CN103408552B - 阿立塞替的制备方法 - Google Patents
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- ZLHFILGSQDJULK-UHFFFAOYSA-N 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid Chemical compound C1=C(C(O)=O)C(OC)=CC(NC=2N=C3C4=CC=C(Cl)C=C4C(=NCC3=CN=2)C=2C(=CC=CC=2F)OC)=C1 ZLHFILGSQDJULK-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 229950009447 alisertib Drugs 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 10
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims abstract description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
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- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 20
- -1 hydrolith Chemical compound 0.000 claims description 18
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
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- WEYUEVARCIVKEP-UHFFFAOYSA-N 1-chloro-2-benzofuran Chemical compound C1=CC=CC2=C(Cl)OC=C21 WEYUEVARCIVKEP-UHFFFAOYSA-N 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
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- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
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- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 2
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
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- 150000002576 ketones Chemical class 0.000 description 6
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Abstract
本发明揭示了一种阿立塞替(Alisertib，I)的制备方法，包括如下步骤：3-[(2-氟-6-甲氧基)苯基]-5-氯苯酞(II)与乙腈加成反应生成1，3-二氢-1-羟基-3-[(2-氟-6-甲氧基)苯基]-5-氯-异苯并呋喃-1-乙腈(III)；中间体(III)与N，N-二甲基甲酰胺二甲基缩醛(DMF-DMA)缩合反应得到3-{[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-2-基}-2-[2-(二甲氨基)亚甲基]-3-氧杂丙腈(IV)；中间体(IV)与4-胍-2-甲氧基苯甲酸盐酸盐(VI)发生环合反应生成4-{[4-[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-5-腈基嘧啶-2-基]氨基}-2-甲氧基苯甲酸(V)；中间体(V)经过还原、氧化及环合得到阿立塞替(I)。该制备方法工艺简洁、原料易得，适合工业化放大的要求。
