WO2018068733A1 - 尼达尼布及其中间体的制备方法 - Google Patents

尼达尼布及其中间体的制备方法 Download PDF

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WO2018068733A1
WO2018068733A1 PCT/CN2017/105723 CN2017105723W WO2018068733A1 WO 2018068733 A1 WO2018068733 A1 WO 2018068733A1 CN 2017105723 W CN2017105723 W CN 2017105723W WO 2018068733 A1 WO2018068733 A1 WO 2018068733A1
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compound
reaction
solvent
group
alkyl group
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PCT/CN2017/105723
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English (en)
French (fr)
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栗增
程小松
何先亮
张继承
黄鲁宁
陶安平
顾虹
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浙江华海药业股份有限公司
上海科胜药物研发有限公司
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Priority claimed from CN201610890758.6A external-priority patent/CN107935908A/zh
Priority claimed from CN201610891645.8A external-priority patent/CN107935909B/zh
Application filed by 浙江华海药业股份有限公司, 上海科胜药物研发有限公司 filed Critical 浙江华海药业股份有限公司
Priority to US16/339,339 priority Critical patent/US10836751B2/en
Priority to CN201780044516.8A priority patent/CN109803954B/zh
Publication of WO2018068733A1 publication Critical patent/WO2018068733A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/61—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • the invention belongs to the technical field of preparation of organic synthesis and drug substance intermediates, in particular to a preparation method of the drug nidanib for treating idiopathic pulmonary fibrosis, a key intermediate thereof and a key intermediate thereof. Preparation.
  • Nintedanib is a new oral drug developed by Boehringer Ingelheim for the treatment of idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fatal lung disease that is severely harmful to humans. The median survival of patients after diagnosis is only 2 to 3 years. Nidanib can block both vascular endothelial growth factor receptor, platelet-derived growth factor receptor and fibroblast growth factor receptor. Blocking of these receptors leads to inhibition of angiogenesis. Nidanibu is the first and only tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis.
  • Nidanibu Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino) a methyl 1-phenyl-methylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate having the formula:
  • the preparation method of nidanib has been reported, and the synthesis method of nidanib and its analogs is given by the original compound patent WO2001027081 and the preparation patents WO2009071523 and WO2009071524.
  • the main synthetic method is obtained by condensation of two key intermediates A and B in the following scheme. Among them, the intermediate A synthesis route is long, the preparation yield of the compound 1-3 is low, the compound 1-4 ring-closing reaction requires high temperature and high pressure hydrogenation, and the preparation of the compound A requires high temperature. The route is costly and complicated to operate.
  • Nidanib is currently a viable preparation route with high cost, so the synthetic route with simple development process, mild conditions and high yield can greatly improve its preparation efficiency, reduce cost, reduce pollution and improve society. And economic benefits.
  • the present invention relates to a novel preparation method of Nindedanib (I), and a key intermediate thereof involved in the method, namely 4-(1-methoxy-1,3-dioxo-3-phenylpropane) Methyl-2-yl)-3-nitrobenzoate (formula IV) and methyl 3-benzoyl-2-oxoindoline-6-carboxylate (formula V), and above key intermediates thereof
  • the preparation method is to solve the problems existing in the prior art.
  • the preparation method of the nidanib of the present invention is as follows:
  • the preparation method of the nidanib includes the following steps:
  • Step 1 Compound II, 4-chloro-3-nitro-benzoic acid methyl ester, is reacted with compound III, 3-oxo-3-phenylpropionate, under the action of a base to form compound IV. , that is, methyl 4-(1-alkoxy-1,3-dioxo-3-phenylpropan-2-yl)-3-nitrobenzoate;
  • X is a halogen, preferably chlorine or bromine; and in the compounds III and IV, R 1 is an alkyl group or a substituted alkyl group, preferably a C1-C6 alkyl group or a C7-C12 aromatic alkyl group, Preferred is methyl or ethyl;
  • the base is NaH, sodium methoxide, potassium t-butoxide, lithium t-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate;
  • the solvent for the reaction is N,N-dimethyl Formamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, 1,2-dichloroethane or acetonitrile;
  • the temperature of the reaction in step 1 is 50-120 ° C, Preferably 60-90 ° C;
  • Step 2 The above compound IV is subjected to a reduction-cyclization reaction in a suitable reducing reagent and a solvent to form a compound V, that is, methyl 3-benzoyl-2-oxoindoline-6-carboxylate;
  • the reducing agent is preferably hydrogen, palladium carbon, platinum carbon, palladium hydroxide carbon, Raney nickel, iron powder, zinc powder, tin powder, aluminum powder, hydrazine hydrate, insurance powder, stannous chloride, sodium sulfide Or formic acid-triethylamine;
  • the solvent is preferably methanol, ethanol, ethyl acetate, acetic acid or N,N-dimethylformamide;
  • the temperature of the reaction is 50-120 ° C, preferably 70-100 ° C;
  • Step 3 The action of the above compound V and the starting compound VI, N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide, in acid In the solvent, the reaction produces Compound I, ie, nidanib;
  • the acid is preferably formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid;
  • the solvent is preferably toluene, xylene, N,N-dimethylformamide, N,N- Dimethylacetamide, N-methylpyrrolidone or 1,4-dioxane;
  • the temperature of the reaction in step 3 is from 60 to 120 ° C, preferably from 80 to 110 ° C.
