WO2023185027A1 - Procédé de préparation d'un composé d'isoquinoléine - Google Patents

Procédé de préparation d'un composé d'isoquinoléine Download PDF

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WO2023185027A1
WO2023185027A1 PCT/CN2022/134145 CN2022134145W WO2023185027A1 WO 2023185027 A1 WO2023185027 A1 WO 2023185027A1 CN 2022134145 W CN2022134145 W CN 2022134145W WO 2023185027 A1 WO2023185027 A1 WO 2023185027A1
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compound
reaction
buchwald
preparing
coupling reaction
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PCT/CN2022/134145
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English (en)
Chinese (zh)
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韦雨萌
孙丽梦
杨蓓蓓
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邦恩泰(山东)生物医药科技集团股份有限公司
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Publication of WO2023185027A1 publication Critical patent/WO2023185027A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

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  • the invention belongs to the technical field of drug synthesis and relates to the synthesis of drugs for preventing or treating Alzheimer's disease, Parkinson's disease and other related diseases, and specifically relates to a preparation method of isoquinoline compounds.
  • isoquinoline compounds have the effect of treating Parkinson's disease and Alzheimer's disease.
  • chemical synthesis method of isoquinoline compounds has not yet been disclosed.
  • preparation methods suitable for industrial large-scale production there are no relevant reports on preparation methods suitable for industrial large-scale production.
  • the object of the present invention is to provide a preparation method of isoquinoline compounds, which can realize large-scale industrial production of isoquinoline compounds.
  • a method for preparing isoquinoline compounds includes the process of using compound II as a raw material to prepare compound VI (i.e., isoquinoline compounds) according to the following reaction route:
  • R is an amino protecting group
  • compound II is prepared through Buchwald-Hartwig coupling reaction to compound III.
  • the main ring of isoquinoline compounds is isoquinoline, and its 2-position N has little effect on the electron cloud distribution of 1 and 3-position C, so the substituted amination reaction at 1 and 3-position is difficult to proceed.
  • the C position is replaced by other elements, for example, the 4-position C of isoquinoline is replaced by N to form quinazoline, which causes a large change in the electron cloud in the main ring structure.
  • the substituted amination reaction at positions 1 and 3 is easier. conduct.
  • N-methyl-N'-tetrahydrofuranoylpropanediamine reacts directly with N-methyl-N'-tetrahydrofuranoylpropanediamine, making the operation simpler.
  • the cost of N-methyl-N'-tetrahydrofuranoylpropanediamine is relatively high.
  • N-methyl-N'-tetrahydrofuranoylpropanediamine is an oily substance, which is difficult to purify. It contains many impurities and easily increases side reactions, resulting in a low yield. Therefore, the present invention uses N-methyl-3-aminopropionitrile as raw material to avoid the problems of high input cost and excessive impurities caused by the use of N-methyl-N'-tetrahydrofuranformylpropanediamine in industrial production.
  • the present invention solves the problem of difficult amination substitution of chlorine at the 3-position C through Buchwald-Hartwig coupling reaction, and then obtains the target product isoquinoline compound through reduction, amidation and de
  • a method for preparing isoquinoline compounds includes using compound II as a raw material to prepare compound VI according to the following reaction route:
  • R is an amino protecting group
  • X is halogen or hydroxyl
  • compound II is prepared through Buchwald-Hartwig coupling reaction to compound VII.
  • the present invention uses methylamine hydrochloride, which has lower feeding cost and higher purity. Higher, side effects are greatly reduced.
  • the problem of difficult amination substitution of chlorine at position 3 was solved through Buchwald-Hartwig coupling reaction, and the target product isoquinoline compound was obtained through substitution reaction and deprotection.
  • the third aspect of the present invention is an isoquinoline compound, and the isoquinoline compound is compound VI obtained by the above preparation method.
  • the present invention avoids directly using N-methyl-N'-tetrahydrofuranoylpropanediamine to carry out amination reaction on the 3-position of isoquinoline, thereby avoiding low yield and high cost in industrial production. question.
  • the preparation method of the present invention can achieve the purpose of industrial large-scale production of isoquinoline compounds, and the isoquinoline compounds prepared have higher yield and high purity.
  • Figure 1 is a graph showing the test results of rats in a Parkinson's disease model in which 6-OHDA was injected with Compound VI in a specific brain area in Example 25 of the present invention during adhesion and standing.
  • Figure 2 is a graph showing test results during exercise of rats in a Parkinson's disease model using Compound VI to inject 6-OHDA into specific brain areas in Example 25 of the present invention.
  • Figure 3 is a graph showing the test results of the grip strength and nervous system balance ability of mice in the Parkinson's disease model using Compound VI for intraperitoneal injection of MPTP in Example 26 of the present invention.
