from water, C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide or a combination thereof;
  • the second solvent is selected from water, C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide or a combination thereof;
  • reaction solution 1a In the presence of a pH adjusting agent system, the reaction solution 1a, the mixture 1b and the mixture 1c are mixed to carry out a cyclization reaction, thereby obtaining a mixture containing the compound of formula (I).
  • the acid described in step (1b) is an inorganic acid, preferably hydrochloric acid.
  • the acid described in step (1c) is an inorganic acid, preferably hydrochloric acid.
  • the pH regulator in step (1d) is selected from the group consisting of: sodium acetate, sodium hydroxide, a combination of sodium acetate and sodium hydroxide.
  • step (1d) the reaction is carried out under the condition of pH 1 to 5, preferably under the condition of pH 3 to 4.
  • the reaction temperature is -20°C to 50°C, preferably 0°C to 30°C, more preferably 5°C to 25°C.
  • the C 1-3 alkyl alcohol in step (1a) is methanol, ethanol or isopropanol.
  • n is 0 or 1.
  • R a is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 2 is methyl, ethyl, propyl or isopropyl.
  • ring A is a benzene ring, a pyridine ring or a naphthalene ring.
  • the compound of formula c has the following structure:
  • a third aspect of the present invention provides a preparation method of a compound of formula (VII), comprising the steps:
  • Ring A is a benzene ring, a pyridine ring or a naphthalene ring;
  • (R a ) n represents that a hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy
  • (R b ) m represents that the hydrogen on the ring is substituted with m R b s, each R b being the same or different, and each independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • R 1 and R 2 are each independently C 1-3 alkyl
  • n are each independently 0, 1 or 2;
  • Z is N or CR 3 ;
  • R 3 is hydrogen, halogen or C 1-3 alkyl;
  • R LG is halogen, amino, hydroxyl, (HO) 2 B-, boronate ester, (NO 2 ) 2 C 6 H 3 O-, CH 3 S(O) 2 O-, CF 3 S(O) 2 O -, p - CH3C6H4S (O)2O-, CH3S (O) 2- , CH3S ( O) - .
  • R a and R b are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 1 and R 2 are each independently methyl, ethyl, propyl or isopropyl.
  • Z is N or CR 3 ;
  • R 3 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl or isopropyl.
  • the compound of formula (V) has the following structure:
  • the compound of formula (VII-a) has the following structure:
  • step (f) the purification is to add acid to the compound of formula (VII-a) or its solution.
  • the acid addition treatment is treatment with an acid-containing solution.
  • the acid-containing solution is a solution containing an acid and a solvent selected from the group consisting of: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1 ,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof .
  • a solvent selected from the group consisting of: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1 ,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonit
  • the acid is selected from organic acids and inorganic acids, wherein the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid; the organic acid is selected from: acetic acid, propionic acid, isobutyl acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and Methanesulfonic acid.
  • the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid
  • the organic acid is selected from: acetic acid, propionic acid, isobutyl acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric
  • the acid is hydrochloric acid.
  • the acid-containing solution is a solution composed of hydrochloric acid and ethyl acetate.
  • the present invention provides another preparation method of the compound of formula (VII), comprising the steps:
  • (R a ) n represents that the hydrogen on the ring A is replaced by n pieces of R a , each R a is the same or different, and each is independently hydrogen, fluorine, chlorine, bromine, iodine, methyl , ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy;
  • (R b ) m represents that the hydrogen on the ring is substituted by m R b , and each R b is the same or different, and each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 1 and R 2 are each independently methyl, ethyl, propyl or isopropyl.
  • R 1 is isopropyl
  • R 2 is methyl
  • ring A is a benzene ring.
  • Z is N.
  • the compound of formula (V-1) has the following structure:
  • the compound of formula (VII) has the following structure:
  • the compound of formula (I) is prepared by the preparation method described in the second aspect of the present invention.
  • step (a) is carried out in a system containing the following reagents: a reducing agent and an inert solvent.
  • the reducing agent is selected from:
  • Tetrabutylamine borohydride sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, potassium borohydride, borane, iso Propanol - aluminum triisopropoxide, lithium aluminum tetrahydrogen, lithium aluminum hydride tri-tert-butoxide, samarium diiodide;
  • the inert solvent is selected from: water, C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1, 2-Dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.
  • the reduction reaction of step (a) is carried out in a system containing the following reagents: a reducing agent and an inert solvent; the reducing agent is sodium borohydride; the inert solvent is methanol.
  • the molar ratio of the compound of formula (I) to the reducing agent in step (a) is 1:(1-3).
  • step (b) the elimination reaction of step (b) is carried out in a system containing the following reagents: a hydroxyl activator, a base and an inert solvent.
  • the hydroxyl activator is a sulfonyl chloride
  • the sulfonyl chloride is selected from: benzenesulfonyl chloride, p-toluenesulfonyl chloride, and methanesulfonyl chloride.
  • the base is selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, tert-butanol Lithium, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine or its combination.
  • DBU 1,8-diazabicyclo[5,4,0]-7-undecene
  • the base is selected from: ammonia water, triethylamine, diisopropylethylamine, N,N-dimethylaniline, tetramethylethylenediamine, tributylamine, sodium methoxide, ethanol Sodium, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), pyrazole, imididine , lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, sodium phenate, sodium benzoate, sodium citrate, N-methylmorpholine, pyridine, or a combination thereof.
  • DBU 1,8-diazabicyclo[5,4,0]-7-undecene
  • the inert solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloromethane Ethyl chloride, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, or combinations thereof.
  • the molar ratio of the compound of formula (III) to the hydroxyl activator in step (b) is 1:(1-2).