  • the preparation method of the nidanib includes the following steps:
  • Step 1 Compound II, 4-chloro-3-nitro-benzoic acid methyl ester, is reacted with compound III, 3-oxo-3-phenylpropionate, under the action of a base to form compound IV. , that is, methyl 4-(1-alkoxy-1,3-dioxo-3-phenylpropan-2-yl)-3-nitrobenzoate;
  • X is a halogen, preferably chlorine or bromine
  • R 1 is an alkyl group or a substituted alkyl group, preferably a C1-C6 alkyl group or a C7-C12 aromatic alkyl group, more preferably a methyl group or an ethyl group
  • It is sodium methoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide or potassium carbonate
  • the solvent is preferably N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1 , 4-dioxane or acetonitrile
  • the temperature of the reaction in step 1 is 50-120 ° C, preferably 60-90 ° C;
  • Step 2 The above compound IV is subjected to a reduction-cyclization reaction in a suitable reducing reagent and a solvent to form a compound V, that is, methyl 3-benzoyl-2-oxoindoline-6-carboxylate;
  • the reducing agent is preferably hydrogen, palladium carbon, platinum carbon, Raney nickel, iron powder, zinc powder, hydrazine hydrate or insurance powder (sodium dithionite);
  • the solvent is preferably methanol, ethanol, ethyl acetate or acetic acid;
  • the temperature of the reaction is 20-120 ° C, preferably 20-80 ° C;
  • Step 3 The above compound V is reacted in a halogenating reagent, a base or a catalyst and a suitable solvent to form an intermediate compound VII, namely (Z/E)-(3-halo-3-phenylmethylene)-2. - oxohydroindoline-6-formic acid methyl ester;
  • X is a halogen
  • X is preferably chlorine or bromine
  • the halogenating agent is preferably phosphorus oxychloride, phosphorus tribromide or phosphorus pentachloride
  • the base is preferably triethylamine, diisopropylethylamine, DBU Second Methylaminopyridine or N,N-dimethylformamide
  • the solvent is preferably toluene, acetonitrile, dioxane or phosphorus oxychloride
  • the reaction temperature is 50-120 ° C, preferably 60-100 ° C;
  • Step 4 The above intermediate compound VII is reacted with compound VI under a base and a suitable solvent to form compound I, ie, nidanib;
  • the base is preferably triethylamine, diisopropylethylamine, sodium hydrogencarbonate, sodium carbonate or potassium carbonate;
  • the solvent is preferably methanol, ethanol, acetonitrile, N,N-dimethylformamide or , 4-dioxane; the temperature of the reaction is 20-80 ° C, preferably 50-70 ° C.
  • step A compound V is formed in a halogenating agent and a base
  • Step B without isolation, the compound VI and the base are directly added to the reaction system of the step A, and the reaction is carried out to form nidanib;
  • the halogenation reaction of the step A is carried out in the absence of a solvent or in an organic solvent selected from the group consisting of toluene, acetonitrile or dioxane, the halogenating agent being selected from phosphorus oxychloride, phosphorus pentoxide or five.
  • Phosphorus chloride preferably phosphorus oxychloride
  • the base is selected from the group consisting of triethylamine, diisopropylethylamine or DBU, preferably diisopropylethylamine.
  • the step B is carried out in one or a mixed solvent selected from the group consisting of methanol, ethanol, acetonitrile, tetrahydrofuran or dichloromethane, and the base used is selected from the group consisting of triethylamine, diisopropylethylamine, sodium hydrogencarbonate, sodium carbonate or Potassium carbonate.
  • a mixed solvent selected from the group consisting of methanol, ethanol, acetonitrile, tetrahydrofuran or dichloromethane
  • the base used is selected from the group consisting of triethylamine, diisopropylethylamine, sodium hydrogencarbonate, sodium carbonate or Potassium carbonate.
  • the present invention also provides a novel compound IV, V and compound VII having the following structural formula:
  • R1 is alkyl or substituted alkyl, preferably C1-C6 alkyl or C7-12 aromatic alkyl, more preferably methyl or ethyl;
  • X is halogen, preferably chlorine or bromine.
  • the compound IV, the compound V or the compound VII provided by the present invention is used for the preparation of a nidanib drug.
  • the use of the above new intermediate compounds shortens the reaction step and avoids the use of dangerous chemical raw materials.
  • the obtained nidanib final product has good quality and high purity, and is suitable for industrial production.
  • the present invention provides the use of Compound IV, V or VII for the preparation of a drug of nidanib.
  • nidanib (I) configuration obtained by the method of the invention has specificity, only the Z-isomer can be obtained, the E-form impurity is not contained, and the product has good purity and has the advantage of product stability.
  • the preparation method of the nidanib (I) provided by the invention has the advantages that the raw materials are easy to obtain, the process is simple, the operation steps are shortened, the operation process is simplified, the production efficiency is improved, and the steps are easy to be purified. High yield, safe and environmentally friendly, suitable for industrial production.
  • raw materials II and III can be purchased in bulk; raw material VI can be synthesized by the method of J. Med. Chem, 2009, 52, 4466-4480 or patent WO2009071523.
  • reaction liquid was evaporated to dryness to ethyl acetate (200 mL), and washed with water (100 mL, 3 times), and then, 6.6 g of anhydrous magnesium sulfate was successively added, and 6.6 g of activated carbon was decolorized.
  • the obtained solution was evaporated to dryness to give methanol/n-heptane crystals to afford 36.8 g of nidanib, yield 85.6%.
  • the reaction liquid was evaporated to dryness to ethyl acetate (200 mL), and washed with water (100 mL, 3 times), and then, 6.6 g of anhydrous magnesium sulfate was successively added, and 6.6 g of activated carbon was decolorized.
  • the obtained solution was evaporated to dryness to give methanol/n-heptane crystals to afford 37.1 g of nidanib, yield 86.1%.
  • reaction mixture was evaporated to dryness to ethyl acetate (200 mL), and washed with water (100 mL) 3 times, then 6.6 g of anhydrous magnesium sulfate, and 6.6 g of activated carbon were decolorized.
  • the obtained solution was evaporated to dryness to give methanol/n-heptane crystals to afford 35.9 g of nidanib, and the yield was 83.5%.
  • reaction mixture was evaporated to dryness to ethyl acetate (200 mL), and washed with water (100 mL) 3 times, then 6.6 g of anhydrous magnesium sulfate, and 6.6 g of activated carbon were decolorized.
  • the obtained solution was evaporated to dryness to give methanol/n-heptane crystals to afford 34.5 g of nidanib, yield 80.2%.
  • reaction mixture was evaporated to dryness to ethyl acetate (200 mL), and washed with water (100 mL) 3 times, then 6.6 g of anhydrous magnesium sulfate, and 6.6 g of activated carbon were decolorized.
