CN115028638A - 一种鲁索替尼中间体的制备方法 - Google Patents
一种鲁索替尼中间体的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- -1 (4-chloro-7H-pyrrolo [2,3-d ] pyrimidine-7-yl) methyl Chemical group 0.000 claims abstract description 33
- ZIUHOMLGOXJJIY-UHFFFAOYSA-N CC1(C)OB(C2=CN(C(CC=O)C3CCCC3)N=C2)OC1(C)C Chemical compound CC1(C)OB(C2=CN(C(CC=O)C3CCCC3)N=C2)OC1(C)C ZIUHOMLGOXJJIY-UHFFFAOYSA-N 0.000 claims abstract description 29
- STNAQNGWDXASLM-UHFFFAOYSA-N 3-cyclopentylprop-2-enal Chemical compound O=CC=CC1CCCC1 STNAQNGWDXASLM-UHFFFAOYSA-N 0.000 claims abstract description 27
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种鲁索替尼中间体的制备方法,首先使用环戊基甲醛与甲酰甲撑基三苯基磷反应生成3‑环戊基丙烯醛,其次3‑环戊基丙烯醛在碱的作用下与4‑吡唑硼酸频那醇酯反应生成3‑环戊基‑3‑(4‑(4,4,5,5‑四甲基‑1,3,2‑二氧硼杂环戊烷‑2‑基)‑1H‑吡唑‑1‑基)丙醛,最后3‑环戊基‑3‑(4‑(4,4,5,5‑四甲基‑1,3,2‑二氧硼杂环戊烷‑2‑基)‑1H‑吡唑‑1‑基)丙醛在催化剂和碱的作用下与(4‑氯‑7H‑吡咯并[2,3‑d]嘧啶‑7‑基)新戊酸甲酯发生偶联反应,生成鲁索替尼中间体。本发明方法采用的原料价廉易得,合成方法操作简单,反应条件温和,适合工业化生产的需求。
Description
技术领域
本发明属于化学药物中间体制备方法技术领域,具体涉及一种鲁索替尼中间体——(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的制备方法。
背景技术
鲁索替尼(Ruxolitinib),是一种口服JAK1和JAK2酪氨酸激酶抑制剂,由美国因塞特公司和瑞士诺华制药公司联合研发,商品名为捷恪卫(Jakafi)。临床上主要用于骨髓纤维化和新型冠状病毒感染肺炎(COVID-19)等疾病的治疗。
骨髓纤维化(MF)简称髓纤,是一种由于骨髓造血组织中胶原增生,其纤维组织严重地影响造血功能所引起的一种骨髓增生性疾病。鲁索替尼通过阻断JAK信号转导及转录激活,抑制Janus相关激酶JAK1和JAK2的表达。作为选择性强、毒副作用小和耐受性良好的口服治疗药物,鲁索替尼适用于治疗中度或高危MF,包括原发性MF、真性红细胞增多性MF和原发性血小板增多性MF,该药的批准上市将为骨髓纤维化的治疗带来希望。
因此开发一条高效、经济、绿色符合工业化生产的合成方法来制备鲁索替尼中间体具有重要意义。
鲁索替尼为(R)-3-环戊基-3-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1-H-吡唑-1-基)丙腈,其结构式为:
专利W02010083283A2报道如下合成路线:
该路线以3-环戊基丙炔酸甲酯为起始原料,依次经Michael加成、不对称氢化还原、水解酰胺化、脱水消除以及脱保护基五步反应得到目标产物鲁索替尼。
该路线最大的缺点在于原料3-环戊基丙炔酸甲酯不易制备,氢化使用的手性催化剂制备困难,成本高,故不适合工业化生产。
文献Angew.Chem.Int.Ed.2015,54,7149-7153,Alexandel M.Haydl等人报道如下合成路线:
该路线以环戊基联烯为起始原料,依次经过Michael加成、Wacker氧化、氧化反应、水解酰胺化、脱水消除、Still偶联、以及Suzuki偶联七步得到目标产物鲁索替尼。
该路线原料不易得,手性拆分纯度不高,中间体纯化困难,成本高,故不适合工业化生产。
专利CN 104496904 A报道如下合成路线:
该路线首先由环戊烷甲酸甲酯为起始原料,依次经过取代、酶催化不对称还原、Mitsunobu反应、Still偶联、以及Suzuki偶联五步得到目标产物鲁索替尼。
该路线反应条件苛刻、催化剂昂贵、成本高、故不适合工业化生产。
专利W02010083283A2报道如下合成路线:
该路线以3-环戊基丙烯腈为起始原料,依次通过Michael加成、手性拆分以及Suzuki偶联反应三步得到目标物鲁索替尼。
该路线需要手性拆分,分离效率低,成本高,故不适合工业化生产。
专利W02007070514报道如下合成路线:
该路线以环戊基甲醛为起始原料,依次经过Witting反应、Michael加成反应、手性拆分以及脱保护基四步得到目标产物鲁索替尼。
该路线的最大缺点在于关键中间体需要手性拆分,效率低,成本高,实际应用价值偏低,故不适合工业化生产。
专利W02010083283A2报道如下合成路线:
该路线以环戊基甲醛为起始原料,依次经Witting反应、Michael加成、氧化反应、水解酰胺化、脱水消除、Still偶联以及Suzuki偶联七步得到目标产物鲁索替尼。
该路线最大缺点在于Michael加成步骤所使用的催化剂制备条件苛刻且不对称加成反应效率低,故不适合工业化生产。
