WO2019174631A1 - Method for preparing norstat - Google Patents

Method for preparing norstat Download PDF

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WO2019174631A1
WO2019174631A1 PCT/CN2019/078261 CN2019078261W WO2019174631A1 WO 2019174631 A1 WO2019174631 A1 WO 2019174631A1 CN 2019078261 W CN2019078261 W CN 2019078261W WO 2019174631 A1 WO2019174631 A1 WO 2019174631A1
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compound
acid
group
reaction
sodium
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PCT/CN2019/078261
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French (fr)
Chinese (zh)
Inventor
杨满勋
谢建树
陆世红
夏广新
刘彦君
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上海医药集团股份有限公司
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Publication of WO2019174631A1 publication Critical patent/WO2019174631A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to the field of organic chemistry and medicinal chemistry, in particular, the present invention relates to a nodstat, ie [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) A method for preparing amino]acetic acid.
  • Nordostatin is a synthetic isoquinoline derivative, hypoxia-inducible factor proline hydroxylase inhibitor (HIF-PHI) regulates hypoxia-inducible factor (HIF) by regulating proline hydroxylase (PHD) Hydroxylation inhibits HIF protein degradation and maintains the biological effects of HIF.
  • HIF-PHI hypoxia-inducible factor proline hydroxylase inhibitor
  • PLD proline hydroxylase
  • EPO blood concentration monitoring found that after using a small amount of HIF-PHI, EPO levels were only 2-3 times normal, while hemoglobin levels rose steadily. At the same time, with the change of hemoglobin, blood pressure did not rise synchronously.
  • Patent CN104892509A (patent holder: Suzhou Mingrui Pharmaceutical Technology Co., Ltd.) reported that tyrosine was used as raw material. In this route, the etherification reaction easily formed an amino substituent, which caused difficulty in purification and introduced phenolic hydroxyl group. Oxygen peroxide oxidation is used to bring safety hazards to industrial production.
  • Patent CN106478504A (patent holder: Shanghai Xunhe Pharmaceutical Technology Co., Ltd.) reported that 1-(3-phenoxyphenyl)ethylamine was used as the raw material. In the ring-closing step, the reaction temperature was above 190 °C. Industrial production conditions are difficult to achieve, and production has potential safety hazards.
  • the present invention provides a method for preparing nodstat, comprising the following steps:
  • Y is -NR 2 R 3 or -OCH 2 CH 2 CH 2 CH 3
  • R 2 and R 3 are each independently selected from H, t-butyl, methyl, ethyl, n-propyl, isopropyl, cyclopropane Base, n-butyl, isobutyl, phenyl and benzyl; further preferably H or tert-butyl;
  • the salt of aminoacetonitrile is a salt of aminoacetonitrile with an organic acid or an inorganic acid, and the salt is selected from one of a hydrochloride, a hydrobromide, a phosphate, a nitrate, a sulfate, and an acetate.
  • X is a halogen, preferably chlorine, bromine or iodine.
  • step (6) the following steps may also be included:
  • step (7)
  • the hydrolysis reaction is carried out under alkaline conditions, and the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide;
  • the hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • step (4) the following steps may also be included:
  • step (3)
  • R 2 and R 3 are the same as described above.
  • the halogenating agent is selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-diiodo-5.
  • One or more of 5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine and elemental iodine a combination, preferably 1,3-dibromo-5,5-dimethylhydantoin;
  • the reaction temperature of the halogenation reaction is from 0 ° C to the reflux temperature of the solvent, and the reaction time is from 0.5 to 24 h;
  • step (3) the following steps may also be included:
  • the condensation reagent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethyl Aminoaminopropyl)carbonyldiimide hydrochloride, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate One of ester, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphorus hexafluorophosphate Or several, preferably benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate;
  • the reaction temperature of the condensation reaction is room temperature to reflux temperature, the reaction time is 2 to 24h;
  • the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, more preferably potassium carbonate;
  • the organic solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetonitrile and acetone.
  • the reaction temperature of the substitution reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • the base is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium methoxide and ethanol.
  • lithium hydroxide, sodium hydroxide and potassium hydroxide sodium carbonate, potassium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium methoxide and ethanol.
  • sodium more preferably sodium methoxide
  • the reaction temperature of the ring closure reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • a method for preparing nodstat which comprises the steps of:
  • R 1 is a carboxy protecting group, preferably an ester residue of a carboxylic acid ester, more preferably any ester residue which is relatively easy to cleave to give a free carboxyl group, and specific examples thereof include methyl group, methoxymethyl group and ethyl group. , ethoxyethyl, iodoethyl, propyl, isopropyl, n-butyl, isobutyl, ethoxyethyl, methylthioethyl, methanesulfonylethyl, trichloroethyl, tert-butyl, etc.
  • R 2 and R 3 are each independently selected from the group consisting of H, tert-butyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, phenyl and benzyl. Further preferably H or tert-butyl;
  • the salt of aminoacetonitrile is selected from the group consisting of aminoacetonitrile and an organic or inorganic acid salt selected from one or more of the hydrochloride, hydrobromide, phosphate, nitrate, sulfate and acetate salts.
  • X is a halogen, preferably chlorine, bromine or iodine
  • step (1)
  • the hydrolysis reaction is carried out under alkaline conditions, and the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide;
  • step (2)
  • the condensation reagent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbon Acyl diimide hydrochloride, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazine One or more of azole-N,N,N',N'-tetramethyluronium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphorus hexafluorophosphate, etc., preferably Is benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate;
  • the reaction temperature of the condensation reaction is from room temperature to reflux temperature, and the reaction time is from 2 to 24 hours.
  • step (3)
  • the halogenating agent is selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-diiodo-5.
  • One or more of 5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine and elemental iodine a combination, preferably 1,3-dibromo-5,5-dimethylhydantoin;
  • the reaction temperature of the halogenation reaction is from 0 ° C to the reflux temperature of the solvent, and the reaction time is from 0.5 to 24 h;
  • step (4)
  • the methylation reaction is carried out in the presence of an organic solvent, a catalyst and an aqueous solution of an inorganic base, and the compound IV is methylated with a methylating reagent to form a compound V;
  • the methylating agent is selected from the group consisting of trimethyl boron, tetramethyl tin, methyl boric acid and isopropyl methyl borate, preferably methyl boric acid;
  • the organic solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol methyl ether, and B.
  • the aqueous solution of the inorganic base is selected from the group consisting of an aqueous solution of one or more of NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Na 3 PO 4 and K 3 PO 4 , preferably Na 2 CO 3 .
  • Aqueous solution of one or more of NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Na 3 PO 4 and K 3 PO 4 , preferably Na 2 CO 3 .
  • the catalyst is a palladium catalyst;
  • the palladium catalyst is selected from the group consisting of bis(triphenylphosphine)palladium chloride, palladium acetate, palladium triphenylphosphine acetate, palladium tetrakis(triphenylphosphine), palladium acetylacetonate , bis(benzonitrile)palladium dichloride, tris(benzylideneacetone)dipalladium, (1,3-bis(diphenylphosphino)propane)palladium chloride, [1,1'-bis(diphenyl) One or more of phosphine)ferrocene]palladium dichloride and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, preferably four (three) Phenylphosphine)palladium;
  • the methylation reaction is a heating reaction, the reaction temperature is 70-120 ° C, preferably the reaction temperature is 80-110 ° C;
  • the methylation reaction time is 6 to 36 h, preferably the reaction time is 8 to 24 h;
  • step (5)
  • the hydrolysis reaction is carried out under acidic conditions, and the acid is selected from one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid; preferably hydrochloric acid;
  • the hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • step (6)
  • the condensation reagent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbon Acyl diimide hydrochloride, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazine One or more of azole-N,N,N',N'-tetramethyluronium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphorus hexafluorophosphate, etc., preferably Is benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate;
  • the reaction temperature of the condensation reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • step (7)
  • the hydrolysis reaction is carried out under alkaline conditions, and the base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably sodium hydroxide;
  • the hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • the reaction of the step (5) when the reaction in the step (4) is completed, the reaction of the step (5) is directly carried out without a purification step.
  • the purification step is not carried out, and the concentration is directly concentrated and then added.
  • the solvent used in the step (5) further reacts the reaction described in the step (5); or, when the same solvent is used in the step (4) and the step (5), the step (4) and the step (5) Implemented using the “one-pot method”.
  • Another preparation method of nodstatin provided by the invention comprises the following steps:
  • X is a halogen
  • the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, more preferably potassium carbonate;
  • lithium hydroxide sodium hydroxide and potassium hydroxide
  • sodium carbonate sodium carbonate
  • potassium carbonate cesium carbonate
  • the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, more preferably potassium carbonate
  • the reaction temperature of the substitution reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • step b)
  • the base is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium methoxide and sodium ethoxide.
  • lithium hydroxide sodium hydroxide and potassium hydroxide
  • sodium carbonate sodium carbonate
  • potassium carbonate cesium carbonate
  • sodium t-butoxide sodium t-butoxide
  • potassium t-butoxide sodium methoxide and sodium ethoxide.
  • the reaction temperature of the ring closure reaction is from room temperature to reflux, and the reaction time is 2 to 24 hours.
  • step c)
  • the halogenating agent is selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-diiodo-5.
  • One or more of 5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine and elemental iodine a combination, preferably 1,3-dibromo-5,5-dimethylhydantoin;
  • the reaction temperature of the halogenation reaction is from 0 ° C to the reflux temperature of the solvent, and the reaction time is from 0.5 to 24 h;
  • step (d)
  • the methylation reaction is carried out in the presence of an organic solvent, a catalyst and an aqueous solution of an inorganic base, and the compound IV is methylated with a methylating reagent to form a compound V;
  • the methylating agent is selected from the group consisting of trimethyl boron, tetramethyl tin, methyl boric acid and isopropyl methyl borate, preferably methyl boric acid;
  • the organic solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol methyl ether, and B.
  • the aqueous solution of the inorganic base is selected from the group consisting of an aqueous solution of one or more of NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Na 3 PO 4 and K 3 PO 4 , preferably Na 2 CO 3 .
  • Aqueous solution of one or more of NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Na 3 PO 4 and K 3 PO 4 , preferably Na 2 CO 3 .
  • the catalyst is a palladium catalyst;
  • the palladium catalyst is selected from the group consisting of bis(triphenylphosphine)palladium chloride, palladium acetate, palladium triphenylphosphine acetate, palladium tetrakis(triphenylphosphine), palladium acetylacetonate , bis(benzonitrile)palladium dichloride, tris(benzylideneacetone)dipalladium, (1,3-bis(diphenylphosphino)propane)palladium chloride, [1,1'-bis(diphenyl) One or more of phosphine)ferrocene]palladium dichloride and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, preferably four (three) Phenylphosphine)palladium;
  • the methylation reaction is a heating reaction, the reaction temperature is 70-120 ° C, preferably the reaction temperature is 80-110 ° C;
  • the methylation reaction time is 6 to 36 h, preferably the reaction time is 8 to 24 h;
  • step (e)
  • the hydrolysis reaction is carried out under acidic conditions, and the acid is selected from one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid; preferably hydrochloric acid;
  • the hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • step (f)
  • the condensation reagent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbon Acyl diimide hydrochloride, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazine One or more of azole-N,N,N',N'-tetramethyluronium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphorus hexafluorophosphate, etc., preferably Is benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate;
  • the reaction temperature of the condensation reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • step (g) In step (g),
  • the hydrolysis reaction is carried out under alkaline conditions, and the base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably sodium hydroxide;
  • the hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • the invention also provides a preparation method of the compound III-1, which comprises the following steps:
  • Compound c is substituted with chloric acid, and then an alcohol is added to effect esterification to obtain compound d;
  • the chloric acid is selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus trichloride, and phosphorus pentachloride And one or more of phosphorus oxychloride and the like, preferably thionyl chloride;
  • the base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, etc., preferably potassium phosphate;
  • the etherification reaction is preferably carried out in the presence of a palladium catalyst selected from the group consisting of bis(triphenylphosphine)palladium chloride, palladium acetate, palladium triphenylphosphine acetate, tetrakis(triphenylphosphine)palladium, Palladium acetylacetonate, bis(benzonitrile)palladium dichloride, tris(benzylideneacetone)dipalladium, (1,3-bis(diphenylphosphino)propane)palladium chloride, [1,1'-double ( One or more of diphenylphosphine)ferrocene]palladium dichloride and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, preferably Palladium acetate;
  • a palladium catalyst selected from the group consisting of bis(triphenylphosphine)
  • the reaction temperature of the etherification reaction is 80 to 150 ° C, and the reaction time is 2 to 24 hours.
  • step b)
  • the base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably sodium hydroxide;
  • the hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • step c)
  • the reaction temperature of the substitution reaction is -10 to 120 ° C, and the reaction time is 2 to 24 hours.
  • the reaction temperature of the esterification reaction is 0 to 65 ° C, and the reaction time is 2 to 24 hours.
  • step d)
  • the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, preferably potassium carbonate;
  • the organic solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetonitrile and acetone.
  • the reaction temperature of the substitution reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
  • step e)
  • the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium methoxide and sodium ethoxide. Preferred is sodium methoxide;
  • the ring-closing reaction is carried out in an organic solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N- One or more of methyl-2-pyrrolidone, acetonitrile, acetone, and the like, preferably acetonitrile;
  • the reaction temperature of the ring closure reaction is from room temperature to reflux, and the reaction time is 2 to 24 hours.
  • step f)
  • the acid is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid, hydrobromic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, etc., preferably sulfuric acid;
  • the reaction temperature of the Ritter reaction is from room temperature to reflux, and the reaction time is 2 to 24 hours.
  • the raw material is easy to obtain, the product has high purity, high yield, no need to use expensive chemical reagents, low cost, low toxicity, low pollution, green environmental protection; and mild reaction conditions, and low requirements on reaction equipment Suitable for industrial production.
  • the sample data was determined by the following instruments: nuclear magnetic resonance spectroscopy ( 1 H NMR) with Bruker Avance III 400 NMR spectrometer, TMS as internal standard, chemical shift unit in ppm; color analysis using WFH-203B three-use UV analysis The instrument has wavelengths of 254 nm and 365 nm. Mass spectrometry was performed using an Agilent Model 6120 mass spectrometer; HPLC was measured using an Agilent Model 1260 High Performance Liquid Chromatograph.
  • TLC silica gel plate is HSGF-254 thin-layer chromatography silica gel plate produced by Yantai Chemical Plant, and chromatography is used for thin layer chromatography.
  • the thickness of the plate is 0.2 ⁇ 0.03mm, and the thickness of the pre-prepared plate for pre-preparation is 0.4-0.5mm; dichloromethane, ethyl acetate, methanol, ethylene glycol methyl ether, benzotriazole hexafluorophosphate- 1-yl-oxytripyrrolidinylphosphine (PyBOP), 1,3-dibromo-5,5-dimethylhydantoin, tripotassium phosphate, aminoacetonitrile hydrochloride, methylboronic acid, thionyl chloride Phenol, cuprous bromide, boron trifluoride etherate, acetylacetone, bromine and toluene were all analytically pure.
  • dichloromethane ethyl acetate, methanol, ethylene glycol methyl ether, benzotriazole hexafluorophosphate- 1-yl-oxytripyrrolidinylpho
  • Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (CAS No.: 1455091-10-7) was purchased from Shanghai Haohao Chemical Co., Ltd.
  • 5-Bromophenylhydrazine (CAS No.: 64169-34-2) was purchased from Shanghai Demer Chemical Co., Ltd.
  • the reagents and solvents used were not specifically treated unless otherwise stated.
  • Example 8 Compound a produces compound b
  • Example 12 Compound e produces compound f
  • Example 25 Compound d produces compound e-1

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention relates to a norstat, namely a method for preparing a [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-formyl)) amino] acetic acid. Said preparation method exhibits low cost, is easy to operate, safe and suitable for industrial production.

Description

一种诺得司他的制备方法Method for preparing nodstatstat 技术领域Technical field
本发明涉及有机化学和药物化学领域，具体而言，本发明涉及一种诺得司他，即[(4-羟基-1-甲基-7-苯氧基异喹啉-3-甲酰基)氨基]乙酸的制备方法。The present invention relates to the field of organic chemistry and medicinal chemistry, in particular, the present invention relates to a nodstat, ie [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formyl) A method for preparing amino]acetic acid.
背景技术Background technique
诺得司他为人工合成的异喹啉衍生物，缺氧诱导因子脯氨酸羟化酶抑制剂(HIF-PHI)通过调控脯氨酸羟化酶(PHD)对缺氧诱导因子(HIF)的羟基化作用，抑制HIF蛋白降解，维持HIF的生物学作用。目前已有多种HIF-PHI在临床试验，初步结果较为满意。EPO血浓度监测发现使用少量HIF-PHI后，EPO水平仅为正常2-3倍，而血色素水平则稳步上升。同时随着血色素改变，血压没有同步上升。Nordostatin is a synthetic isoquinoline derivative, hypoxia-inducible factor proline hydroxylase inhibitor (HIF-PHI) regulates hypoxia-inducible factor (HIF) by regulating proline hydroxylase (PHD) Hydroxylation inhibits HIF protein degradation and maintains the biological effects of HIF. A variety of HIF-PHI have been tested in clinical trials, and the preliminary results are satisfactory. EPO blood concentration monitoring found that after using a small amount of HIF-PHI, EPO levels were only 2-3 times normal, while hemoglobin levels rose steadily. At the same time, with the change of hemoglobin, blood pressure did not rise synchronously.