  • the obtained solution was evaporated to dryness to give methanol/n-heptane crystals to afford 22.2 g of nidanib, yield 81.9%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

本发明提供了一种尼达尼布的制备方法。本发明的方法以4-卤代-3-硝基-苯甲酸甲酯(化合物II)和3-氧代-3-苯基丙酸酯(化合物III)为原料，经由中间体4-(1-烷氧基-1,3-二氧代-3-苯丙烷-2-基)-3-硝基苯甲酸甲酯(化合物IV)和3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯(化合物V)，制备成尼达尼布。本发明提供的尼达尼布(I)的制备方法具有原料易得、工艺简洁，经济环保等优点，适合工业化生产。

Description

尼达尼布及其中间体的制备方法 技术领域
本发明属于有机合成及原料药中间体的制备技术领域，特别涉及一种制备用于治疗特发性肺纤维化的药物尼达尼布的制备方法、其关键中间体、及其关键中间体的制备方法。
背景技术
尼达尼布(nintedanib)是勃林格殷格翰公司开发的一种新型的用于治疗特发性肺纤维化的口服药物。特发性肺纤维化是一种对人类危害严重的致命性肺部疾病，患者在诊断之后的中位生存期仅为2至3年。尼达尼布可同时阻断血管内皮生长因子受体、血小板源性生长因子受体和成纤维细胞生长因子受体。这些受体的阻断会导致血管生成的抑制。尼达尼布是首个也是唯一一个获准用于治疗特发性肺纤维化的酪氨酸激酶抑制剂。
尼达尼布的化学名为：Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-2-氧代-2,3-二氢-1H-吲哚6-甲酸甲酯，其结构式如下式I所示：
Figure PCTCN2017105723-appb-000001
尼达尼布的制备方法已有报道，原研化合物专利WO2001027081和制备专利WO2009071523、WO 2009071524均给出了尼达尼布及其类似物的合成方法。其主要的合成方法是通过如下过程式中的两个关键中间体A和B缩合得到。其中中间体A合成路线较长，化合物1-3的制备收率较低，化合物1-4关环反应需要高温高压氢化，化合物A的制备需要高温。该路线成本较高，操作复杂。
Figure PCTCN2017105723-appb-000002
专利CN104262232A报道了另一种合成方法。如下过程式所示，该方法首先进行两个片段的缩合，然后进行还原和关环反应，但该工艺缩合反应需要高温，取代反应产率较低，不适合工业放大。
Figure PCTCN2017105723-appb-000003
综上，目前尼达尼布可行的制备路线较少，且成本较高，故开发工艺简洁、条件温和、收率较高的合成路线可大大提高其制备效率，降低成本，减少污染，提高社会和经济效益。
发明内容
本发明涉及尼达尼布(Nintedanib，I)的全新制备方法，及其此方法中涉及的关键中间体，即4-(1-甲氧基-1,3-二氧代-3-苯丙烷-2-基)-3-硝基苯甲酸甲酯(式IV)和3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯(式V)，及其以上关键中间体的制备方法，以解决现有技术存在的问题。
第一个方面，本发明的尼达尼布的制备方法，其制备过程如下所示：
Figure PCTCN2017105723-appb-000004
即，所述尼达尼布的制备方法包括以下步骤：
步骤1：将化合物II，即4-卤代-3-硝基-苯甲酸甲酯，与化合物III，即3-氧代-3-苯基丙酸酯，在碱的作用下反应生成化合物IV，即4-(1-烷氧基-1,3-二氧代-3-苯丙烷-2-基)-3-硝基苯甲酸甲酯；
其中，化合物II中，X为卤素，优选为氯或溴；化合物III和IV中，R1为烷基或取代的烷基，优选C1-C6的烷基或C7-C12的芳香烷基，更优选为甲基或乙基；碱为NaH、甲醇钠、叔丁醇钾、叔丁醇锂、氢氧化钠、氢氧化钾、碳酸钾或碳酸钠；反应的溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、1,4-二氧六环、1,2-二氯乙烷或乙腈；步骤1反应的温度为50-120℃，优选为60-90℃；
步骤2：上述化合物IV在适当还原试剂和溶剂中发生还原-环合反应，生成化合物V，即3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯；
其中，所述还原试剂优选为氢气、钯碳、铂炭、氢氧化钯碳、雷尼镍、铁粉、锌粉、锡粉、铝粉、水合肼、保险粉、氯化亚锡、硫化钠或甲酸-三乙胺；溶剂优选为甲醇、乙醇、乙酸乙酯、乙酸或N,N-二甲基甲酰胺；该反应的温度为50-120℃，优选为70-100℃；
步骤3：将上述化合物V与原料化合物VI，即N-(4-氨基苯基)-N-甲基-2-(4-甲基哌嗪-1-基)乙酰胺在酸的作用和适当的溶剂中，反应生成化合物I，即尼达尼布；
其中，酸优选为甲酸、乙酸、三氟乙酸、甲磺酸、三氟甲磺酸、对甲苯磺酸；溶剂优选为甲苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮或1,4-二氧六环；
步骤3反应的温度为60-120℃，优选为80-110℃。
或者，所述制备过程如下所示：
Figure PCTCN2017105723-appb-000005
即，所述尼达尼布的制备方法包括以下步骤：
步骤1：将化合物II，即4-卤代-3-硝基-苯甲酸甲酯，与化合物III，即3-氧代-3-苯基丙酸酯，在碱的作用下反应生成化合物IV，即4-(1-烷氧基-1,3-二氧代-3-苯丙烷-2-基)-3-硝基苯甲酸甲酯；
其中，X为卤素，优选为氯或溴；R1为烷基或取代的烷基，优选C1-C6的烷基或C7-C12的芳香烷基，更优选为甲基或乙基；碱优选为甲醇钠、叔丁醇钾、氢氧化钠、氢氧化钾或碳酸钾；溶剂优选为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、1,4-二氧六环或乙腈；步骤1反应的温度为50-120℃，优选为60-90℃；
步骤2：将上述化合物IV在适当还原试剂和溶剂中发生还原-环合反应，生成化合物V，即3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯；
