WO2016074532A1 - 艾立替尼的制备方法 - Google Patents

艾立替尼的制备方法 Download PDF

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WO2016074532A1
WO2016074532A1 PCT/CN2015/089736 CN2015089736W WO2016074532A1 WO 2016074532 A1 WO2016074532 A1 WO 2016074532A1 CN 2015089736 W CN2015089736 W CN 2015089736W WO 2016074532 A1 WO2016074532 A1 WO 2016074532A1
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ethyl
cyano
indole
morpholin
piperidin
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PCT/CN2015/089736
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English (en)
French (fr)
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许学农
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苏州明锐医药科技有限公司
哲人药业南京有限公司
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Priority to US15/524,749 priority Critical patent/US10221155B2/en
Publication of WO2016074532A1 publication Critical patent/WO2016074532A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of eritinib for treating non-small cell lung cancer.
  • Alectinib is a new anaplastic lymphoma kinase (ALK) inhibitor developed by Chugai Pharmaceutical, a subsidiary of Roche, for the treatment of ALK gene rearrangements.
  • ALK anaplastic lymphoma kinase
  • the drug was granted the status of “breakthrough therapeutic drug” by the US FDA in September 2013, 2014. Approved for listing in Japan in July. Since the drug does not yet have a standard Chinese translation, the applicant hereby transliterates it to "Eritinib".
  • eritinib 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxa-6 , 11-Dihydro-5H-benzo[b]carbazole-3-carbonitrile (I), the structural formula is:
  • the first route is based on 7-methoxy-3,4-dihydronaphthalene-2(1H)-one (1), followed by dimethylation (step 1), 6-bromo ( Step 2) and the cyclization reaction with hydrazine (step 3) to prepare the intermediate 6,6-dimethyl-8-methoxy-9-bromo-11-oxa-6,11-dihydro-5H- Benzo[b]indazol-3-carbonitrile (4) (step 4), intermediate 4 via methoxy hydrolysis (step 5), triflate (step 6) and with piperidine ring Condensation to give the intermediate 6,6-dimethyl-8-(4-morpholinylpiperidin-1-yl)-9-bromo-11-oxa-6,11-dihydro-5H-benzo[b ] carbazole-3-carbonitrile group (7) (step 7).
  • the second route is obtained by condensing 3-iodo-4-ethyl-tert-butylbenzene (9) with mono-tert-butyl malonate (10) to obtain intermediate (11) (Step 1), which is 3-
  • the nitrobenzonitrile is condensed to obtain a 3-carboxyindole derivative (12) (Step 2), and the intermediate 12 is subjected to iodide reaction with 4-morpholine piperidine to obtain an intermediate (13) (Step 3)
  • Step 5 After the hydrolysis of the carboxyl group (Step 4) and cyclization (Step 5), the target compound eritinib (I) is obtained.
  • the above two synthetic routes were analyzed, and the core anthraquinone formation step was carried out by condensation of hydrazine with a carbonyl group (Step 3 of Scheme 1) or condensation of a nitro group (after reduction with an amino group) with a carbonyl group (Step 2 of Route 2) .
  • the two substrates formed in the ring contain a plurality of functional groups such as a halogen, a carbonyl group, a carboxyl group, an amino group and a cyano group, the reaction process is quite complicated, the side reaction is increased, the purification is difficult, and the reaction raw materials and intermediates involved are mostly difficult to obtain. . Therefore, in view of the defects existing in the existing process, the development technology is simple, economical and environmentally friendly, and the quality of the preparation technology, especially the process technology that can adapt to industrial production, has important practical significance for the economic and social benefits of the drug.
  • the object of the present invention is to provide a preparation method of eritinib which is easy to obtain raw materials, simple in process, economical and environmentally friendly, and suitable for industrial production.