  • the molar ratio of the compound of formula (III) to the base in step (b) is 1:(1-2).
  • step (c) is carried out in a system containing the following reagents: a reducing agent and an inert solvent, wherein the reducing agent is selected from:
  • a complex compound selected from the group consisting of palladium, rhodium (such as tris(triphenylphosphine) rhodium chloride), cobalt, nickel, ruthenium, iridium, copper and a hydrogen donor selected from hydrogen, formic acid and formate combination; and
  • the inert solvent is selected from: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2- Dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.
  • the molar ratio of the compound of formula (IV) to the reducing agent in step (c) is 1:(1-10).
  • step (c) is carried out in a system containing a combination of metal magnesium and C 1-4 alkyl alcohol.
  • step (c) is carried out in a system containing a combination of metallic magnesium and methanol.
  • the molar ratio of the compound of formula (IV) to metal magnesium in step (c) is 1:(1-10).
  • the reduction reaction of step (c) is carried out in a system containing the following reagents: a reducing agent, a Lewis acid and an inert solvent, wherein the reducing agent is selected from: potassium borohydride, sodium borohydride and borohydride Lithium; the inert solvent is selected from: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide or a combination thereof; the Lewis acid is selected from: lithium chloride, cobalt chloride, magnesium chloride, chloride Zinc, Cupric Chloride, Aluminum Chloride, Ferrous Chloride, Nickel Chloride and Gallium Dichloride.
  • step (c) the reduction reaction of step (c) is carried out in a system containing sodium borohydride, tetrahydrofuran and lithium chloride.
  • the molar ratio of the compound of formula (IV), reducing agent and Lewis acid in step (c) is 1:(1-8):(1-5).
  • step (c1) is carried out in a system containing the following reagents: a reducing agent and an inert solvent, wherein the reducing agent is selected from:
  • a complex compound selected from the group consisting of palladium, rhodium (such as tris(triphenylphosphine) rhodium chloride), cobalt, nickel, ruthenium, iridium, copper and a hydrogen donor selected from hydrogen, formic acid and formate combination; and
  • the inert solvent is selected from: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2- Dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.
  • step (c1) is carried out in a system containing a combination of metal magnesium and C 1-4 alkyl alcohol.
  • step (c1) is carried out in a system containing a combination of metallic magnesium and methanol.
  • the reduction reaction of step (c1) is carried out in a system containing the following reagents: a reducing agent, a Lewis acid and an inert solvent, wherein the reducing agent is selected from: potassium borohydride, sodium borohydride and borohydride Lithium; the inert solvent is selected from: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1, 2-Dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.
  • a reducing agent is selected from: potassium borohydride, sodium borohydride and borohydride Lithium
  • the inert solvent is selected from: C 1-4 alkyl alcohol, toluene, x
  • the Lewis acid is selected from lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, cupric chloride, aluminum chloride, ferrous chloride, nickel chloride and gallium dichloride.
  • the molar ratio of the compound of formula (IV), reducing agent and Lewis acid in step (c1) is 1:(1-8):(1-5).
  • step (c1) is carried out in a system containing sodium borohydride, tetrahydrofuran and lithium chloride.
  • step (d) or step (d1) is carried out in a system containing the following reagents: a reducing agent and an inert solvent, wherein the reducing agent is selected from:
  • the inert solvent is selected from: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2- Dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.
  • the palladium catalyst is selected from: palladium carbon, tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine) palladium (Pd(PPh 3 ) 4 ), palladium acetate, bis(triphenylphosphine) palladium dichloro, palladium trifluoroacetate, palladium triphenylphosphine acetate, bis(tri-o-benzylphosphine) palladium dichloride, 1,2-bis(bis(di(triphenylphosphine) palladium) Phenylphosphino)ethane palladium dichloride or a combination thereof.
  • step (d) or step (d1) is carried out in a system containing red aluminum and toluene.
  • the molar ratio of the compound of formula (V) or formula (V-1) to the reducing agent in step (d) or step (d1) is 1:(1-5).
  • step (e) or step (e1) is carried out in a system containing the following reagents: a base and an inert solvent, the base is selected from: triethylamine, diisopropylethylamine, Tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene ( DBU), lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, or combinations thereof.
  • a base is selected from: triethylamine, diisopropylethylamine, Tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide
  • the inert solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate , acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, or a combination thereof.
  • step (e) or step (e1) is carried out in a system containing the following reagents: a base and an inert solvent, and the base is sodium tert-butoxide, potassium tert-butoxide or tert-butanol Lithium; the inert solvent is toluene.
  • step (e) or step (e1) is carried out in a system containing sodium tert-butoxide and toluene.
  • the molar ratio of the compound of formula (VI) or formula (VI-1) to the base in the substitution reaction is 1:(1-5).
  • the molar ratio of the compound of formula (VI) or formula (VI-1) to the compound of formula (VIa) in the substitution reaction is 1:(1-2).
  • the compound of formula (VIa) is selected from:
  • the fourth aspect of the present invention provides a compound of formula (VII-a) or a salt thereof:
  • Ring A is a benzene ring, a pyridine ring or a naphthalene ring;
  • (R a ) n represents that a hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy
  • (R b ) m represents that the hydrogen on the ring is substituted with m R b s, each R b being the same or different, and each independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • R 2 is C 1-3 alkyl
  • n are each independently 0, 1 or 2;
  • Z is N or CR 3 ;
  • R 3 is hydrogen, halogen or C 1-3 alkyl;
  • Said salt is a salt formed by the compound of formula (VII-a) and an acid.
  • n is 0 or 1.
  • n 1 or 2.
  • R a and R b are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R a is hydrogen
  • R b is fluorine
  • R 2 is methyl, ethyl, propyl or isopropyl.