  • Figure 4 is a graph illustrating the survival number results of dopamine neurons in mice of the Parkinson's disease model in which MPTP was injected intraperitoneally with Compound VI in Example 26 of the present invention.
  • the present invention proposes a preparation method of isoquinoline compounds.
  • a typical embodiment of the present invention provides a method for preparing isoquinoline compounds, which includes the process of using compound II as a raw material to prepare compound VI (i.e., isoquinoline compounds) according to the following reaction route:
  • R is an amino protecting group
  • compound II is prepared through Buchwald-Hartwig coupling reaction to compound III.
  • the amino protecting group is an amino protecting group, such as benzyl, substituted benzyl, diphenylmethyl, substituted diphenylmethyl, trityl, substituted trityl, tert-butoxycarbonyl, etc.
  • the substituted benzyl group is a benzyl group substituted by an alkoxy group, a halogen group, an alkyl group, an alkyl group, or the like.
  • the substituted benzyl group is a benzyl group substituted by an alkoxy group, a halogen group, an alkyl group, an alkyl group, or the like.
  • the substituted trityl group is a trityl group substituted by an alkoxy group, a halogen group, an alkyl group, an alkyl group, or the like.
  • the present invention uses R-NH 2 to carry out the reaction, which can solve the problem that the reaction temperature is too high and microwave heating is required due to the electron cloud distribution of isoquinoline and the methoxy groups at positions 6 and 7.
  • the amino protecting group is alkoxy or alkyl substituted benzyl. This scheme can ensure a higher yield of compound II.
  • the amino protecting group is preferably 2-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl or 2,4-dimethoxy. Benzyl.
  • the reaction temperature is 100-160°C, preferably 100-130°C.
  • the solvent in the process of preparing compound II from compound I is N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) one or more of them.
  • the molar ratio of compound I to R-NH 2 is 1:2-5, preferably 1:2.5-4.
  • the Buchwald-Hartwig coupling reaction of the present invention is a cross-coupling reaction of an amine and an aromatic halide to form an N-arylation product of the amine under palladium catalysis.
  • the catalyst is Pd(OAc) 2 (palladium acetate), Pd 2 (dba) 3 (tri( Dibenzylideneacetone)dipalladium), Pd(dba) 2 (dibenzylideneacetonepalladium), PdCl 2 (cod) ((1,5-cyclooctadiene)palladium chloride), [Pd(allyl )Cl] 2 (allylpalladium(II) chloride dimer), PdCl 2 ⁇ (CH 3 CN) 2 (bis(acetonitrile)palladium dichloride), Pd(acac) 2 (palladium diacetylacetonate) , Pd(PPh 3 ) 2 Cl 2 (1,1'-bisdiphenylphosphine ferrocene palladium dichloride), PdCl 2 [P(o-To)
  • the base in the Buchwald-Hartwig coupling reaction is sodium tert-butoxide, cesium carbonate, potassium tert-butoxide, Potassium carbonate, potassium phosphate, lithium bistrimethylsilylamide, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or MTBD (7-methyl-1, 5,7-triazabicyclo[4.4.0]dec-5-ene).
  • the ligand in the Buchwald-Hartwig coupling reaction is Xphos (2-bicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl), BrettPhos (2-(dicyclohexylphosphine)3,6-dimethoxy-2',4',6'-triisopropyl-1,1 '-Biphenyl), t-BuBrettPhos (2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-bis phenyl), Me 4 t-BuXphos (2-di-tert-butylphosphonium-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl
  • PPh 3 triphenylphosphine
  • P(o-tolyl) 3 tris(o-methylphenyl)phosphorus
  • RuPhos (2-bicyclohexylphosphine-2',6'-diisopropoxy biphenyl
  • DPEPhos bis(2-diphenylphosphine)phenyl ether), Dppf(1,1'-bis(diphenylphosphine)ferrocene), CyPFt-Bu, Dppp(1,3-bis( Diphenylphosphine)propane), JohnPhos (2-(di-tert-butylphosphine)biphenyl), CyJohnPhos (2-(dicyclohexylphosphino)biphenyl), P(t-Bu) 3 (tri-tert-butyl Phosphine), DavePhos (2-bicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl),
  • the solvent in the Buchwald-Hartwig coupling reaction is toluene, 1,4-dioxane, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) one or more.
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • the temperature in the Buchwald-Hartwig coupling reaction is 90-130°C, preferably 100°C.
  • the molar ratio of compound II and N-methyl-3-aminopropionitrile is 1:1 ⁇ 5, preferably 1:1.5 ⁇ 3.