  • the present invention adopts the following main technical solutions: a preparation method of eritinib (I),
  • the preparation step comprises: using methyl 6-cyano-1H-indole-3-carboxylate or ethyl 6-cyano-1H-indole-3-carboxylate (II) with 4-ethyl-3- (4-morpholin-4-yl-piperidin-1-yl)- ⁇ , ⁇ -dimethylbenzyl alcohol (III) undergoes a condensation reaction under the action of a catalyst to obtain 6-cyano-2-[2- Methyl [4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl]propan-2-yl]-1H-indole-3-carboxylate or 6-cyanide Benzyl-2-[2-[4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)phenyl]propan-2-yl]-1H-indole-3-carboxylate Ethyl ester (IV); 6-cyano-2-[2-[4-ethyl
  • the preparation step of the starting material methyl 3-cyano-1H-indole-3-carboxylate or ethyl 6-cyano-1H-indole-3-carboxylate (II) includes: 6-cyano-1H - ⁇ (VI) is acylated with trichloroacetyl chloride, followed by esterification in methanol or ethanol to obtain methyl 6-cyano-1H-indole-3-carboxylate or 6-cyano -1H-indole-3-carboxylic acid methyl ester (II).
  • the preparation step of the starting material 4-ethyl-3-(4-morpholin-4-yl-piperidin-1-yl)- ⁇ , ⁇ -dimethylbenzyl alcohol (III) includes: 4-acetyl- 2-Bromo-ethylbenzene (VII) is substituted with 4-(morpholin-4-yl)piperidine (VIII) to form 4-acetyl-2-(4-morpholin-4-yl-1-piperidine Ethylbenzene (IX); 4-acetyl-2-(4-morpholin-4-yl-1-piperidyl)ethylbenzene (IX) by Grignard reaction to give 4-ethyl-3-( 4-morpholin-4-yl-piperidin-1-yl)- ⁇ , ⁇ -dimethylbenzyl alcohol (III).
  • the starting material of the condensation reaction is methyl 6-cyano-1H-indole-3-carboxylate or ethyl 6-cyano-1H-indole-3-carboxylate (II) and the compound 4-ethyl-3
  • the molar ratio of (4-morpholin-4-yl-piperidin-1-yl)- ⁇ , ⁇ -dimethylbenzyl alcohol (III) is from 1:0.5 to 1.5, preferably from 1:0.9 to 1.1.
  • the catalyst for the condensation reaction is trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, boron trifluoride or boron trichloride, preferably trifluoroacetic acid or boron trifluoride.
  • the solvent for the condensation reaction is dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, dimethyl carbonate or dioxane, preferably dichloromethane or tetrahydrofuran.
  • the temperature of the condensation reaction is -25 to 50 ° C, preferably 0 to 25 ° C.
  • the solvent for the hydrolysis reaction is methanol, ethanol, isopropanol, trifluoroethanol, hexafluoroisopropanol or 1-fluoro-2-chloroethane, preferably trifluoroethanol.
  • the base accelerator of the cyclization reaction is triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, lithium carbonate or potassium t-butoxide, preferably pyridine Or diisopropylethylamine.
  • the temperature of the cyclization reaction is 50 to 120 ° C, preferably 80 to 100 ° C.
  • the preparation method of eritinib (I) according to the invention has the characteristics of easy availability of raw materials, simple process and economical environmental protection, thereby facilitating the industrial production of the raw material drug and promoting the development of its economic technology. .
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • 6-Cyano-1H-indole (VI) (2.84 g, 20 mmol) and dioxane 50 mL were added to the reaction flask, the temperature was lowered to 5 ° C, and pyridine (16.1 mL, 200 mmol) and trichloroethane were added dropwise with stirring. Acid chloride (11.1 mL, 100 mmol). After the completion of the dropwise addition, the temperature was raised to 70-80 ° C, and the reaction was carried out for 3-4 hours, and the reaction was terminated by TLC. The reaction mixture was poured into ice water, and the mixture was combined with EtOAc. 0.3 g of sodium hydroxide was heated to reflux and reacted for 1 hour.
  • 6-Cyano-1H-indole (VI) (2.84 g, 20 mmol) and dioxane 50 mL were added to the reaction flask, the temperature was lowered to 5 ° C, and pyridine (16.1 mL, 200 mmol) and trichloroethane were added dropwise with stirring. Acid chloride (11.1 mL, 100 mmol). After the completion of the dropwise addition, the temperature was raised to 70-80 ° C, and the reaction was carried out for 3-4 hours, and the reaction was terminated by TLC. The reaction mixture was poured into ice water, and the mixture was combined with EtOAc. 0.4 g of potassium hydroxide was heated to reflux and reacted for 1 hour.