以上所述方法存在原料不易获取,中间体难以制备,手性拆分效率低,或合成步骤较长等缺点,因此开发一种高效的合成方法来制备鲁索替尼具有重要意义。(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯作为鲁索替尼合成的一种重要合成子,具有原料价廉易得,制备简单等优点,因此开发以(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯为原料来制备鲁索替尼的合成工艺具有很好的社会价值与经济效益。
发明内容
本发明针对上述现有技术存在的不足,旨在提供一种鲁索替尼中间体——(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的制备方法。本发明方法原料价廉易得,合成操作简单,反应条件温和,对设备要求较低,经济上合理,适合工业化生产。
本发明鲁索替尼中间体——(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的制备方法,包括如下步骤:
步骤1:将环戊基甲醛与甲酰甲撑基三苯基磷发生Witting反应,生成3-环戊基丙烯醛;
步骤2:将步骤1中得到的3-环戊基丙烯醛在碱的作用下与4-吡唑硼酸频那醇酯发生Michael加成反应,生成3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛;
步骤3:将步骤2中得到的3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛在催化剂和碱的作用下与(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯发生Suzuki偶联反应,生成(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯。
反应路线如下所示:
步骤1中,环戊基甲醛与甲酰甲撑基三苯基磷的摩尔比为1:1.0-1.5。例如1:1.0、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5,优选1:1.0。
步骤1中,反应在溶剂的存在下进行;所述溶剂为二氯甲烷、氯仿、苯、甲苯、二甲苯、乙腈、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、N-甲基吡咯烷酮或六甲基磷酰三胺中的任意一种或几种的组合,优选甲苯。
步骤1中,反应在适当温度下进行,反应温度为室温至所用溶剂的沸点温度区间均可。例如25℃、30℃、35℃、40℃、45℃、50℃、60℃、70℃、75℃、80℃、85℃、90℃等,或者在溶剂沸点即回流状态下进行反应,优选80℃。
步骤2中,3-环戊基丙烯醛、碱和4-吡唑硼酸频那醇酯的摩尔比为1:0.1-0.5:1.0-1.5。例如1:0.1:0.5、1:0.2:0.5、1:0.3:0.5、1:0.4:0.5、1:0.5:0.5、1:0.5:1.0,优选1:0.5:0.5。
步骤2中,所述碱为DBU、三乙胺、N,N-二异丙基乙胺、N,N-二甲基苯胺、吡啶、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯或氢化钠中的任意一种或几种的组合,优选DBU。
步骤2中,反应在溶剂的存在下进行;所述溶剂为二氯甲烷、氯仿、苯、甲苯、二甲苯、乙腈、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、N-甲基吡咯烷酮或六甲基磷酰三胺中的任意一种或几种的组合,优选乙腈。
步骤2中,反应在适当温度下进行,反应温度为室温至所用溶剂的沸点温度区间均可。例如25℃、30℃、35℃、40℃、45℃、50℃、60℃、70℃、75℃、80℃、85℃、90℃等,或者在溶剂沸点即回流状态下进行反应,优选室温。
步骤3中,(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯、催化剂、3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛、碱的摩尔比为1:0.005-0.05:1.0-1.5:1.0-5.0。例如1:0.01:1.1:1.1、1:0.01:1.1:1.5、1:0.01:1.1:2.0、1:0.01:1.1:2.1、1:0.01:1.1:2.5、1:0.01:1.1:3.5、1:0.01:1.1:5,优选1:0.01:1.1:2.1。
步骤3中,所述催化剂为三苯基膦醋酸钯、双(三乙基膦)钯、双(甲基二苯膦)二氯化钯、双(三苯基膦)二氯化钯、四(三苯基膦)钯中的任意一种,优选四(三苯基膦)钯。
步骤3中,所述碱为DBU、三乙胺、N,N-二异丙基乙胺、N,N-二甲基苯胺、吡啶、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯或氢化钠中的任意一种或几种的组合,优选碳酸钾。
步骤3中,反应在溶剂的存在下进行;所述溶剂为水、二氯甲烷、氯仿、苯、甲苯、二甲苯、乙腈、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、N-甲基吡咯烷酮或六甲基磷酰三胺中的任意一种或几种的组合,优选水与1,4-二氧六环。
步骤3中,反应在适当温度下进行,反应温度为室温至所用溶剂的沸点温度区间均可。例如25℃、30℃、35℃、40℃、45℃、50℃、60℃、70℃、75℃、80℃、85℃、90℃等,或者在溶剂沸点即回流状态下进行反应,优选90℃。
