WO2020192129A1 - 一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法及其应用 - Google Patents

一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法及其应用 Download PDF

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WO2020192129A1
WO2020192129A1 PCT/CN2019/115909 CN2019115909W WO2020192129A1 WO 2020192129 A1 WO2020192129 A1 WO 2020192129A1 CN 2019115909 W CN2019115909 W CN 2019115909W WO 2020192129 A1 WO2020192129 A1 WO 2020192129A1
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compound
ethyl
azetidin
piperidin
preparing
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PCT/CN2019/115909
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French (fr)
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梅德盛
刘爱风
孙靖
汪奎
孙高睿
陈林瑞
施佳
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苏州国匡医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the invention relates to a preparation method of pharmaceutical intermediates, in particular to a preparation method of 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol, and Its application in the preparation of anti-tumor drugs.
  • CCR4 chemokine receptor 4
  • T reg Regulatory T cells
  • CCR4 (chemokine receptor 4) antagonists can selectively inhibit T reg in tumor tissues, and can produce a durable anti-tumor immune response, which is an important part of small molecule tumor immunity.
  • ((R)-1-(2,4-Dichlorophenyl)ethyl)-6-(3-((R)-1-(2-hydroxyethyl)piperidin-3-yl)azacyclo Butan-1-yl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile (Compound 6) is an orally effective CCR4 antagonist (WO2018/022922A1).
  • compound 6 alone can effectively inhibit tumor growth; when administered in combination, compound 6 can significantly enhance immune checkpoint inhibitors such as PD-1/PD-L1 and CTLA4, as well as immune agonists such as The anti-tumor effect of anti-4-1BB.
  • Compound 6 can also enhance the immunotherapy effect based on cell therapy strategies such as CAR-T and tumor vaccines.
  • CCR4 antagonists represented by compound 6 have entered clinical studies of tumor immunotherapy and have shown good therapeutic effects.
  • the structure of compound 6 is as follows:
  • Patent WO2018/022992A1 discloses that 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol (compound 1) is prepared by the following method: 3-(piperidine- 3-yl) tert-butyl azetidinyl-1-carboxylate (1251006-73-1) (compound 7) reacts with 2-((tert-butyldimethylsilyl)oxy)acetaldehyde and then NaBH (OAc) 3 is reduced to obtain compound 8; then compound 8 is deprotected under acidic conditions to obtain compound 1.
  • the present invention provides a method for preparing 2-(3-(azetidin-3-yl)piperidine-1- with low-cost and easy-to-obtain reaction materials, mild reaction conditions, simple process and high yield.
  • Yl)ethyl-1-ol (Compound 1).
  • the present invention provides the following technical solutions:
  • a method for preparing 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol which is characterized in that the method comprises the following steps:
  • X is a halogen atom.
  • the halogen atom X in 2-haloethanol in step (1) is chlorine, bromine, or iodine
  • the molar ratio of compound 2 to 2-haloethanol is 1:0.5-3
  • the reaction temperature is 25-120°C .
  • the solvent in step (1) is an organic solvent, preferably selected from acetonitrile, methanol, ethanol, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate , Isopropyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran one or more.
  • organic solvent preferably selected from acetonitrile, methanol, ethanol, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene, ethyl acetate , Isopropyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran one or more.
  • the catalyst in step (2) is a platinum and/or palladium-containing catalyst, preferably PtO 2 , Pd-C, Pd(OAc) 2 , Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , Pd( dba) 2 , PdCl 2 or PdCl 2 (dppf), more preferably PtO 2 , and the mass ratio of the catalyst to the compound 3 is 0.1-20%.
  • the reaction in step (2) is carried out under 1 to 5 atmospheres, preferably normal pressure, and the reaction temperature is 20 to 120°C.
  • the acid catalyst in step (3) is a protic acid, preferably TFA or HCl;
  • the reaction solvent is an organic solvent, preferably methylene chloride, 1,4-dioxane or water;
  • the base is an inorganic base or organic Alkali, preferably one or more of ammonia, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, triethylamine or di(isopropyl)ethylaminekind.
  • the acid and reaction solvent in step (3) are any one of TFA/DCM, HCl/1,4-dioxane or HCl/H 2 O.