Description
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，特别涉及一种阿立塞替(Alisertib)的制备方法。
背景技术
Alisertib(代号MLN8237)是由千禧制药(Millennium)和武田制药(Takeda)联合研发的一种多靶点小分子化合物。因该药物在我国还未正式上市，还不具有标准的中文译名，故本申请人在此将其音译为“阿立塞替”。阿立塞替(Alisertib)是一种极光激酶(Aurora A)、细胞周期和有丝分裂抑制剂。科学研究表明阿立塞替没有常规化疗药物那样巨大的副作用，是一个更温和的抗癌药物。这是因为该化合物专门针对一个关键酶，避免了损伤骨髓和血液中的健康细胞，并且可能会在更低剂量的情况下比之前研究测试的药物更有效。基于评估阿立塞替用于T细胞淋巴癌III期临床研究已经在美国和其它地区展开。
阿立塞替(Alisertib，I)，化学名为4-[[9-氯-7-(2-氟-6-甲氧基苯基)-5H-嘧啶并[5，4-D][2]苯并氮杂卓-2-基]氨基]-2-甲氧基苯甲酸。
千禧制药公司原研的美国专利第US2005256102号报道了阿立塞替的制备方法：以4-氨基-2-甲氧基苯甲酸酯为原料，通过与氨基腈反应得到中间体4-胍-2-甲氧基苯甲酸盐酸盐(VI)；以1-(2-氨基-5-氯苯基)-1-(2，6-二氟苯基)甲酮为原料，通过重氮化、卤代和醚化制备得到中间体1-(2-碘-5-氯苯基)-1-(2-氟-6-甲氧基苯基)甲酮(VII)；中间体(VII)通过Heck烷基化反应和环化反应得到中间体(E)-8-氯-1-(2-氟-6-甲氧基苯基)-3H-苯并[C]氮杂卓-5-(4H)-酮(VIII)，中间体(VIII)与DMF-DMA缩合得到(1E，4E)-8-氯-4-[(二甲基氨基)亚甲基]-1-(2-氟-6-甲氧基苯基)-3H-苯并[C]氮杂卓-5-(4H)-酮(IX)，中间体(IX)与中间体(VI)缩合得到阿立塞替(I)。
世界专利第WO2011103089号和合成化学2012年、第20卷第5期、第652-655页分别对上述合成方法进行了优化和改进。其中，前者在中间体(VII)转化为中间体(VIII)的过程中采用一步反应，提高了反应效率；而后者则在中间体(VI)制备过程中采用不同的保护基团，使副产物减少。由于上述反应路线存在原料不易获得、总收率偏低且需要使用硫酸汞等有毒催化剂，尤其是从中间体(IX)与中间体(VI)缩合制备阿立塞替(I)的反应收率较低，且难提纯，使其工业化难度加大。
发明内容
为了克服现有技术中的缺陷，本发明的目的在于按照绿色化学的合成理念，提供一种新的阿立塞替(I)的制备方法，该制备方法原料易得，工艺简洁，经济环保，利于工业化生产。
为了实现上述目的，本发明所提供的主要技术方案如下：一种阿立塞替(Alisertib，4-[[9-氯-7-(2-氟-6-甲氧基苯基)-5H-嘧啶并[5，4-D][2]苯并氮杂卓-2-基]氨基]-2-甲氧基苯甲酸，I)的制备方法，
其特征在于该制备方法包括如下步骤：3-[(2-氟-6-甲氧基)苯基]-5-氯苯酞(II)与乙腈发生加成反应生成中间体1，3-二氢-1-羟基-3-[(2-氟-6-甲氧基)苯基]-5-氯-异苯并呋喃-1-乙腈(III)；中间体(III)与N，N-二甲基甲酰胺二甲基缩醛(DMF-DMA)进行缩合反应得到中间体3-{[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-2-基}-2-[2-(二甲氨基)亚甲基]-3-氧杂丙腈(IV)；中间体(IV)与4-胍-2-甲氧基苯甲酸盐酸盐(VI)发生环合反应生成中间体4-{[4-[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-5-腈基嘧啶-2-基]氨基}-2-甲氧基苯甲酸(V)；中间体(V)依次经过还原反应、氧化反应及环合反应得到阿立塞替(I)。
此外，本发明还包括如下附属技术方案：
所述3-[(2-氟-6-甲氧基)苯基]-5-氯苯酞(II)与乙腈发生加成反应的碱性促进剂为氨基钠、氨基钾、氢化钠、氢化钙、正丁基锂、苯基锂、叔丁醇钾、甲醇钠，优选氨基钠或氢化钠。
所述缩合反应的温度为45-95℃，优选60-65℃。