进一步地,步骤1中利用环戊基甲醛与甲酰甲撑基三苯基磷发生Witting反应生成3-环戊基丙烯醛,反应包括如下步骤:
将甲酰甲撑基三苯基磷用甲苯溶解,室温下搅拌10min,缓慢滴加环戊基甲醛,加毕,体系升温至80℃,TLC监测应完毕后,结束反应;减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=20:1),即得黄色油状产物3-环戊基丙烯醛。
进一步地,步骤2中利用3-环戊基丙烯醛在碱的作用下与4-吡唑硼酸频那醇酯发生Michael加成反应,得到3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛的反应包括如下步骤:
将4-吡唑硼酸频那醇酯用乙腈溶解,室温下加入碱和3-环戊基丙烯醛,室温反应,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=4:1),即得黄色液体产物3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛。
进一步地,步骤3中利用3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛在催化剂和碱的作用下与(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯发生Suzuki偶联反应,生成(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的反应包括如下步骤:
将3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛、(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯依次用1,4-二氧六环溶解,碳酸钾用水溶解,两相混合均匀,加入四(三苯基膦)钯,升温至90℃,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=2:1),即得黄色发泡状固体(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯。
相对于现有技术,本发明具有以下有益效果:
本发明制备的(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的方法,原料价廉易得,反应操作简单,条件温和,对设备要求低,满足工业化生产的需求。
附图说明
图1为3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛的核磁谱图。
图2为(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的核磁谱图。
具体实施方式
下面通过具体的实施例来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
实施例1:
(1)3-环戊基丙烯醛的制备,具体制备方法如下:
将甲酰甲撑基三苯基磷(15.50g,50.95mmol,1.0eq)用甲苯(100mL)溶解,室温下搅拌10min,缓慢滴加环戊基甲醛(5.00g,50.95mmol,1.0eq),加毕,体系升温至80℃,TLC监测反应完毕后,结束反应;减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=20:1),即可得到黄色液体3-环戊基丙烯醛(4.53g,收率71.58%)。1H NMR(400MHz,DMSO-d6)δ9.49(d,J=7.8Hz,1H),7.02(dd,J=15.5,7.8Hz,1H),6.07(dd,J=15.5,7.8Hz,1H),2.75(q,J=8.0Hz,1H),1.76–1.38(m,8H),13C NMR(101MHz,DMSO-d6)δ195.11,164.11,131.22,43.14,32.38,25.43。
(2)3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛的制备,具体制备方法如下:
将4-吡唑硼酸频那醇酯(2.34g,12.08mmol,1.0eq)用乙腈(50mL)溶解,室温下加入DBU(1.84g,12.08mmol,1.0eq)和3-环戊基丙烯醛(3.00g,24.16mmol 2.0eq),室温反应,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,无水Na2SO4干燥,减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=4:1),即得黄色液体3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛(3.08g,收率:80.05%)。1H NMR(400MHz,Chloroform-d)δ9.61(d,J=1.3Hz,1H),7.75(s,1H),7.71(s,1H),4.42(dd,J=9.8,3.5Hz,1H),3.29(dd,J=17.6,9.7,1.5Hz,1H),2.83(dd,J=17.5,3.5Hz,1H),2.43–2.35(m,1H),1.85–1.51(m,8H),1.29(s,12H)。13C NMR(101MHz,Chloroform-d)δ199.74,145.73,136.69,83.34,61.57,47.63,45.13,30.07,25.36,24.91,24.84.