  • the reaction temperature in step (3) is 0-100°C, preferably room temperature.
  • the present invention also provides a ((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(2-hydroxyethyl)piperidine-
  • the catalyst in step (2) is an organic base, and the reaction temperature is 10-40°C, preferably room temperature.
  • the present invention solves the problem that raw materials are difficult to obtain and expensive in the process of synthesizing 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol in the prior art
  • the reagents used in the present invention such as 2-iodoethanol, 10% Pd-C, and acids such as trifluoroacetic acid or hydrochloric acid, are all conventional reagents, which are cheap and easy to obtain;
  • the hydrogenation reaction product can be obtained in a mild and high yield after pyridine salt is formed.
  • a specific catalyst containing platinum and/or palladium catalyst such as PtO 2 , Pd-C , Pd(OAc) 2 or PdCl 2 , preferably PtO 2
  • PtO 2 platinum and/or palladium catalyst
  • Compound 1 is obtained from compound 2 through 3 steps, with a total yield of over 82%;
  • the process for synthesizing 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol of the present invention has simple process steps and simple operation, and all steps do not require special For the purification, all can be directly reacted to the next step, and the 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol prepared by the present invention can be used directly Synthesis of CCR4 antagonist represented by compound 6.
  • the present invention provides a method for preparing 2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl-1-ol.
  • the method includes the following steps:
  • X is a halogen atom.
  • the halogen atom X in the 2-haloethanol in step (1) is chlorine, bromine, or iodine, preferably an iodine atom, and the molar ratio of compound 2 to 2-haloethanol is 1: 0.5 to 3, preferably 1:1 to 2, the reaction temperature is 25 to 120°C, preferably 50 to 100°C.
  • the solvent in step (1) is an organic solvent, preferably acetonitrile, methanol, ethanol, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene , Ethyl acetate, isopropyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran one or more.
  • organic solvent preferably acetonitrile, methanol, ethanol, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, petroleum ether, benzene, toluene , Ethyl acetate, isopropyl acetate, tetrahydrofuran or 2-methyltetrahydrofuran one or more.
  • the catalyst in step (2) is a catalyst containing palladium and/or platinum, preferably PtO 2 , Pd-C, Pd(OAc) 2 , Pd(PPh 3 ) 4 , Pd 2 ( dba) 3 , Pd(dab) 2 , PdCl 2 or PdCl 2 (dppf), more preferably PtO 2 , and the mass ratio of the catalyst to the compound 3 is 0.1-20%, preferably 0.5-5%.
  • the reaction of step (2) is carried out under 1 to 5 atmospheres, preferably under normal pressure, and the reaction temperature is 20 to 120°C, preferably 40 to 60°C.
  • the acid catalyst in step (3) is a protic acid, preferably TFA or HCl, the acid catalyst is preferably in excess relative to compound 4;
  • the reaction solvent is an organic solvent, preferably dichloromethane , 1,4-dioxane or water;
  • the base is an inorganic base or an organic base, preferably ammonia, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, three One or more of ethylamine or di(isopropyl)ethylamine.
  • the acid catalyst and reaction solvent in step (3) are any one of TFA/DCM, HCl/1,4-dioxane or HCl/H 2 O.
  • the reaction temperature in step (3) is 0-100°C, preferably room temperature.
  • the present invention also provides a ((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(2-hydroxyethyl)piperidine-
  • the alkali in step (2) is ammonia, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium oxide, ammonia, diethylamine, One or more of triethylamine or di(isopropyl)ethylamine, preferably one or more of ammonia, diethylamine, triethylamine or di(isopropyl)ethylamine;
  • the reaction temperature is 10-40°C, preferably room temperature.
  • the 1 H-NMR spectrum Bruker-400 nuclear magnetic resonance instrument used in the present invention, the unit of chemical shift is one part per million, and the internal standard is tetramethylsilane.
  • the coupling constant (J) is close to 0.1 Hz.
  • the abbreviations used are as follows: s, singlet; d, doublet; t, triplet; q, quartet; qu, quintet; m, multiplet; br, broad peak.
  • the mass spectrometer used Quattro MicroTM API triple quadrupole mass spectrometer.