Figure PCTCN2019078261-appb-000001
Figure PCTCN2019078261-appb-000001
国际专利申请WO2013013609(专利权人：浙江贝达医药股份有限公司)中有所报导，以4-硝基邻苯二甲腈为原料，这条合成路线，在合成噁唑环时会产生异构体，分离困难，需要经过柱层析纯化；在氯化反应过程中，使用剧毒的三氯氧膦进行氯化的方法不符合目前提倡的“绿色合成”路线(即低毒、低污染的化学合成)将被淘汰；在甲基化过程中，选用三甲基硼作为甲基化试剂，此方法反应试剂昂贵，不适合工业化生产。International patent application WO2013013609 (patent holder: Zhejiang Beida Pharmaceutical Co., Ltd.) reported that 4-nitrophthalonitrile is used as raw material. This synthetic route will produce isomerism when synthesizing oxazole ring. Body, separation is difficult, need to be purified by column chromatography; in the chlorination reaction, the method of chlorination using highly toxic phosphachlorophosphoric acid does not conform to the current "green synthesis" route (ie low toxicity, low pollution) Chemical synthesis) will be eliminated; in the methylation process, trimethylboron is selected as the methylation reagent. This method is expensive and is not suitable for industrial production.
国际专利申请WO2014014834(专利权人：FibroGen.，Inc.)中有所报导，以4-羟基-7-苯氧基异喹啉-3-甲酸甲酯为原料，这条合成路线，在第二步会产生多种杂质，分离纯化相对比较困难，并且三废较多，回收处理比较麻烦；在第三和第四两步要使用特种设备——高压釜，工业化生产成本较高，风险较大。International patent application WO2014014834 (patentee: FibroGen., Inc.) reported that 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester is used as a raw material, and this synthetic route is in the second Steps will produce a variety of impurities, separation and purification is relatively difficult, and more three waste, recycling is more troublesome; in the third and fourth steps to use special equipment - autoclave, industrial production costs are higher, the risk is greater.
专利CN104892509A(专利权人：苏州明锐医药科技有限公司)中有所报导，以酪氨酸为原料，这条路线中，醚化反应容易生成氨基取代物，给纯化带来困难，并且引入酚羟基时用到双氧水氧化，给工业化生产带来安全隐患。Patent CN104892509A (patent holder: Suzhou Mingrui Pharmaceutical Technology Co., Ltd.) reported that tyrosine was used as raw material. In this route, the etherification reaction easily formed an amino substituent, which caused difficulty in purification and introduced phenolic hydroxyl group. Oxygen peroxide oxidation is used to bring safety hazards to industrial production.
专利CN106478504A(专利权人：上海勋和医药科技有限公司)中有所报导，以1-(3-苯氧基苯基)乙胺为原料，在关环步骤中，反应温度在190℃以上，工业化生产条件难以达到，且生产存在安全隐患。Patent CN106478504A (patent holder: Shanghai Xunhe Pharmaceutical Technology Co., Ltd.) reported that 1-(3-phenoxyphenyl)ethylamine was used as the raw material. In the ring-closing step, the reaction temperature was above 190 °C. Industrial production conditions are difficult to achieve, and production has potential safety hazards.
虽然现有技术已经报道了几种制备诺得司他的方法，但是，它们大多都具有一种或 多种缺点，诸如涉及使用特殊设备、昂贵试剂和大量的保护和脱保护步骤。针对现存的工艺缺陷，需要寻求能够适应工业化生产的制备诺得司他的方法。Although several methods for preparing nostats have been reported in the prior art, most of them have one or more disadvantages, such as involving the use of special equipment, expensive reagents, and numerous protection and deprotection steps. In view of existing process deficiencies, it is necessary to find a method for preparing nodstat that can be adapted to industrial production.
发明内容Summary of the invention
本发明的目的是提供一种方法简单、成本低廉的制备诺得司他的方法，以克服现有技术的问题。It is an object of the present invention to provide a process for the preparation of Nordostatin which is simple and inexpensive to overcome the problems of the prior art.
为了达到上述的目的，本发明提供了一种诺得司他的制备方法，包括如下步骤：In order to achieve the above object, the present invention provides a method for preparing nodstat, comprising the following steps:
(4)化合物IV与甲基化试剂发生甲基化反应生成化合物V；(4) Compound IV is methylated with a methylating reagent to form a compound V;
Figure PCTCN2019078261-appb-000002
Figure PCTCN2019078261-appb-000002
(5)化合物V发生水解反应，生成化合物VI；(5) Compound V undergoes a hydrolysis reaction to form compound VI;
Figure PCTCN2019078261-appb-000003
Figure PCTCN2019078261-appb-000003
(6)化合物VI与氨基乙腈或氨基乙腈的盐，发生缩合反应，生成化合物VII；(6) a compound VI with a salt of aminoacetonitrile or aminoacetonitrile, a condensation reaction to form a compound VII;
Figure PCTCN2019078261-appb-000004
Figure PCTCN2019078261-appb-000004
其中，among them,
Y为-NR 2R 3或-OCH 2CH 2CH 2CH 3，R 2和R 3各自独立地选自H、叔丁基、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、苯基和苄基；进一步优选为H或叔丁基； Y is -NR 2 R 3 or -OCH 2 CH 2 CH 2 CH 3 , and R 2 and R 3 are each independently selected from H, t-butyl, methyl, ethyl, n-propyl, isopropyl, cyclopropane Base, n-butyl, isobutyl, phenyl and benzyl; further preferably H or tert-butyl;
所述氨基乙腈的盐为氨基乙腈与有机酸或无机酸成的盐，所述盐选自盐酸盐、氢溴酸盐、磷酸盐、硝酸盐、硫酸盐和乙酸盐中的一种或几种；The salt of aminoacetonitrile is a salt of aminoacetonitrile with an organic acid or an inorganic acid, and the salt is selected from one of a hydrochloride, a hydrobromide, a phosphate, a nitrate, a sulfate, and an acetate. Several
X为卤素，优选为氯、溴或碘。X is a halogen, preferably chlorine, bromine or iodine.
优选地，在步骤(6)之后还可以包括如下步骤：Preferably, after step (6), the following steps may also be included:
(7)化合物VII发生水解反应，生成化合物VIII；(7) Compound VII undergoes a hydrolysis reaction to form compound VIII;
Figure PCTCN2019078261-appb-000005
Figure PCTCN2019078261-appb-000005
步骤(7)中，In step (7),
所述的水解反应在碱性条件下进行，碱选自氢氧化锂、氢氧化钠和氢氧化钾等中的一种或几种，优选为氢氧化钠；The hydrolysis reaction is carried out under alkaline conditions, and the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide;
所述的水解反应的反应温度为室温到回流，反应时间为2～24h。The hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
优选地，在步骤(4)之前还可以包括如下步骤：Preferably, before step (4), the following steps may also be included:
(3)化合物III与卤化试剂发生卤化反应，生成化合物IV；(3) Compound III is halogenated with a halogenating reagent to form compound IV;
Figure PCTCN2019078261-appb-000006
Figure PCTCN2019078261-appb-000006
其中，Y的定义如前所述。Among them, the definition of Y is as described above.
步骤(3)中，In step (3),
R 2和R 3的定义与前述相同。 The definitions of R 2 and R 3 are the same as described above.
所述的卤化试剂选自1,3-二氯-5,5-二甲基海因、1,3-二溴-5,5-二甲基海因、1,3-二碘-5,5-二甲基海因、N-氯代丁二酰亚胺、N-溴代丁二酰亚胺、N-碘代丁二酰亚胺、溴素和单质碘中的一种或几种的组合，优选为1,3-二溴-5,5-二甲基海因；The halogenating agent is selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-diiodo-5. One or more of 5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine and elemental iodine a combination, preferably 1,3-dibromo-5,5-dimethylhydantoin;
所述的卤化反应的反应温度为0℃至溶剂的回流温度，反应时间为0.5～24h；The reaction temperature of the halogenation reaction is from 0 ° C to the reflux temperature of the solvent, and the reaction time is from 0.5 to 24 h;
优选地，在步骤(3)之前还可以包括如下步骤：Preferably, before step (3), the following steps may also be included:
(2)当Y为-NR 2R 3时，化合物II与胺HNR 2R 3发生缩合反应，生成化合物III，R 2和R 3的定义与前述相同； (2) When Y is -NR 2 R 3 , the compound II is condensed with the amine HNR 2 R 3 to form a compound III, and the definitions of R 2 and R 3 are the same as described above;
Figure PCTCN2019078261-appb-000007
Figure PCTCN2019078261-appb-000007
当Y为-OCH 2CH 2CH 2CH 3时，化合物d与甲苯-4-磺酰胺乙酸丁酯在碱和有机溶剂存在下发生取代反应，得到化合物e-1；化合物e-1在碱存在下发生关环反应，得到化合物III； When Y is -OCH 2 CH 2 CH 2 CH 3 , compound d is substituted with toluene-4-sulfonamide butyl acetate in the presence of a base and an organic solvent to give compound e-1; compound e-1 is present in the base A ring-closing reaction occurs to obtain a compound III;
Figure PCTCN2019078261-appb-000008
Figure PCTCN2019078261-appb-000008
优选地，所述缩合反应中，缩合试剂选自N,N'-二环己基碳二亚胺、N,N'-二异丙基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、2-(7-氮杂-1H-苯并三氮唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐和六氟磷酸苯并***-1-基-氧基三吡咯烷基磷等中的一种或几种，优选为六氟磷酸苯并***-1-基-氧基三吡咯烷基磷；Preferably, in the condensation reaction, the condensation reagent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethyl Aminoaminopropyl)carbonyldiimide hydrochloride, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate One of ester, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphorus hexafluorophosphate Or several, preferably benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate;
所述的缩合反应的反应温度为室温到回流温度，反应时间为2～24h；The reaction temperature of the condensation reaction is room temperature to reflux temperature, the reaction time is 2 to 24h;
优选地，所述取代反应中，所述碱选自氢氧化锂、氢氧化钠和氢氧化钾、碳酸钠、碳酸钾和碳酸铯中的一种或几种，更优选为碳酸钾；所述有机溶剂选自四氢呋喃、2-甲基四氢呋喃、二氯甲烷、乙酸乙酯、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮、乙腈和丙酮中的一种或几种，更优选为乙腈；Preferably, in the substitution reaction, the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, more preferably potassium carbonate; The organic solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetonitrile and acetone. One or more, more preferably acetonitrile;
优选地，所述的取代反应的反应温度为室温到回流，反应时间为2～24h。Preferably, the reaction temperature of the substitution reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
优选地，所述关环反应中，所述碱选自氢氧化锂、氢氧化钠和氢氧化钾、碳酸钠、碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、甲醇钠和乙醇钠中的一种或几种，更优选为甲醇钠；Preferably, in the ring closure reaction, the base is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium methoxide and ethanol. One or more of sodium, more preferably sodium methoxide;
优选地，所述的关环反应的反应温度为室温到回流，反应时间为2～24h。Preferably, the reaction temperature of the ring closure reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
本发明一优选实施方式中，提供了这样一种诺得司他制备方法，其包括以下步骤：In a preferred embodiment of the present invention, there is provided a method for preparing nodstat, which comprises the steps of:
(1)化合物I发生水解反应，生成化合物II；(1) Compound I undergoes a hydrolysis reaction to form compound II;
Figure PCTCN2019078261-appb-000009
Figure PCTCN2019078261-appb-000009
(2)化合物II与胺HNR 2R 3发生缩合反应，生成化合物III； (2) a compound II is condensed with an amine HNR 2 R 3 to form a compound III;
Figure PCTCN2019078261-appb-000010
Figure PCTCN2019078261-appb-000010
(3)化合物III与卤化试剂发生卤化反应，生成化合物IV；(3) Compound III is halogenated with a halogenating reagent to form compound IV;
Figure PCTCN2019078261-appb-000011
Figure PCTCN2019078261-appb-000011
(4)化合物IV与甲基化试剂发生甲基化反应生成化合物V；(4) Compound IV is methylated with a methylating reagent to form a compound V;
Figure PCTCN2019078261-appb-000012
Figure PCTCN2019078261-appb-000012
(5)化合物V发生水解反应，生成化合物VI；(5) Compound V undergoes a hydrolysis reaction to form compound VI;
Figure PCTCN2019078261-appb-000013
Figure PCTCN2019078261-appb-000013
(6)化合物VI与氨基乙腈或氨基乙腈的盐，发生缩合反应，生成化合物VII；(6) a compound VI with a salt of aminoacetonitrile or aminoacetonitrile, a condensation reaction to form a compound VII;
Figure PCTCN2019078261-appb-000014
Figure PCTCN2019078261-appb-000014
(7)化合物VII发生水解反应，生成化合物VIII；(7) Compound VII undergoes a hydrolysis reaction to form compound VIII;
Figure PCTCN2019078261-appb-000015
Figure PCTCN2019078261-appb-000015
其中，among them,
R 1为羧基保护基，优选为羧酸酯的酯残基，更优选为比较容易裂解产生对于的游离羧基的任何酯残基，具体可以列举的有：甲基、甲氧甲基、乙基、乙氧乙基、碘乙基、丙基、异丙基、正丁基、异丁基、乙氧乙基、甲硫乙基、甲磺酰乙基、三氯乙基、叔丁基等1～8个碳的烷基；丙烯基、烯基、异丙烯基、己烯基、苯丙烯基、二甲基己烯基等3～8个碳的链烯基；苄基、甲基苄基、二甲基苄基、甲氧基苄基、乙氧基苄基、硝 基苄基、氨基苄基、二苯甲基、苯乙基、三苯甲基、二叔丁基羟基苄基、2-苯并[c]呋喃酮基、苯甲酰甲基等7～19个碳的芳烷基；苯基、甲苯基、二异丙基苯基、二甲苯基、三氯苯基、五氯苯基、2，3-二氢茚基等6～12个碳的芳基；R 1优选为甲基、乙基、丙基、异丙基、正丁基、异丁基或叔丁基；进一步优选为甲基； R 1 is a carboxy protecting group, preferably an ester residue of a carboxylic acid ester, more preferably any ester residue which is relatively easy to cleave to give a free carboxyl group, and specific examples thereof include methyl group, methoxymethyl group and ethyl group. , ethoxyethyl, iodoethyl, propyl, isopropyl, n-butyl, isobutyl, ethoxyethyl, methylthioethyl, methanesulfonylethyl, trichloroethyl, tert-butyl, etc. An alkyl group of 1 to 8 carbons; an alkenyl group of 3 to 8 carbons such as a propenyl group, an alkenyl group, an isopropenyl group, a hexenyl group, a phenylpropenyl group or a dimethylhexenyl group; a benzyl group and a methylbenzyl group; , dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, benzhydryl, phenethyl, trityl, di-tert-butylhydroxybenzyl a 7- to 19-carbon aralkyl group such as 2-benzo[c]furanone or benzoylmethyl; phenyl, tolyl, diisopropylphenyl, xylyl, trichlorophenyl, An aryl group of 6 to 12 carbons such as pentachlorophenyl or 2,3-dihydroindenyl; and R 1 is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Further preferably a methyl group;
R 2和R 3各自独立地选自H、叔丁基、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、苯基和苄基；进一步优选为H或叔丁基； R 2 and R 3 are each independently selected from the group consisting of H, tert-butyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, phenyl and benzyl. Further preferably H or tert-butyl;
氨基乙腈的盐选自氨基乙腈与有机酸或无机酸成的盐，所述盐选自盐酸盐、氢溴酸盐、磷酸盐、硝酸盐、硫酸盐和乙酸盐中的一种或几种；The salt of aminoacetonitrile is selected from the group consisting of aminoacetonitrile and an organic or inorganic acid salt selected from one or more of the hydrochloride, hydrobromide, phosphate, nitrate, sulfate and acetate salts. Species
X为卤素，优选为氯、溴或碘；X is a halogen, preferably chlorine, bromine or iodine;
步骤(1)中，In step (1),
所述的水解反应在碱性条件下进行，碱选自氢氧化锂、氢氧化钠和氢氧化钾中的一种或几种；The hydrolysis reaction is carried out under alkaline conditions, and the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide;
步骤(2)中，In step (2),
所述的缩合试剂选自N,N'-二环己基碳二亚胺、N,N'-二异丙基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、2-(7-氮杂-1H-苯并三氮唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐和六氟磷酸苯并***-1-基-氧基三吡咯烷基磷等中的一种或几种，优选为六氟磷酸苯并***-1-基-氧基三吡咯烷基磷；The condensation reagent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbon Acyl diimide hydrochloride, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazine One or more of azole-N,N,N',N'-tetramethyluronium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphorus hexafluorophosphate, etc., preferably Is benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate;
所述的缩合反应的反应温度为室温到回流温度，反应时间为2～24h。The reaction temperature of the condensation reaction is from room temperature to reflux temperature, and the reaction time is from 2 to 24 hours.
