CN109232579B - 一种合成培美曲塞中间体培美苯甲酸的方法 - Google Patents
一种合成培美曲塞中间体培美苯甲酸的方法 Download PDFInfo
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title claims description 26
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Classifications
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种合成培美曲塞中间体培美苯甲酸的方法,包括下列步骤:步骤1,将式(II)化合物和醋酸胍溶在有机溶剂中,回流反应得式(III)化合物;步骤2,将式(III)化合物与式(IV)所示的烷基硼酸溶于混合溶剂中,在催化剂和碱作用下发生Suzuki偶联反应,制得式(V)化合物;步骤3,式(V)化合物与氢氧化钠发生酯水解反应,而后经酸化即制得目标产物。本发明提供的培美曲塞重要中间体培美苯甲酸的合成方法步骤短、合成效率高、无细胞毒性物质产生,杂质少,工艺稳定,适于工业化生产,为制备培美曲塞及中间体提供了一条新的途径。
Description
技术领域
本发明属于药物制备技术领域,具体涉及一种培美曲塞中间体培美苯甲酸的合成新方法。
背景技术
培美曲塞,化学名为N-[4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯并[2,3-d]嘧啶-5-烷基)乙基]苯甲酰基]-L-谷氨酸,英文名称为ALIMTA,中文名为力比泰,系礼来公司研制开发,2004年在美国首次上市。临床上主要用其二钠盐。培美曲塞二钠是一种新型的多靶位抗叶酸制剂,通过破坏细胞内叶酸依赖性的正常代谢过程,阻断癌细胞分裂和增生过程中需要的多种酶,抑制细胞复制,从而抑制肿瘤的生长,目前临床上主要用于四个适应症:一是与顺铂联用,治疗不宜手术的恶性胸膜间皮瘤,已成为治疗恶性胸膜间皮瘤的第一个也是唯一的一个药物;二是单独用于治疗局部晚期或转移性非小细胞性肺癌;三是与顺铂联用,一线治疗非小细胞性肺癌;四是维持治疗晚期或转移性非鳞癌型非小细胞性肺癌,培美曲塞二钠是具有该适应症的第一个药物。
式(I)化合物4-(2-(2-氨基-4-氧代-4,7-二氢-氯-6-溴-8-环戊基-5-甲基-1H-吡咯并[2,3-d]嘧啶-5-基)乙基苯甲酸,又名培美苯甲酸,是合成培美曲塞的关键中间体,对于培美曲塞的化学合成具有重要意义。
目前文献报道的式(I)化合物培美苯甲酸的合成方法主要为专利Drugs future,1998,23(5),498的方法,该方法是以对溴苯甲酸甲酯为起始原料,与3-丁烯醇在醋酸钯、氯化锂、醋酸锂和相转移催化剂作用下,发生缩合反应得到4-(4-甲氧基)苯基丁醛后与饱和亚硫酸氢钠反应、与溴素发生溴代反应、再与2,4-二氨基-6-羟基嘧啶在碱作用下发生环合成环,得到培美苯甲酸甲酯,然后进行水解等5步反应制得式(I)化合物培美苯甲酸。
该合成方法工艺路线长,总收率低于20%,最大缺点还在于第一步缩合反应中得到中间体4-(4-甲氧基)苯基丁醛,还会产生杂质3-甲基-3-(4-甲氧基)苯基丙醛,与4-(4-甲氧基)苯基丁醛为很难分离的同分异构体;这两种醛还皆为具有严重细胞毒性的物质;另外,溴代后得到的溴代芳基丁醛更不稳定,也具有严重细胞毒性,因此,使得该合成工艺稳定性较差,安全性也不高。
发明内容
本发明所要解决的技术问题是克服现有报道的制备式(I)化合物培美苯甲酸的技术中存在的工艺步骤多、收率低、易产生细胞毒性物质、工艺不稳定,不利于工业化规模生产的缺陷,提供一种有效的制备培美苯甲酸的方法,该方法步骤短、收率高、杂质少,工艺稳定,适合工业化生产。
本发明的技术方案概述如下:
步骤(1),将式(II)化合物2-氨基-4溴-1H-吡咯-3-甲酸乙酯和醋酸胍溶在有机溶剂中,回流反应得式(III)化合物2-氨基-5溴-1H-吡咯并[2,3-d]嘧啶-4(7H)-酮;步骤(2),式(III)化合物与式(IV)所示的烷基硼酸在催化剂和碱作用下发生Suzuki偶联反应,制得式(V)化合物培美苯甲酸乙酯;步骤(3),式(V)化合物培美苯甲酸乙酯与氢氧化钠发生酯水解反应即制得式(I)化合物培美苯甲酸。
合成路线为:
所述的步骤(1)中的溶剂为乙醇、乙腈、二卤代烷等常用的极性有机溶剂,其中优选乙醇。
所述的步骤(2)中的催化剂为零价Pd(0)和Ni(0)的化合物,Pd(0)包括Pd(PPh3)4、Pd(dppf)Cl2、POPd2、Pd(OAC)2等;Ni(0)包括NiCl2、NiBr2、NiI2、NiCl2(PCy3)2、Ni(cod)2等;其中优选Pd(dppf)Cl2,且其用量为式(II)化合物物质的量的2%-5%。
所述的步骤(2)中的碱为有机胺、醇钠、碱金属的碳酸盐、碳酸氢盐、磷酸盐等;
