CN106928184B - 一种艾乐替尼的制备方法 - Google Patents
一种艾乐替尼的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 74
- YYBXNWIRMJXEQJ-UHFFFAOYSA-N 4-piperidin-4-ylmorpholine Chemical compound C1CNCCC1N1CCOCC1 YYBXNWIRMJXEQJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 239000002585 base Substances 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
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- AGZVMFHCESVRRI-UHFFFAOYSA-N [Na].CC(C)O Chemical compound [Na].CC(C)O AGZVMFHCESVRRI-UHFFFAOYSA-N 0.000 description 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- KDGFLJKFZUIJMX-UHFFFAOYSA-N alectinib Chemical compound CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 KDGFLJKFZUIJMX-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
Abstract
本发明公开了一种艾乐替尼的制备方法。该方法将4‑(4‑乙基‑3‑碘苯基)‑4‑甲基‑3‑氧代戊酸叔丁酯与4‑(4‑哌啶基)吗啉进行取代反应；将得到的4‑{4‑乙基‑3‑[4‑(吗啉‑4‑基)哌啶‑1‑基]苯基}‑4‑甲基‑3‑氧代戊酸叔丁酯进行环化反应和水解反应，将得到的6‑氰基‑2‑{2‑[4‑乙基‑3‑(4‑(吗啉‑4‑基)哌啶‑1‑基)苯基]丙‑2‑基}‑1H‑吲哚‑3‑羧酸进行环化反应，得到艾乐替尼。该方法操作简化，成本较低，是一种绿色环保工艺方法，适用于工业化生产。
Description
技术领域
本发明属于药物化学合成技术领域，具体涉及一种艾乐替尼的制备方法。
背景技术
新型间变性淋巴瘤激酶(ALK)抑制剂艾乐替尼(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-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈，其化学结构式为：
艾乐替尼是罗氏制药公司的分公司Chugai Pharmaceutical发明的创新药物，已经获得了美国FDA突破性治疗药物资格认定，加速审批作为口服抗肺癌新药，用于治疗ALK基因突变的晚期(转移性)非小细胞肺癌(NSCLC)，或对克里唑替尼耐受的患者的治疗。
专利US20130143877和WO2012023597A1公开的一种制备艾乐替尼的合成路线：以7-甲氧基-3,4-二氢-2-萘酮为起始原料，通过双甲基化和溴化反应，然后与苯肼的Fischer吲哚合成法进行环合反应，接着经过氧化引入11-羰基，再通过甲氧基水解得到的羟基进行三氟甲磺酸酯化，与4-(4-哌啶基)吗啉缩合，最后9-溴基被乙炔基取代，再经还原反应得到艾乐替尼，工艺路线如下所示：
由于整个合成路线步骤较长，操作繁琐，成本较高，不利于放大生产和产业化推广。
专利US20120083488公开的艾乐替尼的合成路线，以丙二酸单叔丁酯和3-碘-4乙基叔丁基苯为起始原料，经过缩合、环合、与4-(4-哌啶基)吗啉的缩合，最后环合，得到艾乐替尼，工艺路线如下所示：
专利CN104402862A公开的艾乐替尼的合成路线如下所示，其中需要用到吲哚母核化合物作为起始物原料：
以上两组合成路线的起始原料均比较昂贵，不易获得，因而需要合成制备；由于两组合成路线的中间体产物和最终产品含杂质和副产物较多，因而纯化需要使用大量溶剂，操作繁琐，收率较低，不利于产业化生产推广，因此有必要探索工艺流程短、操作简单、成本低廉而藉以适合工业化生产的艾乐替尼的制备方法。
发明内容
本发明旨在克服现有技术的不足，提供一种艾乐替尼的制备方法。
为了达到上述目的，本发明提供的技术方案为：
所述艾乐替尼的制备方法包括如下步骤：
(1)制备4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯：将4-(4-乙基-3-碘苯基)-4-甲基-3-氧代戊酸叔丁酯与4-(4-哌啶基)吗啉在缚酸剂碱和溶剂组成的体系中进行取代反应，得到4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯，反应式为：
(2)制备6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸：将4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯与3-氰基苯肼在酸催化剂的作用下进行环化反应，接着进行水解反应，得到6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸，反应式为：
(3)制备艾乐替尼：将6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸在酸催化剂和溶剂组成的体系中进行环化反应，得到艾乐替尼，反应式为：
优选地，步骤(1)所述的缚酸剂碱为甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾或异丙醇钠；所述的溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲苯或1,4-二氧六环；其中，4-(4-乙基-3-碘苯基)-4-甲基-3-氧代戊酸叔丁酯、4-(4-哌啶基)吗啉、缚酸剂碱之间的摩尔比为1.0∶(1.8～2.7)∶(2.0～3.0)，溶剂为反应的媒介、不参与反应，不需限定其与反应物和试剂的摩尔比例。