  • R 2 is methyl
  • ring A is a benzene ring.
  • the acid is an inorganic acid.
  • the inorganic acid is hydrochloric acid.
  • Z is N or CR 3 ;
  • R 3 is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl or isopropyl.
  • Z is N.
  • the compound of formula (VII-a) has the following structure:
  • the present invention also provides a compound of formula (VII) or a salt thereof:
  • the salt is a salt of a compound of formula (VII) with an acid.
  • the acid is an inorganic acid.
  • the inorganic acid is hydrochloric acid.
  • n is 0 or 1.
  • n 1 or 2.
  • R a and R b are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R a is hydrogen
  • R b is fluorine
  • R 2 is methyl, ethyl, propyl or isopropyl.
  • R 2 is methyl
  • ring A is a benzene ring.
  • Z is N.
  • the compound of formula (VII) has the following structure:
  • a fifth aspect of the present invention provides a method for preparing a compound of formula (VII-a), the method comprising the steps of: substituting the compound of formula (VI) with the compound of formula (VIa) in an inert solvent in the presence of a base reaction, thereby obtaining the compound of formula (VII-a);
  • ring A is a benzene ring, a pyridine ring or a naphthalene ring;
  • (R a ) n represents that a hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy
  • (R b ) m represents that the hydrogen on the ring is substituted with m R b s, each R b being the same or different, and each independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • R 2 is C 1-3 alkyl
  • n are each independently 0, 1 or 2;
  • Z is N or CR 3 ;
  • R 3 is hydrogen, halogen or C 1-3 alkyl;
  • R LG is halogen, amino, hydroxyl, (HO) 2 B-, boronate ester, (NO 2 ) 2 C 6 H 3 O-, CH 3 S(O) 2 O-, CF 3 S(O) 2 O -, p - CH3C6H4S (O)2O-, CH3S (O) 2- , CH3S ( O) - .
  • the present invention also provides a method for preparing the compound of formula (VII), the method comprising the steps of: purifying the compound of formula (VII-a) to obtain the compound of formula (VII);
  • the compound of formula (VII-a) is prepared by the above-mentioned preparation method.
  • the purification is to add acid to the compound of formula (VII-a) or its solution.
  • the acid addition treatment is treatment with an acid-containing solution.
  • the acid is selected from organic acids and inorganic acids, wherein the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid; the organic acid is selected from: acetic acid, propionic acid, isobutyl acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and Methanesulfonic acid.
  • the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid
  • the organic acid is selected from: acetic acid, propionic acid, isobutyl acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric
  • R a and R b are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 2 is methyl, ethyl, propyl or isopropyl.
  • R 2 is methyl
  • ring A is a benzene ring.
  • Z is N.
  • the compound of formula (VIa) is selected from:
  • the substitution reaction is carried out in a system containing the following reagents: a base and an inert solvent, the base is selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, ethanol Sodium, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), lithium hydroxide, hydrogen Sodium oxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, or a combination thereof;
  • a base is selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, ethanol Sodium, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-di
  • the inert solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate , acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, or a combination thereof.
  • the preparation method further comprises the step of forming a salt of the compound of formula (VII) with an acid to obtain a salt of the compound of formula (VII).
  • the acid is an inorganic acid.
  • the inorganic acid is hydrochloric acid.
  • the compound of formula (VI) is prepared by a method comprising the following steps:
  • ring A is a benzene ring, a pyridine ring or a naphthalene ring;
  • R a represents that the hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • n 0, 1 or 2;
  • R 1 and R 2 are each independently C 1-3 alkyl.
  • n 0.
  • R a is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 1 and R 2 are each independently methyl, ethyl, propyl or isopropyl.
  • R 1 is isopropyl
  • R 2 is methyl
  • ring A is a benzene ring.
  • the compound of formula (I) is prepared by a method comprising the following steps:
  • ring A is a benzene ring, a pyridine ring or a naphthalene ring;
  • R a represents that the hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • R 1 and R 2 are each independently C 1-3 alkyl
  • n 0, 1 or 2;
  • the acid is an inorganic acid.
  • the inorganic acid is hydrochloric acid.
  • the compound of formula a is prepared by a method comprising the following steps:
  • R 1 is a C 1-3 alkyl group.
  • the mixture containing the compound of formula (I) further comprises the isomer represented by formula (II),
  • Rings A, R a , n, R 1 and R 2 are as defined in the above specification.
  • the sixth aspect of the present invention provides a preparation method of a compound of formula (IX), the method comprising the steps of: in a solvent, the compound of formula (VII) or its salt is removed from the substituent on the nitrogen atom, thereby obtaining the formula ( IX) compounds;
  • Ring A is a benzene ring, a pyridine ring or a naphthalene ring;
  • R a represents that the hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • R b represents that the hydrogen on the ring is replaced by m R b , each R b is the same or different, and each R b is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • R 2 is C 1-3 alkyl
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • Z is N or CR 3 ;
  • R 3 is hydrogen, halogen or C 1-3 alkyl.
  • the compound of formula (VII) is prepared by the preparation method described in the fifth aspect of the present invention.
  • the salt is a salt formed by the compound of formula (VII) and an inorganic acid.
  • the inorganic acid is hydrochloric acid.
  • reaction is carried out in a system containing a palladium catalyst and selected from hydrogen, formic acid, and ammonium formate.
  • the palladium catalyst is selected from: palladium carbon, tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine) palladium (Pd(PPh 3 ) 4 ), palladium acetate, bis(triphenylphosphine) palladium dichloro, palladium trifluoroacetate, palladium triphenylphosphine acetate, bis(tri-o-benzylphosphine) palladium dichloride, 1,2-bis(bis(di(triphenylphosphine) palladium) Phenylphosphino)ethane palladium dichloride or a combination thereof.
