CN1325844A - (±)对氟－2－(2－甲基－丙酰基)－4－氧－n,3－二苯基－苯丁酰胺的新合成方法以及其中的中间体 - Google Patents
(±)对氟－2－(2－甲基－丙酰基)－4－氧－n,3－二苯基－苯丁酰胺的新合成方法以及其中的中间体 Download PDFInfo
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Abstract
本发明涉及一种制备(±)对氟－2－(2－甲基－3－氧丙基)－4－氧－N,3－二苯基－苯丁酰胺(1)的方法,其包括以下步骤:新制的苯乙酰氯与氟苯在AlCl3催化下进行Friedle－Craft酰化反应,得到对4－氟－苯基苄基酮(4);化合物(4)在少量AlCl3催化下进行羰基α位溴化,得到α－溴－4－氟－苯基苄基酮(5);然后(3)异丁酰乙酰苯胺在乙醇钠作用下与化合物(5)进行缩合。本发明的方法具有成本低、产率高的优点。本发明还包括中间体化合物(5)。
Description
本发明涉及(±)对氟-2-(2-甲基-丙酰基)-4-氧-N,3-二苯基-苯丁酰胺的新合成方法以及其中的中间体。
阿伐他定(atorvastatin)是一种具有肝脏组织选择性的HMG-CoA还原酶抑制剂，临床用于治疗高胆固醇和高血脂(Roth,BD,Blankley,CJ,Chucholowski,AW,Ferguson,E,Hoefle,ML,Ortwine,DF,Newton,RS,Sekerke,CS,Sliskovic,DR,Stratton,CD,Wilson,M W.Inhibitors ofcholesterol biosynthesis,J.Med.Chem.1991,34,357-366.)。
据文献报道该化合物的合成有两类不同的策略：一类是线形合成路线，另一类是会聚合成路线(Butler,DE,Le,TV,Millar,A,Nanninga,TN.Process forthe synthesis of(5R)-l,l-dimethylethyl-6-cyno-5-hydroxy-3-oxo-hexanoate,US:5155251,1992-10-13；Butler,DE,Deering,CF,Millar,A,Nanninga,TN,Roth,BD,Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis,US:5097045,1992-05-17.)，但这两类合成方法中有数条合成路线均使用了一个共同的中间体化合物(1)。
在US5155251中，化合物(1)的合成是以异丁酰乙酰苯胺为起始原料，在β-丙氨酸的催化下与苯甲醛进行Knoevengale缩合，缩合产物与对氟苯甲醛进行Stetter加成得到化合物(1)的立体异构体的混合物：
但是，该方法中使用的作为起始原料的4-氟苯甲醛价格较贵，不适合大规模的生产。另外，Stetter加成所用的催化剂也是非市售试剂。
因此，本发明的目的在于提供一种新的制备化合物(1)的方法，其中所用的试剂均为常用的价格低廉的市售试剂。
本发明的另一个目的是提供上述制备方法中涉及的中间体。
根据本发明，其提供一种制备化合物(1)的新方法，其包括以下步骤：
(1)新制的苯乙酰氯与氟苯在AlCl3催化下进行Friedle-Craft酰化反应，得到对位酰化产物(4)；
(2)化合物(4)在少量AlCl3催化下进行羰基α位溴化，得到化合物(5)；然后
(3)异丁酰乙酰苯胺在乙醇钠作用下与化合物(5)缩合得到化合物(1)。