其中优选碳酸钠。
所述的步骤(2)中的溶剂为二氧六环、乙腈、二卤代烷、醇、甲苯等常用的有机溶剂和水的混合物,其中优选二氧六环和水的混合物,且水和溶剂的体积比为1:1~3。
用本工艺制备的式(I)化合物培美苯甲酸只需3步,杂质少,易控制,总收率达60%以上。
具体实施方式
下面结合实施具体实施例,进一步说明本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例中所用的原料或试剂除特别说明之外,均市售可得。
实施例1式(III)化合物2-氨基-5溴-1H-吡咯并[2,3-d]嘧啶-4(7H)-酮的制备
将50mmol式(II)化合物2-氨基-4溴-1H-吡咯-3-甲酸乙酯、75mmol醋酸胍和200mL干燥乙醇加入反应瓶中,搅拌混合均匀。加热,将体系温度升至回流,并在此温下搅拌回流反应10h,TLC检测反应终点,停止加热,冷却至室温,抽滤析出的固体,并用乙醇洗涤滤饼,干燥后用蒸馏水重结晶,得式(III)化合物,收率88%。化合物结构通过MS和1HNMR确证。MS[M+H]=229.9987;1HNMR(DMSO-d6):δ7.39(s,1H),7.56(br s,2H),9.55(br s,1H),9.68(br s,1H)。
实施例2式(III)化合物2-氨基-5溴-1H-吡咯并[2,3-d]嘧啶-4(7H)-酮的制备
将50mmol式(II)化合物2-氨基-4溴-1H-吡咯-3-甲酸乙酯、65mmol醋酸胍和200mL干燥乙腈加入反应瓶中,搅拌混合均匀。加热,将体系温度升至回流,并搅拌回流反应16h,TLC检测反应终点,停止加热,冷却至室温,抽滤析出的固体,并用乙腈洗涤滤饼,干燥后用蒸馏水重结晶,得式(III)化合物,收率73%。化合物结构通过MS和1HNMR确证。
实施例3式(V)化合物培美苯甲酸乙酯的制备
在氮气保护下,将50mmol式(III)化合物、55mmol式(IV)化合物、2mmol Pd(dppf)Cl2、2M碳酸钠75mL和100mL二氧六环加入反应瓶中,搅拌混合均匀。加热,将反应体系温度升至回流,并搅拌回流反应10h,TLC检测反应终点,停止加热,冷却至室温,向反应体现中加入乙酸乙酯100mL,分出有机层,并用30mL乙酸乙酯洗涤,无水硫酸钠干燥。过滤后减压蒸去溶剂,得式(V)粗产物,该粗产物不用纯化,直接进行下一步的实验。
实施例4式(V)化合物培美苯甲酸乙酯的制备
在氮气保护下,将50mmol式(III)化合物、60mmol式(IV)化合物、2.5mmol Pd(OAC)2、2M磷酸钾50mL和100mL甲苯加入反应瓶中,搅拌混合均匀。加热,将体系温度升至回流,并在此温下搅拌回流反应13h,TLC检测反应终点,停止加热,冷却至室温,向反应体现中加入乙酸乙酯100mL,分出有机层,并用30mL乙酸乙酯洗涤,无水硫酸钠干燥。过滤后减压蒸去溶剂,得式(V)粗产物,该粗产物不用纯化,直接进行下一步的实验。
实施例5式(I)化合物培美苯甲酸的制备
将实施例3中制备的式(V)化合物、2N氢氧化钠50mL加入反应瓶中,于30℃搅拌反应2h,TLC检测至原料点消失,过滤过滤出不溶物,向滤液中加入50mL乙醇冷却至10℃,搅拌下滴加6N的盐酸10mL,再用1N的盐酸调节pH至4,析出大量固体,过滤,滤饼用少量乙醇洗涤,干燥后用乙酸乙酯和石油醚的混合溶液重结晶,得式(I)化合物,收率69%[以式(III)化合物计]。化合物结构通过MS和1H NMR确证。MS[M+H]=299.1322;1H NMR(DMSO-d6):δ2.89(t,2H,J=7.4Hz),2.99(t,2H,J=7.4Hz),6.93(br s,2H),7.34(d,2H,J=8.0Hz),7.86(d,2H,J=8.0Hz),8.17(s,1H),9.37(br s,1H),9.25(br s,1H),11.18(br s,1H)。高压液相检测显示纯度大于98%。
实施例6式(I)化合物培美苯甲酸的制备
将实施例4中制备的式(V)化合物、2N氢氧化钠50mL加入反应瓶中,于30℃搅拌反应2h,TLC至原料点消失,加入50mL乙醇冷却至10℃,搅拌下滴加6N的盐酸10mL,再用1N的盐酸调节pH至4,析出大量固体,过滤,滤饼用少量乙醇洗涤,干燥后用乙酸乙酯和石油醚的混合溶液重结晶,得式(I)化合物,收率60%[以式(III)化合物计]。化合物结构通过MS和1HNMR确证。高压液相检测显示纯度大于98%。
Claims (3)
2.根据权利要求1所述的培美曲塞二钠中间体培美苯甲酸的合成方法,其特征在于:所述的步骤(1)中有机溶剂为乙醇、乙腈。
3.根据权利要求1所述的培美曲塞二钠中间体培美苯甲酸的合成方法,其特征在于:所述的步骤(2)中的混合溶剂为二氧六环、乙腈、甲苯与水的混合物,且水和有机溶剂的体积比为1:1~3。
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