  • Example 3 Except that Pd(OAc) 2 is used instead of PtO 2 , the operation of Example 3 is the same as that of Example 2, and the yield is 90%.
  • Example 4 Except that 10% Pd-C is used instead of PtO 2 , the operation of Example 4 is the same as that of Example 2, and the yield is 85%. This reaction may have poor reproducibility.
  • Example 6 was the same as that of Example 5. .
  • the yield was 96%.

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Abstract

本发明提供了一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，其特征在于，所述方法包括以下步骤： (1)化合物2与2-卤代乙醇在溶剂中反应得到化合物3； (2)化合物3在催化剂的作用下，经氢化反应得到化合物4； (3)化合物4在酸的条件下，脱去Boc保护基后经真空除去酸或经碱中和得到化合物1，即2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇，反应合成路线为： (2), (3), (4), (1) 其中，X为卤素原子。所述方法原料便宜易得，反应条件温和，操作简便，收率高。

Description

一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法及其应用 技术领域
本发明涉及一种医药中间体的制备方法，具体涉及一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，以及其在制备抗肿瘤药物中的应用。
背景技术
调节性T细胞(T reg)在肿瘤免疫中具有重要作用。CCR4(趋化因子受体4)拮抗剂能选择性地抑制肿瘤组织中的T reg，并能产生持久的抗肿瘤免疫反应，是小分子肿瘤免疫的重要组成部分。((R)-1-(2,4-二氯苯基)乙基)-6-(3-((R)-1-(2-羟基乙基)哌啶-3-基)氮杂环丁烷-1-基)-1H-吡唑并[3,4-b]吡嗪-3-甲腈(化合物6)是一种口服有效的CCR4拮抗剂(WO2018/022922A1)。在临床前研究中，单独给药化合物6时能有效抑制肿瘤的生长；联合给药时，化合物6能显著增强免疫检查点抑制剂如PD-1/PD-L1和CTLA4，以及免疫激动剂如anti-4-1BB的抗肿瘤效果。化合物6还可以增强基于细胞治疗策略如CAR-T和肿瘤疫苗的免疫治疗效果。以化合物6为代表的CCR4拮抗剂目前已进入肿瘤免疫治疗的临床研究，并已显示出良好的治疗效果，化合物6的结构如下：
Figure PCTCN2019115909-appb-000001
2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇(化合物1)是制备((R)-1-(2,4-二氯苯基)乙基)-6-(3-((R)-1-(2-羟基乙基)哌啶-3-基)氮杂环丁烷-1- 基)-1H-吡唑并[3,4-b]吡嗪-3-甲腈(化合物6)的N-1步重要中间体，化合物1的结构为：
Figure PCTCN2019115909-appb-000002
专利WO2018/022992A1公开了2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇(化合物1)通过如下方法制备：3-(哌啶-3-基)氮杂环丁烷基-1-羧酸叔丁酯(1251006-73-1)(化合物7)与2-((叔丁基二甲硅基)氧)乙醛反应后经NaBH(OAc) 3还原得到化合物8；继而化合物8用酸性条件脱保护基得到化合物1。
Figure PCTCN2019115909-appb-000003
但商品化的3-(哌啶-3-基)氮杂环丁烷基-1-羧酸叔丁酯(化合物7)极难获得，即使可获得也存在价位高启的显著问题；起始原料(化合物7)的采购成本过高必然导致最终目标产物如临床药物化合物6的生产成本急剧攀升。