Abstract

一种艾立替尼(Alectinib，I)的制备方法，其制备步骤包括：6-氰基-1H-吲哚-3-羧酸酯与4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇经缩合、水解和环合反应制得艾立替尼(I)。该制备方法原料易得，工艺简洁，经济环保，适合工业化生产。

Description

艾立替尼的制备方法 技术领域
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种用于治疗非小细胞肺癌的药物艾立替尼的制备方法。
背景技术
艾立替尼(Alectinib)是由罗氏公司(Roche)的分公司日本中外制药株式会社(Chugai Pharmaceutical)开发的一种新间变性淋巴瘤激酶(ALK)抑制剂，用于治疗ALK基因重排的非小细胞肺癌患者，由于其对克唑替尼(Crizotinib)耐药的患者仍然有效，且能显著减少脑转移，该药2013年9月被美国FDA授予“突破性治疗药物”的地位，2014年7月在日本获准上市。因该药还不具有标准的中文译名，故本申请人在此将其音译为“艾立替尼”。
艾立替尼(Alectinib)的化学名为：9-乙基-6，6-二甲基-8-(4-吗啉-4-基-哌啶-1-基)-11-氧杂-6，11-二氢-5H-苯并[b]咔唑-3-甲腈(I)，其结构式为：
Figure PCTCN2015089736-appb-000001
原研公司的PCT专利WO2010143664和WO2012023597以及《Bioorganic&Medicinal Chemistry》2012年第20卷第1271-1280页和《J.Med.Chem.》2011年第54卷第6286-6294页等文献均报道了艾立替尼的合成方法，其制备主要有两条合成路线。
第一条路线是以7-甲氧基-3，4-二氢萘-2(1H)-酮(1)为起始原料，经双甲基化反应(step 1)、6-溴代(step 2)以及与肼的环合反应(step 3)制得中间体6，6-二甲基-8-甲氧基-9-溴-11-氧杂-6，11-二氢-5H-苯并[b]咔唑-3-腈基(4)(step 4)，中间体4经甲氧基水解(step 5)、三氟甲磺酸酯化(step 6)和与哌啶环的缩合制得中间体6，6-二甲基-8-(4-吗啡啉哌啶-1-基)-9-溴-11-氧杂-6，11-二氢-5H-苯并[b]咔唑-3-腈基(7)(step 7)。中间体7与(三异丙基甲硅烷基)乙炔在钯催化剂、2-二环己基磷-2，4，6-三异丙基联苯配体以及碳酸铯等作用下，发生偶联反应生成炔烃衍生物(8)，化 合物8经炔基还原成乙基从而制得目标化合物艾立替尼(I)。
Figure PCTCN2015089736-appb-000002
第二条路线通过3-碘-4-乙基叔丁基苯(9)与丙二酸单叔丁酯(10)缩合制得中间体(11)(Step 1)，该中间体与3-硝基苯腈缩合制得3-羧基吲哚衍生物(12)(Step 2)，中间体12通过其中的碘与4-吗啡啉哌啶发生碘代反应制得中间体(13)(Step 3)，后经羧基水解(Step 4)和环化(Step 5)得到目标化合物艾立替尼(I)。
Figure PCTCN2015089736-appb-000003
分析上述两条合成路线，核心的吲哚环形成步骤，分别采用了肼与羰基的缩合(路线一的Step 3)或硝基(还原后成氨基)与羰基的缩合(路线二的Step 2)。由于成环的两个底物分别含有卤素、羰基、羧基、氨基、氰基等多个官能团，使得反应过程相当复杂，副反应增多，纯化困难，而且涉及的反应原料及中间体大多较难获得。所以针对现存工艺中存在的缺陷，开发工艺简洁、经济环保且质量上乘的制备技术，尤其是寻求能够适应工业化生产的工艺技术，对该药品的经济和社会效益提高有着重要的现实意义。
发明内容
本发明的目的在于提供一种原料易得、工艺简洁、经济环保且适合工业化生产的艾立替尼的制备方法。
为实现上述发明目的，本发明采用了如下主要技术方案：一种艾立替尼(Alectinib，I)的制备方法，
Figure PCTCN2015089736-appb-000004