  • reaction is carried out in a system containing palladium on carbon and ammonium formate.
  • R a is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R b is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • n 0.
  • n 1
  • R 2 is methyl, ethyl, propyl or isopropyl.
  • R 2 is methyl
  • Z is N.
  • ring A is a benzene ring.
  • the compound of formula (IX) has the following structure:
  • a seventh aspect of the present invention provides a method for preparing a compound of formula (X), comprising the steps of: in an inert solvent, mixing the compound of formula (IX) or its salt with compound 5-methyl-2-(pyrimidin-2-yl) ) benzoic acid carries out condensation reaction, thereby obtains the compound of formula (X);
  • R b represents that the hydrogen on the ring is replaced by m R b , each R b is the same or different, and each R b is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • n 0, 1 or 2;
  • Z is N or CR 3 ;
  • R 3 is hydrogen, halogen or C 1-3 alkyl.
  • R b is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • n 1 or 2.
  • Z is N.
  • the compound of formula (X) has the following structure:
  • the compound of formula (IX) is prepared by the method described in the sixth aspect of the present invention.
  • FIG. 1 is an ellipsoid diagram of the three-dimensional structure of a compound 12 single crystal.
  • alkyl refers to straight and branched chain saturated aliphatic hydrocarbon groups, C 1-10 alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C 1-6 alkyl, more preferably C1-3 alkyl, similarly defined; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-di
  • alkoxy refers to -O-alkyl, wherein alkyl is as defined above.
  • a C 1-6 alkoxy group is preferable, and a C 1-3 alkoxy group is more preferable.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • boronic esters include (CH3O) 2B- , ( CH3CH2O ) 2B- , Wait.
  • treating is a free process, specifically, for example, after treating the salt of the compound of formula (I) with a suitable base or a solution of the base
  • the compound of formula (I) is obtained in free base form.
  • the present invention provides a method for preparing a compound of formula (VII), using compounds of formula a, formula b and formula c as starting materials, through cyclization reaction, reduction reaction, elimination reaction, two-step reduction reaction, and substitution reaction to obtain formula (VII) compound, the method comprises the steps of: in an inert solvent (such as water, ethyl acetate, etc.), at a certain temperature (such as -10 ° C to 25 ° C), the reaction solution containing the compound of formula a is treated with acid.
  • an inert solvent such as water, ethyl acetate, etc.
  • the obtained mixture of the compound of formula b and the solvent, and the mixture of the compound of formula c obtained by acid treatment and the solvent are mixed, and the pH of the reaction solution is controlled to be 1-5, and the reaction is carried out for a period of time (such as 0.5 hours to 24 hours), thereby obtaining a mixture comprising:
  • a mixture of compounds of formula (I) the resulting mixture is treated with an acid to give a salt of a compound of formula (I), and the resulting salt is treated (or "free") to give a compound of formula (I).
  • Described inert solvent refers to the solvent that does not participate in or influence above-mentioned ring-forming reaction, including but not limited to water, ethyl acetate.
  • Ring A is a benzene ring, a pyridine ring or a naphthalene ring;
  • (R a ) n represents that the hydrogen on the ring A is substituted by n R a , and each R a is the same or different, and is independently hydrogen, halogen, C 1 -3 alkyl or C 1-3 alkoxy;
  • R 1 and R 2 are each independently C 1-3 alkyl;
  • n is 0, 1 or 2;
  • the acid is an inorganic acid, most preferably hydrochloric acid.
  • the compound of formula (I) is reacted with a reducing agent in an inert solvent at a temperature (eg -20°C to 50°C, preferably -10°C to 5°C) for a period of time (eg 0.5 hours to 6 hours, preferably 2 hours to 4 hours), thereby obtaining the compound of formula (III);
  • a temperature eg -20°C to 50°C, preferably -10°C to 5°C
  • a period of time eg 0.5 hours to 6 hours, preferably 2 hours to 4 hours
  • the inert solvent and the reducing agent may be known in the art, suitable for various combinations of reducing agents and inert solvents for the selective reduction of carbonyl groups when both ester groups and carbonyl groups are present, wherein the reducing agent may be selected from, for example, tetrabutyl borohydride Amine salts, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, potassium borohydride, borane, isopropanol-triisopropoxide aluminum , a combination of lithium aluminum tetrahydride, lithium aluminum tri-tert-butoxide, samarium diiodide, zinc and a Lewis acid (such as antimony trichloride, etc.), a catalyst selected from the group consisting of metal palladium, nickel, platinum and lead and a catalyst selected from Combination of hydrogen donors of hydrogen, formic acid, formate, etc.
  • the reducing agent may be
  • the inert solvent can be selected from, for example, water, C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2- Dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof.
  • the reaction is carried out in the presence of a reducing agent selected from the group consisting of sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride and potassium borohydride and C 1-
  • a reducing agent selected from the group consisting of sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride and potassium borohydride and C 1-
  • the reaction is carried out in a system containing 4 alkyl alcohols, more preferably in a system containing sodium borohydride and methanol.
  • the compound of formula (III) is subjected to an elimination reaction for a period of time (eg 0.5 hours to 24 hours), thereby to obtain the compound of formula (IV);
  • the elimination reaction can be carried out in any system known in the art that is suitable for the ⁇ -elimination reaction, such as in a reaction system containing a hydroxyl activator and a base, wherein the hydroxyl activator can be sulfonyl chloride, etc., and the sulfonyl chloride can be selected Such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride and the like.