所述3-{[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲酮]-2-基}-2-[2-(二甲氨基)亚甲基]-3-氧杂丙腈(IV)与4-胍-2-甲氧基苯甲酸盐酸盐(VI)发生环合反应的投料摩尔比为1∶1-2，优选1∶1.1-1.3。
所述环合反应的催化剂为三乙胺、吡啶、N-甲基吗啡啉、二异丙基乙胺、氢氧化钠、甲醇钠、叔丁醇钾、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠或碳酸钾，优选碳酸钾或叔丁醇钾。
所述还原反应的还原剂为硼氢化钠、硼氢化钾、氰基硼氢化钠、硼烷或四氢铝锂，优选四氢铝锂。
所述还原反应可采用催化氢化来实现。
所述催化氢化反应的催化剂为雷尼镍、钯炭、铂炭或氢氧化钯炭，优选雷尼镍。
所述氧化反应的氧化剂为双氧水、双氧水和三氯化铁、过氧苯甲酸、间氯过氧苯甲酸、次氯酸、活性二氧化锰、三氧化铬、高锰酸钾、重铬酸钾、氯铬酸吡啶(PCC)、氯重铬酸吡啶(PDC)、二甲亚砜/草酰氯(Swern)、2-碘酰基苯甲酸(IBX)、戴斯-马丁氧化剂(Dess-MartinPeriodinane)、三氧化硫/吡啶络合物(Collins)或四甲基哌啶氧化物(TEMPO)，优选氯铬酸吡啶或活性二氧化锰。
相比于现有技术，本发明所涉及的阿立塞替(Alisertib)的制备方法，其优点主要是原料易得，工艺简洁，经济环保，利于工业化生产。
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3-[(2-氟-6-甲氧基)苯基]-5-氯苯酞(II)可参见本申请人同日提交的名称为“3-[(2-氟-6-甲氧基)苯基]-5-氯苯酞及其制备方法”的发明专利申请。
实施例一：
-20℃及干燥氮气气氛中，于反应瓶中加入氢化钠(0.5g，20mmol)和乙腈5mL，搅拌30分钟后缓慢升至0℃，滴加3-[(2-氟-6-甲氧基)苯基]-5-氯苯酞(II)(2.92g，10mmol)的乙腈20mL溶液，升至室温，搅拌24小时，TLC检测反应结束。加入二氯甲烷和水淬灭反应，分出有机相，水相用盐酸调节pH至7.5-8.5，再用二氯甲烷萃取三次。无水硫酸钠干燥，减压蒸馏回收溶剂，残余物用二氯甲烷和石油醚重结晶，得类白色固体1，3-二氢-1-羟基-3-[(2-氟-6-甲氧基)苯基]-5-氯-异苯并呋喃-1-乙腈(III)2.10g，收率为63.1％。
实施例二：
室温下，于反应瓶中加入1，3-二氢-1-羟基-3-[(2-氟-6-甲氧基)苯基]-5-氯-异苯并呋喃-1-乙腈(III)(1.67g，5mmol)和N，N-二甲基甲酰胺二甲基缩醛(DMF-DMA)15mL，升温至60-65℃，搅拌反应18小时，TLC检测反应结束。减压除去未反应的N，N-二甲基甲酰胺二甲基缩醛。降至室温，用水淬灭反应，再用二氯甲烷萃取3次，干燥。减压回收溶剂，得到粗品油状物3-{[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-2-基}-2-[2-(二甲氨基)亚甲基]-3-氧杂丙腈(IV)1.75g，收率90.2％。
实施例三：
室温下，于反应瓶中加入3-{[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-2-基}-2-[2-(二甲氨基)亚甲基]-3-氧杂丙腈(IV)(1.94g，5mmol)、4-胍-2-甲氧基苯甲酸盐酸盐(VI)(1.27g，6.25mmol)、叔丁醇钾(1.4g，12.5mmol)和甲醇50mL，升温至回流，搅拌反应18小时，TLC检测反应结束。用水淬灭反应，盐酸调节pH至1-2，用乙酸乙酯萃取3次。合并有机相，无水硫酸钠干燥，减压回收溶剂，剩余物用乙酸乙酯和正己烷重结晶，得到类白色固体4-{[4-[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-5-腈基嘧啶-2-基]氨基}-2-甲氧基苯甲酸(V)2.08g，收率77.9％。
实施例四：