同时，关于化合物7的制备尚未有文献报告。本专利申请人在前期研究中，曾探索用3-(吡啶-3基)氮杂环丁基-1羧酸叔丁酯(化合物2)在铂/钯催化剂如PtO 2,Pd(PPh 3) 4，Pd(OAC) 2等条件下用高压(80atm)、长时间(60小时)加热(80℃)进行催化氢化，均未反应，未能得到目标产物3-(吡啶-3基)氮杂环丁基-1羧酸叔丁酯(化合物7)。
Figure PCTCN2019115909-appb-000004
因此，探索一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇(化合物1)的经济、温和与简便的制备方法，具有重要的实际价值。
发明内容
发明要解决的问题
为了解决上述技术问题，本发明提供了一种反应原料廉价易得、反应条件温和、工艺简单且收率高地制备2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇(化合物1)的方法。
用于解决问题的方案
为了解决上述技术问题，本发明提供了如下技术方案：
一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，其特征在于，所述方法包括以下步骤：
(1)化合物2与2-卤代乙醇在溶剂中反应得到化合物3；
(2)化合物3在催化剂的作用下，经氢化反应得到化合物4；
(3)化合物4在酸的条件下，脱去Boc保护基后经真空除去酸或经碱中和得到化合物1，即2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇，反应合成路线为：
Figure PCTCN2019115909-appb-000005
其中，X为卤素原子。
优选的，步骤(1)中2-卤代乙醇中的卤素原子X为氯、溴、碘，化合物2与2-卤代乙醇的摩尔比为1:0.5～3，反应温度为25～120℃。
优选的，步骤(1)中的溶剂为有机溶剂，优选为选自乙腈、甲醇、乙醇、乙醚、甲基叔丁基醚、乙二醇二甲醚、石油醚、苯、甲苯、乙酸乙酯、乙酸异丙酯、四氢呋喃或2-甲基四氢呋喃中的一种或多种。
优选的，步骤(2)中的催化剂为含铂和/或钯催化剂，优选为PtO 2、Pd-C、Pd(OAc) 2、Pd(PPh 3) 4、Pd 2(dba) 3、Pd(dba) 2、PdCl 2或PdCl 2(dppf)，更优选为PtO 2，催化剂与化合物3的质量比为0.1～20％。
优选的，步骤(2)的反应在1～5个大气压下进行，优选为常压，反应温度为20～120℃。
优选的，步骤(3)中的酸催化剂为质子酸，优选为TFA或HCl；反应溶剂为有机溶剂，优选为二氯甲烷、1,4-二氧六环或水；碱为无机碱或有机碱，优选为氨水、碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、氢氧化钠、氢氧化钾、氧化钙、三乙胺或二(异丙基)乙基胺中的一种或多种。
优选的，步骤(3)中的酸和反应溶剂为TFA/DCM,HCl/1,4-二氧六环或HCl/H 2O中的任一种。
优选的，步骤(3)中的反应温度为0～100℃，优选为室温。
本发明还提供了一种((R)-1-(2,4-二氯苯基)乙基)-6-(3-((R)-1-(2-羟基乙基)哌啶-3-基)氮杂环丁烷-1-基)-1H-吡唑并[3,4-b]吡嗪-3-甲腈的制备方法，所述方法包括：
(1)采用权利要求1-8任一项所述的方法制备化合物1的步骤；
(2)化合物1和化合物5在碱作用下制备化合物6，即((R)-1-(2,4-二氯苯基)乙基)-6-(3-((R)-1-(2-羟基乙基)哌啶-3-基)氮杂环丁烷-1-基)-1H-吡唑并[3,4-b]吡嗪-3-甲腈的步骤，所述碱为有机碱或无机碱，反应路线如下：
Figure PCTCN2019115909-appb-000006
优选的，步骤(2)中的催化剂为有机碱，反应温度为10～40℃，优选为室温。
发明的效果
1、本发明解决了现有技术合成2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的工艺中原料不易获取且价格昂贵的问题，本发明所用到的试剂如2-碘乙醇、10％Pd-C和酸如三氟醋酸或盐酸等，均为常规试剂，便宜易得；
2、本发明并创造性地发现吡啶成盐后可以温和、高收率地得到氢化反应的产物，如在常压下，使用特定的催化剂含铂和/或钯催化剂，如PtO 2、Pd-C、Pd(OAc) 2或PdCl 2，优选为PtO 2，可以获得极好的反应收率，从化合物2经3步反应得到化合物1，总收率高达82％以上；