其中，所述还原试剂优选为氢气、钯碳、铂炭、雷尼镍、铁粉、锌粉、水合肼或保险粉(连二亚硫酸钠)；溶剂优选为甲醇、乙醇、乙酸乙酯或乙酸；该反应的温度为20-120℃，优选为20-80℃；
步骤3：将上述化合物V在卤化试剂、碱或催化剂和适当的溶剂中反应，生成中间体化合物VII，即(Z/E)-(3-卤代-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯；
其中，其中X为卤素，X优选为氯或溴；卤化试剂优选为三氯氧磷、三溴化磷或五氯化磷；所述碱优选为三乙胺、二异丙基乙胺、DBU、二 甲氨基吡啶或N,N-二甲基甲酰胺；溶剂优选为甲苯、乙腈、二氧六环或三氯氧磷；反应的温度为50-120℃，优选为60-100℃；
步骤4：将上述中间体化合物VII在碱和适当的溶剂条件下，与化合物VI反应生成化合物I，即尼达尼布；
其中，所述碱优选为三乙胺、二异丙基乙胺、碳酸氢钠、碳酸钠或碳酸钾；所述溶剂优选为甲醇、乙醇、乙腈、N,N-二甲基甲酰胺或1,4-二氧六环；该反应的温度为20-80℃，优选为50-70℃。
优选地，从化合物V生成化合物VII过程中，可不经过分离处理直接进行下一步反应；具体反应式如下：
Figure PCTCN2017105723-appb-000006
其中，步骤A：将化合物V在卤化剂及碱中生成化合物VII；
步骤B：不经分离，在步骤A的反应后体系中直接加入化合物VI和碱，反应生成尼达尼布；
其中，所述步骤A的卤化反应在无溶剂的条件下或在选自甲苯、乙腈或二氧六环的有机溶剂中进行，所述卤化剂选自三氯氧磷、五氧化二磷或五氯化磷，优选三氯氧磷；碱选自三乙胺、二异丙基乙胺或DBU，优选二异丙基乙胺。
所述步骤B在选自甲醇、乙醇、乙腈、四氢呋喃或二氯甲烷中一种或混合溶剂中反应，所用的碱选自三乙胺、二异丙基乙胺、碳酸氢钠、碳酸钠或碳酸钾。
在另一方面，本发明还提供一种新的化合物IV、V及化合物VII，其结构式如下：
Figure PCTCN2017105723-appb-000007
其中，R1为烷基或取代的烷基，优选C1-C6的烷基或C7-12的芳香烷基，更优选甲基或乙基；X为卤素，优选为氯或溴。
本发明提供的化合物IV、化合物V或化合物VII用于制备尼达尼布药物。使用以上新的中间体化合物，缩短了反应步骤，避免使用危险的化学品原料，得到的尼达尼布终产物质量好，纯度高，适合工业化生产。
因此，本发明提供化合物IV、V或VII在制备尼达尼布药物中的应用。
通过本发明方法得到的尼达尼布(I)构型具有特异性，仅可得到Z型异构体，不含有E构型杂质，且产品纯度好，具有产品稳定的优点。
相比于已有技术，本发明提供的尼达尼布(I)的制备方法具有原料易得、工艺简洁，缩短了操作步骤，简化了操作过程，提高了生产效率；另外各步骤易于纯化，收率高，安全环保，适合工业化生产。
具体实施方式
以下通过数个具体实施例对本发明的技术方案进行非限制性的具体说明。其中，原料II、III均可大宗采购；原料VI可参考文献J.Med.Chem,2009,52,4466-4480或专利WO2009071523中的方法合成。
实施例1：4-(1-甲氧基-1,3-二氧代-3-苯丙烷-2-基)-3-硝基苯甲酸甲酯(IV)的制备
在500mL反应瓶中加入N,N-二甲基甲酰胺160mL和4-氯代-3-硝基-苯甲酸甲酯18.8g，25℃时搅拌至溶清。再依次加入3-氧代-3-苯基丙酸酯17.1g和无水碳酸钾24.1g，将反应升温至80-90开始反应4-6小时直至TLC显示原料消失。向反应液中加入冰醋酸调节pH至中性，加入600mL水后用200mL*3次乙酸乙酯萃取。合并乙酸乙酯层以300mL*2次的5％NaCl溶液水洗。将乙酸乙酯层以无水硫酸镁干燥后旋干溶剂得化合物IV 28.7g，收率92.1％。1H NMR(400MHz,CDCl3):δ8.38-8.33(m,2H),7.98-7.93(m,2H),7.79(d,J＝7.6,1H),7.64-7.56(m,1H),7.50(m,2H), 5.16(d,J＝0.9Hz,1H),3.95(s,3H),3.75(s,3H).Mass:358.0[M+H+]。
实施例2：尼达尼布(I)的制备
在500mL反应瓶中将21.2g化合物V溶解于210mL甲苯中，加入20.7g化合物IV和2.47g对甲苯磺酸，将反应加热至100-110度回流反应并用Dean-Stark分去生成的水。反应28小时后TLC显示原料转化完全。降至室温后用5％NaHCO3溶液水洗一次，5％NaCl溶液水洗两次后，用10g无水硫酸镁干燥。将甲苯蒸干后加入120mL甲醇/正庚烷重结晶得到产品尼达尼布24.7g，收率63.8％。1H NMR(400MHz,DMSO-d6):12.17(s,1H),11.03(s,1H),7.64–7.59(t,J＝7.6Hz,2H),7.56–7.52(t,J＝7.6Hz,2H),7.50–7.45(d,J＝7.6Hz,1H),7.43–7.40(d,J＝1.6Hz,1H),7.21–7.17(d,J＝8.3Hz,1H),7.15–7.07(m,2H),6.82–6.77(m,2H),5.85–5.83(d,J＝8.3Hz,1H),3.79(s,3H),3.11–3.04(m,3H),2.75–2.66(m,2H),2.27–2.19(m,5H),2.16–2.11(m,3H),2.10(s,3H).Mass:540.2[M+H+]。
实施例3：4-(1-乙氧基-1,3-二氧代-3-苯丙烷-2-基)-3-硝基苯甲酸甲酯(IV)的制备
在250mL反应瓶中加入N,N-二甲基乙酰胺120mL和4-溴代-3-硝基-苯甲酸甲酯12.0g，25℃时搅拌至溶清。再依次加入3-氧代-3-苯基丙酸乙酯15.3g和甲醇钠7.7g，将反应升温至80-90开始反应4-6小时直至TLC显示原料消失。向反应液中加入冰醋酸调节pH至中性，加入300mL水后用100mL*3次乙酸乙酯萃取。合并乙酸乙酯层以200mL*2次的5％NaCl溶液水洗。将乙酸乙酯层以无水硫酸镁干燥后旋干溶剂得化合物IV 15.3g，收率89.3％。1H-NMR(500MHz,Chloroform-d)δ8.36(s,1H),8.38–8.32(m,1H),7.80(ddd,J＝16.0,7.3,1.6Hz,3H),7.64–7.56(m,1H),7.50(t,J＝7.4Hz,2H),5.05(d,J＝1.1Hz,1H),4.53(dq,J＝12.5,8.0Hz,1H),3.95(s,3H),3.77(dq,J＝12.5,8.0Hz,1H),1.22(t,J＝8.0Hz,3H).Mass:371.3[M+H+]。
