CN116496234A - 一种盐酸乌拉地尔关键中间体的制备方法 - Google Patents
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
本发明涉及一种盐酸乌拉地尔关键中间体的制备,所述方法的化学反应式如下所示。以Boc‑β‑丙氨酸(2)和1‑(2‑甲氧基苯基)哌嗪盐酸盐(3)为起始原料,经过缩合、酰胺还原、脱保护,得到盐酸乌拉地尔关键中间体化合物1,3‑(4‑(2‑甲氧基苯基)‑1‑哌嗪基)丙胺三盐酸盐。目标产物结构经HPLC、1H‑NMR、13C‑NMR和MS确证。该工艺解决了盐酸乌拉地尔关键中间体国产化的技术问题,提高了产品纯度,避开了危险氯化工艺和强卤试剂的使用,大幅度增加了工业化生产的可行性。
Description
技术领域
本发明属于医药化工技术领域,具体涉及一种盐酸乌拉地尔关键中间体3-(4-(2-甲氧基苯基)-1-哌嗪基)丙胺三盐酸盐的制备方法。
背景技术
盐酸乌拉地尔,是一种选择性α受体阻滞剂,该药是第一个上市的具有中枢和外周双重降压机制的降压药物,目前已在德、日、英等许多国家上市,临床主要用于治疗原发性高血压、肾性高血压等。盐酸乌拉地尔注射液用药简单方便,起效迅速,持续作用时间适中,安全平稳,容易调控降压速度和幅度,是迄今为止较为理想的静脉降压药物。
盐酸乌拉地尔,化学名6-[[3-[4-(2-甲氧基苯基)-1-哌嗪基]丙基]氨基]-1,3-二甲基-2,4(1H,3H)嘧啶二酮盐酸盐,由德国Byk GulolenLombery公司研制,商品名为亚宁丁(Ebrantil)。
专利US3957786首次公开并保护了乌拉地尔的合成路线,也是目前为止最重要的两种路线,具体如下:
路线一:采用6-(3-氯丙基氨基)-1,3-二甲基尿嘧啶与1-(2-甲氧基苯基)哌嗪或其盐酸盐缩合得到目标乌拉地尔。
盐酸乌拉地尔,是一种选择性α受体阻滞剂,该药是第一个上市的具有中枢和外周双重降压机制的降压药物,目前已在德、日、英等许多国家上市,临床主要用于治疗原发性高血压、肾性高血压等。盐酸乌拉地尔注射液用药简单方便,起效迅速,持续作用时间适中,安全平稳,容易调控降压速度和幅度,是迄今为止较为理想的静脉降压药物。
盐酸乌拉地尔,化学名6-[[3-[4-(2-甲氧基苯基)-1-哌嗪基]丙基]氨基]-1,3-二甲基-2,4(1H,3H)嘧啶二酮盐酸盐,由德国Byk GulolenLombery公司研制,商品名为亚宁丁(Ebrantil)。
专利US3957786首次公开并保护了乌拉地尔的合成路线,也是目前为止最重要的两种路线,具体如下:
路线一:采用6-(3-氯丙基氨基)-1,3-二甲基尿嘧啶与1-(2-甲氧基苯基)哌嗪或其盐酸盐缩合得到目标乌拉地尔。
该方法的两个原料最早实现商业化生产,但因6-(3-氯丙基氨基)-1,3-二甲基尿嘧啶的生产使用了强卤试剂氯化亚砜或三氯氧磷,反应本身选择性较差,工艺副产物较多,产品质量难以保证;同时氯化工艺属于危险化工工艺,在安全、环保要求与日俱增的当下,大大增加了该工艺通过安全评价等合规流程的难度,将逐渐被淘汰。
路线二:采用6-氯-1,3-二甲基尿嘧啶与1-(3-氨基)-4-(2-甲氧基苯基)哌嗪在Et3N,K2CO3,Na2CO3,KOH或NaOH等碱存在的情况下缩合得到乌拉地尔。
该路线所用原料1-(3-氨基)-4-(2-甲氧基苯基)哌嗪国内无生产,国外产品价格昂贵,且该化合物为油状液体,纯度不易提高。
随后,He等在Bioorg. Med. Chem. Lett公开过路线二中重要中间体1-(3-氨基)-4-(2-甲氧基苯基)哌嗪的合成路线,采用N-(3-溴丙基)邻苯二甲酰亚胺与1-(2-甲氧基苯基)哌嗪,经N-烷基化反应后,再与水合肼反应制得中间体1-(3-氨基)-4-(2-甲氧基苯基)哌嗪。