步骤(3)中，In step (3),
所述的卤化试剂选自1,3-二氯-5,5-二甲基海因、1,3-二溴-5,5-二甲基海因、1,3-二碘-5,5-二甲基海因、N-氯代丁二酰亚胺、N-溴代丁二酰亚胺、N-碘代丁二酰亚胺、溴素和单质碘中的一种或几种的组合，优选为1,3-二溴-5,5-二甲基海因；The halogenating agent is selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-diiodo-5. One or more of 5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine and elemental iodine a combination, preferably 1,3-dibromo-5,5-dimethylhydantoin;
所述的卤化反应的反应温度为0℃至溶剂的回流温度，反应时间为0.5～24h；The reaction temperature of the halogenation reaction is from 0 ° C to the reflux temperature of the solvent, and the reaction time is from 0.5 to 24 h;
步骤(4)中，In step (4),
所述甲基化反应是在有机溶剂、催化剂和无机碱的水溶液的存在下进行，化合物IV与甲基化试剂发生甲基化反应生成化合物V；The methylation reaction is carried out in the presence of an organic solvent, a catalyst and an aqueous solution of an inorganic base, and the compound IV is methylated with a methylating reagent to form a compound V;
所述甲基化试剂选自三甲基硼、四甲基锡、甲基硼酸和甲基硼酸异丙酯，优选为甲基硼酸；The methylating agent is selected from the group consisting of trimethyl boron, tetramethyl tin, methyl boric acid and isopropyl methyl borate, preferably methyl boric acid;
所述的有机溶剂选自N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮、甲苯、四氢呋喃、乙二醇二甲醚、乙二醇甲醚、乙二醇二***、乙二醇***和乙二醇的中一种或几种，优选为乙二醇二甲醚；The organic solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol methyl ether, and B. One or more of diol diethyl ether, ethylene glycol ethyl ether and ethylene glycol, preferably ethylene glycol dimethyl ether;
所述的无机碱的水溶液选自NaOH、KOH、LiOH、Na 2CO 3、K 2CO 3、Na 3PO 4和K 3PO 4 中的一种或几种的水溶液，优选为Na 2CO 3的水溶液； The aqueous solution of the inorganic base is selected from the group consisting of an aqueous solution of one or more of NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Na 3 PO 4 and K 3 PO 4 , preferably Na 2 CO 3 . Aqueous solution
所述的催化剂为钯类催化剂；所述的钯类催化剂选自二(三苯基膦)氯化钯、乙酸钯、三苯基膦醋酸钯、四(三苯基膦)钯、乙酰丙酮钯、双(苄腈)二氯化钯、三(苄亚基丙酮)二钯、(1,3-双(二苯基膦)丙烷)氯化钯、[1,1′-双(二苯基膦)二茂铁]二氯化钯和[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物的一种或几种，优选为四(三苯基膦)钯；The catalyst is a palladium catalyst; the palladium catalyst is selected from the group consisting of bis(triphenylphosphine)palladium chloride, palladium acetate, palladium triphenylphosphine acetate, palladium tetrakis(triphenylphosphine), palladium acetylacetonate , bis(benzonitrile)palladium dichloride, tris(benzylideneacetone)dipalladium, (1,3-bis(diphenylphosphino)propane)palladium chloride, [1,1'-bis(diphenyl) One or more of phosphine)ferrocene]palladium dichloride and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, preferably four (three) Phenylphosphine)palladium;
所述的甲基化反应为加热反应，反应温度为70～120℃，优选反应温度为80～110℃；The methylation reaction is a heating reaction, the reaction temperature is 70-120 ° C, preferably the reaction temperature is 80-110 ° C;
所述的甲基化反应时间为6～36h，优选反应时间为8～24h；The methylation reaction time is 6 to 36 h, preferably the reaction time is 8 to 24 h;
步骤(5)中，In step (5),
所述的水解反应在酸性条件下进行，酸选自盐酸、硫酸、三氟乙酸、甲磺酸和三氟甲磺酸等中的一种或几种；优选为盐酸；The hydrolysis reaction is carried out under acidic conditions, and the acid is selected from one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid; preferably hydrochloric acid;
所述的水解反应的反应温度为室温到回流，反应时间为2～24h。The hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
步骤(6)中，In step (6),
所述的缩合试剂选自N,N'-二环己基碳二亚胺、N,N'-二异丙基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、2-(7-氮杂-1H-苯并三氮唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐和六氟磷酸苯并***-1-基-氧基三吡咯烷基磷等中的一种或几种，优选为六氟磷酸苯并***-1-基-氧基三吡咯烷基磷；The condensation reagent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbon Acyl diimide hydrochloride, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazine One or more of azole-N,N,N',N'-tetramethyluronium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphorus hexafluorophosphate, etc., preferably Is benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate;
所述的缩合反应的反应温度为室温到回流，反应时间为2～24h。The reaction temperature of the condensation reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
步骤(7)中，In step (7),
所述的水解反应在碱性条件下进行，碱选自氢氧化锂、氢氧化钠、氢氧化钾等中的一种或几种，优选为氢氧化钠；The hydrolysis reaction is carried out under alkaline conditions, and the base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably sodium hydroxide;
所述的水解反应的反应温度为室温到回流，反应时间为2～24h。The hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
在本发明一优选实施方式中，当步骤(4)反应完成后不经过纯化步骤，直接进行步骤(5)的反应，例如，当步骤(4)反应完成后不经过纯化步骤，直接浓缩再加入步骤(5)中所采用的溶剂，进一步发生步骤(5)中所述的反应；或，当步骤(4)和步骤(5)使用同一溶剂时，所述步骤(4)和步骤(5)采用“一锅法”实施。In a preferred embodiment of the present invention, when the reaction in the step (4) is completed, the reaction of the step (5) is directly carried out without a purification step. For example, when the reaction of the step (4) is completed, the purification step is not carried out, and the concentration is directly concentrated and then added. The solvent used in the step (5) further reacts the reaction described in the step (5); or, when the same solvent is used in the step (4) and the step (5), the step (4) and the step (5) Implemented using the “one-pot method”.
本发明提供的另一种诺得司他的制备方法，其包括以下步骤：Another preparation method of nodstatin provided by the invention comprises the following steps:
Figure PCTCN2019078261-appb-000016
Figure PCTCN2019078261-appb-000016
a)化合物d与甲苯-4-磺酰胺乙酸丁酯在碱和有机溶剂存在下发生取代反应，得到化合物e-1；a) compound d and toluene-4-sulfonamide butyl acetate in the presence of a base and an organic solvent substitution reaction to give compound e-1;
b)化合物e-1在碱存在下发生关环反应，得到化合物III；b) compound e-1 in the presence of a base to form a ring closure reaction to give compound III;
c)化合物III与卤化试剂发生卤化反应，得到化合物I-3；c) compound III is halogenated with a halogenating reagent to give compound I-3;
d)化合物I-3与甲基化试剂发生甲基化反应，得到化合物I-4；d) methylation of compound I-3 with a methylating reagent to give compound I-4;
e)化合物I-4在碱存在下发生水解反应，得到化合物VI；e) compound I-4 is hydrolyzed in the presence of a base to give compound VI;
f)化合物VI与氨基乙腈或氨基乙腈的盐，发生缩合反应，生成化合物VII；f) a compound VI with a salt of aminoacetonitrile or aminoacetonitrile, a condensation reaction to form a compound VII;
g)化合物VII发生水解反应，生成化合物VIII；g) compound VII undergoes a hydrolysis reaction to form compound VIII;
其中，X为卤素。Wherein X is a halogen.
优选地，Preferably,
步骤a)中，In step a),
所述取代反应中，所述碱选自氢氧化锂、氢氧化钠和氢氧化钾、碳酸钠、碳酸钾和碳酸铯中的一种或几种，更优选为碳酸钾；所述有机溶剂选自四氢呋喃、2-甲基四氢呋喃、二氯甲烷、乙酸乙酯、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮、乙腈和丙酮中的一种或几种，更优选为乙腈；In the substitution reaction, the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, more preferably potassium carbonate; One of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetonitrile and acetone or Several, more preferably acetonitrile;
所述的取代反应的反应温度为室温到回流，反应时间为2～24h。The reaction temperature of the substitution reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
步骤b)中，In step b),
所述关环反应中，所述碱选自氢氧化锂、氢氧化钠和氢氧化钾、碳酸钠、碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、甲醇钠和乙醇钠中的一种或几种，更优选为甲醇钠；In the ring closure reaction, the base is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium methoxide and sodium ethoxide. One or more, more preferably sodium methoxide;
所述的关环反应的反应温度为室温到回流，反应时间为2～24h。The reaction temperature of the ring closure reaction is from room temperature to reflux, and the reaction time is 2 to 24 hours.
步骤c)中，In step c),
所述的卤化试剂选自1,3-二氯-5,5-二甲基海因、1,3-二溴-5,5-二甲基海因、1,3-二碘-5,5-二甲基海因、N-氯代丁二酰亚胺、N-溴代丁二酰亚胺、N-碘代丁二酰亚胺、溴素和单质碘中的一种或几种的组合，优选为1,3-二溴-5,5-二甲基海因；The halogenating agent is selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-diiodo-5. One or more of 5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine and elemental iodine a combination, preferably 1,3-dibromo-5,5-dimethylhydantoin;
所述的卤化反应的反应温度为0℃至溶剂的回流温度，反应时间为0.5～24h；The reaction temperature of the halogenation reaction is from 0 ° C to the reflux temperature of the solvent, and the reaction time is from 0.5 to 24 h;
步骤(d)中，In step (d),
所述甲基化反应是在有机溶剂、催化剂和无机碱的水溶液的存在下进行，化合物IV与甲基化试剂发生甲基化反应生成化合物V；The methylation reaction is carried out in the presence of an organic solvent, a catalyst and an aqueous solution of an inorganic base, and the compound IV is methylated with a methylating reagent to form a compound V;
所述甲基化试剂选自三甲基硼、四甲基锡、甲基硼酸和甲基硼酸异丙酯，优选为甲基硼酸；The methylating agent is selected from the group consisting of trimethyl boron, tetramethyl tin, methyl boric acid and isopropyl methyl borate, preferably methyl boric acid;
所述的有机溶剂选自N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮、甲苯、四氢呋喃、乙二醇二甲醚、乙二醇甲醚、乙二醇二***、乙二醇***和乙二醇的中一种或几种，优选为乙二醇二甲醚；The organic solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol methyl ether, and B. One or more of diol diethyl ether, ethylene glycol ethyl ether and ethylene glycol, preferably ethylene glycol dimethyl ether;
所述的无机碱的水溶液选自NaOH、KOH、LiOH、Na 2CO 3、K 2CO 3、Na 3PO 4和K 3PO 4中的一种或几种的水溶液，优选为Na 2CO 3的水溶液； The aqueous solution of the inorganic base is selected from the group consisting of an aqueous solution of one or more of NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Na 3 PO 4 and K 3 PO 4 , preferably Na 2 CO 3 . Aqueous solution
所述的催化剂为钯类催化剂；所述的钯类催化剂选自二(三苯基膦)氯化钯、乙酸钯、三苯基膦醋酸钯、四(三苯基膦)钯、乙酰丙酮钯、双(苄腈)二氯化钯、三(苄亚基丙酮)二钯、(1,3-双(二苯基膦)丙烷)氯化钯、[1,1′-双(二苯基膦)二茂铁]二氯化钯和[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物的一种或几种，优选为四(三苯基膦)钯；The catalyst is a palladium catalyst; the palladium catalyst is selected from the group consisting of bis(triphenylphosphine)palladium chloride, palladium acetate, palladium triphenylphosphine acetate, palladium tetrakis(triphenylphosphine), palladium acetylacetonate , bis(benzonitrile)palladium dichloride, tris(benzylideneacetone)dipalladium, (1,3-bis(diphenylphosphino)propane)palladium chloride, [1,1'-bis(diphenyl) One or more of phosphine)ferrocene]palladium dichloride and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, preferably four (three) Phenylphosphine)palladium;
所述的甲基化反应为加热反应，反应温度为70～120℃，优选反应温度为80～110℃；The methylation reaction is a heating reaction, the reaction temperature is 70-120 ° C, preferably the reaction temperature is 80-110 ° C;
所述的甲基化反应时间为6～36h，优选反应时间为8～24h；The methylation reaction time is 6 to 36 h, preferably the reaction time is 8 to 24 h;
步骤(e)中，In step (e),
所述的水解反应在酸性条件下进行，酸选自盐酸、硫酸、三氟乙酸、甲磺酸和三氟甲磺酸等中的一种或几种；优选为盐酸；The hydrolysis reaction is carried out under acidic conditions, and the acid is selected from one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid; preferably hydrochloric acid;
所述的水解反应的反应温度为室温到回流，反应时间为2～24h。The hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
步骤(f)中，In step (f),
所述的缩合试剂选自N,N'-二环己基碳二亚胺、N,N'-二异丙基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、2-(7-氮杂-1H-苯并三氮唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐和六氟磷酸苯并***-1-基-氧基三吡咯烷基磷等中的一种或几种，优选为六氟磷酸苯并***-1-基-氧基三吡咯烷基磷；The condensation reagent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbon Acyl diimide hydrochloride, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazine One or more of azole-N,N,N',N'-tetramethyluronium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphorus hexafluorophosphate, etc., preferably Is benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate;
所述的缩合反应的反应温度为室温到回流，反应时间为2～24h。The reaction temperature of the condensation reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
步骤(g)中，In step (g),
所述的水解反应在碱性条件下进行，碱选自氢氧化锂、氢氧化钠、氢氧化钾等中的一种或几种，优选为氢氧化钠；The hydrolysis reaction is carried out under alkaline conditions, and the base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably sodium hydroxide;
所述的水解反应的反应温度为室温到回流，反应时间为2～24h。The hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
在化合物III中，当R 2为H，R 3为叔丁基时，即为化合物III-1所示的结构： In the compound III, when R 2 is H and R 3 is a tert-butyl group, it is a structure represented by the compound III-1:
Figure PCTCN2019078261-appb-000017
Figure PCTCN2019078261-appb-000017
本发明还提供了所述化合物III-1的制备方法，其包括如下步骤：The invention also provides a preparation method of the compound III-1, which comprises the following steps:
Figure PCTCN2019078261-appb-000018
Figure PCTCN2019078261-appb-000018
a)化合物a与苯酚在碱存在下发生醚化反应，得到化合物b；a) Compound a and phenol are etherified in the presence of a base to give compound b;
b)化合物b在碱存在下发生水解反应，得到化合物c；b) compound b is hydrolyzed in the presence of a base to give compound c;
c)化合物c与含氯酸发生取代反应，然后再加入醇，发生酯化反应，得到化合物d；所述含氯酸选自氯化亚砜、草酰氯、三氯化磷、五氯化磷和三氯氧磷等中的一种或几种，优选为氯化亚砜；c) Compound c is substituted with chloric acid, and then an alcohol is added to effect esterification to obtain compound d; the chloric acid is selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus trichloride, and phosphorus pentachloride And one or more of phosphorus oxychloride and the like, preferably thionyl chloride;
d)化合物d与N-氰甲基-4-甲基苯磺酰胺在碱和有机溶剂存在下发生取代反应，得到化合物e；d) Compound d and N-cyanomethyl-4-methylbenzenesulfonamide are substituted in the presence of a base and an organic solvent to obtain a compound e;
e)化合物e在碱存在下发生关环反应，得到化合物f；e) Compound e is subjected to a ring closure reaction in the presence of a base to give compound f;
f)化合物f与叔丁醇或异丁烯在酸存在下发生Ritter反应，得到化合物III-1。f) Ritter reaction of compound f with t-butanol or isobutylene in the presence of an acid to give compound III-1.
步骤a)中，In step a),
所述碱选自氢氧化锂、氢氧化钠、氢氧化钾、磷酸钠和磷酸钾等中的一种或几种，优选为磷酸钾；The base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, etc., preferably potassium phosphate;
所述的醚化反应优选在钯催化剂存在下进行，所述钯催化剂选自二(三苯基膦)氯化钯、乙酸钯、三苯基膦醋酸钯、四(三苯基膦)钯、乙酰丙酮钯、双(苄腈)二氯化钯、三(苄亚基丙酮)二钯、(1,3-双(二苯基膦)丙烷)氯化钯、[1,1′-双(二苯基膦)二茂铁]二氯化钯和[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物的一种或几种，优选为乙酸钯；The etherification reaction is preferably carried out in the presence of a palladium catalyst selected from the group consisting of bis(triphenylphosphine)palladium chloride, palladium acetate, palladium triphenylphosphine acetate, tetrakis(triphenylphosphine)palladium, Palladium acetylacetonate, bis(benzonitrile)palladium dichloride, tris(benzylideneacetone)dipalladium, (1,3-bis(diphenylphosphino)propane)palladium chloride, [1,1'-double ( One or more of diphenylphosphine)ferrocene]palladium dichloride and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, preferably Palladium acetate;
所述的醚化反应的反应温度为80～150℃，反应时间为2～24h。The reaction temperature of the etherification reaction is 80 to 150 ° C, and the reaction time is 2 to 24 hours.
步骤b)中，In step b),
所述碱选自氢氧化锂、氢氧化钠和氢氧化钾等中的一种或几种，优选为氢氧化钠；The base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably sodium hydroxide;
所述的水解反应的反应温度为室温到回流，反应时间为2～24h。The hydrolysis reaction has a reaction temperature of from room temperature to reflux, and the reaction time is from 2 to 24 hours.
步骤c)中，In step c),
所述取代反应的反应温度为-10～120℃，反应时间为2～24h。The reaction temperature of the substitution reaction is -10 to 120 ° C, and the reaction time is 2 to 24 hours.
所述酯化反应的反应温度为0～65℃，反应时间为2～24h。The reaction temperature of the esterification reaction is 0 to 65 ° C, and the reaction time is 2 to 24 hours.
步骤d)中，In step d),
所述碱选自氢氧化锂、氢氧化钠和氢氧化钾、碳酸钠、碳酸钾和碳酸铯等中的一种或几种，优选为碳酸钾；The base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, preferably potassium carbonate;
所述有机溶剂选自四氢呋喃、2-甲基四氢呋喃、二氯甲烷、乙酸乙酯、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮、乙腈和丙酮等中的一种或几种，优选为乙腈；The organic solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetonitrile and acetone. One or more of the others, preferably acetonitrile;
所述的取代反应的反应温度为室温到回流，反应时间为2～24h。The reaction temperature of the substitution reaction is from room temperature to reflux, and the reaction time is from 2 to 24 hours.
步骤e)中，In step e),
所述碱选自氢氧化锂、氢氧化钠和氢氧化钾、碳酸钠、碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、甲醇钠和乙醇钠等中的一种或几种，优选为甲醇钠；The base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium methoxide and sodium ethoxide. Preferred is sodium methoxide;
所述的关环反应在有机溶剂中进行，有机溶剂选自四氢呋喃、2-甲基四氢呋喃、二氯甲烷、乙酸乙酯、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮、乙腈和丙酮等中的一种或几种，优选为乙腈；The ring-closing reaction is carried out in an organic solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N- One or more of methyl-2-pyrrolidone, acetonitrile, acetone, and the like, preferably acetonitrile;
所述的关环反应的反应温度为室温到回流，反应时间为2～24h。The reaction temperature of the ring closure reaction is from room temperature to reflux, and the reaction time is 2 to 24 hours.