3、本发明的合成2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的工艺，工艺步骤简单，操作简便，所有步骤均无需特别的纯化，均直接往下步反应即可，同时本发明制备得到的2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇可以 直接用于化合物6为代表的CCR4拮抗剂的合成。
附图说明
图1化合物1的质谱图；
图2化合物6的核磁图；
图3化合物6的质谱图。
具体实施方式
本发明提供了一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，所述方法包括以下步骤：
(1)化合物2与2-卤代乙醇在溶剂中反应得到化合物3；
(2)化合物3在催化剂的作用下，经氢化反应得到化合物4；
(3)化合物4在酸的条件下，脱去Boc保护基后经真空除去酸或经碱中和得到化合物1，即2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇，反应合成路线为：
Figure PCTCN2019115909-appb-000007
其中，X为卤素原子。
在一项优选的实施方案中，步骤(1)中2-卤代乙醇中的卤素原子X为氯、溴、碘，优选为碘原子，化合物2与2-卤代乙醇的摩尔比为1:0.5～3，优选为1:1～2，反应温度为25～120℃，优选为50～100℃。
在一项优选的实施方案中，步骤(1)中的溶剂为有机溶剂，优选为乙 腈、甲醇、乙醇、乙醚、甲基叔丁基醚、乙二醇二甲醚、石油醚、苯、甲苯、乙酸乙酯、乙酸异丙酯、四氢呋喃或2-甲基四氢呋喃中的一种或多种。
在一项优选的实施方案中，步骤(2)中的催化剂为含钯和/或铂催化剂，优选为PtO 2、Pd-C、Pd(OAc) 2、Pd(PPh 3) 4、Pd 2(dba) 3、Pd(dab) 2、PdCl 2或PdCl 2(dppf)，更优选为PtO 2，催化剂与化合物3的质量比为0.1～20％，优选为0.5～5％。
在一项优选的实施方案中，步骤(2)的反应在1～5个大气压下进行，优选在常压下进行，反应温度为20～120℃，优选为40～60℃。
在一项优选的实施方案中，步骤(3)中的酸催化剂为质子酸，优选为TFA或HCl，酸催化剂相对于化合物4最好是过量的；反应溶剂为有机溶剂，优选为二氯甲烷、1,4-二氧六环或水；碱为无机碱或有机碱，优选为氨水、碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、氢氧化钠、氢氧化钾、氧化钙、三乙胺或二(异丙基)乙基胺中的一种或多种。
在一项更优选的实施方案中，步骤(3)中的酸催化剂和反应溶剂为TFA/DCM,HCl/1,4-二氧六环或HCl/H 2O中的任一种。
在一项优选的实施方案中，步骤(3)中的反应温度为0～100℃，优选为室温。
本发明还提供了一种((R)-1-(2,4-二氯苯基)乙基)-6-(3-((R)-1-(2-羟基乙基)哌啶-3-基)氮杂环丁烷-1-基)-1H-吡唑并[3,4-b]吡嗪-3-甲腈的制备方法，所述方法包括：
(1)采用以上任意的方法制备化合物1的步骤；
(2)化合物1和化合物5在碱的作用下制备化合物6，即((R)-1-(2,4-二氯苯基)乙基)-6-(3-((R)-1-(2-羟基乙基)哌啶-3-基)氮杂环丁烷-1-基)-1H-吡唑并[3,4-b]吡嗪-3-甲腈的步骤，所述碱为有机碱或无机碱，反应路线如下：
Figure PCTCN2019115909-appb-000008
在一项优选的实施方案中，步骤(2)中的碱为氨水、碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、氢氧化钠、氢氧化钾、氧化钙、氨水、二乙胺、三乙胺或二(异丙基)乙基胺中的一种或多种，优选为氨水、二乙胺、三乙胺或二(异丙基)乙基胺中的一种或多种；反应温度为10～40℃，优选为室温。
以下的这些实施例仅供例证说明的目的，并不限定在此提供的权利要求的范围。
概述本发明所用的 1H-NMR谱Bruker-400核磁共振仪，化学位移的单位是百万分之一，内标是四甲基硅烷。耦合常数(J)接近0.1Hz。使用的缩略语如下说明：s,单重峰；d，双重峰；t,三重峰；q,四重峰；qu，五重峰；m，多重峰；br，宽峰。质谱使用Quattro MicroTM API三重四极杆质谱仪。
实施例1化合物3的制备
Figure PCTCN2019115909-appb-000009
将3-(吡啶-3基)氮杂环丁基-1羧酸叔丁酯(化合物2)(1.0g，4.0mmoL)和2-碘乙醇(1.1g,6mmoL)加入到乙腈(10.0mL)中，在80℃油浴下加热过夜。TLC检测反应完全，减压蒸去溶剂。残留物用正己烷/乙酸乙酯＝5/1混合体系洗去过量的2-碘乙醇，得到棕色油状物1.62g,收率为100％。