实施例4：4-(1-甲氧基-1,3-二氧代-3-苯丙烷-2-基)-3-硝基苯甲酸甲酯(IV)的制备
在250mL反应瓶中加入N-甲基吡咯烷酮120mL和4-氯代-3-硝基- 苯甲酸甲酯12.0g，25℃时搅拌至溶清。再依次加入3-氧代-3-苯基丙酸甲酯10.9g和叔丁醇钾7.5g，将反应升温至80-90开始反应2-3小时直至TLC显示原料消失。向反应液中加入冰醋酸调节pH至中性，加入300mL水后用100mL*3次乙酸乙酯萃取。合并乙酸乙酯层以200mL*2次的5％NaCl溶液水洗。将乙酸乙酯层以无水硫酸镁干燥后旋干溶剂得化合物IV17.9g，收率90.0％。1H NMR(400MHz,CDCl3):δ8.38-8.33(m,2H),7.98-7.93(m,2H),7.79(d,J＝7.6,1H),7.64-7.56(m,1H),7.50(m,2H),5.16(d,J＝0.9Hz,1H),3.95(s,3H),3.75(s,3H).Mass:358.3[M+H+]。
实施例5：4-(1-甲氧基-1,3-二氧代-3-苯丙烷-2-基)-3-硝基苯甲酸甲酯(IV)的制备
在250mL反应瓶中加入1,4-二氧六环120mL和4-氯代-3-硝基-苯甲酸甲酯12.0g，25℃时搅拌至溶清。再依次加入3-氧代-3-苯基丙酸乙酯10.9g和氢氧化钾4.7g，将反应升温至80-90开始反应2-3小时直至TLC显示原料消失。向反应液中加入冰醋酸调节pH至中性，加入300mL水后用100mL*3次乙酸乙酯萃取。合并乙酸乙酯层以200mL*2次的5％NaCl溶液水洗。将乙酸乙酯层以无水硫酸镁干燥后旋干溶剂得化合物IV18.0g，收率90.5％。1H NMR(400MHz,CDCl3):δ8.38-8.33(m,2H),7.98-7.93(m,2H),7.79(d,J＝7.6,1H),7.64-7.56(m,1H),7.50(m,2H),5.16(d,J＝0.9Hz,1H),3.95(s,3H),3.75(s,3H).Mass:358.3[M+H+]。
实施例6：4-(1-甲氧基-1,3-二氧代-3-苯丙烷-2-基)-3-硝基苯甲酸甲酯(IV)的制备
在250mL反应瓶中加入乙腈120mL和4-氯代-3-硝基-苯甲酸甲酯12.0g，25℃时搅拌至溶清。再依次加入3-氧代-3-苯基丙酸乙酯10.9g和氢氧化钠3.3g，将反应升温至80-90开始反应2-3小时直至TLC显示原料消失。向反应液中加入冰醋酸调节pH至中性，加入300mL水后用100mL*3次乙酸乙酯萃取。合并乙酸乙酯层以200mL*2次的5％NaCl溶液水洗。将乙酸乙酯层以无水硫酸镁干燥后旋干溶剂得化合物IV18.4g，收率92.5％。1H NMR(400MHz,CDCl3):δ8.38-8.33(m,2H),7.98-7.93(m,2H),7.79(d,J＝7.6,1H),7.64-7.56(m,1H),7.50(m,2H),5.16(d,J＝0.9Hz,1H),3.95(s,3H),3.75(s,3H).Mass:358.3[M+H+]。
实施例7：3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯(V)的制备
在500mL反应瓶中将24.0g化合物IV溶解于240mL乙酸乙酯中，加入2.4g 10％的钯炭催化剂，将反应置于3个大气压的氢气氛围中于20-30度反应16小时至TLC显示原料完全转化后生成中间体。再将反应升温至70-80度反应4-6小时至TLC显示中间体完全转化。降至室温后过滤出去钯炭催化剂后蒸干乙酸乙酯溶液，置换为甲基叔丁基醚将产品重结晶得到16.2g白色晶体，收率81.7％。1H NMR(400MHz,CDCl3)δ8.55(br,1H),8.13(s,1H),8.09–8.01(m,2H),7.88(dd,J＝7.6,1.6Hz,1H),7.76–7.65(m,2H),7.52–7.40(m,2H),5.33(s,1H),3.87(s,3H).Mass:296.3[M+H+]。
实施例8：3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯(V)的制备
在100mL反应瓶中将5.0g化合物IV溶解于50mL甲醇中，加入0.5g 10％的铂炭催化剂，将反应置于8个大气压的氢气氛围中于20-30度反应4小时至TLC显示原料完全转化后生成中间体。再将反应升温至60-70度反应2小时至中间体完全转化。降至室温后过滤出去催化剂后蒸干乙酸乙酯溶液，置换为甲基叔丁基醚将产品重结晶得到3.6g白色晶体，收率87.1％。1H NMR(400MHz,CDCl3)δ8.55(br,1H),8.13(s,1H),8.09–8.01(m,2H),7.88(dd,J＝7.6,1.6Hz,1H),7.76–7.65(m,2H),7.52–7.40(m,2H),5.33(s,1H),3.87(s,3H).Mass:296.3[M+H+]。
实施例9：3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯(V)的制备
在100mL反应瓶中将5.0g化合物IV溶解于50mL乙酸中，加入3.1g Fe粉，将反应升温至60-70度反应20小时至完全转化。降至室温后过滤出去Fe粉，将乙酸蒸干后，以乙酸乙酯/饱和碳酸氢钠萃取得有机层，再将乙酸乙酯置换为甲基叔丁基醚将产品重结晶得到2.9g白色晶体，收率70.2％。1H NMR(400MHz,CDCl3)δ8.55(br,1H),8.13(s,1H),8.09–8.01(m,2H),7.88(dd,J＝7.6,1.6Hz,1H),7.76–7.65(m,2H),7.52–7.40(m,2H),5.33(s,1H),3.87(s,3H).Mass:296.3[M+H+]。
实施例10：3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯(V)的制备
在100mL反应瓶中将5.0g化合物IV溶解于50mL甲醇中，加入0.5g 10％的雷尼镍催化剂，将反应置于5个大气压的氢气氛围中于20-30度 反应1小时至TLC显示原料完全转化后生成中间体。再将反应升温至60-70度反应1小时至中间体完全转化。降至室温后过滤出去催化剂后蒸干乙酸乙酯溶液，置换为甲基叔丁基醚将产品重结晶得到3.2g白色晶体，收率77.4％。1H NMR(400MHz,CDCl3)δ8.55(br,1H),8.13(s,1H),8.09–8.01(m,2H),7.88(dd,J＝7.6,1.6Hz,1H),7.76–7.65(m,2H),7.52–7.40(m,2H),5.33(s,1H),3.87(s,3H).Mass:296.0[M+H+]。