步骤f)中，In step f),
所述酸选自盐酸、硫酸和磷酸、氢溴酸、甲磺酸、乙酸、三氟乙酸、苯磺酸、三氟甲磺酸和对甲苯磺酸等中的一种或几种，优选为硫酸；The acid is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid, hydrobromic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, etc., preferably sulfuric acid;
所述的Ritter反应的反应温度为室温到回流，反应时间为2～24h。The reaction temperature of the Ritter reaction is from room temperature to reflux, and the reaction time is 2 to 24 hours.
有益效果Beneficial effect
使用本发明的制备方法，原料易得，产物纯度高、收率高，不需要使用昂贵的化学试剂，成本低；低毒低污染，绿色环保；并且反应条件温和，同时对反应设备要求不高，适合工业化生产。By using the preparation method of the invention, the raw material is easy to obtain, the product has high purity, high yield, no need to use expensive chemical reagents, low cost, low toxicity, low pollution, green environmental protection; and mild reaction conditions, and low requirements on reaction equipment Suitable for industrial production.
具体实施方式detailed description
下面结合具体实施例对本发明作进一步阐述，但不限制本发明。The invention is further illustrated by the following specific examples, without limiting the invention.
样品数据由以下仪器测定：核磁共振氢谱( 1H NMR)用Bruker Avance III 400核磁共振仪，以TMS为内标，化学位移单位为ppm；显色使用的精科WFH-203B三用紫外分析仪，波长为254nm和365nm。质谱的测定使用安捷伦6120型质谱仪；HPLC的测定用安捷伦1260型高效液相色谱仪。 The sample data was determined by the following instruments: nuclear magnetic resonance spectroscopy ( 1 H NMR) with Bruker Avance III 400 NMR spectrometer, TMS as internal standard, chemical shift unit in ppm; color analysis using WFH-203B three-use UV analysis The instrument has wavelengths of 254 nm and 365 nm. Mass spectrometry was performed using an Agilent Model 6120 mass spectrometer; HPLC was measured using an Agilent Model 1260 High Performance Liquid Chromatograph.
柱层析硅胶(100-200目，300-400目)为青岛海洋化工厂生产；TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析硅胶板，薄层层析使用的层析板厚度为0.2±0.03mm，预制备使用的薄层层析预制备板厚度为0.4-0.5mm；二氯甲烷，乙酸乙酯，甲醇，乙二醇甲醚，六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBOP)，1,3-二溴-5,5-二甲基海因，磷酸三钾，氨基乙腈盐酸盐，甲基硼酸、氯化亚砜、苯酚、溴化亚铜、三氟化硼***、乙酰丙酮、溴素、甲苯均为分析纯。4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(CAS号:1455091-10-7)购自上海匡豪化学有限公司。5-溴苯酞(CAS号：64169-34-2)购自上海德默化学有限公司。所用试剂和溶剂除特别说明外，均未经特别处理。Column chromatography silica gel (100-200 mesh, 300-400 mesh) is produced by Qingdao Marine Chemical Plant; TLC silica gel plate is HSGF-254 thin-layer chromatography silica gel plate produced by Yantai Chemical Plant, and chromatography is used for thin layer chromatography. The thickness of the plate is 0.2±0.03mm, and the thickness of the pre-prepared plate for pre-preparation is 0.4-0.5mm; dichloromethane, ethyl acetate, methanol, ethylene glycol methyl ether, benzotriazole hexafluorophosphate- 1-yl-oxytripyrrolidinylphosphine (PyBOP), 1,3-dibromo-5,5-dimethylhydantoin, tripotassium phosphate, aminoacetonitrile hydrochloride, methylboronic acid, thionyl chloride Phenol, cuprous bromide, boron trifluoride etherate, acetylacetone, bromine and toluene were all analytically pure. Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (CAS No.: 1455091-10-7) was purchased from Shanghai Haohao Chemical Co., Ltd. 5-Bromophenylhydrazine (CAS No.: 64169-34-2) was purchased from Shanghai Demer Chemical Co., Ltd. The reagents and solvents used were not specifically treated unless otherwise stated.
实施例1Example 1
化合物I-1生成化合物II-1Compound I-1 produces compound II-1
Figure PCTCN2019078261-appb-000019
Figure PCTCN2019078261-appb-000019
向100mL三口烧瓶中，加入水30mL和氢氧化钠2.4g，搅拌溶清，再加入甲醇30mL和4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(化合物I-1)5.90g，不全溶。加热回流8h，再降到0～10℃，加入1N盐酸调pH＝2～3，搅拌0.5h。抽滤，滤饼用水洗20mL和甲醇20mL淋洗，真空干燥，得白色固体5.04g产率：90％。MS(+):m/z 282.26(M+1)；核磁数据( 1H NMR,TFA-d,400MHz):δppm 9.035(1H,s,CH),8.838-8.861(1H,d,J＝9.2Hz,CH),8.153-8.182(1H,dd,J＝2.4Hz,CH),7.729-7.734(1H,d,J＝2.0Hz,CH),7.601-7.640(2H,t,J＝8Hz,CH),7.459-7.495(1H,t,J＝7.2Hz,CH),7.269-7.289(2H,t,J＝8Hz,CH)。 To a 100 mL three-necked flask, 30 mL of water and 2.4 g of sodium hydroxide were added, and the mixture was stirred and dissolved, and then 30 mL of methanol and methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (Compound I-1) 5.90 were added. g, not fully soluble. Heated to reflux for 8 h, then lowered to 0 ~ 10 ° C, added 1N hydrochloric acid to adjust pH = 2 ~ 3, stirred for 0.5 h. After suction filtration, the filter cake was washed with water (20 mL) and methanol (20 mL) and dried in vacuo. MS (+): m / z 282.26 (M + 1); NMR data (1 H NMR, TFA-d , 400MHz): δppm 9.035 (1H, s, CH), 8.838-8.861 (1H, d, J = 9.2 Hz, CH), 8.153-8.182 (1H, dd, J = 2.4 Hz, CH), 7.729-7.734 (1H, d, J = 2.0 Hz, CH), 7.601-7.640 (2H, t, J = 8 Hz, CH ), 7.459-7.495 (1H, t, J = 7.2 Hz, CH), 7.269-7.289 (2H, t, J = 8 Hz, CH).
实施例2化合物II-1生成化合物III-1Example 2 Compound II-1 produces compound III-1
Figure PCTCN2019078261-appb-000020
Figure PCTCN2019078261-appb-000020
向250mL三口烧瓶中，加入二氯甲烷80mL、化合物II-1 5.62g、PyBOP 12.48g、叔丁胺2.92g和N，N-二异丙基乙胺7.75g，搅拌，不全溶，室温过夜。抽滤，滤液中加入水80mL，分层，有机层用1N盐酸洗2×40mL，饱和碳酸氢钠洗2×40mL，纯净水洗40mL，旋干，得白色固体。加入甲醇56mL打浆，抽滤，滤饼真空烘干，得淡黄色固体5.1g，产率：75.8％。MS(+):m/z 337.38(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 13.593(1H,s,OH),8.423(1H,s,CH),8.355-8.377(1H,d,J＝8.8Hz,CH),8.004(1H,s,NH),7.436-7.508(3H,q,CH),7.237-7.285(2H,q,CH),7.139-7.158(2H,d,J＝7.6Hz,CH),1.556(9H,s,-C(CH) 3)。 To a 250 mL three-necked flask, 80 mL of dichloromethane, 5.62 g of Compound II-1, 12.48 g of PyBOP, 2.92 g of t-butylamine, and 7.75 g of N,N-diisopropylethylamine were added, stirred, not fully dissolved, and allowed to stand overnight at room temperature. After suction filtration, 80 mL of water was added to the filtrate, and the layers were separated. The organic layer was washed 2×40 mL with 1N hydrochloric acid, 2×40 mL of saturated sodium hydrogen carbonate, and 40 mL of purified water, and dried to give a white solid. After adding 56 mL of methanol, the mixture was beaten, suction filtered, and the filter cake was vacuum dried to give a pale yellow solid, 5.1 g, yield: 75.8%. MS (+): m / z 337.38 (M + 1); NMR data (1 H NMR, CDCl 3, 400MHz): δppm 13.593 (1H, s, OH), 8.423 (1H, s, CH), 8.355-8.377 (1H, d, J = 8.8 Hz, CH), 8.84 (1H, s, NH), 7.436-7.508 (3H, q, CH), 7.237-7.285 (2H, q, CH), 7.139-7.158 (2H, d, J = 7.6 Hz, CH), 1.556 (9H, s, -C(CH) 3 ).
实施例3化合物III-1生成化合物IV-1Example 3 Compound III-1 produces compound IV-1
Figure PCTCN2019078261-appb-000021
Figure PCTCN2019078261-appb-000021
向100mL三口烧瓶中，加入二氯甲烷35mL和化合物III-1 3.36g，溶清，加入1，3-二溴-5，5-二甲基海因1.72g，搅拌加热回流6h。降到0～10℃，抽滤，滤液旋干得淡红色固体3.5g，产率：84.3％。MS(+):m/z 416.28(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 13.593(1H,s,OH),8.353-8.376(1H,d,J＝9.2Hz,CH),7.667(1H,s,NH),7.647-7.653(1H,d,J＝2.4Hz,CH),7.449-7.513(3H,q,CH),7.287(1H,s,CH),7.143-7.167(2H,q,CH),1.549(9H,s,-C(CH) 3)。 To a 100 mL three-necked flask, 35 mL of dichloromethane and 3.36 g of Compound III-1 were added, and the solution was dissolved, and 1.72 g of 1,3-dibromo-5,5-dimethylhydantoin was added thereto, and the mixture was heated under reflux for 6 hours. The mixture was dropped to 0 to 10 ° C, suction filtered, and the filtrate was dried to give a pale red solid, 3.5 g, yield: 84.3%. MS (+): m/z 416.28 (M+1); NMR ( 1 H NMR, CDCl 3 , 400 MHz): δ ppm 13.593 (1H, s, OH), 8.353-8.376 (1H, d, J = 9.2 Hz ,CH), 7.667 (1H, s, NH), 7.647-7.653 (1H, d, J = 2.4 Hz, CH), 7.449-7.513 (3H, q, CH), 7.287 (1H, s, CH), 7.143 -7.167 (2H, q, CH), 1.549 (9H, s, -C(CH) 3 ).
实施例4化合物IV-1生成化合物V-1Example 4 Compound IV-1 produces compound V-1
Figure PCTCN2019078261-appb-000022
Figure PCTCN2019078261-appb-000022
向50mL三口烧瓶中，加入乙二醇二甲醚10mL、纯净水0.4g、碳酸钠0.64g、甲基硼酸0.36g和化合物IV-1 0.83g，最后加入四三苯基膦钯0.08g。氮气置换三次，搅拌加热，温度升至80～85℃，过夜。降到室温，加入1N盐酸调pH＝2～3，加入二氯甲烷30mL萃取，水洗20mL，旋干，柱层析(EA：PE(v:v)＝1：10)，得类白色固体0.6g，产 率：85.7％。MS(+):m/z 351.41(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 13.425(1H,s,OH),8.369-8.391(1H,d,J＝8.8Hz,CH),8.125(1H,s,NH),7.420-7.483(4H,q,CH),7.212-7.249(1H,t,J＝7.6Hz,CH),7.116-7.140(2H,t,J＝1.2Hz,CH),2.717(3H,s,CH 3),1.560(9H,s,-C(CH) 3)。 To a 50 mL three-necked flask, 10 mL of ethylene glycol dimethyl ether, 0.4 g of purified water, 0.64 g of sodium carbonate, 0.36 g of methylboronic acid, and 0.83 g of compound IV-1 were added, and finally, 0.08 g of tetrakistriphenylphosphine palladium was added. The mixture was replaced with nitrogen three times, heated with stirring, and the temperature was raised to 80 to 85 ° C overnight. The temperature was lowered to room temperature, pH was adjusted to 2 to 3 by adding 1N hydrochloric acid, 30 mL of dichloromethane was added for extraction, 20 mL of water was washed, and it was spin-dried, and column chromatography (EA: PE (v: v) = 1:10) gave a white solid. g, yield: 85.7%. MS (+): m / z 351.41 (M + 1); NMR data (1 H NMR, CDCl 3, 400MHz): δppm 13.425 (1H, s, OH), 8.369-8.391 (1H, d, J = 8.8Hz , CH), 8.125 (1H, s, NH), 7.420-7.483 (4H, q, CH), 7.212-7.249 (1H, t, J = 7.6 Hz, CH), 7.116-7.140 (2H, t, J = 1.2 Hz, CH), 2.718 (3H, s, CH 3 ), 1.560 (9H, s, -C(CH) 3 ).
实施例5化合物V-1生成化合物VIExample 5 Compound V-1 produces compound VI
Figure PCTCN2019078261-appb-000023
Figure PCTCN2019078261-appb-000023
向50mL三口烧瓶中，加入冰乙酸10mL、纯净水2mL、浓盐酸2mL和化合物V-1 0.5g，搅拌加热，温度升至80～85℃，过夜。降到室温，旋去溶剂，加入10mL乙腈搅拌0.5h。抽滤，滤饼用2mL乙腈淋洗，得类白色固体0.3g，产率：71.4％。MS(+):m/z 296.29(M+1)；核磁数据( 1H NMR,TFA-d,400MHz):δppm 8.766-8.789(1H,d,J＝9.2Hz,CH),8.005-8.028(1H,dd,J＝2.4Hz,CH),7.832-7.838(1H,d,J＝2.4Hz,CH),7.550-7.589(2H,t,J＝8Hz,CH),7.398-7.435(1H,t,J＝7.2Hz,CH),7.220-7.239(2H,d,J＝7.6Hz,CH),3.130(3H,s,CH 3)。 To a 50 mL three-necked flask, 10 mL of glacial acetic acid, 2 mL of purified water, 2 mL of concentrated hydrochloric acid, and 0.5 g of Compound V-1 were added, stirred and heated, and the temperature was raised to 80 to 85 ° C overnight. After cooling to room temperature, the solvent was removed, and 10 mL of acetonitrile was added and stirred for 0.5 h. After suction filtration, the filter cake was rinsed with 2 mL of acetonitrile to give a white solid, 0.3 g, yield: 71.4%. MS (+): m / z 296.29 (M + 1); NMR data (1 H NMR, TFA-d , 400MHz): δppm 8.766-8.789 (1H, d, J = 9.2Hz, CH), 8.005-8.028 ( 1H, dd, J = 2.4 Hz, CH), 7.832-7.838 (1H, d, J = 2.4 Hz, CH), 7.550-7.589 (2H, t, J = 8 Hz, CH), 7.398-7.435 (1H, t , J = 7.2Hz, CH), 7.220-7.239 (2H, d, J = 7.6Hz, CH), 3.130 (3H, s, CH 3).
实施例6化合物VI生成化合物VIIExample 6 Compound VI produces compound VII
Figure PCTCN2019078261-appb-000024
Figure PCTCN2019078261-appb-000024
向50mL三口烧瓶中，加入二氯甲烷10mL、化合物VI 0.29g、PyBOP 0.67g、氨基乙腈盐酸盐0.11g和N，N-二异丙基乙胺0.5g，搅拌，溶清，室温过夜。反应液中加入水5mL，分层，有机层用1N盐酸洗2×5mL，饱和碳酸氢钠洗2×5mL，纯净水洗5mL，旋干，得淡黄色固体0.25，产率：75.0％。MS(+):m/z 334.34(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 12.234(1H,s,OH),8.450(1H,s,NH),8.363-8.387(1H,d,J＝7.6Hz,CH),7.435-7.489(4H,q,CH),7.236-7.273(1H,t,J＝7.2Hz,CH),7.126-7.150(2H,q,CH),4.438-4.454(2H,d,J＝6.4Hz,CH 2),2.701(3H,s,CH 3)。 To a 50 mL three-necked flask, 10 mL of dichloromethane, 0.29 g of compound VI, 0.67 g of PyBOP, 0.11 g of aminoacetonitrile hydrochloride and 0.5 g of N,N-diisopropylethylamine were added, stirred, and dissolved at room temperature overnight. 5 mL of water was added to the reaction mixture, and the layers were separated. The organic layer was washed 2×5 mL with 1N hydrochloric acid, 2×5 mL of saturated sodium hydrogencarbonate, 5 mL of purified water, and dried to give a pale yellow solid 0.25. Yield: 75.0%. MS (+): m / z 334.34 (M + 1); NMR data (1 H NMR, CDCl 3, 400MHz): δppm 12.234 (1H, s, OH), 8.450 (1H, s, NH), 8.363-8.387 (1H, d, J = 7.6 Hz, CH), 7.435-7.489 (4H, q, CH), 7.236-7.273 (1H, t, J = 7.2 Hz, CH), 7.126-7.150 (2H, q, CH) , 4.438-4.454 (2H, d, J = 6.4 Hz, CH 2 ), 2.701 (3H, s, CH 3 ).
实施例7化合物VII生成化合物VIIIExample 7 Compound VII produces Compound VIII
Figure PCTCN2019078261-appb-000025
Figure PCTCN2019078261-appb-000025
向50mL三口烧瓶中，加入水6mL和氢氧化钠0.3g，搅拌溶清，再加入甲醇10mL和化合物VII 0.25g，溶清。加热回流过夜。降到0～10℃，加入1N盐酸调pH＝2～3，搅拌0.5h。抽滤，滤饼用水洗5mL和甲醇5mL淋洗，真空干燥，得淡黄色固体0.21g，产率：79.5％，产物经HPLC测定纯度为99.5％。MS(+):m/z 353.34(M+1)；核磁数据( 1H NMR,DMSO-d 6,400MHz):δppm 13.267(1H,s,OH),12.806(1H,s,br,COOH),9.044-9.075(1H,t,NH),8.241-8.263(1H,d,J＝8.8Hz,CH),7.566-7.571(1H,d,J＝2.0Hz,CH),7.452-7.507(3H,m,CH),7.224-7.261(1H,t,J＝7.6Hz,CH),7.156-7.178(2H,d,J＝8.8Hz,CH),4.060-4.075(2H,d,J＝6.0Hz,CH 2)，2.675(3H,s,CH 3)。 To a 50 mL three-necked flask, 6 mL of water and 0.3 g of sodium hydroxide were added, and the mixture was stirred and dissolved, and then 10 mL of methanol and 0.25 g of Compound VII were added to dissolve. Heat to reflux overnight. Drop to 0 ~ 10 ° C, add 1N hydrochloric acid to adjust pH = 2 ~ 3, stir for 0.5h. After suction filtration, the filter cake was washed with water (5 mL) and methanol (5 mL) and dried in vacuo to give a pale yellow solid (0.21 g, yield: 79.5%). MS (+): m / z 353.34 (M + 1); NMR data (1 H NMR, DMSO-d 6, 400MHz): δppm 13.267 (1H, s, OH), 12.806 (1H, s, br, COOH) , 9.044-9.075 (1H, t, NH), 8.241-8.263 (1H, d, J = 8.8 Hz, CH), 7.566-7.571 (1H, d, J = 2.0 Hz, CH), 7.452-7.507 (3H, m, CH), 7.224-7.261 (1H, t, J = 7.6 Hz, CH), 7.156-7.178 (2H, d, J = 8.8 Hz, CH), 4.060-4.075 (2H, d, J = 6.0 Hz, CH 2 ), 2.675 (3H, s, CH 3 ).