  • the base can be selected from: ammonia water, triethylamine, diisopropylethylamine, N,N-dimethylaniline, tetramethylethylenediamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, tert-butanol Sodium, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), pyrazole, imididine, lithium hydroxide, sodium hydroxide , potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, sodium phenate, sodium benzoate, sodium citrate, N-methylmorpholine, pyridine, etc., or a combination thereof.
  • DBU 1,8-diazabicyclo[5,4,0]-7-undecene
  • the inert solvent may be selected from, for example, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile , dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, etc., or a combination thereof.
  • the hydroxyl activator is preferably p-toluenesulfonyl chloride or methanesulfonyl chloride.
  • the base is preferably triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicycle [5,4,0]-7-undecene (DBU), sodium hydroxide or potassium hydroxide.
  • the inert solvent is preferably toluene, tetrahydrofuran, 1,4-dioxane or dichloromethane.
  • the compound of formula (IV) is reacted with a reducing agent in an inert solvent at a temperature (eg -20°C to 25°C, preferably -10°C to 10°C) for a period of time (eg 0.5 hours to 48 hours), thereby to obtain the compound of formula (V);
  • a temperature eg -20°C to 25°C, preferably -10°C to 10°C
  • a period of time eg 0.5 hours to 48 hours
  • the inert solvent and reducing agent can be known in the art, and are suitable for the combination of various reducing agents and inert solvents that can selectively reduce unsaturated double bonds or triple bonds in ⁇ , ⁇ -unsaturated esters, wherein the reducing agent is optional Metals such as magnesium, alkyl silicon hydrides, hydrides of tin, selenium or tellurium, zinc and a combination of a hydrogen donor selected from formic acid, formate, a combination of tin, carbon monoxide and water, selected from palladium, rhodium (such as A combination of a complex of tris(triphenylphosphine) rhodium chloride), cobalt, nickel, ruthenium, iridium, copper and a hydrogen donor selected from hydrogen, formic acid and formate, a catalyst selected from palladium, nickel and The combination of hydrogen donors selected from hydrogen, formic acid, formate, borane, hydrosulfite, ethylenic reductase,
  • the inert solvent can be selected from, for example, C 1-4 alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloromethane Ethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof.
  • the reaction is carried out in a system containing metal magnesium and C 1-4 alkyl alcohol, or in a system containing palladium catalyst/hydrogen and C 1-4 alkyl alcohol, wherein the palladium catalyst can be palladium carbon, Tris(dibenzylideneacetone)dipalladium(Pd2(dba)3), tetrakis(triphenylphosphine)palladium(Pd(PPh3)4), palladium acetate, dichlorobis(triphenylphosphine)palladium, trifluoro Palladium acetate, triphenylphosphine palladium acetate, bis(tri-o-benzylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethane palladium dichloride, etc., or a combination thereof.
  • the reaction is more preferably carried out in a system containing metallic magnesium and methanol.
  • the reducing agent can also be potassium borohydride, sodium borohydride or a combination of lithium borohydride and Lewis acid;
  • the Lewis acid is selected from: lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, copper chloride, chloride Aluminum, ferrous chloride, nickel chloride and gallium dichloride.
  • the inert solvent is selected from: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2- Dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.
  • the reaction is carried out in a system containing sodium borohydride and lithium chloride.
  • the compound of formula (IV) is reacted with a reducing agent in an inert solvent at a temperature (eg -20°C to 25°C, preferably -10°C to 10°C) for a period of time (eg 0.5 hours to 48 hours), thereby to obtain the compound of formula (V-1);
  • a temperature eg -20°C to 25°C, preferably -10°C to 10°C
  • a period of time eg 0.5 hours to 48 hours
  • the reducing agent is potassium borohydride, sodium borohydride or a combination of lithium borohydride and Lewis acid;
  • the Lewis acid is selected from: lithium chloride, cobalt chloride, magnesium chloride, zinc chloride, copper chloride, aluminum chloride, Ferric chloride, nickel chloride and gallium dichloride.
  • the inert solvent is selected from: C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2- Dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or a combination thereof.
  • the reaction is carried out in a system containing sodium borohydride and lithium chloride.
  • the reducing agent can also be a combination of metal magnesium and methanol.
  • the compound of formula (V) is reacted with a reducing agent in an inert solvent at a temperature (eg -20°C to 25°C, preferably -10°C to 10°C) for a period of time (eg 0.5 hours to 24 hours), thereby to obtain the compound of formula (VI);
  • a temperature eg -20°C to 25°C, preferably -10°C to 10°C
  • a period of time eg 0.5 hours to 24 hours
  • the compound of formula (V-1) is reacted with a reducing agent for a period of time (such as 0.5 hours to 24 hours). ), thereby obtaining the compound of formula (VI-1);
  • the inert solvent and the reducing agent can be known in the art, suitable for reducing the ester group to a combination of various reducing agents and inert solvents, wherein the reducing agent can be selected from the combination of red aluminum, palladium catalyst and hydrogen, propylene Sodium diacyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium borohydride, lithium triethylborohydride, lithium trisec-butylborohydride, sodium borohydride, boron A combination of potassium hydride or lithium borohydride and a Lewis acid, borane, diisobutylaluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium aluminum tetrahydride, potassium hydroxide-diglycol, samarium diiodide, [ A combination of CpFe(CO) 2 (PCy 3 )][BF 4 ] and phenylsilane, and the like
  • the inert solvent can be selected from, for example, C 1-4 alkyl alcohols, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloromethane Ethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof.
  • the reaction is carried out in a reaction containing red aluminum and selected from the group consisting of toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane alkane and acetonitrile in an inert solvent system.
  • a reaction containing red aluminum selected from the group consisting of toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane alkane and acetonitrile in an inert solvent system.