1H NMR(CDCl 3,400MHz)δ＝9.23(s,1H),9.04(d,J＝8.0Hz,1H),8.53(d, J＝8.0Hz,1H),8.13(dd,J 1＝4.0Hz,J 2＝8.0Hz,1H),4.96-4.94(m,2H),4.46(t,J＝8.0Hz,2H),4.16-4.12(m,2H),4.05-4.01(m,2H),3.83(t,J＝4.0Hz,3H),1.45(s,9H)。
实施例2化合物4的制备
Figure PCTCN2019115909-appb-000010
将化合物3(1.5g,3.74mmoL)和PtO 2(0.15g，10％,w/w)加入到乙醇(10.0mL)中，于油浴50℃和常压下催化氢化过夜。TLC检测反应完全。过滤除去催化剂，催化剂用乙醇洗涤，滤液减压蒸去溶剂，残留物高真空干燥，得油状物980mg，收率为92％。不做纯化，直接用于下步反应。
1H NMR(CDCl 3,400MHz)δ＝3.98-3.93(m,2H),3.78-3.71(m,2H),3.69-3.65(m,3H),3.11-3.02(m,2H),2.76-2.73(m,2H),2.30-1.77(m,8H),1.43(s,9H).ESI-MS:285.2[M+H] +。
实施例3化合物4的制备
Figure PCTCN2019115909-appb-000011
除了用Pd(OAc) 2替代PtO 2外，实施例3的操作同实施例2，收率为90％。
实施例4化合物4的制备
Figure PCTCN2019115909-appb-000012
除了用10％Pd-C替代PtO 2外，实施例4的操作同实施例2，收率为85％。此反应可能存在重复性差的问题。
实施例5化合物1的制备
Figure PCTCN2019115909-appb-000013
将化合物4(980mg，3.45mmoL)加入到三氟醋酸(2.0mL)和二氯甲烷(2.0mL)的混合溶液中，室温搅拌2小时。TLC检测反应完全。减压蒸去溶剂，残留物在油浴45℃油浴下高真空干燥3小时以上，得油状物570mg，收率为89％。不做纯化，直接用于下步反应。
1H NMR(DMSO-d6,400MHz)δ＝4.71(t,J＝8.0Hz,1H),3.98-3.70(m,6H),3.50-3.35(m,2H),3.12-3.07(m,1H),2.93-2.78(m,1H),2.65-2.49(m,3H),2.09-2.00(m,1H),1.90-1.82(m,1H),1.73-1.64(m,2H),1.02-0.92(m,1H).
ESI-MS:185.0[M+H] +。
实施例6化合物1的制备
Figure PCTCN2019115909-appb-000014
除了用HCl/1,4-二氧六环替代三氟醋酸外，以及在后处理中将残留物加入到水中用氨水中和后经旋转蒸去水外，实施例6的操作同实施例5。收率为96％。
实施例7((R)-1-(2,4-二氯苯基)乙基)-6-(3-((R)-1-(2-羟基乙基)哌啶-3-基)氮杂环丁烷-1-基)-1H-吡唑并[3,4-b]吡嗪-3-甲腈(化合物6)的制备
Figure PCTCN2019115909-appb-000015
将化合物5(130mg,0.37mmoL),化合物1(136mg,0.74mmoL)和DIPEA(111mg,1.11mmoL)加入到DMF(10mL)中。室温搅拌过夜，TLC检测反应完全。减压蒸去溶剂，残留物用快速柱层析分离，洗脱剂为DCM/MeOH＝10/1，得白色固体137mg,收率为74％。
1H NMR(CD 3OD,400MHz)δ＝7.92(s,1H),7.45(dd,J 1＝J 2＝4.0Hz,1H),7.34(dd,J 1＝4.0Hz,J 2＝8.0Hz,1H),7.28(dd,J 1＝4.0Hz,J 2＝8.0Hz,1H),6.42(q,J＝8.0Hz,1H),4.30-4.24(m,2H),4.01-3.95(m,2H),3.77(t,J＝8.0Hz,2H),3.69-3.65(m,1H),3.24-3.16(m,1H),2.89(brs,2H),2.64-2.60(m,1H),2.49(brs,1H),2.24(brs,1H),2.00-1.97(m,1H),1.88-1.86(m,5H),1.72-1.65(m,1H), 1.10-1.04(m,1H).ESI-MS:500.0[M+H] +。HPLC(化学纯):99.3％。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。