实施例11：3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯(V)的制备
在100mL反应瓶中将5.0g化合物IV溶解于50mL乙酸中，加入3.6g Zn粉，将反应升温至60-70度反应48小时至完全转化。降至室温后过滤出去Zn粉，将乙酸蒸干后，以乙酸乙酯/饱和碳酸氢钠萃取得有机层，再将乙酸乙酯置换为甲基叔丁基醚将产品重结晶得到3.1g白色晶体，收率75.2％。1H NMR(400MHz,CDCl3)δ8.55(br,1H),8.13(s,1H),8.09–8.01(m,2H),7.88(dd,J＝7.6,1.6Hz,1H),7.76–7.65(m,2H),7.52–7.40(m,2H),5.33(s,1H),3.87(s,3H).Mass:296.3[M+H+]。
实施例12：3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯(V)的制备
在100mL反应瓶中将5.0g化合物IV溶解于50mL甲醇中，加入0.5g 10％的钯炭催化剂粉和2.0eq的水合肼，将反应升温至60-70度反应20小时至完全转化。降至室温后过滤出去催化剂，将甲醇蒸干后，以乙酸乙酯/1N稀盐酸萃取得有机层，再将乙酸乙酯置换为甲基叔丁基醚将产品重结晶得到2.8g白色晶体，收率67.8％。1H NMR(400MHz,CDCl3)δ8.55(br,1H),8.13(s,1H),8.09–8.01(m,2H),7.88(dd,J＝7.6,1.6Hz,1H),7.76–7.65(m,2H),7.52–7.40(m,2H),5.33(s,1H),3.87(s,3H).Mass:296.3[M+H+]。
实施例13：3-苯甲酰基-2-氧代二氢吲哚-6-甲酸甲酯(V)的制备
在100mL反应瓶中将5.0g化合物IV溶解于50mL甲醇中，加入9.8g保险粉(连二亚硫酸钠)，将反应升温至60-70度反应40小时至完全转化。降至室温后将甲醇蒸干，以乙酸乙酯/1N稀盐酸萃取得有机层，再将乙酸乙酯置换为甲基叔丁基醚将产品重结晶得到3.3g白色晶体，收率79.9％。1H NMR(400MHz,CDCl3)δ8.55(br,1H),8.13(s,1H),8.09–8.01(m,2H),7.88(dd,J＝7.6,1.6Hz,1H),7.76–7.65(m,2H),7.52–7.40(m, 2H),5.33(s,1H),3.87(s,3H).Mass:296.3[M+H+]。
实施例14：(3-氯-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯(VII)的制备
在500mL反应瓶中将33.1g化合物V溶于132mL三氯氧磷和66mL二异丙基乙胺中，在氮气保护下加热至60-80℃反应1-2小时。TLC显示原料完全转化后，将溶剂蒸干，用乙酸乙酯/水萃取得到有机相，蒸干后得到棕色油状物中间体VII。1H NMR(500MHz,Chloroform-d)δ8.59(s,1H),7.73(dt,J＝4.1,1.8Hz,2H),7.42–7.31(m,4H),7.11(tt,J＝7.2,2.3Hz,1H),6.95(d,J＝7.9Hz,1H),3.95(s,3H).Mass:314.0[M+H+]。直接用于下一步反应。
实施例15：(3-氯-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯(VII)的制备
在500mL反应瓶中将33.1g化合物V溶于132mL三氯氧磷和66mL三乙胺中，在氮气保护下加热至80-100℃反应1-2小时。TLC显示原料完全转化后，将溶剂蒸干，用乙酸乙酯/水萃取得到有机相，蒸干后得到棕色油状物中间体VII。1H NMR(500MHz,Chloroform-d)δ8.59(s,1H),7.73(dt,J＝4.1,1.8Hz,2H),7.42–7.31(m,4H),7.11(tt,J＝7.2,2.3Hz,1H),6.95(d,J＝7.9Hz,1H),3.95(s,3H).Mass:314.0[M+H+]。直接用于下一步反应。
实施例16：(3-溴-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯(VII)的制备
在500mL反应瓶中将33.1g化合物V溶于99mL乙腈中，加入27.3g三溴化磷和66mL三乙胺，在氮气保护下加热至60-80℃反应3-4小时。TLC显示原料完全转化后，将溶剂蒸干，用乙酸乙酯/水萃取得到有机相，蒸干后得到棕色油状物中间体VII。1H NMR(500MHz,Chloroform-d)δ8.59(s,1H),7.73(dq,J＝2.8,1.6Hz,2H),7.42–7.34(m,2H),7.35–7.28(m,2H),7.11(tt,J＝7.3,2.1Hz,1H),6.98(d,J＝7.9Hz,1H),3.95(s,3H).Mass:358.0[M+H+]。直接用于下一步反应。
实施例17：(3-溴-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯(VII) 的制备
在500mL反应瓶中将33.1g化合物V溶于99mL二氧六环中，加入27.3g三溴化磷和66mL的DBU，在氮气保护下加热至80-100℃反应1-2小时。TLC显示原料完全转化后，将溶剂蒸干，用乙酸乙酯/水萃取得到有机相，蒸干后得到棕色油状物中间体VII。1H NMR(500MHz,Chloroform-d)δ8.59(s,1H),7.73(dq,J＝2.8,1.6Hz,2H),7.42–7.34(m,2H),7.35–7.28(m,2H),7.11(tt,J＝7.3,2.1Hz,1H),6.98(d,J＝7.9Hz,1H),3.95(s,3H).Mass:358.0[M+H+]。直接用于下一步反应。
实施例18：(3-氯-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯(VII)的制备
在500mL反应瓶中将10.2g化合物V溶于41mL三氯氧磷和2mL二甲氨基吡啶中，在氮气保护下加热至60-80℃反应1-2小时。TLC显示原料完全转化后，将溶剂蒸干，用乙酸乙酯/水萃取得到有机相，蒸干后得到棕色油状物中间体VII。1H NMR(500MHz,Chloroform-d)δ8.59(s,1H),7.73(dt,J＝4.1,1.8Hz,2H),7.42–7.31(m,4H),7.11(tt,J＝7.2,2.3Hz,1H),6.95(d,J＝7.9Hz,1H),3.95(s,3H).Mass:314.0[M+H+]。直接用于下一步反应。