(3)(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的制备,具体制备方法如下:
将(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯(2.29g,8.57mmol,1.0eq)与3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛(3.00g,9.43mmol,1.1eq)先后溶解在1,4-二氧六环(80mL)中,碳酸钾(2.49g,18.00mmol,2.1eq)溶解在水(40mL)中,两相混合均匀,加入四(三苯基膦)钯(100mg,0.0857mmol,0.01eq)。加毕,氮气保护,升温至90℃,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,无水Na2SO4干燥,减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=2:1),即得黄色发泡状固体(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯(2.52g,收率:69.33%)。1H NMR(400MHz,Chloroform-d)δ9.71(d,J=1.1Hz,1H),8.86(s,1H),8.27(s,1H),8.23(s,1H),7.46(d,J=3.8Hz,1H),6.75(d,J=3.8Hz,1H),6.24(s,2H),4.55(td,J=9.8,3.4Hz,1H),3.40(ddd,J=17.9,9.7,1.4Hz,1H),2.93(dd,J=17.9,3.3Hz,1H),2.38–2.26(m,1H),1.94–1.80(m,1H),1.72–1.56(m,7H),1.15(s,9H)。13C NMR(101MHz,Chloroform-d)δ199.37,178.52,152.13,152.10,151.40,139.57,130.87,129.19,120.56,114.31,101.42,65.81,62.12,47.51,44.99,38.94,30.11,29.77,26.95,25.40,24.92.
实施例2:
(1)3-环戊基丙烯醛的制备,具体制备方法如下:
将甲酰甲撑基三苯基磷(9.30g,30.57mmol,1.0eq)用N,N-二甲基甲酰胺(50mL)溶解,室温下搅拌10min,缓慢滴加环戊基甲醛(3.00g,30.57mmol,1.0eq),加毕,体系升温至80℃,TLC监测反应完毕后,结束反应;减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=20:1),即可得到黄色液体3-环戊基丙烯醛(2.08g,收率54.74%)。1H NMR(400MHz,DMSO-d6)δ9.49(d,J=7.8Hz,1H),7.02(dd,J=15.5,7.8Hz,1H),6.07(dd,J=15.5,7.8Hz,1H),2.75(q,J=8.0Hz,1H),1.76–1.38(m,8H),13C NMR(101MHz,DMSO-d6)δ195.11,164.11,131.22,43.14,32.38,25.43。
(2)3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛的制备,具体制备方法如下:
将4-吡唑硼酸频那醇酯(735mg,3.79mmol,1.0eq)用N,N-二甲基甲酰胺(50mL)溶解,室温下加入DBU(577mg,3.79mmol,1.0eq)和3-环戊基丙烯醛(0.94g,7.57mmol 2.0eq),室温反应,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,无水Na2SO4干燥,减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=4:1),即得黄色液体3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛(791mg,收率:65.59%)。1H NMR(400MHz,Chloroform-d)δ9.61(d,J=1.3Hz,1H),7.75(s,1H),7.71(s,1H),4.42(dd,J=9.8,3.5Hz,1H),3.29(dd,J=17.6,9.7,1.5Hz,1H),2.83(dd,J=17.5,3.5Hz,1H),2.43–2.35(m,1H),1.85–1.51(m,8H),1.29(s,12H)。13C NMR(101MHz,Chloroform-d)δ199.74,145.73,136.69,83.34,61.57,47.63,45.13,30.07,25.36,24.91,24.84.
(3)(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的制备,具体制备方法如下:
将(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯(383mg,1.43mmol,1.0eq)、3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛(500mg,1.57mmol,1.1eq)以及碳酸钾(415mg,3.00mmol,2.1eq)先后溶解在1,4-二氧六环(40mL)中,加入四(三苯基膦)钯(17mg,0.0143mmol,0.01eq)。加毕,氮气保护,升温至90℃,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,无水Na2SO4干燥,减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=2:1),即得黄色发泡状固体(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯(299mg,收率:49.30%)。1H NMR(400MHz,Chloroform-d)δ9.71(d,J=1.1Hz,1H),8.86(s,1H),8.27(s,1H),8.23(s,1H),7.46(d,J=3.8Hz,1H),6.75(d,J=3.8Hz,1H),6.24(s,2H),4.55(td,J=9.8,3.4Hz,1H),3.40(ddd,J=17.9,9.7,1.4Hz,1H),2.93(dd,J=17.9,3.3Hz,1H),2.38–2.26(m,1H),1.94–1.80(m,1H),1.72–1.56(m,7H),1.15(s,9H)。13C NMR(101MHz,Chloroform-d)δ199.37,178.52,152.13,152.10,151.40,139.57,130.87,129.19,120.56,114.31,101.42,65.81,62.12,47.51,44.99,38.94,30.11,29.77,26.95,25.40,24.92.