  • the molar ratio of compound II and catalyst is 1:0.0.05 ⁇ 0.5, preferably 1:0.05 ⁇ 0.2.
  • the molar ratio of compound II and ligand is 1:0.1-1.1, preferably 1:0.1-0.4.
  • the molar ratio of compound II to the base is 1:1 ⁇ 4, preferably 1:2.
  • the mass/volume ratio of compound II and reaction solvent is 1:5 ⁇ 100kg/L, preferably 1:10 ⁇ 20kg/L;
  • compound III is heated to 60-80°C with hydrogen or hydrazine hydrate under the action of a catalyst to react to obtain compound IV.
  • the catalyst in the process of preparing compound IV from compound III, is a Raney nickel catalyst (Raney Ni), platinum dioxide, rhodium catalyst or nickel catalyst, preferably a Raney nickel catalyst (Raney Ni).
  • the mass/volume ratio of compound III to the reaction solvent is 1:5 ⁇ 1:100kg/L, preferably 1:10 ⁇ 1:20kg/ L.
  • the reaction solvent is liquid ammonia ethanol solution, liquid ammonia methanol solution or methanol sodium hydroxide solution.
  • the process of preparing compound V from compound IV is as follows: after mixing compound IV, 2-tetrahydrofurancarboxylic acid and a base evenly, 1-propyl phosphoric acid cyclic anhydride (T3P) is added dropwise and the reaction is carried out.
  • T3P 1-propyl phosphoric acid cyclic anhydride
  • the base in the process of preparing compound V from compound IV, is triethylamine, diisopropylethylamine (DIPEA), pyridine, N,N-dimethylaminopyridine, piperidine, 2 ,6-dimethylpiperidine or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).
  • DIPEA diisopropylethylamine
  • pyridine N,N-dimethylaminopyridine
  • piperidine 2 ,6-dimethylpiperidine
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • the ratio of compound IV to 2-tetrahydrofurancarboxylic acid is 1:1-3; preferably 1:1.1-2.
  • the ratio of compound IV to T3P is 1:1-3; preferably 1:1.5.
  • the ratio of compound IV to triethylamine is 1:1-6; preferably 1:3.
  • the process of preparing compound V from compound IV is as follows: heating compound IV, 2-tetrahydrofurancarboxylic acid and carbonyldiimidazole to 40-45°C for reaction to obtain.
  • the ratio of compound IV to carbonyldiimidazole is 1:1-3; preferably 1:1.5.
  • the process of preparing compound V from compound IV is as follows: performing an acid chlorination reaction on compound IV and a chlorine source, then lowering the temperature to 0-10°C, adding 2-tetrahydrofurancarboxylic acid, and a base at 0-30 The reaction is carried out at °C to obtain; the chlorine source is thionyl chloride, oxalyl chloride or phosphorus oxychloride.
  • the base selection is the same as described above.
  • the process of preparing compound V from compound IV is: mixing pivaloyl chloride, ethyl chloroformate, acetic anhydride, isobutyl chloroformate or Boc anhydride and 2-tetrahydrofurancarboxylic acid at 0-10°C Evenly, then add base and compound IV to react at 0-30°C to obtain.
  • the molar ratio of compound IV to pivaloyl chloride is 1:1-2; preferably 1:1.2.
  • the process of preparing compound V from compound IV is as follows: reacting 2-tetrahydrofurancarboxylic acid, a condensing agent and compound IV at 0-30°C; the condensing agent is HBTU, HATU, HCTU, TBTU , TPTU, HOBt/DCC, HOBt/EDCl, HOBt/DICL.
  • the molar ratio of compound IV to the condensing agent is 1:1 ⁇ 3; preferably 1:1.5.
  • the process of preparing compound V from compound IV is as follows: mixing 2-tetrahydrofurancarboxylic acid, boric acid and compound IV, and then heating and refluxing to react.
  • the molar ratio of compound IV to boric acid is 1:0.05-0.4; preferably 1:0.1-0.2.
  • the process of removing the amino protecting group of Compound V to obtain Compound VI is: reacting Compound V in a reaction solvent, and then using a saturated NaHCO 3 solution to adjust the pH to 7-8 to obtain;
  • the reaction solvent is trifluoroacetic acid, triethylsilyl hydrogen, methanesulfonic acid, trifluoromethanesulfonic acid, a mixed solvent of trifluoroacetic acid/dichloromethane, a mixed solvent of methanesulfonic acid/dichloromethane, or triethylsilyl hydrogen. /trifluoroacetic acid mixed solvent.
  • Another embodiment of the present invention provides a method for preparing isoquinoline compounds, which includes the process of preparing compound VI using compound II as a raw material according to the following reaction route:
  • R is an amino protecting group
  • X is halogen or hydroxyl
  • compound II is prepared through Buchwald-Hartwig coupling reaction to compound VII.