优选地，步骤(2)所述的酸催化剂为三氟乙酸、乙酸、甲酸、草酸、丙酸、正丁酸或异丁酸；其中，4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯、3-氰基苯肼、酸催化剂之间的摩尔比为1.0∶(1.1～1.4)∶(40.0～70.0)。
优选地，步骤(3)所述的酸催化剂为三氟乙酸、三氟乙酸酐、乙酸、醋酸酐、甲酸、草酸、草酰氯、五氧化二磷、三氯氧磷、氯化亚砜、五氯化磷、三氯化磷、、多聚磷酸、对甲苯磺酸、对甲苯磺酰氯、甲磺酸或甲磺酰氯；所述的溶剂为甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或1,4-二氧六环；其中，6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸、酸催化剂之间的摩尔比为1.0∶(2.0～10.0)，溶剂为反应的媒介、不参与反应，不需限定其与反应物和试剂的摩尔比例。
优选地，步骤(1)所述的取代反应的温度为90～110℃，反应时间为6～18小时；步骤(2)所述的环化反应的温度为90～120℃，反应时间为6～12小时；所述的水解反应的温度为50～70℃，反应时间为2～4小时；步骤(3)所述的环化反应的温度为100～120℃，反应时间为12～20小时。
下面对本发明作进一步说明：
本发明所述的一种艾乐替尼的制备方法，首先以4-(4-乙基-3-碘苯基)-4-甲基-3-氧代戊酸叔丁酯和4-(4-哌啶基)吗啉为原料，制备得到4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯，接着通过经典反应Fischer吲哚合成方法，羰基与苯肼在酸催化下环化形成吲哚母核，最后经过再环化，制备艾乐替尼，该路线方法设计合理简化，原料易得，反应条件容易有效控制。
本发明提供的技术方案具有以下技术效果：其一，由于各步反应完成之后只作常规性的后处理和纯化而不需要层析柱纯化，杂质较少、可控，可直接进行下一步反应，因此简化了操作，同时每一步都能获得较高的收率；其二，本发明的工艺路线起始原料和所用的试剂易得，合成反应的技术方案合理，可以大量生产来满足原料药的使用需求，适用于工业化生产；其三，由于在制备过程中不会产生污染物，因而可以体现绿色环保效果。
具体实施方式
实施例1
A)制备4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯：
4-(4-乙基-3-碘苯基)-4-甲基-3-氧代戊酸叔丁酯(10.0g,24mmol)溶于N,N-二甲基甲酰胺(200mL)，加入4-(4-哌啶基)吗啉(9.2g,54mmol)、甲醇钠(3.2g,59mmol)，反应混合物100℃搅拌反应12小时，反应液降至室温，加入水(40mL)，冷却至-10℃析晶3小时，过滤，得4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯，白色固体(9.6g)，收率87％。
B)制备6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸：
4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯(9.0g,20mmol)、3-氰基苯肼(3.3g,25mmol)与三氟乙酸(123.1g,1080mmol)混合，反应混合物105℃搅拌反应9小时，反应液降至60℃，加入水(100mL)，保温反应3小时，旋蒸浓缩至干，加入饱和碳酸氢钠溶液中和，加入乙酸乙酯萃取，硫酸镁干燥，旋蒸浓缩至干，用乙酸乙酯和正己烷混合溶剂重结晶，得6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸，类白色固体(9.4g)，收率94％。
C)制备艾乐替尼：
6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸(9.0g,18mmol)、三氟乙酸(12.2g,107mmol)溶于甲苯(150mL)，加热至110℃搅拌反应16小时，旋蒸浓缩至干，加入饱和碳酸氢钠溶液中和，加入乙酸乙酯萃取，硫酸镁干燥，旋蒸浓缩至干，用乙酸乙酯和正己烷混合溶剂重结晶，得艾乐替尼，类白色固体(7.6g)，收率88％。
实施例2
A)制备4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯：
4-(4-乙基-3-碘苯基)-4-甲基-3-氧代戊酸叔丁酯(5.0g,12mmol)溶于甲苯(100mL)，加入4-(4-哌啶基)吗啉(5.5g,32mmol)、乙醇钠(2.4g,35mmol)，反应混合物110℃搅拌反应6小时，反应液降至室温，加入水(50mL)，冷却至-10℃析晶4小时，过滤，得4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯，白色固体(5.0g)，收率91％。
B)制备6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸：
4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯(5.0g,11mmol)、3-氰基苯肼(2.0g,15mmol)与乙酸(45.8g,763mmol)混合，反应混合物120℃搅拌反应6小时，反应液降至70℃，加入水(55mL)，保温反应2小时，旋蒸浓缩至干，加入饱和碳酸氢钠溶液中和，加入乙酸乙酯萃取，硫酸镁干燥，旋蒸浓缩至干，用乙酸乙酯和正己烷混合溶剂重结晶，得6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸，类白色固体(5.1g)，收率93％。