实施例8化合物a生成化合物bExample 8 Compound a produces compound b
Figure PCTCN2019078261-appb-000026
Figure PCTCN2019078261-appb-000026
向500mL三口烧瓶中，搅拌下加入甲苯300mL、化合物a 21.3g、苯酚11.3g、2-二叔丁基膦联苯0.85g、磷酸钾42.4g和乙酸钯0.43g，氮气置换三次，回流过夜。降到室温，加水150mL，加入二氯甲烷150mL，分层，有机层用水洗100mL*2，无水硫酸钠干燥，旋干，得白色固体20.1g，产率：88.9％。MS(+):m/z 227.22(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 7.880-7.859(1H,d,J＝8.4Hz,CH),7.471-7.430(2H,m,CH),7.286-7.265(1H,t,J＝4.2Hz,CH),7.152-7.102(3H,m,CH),6.961(1H,s,CH),5.243(2H,s,CH 2)。 To a 500 mL three-necked flask, 300 mL of toluene, 21.3 g of compound a, 11.3 g of phenol, 11.5 g of 2-di-tert-butylphosphine biphenyl, 42.4 g of potassium phosphate, and 0.43 g of palladium acetate were added under stirring, and the mixture was replaced with nitrogen three times, and refluxed overnight. The mixture was cooled to room temperature, 150 mL of water was added, 150 mL of dichloromethane was added, and the layers were separated, and the organic layer was washed with water (100 mL*2), dried over anhydrous sodium sulfate and evaporated to give a white solid (20.1 g). MS (+): m/z 227.22 (M + 1); NMR data ( 1 H NMR, CDCl 3 , 400 MHz): δ ppm 7.880-7.859 (1H, d, J = 8.4 Hz, CH), 7.471-7.430 (2H , m, CH), 7.286-7.265 (1H, t, J = 4.2 Hz, CH), 7.152-7.102 (3H, m, CH), 6.961 (1H, s, CH), 5.243 (2H, s, CH 2 ).
实施例9化合物b生成化合物cExample 9 Compound b produces compound c
Figure PCTCN2019078261-appb-000027
Figure PCTCN2019078261-appb-000027
向500mL三口烧瓶中，搅拌下加入甲醇100mL、化合物b 20.1g、氢氧化钠5.0g和水100mL，回流6h。降到室温，加1N盐酸调pH＝2-3，搅拌30分钟，抽滤，滤饼用水100mL淋洗。真空干燥，得白色固体19.6g，产率：90.3％。MS(+):m/z 245.24(M+1)； 核磁数据( 1H NMR,DMSO-d6,400MHz):δppm 12.831(1H,br,-COOH),7.935-7.914(1H,d,J＝8.4Hz,CH),7.479-7.434(2H,m,CH),7.320-7.313(1H,d,J＝2.8Hz,CH),7.258-7.253(1H,t,CH),7.237-7.110(2H,m,CH 2),6.913-6.884(1H,q,CH 2),5.287(1H,br.–OH),4.835(2H,s,CH 2)。 To a 500 mL three-necked flask, 100 mL of methanol, 20.1 g of Compound b, 5.0 g of sodium hydroxide, and 100 mL of water were added with stirring, and the mixture was refluxed for 6 hours. Reduce to room temperature, add 1N hydrochloric acid to adjust pH = 2-3, stir for 30 minutes, suction filtration, filter cake with 100 mL of water rinse. Drying in vacuo gave 19.6 g of a white solid. Yield: 90.3%. MS (+): m / z 245.24 (M + 1); NMR data (1 H NMR, DMSO-d6,400MHz ): δppm 12.831 (1H, br, -COOH), 7.935-7.914 (1H, d, J = 8.4 Hz, CH), 7.479-7.434 (2H, m, CH), 7.320-7.313 (1H, d, J = 2.8 Hz, CH), 7.258-7.253 (1H, t, CH), 7.237-7.110 (2H, m, CH 2 ), 6.913-6.884 (1H, q, CH 2 ), 5.287 (1H, br. - OH), 4.835 (2H, s, CH 2 ).
实施例10化合物c生成化合物dExample 10 Compound c produces compound d
Figure PCTCN2019078261-appb-000028
Figure PCTCN2019078261-appb-000028
向250mL三口烧瓶中，搅拌下加入甲苯150mL、化合物c 15.6g、三氟化硼***8.5g和苄基三乙基氯化铵1.0g。降到0～10℃，滴加氯化亚砜21.4g，搅拌30分钟，升温到90～100℃，过夜。旋去溶剂，再加入甲苯100mL，冷却到0～10℃，加入甲醇20mL，回流2h，再旋去溶剂，加入二氯甲烷150mL，加入饱和碳酸氢钠洗50mL*2，饱和食盐水洗50mL，无水硫酸钠干燥，得淡黄色液体13.3g。产率：80％。MS(+):m/z 277.71(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 8.016-7.994(1H,d,J＝8.8Hz，CH),7.450-7.409(2H,m,CH),7.236-7.195(2H,m,CH),7.115-7.090(2H,m,CH),6.951-6.923(1H,m,CH),5.040(1H,s.CH 2),3.931(3H,s,CH 3)。 To a 250 mL three-necked flask, 150 mL of toluene, 15.6 g of compound c, 8.5 g of boron trifluoride etherate, and 1.0 g of benzyltriethylammonium chloride were added with stirring. The temperature was lowered to 0 to 10 ° C, 21.4 g of thionyl chloride was added dropwise, stirred for 30 minutes, and the temperature was raised to 90 to 100 ° C overnight. Dissolve the solvent, add 100 mL of toluene, cool to 0 ~ 10 ° C, add methanol 20 mL, reflux for 2 h, then spin off the solvent, add 150 mL of dichloromethane, add saturated sodium bicarbonate wash 50 mL * 2, saturated brine wash 50 mL, no The aqueous sodium sulfate was dried to give a pale yellow liquid, 13.3 g. Yield: 80%. MS (+): m/z 277.71 (M + 1); NMR data ( 1 H NMR, CDCl 3 , 400 MHz): δ ppm 8.016-7.994 (1H, d, J = 8.8 Hz, CH), 7.450-7.409 (2H , m, CH), 7.236-7.195 (2H, m, CH), 7.115-7.090 (2H, m, CH), 6.951-6.923 (1H, m, CH), 5.040 (1H, s.CH 2 ), 3.931 (3H, s, CH 3 ).
实施例11化合物d生成化合物eExample 11 Compound d produces compound e
Figure PCTCN2019078261-appb-000029
Figure PCTCN2019078261-appb-000029
向250mL三口烧瓶中，搅拌下加入乙腈100mL、化合物d 10.2g、N-氰甲基-4-甲基苯磺酰胺(CAS：20228-87-9)7.7g、碳酸钾6.0g和碘化钠0.5g，加热回流8h。抽滤，旋去溶剂，得类白色固体14.8g。产率：91.3％。MS(+):m/z 451.51(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 7.926-7.904(1H,d,J＝8.8Hz，CH),7.754-7.733(2H,d,J＝8.4Hz，CH),7.441-7.402(2H,t,J＝7.2Hz，CH),7.311-7.286(3H,m,CH),7.241-7.204(1H,t,J＝7.2Hz，CH),7.084-7.060(2H,d,J＝8.4Hz，CH),6.867-6.839(1H,q,CH),4.918(2H,s.CH 2),4.023(2H,s.CH 2),3.851(3H,s,CH 3),2.437(3H,s,CH 3)。 Into a 250 mL three-necked flask, 100 mL of acetonitrile, 10.2 g of compound d, 7.7 g of N-cyanomethyl-4-methylbenzenesulfonamide (CAS: 20228-87-9), 6.0 g of potassium carbonate, and sodium iodide were added thereto with stirring. 0.5 g, heated to reflux for 8 h. After suction filtration, the solvent was evaporated to give a white solid (14.8 g). Yield: 91.3%. MS (+): m/z 451.51 (M+1); NMR data ( 1 H NMR, CDCl 3 , 400 MHz): δ ppm 7.926-7.904 (1H, d, J = 8.8 Hz, CH), 7.754-7.733 (2H ,d,J=8.4Hz,CH),7.441-7.402(2H,t,J=7.2Hz,CH),7.311-7.286(3H,m,CH),7.241-7.204(1H,t,J=7.2Hz , CH), 7.084-7.060 (2H, d, J = 8.4 Hz, CH), 6.867-6.839 (1H, q, CH), 4.918 (2H, s. CH 2 ), 4.023 (2H, s. CH 2 ) , 3.851 (3H, s, CH 3 ), 2.437 (3H, s, CH 3 ).
实施例12化合物e生成化合物fExample 12 Compound e produces compound f
Figure PCTCN2019078261-appb-000030
Figure PCTCN2019078261-appb-000030
向250mL三口烧瓶中，搅拌下加入甲醇100mL、化合物e 14.8g、二甲亚砜10mL和甲醇钠5.0g，室温搅拌过夜。旋去大半溶剂，加水50mL，用乙酸调pH＝2-3,加入二氯甲烷50mL萃取，水洗三次30Ml*3,无水硫酸钠干燥。旋去溶剂，得到白色固体7.4g。产率：86.0％。MS(+):m/z 263.26(M+1)；核磁数据( 1H NMR,TFA-d,400MHz):δppm 9.048(1H,s,CH),8.880-8.856(1H,d,J＝9.6Hz，CH),8.199-8.170(1H,q,CH),7.737-7.732(1H,d,J＝2.0Hz，CH),7.643-7.604(2H,m,CH),7.498-7.480(1H,t,J＝3.6Hz，CH),7.290-7.270(2H,d,J＝8.0Hz，CH)。 To a 250 mL three-necked flask, 100 mL of methanol, 14.8 g of compound e, 10 mL of dimethyl sulfoxide and 5.0 g of sodium methoxide were added with stirring, and the mixture was stirred at room temperature overnight. The larger half of the solvent was rotated, 50 mL of water was added, pH was adjusted to 2-3 with acetic acid, 50 mL of dichloromethane was added for extraction, and 30 Ml*3 was washed three times with water and dried over anhydrous sodium sulfate. The solvent was evaporated to give 7.4 g of a white solid. Yield: 86.0%. MS (+): m / z 263.26 (M + 1); NMR data (1 H NMR, TFA-d , 400MHz): δppm 9.048 (1H, s, CH), 8.880-8.856 (1H, d, J = 9.6 Hz, CH), 8.199-8.170 (1H, q, CH), 7.737-7.732 (1H, d, J = 2.0 Hz, CH), 7.643-7.604 (2H, m, CH), 7.498-7.480 (1H, t , J = 3.6 Hz, CH), 7.290-7.270 (2H, d, J = 8.0 Hz, CH).
实施例13化合物f生成化合物III-1Example 13 Compound f produces Compound III-1
Figure PCTCN2019078261-appb-000031
Figure PCTCN2019078261-appb-000031
向100mL三口烧瓶中，搅拌下加入叔丁醇50mL、化合物f 2.6g和浓硫酸5mL，加热回流8h。旋去溶剂，加入二氯甲烷50mL，分层，有机层用饱和碳酸氢钠洗50mL*2，饱和食盐水洗50mL，无水硫酸钠干燥。旋干，得淡黄色固体3.0g。产率：89.2％。MS(+):m/z 337.38(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 13.593(1H,s,OH),8.423(1H,s,CH),8.355-8.377(1H,d,J＝8.8Hz,CH),8.004(1H,s,NH),7.436-7.508(3H,q,CH),7.237-7.285(2H,q,CH),7.139-7.158(2H,d,J＝7.6Hz,CH),1.556(9H,s,-C(CH) 3)。 Into a 100 mL three-necked flask, 50 mL of t-butanol, 2.6 g of compound f and 5 mL of concentrated sulfuric acid were added under stirring, and the mixture was heated under reflux for 8 hours. The solvent was evaporated, and 50 mL of dichloromethane was added, and the layers were separated. The organic layer was washed with saturated sodium bicarbonate (50 mL), and 50 mL of saturated brine. It was dried to give a pale yellow solid (3.0 g). Yield: 89.2%. MS (+): m / z 337.38 (M + 1); NMR data (1 H NMR, CDCl 3, 400MHz): δppm 13.593 (1H, s, OH), 8.423 (1H, s, CH), 8.355-8.377 (1H, d, J = 8.8 Hz, CH), 8.84 (1H, s, NH), 7.436-7.508 (3H, q, CH), 7.237-7.285 (2H, q, CH), 7.139-7.158 (2H, d, J = 7.6 Hz, CH), 1.556 (9H, s, -C(CH) 3 ).
实施例14化合物a生成化合物bExample 14 Compound a produces compound b
Figure PCTCN2019078261-appb-000032
Figure PCTCN2019078261-appb-000032
向500mL三口烧瓶中，搅拌下加入DMF 215mL、化合物a 42.6g、苯酚22.6g、溴化亚铜4.5g、乙酰丙酮5mL和碳酸钾41.4g，氮气置换三次，加热到90～100℃保温8h。降到室温，加水860mL，抽滤，滤饼用100mL水淋洗，滤饼加入二氯甲烷300mL溶解，用1N盐酸100mL洗，水洗100mL，无水硫酸钠干燥，旋干，得类白色固体21.2g。产率：46.9％。MS(+):m/z 227.22(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm  7.880-7.859(1H,d,J＝8.4Hz,CH),7.471-7.430(2H,m,CH),7.286-7.265(1H,t,J＝4.2Hz,CH),7.152-7.102(3H,m,CH),6.961(1H,s,CH),5.243(2H,s,CH 2)。 To a 500 mL three-necked flask, 215 mL of DMF, 42.6 g of Compound a, 22.6 g of phenol, 4.5 g of cuprous bromide, 5 mL of acetylacetone and 41.4 g of potassium carbonate were added with stirring, and the mixture was replaced with nitrogen three times, and heated to 90 to 100 ° C for 8 hours. Reduced to room temperature, add water 860mL, suction filtration, filter cake with 100mL water rinse, filter cake added to 300mL of dichloromethane dissolved, washed with 1N hydrochloric acid 100mL, washed with water 100mL, dried anhydrous sodium sulfate, spin dry, to obtain a white solid 21.2 g. Yield: 46.9%. MS (+): m/z 227.22 (M + 1); NMR data ( 1 H NMR, CDCl 3 , 400 MHz): δ ppm 7.880-7.859 (1H, d, J = 8.4 Hz, CH), 7.471-7.430 (2H , m, CH), 7.286-7.265 (1H, t, J = 4.2 Hz, CH), 7.152-7.102 (3H, m, CH), 6.961 (1H, s, CH), 5.243 (2H, s, CH 2 ).
实施例15化合物b生成化合物dExample 15 Compound b produces compound d
Figure PCTCN2019078261-appb-000033
Figure PCTCN2019078261-appb-000033
向50mL三口烧瓶中，搅拌下加入甲苯20mL、化合物b 2.26g、硼酸三甲酯0.2g、三苯基二氯化瞵0.6g和碳酸钾2.8g。降到0～10℃，滴加氯化亚砜1.68g，搅拌30分钟，升温到90～100℃，过夜。旋去溶剂，再加入甲苯15mL，冷却到0～10℃，加入甲醇1mL，回流2h，再旋去溶剂，柱层析(EA：PE(v:v)＝1：5)，得淡黄色液体0.4g。产率：14.5％。MS(+):m/z 277.71(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 8.016-7.994(1H,d,J＝8.8Hz，CH),7.450-7.409(2H,m,CH),7.236-7.195(2H,m,CH),7.115-7.090(2H,m,CH),6.951-6.923(1H,m,CH),5.040(1H,s.CH 2),3.931(3H,s,CH 3)。 To a 50 mL three-necked flask, 20 mL of toluene, 2.26 g of compound b, 0.2 g of trimethyl borate, 0.6 g of triphenylphosphonium chloride, and 2.8 g of potassium carbonate were added with stirring. The temperature was lowered to 0 to 10 ° C, and 1.68 g of thionyl chloride was added dropwise thereto, and the mixture was stirred for 30 minutes, and the temperature was raised to 90 to 100 ° C overnight. Dissolve the solvent, add 15 mL of toluene, cool to 0-10 ° C, add 1 mL of methanol, reflux for 2 h, then spin off the solvent, column chromatography (EA: PE (v: v) = 1:5), to obtain a pale yellow liquid 0.4g. Yield: 14.5%. MS (+): m/z 277.71 (M + 1); NMR data ( 1 H NMR, CDCl 3 , 400 MHz): δ ppm 8.016-7.994 (1H, d, J = 8.8 Hz, CH), 7.450-7.409 (2H , m, CH), 7.236-7.195 (2H, m, CH), 7.115-7.090 (2H, m, CH), 6.951-6.923 (1H, m, CH), 5.040 (1H, s.CH 2 ), 3.931 (3H, s, CH 3 ).