Claims (10)

  1. 一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，其特征在于，所述方法包括以下步骤：
    (1)化合物2与2-卤代乙醇在溶剂中反应得到化合物3；
    (2)化合物3在催化剂的作用下，经氢化反应得到化合物4；
    (3)化合物4在酸的条件下，脱去Boc保护基后经真空除去酸或经碱中和得到化合物1，即2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇，反应合成路线为：
    Figure PCTCN2019115909-appb-100001
    其中，X为卤素原子。
  2. 如权利要求1所述的一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，其特征在于，步骤(1)中2-卤代乙醇中的卤素原子X为氯、溴、碘，化合物2与2-卤代乙醇的摩尔比为1:0.5～3，反应温度为25～120℃。
  3. 如权利要求1所述的一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，其特征在于，步骤(1)中的溶剂为有机溶剂，优选为选自乙腈、甲醇、乙醇、乙醚、甲基叔丁基醚、乙二醇二甲醚、石油醚、苯、甲苯、乙酸乙酯、乙酸异丙酯、四氢呋喃或2-甲基四氢呋喃中的一种或多种。
  4. 如权利要求1所述的一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，其特征在于，步骤(2)中的催化剂为含铂和/或钯催化剂，优选为PtO 2、Pd-C、Pd(OAc) 2、Pd(PPh 3) 4、Pd 2(dba) 3、Pd(dba) 2、PdCl 2或PdCl 2(dppf)， 更优选为PtO 2，催化剂与化合物3的质量比为0.1～20％。
  5. 如权利要求1所述的一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，其特征在于，步骤(2)的反应在1～5个大气压下进行，优选为常压，反应温度为20～120℃。
  6. 如权利要求1所述的一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，其特征在于，步骤(3)中的酸催化剂为质子酸，优选为TFA或HCl；反应溶剂为有机溶剂，优选为二氯甲烷、1,4-二氧六环或水；碱为无机碱或有机碱，优选为氨水、碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、氢氧化钠、氢氧化钾、氧化钙、三乙胺或二(异丙基)乙基胺中的一种或多种。
  7. 如权利要求6所述的一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，其特征在于，步骤(3)中的酸和反应溶剂为TFA/DCM,HCl/1,4-二氧六环或HCl/H 2O中的任一种。
  8. 如权利要求1所述的一种2-(3-(氮杂环丁烷-3-基)哌啶-1-基)乙基-1-醇的制备方法，其特征在于，步骤(3)中的反应温度为0～100℃，优选为室温。
  9. 一种((R)-1-(2,4-二氯苯基)乙基)-6-(3-((R)-1-(2-羟基乙基)哌啶-3-基)氮杂环丁烷-1-基)-1H-吡唑并[3,4-b]吡嗪-3-甲腈的制备方法，所述方法包括：
    (1)采用权利要求1-8任一项所述的方法制备化合物1的步骤；
    (2)化合物1和化合物5在碱作用下制备化合物6，即((R)-1-(2,4-二氯苯基)乙基)-6-(3-((R)-1-(2-羟基乙基)哌啶-3-基)氮杂环丁烷-1-基)-1H-吡唑并[3,4-b]吡嗪-3-甲腈的步骤，所述碱为有机碱或无机碱，反应路线如下：
    Figure PCTCN2019115909-appb-100002
  10. 如权利要求9所述的一种((R)-1-(2,4-二氯苯基)乙基)-6-(3-((R)-1-(2-羟基乙基)哌啶-3-基)氮杂环丁烷-1-基)-1H-吡唑并[3,4-b]吡嗪-3-甲腈的制备 方法，其特征在于，步骤(2)中的催化剂为有机碱，反应温度为10～40℃，优选为室温。
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