其制备步骤包括：用6-氰基-1H-吲哚-3-羧酸甲酯或6-氰基-1H-吲哚-3-羧酸乙酯(II)与4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇(III)在催化剂作用下发生缩合反应分别制得6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸甲酯或6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸乙酯(IV)；6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸甲酯或6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸乙酯(IV)经水解反应均制得6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸(V)；6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸(V)在碱促进剂作用下发生环合反应制得艾立替尼(I)。
Figure PCTCN2015089736-appb-000005
此外，本发明还提出如下附属技术方案：
所述原料6-氰基-1H-吲哚-3-羧酸甲酯或6-氰基-1H-吲哚-3-羧酸乙酯(II)的制备步骤包括：6-氰基-1H-吲哚(VI)经与三氯乙酰氯发生酰化反应，继而分别于甲醇或乙醇发生酯化反应制得6-氰基-1H-吲哚-3-羧酸甲酯或6-氰基-1H-吲哚-3-羧酸甲酯(II)。
Figure PCTCN2015089736-appb-000006
所述原料4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇(III)的制备步骤包括：4-乙酰基-2-溴-乙苯(VII)与4-(吗啉-4-基)哌啶(VIII)发生取代反应生成4-乙酰基-2-(4-吗啉-4-基-1-哌啶基)乙苯(IX)；4-乙酰基-2-(4-吗啉-4-基-1-哌啶基)乙苯(IX)经格氏反应制得4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇(III)。
Figure PCTCN2015089736-appb-000007
所述缩合反应的原料6-氰基-1H-吲哚-3-羧酸甲酯或6-氰基-1H-吲哚-3-羧酸乙酯(II)与化合物4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇(III)的投料摩尔比为1∶0.5-1.5，优选1∶0.9-1.1。
所述缩合反应的催化剂为三氟醋酸、三氟甲磺酸、甲基磺酸、三氟化硼或三氯化硼，优选三氟醋酸或三氟化硼。
所述缩合反应的溶剂为二氯甲烷、氯仿、1，2-二氯乙烷、乙腈、甲苯、四氢呋喃、碳酸二甲酯或二氧六环，优选二氯甲烷或四氢呋喃。
所述缩合反应的温度为-25～50℃，优选0～25℃。
所述水解反应的溶剂为甲醇、乙醇、异丙醇、三氟乙醇、六氟异丙醇、1-氟-2-氯乙烷，优选三氟乙醇。
所述环合反应的碱促进剂为三乙胺、吡啶、N-甲基吗啡啉、二异丙基乙胺、4-二甲氨基吡啶、碳酸钾、碳酸锂或叔丁醇钾，优选吡啶或二异丙基乙胺。
所述环合反应的的温度为50～120℃，优选80～100℃。
相比于现有技术，本发明所涉及的艾立替尼(I)的制备方法，具有原料易得、工艺简洁和经济环保等特点，故而利于该原料药的工业化生产，促进其经济技术的发展。
具体实施方式
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。其中起始原料6-氰基-1H-吲哚(VI)和4-(吗啉-4-基)哌啶(VIII)的制备可分别参见文献“Organic Letters，8(10)，1975-1978，2006”和“Bioorganic&Medicinal Chemistry Letters，22(9)，3157-3162，2012”对相同化合物的制备方法。
实施例一：
于反应瓶中加入6-氰基-1H-吲哚-3-羧酸甲酯(II)(2.0g，10mmol)、4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇(III)(3.3g，10mmol)和二氯甲烷50mL，降温至0-5℃，加入三氟醋酸(0.12g，1mmol)，搅拌反应30分钟，升至室温，继续反应2-4小时，TLC检测反应结束。反应体系分别用水、10％碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，有固体析出，所得粗品用正己烷和乙酸乙酯(1∶1，V/V)重结晶，真空干燥得类白色固体6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸甲酯(IV)4.1g，收率79.8％；质谱(EI)：m/z 515(M+H)。