该路线反应时间长,能耗高;反应试剂水合肼为易制爆化学品,后处理提取步骤用到限制级二类试剂氯仿,故该路线不适合大规模生产。
发明内容
本发明的目的重点在于解决路线二中关键中间体国内无生产的问题,设计出一种绿色、友好、纯度高、适合工业化生产的新路线。以Boc-β-丙氨酸(2)和1-(2-甲氧基苯基)哌嗪盐酸盐(3)为起始原料,经过缩合、酰胺还原、脱保护,得到盐酸乌拉地尔关键中间体化合物1,3-(4-(2-甲氧基苯基)-1-哌嗪基)丙胺三盐酸盐。
反应式如下:
本发明采用以下技术方案:
步骤1,以Boc-β-丙氨酸(2)为原料,通过活性酯法,与1-(2-甲氧基苯基)哌嗪盐酸盐(3)缩合得到化合物4;
步骤2,将上述化合物4经过酰胺还原反应,得到化合物5;
步骤3,上述化合物5脱除Boc保护基,得到盐酸乌拉地尔关键中间体化合物1,3-(4-(2-甲氧基苯基)-1-哌嗪基)丙胺三盐酸盐。
上述步骤1中所述的N,N-羰基二咪唑(CDI)与式(2)、式(3)的摩尔比为1:1:0.8-1.0。
上述步骤1中所述的反应溶剂为乙腈,四氢呋喃,二氯甲烷中至少一种。
上述步骤1中所述的反应温度为10℃~30℃;所述的反应时间为2h~4h。
上述步骤2中所述的式(4)与氢化铝锂的摩尔比为1:2。
上述步骤2中所述的反应溶剂为四氢呋喃;所述的反应温度为-5℃~5℃;所述的反应时间为1h~2h。
上述步骤3中所述的反应溶剂为乙醇、甲醇、乙酸乙酯中至少一种。
上述步骤3中所述的盐酸浓度为2N~6N。
相对于现有工艺,本发明具有以下技术优势:
(1)本发明解决了盐酸乌拉地尔该中间体国产化的技术问题;
(2)本发明进一步制得该中间体的盐酸盐固体,解决了原中间体为油状液体,纯度不易提高的问题;
(3)本发明符合绿色工艺理念,未使用氯化亚砜等强卤试剂,有利于减小设备腐蚀和环境污染;
(4)本发明安全性高,未涉及危险化工工艺,降低了工艺通过安全评价等合规流程的难度,大幅提高了工业化生产的可行性。
附图说明
为了更清楚地说明本发明实施例,以下将对实施例描述中所需要使用的附图作简单地介绍。
本发明实施例1中制备出的化合物4:图1为HPLC图谱,图2为1H-NMR图谱,图3为13C-NMR图谱,图4为MS图谱;实施例1中制备出的化合物5:图5为HPLC图谱,图6为1H-NMR图谱,图7为13C-NMR图谱,图8为MS图谱;实施例1中制备出的化合物1:图9为HPLC图谱,图10为1H-NMR图谱,图11为13C-NMR图谱,图12为MS图谱;实施例2中制备出的化合物4:图13为HPLC图谱;实施例2中制备出的化合物5:图14为HPLC图谱;实施例2中制备出的化合物1:图15为HPLC图谱。
具体实施方式
实施例1
步骤1,(3-(4-(2-甲氧基苯基)哌嗪-1-基)-3-氧代丙基)氨基甲酸叔丁酯(化合物4)的合成
将50g Boc-β-丙氨酸(1.0eq)溶于200g二氯甲烷中,加入至500mL三口瓶中搅拌,温度控制在10℃~30℃,分批加入N,N-羰基二咪唑(CDI)42.85g(1.0eq),加完保温搅拌1h,体系溶清,在10℃~30℃条件下,加入1-(2-甲氧基苯基)哌嗪盐酸盐54.40g(0.9eq),反应1~3h,TLC监控原料反应完全,缓慢加入200mL纯化水淬灭反应,搅拌后静置分层,取下层有机相,重复纯化水洗涤有机相1次,有机相减压浓缩至干,得到浅黄色油状液体,加入100mL正己烷升温打浆30min,抽滤后真空干燥,得到类白色固体,即化合物4(83.00 g,96.02%),纯度98.01%。