实施例16化合物b生成化合物dExample 16 Compound b produces compound d
Figure PCTCN2019078261-appb-000034
Figure PCTCN2019078261-appb-000034
向50mL三口烧瓶中，搅拌下加入甲苯20mL、化合物b 2.26g、硼酸三甲酯0.2g、三苯基二氯化瞵0.6g和三乙胺3.0g。降到0～10℃，滴加氯化亚砜1.68g，搅拌30分钟，升温到90～100℃，过夜。旋去溶剂，再加入甲苯15mL，冷却到0～10℃，加入甲醇1mL，回流2h，再旋去溶剂，加入二氯甲烷20mL，用1N盐酸10mL洗，水洗10mL，无水硫酸钠干燥，旋干，柱层析(EA：PE(v:v)＝1：5)，得淡黄色液体0.5g。产率：18.1％。MS(+):m/z 277.71(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 8.016-7.994(1H,d,J＝8.8Hz，CH),7.450-7.409(2H,m,CH),7.236-7.195(2H,m,CH),7.115-7.090(2H,m,CH),6.951-6.923(1H,m,CH),5.040(1H,s.CH 2),3.931(3H,s,CH 3)。 To a 50 mL three-necked flask, 20 mL of toluene, 2.26 g of compound b, 0.2 g of trimethyl borate, 0.6 g of triphenylphosphonium chloride and 3.0 g of triethylamine were added with stirring. The temperature was lowered to 0 to 10 ° C, and 1.68 g of thionyl chloride was added dropwise thereto, and the mixture was stirred for 30 minutes, and the temperature was raised to 90 to 100 ° C overnight. Dissolve the solvent, add 15 mL of toluene, cool to 0 to 10 ° C, add 1 mL of methanol, reflux for 2 h, then spin off the solvent, add 20 mL of dichloromethane, wash with 10 mL of 1N hydrochloric acid, wash 10 mL with water, dry with anhydrous sodium sulfate, spin Dry, column chromatography (EA: PE (v: v) = 1: 5) gave a pale yellow liquid 0.5 g. Yield: 18.1%. MS (+): m/z 277.71 (M + 1); NMR data ( 1 H NMR, CDCl 3 , 400 MHz): δ ppm 8.016-7.994 (1H, d, J = 8.8 Hz, CH), 7.450-7.409 (2H , m, CH), 7.236-7.195 (2H, m, CH), 7.115-7.090 (2H, m, CH), 6.951-6.923 (1H, m, CH), 5.040 (1H, s.CH 2 ), 3.931 (3H, s, CH 3 ).
实施例17化合物b生成化合物dExample 17 Compound b produces compound d
Figure PCTCN2019078261-appb-000035
Figure PCTCN2019078261-appb-000035
向50mL三口烧瓶中，搅拌下加入甲苯20mL、化合物b 2.26g、三氟化硼***0.3g、苄基三乙基氯化铵0.6g。降到0～10℃，滴加氯化亚砜1.68g，搅拌30分钟，升温到90～100℃，过夜。旋去溶剂，再加入甲苯15mL，冷却到0～10℃，加入甲醇1mL，回流2h，再旋去溶剂，加入二氯甲烷20mL，用饱和碳酸氢钠10mL洗，水洗10mL，无水硫酸钠干燥，旋干，柱层析(EA：PE(v:v)＝1：5)，得淡黄色液体0.6g。产率：21.6％。MS(+):m/z 277.71(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 8.016-7.994(1H,d,J＝8.8Hz，CH),7.450-7.409(2H,m,CH),7.236-7.195(2H,m,CH),7.115-7.090(2H,m,CH),6.951-6.923(1H,m,CH),5.040(1H,s.CH 2),3.931(3H,s,CH 3)。 To a 50 mL three-necked flask, 20 mL of toluene, 2.26 g of compound b, 0.3 g of boron trifluoride etherate, and 0.6 g of benzyltriethylammonium chloride were added with stirring. The temperature was lowered to 0 to 10 ° C, and 1.68 g of thionyl chloride was added dropwise thereto, and the mixture was stirred for 30 minutes, and the temperature was raised to 90 to 100 ° C overnight. The solvent was removed, 15 mL of toluene was added, and the mixture was cooled to 0 to 10 ° C. 1 mL of methanol was added and refluxed for 2 h, then the solvent was evaporated, 20 mL of dichloromethane was added, washed with saturated sodium hydrogen carbonate (10 mL), washed with water (10 mL) and dried over anhydrous sodium sulfate , spin-drying, column chromatography (EA: PE (v: v) = 1: 5) gave a pale yellow liquid (0.6 g). Yield: 21.6%. MS (+): m/z 277.71 (M + 1); NMR data ( 1 H NMR, CDCl 3 , 400 MHz): δ ppm 8.016-7.994 (1H, d, J = 8.8 Hz, CH), 7.450-7.409 (2H , m, CH), 7.236-7.195 (2H, m, CH), 7.115-7.090 (2H, m, CH), 6.951-6.923 (1H, m, CH), 5.040 (1H, s.CH 2 ), 3.931 (3H, s, CH 3 ).
实施例18化合物f生成化合物III-1Example 18 Compound f produces Compound III-1
Figure PCTCN2019078261-appb-000036
Figure PCTCN2019078261-appb-000036
向50mL三口烧瓶中，搅拌下加入冰乙酸26mL、化合物f 2.6g和浓硫酸1mL，加热70～80℃，通入异丁烯，直到原料消失。加水50mL，加入二氯甲烷50mL，分层，有机层用饱和碳酸氢钠洗50mL*2，饱和食盐水洗50mL，无水硫酸钠干燥。旋干，得淡黄色固体3.2g。产率：95.2％。MS(+):m/z 337.38(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 13.593(1H,s,OH),8.423(1H,s,CH),8.355-8.377(1H,d,J＝8.8Hz,CH),8.004(1H,s,NH),7.436-7.508(3H,q,CH),7.237-7.285(2H,q,CH),7.139-7.158(2H,d,J＝7.6Hz,CH),1.556(9H,s,-C(CH) 3)。 To a 50 mL three-necked flask, 26 mL of glacial acetic acid, 2.6 g of compound f and 1 mL of concentrated sulfuric acid were added with stirring, and the mixture was heated at 70 to 80 ° C, and isobutylene was introduced until the starting material disappeared. 50 mL of water was added, 50 mL of dichloromethane was added, and the layers were separated. The organic layer was washed with saturated sodium bicarbonate (50 mL), and 50 mL of saturated brine. Spin dry to give a pale yellow solid 3.2 g. Yield: 95.2%. MS (+): m / z 337.38 (M + 1); NMR data (1 H NMR, CDCl 3, 400MHz): δppm 13.593 (1H, s, OH), 8.423 (1H, s, CH), 8.355-8.377 (1H, d, J = 8.8 Hz, CH), 8.84 (1H, s, NH), 7.436-7.508 (3H, q, CH), 7.237-7.285 (2H, q, CH), 7.139-7.158 (2H, d, J = 7.6 Hz, CH), 1.556 (9H, s, -C(CH) 3 ).
实施例19化合物f生成化合物III-1Example 19 Compound f produces compound III-1
Figure PCTCN2019078261-appb-000037
Figure PCTCN2019078261-appb-000037
向50mL三口烧瓶中，搅拌下加入乙酸异丁酯26mL、化合物f 2.6g和浓硫酸5mL，加热到70～80℃，过夜。加水50mL，分层，有机层用饱和碳酸氢钠洗50mL*2，饱和食盐水洗50mL，无水硫酸钠干燥。旋干，柱层析(EA：PE(v:v)＝1：5)，得淡黄色固体0.68g。产率：20.2％。MS(+):m/z 337.38(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 13.593(1H,s,OH),8.423(1H,s,CH),8.355-8.377(1H,d,J＝8.8Hz,CH),8.004(1H,s,NH),7.436-7.508(3H,q,CH),7.237-7.285(2H,q,CH),7.139-7.158(2H,d,J＝7.6Hz,CH),1.556(9H,s,-C(CH) 3)。 To a 50 mL three-necked flask, 26 mL of isobutyl acetate, 2.6 g of compound f and 5 mL of concentrated sulfuric acid were added with stirring, and the mixture was heated to 70 to 80 ° C overnight. 50 mL of water was added, and the layers were separated. The organic layer was washed with saturated sodium bicarbonate (50 mL), and 50 mL of saturated brine. Spin-drying, column chromatography (EA: EtOAc (EtOAc: EtOAc) Yield: 20.2%. MS (+): m / z 337.38 (M + 1); NMR data (1 H NMR, CDCl 3, 400MHz): δppm 13.593 (1H, s, OH), 8.423 (1H, s, CH), 8.355-8.377 (1H, d, J = 8.8 Hz, CH), 8.84 (1H, s, NH), 7.436-7.508 (3H, q, CH), 7.237-7.285 (2H, q, CH), 7.139-7.158 (2H, d, J = 7.6 Hz, CH), 1.556 (9H, s, -C(CH) 3 ).
实施例20化合物II生成化合物III-1Example 20 Compound II produces compound III-1
Figure PCTCN2019078261-appb-000038
Figure PCTCN2019078261-appb-000038
向250mL三口烧瓶中，加入二氯甲烷80mL、化合物II 5.62g、HATU 9.12g、叔丁胺2.92g和N，N-二异丙基乙胺7.75g，搅拌，不全溶，室温过夜。抽滤，滤液中加入水80mL，分层，有机层用1N盐酸洗2×40mL，饱和碳酸氢钠洗2×40mL，纯净水洗40mL，旋干，得白色固体。加入甲醇56mL打浆，抽滤，滤饼真空烘干，得淡黄色固体4.8g。产率：71.4％。MS(+):m/z 337.38(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 13.593(1H,s,OH),8.423(1H,s,CH),8.355-8.377(1H,d,J＝8.8Hz,CH),8.004(1H,s,NH),7.436-7.508(3H,q,CH),7.237-7.285(2H,q,CH),7.139-7.158(2H,d,J＝7.6Hz,CH),1.556(9H,s,-C(CH) 3)。 To a 250 mL three-necked flask, 80 mL of dichloromethane, 5.62 g of Compound II, 9.12 g of HATU, 2.92 g of t-butylamine and 7.75 g of N,N-diisopropylethylamine were added, stirred, not fully dissolved, and allowed to stand overnight at room temperature. After suction filtration, 80 mL of water was added to the filtrate, and the layers were separated. The organic layer was washed 2×40 mL with 1N hydrochloric acid, 2×40 mL of saturated sodium hydrogen carbonate, and 40 mL of purified water, and dried to give a white solid. After adding 56 mL of methanol, the mixture was beaten, suction filtered, and the cake was vacuum dried to give a pale yellow solid 4.8 g. Yield: 71.4%. MS (+): m / z 337.38 (M + 1); NMR data (1 H NMR, CDCl 3, 400MHz): δppm 13.593 (1H, s, OH), 8.423 (1H, s, CH), 8.355-8.377 (1H, d, J = 8.8 Hz, CH), 8.84 (1H, s, NH), 7.436-7.508 (3H, q, CH), 7.237-7.285 (2H, q, CH), 7.139-7.158 (2H, d, J = 7.6 Hz, CH), 1.556 (9H, s, -C(CH) 3 ).
实施例21化合物II生成化合物III-1Example 21 Compound II produces compound III-1
Figure PCTCN2019078261-appb-000039
Figure PCTCN2019078261-appb-000039
向250mL三口烧瓶中，加入二氯甲烷80mL、化合物II 5.62g、HBTU 9.09g、叔丁胺2.92g和N，N-二异丙基乙胺7.75g，搅拌，不全溶，室温过夜。抽滤，滤液中加入水80mL，分层，有机层用1N盐酸洗2×40mL，饱和碳酸氢钠洗2×40mL，纯净水洗40mL，旋干，得白色固体。加入甲醇56mL打浆，抽滤，滤饼真空烘干，得淡黄色固体4.7g。产率：69.9％。MS(+):m/z 337.38(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 13.593(1H,s,OH),8.423(1H,s,CH),8.355-8.377(1H,d,J＝8.8Hz,CH),8.004(1H,s,NH),7.436-7.508(3H,q,CH),7.237-7.285(2H,q,CH),7.139-7.158(2H,d,J＝7.6Hz,CH),1.556(9H,s,-C(CH) 3)。 To a 250 mL three-necked flask, 80 mL of dichloromethane, 5.62 g of Compound II, 9.09 g of HBTU, 2.92 g of t-butylamine and 7.75 g of N,N-diisopropylethylamine were added, stirred, not fully dissolved, and allowed to stand overnight at room temperature. After suction filtration, 80 mL of water was added to the filtrate, and the layers were separated. The organic layer was washed 2×40 mL with 1N hydrochloric acid, 2×40 mL of saturated sodium hydrogen carbonate, and 40 mL of purified water, and dried to give a white solid. After adding 56 mL of methanol, the mixture was beaten, suction filtered, and the cake was vacuum dried to give a pale yellow solid 4.7 g. Yield: 69.9%. MS (+): m / z 337.38 (M + 1); NMR data (1 H NMR, CDCl 3, 400MHz): δppm 13.593 (1H, s, OH), 8.423 (1H, s, CH), 8.355-8.377 (1H, d, J = 8.8 Hz, CH), 8.84 (1H, s, NH), 7.436-7.508 (3H, q, CH), 7.237-7.285 (2H, q, CH), 7.139-7.158 (2H, d, J = 7.6 Hz, CH), 1.556 (9H, s, -C(CH) 3 ).
实施例22化合物III-1生成化合物IV-1Example 22 Compound III-1 produces compound IV-1
Figure PCTCN2019078261-appb-000040
Figure PCTCN2019078261-appb-000040
向100mL三口烧瓶中，加入二氯甲烷35mL和化合物III-1 3.36g，溶清，加入溴素1.76g，搅拌加热回流2h。降到室温，加入饱和亚硫酸氢钠洗20mL*2，水洗20mL， 无水硫酸钠干燥，旋干得淡红色固体3.7g。产率：89.1％。MS(+):m/z 416.28(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 13.593(1H,s,OH),8.353-8.376(1H,d,J＝9.2Hz,CH),7.667(1H,s,NH),7.647-7.653(1H,d,J＝2.4Hz,CH),7.449-7.513(3H,q,CH),7.287(1H,s,CH),7.143-7.167(2H,q,CH),1.549(9H,s,-C(CH) 3)。 To a 100 mL three-necked flask, 35 mL of dichloromethane and 3.36 g of Compound III-1 were added, and the solution was dissolved, and 1.76 g of bromine was added thereto, and the mixture was heated under reflux for 2 hours. The mixture was cooled to room temperature, washed with saturated sodium hydrogen sulfite (20 mL), washed with water (20 mL), dried over anhydrous sodium sulfate and evaporated to dryness. Yield: 89.1%. MS (+): m/z 416.28 (M+1); NMR ( 1 H NMR, CDCl 3 , 400 MHz): δ ppm 13.593 (1H, s, OH), 8.353-8.376 (1H, d, J = 9.2 Hz ,CH), 7.667 (1H, s, NH), 7.647-7.653 (1H, d, J = 2.4 Hz, CH), 7.449-7.513 (3H, q, CH), 7.287 (1H, s, CH), 7.143 -7.167 (2H, q, CH), 1.549 (9H, s, -C(CH) 3 ).
实施例23化合物III-1生成化合物IV-1Example 23 Compound III-1 produces compound IV-1
Figure PCTCN2019078261-appb-000041
Figure PCTCN2019078261-appb-000041
向100mL三口烧瓶中，加入二氯甲烷35mL和化合物III-1 3.36g，溶清，加入NBS2.14g，搅拌加热回流4h。降到0～10℃，抽滤，滤液旋干得淡红色固体3.6g。产率：86.7％。MS(+):m/z 416.28(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 13.593(1H,s,OH),8.353-8.376(1H,d,J＝9.2Hz,CH),7.667(1H,s,NH),7.647-7.653(1H,d,J＝2.4Hz,CH),7.449-7.513(3H,q,CH),7.287(1H,s,CH),7.143-7.167(2H,q,CH),1.549(9H,s,-C(CH) 3)。 To a 100 mL three-necked flask, 35 mL of dichloromethane and 3.36 g of Compound III-1 were added, and the solution was dissolved, and 2.14 g of NBS was added thereto, and the mixture was heated under reflux for 4 hours. The mixture was dropped to 0 to 10 ° C, suction filtered, and the filtrate was dried to give a pale red solid 3.6 g. Yield: 86.7%. MS (+): m/z 416.28 (M+1); NMR ( 1 H NMR, CDCl 3 , 400 MHz): δ ppm 13.593 (1H, s, OH), 8.353-8.376 (1H, d, J = 9.2 Hz ,CH), 7.667 (1H, s, NH), 7.647-7.653 (1H, d, J = 2.4 Hz, CH), 7.449-7.513 (3H, q, CH), 7.287 (1H, s, CH), 7.143 -7.167 (2H, q, CH), 1.549 (9H, s, -C(CH) 3 ).
实施例24化合物V-1生成化合物VIExample 24 Compound V-1 produces compound VI
Figure PCTCN2019078261-appb-000042
Figure PCTCN2019078261-appb-000042
向50mL三口烧瓶中，加入乙腈10mL，纯净水5mL、浓硫酸5mL和化合物V-1 1.5g，搅拌加热，温度升至40～50℃，过夜。降到室温，旋去溶剂，抽滤，滤饼加入10mL乙腈搅拌0.5h。抽滤，滤饼用1mL乙腈淋洗，得类白色固体1.0g。产率：79.3％。MS(+):m/z 296.29(M+1)；核磁数据( 1H NMR,TFA-d,400MHz):δppm 8.766-8.789(1H,d,J＝9.2Hz,CH),8.005-8.028(1H,dd,J＝2.4Hz,CH),7.832-7.838(1H,d,J＝2.4Hz,CH),7.550-7.589(2H,t,J＝8Hz,CH),7.398-7.435(1H,t,J＝7.2Hz,CH),7.220-7.239(2H,d,J＝7.6Hz,CH),3.130(3H,s,CH 3)。 To a 50 mL three-necked flask, 10 mL of acetonitrile, 5 mL of purified water, 5 mL of concentrated sulfuric acid, and 1.5 g of Compound V-1 were added, stirred and heated, and the temperature was raised to 40 to 50 ° C overnight. The temperature was lowered to room temperature, the solvent was removed, and the mixture was filtered with suction. After suction filtration, the cake was washed with 1 mL of acetonitrile to give a white solid. Yield: 79.3%. MS (+): m / z 296.29 (M + 1); NMR data (1 H NMR, TFA-d , 400MHz): δppm 8.766-8.789 (1H, d, J = 9.2Hz, CH), 8.005-8.028 ( 1H, dd, J = 2.4 Hz, CH), 7.832-7.838 (1H, d, J = 2.4 Hz, CH), 7.550-7.589 (2H, t, J = 8 Hz, CH), 7.398-7.435 (1H, t , J = 7.2Hz, CH), 7.220-7.239 (2H, d, J = 7.6Hz, CH), 3.130 (3H, s, CH 3).