实施例二：
于反应瓶中加入6-氰基-1H-吲哚-3-羧酸乙酯(II)(2.2g，10mmol)、4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇(III)(3.3g，10mmol)和四氢呋喃50mL，降温至0-5℃，加入三氟化硼(1.4g，10mmol)的乙醚溶液，搅拌反应30分钟，升至室温，继续反应2-4小时，TLC检测反应结束。用水淬灭反应，二氯甲烷萃取三次，有机相分别用水、10％碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，有固体析出，所得粗品用正己烷和乙酸乙酯(1∶1，V/V)重结晶，真空干燥得类白色固体6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸乙酯(IV)3.82g，收率72.3％；质谱(EI)：m/z 529(M+H)。
实施例三：
氮气氛中，于反应瓶中加入6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸甲酯(IV)(2.57g，5mmol)和三氟乙醇15mL，5-10℃下加入三甲基氯硅烷2mL，搅拌反应3小时。加入丙酮15mL，滴加1M的氢氧化钠溶液9mL和1M的磷酸二氢钾溶液3mL，缓慢搅拌下有固体析出。过滤，所得固体用水和丙酮(1∶1，V/V)洗涤，真空干燥得类白色固体6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸(V)2.36g，收率94.4％；质谱(EI)：m/z 501(M+H)。
实施例四：
氮气氛中，于反应瓶中加入6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸(V)(2.5g，5mmol)、醋酐1.5mL、N，N-二异丙基乙胺6mL和N，N-二甲基乙酰胺50mL，升温至90-95℃，搅拌反应1-2小时。冷却至 室温，加入甲醇20mL和水30mL，析出固体。过滤，粗品用甲醇和水重结晶，得到白色固体艾立替尼(I)2.1g，收率87.1％；质谱(EI)：m/z 483(M+H)。
实施例五：
于反应瓶中加入6-氰基-1H-吲哚(VI)(2.84g，20mmol)和二氧六环50mL，降温至5℃，搅拌下滴加吡啶(16.1mL，200mmol)和三氯乙酰氯(11.1mL，100mmol)。滴毕，升温至70-80℃，反应3-4小时，TLC检测反应结束。降至室温，将反应液倾入冰水中，用乙酸乙酯萃取三次，合并有机相，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩至干，所得残渣溶解于甲醇100mL中，加入氢氧化钠0.3g，加热至回流，反应1小时。常压蒸出大部分溶剂，加入乙酸乙酯，用水洗涤两次。无水硫酸钠干燥，浓缩去除溶剂，残余物用乙酸乙酯和正己烷重结晶得白色固体6-氰基-1H-吲哚-3-羧酸甲酯(II)3.72g，收率93.0％；质谱(EI)：m/z 201(M+H)。
实施例六：
于反应瓶中加入6-氰基-1H-吲哚(VI)(2.84g，20mmol)和二氧六环50mL，降温至5℃，搅拌下滴加吡啶(16.1mL，200mmol)和三氯乙酰氯(11.1mL，100mmol)。滴毕，升温至70-80℃，反应3-4小时，TLC检测反应结束。降至室温，将反应液倾入冰水中，用乙酸乙酯萃取三次，合并有机相，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩至干，所得残渣溶解于乙醇100mL中，加入氢氧化钾0.4g，加热至回流，反应1小时。常压蒸出大部分溶剂，加入乙酸乙酯，用水洗涤两次。无水硫酸钠干燥，浓缩去除溶剂，残余物用乙酸乙酯和正己烷重结晶得白色固体6-氰基-1H-吲哚-3-羧酸乙酯(II)3.86g，收率90.2％；质谱(EI)：m/z 215(M+H)。
实施例七：
于微波反应瓶中加入4-乙酰基-2-溴-乙苯(VII)(2.26g，10mmol)、4-(吗啉-4-基)哌啶(VIII)(2.55g，15mmol)、叔丁醇钾(2.24g，20mmol)和二甲亚砜50mL，将该反应瓶置于微波反应器(700瓦)中，反应5-10分钟。冷却至室温，将反应液倾入冰水中，搅拌10分钟，过滤除去不溶物，用乙酸乙酯萃取三次，合并有机相，依次用水、饱和氯化铵和饱和食盐水洗涤，无水硫酸钠干燥，浓缩至干，所得残余物用乙酸乙酯和正己烷重结晶得白色固体4-乙酰基-2-(4-吗啉-4-基-1-哌啶基)乙苯(IX)3.0g，收率94.9％；质谱(EI)：m/z317(M+H)。