1H-NMR(400 MHz, DMSO-d6)δ (ppm):1.38(s, 9H), 2.51(t, 2H), 2.89(t,2H), 2.95(t, 2H), 3.16(dd, 2H), 3.57(t, 4H), 3.79(s, 3H),6.72(t, 1H), 6.88(d,2H), 6.94~7.02(m, 2H);13C-NMR(100 MHz, DMSO-d6)δ (ppm):28.71, 33.25, 37.01,41.63, 45.65, 50.48, 50.93, 55.80,78.07, 112.34, 118.70, 121.27, 123.33,135.60, 141.26, 152.48, 155.93, 169.52, 173.33。ES-MS m/z:364.33[M+H]+。
步骤2,叔丁基(3-(4-(2-甲氧基苯基)哌嗪-1-基)丙基)氨基甲酸酯(化合物5)的合成
将60.0g 化合物4(1.0eq)溶于360g四氢呋喃中,加入至1L三口瓶中搅拌,冰浴降温至-5℃~5℃,分批缓慢加入氢化锂铝12.53g(2.0eq),加毕,在-5℃~5℃条件下,保温反应1~2h,TLC监控原料反应完全,缓慢滴加200mL纯化水淬灭反应,过滤得滤液;滤液用二氯甲烷萃取两次(200mL*2),静置分层,取下层有机相,合并有机相,向有机相中加入5%稀盐酸水溶液200mL,搅拌后静置分层,取下层有机相,减压浓缩至干,得到类白色固体,即化合物5(50.13g,86.9%),纯度97.80%。1H-NMR(400 MHz, CDCl3)δ (ppm):1.45(s, 9H), 1.99(t,2H), 3.06(t, 2H), 3.25~3.32(m, 10H),3.87(s, 3H), 5.44(s, 1H), 6.88~6.94(m,3H), 7.04~7.08(m, 1H);13C-NMR(100 MHz, CDCl3)δ (ppm):24.94, 28.39, 37.88,48.49, 53.21, 55.47, 55.70, 79.86, 111.46, 118.69, 121.15, 124.12, 139.37,152.23, 157.18。ES-MS m/z:350.73 [M+H]+。
步骤3,3-(4-(2-甲氧基苯基)-1-哌嗪基)丙胺三盐酸盐(化合物1)的合成
将45.00g 化合物5(1.0eq)溶于90g无水乙醇中,加入至1L三口瓶中搅拌,配制2N盐酸536.00g(8.0eq),在15℃~25℃条件下,滴加至三口瓶中,反应2~3h,TLC监控原料反应完全,反应液减压浓缩至有大量固体析出,降温至0~10℃并保温1h,抽滤得淡黄色固体,即化合物1(41.85g,90.6%),氯离子30.5%,纯度99.15%。1H-NMR(400 MHz, DMSO-d6)δ(ppm):2.12(t, 2H), 2.92(d, 2H), 3.14(d, 4H), 3.26(t, 2H), 3.47 (d, 4H), 3.79(s, 3H), 6.91~7.02(m, 4H), 8.32(s, 2H) , 11.38(s, 1H);13C-NMR(100 MHz, DMSO-d6)δ (ppm):21.79, 36.76, 47.13, 51.63, 53.04, 55.88, 112.42, 118.69,121.32,123.95, 139.84, 152.27。ES-MS m/z:250.9 [M+H]+。
实施例2
步骤1,(3-(4-(2-甲氧基苯基)哌嗪-1-基)-3-氧代丙基)氨基甲酸叔丁酯(化合物4)的合成