实施例25化合物d生成化合物e-1Example 25 Compound d produces compound e-1
Figure PCTCN2019078261-appb-000043
Figure PCTCN2019078261-appb-000043
向100mL三口烧瓶中，搅拌下加入乙腈30mL、化合物d 2.76g、甲苯-4-磺酰胺乙 酸丁酯(CAS：92198-71-5)2.85g、碳酸钾2.76g和碘化钠0.2g，加热回流8h。抽滤，旋去溶剂，得类白色固体4.8g，直接用于下一步。产率：91.4％。MS(+):m/z 526.61(M+1)；To a 100 mL three-necked flask, 30 mL of acetonitrile, 2.76 g of compound d, 2.85 g of toluene-4-sulfonamide acetate (CAS: 92198-71-5), 2.76 g of potassium carbonate, and 0.2 g of sodium iodide were added while stirring. Reflux for 8 h. After suction filtration, the solvent was evaporated to give 4.8 g of white solid. Yield: 91.4%. MS (+): m / z 526.61 (M + 1);
实施例26化合物e-1生成化合物I-2Example 26, compound e-1, gave compound I-2
Figure PCTCN2019078261-appb-000044
Figure PCTCN2019078261-appb-000044
向100mL三口烧瓶中，搅拌下加入甲醇48mL、化合物e-1 4.8g、二甲亚砜5mL和甲醇钠1.48g，室温搅拌过夜。旋去大半溶剂，加水15mL，用乙酸调pH＝2-3,加入二氯甲烷50mL萃取，水洗三次30mL*3,无水硫酸钠干燥。旋去溶剂，乙醇结晶，得到白色固体2.5g。产率：86.0％。MS(+):m/z 263.26(M+1)；核磁数据( 1H NMR,CDCl 3-d,400MHz):δppm 11.893(1H,s,OH),8.615(1H,s,CH)，8.362-8.382(1H,d,J＝8.0Hz,CH)，7.102-7.534(7H,m,CH)，4.476-4.496(2H,t,J＝4.0Hz,CH 2)，1.865-1.885(2H,m,CH 2)，1.463-1.483(2H,m,CH 2)，0.965-0.985(3H,t,J＝4.0Hz,CH 3)。 To a 100 mL three-necked flask, 48 mL of methanol, 4.8 g of compound e-1, 5 mL of dimethyl sulfoxide and 1.48 g of sodium methoxide were added with stirring, and the mixture was stirred at room temperature overnight. The larger half of the solvent was rotated, 15 mL of water was added, pH was adjusted to 2-3 with acetic acid, 50 mL of dichloromethane was added for extraction, washed with water three times 30 mL*3, and dried over anhydrous sodium sulfate. The solvent was evaporated, and ethanol crystallized to give a white solid (2.5 g). Yield: 86.0%. MS (+): m / z 263.26 (M + 1); NMR data (1 H NMR, CDCl 3 -d , 400MHz): δppm 11.893 (1H, s, OH), 8.615 (1H, s, CH), 8.362 -8.382 (1H, d, J = 8.0 Hz, CH), 7.102-7.534 (7H, m, CH), 4.476-4.496 (2H, t, J = 4.0 Hz, CH 2 ), 1.865-1.885 (2H, m , CH 2 ), 1.463-1.483 (2H, m, CH 2 ), 0.965-0.985 (3H, t, J = 4.0 Hz, CH 3 ).
实施例27化合物I-2生成化合物IIExample 27, Compound I-2, Compound II
Figure PCTCN2019078261-appb-000045
Figure PCTCN2019078261-appb-000045
向100mL三口烧瓶中，加入水20mL和氢氧化钠1.2g，搅拌溶清，再加入甲醇30mL和化合物I-2 3.37g，不全溶。加热回流8h，再降到0～10℃，加入1N盐酸调pH＝2～3，搅拌0.5h。抽滤，滤饼用水洗10mL和甲醇10mL淋洗，真空干燥，得白色固体2.53g产率：90％。MS(+):m/z 282.26(M+1)；核磁数据( 1H NMR,TFA-d,400MHz):δppm 9.035(1H,s,CH),8.838-8.861(1H,d,J＝9.2Hz,CH),8.153-8.182(1H,dd,J＝2.4Hz,CH),7.729-7.734(1H,d,J＝2.0Hz,CH),7.601-7.640(2H,t,J＝8Hz,CH),7.459-7.495(1H,t,J＝7.2Hz,CH),7.269-7.289(2H,t,J＝8Hz,CH)。 To a 100 mL three-necked flask, 20 mL of water and 1.2 g of sodium hydroxide were added, and the mixture was stirred and dissolved, and then 30 mL of methanol and 3.37 g of Compound I-2 were added, and the solution was not completely dissolved. Heated to reflux for 8 h, then lowered to 0 ~ 10 ° C, added 1N hydrochloric acid to adjust pH = 2 ~ 3, stirred for 0.5 h. After suction filtration, the filter cake was washed with water (10 mL) and methanol (10 mL) and dried in vacuo to give white crystals. MS (+): m / z 282.26 (M + 1); NMR data (1 H NMR, TFA-d , 400MHz): δppm 9.035 (1H, s, CH), 8.838-8.861 (1H, d, J = 9.2 Hz, CH), 8.153-8.182 (1H, dd, J = 2.4 Hz, CH), 7.729-7.734 (1H, d, J = 2.0 Hz, CH), 7.601-7.640 (2H, t, J = 8 Hz, CH ), 7.459-7.495 (1H, t, J = 7.2 Hz, CH), 7.269-7.289 (2H, t, J = 8 Hz, CH).
实施例28化合物I-2生成化合物I-3Example 28 Compound I-2 produces compound I-3
Figure PCTCN2019078261-appb-000046
Figure PCTCN2019078261-appb-000046
向100mL三口烧瓶中，加入50mL二氯甲烷，再加入化合物I-2 3.37g，搅拌溶清。To a 100 mL three-necked flask, 50 mL of dichloromethane was added, and 3.37 g of Compound I-2 was further added thereto, and the mixture was stirred and dissolved.
再降到0～10℃，滴加溴素1.6g，室温搅拌过夜。用饱和亚硫酸氢钠20mL*2洗，水洗20mL，无水硫酸钠干燥，旋干，得类白色固体3.83g产率：92.2％。MS(+):m/z 417.27(M+1)；核磁数据( 1H NMR,CDCl 3-d,400MHz):δppm 11.902(1H,s,OH),8.357-8.377(1H,d,J＝8.0Hz,CH)，7.632-7.082(7H,m,CH)，4.471-4.491(2H,t,J＝4.0Hz,CH 2)，1.845-1.865(2H,m,CH 2)，1.456-1.476(2H,m,CH 2)，0.925-0.945(3H,t,J＝4.0Hz,CH 3)。 After further dropping to 0 to 10 ° C, 1.6 g of bromine was added dropwise, and the mixture was stirred at room temperature overnight. It was washed with saturated sodium hydrogen sulfite 20 mL*2, washed with water (20 mL), dried over anhydrous sodium sulfate and evaporated to give white crystals. MS (+): m/z 417.27 (M + 1); NMR ( 1 H NMR, CDCl 3 -d, 400 MHz): δ ppm 11.902 (1H, s, OH), 8.357-8.377 (1H, d, J = 8.0 Hz, CH), 7.632-7.082 (7H, m, CH), 4.471-4.491 (2H, t, J = 4.0 Hz, CH 2 ), 1.845-1.865 (2H, m, CH 2 ), 1.456-1.476 ( 2H, m, CH 2 ), 0.925-0.945 (3H, t, J = 4.0 Hz, CH 3 ).
实施例29化合物I-3生成化合物I-4Example 29, Compound 1-3, gave Compound I-4
Figure PCTCN2019078261-appb-000047
Figure PCTCN2019078261-appb-000047
向100mL三口烧瓶中，加入DMF 40mL、碳酸钾2.76g、甲基硼酸1.20g和化合物I-3 4.16g，最后加入四三苯基膦钯0.08g。氮气置换三次，搅拌加热，温度升至120～130℃，过夜。降到室温，旋去大部分溶剂，加入二氯甲烷100mL萃取，1N HCl洗50mL*2，水洗50mL*3，旋干，得类白色固体2.8g，产率：79.8％。MS(+):m/z 352.40(M+1)；核磁数据( 1H NMR,DMSO-d 6,400MHz):δppm 12.105(1H,s,OH),8.257-8.277(1H,d,J＝8.0Hz,CH)，7.412-7.183(7H,m,CH)，4.234-4.254(2H,t,J＝4.0Hz,CH 2)，3.155(3H,s,CH 3)，1.805-1.825(2H,m,CH 2)，1.456-1.476(2H,m,CH 2)，0.915-0.935(3H,t,J＝4.0Hz,CH 3)。 To a 100 mL three-necked flask, 40 mL of DMF, 2.76 g of potassium carbonate, 1.20 g of methylboronic acid, and 4.16 g of Compound I-3 were added, and finally, 0.08 g of tetrakistriphenylphosphine palladium was added. The mixture was replaced with nitrogen three times, stirred and heated, and the temperature was raised to 120 to 130 ° C overnight. After dropping to room temperature, most of the solvent was removed, and 100 mL of dichloromethane was added for extraction, 1 mL of HCl was washed 50 mL*2, washed with water (50 mL*3), and dried to give 2.8 g of white solid, yield: 79.8%. MS (+): m / z 352.40 (M + 1); NMR data (1 H NMR, DMSO-d 6, 400MHz): δppm 12.105 (1H, s, OH), 8.257-8.277 (1H, d, J = 8.0 Hz, CH), 7.412-7.183 (7H, m, CH), 4.234-4.254 (2H, t, J = 4.0 Hz, CH 2 ), 3.155 (3H, s, CH 3 ), 1.805-1.825 (2H, m, CH 2 ), 1.456-1.476 (2H, m, CH 2 ), 0.915-0.935 (3H, t, J = 4.0 Hz, CH 3 ).
实施例30化合物I-4生成化合物VIExample 30, Compound I-4, Compound VI
Figure PCTCN2019078261-appb-000048
Figure PCTCN2019078261-appb-000048
向100mL三口烧瓶中，加入水20mL和氢氧化钠1.2g，搅拌溶清，再加入甲醇30mL和化合物I-4 3.51g，不全溶。加热回流8h，再降到0～10℃，加入1N盐酸调pH＝2～3，搅拌0.5h。抽滤，滤饼用水洗10mL和甲醇10mL淋洗，真空干燥，得白色固体2.66g产率：90.2％。MS(+):m/z 296.29(M+1)；核磁数据( 1H NMR,TFA-d,400MHz):δppm 8.766-8.789(1H,d,J＝9.2Hz,CH),8.005-8.028(1H,dd,J＝2.4Hz,CH),7.832-7.838(1H,d,J＝2.4Hz,CH),7.550-7.589(2H,t,J＝8Hz,CH),7.398-7.435(1H,t,J＝7.2Hz,CH),7.220-7.239(2H,d,J＝7.6Hz,CH),3.130(3H,s,CH 3)。 To a 100 mL three-necked flask, 20 mL of water and 1.2 g of sodium hydroxide were added, and the mixture was stirred and dissolved, and then 30 mL of methanol and 3.51 g of Compound I-4 were added, which was not completely dissolved. Heated to reflux for 8 h, then lowered to 0 ~ 10 ° C, added 1N hydrochloric acid to adjust pH = 2 ~ 3, stirred for 0.5 h. After suction filtration, the filter cake was washed with water (10 mL) and methanol (10 mL) and dried in vacuo to give white solid. MS (+): m / z 296.29 (M + 1); NMR data (1 H NMR, TFA-d , 400MHz): δppm 8.766-8.789 (1H, d, J = 9.2Hz, CH), 8.005-8.028 ( 1H, dd, J = 2.4 Hz, CH), 7.832-7.838 (1H, d, J = 2.4 Hz, CH), 7.550-7.589 (2H, t, J = 8 Hz, CH), 7.398-7.435 (1H, t , J = 7.2Hz, CH), 7.220-7.239 (2H, d, J = 7.6Hz, CH), 3.130 (3H, s, CH 3).
实施例31化合物VI生成化合物VIIExample 31 Compound VI produces compound VII
Figure PCTCN2019078261-appb-000049
Figure PCTCN2019078261-appb-000049
向50mL三口烧瓶中，加入二氯甲烷30mL、化合物VI 2.95g、HATU 4.56g、氨基乙腈盐酸盐1.1g和N，N-二异丙基乙胺5.0g，搅拌，溶清，室温过夜。反应液中加入水20mL，分层，有机层用1N盐酸洗2×20mL，饱和碳酸氢钠洗2×20mL，纯净水洗20mL，旋干，得淡黄色固体2.8g。产率：84.0％。MS(+):m/z 334.34(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 12.234(1H,s,OH),8.450(1H,s,NH),8.363-8.387(1H,d,J＝7.6Hz,CH),7.435-7.489(4H,q,CH),7.236-7.273(1H,t,J＝7.2Hz,CH),7.126-7.150(2H,q,CH),4.438-4.454(2H,d,J＝6.4Hz,CH 2),2.701(3H,s,CH 3)。 To a 50 mL three-necked flask, 30 mL of dichloromethane, 2.95 g of compound VI, 4.56 g of HATU, 1.1 g of aminoacetonitrile hydrochloride and 5.0 g of N,N-diisopropylethylamine were added, stirred, and dissolved at room temperature overnight. 20 mL of water was added to the reaction mixture, and the layers were separated. The organic layer was washed 2×20 mL with 1N hydrochloric acid, 2×20 mL of saturated sodium hydrogencarbonate, 20 mL of purified water, and dried to give 2.8 g of pale yellow solid. Yield: 84.0%. MS (+): m / z 334.34 (M + 1); NMR data (1 H NMR, CDCl 3, 400MHz): δppm 12.234 (1H, s, OH), 8.450 (1H, s, NH), 8.363-8.387 (1H, d, J = 7.6 Hz, CH), 7.435-7.489 (4H, q, CH), 7.236-7.273 (1H, t, J = 7.2 Hz, CH), 7.126-7.150 (2H, q, CH) , 4.438-4.454 (2H, d, J = 6.4 Hz, CH 2 ), 2.701 (3H, s, CH 3 ).
实施例32化合物VI生成化合物VIIExample 32, Compound VI, Compound VII
Figure PCTCN2019078261-appb-000050
Figure PCTCN2019078261-appb-000050
向50mL三口烧瓶中，加入二氯甲烷30mL、化合物VI 2.95g、HBTU 4.54g、氨基乙腈盐酸盐1.1g和N，N-二异丙基乙胺5.0g，搅拌，溶清，室温过夜。反应液中加入水20mL，分层，有机层用1N盐酸洗2×20mL，饱和碳酸氢钠洗2×20mL，纯净水洗20mL，旋干，得淡黄色固体2.7g。产率：81.0％。MS(+):m/z 334.34(M+1)；核磁数据( 1H NMR,CDCl 3,400MHz):δppm 12.234(1H,s,OH),8.450(1H,s,NH),8.363-8.387(1H,d,J＝7.6Hz,CH),7.435-7.489(4H,q,CH),7.236-7.273(1H,t,J＝7.2Hz,CH),7.126-7.150(2H,q,CH),4.438-4.454(2H,d,J＝6.4Hz,CH 2),2.701(3H,s,CH 3)。 To a 50 mL three-necked flask, 30 mL of dichloromethane, 2.95 g of compound VI, 4.54 g of HBTU, 1.1 g of aminoacetonitrile hydrochloride and 5.0 g of N,N-diisopropylethylamine were added, stirred, and dissolved at room temperature overnight. 20 mL of water was added to the reaction mixture, and the layers were separated. The organic layer was washed 2×20 mL with 1N hydrochloric acid, 2×20 mL of saturated sodium hydrogencarbonate, 20 mL of purified water, and dried to give 2.7 g of pale yellow solid. Yield: 81.0%. MS (+): m / z 334.34 (M + 1); NMR data (1 H NMR, CDCl 3, 400MHz): δppm 12.234 (1H, s, OH), 8.450 (1H, s, NH), 8.363-8.387 (1H, d, J = 7.6 Hz, CH), 7.435-7.489 (4H, q, CH), 7.236-7.273 (1H, t, J = 7.2 Hz, CH), 7.126-7.150 (2H, q, CH) , 4.438-4.454 (2H, d, J = 6.4 Hz, CH 2 ), 2.701 (3H, s, CH 3 ).