实施例3:
(1)3-环戊基丙烯醛的制备,具体制备方法如下:
采用与实施例1步骤(1)相同的方法制备化合物3-环戊基丙烯醛
(2)3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛的制备,具体制备方法如下:
将4-吡唑硼酸频那醇酯(156mg,0.80mmol,1.0eq)用乙腈(50mL)溶解,室温下加入三乙胺(163mg,1.61mmol,1.0eq)和3-环戊基丙烯醛(200mg,1.61mmol 2.0eq),室温反应,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,无水Na2SO4干燥,减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=4:1),即得黄色液体3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛(159mg,收率:62.50%)。1H NMR(400MHz,Chloroform-d)δ9.61(d,J=1.3Hz,1H),7.75(s,1H),7.71(s,1H),4.42(dd,J=9.8,3.5Hz,1H),3.29(dd,J=17.6,9.7,1.5Hz,1H),2.83(dd,J=17.5,3.5Hz,1H),2.43–2.35(m,1H),1.85–1.51(m,8H),1.29(s,12H)。13C NMR(101MHz,Chloroform-d)δ199.74,145.73,136.69,83.34,61.57,47.63,45.13,30.07,25.36,24.91,24.84.
(3)(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的制备,具体制备方法如下:
将(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯(200mg,0.75mmol,1.0eq)与3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛(264g,0.83mmol,1.1eq)先后溶解在1,4-二氧六环(40mL)中,碳酸钠(994mg,1.58mmol,2.1eq)溶解在水(20mL)中,两相混合均匀,加入四(三苯基膦)钯(9mg,0.0075mmol,0.01eq)。加毕,氮气保护,升温至90℃,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,无水Na2SO4干燥,减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=2:1),即得黄色发泡状固体(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯(187mg,收率:58.73%)。1H NMR(400MHz,Chloroform-d)δ9.71(d,J=1.1Hz,1H),8.86(s,1H),8.27(s,1H),8.23(s,1H),7.46(d,J=3.8Hz,1H),6.75(d,J=3.8Hz,1H),6.24(s,2H),4.55(td,J=9.8,3.4Hz,1H),3.40(ddd,J=17.9,9.7,1.4Hz,1H),2.93(dd,J=17.9,3.3Hz,1H),2.38–2.26(m,1H),1.94–1.80(m,1H),1.72–1.56(m,7H),1.15(s,9H)。13C NMR(101MHz,Chloroform-d)δ199.37,178.52,152.13,152.10,151.40,139.57,130.87,129.19,120.56,114.31,101.42,65.81,62.12,47.51,44.99,38.94,30.11,29.77,26.95,25.40,24.92.
实施例4:
(1)3-环戊基丙烯醛的制备,具体制备方法如下:
采用与实施例1步骤(1)相同的方法制备化合物3-环戊基丙烯醛。
(2)3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛的制备,具体制备方法如下:
采用与实施例1步骤(2)相同的方法制备化合物3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛。
(3)(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的制备,具体制备方法如下:
将(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯(200mg,0.75mmol,1.0eq)与3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛(264g,0.83mmol,1.1eq)先后溶解在1,4-二氧六环(40mL)中,碳酸钾(218mg,1.58mmol,2.1eq)溶解在水(20mL)中,两相混合均匀,加入双(三苯基膦)二氯化钯(6mg,0.0075mmol,0.01eq)。加毕,氮气保护,升温至90℃,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,无水Na2SO4干燥,减压浓缩,浓度梯度洗脱(洗脱液为石油醚:乙酸乙酯=2:1),即得黄色发泡状固体(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯(189mg,收率:59.37%)。1H NMR(400MHz,Chloroform-d)δ9.71(d,J=1.1Hz,1H),8.86(s,1H),8.27(s,1H),8.23(s,1H),7.46(d,J=3.8Hz,1H),6.75(d,J=3.8Hz,1H),6.24(s,2H),4.55(td,J=9.8,3.4Hz,1H),3.40(ddd,J=17.9,9.7,1.4Hz,1H),2.93(dd,J=17.9,3.3Hz,1H),2.38–2.26(m,1H),1.94–1.80(m,1H),1.72–1.56(m,7H),1.15(s,9H)。13C NMR(101MHz,Chloroform-d)δ199.37,178.52,152.13,152.10,151.40,139.57,130.87,129.19,120.56,114.31,101.42,65.81,62.12,47.51,44.99,38.94,30.11,29.77,26.95,25.40,24.92.