将50g Boc-β-丙氨酸(1.0eq)溶于200g二氯甲烷中,加入至500mL三口瓶中搅拌,温度控制在10℃~30℃,分批加入N,N-羰基二咪唑(CDI)42.84g(1.0eq),加完保温搅拌1h,体系溶清,在10℃~30℃条件下,加入1-(2-甲氧基苯基)哌嗪盐酸盐48.35g(0.8eq),反应1~3h,TLC监控原料反应完全,缓慢加入200mL纯化水淬灭反应,搅拌后静置分层,取下层有机相,重复纯化水洗涤有机相1次,有机相减压浓缩至干,得到浅黄色油状液体,加入100mL正己烷升温打浆30min,抽滤后真空干燥,得到类白色固体,即化合物4(73.40 g,95.53%),纯度96.94%。光谱数据同实施例1。
步骤2,叔丁基(3-(4-(2-甲氧基苯基)哌嗪-1-基)丙基)氨基甲酸酯(化合物5)的合成
将50.0g 化合物4(1.0eq)溶于300g四氢呋喃中,加入至1L三口瓶中搅拌,冰浴降温至-5℃~5℃,分批缓慢加入氢化锂铝10.44g(2.0eq),加毕,在-5℃~5℃条件下,保温反应1~2h,TLC监控原料反应完全,缓慢滴加200mL纯化水淬灭反应,过滤得滤液;滤液用二氯甲烷萃取两次(180mL*2),静置分层,取下层有机相,合并有机相,向有机相中加入5%稀盐酸水溶液180mL,搅拌后静置分层,取下层有机相,减压浓缩至干,得到类白色固体,即化合物5(39.47g,82.1%),纯度96.60%。光谱数据同实施例1。
步骤3,3-(4-(2-甲氧基苯基)-1-哌嗪基)丙胺三盐酸盐(化合物1)的合成
将35.00g 化合物5(1.0eq)溶于70g无水乙醇中,加入至500mL三口瓶中搅拌,配制6N盐酸148.00g(8.0eq),在15℃~25℃条件下,滴加至三口瓶中,反应2~3h,TLC监控原料反应完全,反应液减压浓缩至有大量固体析出,降温至0~10℃并保温1h,抽滤得淡黄色固体,即化合物1(31.69g,88.2%),纯度98.64%。光谱数据同实施例1。
以上实施例是对本发明所提供的一种合成盐酸乌拉地尔关键中间体的方法进行的详细介绍。对比现有技术,本发明所具备的优势,实施方式及优选条件进行了阐述,实施例的说明在于帮助理解本发明的方法及核心思想。
Claims (8)
1.一种合成盐酸乌拉地尔关键中间体化合物1的方法,其特征在于,反应式为:
具体步骤如下:
步骤1,以Boc-β-丙氨酸(2)为原料,通过活性酯法,与1-(2-甲氧基苯基)哌嗪盐酸盐(3)缩合得到化合物4;
步骤2,上述化合物4通过还原反应,得到化合物5;
步骤3,上述化合物5 脱除Boc,得到盐酸乌拉地尔关键中间体化合物1,3-(4-(2-甲氧基苯基)-1-哌嗪基)丙胺三盐酸盐。
2.根据权利要求1所述的步骤1中,其特征在于,所述的N,N-羰基二咪唑(CDI)与式(2)、式(3)的摩尔比为1:1:0.8-1.0。
3.根据权利要求1所述的步骤1中,其特征在于,所述的反应溶剂为乙腈,四氢呋喃,二氯甲烷中至少一种。
4.根据权利要求1所述的步骤1中,其特征在于,所述的反应温度为10℃~30℃;所述的反应时间为2h~4h。
5.根据权利要求1所述的步骤2中,其特征在于,所述的式(4)与氢化铝锂的摩尔比为1:2。
6.根据权利要求1所述的步骤2中,其特征在于,所述的反应溶剂为四氢呋喃;所述的反应温度为-5℃~5℃;所述的反应时间为1h~2h。
7.根据权利要求1所述的步骤3中,其特征在于,所述的反应溶剂为乙醇、甲醇、乙酸乙酯中至少一种。
8.根据权利要求1所述的步骤3中,其特征在于,所述的盐酸浓度为2N~6N。
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