实施例19：(3-氯-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯(VII)的制备
在500mL反应瓶中将10.2g化合物V溶于41mL三氯氧磷和2mL的N,N-二甲基甲酰胺，在氮气保护下加热至60-80℃反应1-2小时。TLC显示原料完全转化后，将溶剂蒸干，用乙酸乙酯/水萃取得到有机相，蒸干后得到棕色油状物中间体VII。1H NMR(500MHz,Chloroform-d)δ8.59(s,1H),7.73(dt,J＝4.1,1.8Hz,2H),7.42–7.31(m,4H),7.11(tt,J＝7.2,2.3Hz,1H),6.95(d,J＝7.9Hz,1H),3.95(s,3H).Mass:314.0[M+H+]。直接用于下一步反应。
实施例20：尼达尼布(I)的制备
在500mL反应瓶中，向上步反应旋蒸得到的25.0g(3-氯-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯油状物中加入200mL乙醇搅拌至全溶，加入20.9g化合物VI和12.1g三乙胺，将反应升温至60-70℃反应6小时 直至TLC显示原料消失。将反应液蒸干置换为200mL乙酸乙酯，以100mL*3次水洗后，依次加入6.6g无水硫酸镁干燥、和6.6g活性炭脱色。所得溶液蒸干置换为甲醇/正庚烷结晶得到尼达尼布36.8g，收率85.6％。1H NMR(400MHz,DMSO-d6):12.17(s,1H),11.03(s,1H),7.64–7.59(t,J＝7.6Hz,2H),7.56–7.52(t,J＝7.6Hz,2H),7.50–7.45(d,J＝7.6Hz,1H),7.43–7.40(d,J＝1.6Hz,1H),7.21–7.17(d,J＝8.3Hz,1H),7.15–7.07(m,2H),6.82–6.77(m,2H),5.85–5.83(d,J＝8.3Hz,1H),3.79(s,3H),3.11–3.04(m,3H),2.75–2.66(m,2H),2.27–2.19(m,5H),2.16–2.11(m,3H),2.10(s,3H).Mass:540.2[M+H+]。
实施例21：尼达尼布(I)的制备
在500mL反应瓶中，向上步反应旋蒸得到的25.0g(3-氯-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯油状物中加入200mL甲醇搅拌至全溶，加入20.9g化合物VI和15.5g二异丙基乙胺，将反应升温至50-60℃反应10小时直至TLC显示原料消失。将反应液蒸干置换为200mL乙酸乙酯，以100mL*3次水洗后，依次加入6.6g无水硫酸镁干燥、和6.6g活性炭脱色。所得溶液蒸干置换为甲醇/正庚烷结晶得到尼达尼布37.1g，收率86.1％。1H NMR(400MHz,DMSO-d6):12.17(s,1H),11.03(s,1H),7.64–7.59(t,J＝7.6Hz,2H),7.56–7.52(t,J＝7.6Hz,2H),7.50–7.45(d,J＝7.6Hz,1H),7.43–7.40(d,J＝1.6Hz,1H),7.21–7.17(d,J＝8.3Hz,1H),7.15–7.07(m,2H),6.82–6.77(m,2H),5.85–5.83(d,J＝8.3Hz,1H),3.79(s,3H),3.11–3.04(m,3H),2.75–2.66(m,2H),2.27–2.19(m,5H),2.16–2.11(m,3H),2.10(s,3H).Mass:540.2[M+H+]。
实施例22：尼达尼布(I)的制备
在500mL反应瓶中，向上步反应旋蒸得到的25.0g(3-氯-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯油状物中加入200mL乙腈搅拌至全溶，加入20.9g化合物VI和10.1g碳酸氢钠，将反应升温至60-70℃反应16小时直至TLC显示原料消失。过滤除盐后将反应液蒸干置换为200mL乙酸乙酯，以100mL*3次水洗后，依次加入6.6g无水硫酸镁干燥、和6.6g活性炭脱色。所得溶液蒸干置换为甲醇/正庚烷结晶得到尼达尼布35.9g，收率83.5％。1H NMR(400MHz,DMSO-d6):12.17(s,1H),11.03(s,1H),7.64–7.59(t,J＝7.6Hz,2H),7.56–7.52(t,J＝7.6Hz,2H),7.50–7.45(d, J＝7.6Hz,1H),7.43–7.40(d,J＝1.6Hz,1H),7.21–7.17(d,J＝8.3Hz,1H),7.15–7.07(m,2H),6.82–6.77(m,2H),5.85–5.83(d,J＝8.3Hz,1H),3.79(s,3H),3.11–3.04(m,3H),2.75–2.66(m,2H),2.27–2.19(m,5H),2.16–2.11(m,3H),2.10(s,3H).Mass:540.2[M+H+]。
实施例23：尼达尼布(I)的制备
在500mL反应瓶中，向上步反应旋蒸得到的25.0g(3-氯-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯油状物中加入200mL N,N-二甲基甲酰胺搅拌至全溶，加入20.9g化合物VI和12.7g碳酸钠，将反应升温至60-70℃反应5-6小时直至TLC显示原料消失。过滤除盐后将反应液蒸干置换为200mL乙酸乙酯，以100mL*3次水洗后，依次加入6.6g无水硫酸镁干燥、和6.6g活性炭脱色。所得溶液蒸干置换为甲醇/正庚烷结晶得到尼达尼布34.5g，收率80.2％。1H NMR(400MHz,DMSO-d6):12.17(s,1H),11.03(s,1H),7.64–7.59(t,J＝7.6Hz,2H),7.56–7.52(t,J＝7.6Hz,2H),7.50–7.45(d,J＝7.6Hz,1H),7.43–7.40(d,J＝1.6Hz,1H),7.21–7.17(d,J＝8.3Hz,1H),7.15–7.07(m,2H),6.82–6.77(m,2H),5.85–5.83(d,J＝8.3Hz,1H),3.79(s,3H),3.11–3.04(m,3H),2.75–2.66(m,2H),2.27–2.19(m,5H),2.16–2.11(m,3H),2.10(s,3H).Mass:540.2[M+H+]。