Claims (12)

  1. 一种诺得司他的制备方法，其特征在于，所述方法包括如下步骤：A method for preparing nodstatstat, characterized in that the method comprises the following steps:
    (4)化合物IV与甲基化试剂发生甲基化反应生成化合物V；(4) Compound IV is methylated with a methylating reagent to form a compound V;
    Figure PCTCN2019078261-appb-100001
    Figure PCTCN2019078261-appb-100001
    (5)化合物V发生水解反应，生成化合物VI；(5) Compound V undergoes a hydrolysis reaction to form compound VI;
    Figure PCTCN2019078261-appb-100002
    Figure PCTCN2019078261-appb-100002
    (6)化合物VI与氨基乙腈或氨基乙腈的盐，发生缩合反应，生成化合物VII；(6) a compound VI with a salt of aminoacetonitrile or aminoacetonitrile, a condensation reaction to form a compound VII;
    Figure PCTCN2019078261-appb-100003
    Figure PCTCN2019078261-appb-100003
    其中，among them,
    Y为-NR 2R 3或-OCH 2CH 2CH 2CH 3，R 2和R 3各自独立地选自H、叔丁基、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、苯基和苄基； Y is -NR 2 R 3 or -OCH 2 CH 2 CH 2 CH 3 , and R 2 and R 3 are each independently selected from H, t-butyl, methyl, ethyl, n-propyl, isopropyl, cyclopropane Base, n-butyl, isobutyl, phenyl and benzyl;
    氨基乙腈的盐选自氨基乙腈与有机酸或无机酸成的盐；a salt of aminoacetonitrile selected from the group consisting of aminoacetonitrile and an organic or inorganic acid;
    X为卤素。X is a halogen.
  2. 如权利要求1所述的制备方法，其特征在于，在步骤(6)之后还包括如下步骤：The preparation method according to claim 1, further comprising the following steps after the step (6):
    (7)化合物VII发生水解反应，生成化合物VIII；(7) Compound VII undergoes a hydrolysis reaction to form compound VIII;
    Figure PCTCN2019078261-appb-100004
    Figure PCTCN2019078261-appb-100004
  3. 如权利要求1或2所述的制备方法，其特征在于，在步骤(4)之前还包括如下步骤：The preparation method according to claim 1 or 2, further comprising the following steps before the step (4):
    (3)化合物III与卤化试剂发生卤化反应，生成化合物IV；(3) Compound III is halogenated with a halogenating reagent to form compound IV;
    Figure PCTCN2019078261-appb-100005
    Figure PCTCN2019078261-appb-100005
    其中，Y的定义如权利要求1或2所述。Wherein Y is as defined in claim 1 or 2.
  4. 如权利要求3所述的制备方法，其特征在于，在步骤(3)之前还包括如下步骤：The preparation method according to claim 3, further comprising the following steps before the step (3):
    (2)当Y为-NR 2R 3时，化合物II与胺HNR 2R 3发生缩合反应，生成化合物III，R 2和R 3的定义如权利要求3所述； (2) when Y is -NR 2 R 3 , the compound II is condensed with the amine HNR 2 R 3 to form a compound III, and R 2 and R 3 are as defined in claim 3;
    Figure PCTCN2019078261-appb-100006
    Figure PCTCN2019078261-appb-100006
    当Y为-OCH 2CH 2CH 2CH 3时，化合物d与甲苯-4-磺酰胺乙酸丁酯在碱和有机溶剂存在下发生取代反应，得到化合物e-1；化合物e-1在碱存在下发生关环反应，得到化合物III； When Y is -OCH 2 CH 2 CH 2 CH 3 , compound d is substituted with toluene-4-sulfonamide butyl acetate in the presence of a base and an organic solvent to give compound e-1; compound e-1 is present in the base A ring-closing reaction occurs to obtain a compound III;
    Figure PCTCN2019078261-appb-100007
    Figure PCTCN2019078261-appb-100007
    优选地，所述取代反应中，所述碱选自氢氧化锂、氢氧化钠和氢氧化钾、碳酸钠、碳酸钾和碳酸铯中的一种或几种，更优选为碳酸钾；所述有机溶剂选自四氢呋喃、2-甲基四氢呋喃、二氯甲烷、乙酸乙酯、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮、乙腈和丙酮中的一种或几种，更优选为乙腈；Preferably, in the substitution reaction, the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, more preferably potassium carbonate; The organic solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetonitrile and acetone. One or more, more preferably acetonitrile;
    优选地，所述关环反应中，所述碱选自氢氧化锂、氢氧化钠和氢氧化钾、碳酸钠、碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、甲醇钠和乙醇钠中的一种或几种， 更优选为甲醇钠。Preferably, in the ring closure reaction, the base is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium methoxide and ethanol. One or more of sodium, more preferably sodium methoxide.
  5. 如权利要求1所述的制备方法，其特征在于，R 2和R 3各自独立地选自H或叔丁基； The process according to claim 1, wherein R 2 and R 3 are each independently selected from H or a t-butyl group;
    氨基乙腈的盐选自氨基乙腈盐酸盐、氨基乙腈氢溴酸盐、氨基乙腈磷酸盐、氨基乙腈硝酸盐、氨基乙腈硫酸盐和氨基乙腈乙酸盐中的一种或几种；The salt of aminoacetonitrile is selected from one or more of aminoacetonitrile hydrochloride, aminoacetonitrile hydrobromide, aminoacetonitrile phosphate, aminoacetonitrile nitrate, aminoacetonitrile sulfate and aminoacetonitrile acetate;
    X为氯、溴或碘。X is chlorine, bromine or iodine.
  6. 如权利要求1所述的制备方法，其特征在于，The preparation method according to claim 1, wherein
    优选地，所述的步骤(4)中，Preferably, in the step (4),
    所述甲基化反应是在有机溶剂、催化剂和无机碱的水溶液的存在下进行，化合物IV与甲基化试剂发生甲基化反应生成化合物V；The methylation reaction is carried out in the presence of an organic solvent, a catalyst and an aqueous solution of an inorganic base, and the compound IV is methylated with a methylating reagent to form a compound V;
    所述甲基化试剂选自三甲基硼、四甲基锡、甲基硼酸和甲基硼酸异丙酯；The methylating agent is selected from the group consisting of trimethylboron, tetramethyltin, methylboronic acid and isopropyl methacrylate;
    所述的有机溶剂选自N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮、甲苯、四氢呋喃、乙二醇二甲醚、乙二醇甲醚、乙二醇二***、乙二醇***和乙二醇的中一种或几种；The organic solvent is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol methyl ether, and B. One or more of diol diethyl ether, ethylene glycol ether and ethylene glycol;
    所述的无机碱的水溶液选自NaOH、KOH、LiOH、Na 2CO 3、K 2CO 3、Na 3PO 4和K 3PO 4中的一种或几种的水溶液； The aqueous solution of the inorganic base is selected from the group consisting of an aqueous solution of one or more of NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Na 3 PO 4 and K 3 PO 4 ;
    所述的催化剂为钯类催化剂；The catalyst is a palladium catalyst;
    优选地，所述的步骤(5)中，Preferably, in the step (5),
    所述的水解反应在酸性条件下进行，酸选自盐酸、硫酸、三氟乙酸、甲磺酸和三氟甲磺酸中的一种或几种；The hydrolysis reaction is carried out under acidic conditions, and the acid is selected from one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid;
    优选地，所述的步骤(6)中，Preferably, in the step (6),
    所述的缩合试剂选自N,N'-二环己基碳二亚胺、N,N'-二异丙基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、2-(7-氮杂-1H-苯并三氮唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐和六氟磷酸苯并***-1-基-氧基三吡咯烷基磷中的一种或几种。The condensation reagent is selected from the group consisting of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbon Acyl diimide hydrochloride, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazine One or more of azole-N,N,N',N'-tetramethyluronium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate.
  7. 一种诺得司他的制备方法，其特征在于，所述方法包括以下步骤：A method for preparing nodstatstat, characterized in that the method comprises the following steps:
    (1)化合物I发生水解反应，生成化合物II；(1) Compound I undergoes a hydrolysis reaction to form compound II;
    Figure PCTCN2019078261-appb-100008
    Figure PCTCN2019078261-appb-100008
    (2)化合物II与胺HNR 2R 3发生缩合反应，生成化合物III； (2) a compound II is condensed with an amine HNR 2 R 3 to form a compound III;
    Figure PCTCN2019078261-appb-100009
    Figure PCTCN2019078261-appb-100009
    (3)化合物III与卤化试剂发生卤化反应，生成化合物IV；(3) Compound III is halogenated with a halogenating reagent to form compound IV;
    Figure PCTCN2019078261-appb-100010
    Figure PCTCN2019078261-appb-100010
    (4)化合物IV与甲基化试剂发生甲基化反应生成化合物V；(4) Compound IV is methylated with a methylating reagent to form a compound V;
    Figure PCTCN2019078261-appb-100011
    Figure PCTCN2019078261-appb-100011
    (5)化合物V发生水解反应，生成化合物VI；(5) Compound V undergoes a hydrolysis reaction to form compound VI;
    Figure PCTCN2019078261-appb-100012
    Figure PCTCN2019078261-appb-100012
    (6)化合物VI与氨基乙腈或氨基乙腈的盐，发生缩合反应，生成化合物VII；(6) a compound VI with a salt of aminoacetonitrile or aminoacetonitrile, a condensation reaction to form a compound VII;
    Figure PCTCN2019078261-appb-100013
    Figure PCTCN2019078261-appb-100013
    (7)化合物VII发生水解反应，生成化合物VIII；(7) Compound VII undergoes a hydrolysis reaction to form compound VIII;
    Figure PCTCN2019078261-appb-100014
    Figure PCTCN2019078261-appb-100014
    其中，among them,
    R 1为羧基保护基，选自1～8个碳的烷基；3～8个碳的链烯基；7～19个碳的芳烷基；6～12个碳的芳基； R 1 is a carboxy protecting group, an alkyl group selected from 1 to 8 carbons; an alkenyl group of 3 to 8 carbons; an aralkyl group of 7 to 19 carbons; an aryl group of 6 to 12 carbons;
    R 2和R 3各自独立地选自H、叔丁基、甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、苯基和苄基； R 2 and R 3 are each independently selected from the group consisting of H, tert-butyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, phenyl and benzyl. base;
    氨基乙腈的盐选自氨基乙腈与有机酸或无机酸成的盐，所述盐选自盐酸盐、氢溴酸盐、磷酸盐、硝酸盐、硫酸盐和乙酸盐中的一种或几种；The salt of aminoacetonitrile is selected from the group consisting of aminoacetonitrile and an organic or inorganic acid salt selected from one or more of the hydrochloride, hydrobromide, phosphate, nitrate, sulfate and acetate salts. Species
    X为卤素；X is a halogen;
    优选地，R 1为甲基、甲氧甲基、乙基、乙氧乙基、碘乙基、丙基、异丙基、正丁基、异丁基、乙氧乙基、甲硫乙基、甲磺酰乙基、三氯乙基、叔丁基；丙烯基、烯基、异丙烯基、己烯基、苯丙烯基、二甲基己烯基；苄基、甲基苄基、二甲基苄基、甲氧基苄基、乙氧基苄基、硝基苄基、氨基苄基、二苯甲基、苯乙基、三苯甲基、二叔丁基羟基苄基、2-苯并[c]呋喃酮基、苯甲酰甲基；苯基、甲苯基、二异丙基苯基、二甲苯基、三氯苯基、五氯苯基、2，3-二氢茚基；优选为甲基、乙基、丙基、异丙基、正丁基、异丁基或叔丁基； Preferably, R 1 is methyl, methoxymethyl, ethyl, ethoxyethyl, iodoethyl, propyl, isopropyl, n-butyl, isobutyl, ethoxyethyl, methylthioethyl , methanesulfonylethyl, trichloroethyl, tert-butyl; propenyl, alkenyl, isopropenyl, hexenyl, phenylpropenyl, dimethylhexenyl; benzyl, methylbenzyl, Methylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl, phenethyl, trityl, di-tert-butylhydroxybenzyl, 2- Benzo[c]furanone, benzoylmethyl; phenyl, tolyl, diisopropylphenyl, xylyl, trichlorophenyl, pentachlorophenyl, 2,3-dihydroindenyl ; preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
    R 2和R 3各自独立地选自H或叔丁基； R 2 and R 3 are each independently selected from H or tert-butyl;
    X为氯、溴或碘。X is chlorine, bromine or iodine.
  8. 如权利要求7所述的制备方法，其特征在于，The preparation method according to claim 7, wherein
    优选地，所述的步骤(3)中，Preferably, in the step (3),
    所述的卤化试剂选自1,3-二氯-5,5-二甲基海因、1,3-二溴-5,5-二甲基海因、1,3-二碘-5,5-二甲基海因、N-氯代丁二酰亚胺、N-溴代丁二酰亚胺、N-碘代丁二酰亚胺、溴素和单质碘中的一种或几种的组合；The halogenating agent is selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-diiodo-5. One or more of 5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine and elemental iodine The combination;
    优选地，所述的步骤(7)中，所述的水解反应在碱性条件下进行，碱选自氢氧化锂、氢氧化钠和氢氧化钾中的一种或几种。Preferably, in the step (7), the hydrolysis reaction is carried out under alkaline conditions, and the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.
  9. 一种化合物，所述的化合物为化合物III-1所示的结构，a compound which is a structure represented by the compound III-1,
    Figure PCTCN2019078261-appb-100015
    Figure PCTCN2019078261-appb-100015
  10. 权利要求9所述化合物III-1的制备方法，其特征在于，包括如下步骤：The method for preparing a compound III-1 according to claim 9, comprising the steps of:
    Figure PCTCN2019078261-appb-100016
    Figure PCTCN2019078261-appb-100016
    a)化合物a与苯酚在碱存在下发生醚化反应，得到化合物b；a) Compound a and phenol are etherified in the presence of a base to give compound b;
    b)化合物b在碱存在下发生水解反应，得到化合物c；b) compound b is hydrolyzed in the presence of a base to give compound c;
    c)化合物c与含氯酸发生取代反应，然后再加入醇，发生酯化反应，得到化合物d；所述含氯酸选自氯化亚砜、草酰氯、三氯化磷、五氯化磷和三氯氧磷中的一种或几种，优选为氯化亚砜；c) Compound c is substituted with chloric acid, and then an alcohol is added to effect esterification to obtain compound d; the chloric acid is selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus trichloride, and phosphorus pentachloride And one or more of phosphorus oxychloride, preferably thionyl chloride;
    d)化合物d与N-氰甲基-4-甲基苯磺酰胺在碱和有机溶剂存在下发生取代反应，得到化合物e；d) Compound d and N-cyanomethyl-4-methylbenzenesulfonamide are substituted in the presence of a base and an organic solvent to obtain a compound e;
    e)化合物e在碱存在下发生关环反应，得到化合物f；e) Compound e is subjected to a ring closure reaction in the presence of a base to give compound f;
    f)化合物f与叔丁醇或异丁烯在酸存在下发生Ritter反应，得到化合物III-1。f) Ritter reaction of compound f with t-butanol or isobutylene in the presence of an acid to give compound III-1.
  11. 如权利要求10所述的制备方法，其特征在于：The preparation method according to claim 10, wherein:
    优选地，步骤a)中，Preferably, in step a),
    所述碱选自氢氧化锂、氢氧化钠、氢氧化钾、磷酸钠和磷酸钾中的一种或几种，优选为磷酸钾；The base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium phosphate and potassium phosphate, preferably potassium phosphate;
    所述的醚化反应在钯催化剂存在下进行，所述钯催化剂选自二(三苯基膦)氯化钯、乙酸钯、三苯基膦醋酸钯、四(三苯基膦)钯、乙酰丙酮钯、双(苄腈)二氯化钯、三(苄亚基丙酮)二钯、(1,3-双(二苯基膦)丙烷)氯化钯、[1,1′-双(二苯基膦)二茂铁]二氯化钯和[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物的一种或几种，优选为乙酸钯；The etherification reaction is carried out in the presence of a palladium catalyst selected from the group consisting of bis(triphenylphosphine)palladium chloride, palladium acetate, palladium triphenylphosphine acetate, tetrakis(triphenylphosphine)palladium, acetyl Acetone palladium, bis(benzonitrile)palladium dichloride, tris(benzylideneacetone)dipalladium, (1,3-bis(diphenylphosphino)propane)palladium chloride, [1,1'-double (two One or more of phenylphosphine)ferrocene]palladium dichloride and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, preferably acetic acid palladium;
    优选地，步骤b)中，Preferably, in step b),
    所述碱选自氢氧化锂、氢氧化钠和氢氧化钾中的一种或几种，优选为氢氧化钠；The base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide;
    优选地，步骤d)中，Preferably, in step d),
    所述碱选自氢氧化锂、氢氧化钠和氢氧化钾、碳酸钠、碳酸钾和碳酸铯中的一种或几种，优选为碳酸钾；The base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, preferably potassium carbonate;
    所述有机溶剂选自四氢呋喃、2-甲基四氢呋喃、二氯甲烷、乙酸乙酯、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮、乙腈和丙酮中的一种或几种，优选为乙腈；The organic solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetonitrile and acetone. One or more of them, preferably acetonitrile;
    优选地，步骤e)中，Preferably, in step e),
    所述碱选自氢氧化锂、氢氧化钠和氢氧化钾、碳酸钠、碳酸钾、碳酸铯、叔丁醇钠、叔丁醇钾、甲醇钠和乙醇钠中的一种或几种，优选为甲醇钠；The base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium methoxide and sodium ethoxide, preferably Is sodium methoxide;
    所述的关环反应在有机溶剂中进行，有机溶剂选自四氢呋喃、2-甲基四氢呋喃、二氯甲烷、乙酸乙酯、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基-2-吡咯烷酮、乙腈和丙酮中的一种或几种，优选为乙腈；The ring-closing reaction is carried out in an organic solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N- One or more of methyl-2-pyrrolidone, acetonitrile and acetone, preferably acetonitrile;
    优选地，步骤f)中，Preferably, in step f),
    所述酸选自盐酸、硫酸和磷酸、氢溴酸、甲磺酸、乙酸、三氟乙酸、苯磺酸、三氟甲磺酸和对甲苯磺酸中的一种或几种，优选为硫酸。The acid is selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid, hydrobromic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, preferably sulfuric acid. .
  12. 一种化合物，所述的化合物为化合物VII所示的结构，a compound which is a structure represented by the compound VII,
    Figure PCTCN2019078261-appb-100017
    Figure PCTCN2019078261-appb-100017
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