  • the compound of formula (VI) is reacted with the compound of formula (VIa) in the presence of a base for a period of time (such as 0.5 hours to 24 hours), thereby obtaining the compound of formula (VII-a), and then purifying the compound of formula (VII-a) to obtain the compound of formula (VII);
  • the compound of formula (VI-1) is reacted with the compound of formula (VIa) in the presence of a base for a period of time (eg 0.5 hours to 24 hours), thereby obtaining the compound of formula (VII);
  • R b is hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy
  • Z is N or CR 3
  • R 3 is hydrogen, halogen or C 1-3 alkyl
  • m is 0, 1 or 2
  • R LG represents a leaving group, such as halogen, amino, hydroxyl, (HO) 2 B-, boronate, (NO 2 ) 2 C 6 H 3 O-, CH 3 S(O) 2 O-, CF 3 S(O) 2 O-, p-CH 3 C 6 H 4 S(O) 2 O-, CH 3 S(O) 2 - , CH 3 S(O)-, etc.
  • the base in this reaction can be, for example, triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8- Diazabicyclo[5,4,0]-7-undecene (DBU), lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N-methylmorpholine, pyridine, etc., or its combination.
  • DBU 1,8- Diazabicyclo[5,4,0]-7-undecene
  • the inert solvent may be, for example, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile , dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, etc., or a combination thereof.
  • the compound of formula (VII-a) can be purified to the compound of formula (VII) by various purification methods known in the art, including, for example, chromatographic column separation and purification.
  • the preferred purification method is to purify the compound of formula (VII-a)
  • the compound or its solution is subjected to acid treatment.
  • the acid addition treatment is treatment with an acid-containing solution.
  • Described acid is selected from organic acid and inorganic acid, wherein inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid; Organic acid is selected from: acetic acid, propionic acid, isobutyric acid, maleic acid, propionic acid Diacid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid.
  • inorganic acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid
  • Organic acid is selected from: acetic acid, propionic acid, isobutyric acid, maleic acid, propionic acid Diacid, benzoic acid, succinic acid, suberic acid
  • the acid-containing solution is a solution containing an acid and a solvent selected from the group consisting of C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane , ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof.
  • a solvent selected from the group consisting of C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane , ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N
  • the present invention provides a preparation method of the compound of formula (X), which takes the compound of formula (VII) as a starting material, and obtains the compound of formula (X) through deprotection reaction and condensation reaction, and the method comprises the steps:
  • the compound of formula (VII) is subjected to a deprotection reaction for a period of time (such as 0.5 hours to 48 hours), Thereby the compound of formula (IX) is obtained;
  • ring A is a benzene ring, a pyridine ring or a naphthalene ring;
  • (R a ) n represents that a hydrogen on ring A is substituted with n R a , each of which is the same or different, and each is independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy
  • (R b ) m represents that the hydrogen on the ring is substituted with m R b s, each R b being the same or different, and each independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • R 2 is C 1-3 alkyl
  • n are each independently 0, 1 or 2;
  • Z is N or CR 3 ;
  • R 3 is hydrogen, halogen or C 1-3 alkyl;
  • reaction is carried out in a system comprising a palladium catalyst and a system selected from hydrogen and ammonium formate.
  • the compound of formula (IX) is combined with compound 5-methyl-2-(pyrimidin-2-yl)benzene in an inert solvent at a certain temperature (eg -10°C to 100°C, preferably 0°C to 80°C)
  • a certain temperature eg -10°C to 100°C, preferably 0°C to 80°C
  • Formic acid is subjected to condensation reaction, and the compound of formula (X) is obtained after the reaction for a period of time (such as 0.5 hours to 24 hours);
  • (R b ) m represents that hydrogen on the ring is substituted with m R b s, each R b being the same or different, and each independently being hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy; m is 0, 1 or 2; Z is N or CR 3 ; R 3 is hydrogen, halogen or C 1-3 alkyl.
  • the condensing agent may be selected from T3P , CDI, EDCI, HOBt, HATU and the like.
  • the inert solvent can be selected such as toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile , dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, etc., or a combination thereof.
  • the present invention provides a method for preparing the compound of formula (IX) by adopting novel intermediate compounds of formula (I) and formula (VII). Compared with the prior art, this synthetic method has the following advantages:
  • the preparation process of the starting material is simpler, and it is easier to purify to obtain the desired isomer intermediate product, which overcomes the disadvantage that the prior art cannot separate and purify the desired configuration intermediate in the previous synthesis step and avoids the
  • the prior art requires a large amount of organic solvent consumption and a long purification process caused by column chromatography purification, which is more conducive to scale-up production.
  • the intermediates prepared from the starting materials of the present invention are easier to separate and purify in the early steps of the reaction to obtain the desired isomer intermediate products, which greatly reduces the amount of by-products (isomers) produced in the later steps.
  • the separation and purification are difficult, the atom economy of the reaction is improved, and the generation of three wastes is reduced.
  • LC-MS Agilent 1290 HPLC System/6130/6150MS Liquid Mass Spectrometer (manufacturer: Agilent), column Waters BEH/CHS, 50 ⁇ 2.1 mm, 1.7 ⁇ m.
  • HPLC analysis adopts Agilent 1260 Infinity HPLC, OpenLAB CDS Chemstation workstation, chromatographic column XBridge C18 4.6*250mm, ID 5 ⁇ m column, detector DAD.
  • ISCO Combiflash-Rf75 or Rf200 automatic column passing instrument Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.
  • the specific rotation was measured by a Rudolf Autopol VI polarimeter at a detection temperature of 20 °C.
  • the single crystal structure was tested using a D8 Venture X-ray single crystal diffractometer.