本发明通过上述实施例来说明本发明的3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛的制备方法,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (10)
1.一种鲁索替尼中间体的制备方法,其特征在于包括如下步骤:
步骤1:将环戊基甲醛与甲酰甲撑基三苯基磷发生Witting反应,生成3-环戊基丙烯醛;
步骤2:将步骤1中得到的3-环戊基丙烯醛在碱的作用下与4-吡唑硼酸频那醇酯发生Michael加成反应,生成3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛;
步骤3:将步骤2中得到的3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛在催化剂和碱的作用下与(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯发生Suzuki偶联反应,生成鲁索替尼中间体——(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯;
反应路线如下所示:
2.根据权利要求1所述的制备方法,其特征在于:
步骤1中,环戊基甲醛与甲酰甲撑基三苯基磷的摩尔比为1:1.0-1.5。
3.根据权利要求1所述的制备方法,其特征在于:
步骤2中,所述碱为DBU、三乙胺、N,N-二异丙基乙胺、N,N-二甲基苯胺、吡啶、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯或氢化钠中的任意一种或几种的组合。
4.根据权利要求1所述的制备方法,其特征在于:
步骤2中,3-环戊基丙烯醛、碱和4-吡唑硼酸频那醇酯的摩尔比为1:0.1-0.5:1.0-1.5。
5.根据权利要求1所述的制备方法,其特征在于:
步骤3中,(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯、催化剂、3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛、碱的摩尔比为1:0.005-0.05:1.0-1.5:1.0-5.0。
6.根据权利要求1所述的制备方法,其特征在于:
步骤3中,所述催化剂为三苯基膦醋酸钯、双(三乙基膦)钯、双(甲基二苯膦)二氯化钯、双(三苯基膦)二氯化钯、四(三苯基膦)钯中的任意一种。
7.根据权利要求1所述的制备方法,其特征在于:
步骤3中,所述碱为DBU、三乙胺、N,N-二异丙基乙胺、N,N-二甲基苯胺、吡啶、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯或氢化钠中的任意一种或几种的组合。
8.根据权利要求1或2所述的制备方法,其特征在于:
步骤1中利用环戊基甲醛与甲酰甲撑基三苯基磷发生Witting反应生成3-环戊基丙烯醛,反应包括如下步骤:
将甲酰甲撑基三苯基磷用甲苯溶解,室温下搅拌10min,缓慢滴加环戊基甲醛,加毕,体系升温至80℃,TLC监测应完毕后,结束反应;减压浓缩,浓度梯度洗脱,即得黄色油状产物3-环戊基丙烯醛。
9.根据权利要求1、3或4所述的制备方法,其特征在于:
步骤2中利用3-环戊基丙烯醛在碱的作用下与4-吡唑硼酸频那醇酯发生Michael加成反应,得到3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛的反应包括如下步骤:
将4-吡唑硼酸频那醇酯用乙腈溶解,室温下加入碱和3-环戊基丙烯醛,室温反应,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,减压浓缩,浓度梯度洗脱,即得黄色液体产物3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛。
10.根据权利要求1、5、6或7所述的制备方法,其特征在于:
步骤3中利用3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛在催化剂和碱的作用下与(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯发生Suzuki偶联反应,生成(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯的反应包括如下步骤:
将3-环戊基-3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙醛、(4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯依次用1,4-二氧六环溶解,碳酸钾用水溶解,两相混合均匀,加入四(三苯基膦)钯,升温至90℃,TLC监测反应完毕后,缓慢加入2倍体积水淬灭,再使用甲基叔丁基醚萃取,减压浓缩,浓度梯度洗脱,即得黄色发泡状固体(4-(1-(1-环戊基-3-氧丙基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-7-基)新戊酸甲酯。
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