实施例24：尼达尼布(I)的制备
在500mL反应瓶中，向上步反应旋蒸得到的25.0g油状物(3-溴-3-苯基亚甲基)-2-氧代二氢吲哚-6-甲酸甲酯中加入150mL1,4-二氧六环搅拌至全溶，加入13.2g化合物VI和10.4g碳酸钾，将反应升温至50-60℃反应1-2小时直至TLC显示原料消失。过滤除盐后将反应液蒸干置换为200mL乙酸乙酯，以100mL*3次水洗后，依次加入6.6g无水硫酸镁干燥、和6.6g活性炭脱色。所得溶液蒸干置换为甲醇/正庚烷结晶得到尼达尼布22.2g，收率81.9％。1H NMR(400MHz,DMSO-d6):12.17(s,1H),11.03(s,1H),7.64–7.59(t,J＝7.6Hz,2H),7.56–7.52(t,J＝7.6Hz,2H),7.50–7.45(d,J＝7.6Hz,1H),7.43–7.40(d,J＝1.6Hz,1H),7.21–7.17(d,J＝8.3Hz,1H),7.15–7.07(m,2H),6.82–6.77(m,2H),5.85–5.83(d,J＝8.3Hz,1H),3.79(s,3H),3.11–3.04(m,3H),2.75–2.66(m,2H),2.27–2.19(m,5H),2.16–2.11(m,3H),2.10(s,3H).Mass:540.2[M+H+]。

Claims (9)

  1. 尼达尼布的制备方法，其制备过程如下所示：
    Figure PCTCN2017105723-appb-100001
    其中，
    步骤1：将化合物II与化合物III在碱的作用下反应生成化合物IV；
    其中，化合物II中，X为卤素；化合物III和IV中，R1为烷基或取代的烷基；所述碱为NaH、甲醇钠、叔丁醇钾、叔丁醇锂、氢氧化钠、氢氧化钾、碳酸钾或碳酸钠；反应的溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、1,4-二氧六环、1,2-二氯乙烷或乙腈；步骤1反应的温度为50-120℃，优选为60-90℃；
    步骤2：将化合物IV在还原试剂和溶剂中发生还原-环合反应，生成化合物V；
    其中，所述还原试剂为氢气、钯碳、铂炭、氢氧化钯碳、雷尼镍、铁粉、锌粉、锡粉、铝粉、水合肼、保险粉、氯化亚锡、硫化钠或甲酸-三乙胺；所述溶剂为甲醇、乙醇、乙酸乙酯、乙酸或N,N-二甲基甲酰胺；该反应的温度为50-120℃，优选为70-100℃；
    步骤3：将化合物V与原料化合物VI在酸的作用和适当的溶剂中，反应生成尼达尼布；
    其中，所述酸为甲酸、乙酸、三氟乙酸、甲磺酸、三氟甲磺酸或对甲苯磺酸；所述溶剂为甲苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮或1,4-二氧六环；
    步骤3反应的温度为60-120℃，优选为80-110℃。
  2. 根据权利要求1所述的方法，其中，步骤1中，化合物II中，X为氯或溴；化合物III和IV中，R1为C1-C6的烷基或C7-C12的芳香烷基，优选为甲基或乙基。
  3. 尼达尼布的制备方法，其制备过程如下所示：
    Figure PCTCN2017105723-appb-100002
    其中，
    步骤1：将化合物II与化合物III在碱的作用下反应生成化合物IV；
    其中，化合物II中，X为卤素；化合物III和化合物IV中，R1为烷基或取代的烷基；碱选自甲醇钠、叔丁醇钾、氢氧化钠、氢氧化钾或碳酸钾；溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、1,4-二氧六环或乙腈；步骤1的反应温度为50-120℃，优选为60-90℃；
    步骤2：将化合物IV在还原试剂和溶剂中发生还原-环合反应，生成化合物V；
    其中，所述还原试剂为氢气、钯碳、铂炭、雷尼镍、铁粉、锌粉、水合肼或连二亚硫酸钠；所述溶剂选自甲醇、乙醇、乙酸乙酯或乙酸；该反应的温度为20-120℃，优选为20-80℃；
    步骤3：将上述化合物V在卤化试剂、碱或催化剂和适当的溶剂中反应，生成中间体化合物VII；
    其中，其中化合物VII中，X为卤素；所述卤化试剂选自三氯氧磷、三溴化磷或五氯化磷；所述碱选自三乙胺、二异丙基乙胺、DBU、二甲氨基吡啶或N,N-二甲基甲酰胺；所述溶剂选自甲苯、乙腈、二氧六环或三氯氧磷；反应的温度为50-120℃，优选为60-100℃；
    步骤4：将上述中间体化合物VII在碱和适当的溶剂条件下，与化合物VI反应生成尼达尼布；
    其中，所述碱为三乙胺、二异丙基乙胺、碳酸氢钠、碳酸钠或碳酸钾；所述溶剂为甲醇、乙醇、乙腈、N,N-二甲基甲酰胺或1,4-二氧六环；该反应的温度为20-80℃，优选为50-70℃。
  4. 根据权利要求3所述的方法，其中，化合物II和VII中，X为氯或溴；化合物III和化合物IV中，R1为C1-C6的烷基或C7-C12的芳香烷基，优选为甲基或乙基。
  5. 一种尼达尼布化合物的制备方法：
    Figure PCTCN2017105723-appb-100003
    该制备方法中包括：
    步骤A：将化合物V在卤化剂及碱中生成化合物VII；
    步骤B：不经分离，在步骤A的反应后体系中直接加入化合物VI和碱，反应生成尼达尼布；
    其中，所述步骤A在无溶剂的条件下或选自甲苯、乙腈或二氧六环有机溶剂中进行，其中所述卤化剂选自三氯氧磷、五氧化二磷或五氯化磷；所述碱选自三乙胺、二异丙基乙胺或DBU；
    所述步骤B在选自甲醇、乙醇、乙腈、四氢呋喃或二氯甲烷中一种或混合溶剂中反应，所用的碱选自三乙胺、二异丙基乙胺、碳酸氢钠、碳酸钠或碳酸钾。
  6. 一种化合物IV，其结构式如下：
    Figure PCTCN2017105723-appb-100004
    其中，R1为烷基或取代的烷基，优选C1-C6的烷基或C7-C12的芳香烷基，更优选甲基和乙基。
  7. 一种化合物V，其结构式如下所示：
    Figure PCTCN2017105723-appb-100005
  8. 一种化合物VII，其结构式如下所示：
    Figure PCTCN2017105723-appb-100006
  9. 化合物IV、化合物V或化合物VII在制备尼达尼布药物中的应用。
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