  • the process of preparing N-3-substituted propyl-2-tetrahydrofurancarboxamide according to the following reaction formula includes 2-tetrahydrofurancarboxylic acid and 3-substituted propylamine as raw materials:
  • X is as mentioned above.
  • 2-tetrahydrofurancarboxylic acid, 3-substituted propylamine and alkali are reacted at 0 to 25°C, and then 1-propylphosphoric acid cyclic anhydride is added dropwise, and the reaction is continued to obtain.
  • the base is preferably triethylamine or diisopropylethylamine (DIPEA).
  • compound VII, N-3-substituted propyl-2-tetrahydrofurancarboxamide, sodium iodide and alkali are heated to 90-100°C under an inert atmosphere to react to obtain compound V.
  • the base is as previously described.
  • the reaction solvent is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene or 1,4-dioxane. Avoid the boiling point of the solvent being too low to reach the reaction temperature.
  • the molar ratio of compound VII to the base is 1:1.1-4, preferably 1:2.
  • the molar ratio of compound VII and sodium iodide is 1:0.1 ⁇ 1, preferably 1:0.2 ⁇ 0.5.
  • the molar ratio of compound VII and N-3-chloropropyl-2-tetrahydrofurancarboxamide is preferably 1:1 to 4, preferably 1:1.5 to 2.0.
  • the third embodiment of the present invention provides an isoquinoline compound, which is compound VI obtained by the above preparation method.
  • the post-treatment was cooled to 20-30°C, filtered directly, and water (60L) and ethyl acetate ( 50L) into the filtrate, collect the organic phase, add citric acid solution, adjust the pH value of the system to 3-4, separate the liquids, take the aqueous phase, extract the organic phase twice with water (30L ⁇ 2), combine the aqueous phases, and use ethyl acetate to Wash once with ester (30L), add sodium carbonate solution and ethyl acetate (50L) to the aqueous phase, adjust the pH value of the system to 7-8, collect the organic phase by liquid separation, and extract the aqueous phase twice with ethyl acetate (30L ⁇ 2), combine the organic phases, use vacuum rotary evaporation, rotary evaporate the solvent, and then recrystallize with n-heptane and ethyl acetate to obtain 4.4 kg of product compound ⁇ , with a yield of 68.1%.
  • the post-processing is cooled to 20-30°C, filtered directly, and water (60L) and ethyl acetate (50L) are added to In the filtrate, collect the organic phase, add citric acid solution, adjust the pH value of the system to 3-4, separate the liquids, take the aqueous phase, extract the organic phase twice with water (30L ⁇ 2), combine the aqueous phases, and use ethyl acetate (30L ), wash once, add sodium carbonate solution and ethyl acetate (50L) to the water phase, adjust the pH value of the system to 7-8, collect the organic phase by liquid separation, and extract the water phase twice with ethyl acetate (30L ⁇ 2) , combine the organic phases, use vacuum rotary evaporation, rotary evaporate the solvent, and then purify with n-heptane and ethyl acetate to obtain 3.4 kg of product compound VII, with a yield of 62.7%.
  • the substantia nigra compacta (SNpc) was stained with dopamine antibodies, and the results are shown in Figure 4. Compared with normal mice, the number of dopamine neurons after MPTP treatment was significantly reduced; while the number of dopamine neurons in mice treated with Compound VI orally (MPTP-treated mice + Compound VI) was significantly increased, indicating that MPTP treatment with Compound VI There was a significant difference in dopamine neuron survival rate between mice treated with MPTP and mice not given compound VI (p ⁇ 0.01).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne la synthèse de médicaments pour la prévention ou le traitement de la maladie d'Alzheimer, de la maladie de Parkinson et d'autres maladies associées, et en particulier un procédé de préparation d'un composé d'isoquinoléine. Dans le procédé, le composé II est utilisé en tant que matière première pour préparer le composé VI (c'est-à-dire le composé d'isoquinoléine), de façon à obtenir une production industrielle du composé d'isoquinoléine à grande échelle, le rendement est supérieur, et la pureté est élevée.
PCT/CN2022/134145 2022-03-30 2022-11-24 Procédé de préparation d'un composé d'isoquinoléine WO2023185027A1 (fr)

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CN114573506B (zh) * 2022-03-21 2022-09-30 邦恩泰(山东)生物医药科技集团股份有限公司 药物中间体及合成方法、异喹啉类衍生物及其合成方法
CN114573569B (zh) * 2022-03-30 2023-07-04 邦恩泰(山东)生物医药科技集团股份有限公司 一种异喹啉类化合物的制备方法

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