C)制备艾乐替尼：
6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸(5.0g,10mmol)、三氟乙酸酐(21.0g,100mmol)溶于N,N-二甲基甲酰胺(90mL)，加热至120℃搅拌反应12小时，旋蒸浓缩至干，加入饱和碳酸氢钠溶液中和，加入乙酸乙酯萃取，硫酸镁干燥，旋蒸浓缩至干，用乙酸乙酯和正己烷混合溶剂重结晶，得艾乐替尼，类白色固体(4.4g)，收率91％。
实施例3
A)制备4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯：
4-(4-乙基-3-碘苯基)-4-甲基-3-氧代戊酸叔丁酯(13.5g,32mmol)溶于1,4-二氧六环(250mL)，加入4-(4-哌啶基)吗啉(10.0g,59mmol)、叔丁醇钠(6.2g,65mmol)，反应混合物90℃搅拌反应18小时，反应液降至室温，加入水(120mL)，冷却至-5℃析晶4小时，过滤，得4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯，白色固体(12.6g)，收率86％。
B)制备6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸：
4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯(12.5g,27mmol)、3-氰基苯肼(4.0g,30mmol)与甲酸(50.2g,1091mmol)混合，反应混合物90℃搅拌反应12小时，反应液降至50℃，加入水(140mL)，保温反应4小时，旋蒸浓缩至干，加入饱和碳酸氢钠溶液中和，加入乙酸乙酯萃取，硫酸镁干燥，旋蒸浓缩至干，用乙酸乙酯和正己烷混合溶剂重结晶，得6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸，类白色固体(12.4g)，收率92％。
C)制备艾乐替尼：
6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸(12.0g,24mmol)、乙酸(2.9g,48mmol)溶于1,4-二氧六环(200mL)，加热至100℃搅拌反应20小时，旋蒸浓缩至干，加入饱和碳酸氢钠溶液中和，加入乙酸乙酯萃取，硫酸镁干燥，旋蒸浓缩至干，用乙酸乙酯和正己烷混合溶剂重结晶，得艾乐替尼，类白色固体(9.7g)，收率84％。
Claims (7)
1.一种艾乐替尼的制备方法，其特征在于，所述方法包括如下步骤：
(1)制备4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯：将4-(4-乙基-3-碘苯基)-4-甲基-3-氧代戊酸叔丁酯与4-(4-哌啶基)吗啉在缚酸剂碱和溶剂组成的体系中进行取代反应，得到4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯；
(2)制备6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸：将4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯与3-氰基苯肼在酸催化剂的作用下进行环化反应，接着进行水解反应，得到6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸；
(3)制备艾乐替尼：将6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸在酸催化剂和溶剂组成的体系中进行环化反应，得到艾乐替尼。
2.根据权利要求1所述的一种艾乐替尼的制备方法，其特征在于，步骤(1)所述的缚酸剂碱为甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾或异丙醇钠；所述的溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲苯或1,4-二氧六环；其中，4-(4-乙基-3-碘苯基)-4-甲基-3-氧代戊酸叔丁酯、4-(4-哌啶基)吗啉、缚酸剂碱之间的摩尔比为1.0∶(1.8～2.7)∶(2.0～3.0)。
3.根据权利要求1所述的一种艾乐替尼的制备方法，其特征在于，步骤(2)所述的酸催化剂为三氟乙酸、乙酸、甲酸、草酸、丙酸、正丁酸或异丁酸；其中，4-{4-乙基-3-[4-(吗啉-4-基)哌啶-1-基]苯基}-4-甲基-3-氧代戊酸叔丁酯、3-氰基苯肼、酸催化剂之间的摩尔比为1.0∶(1.1～1.4)∶(40.0～70.0)。
4.根据权利要求1所述的一种艾乐替尼的制备方法，其特征在于，步骤(3)所述的酸催化剂为三氟乙酸、三氟乙酸酐、乙酸、醋酸酐、甲酸、草酸、草酰氯、五氧化二磷、三氯氧磷、氯化亚砜、五氯化磷、三氯化磷、多聚磷酸、对甲苯磺酸、对甲苯磺酰氯、甲磺酸或甲磺酰氯；所述的溶剂为甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或1,4-二氧六环；其中，6-氰基-2-{2-[4-乙基-3-(4-(吗啉-4-基)哌啶-1-基)苯基]丙-2-基}-1H-吲哚-3-羧酸、酸催化剂之间的摩尔比为1.0∶(2.0～10.0)。
5.根据权利要求1所述的一种艾乐替尼的制备方法，其特征在于，步骤(1)所述的取代反应的温度为90～110℃，反应时间为6～18小时。
6.根据权利要求1所述的一种艾乐替尼的制备方法，其特征在于，步骤(2)所述的环化反应的温度为90～120℃，反应时间为6～12小时；所述的水解反应的温度为50～70℃，反应时间为2～4小时。
7.根据权利要求1所述的一种艾乐替尼的制备方法，其特征在于，步骤(3)所述的环化反应的温度为100～120℃，反应时间为12～20小时。
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