  • Light source Cu target
  • resolution Current and voltage: 50kV, 1.2mA, exposure time 10s, distance from surface detector to sample 40mm, test temperature 150(2)K.
  • Known starting materials can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc) and Darui Chemicals, etc. company.
  • DMB is 2,4-dimethoxybenzyl
  • THF is tetrahydrofuran
  • EA is ethyl acetate
  • PE petroleum ether
  • Ac2O is acetic anhydride
  • NBS is N-bromosuccinimide
  • DCM is dichloromethane
  • AIBN is azobisisobutyronitrile
  • Pd(dppf)Cl is 1,1' - bis(diphenylphosphonium)ferrocene]palladium dichloride
  • TFA is trifluoroacetic acid
  • TBSCl is tert-butyldimethylsilyl chloride
  • NCS is N - chlorosuccinimide
  • DHP is dihydrotetrahydropyran
  • LiAlH is lithium aluminum hydride
  • PMB is p-methoxybenzyl
  • LiHMDS is two (trimethylsilyl) lithium amide
  • Pd 2 (dba) 3 is tris
  • room temperature refers to about 20-25°C.
  • Step 1 Cool the mixture of 200 g of 1,3-propanedicarboxylic acid, 280 mL of acetic acid and 200 mL of toluene to 5-10 °C, slowly add 220 mL of acetic anhydride dropwise, and continue stirring for 4 to 10 h after the dropwise addition; The filter cake was dried under reduced pressure at 40-50° C. for 6 hours to obtain 224 g of compound 1-a as a white solid with a yield of 87%. MS m/z (ESI): 129 [M+H] + .
  • Step 2 Add 107 g of compound 1-a into the reaction flask, drop 215 mL of isopropanol at 0-15 °C, control the internal temperature to 5-20 °C, stir until dissolved, add 300 mL of ice water, store at 0-10 °C, no need Purification was used directly in the next reaction.
  • Step 1.1 Add 33.2 mL of concentrated hydrochloric acid and 177.3 mL of water into the reaction flask 1, then add 86.3 g of compound b, heat up to 50-55 °C, stir for 3 hours and then drop to about 25 °C, add 430 mL of water for later use.
  • Step 1.2 Add 140 mL of concentrated hydrochloric acid and 740 mL of water into the reaction flask 2, cool the temperature to 5-15° C., and add 79.1 g of compound 3 dropwise with stirring for later use.
  • Step 1.3 Slowly drop the solution of the reaction flask 1 prepared in step 1.1 into the solution of the reaction flask 2 prepared in step 1.2, stir for 0.5 hours, add the solution prepared in Example 1 to the reaction flask 2, and then add the solution to the reaction flask 2.
  • 250 mL of an aqueous solution containing 53.5 g of sodium acetate was added, and then 40% sodium hydroxide solution was added dropwise to adjust the pH to about 3-4, and the internal temperature was maintained at 5 to 15° C. and stirred for 12 hours.
  • Step 2 Add 203.5 g of the obtained mixture and 500 mL of ethyl acetate into the reaction flask, and slowly add 330 mL of HCl/ethyl acetate (concentration 2.0 mol/L) dropwise at 0 to 5 °C; °C continue to stir for 3-4 hours, filter, wash the filter cake with EA, and vacuum dry the filter cake at 50 °C to obtain 79.5 g of the hydrochloride salt of compound 4-1 as a pale yellow solid with a purity of 97.5%.
  • Step 3 Mix and stir 60.0 g of the hydrochloride of compound 4-1 and 300 mL of ethyl acetate, add dropwise 20% sodium hydroxide solution at 0 to 10 ° C until the pH value is alkaline, stir for 0.5 hours, and let stand The layers were separated, the aqueous phase was extracted with ethyl acetate 300 mL ⁇ 2, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain 52 g of compound 4-1, which was a red oil, yield 96.6%, purity 97.3%.
  • Step 1.1 Add 7.5 mL of concentrated hydrochloric acid and 40 mL of water into the reaction flask 3, then add 20.2 g of compound b, heat up to 50-55 °C, stir for 3 hours and then drop to about 25 °C, add 100 mL of water for later use.
  • Step 1.2 32 mL of concentrated hydrochloric acid and 168 mL of water were added to the reaction flask 4, cooled to 5-15° C., and 18.5 g of compound 3 was added dropwise with stirring for later use.
  • Step 1.3 Slowly drop the solution of the reaction flask 3 prepared in step 1.1 into the solution of the reaction flask 4 prepared in step 1.2, stir for 0.5 hours, add the solution prepared in Example 2 to the reaction flask 4, and then add the solution to the reaction flask 4.
  • 65 mL of an aqueous solution containing 12.5 g of sodium acetate was added, and then 40% sodium hydroxide solution was added dropwise to adjust the pH to about 3-4, and the mixture was stirred at room temperature overnight.
  • Step 1.1 Add 20 mL of concentrated hydrochloric acid and 100 mL of water into the reaction flask 5, then add 50 g of compound b, heat up to 50-55 °C, stir for 3 hours and then drop to about 25 °C, add 250 mL of water for later use.
  • Step 1.2 Add 80 mL of concentrated hydrochloric acid and 420 mL of water into the reaction flask 6, cool down to 5-15 °C, and add 45.8 g of compound 3 dropwise with stirring for later use.
  • Step 1.3 Slowly drop the solution of the reaction flask 5 prepared in step 1.1 into the solution of the reaction flask 6 prepared in step 1.2, stir for 0.5 hours, and add 250 mL of an aqueous solution containing 70.8 g of 1,3-propanedicarboxylic acid. Add it to the reaction flask 6, then add 150 mL of an aqueous solution containing 31 g of sodium acetate, and then add dropwise 40% sodium hydroxide solution to adjust the pH to about 3-4, and stir at room temperature overnight.