实施例八：
于反应瓶中加入4-乙酰基-2-(4-吗啉-4-基-1-哌啶基)乙苯(IX)(1.58g，5mmol)和四氢呋喃50mL，降温至0-5℃，搅拌下滴加甲基氯化镁(0.4mL，10mmol)的四氢呋喃10mL溶液。滴毕，室温反应2小时。将反应液倾入冰盐水中，用乙酸乙酯萃取三次，合并有机相，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩至干，所得残余物用正己烷重结晶得灰白色固体4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇(III)1.44g，收率86.5％；质谱(EI)：m/z 333(M+H)。
需要指出的是，上述实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 一种艾立替尼(I)的制备方法，
    Figure PCTCN2015089736-appb-100001
    其制备步骤包括：6-氰基-1H-吲哚-3-羧酸甲酯或6-氰基-1H-吲哚-3-羧酸乙酯与4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇在催化剂作用下发生缩合反应分别制得6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸甲酯或6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸乙酯；6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸甲酯或6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸乙酯经水解反应均制得6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸；6-氰基-2-[2-[4-乙基-3-(4-吗啉-4-基-哌啶-1-基)苯基]丙烷-2-基]-1H-吲哚-3-羧酸在碱促进剂作用下发生环合反应制得艾立替尼(I)。
  2. 如权利要求1所述艾立替尼(I)的制备方法，所述原料6-氰基-1H-吲哚-3-羧酸甲酯或6-氰基-1H-吲哚-3-羧酸乙酯的制备步骤包括：6-氰基-1H-吲哚先与三氯乙酰氯发生酰化反应，继而分别与甲醇或乙醇发生酯化反应制得6-氰基-1H-吲哚-3-羧酸甲酯或6-氰基-1H-吲哚-3-羧酸乙酯。
  3. 如权利要求1所述艾立替尼(I)的制备方法，所述原料4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇的制备步骤包括：4-乙酰基-2-溴-乙苯与4-(吗啉-4-基)哌啶发生取代反应生成4-乙酰基-2-(4-吗啉-4-基-1-哌啶基)乙苯；4-乙酰基-2-(4-吗啉-4-基-1-哌啶基)乙苯经格氏反应制得4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇。
  4. 如权利要求1所述艾立替尼(I)的制备方法，所述缩合反应的原料6-氰基-1H-吲哚-3-羧酸甲酯或6-氰基-1H-吲哚-3-羧酸乙酯与化合物4-乙基-3-(4-吗啉-4-基-哌啶-1-基)-α，α-二甲基苯甲醇的投料摩尔比为1∶0.5-1.5。
  5. 如权利要求1所述艾立替尼(I)的制备方法，所述缩合反应的催化剂为三氟醋酸、三氟甲磺酸、甲基磺酸、三氟化硼或三氯化硼。
  6. 如权利要求1所述艾立替尼(I)的制备方法，所述缩合反应的溶剂为二氯甲烷、氯仿、1，2-二氯乙烷、乙腈、甲苯、四氢呋喃、碳酸二甲酯或二氧六环。
  7. 如权利要求1所述艾立替尼(I)的制备方法，所述缩合反应的温度为-25～50℃。
  8. 如权利要求1所述艾立替尼(I)的制备方法，所述水解反应的溶剂为甲醇、乙醇、异丙醇、三氟乙醇、六氟异丙醇、1-氟-2-氯乙烷。
  9. 如权利要求1所述艾立替尼(I)的制备方法，所述环合反应的碱促进剂为三乙胺、吡啶、N-甲基吗啡啉、二异丙基乙胺、4-二甲氨基吡啶、碳酸钾、碳酸锂或叔丁醇钾。
  10. 如权利要求1所述艾立替尼(I)的制备方法，所述环合反应的的温度为50～120℃。
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