于氢化反应器中加入4-{[4-[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-5-腈基嘧啶-2-基]氨基}-2-甲氧基苯甲酸(V)(1.33g，2.5mmol)、钯炭0.1g和醋酸25mL，45-50℃及5Kg压力下氢化反应8小时，TLC检测反应结束。过滤回收催化剂，用氨水调节pH至8-9，二氯甲烷萃取3次，无水硫酸钠干燥。减压除去溶剂，剩余物在甲醇中回流30分钟，蒸馏除去溶剂，改用二氯甲烷25mL溶解，加入活性二氧化锰4g和二氯甲烷25mL，回流反应4小时。过滤回收二氧化锰，滤液再通过硅藻土过滤一次。所得液体浓缩得到油状物经过乙酸乙酯和正己烷混合溶剂重结晶得到类白色固体阿立塞替(I)0.72g，收率55.6％
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 (8)
1.一种阿立塞替的制备方法，所述阿立塞替为4-[[9-氯-7-(2-氟-6-甲氧基苯基)-5H-嘧啶并[5,4-D][2]苯并氮杂卓-2-基]氨基]-2-甲氧基苯甲酸，结构如Alisertib，I：
其特征在于该制备方法包括如下步骤：
3-[(2-氟-6-甲氧基)苯基]-5-氯苯酞(II)与乙腈在碱促进剂存在下进行加成反应生成1,3-二氢-1-羟基-3-[(2-氟-6-甲氧基)苯基]-5-氯-异苯并呋喃-1-乙腈(III)；所述1,3-二氢-1-羟基-3-[(2-氟-6-甲氧基)苯基]-5-氯-异苯并呋喃-1-乙腈(III)与N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA)进行缩合反应得到3-{[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-2-基}-2-[2-(二甲氨基)亚甲基]-3-氧杂丙腈(IV)；所述3-{[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-2-基}-2-[2-(二甲氨基)亚甲基]-3-氧杂丙腈(IV)与4-胍-2-甲氧基苯甲酸盐酸盐(VI)在催化剂作用下发生环合反应生成4-{[4-[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-5-腈基嘧啶-2-基]氨基}-2-甲氧基苯甲酸(V)；所述4-{[4-[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-5-腈基嘧啶-2-基]氨基}-2-甲氧基苯甲酸(V)依次经过还原反应、氧化反应及环合反应得到阿立塞替(I)。
2.根据权利要求1所述阿立塞替的制备方法，其特征在于：所述3-[(2-氟-6-甲氧基)苯基]-5-氯苯酞(II)与乙腈进行加成反应的碱性促进剂为氨基钠、氨基钾、氢化钠、氢化钙、正丁基锂、苯基锂、叔丁醇钾、甲醇钠。
3.根据权利要求1所述阿立塞替的制备方法，其特征在于：所述缩合反应的温度为45-95℃。
4.根据权利要求1所述阿立塞替的制备方法，其特征在于：所述3-{[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-2-基}-2-[2-(二甲氨基)亚甲基]-3-氧杂丙腈(IV)与4-胍-2-甲氧基苯甲酸盐酸盐(VI)发生环合反应的投料摩尔比为1:1-2。
5.根据权利要求1所述阿立塞替的制备方法，其特征在于：所述3-{[1-(4-氯苯基)-1’-(2-氟-6-甲氧基苯基)甲醇]-2-基}-2-[2-(二甲氨基)亚甲基]-3-氧杂丙腈(IV)与4-胍-2-甲氧基苯甲酸盐酸盐(VI)发生环合反应的催化剂为三乙胺、吡啶、N-甲基吗啡啉、二异丙基乙胺、氢氧化钠、甲醇钠、氢氧化钾、碳酸钠、碳酸氢钠或碳酸钾。
6.根据权利要求1所述阿立塞替的制备方法，其特征在于：所述还原反应的还原剂为硼氢化钠、硼氢化钾、氰基硼氢化钠、硼烷、四氢铝锂或氢气。
7.根据权利要求6所述阿立塞替的制备方法，其特征在于：所述还原反应的还原剂为氢气时，采用雷尼镍、钯炭、铂炭或氢氧化钯炭为催化剂进行催化氢化。
8.根据权利要求1所述阿立塞替的制备方法，其特征在于：所述氧化反应的氧化剂为双氧水、双氧水和三氯化铁、过氧苯甲酸、间氯过氧苯甲酸、次氯酸、活性二氧化锰、三氧化铬、高锰酸钾、重铬酸钾、氯铬酸吡啶、氯重铬酸吡啶、二甲亚砜/草酰氯、2-碘酰基苯甲酸、戴斯-马丁氧化剂、三氧化硫/吡啶络合物或四甲基哌啶氧化物。
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