  • Step 2 Add 20ml of anhydrous toluene into a 100ml three-necked flask, add 0.5g of NaH in batches under nitrogen protection, and dropwise add 0.8g of diethyl carbonate at the same time. After the addition, stir until no more bubbles are released. The temperature was raised to 85-95°C, and a solution prepared by dissolving 1.0 g of compound 13 in 5 mL of toluene was added dropwise, and the temperature was controlled to be about 95°C. After the addition was completed, stirring was continued for 1 hour at this temperature, and sampling was carried out for detection, and the reaction was complete.
  • the reaction solution was cooled to about 60 °C, poured into a mixture of 60 mL of ice water, 30 mL of ethyl acetate and 5 mL of hydrochloric acid for quenching, and the temperature was kept below 10 °C with constant stirring. After the quenching was completed, it was left to stand for separation, and the aqueous phase was extracted with 30 mL of ethyl acetate. The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at 55 °C to obtain 1.0 g of red oil.
  • Step 1 Add 52 g of compound 4-1 and 250 mL of methanol into a three-necked flask, under nitrogen protection, add 12.5 g of sodium borohydride in batches while stirring at -10°C, stir for 2 hours, and LCMS monitors the completion of the reaction.
  • the internal temperature was controlled at -10 to 0°C, and 80 mL of water and 40 mL of saturated ammonium chloride solution were added dropwise to quench the reaction.
  • reaction solution was concentrated, 300 mL of ethyl acetate was added for extraction, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filter cake was washed with ethyl acetate, and concentrated under reduced pressure to obtain 52.2 g of a reddish-brown oil (compound 5), purity: 86.6% , the yield is 100%.
  • Step 2 Add 47.3 g of compound 5 and 250 mL of toluene into the reaction flask and stir, add 18.6 g of sodium tert-butoxide at 0 to 10 °C, and slowly dropwise add 120 mL of a toluene solution containing 34.1 g of p-toluenesulfonyl chloride, and the dropwise addition is completed. , stirred for 1 hour at 0-10° C., added 20.0 g of sodium tert-butoxide, stirred overnight, and monitored the reaction by LCMS.
  • Step 3 Dissolve 21.4 g of compound 6 in 160 mL of methanol, add 15.4 g of magnesium chips in batches at 0 to 10° C., and continue stirring until the reaction is complete. Quench with 90 mL of acetic acid and 45 mL of water. Concentrate under reduced pressure to remove methanol, add 215 mL of ethyl acetate to the residue, and dropwise add 20% potassium carbonate solution to pH 6-7. The layers were left to stand, the organic layer was washed with 150 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 18.1 g of a red oil (compound 7). The yield was 84.2%, and the purity was 82.5%. MS m/z (ESI): 302.2 [M+H] + .
  • Step 4 Under nitrogen protection, 18.1g of compound 7 (1.0eq) and 180mL of toluene were added to the reaction flask, and 52g of toluene solution containing 70% red aluminum (3.0eq) was added dropwise at 0 to 5°C, and the reaction solution was at room temperature. under stirring for 18 hours. 20% sodium hydroxide solution was added dropwise at 0 to 10° C. to adjust the pH value to be greater than 12.
  • Step 1 Under nitrogen protection, add 14.7 g of compound 8 and 300 mL of toluene into the reaction flask and stir, and add 11.0 g of 2,5-difluoropyridine (compound 9) and 23.1 g of sodium tert-butoxide at 0-10 °C, Stir at room temperature until the reaction is complete.
  • Step 2 Add 18.3 g of compound 10 and 180 mL of ethyl acetate into a 500 mL three-necked flask and stir, add dropwise 2mol/L HCl/40 mL of ethyl acetate under an ice bath, a large amount of solids are precipitated, and continue to stir under an ice water bath for 3 to 4 hours , filtered with suction, and the solid was dried under vacuum at 50°C. 19.0 g of compound 10-1 hydrochloride was obtained with a yield of 93.8% and a purity of 82.9%.
  • the chirality detection method is as follows:
  • Step 3 Add 5.0 g of compound 10-1 hydrochloride, 100 mL of methanol, and 0.5 g of palladium carbon into a 250 mL three-necked flask, stir at room temperature, add 4.2 g of ammonium formate, and stir overnight. Suction filtration, adding 50 mL of water, rotary evaporation to remove most of the methanol, dropwise addition of NaOH solution (2M) until the pH is basic, extraction with ethyl acetate (100 mL, 50 x 2), and the organic phase is washed with saturated NaCl solution (50 mL). , dried over anhydrous sodium sulfate, and rotary-evaporated to obtain 3.13 g of compound 11, which is a colorless transparent liquid, yield: 100%, purity: 95.1%.

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un intermédiaire d'un composé azabicyclo[3.2.1]octane substitué, et son procédé de préparation. Plus particulièrement, la présente invention concerne un intermédiaire (le composé de formule (I)), son procédé de préparation, et un procédé de préparation d'un composé azabicyclo[3.2.1]octane au moyen de l'intermédiaire. Les définitions des groupes dans la formule sont détaillées dans la description et les revendications.
PCT/CN2021/133949 2020-11-30 2021-11-29 Composé d'azabicyclooctane substitué, son procédé de préparation, et intermédiaire et son procédé de préparation WO2022111683A1 (fr)

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WO2004031185A1 (fr) * 2002-10-04 2004-04-15 Merck Sharp & Dohme Limited Derives d'ether 8-azabicyclo[3.2.1]octane et leur utilisation en tant qu'antagonistes de recepteur de neurokinine
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