根据本发明的方法与US 5155251中的方法相比具有以下优点：(1)虽路线较长，但总收率为64.4％，仍然与文献方法的68％相当；(2)起始原料价廉，氟苯的价格仅为4-氟苯甲醛的十分之一；和(3)所用试剂均为常用试剂，避免了β-丙氨酸和3-乙基-4-甲基-5-噻唑乙醇溴化季铵盐的使用。因此，本发明的方法更适合大量合成，为阿伐他定合成关键中间体提供了一个具有实用价值的合成方法。
根据化合物(1)的结构，我们对其进行反向了设计：
并基于以上设计发明了本方法，具体而言，是将苯乙酸(2)和氯化亚砜作用而形成的新鲜制备的苯乙酰氯(3)与氟苯在AlCl3催化下进行Friedle-Craft酰化反应，得到对位酰化产物(4)。化合物(4)在少量AlCl3催化下进行羰基α位溴化得到化合物(5)。然后将按照已知方法(US5155251)制备的化合物(6)在乙醇钠作用下与化合物(5)缩合得到化合物(1)。
根据本发明的另一个方面，其还提供上述中间体(5)，即α-溴-4-氟苯基苄基酮。
以下将参考实施例具体描述本发明的方法。实施例1:4-氟-苯基苄基酮(4)的制备
将苯乙酸13.6g(0.10mol)溶于14.5ml(0.20mol)氯化亚砜中，加热回流1小时，减压蒸除剩余的氯化亚砜。残余物加入30ml氟苯备用。
将16g(0.12mol)AlCl3和17ml氟苯加入反应瓶，冰浴冷却下滴加苯乙酰氯的氟苯溶液，约40分钟加完。反应液在5～10℃搅拌3小时，升至室温，倾入100g碎冰中，加入50ml乙醚，分去水层，有机相以1N HCl(50ml×3)洗，饱和NaHCO3洗，饱和NaCl水溶液洗至中性，无水Na2SO4干燥，浓缩。所得固体以75％乙醇重结晶得17.5g产物，收率81.7％。熔点80～82℃。1H NMR(300MHz,CDCl3)δ8.04(dd,J=8.4,5.4Hz,2H),7.40～7.20(m,5H),7.12(t,J=8.4Hz,2H),4.26(s,2H).实施例2:α-溴-4-氟-苯基苄基酮(5)的制备
将化合物(4)17.5g(0.08mol)溶于300mL无水乙醚，冰浴冷却下加入0.12g(0.81mmol)AlCl3，搅拌下滴加溴(13g,0.08mol)，1小时加完，继续搅拌30分钟，减压蒸去乙醚。残余物溶于乙酸乙酯，饱和NaCl溶液洗至pH5，无水Na2SO4干燥，浓缩。所得粗产物具有足够纯度用于下步反应。1H NMR(300MHz,CDCl3)δ7.93(dd,J=8.7,5.1Hz,2H),7.50～7.20(m,5H),7.02(t,J=8.7Hz,2H),6.23(s,1H)。实施例3:(±)-对-氟-2-(2-甲基-3-氧丙基)-4-氧-N,3-二苯基-苯丁酰胺
(1)的制备
将2.3g(0.1mol)金属钠溶于30mL无水乙醇中，室温下加入异丁酰乙酰苯胺的无水乙醇溶液(25g,0.12mol,50mL)，搅拌10分钟，加入上步反应所得化合物(5)的无水乙醇溶液(200mL)。反应混合物室温搅拌反应1小时，减压浓缩。残余物溶于200mL乙酸乙酯，水洗至中性，无水Na2SO4干燥，柱层析得26.5g产物，收率78.8％。熔点206～208℃。1H NMR(300MHz,CDCl3)δ7.98(dd,J=8.7,5.4Hz,2H),7.3～7.10(m,10H),7.03(t,J=8.7Hz,2H),5.35(d,J=10.7Hz,1H),4.52(d,J=10.7Hz,1H),2.99(qintet,J=6.8Hz,1H),1.23(d,J=6.8Hz,3H),1.15(d,J=6.8Hz,3H)。
Claims (2)
1、一种制备(±)对氟-2-(2-甲基-丙酰基)-4-氧-N,3-二苯基-苯丁酰胺的方法，其包括以下步骤：
(1)新制的苯乙酰氯与氟苯在AlCl3催化下进行Friedle-Craft酰化反应，得到对4-氟-苯基苄基酮(4)；
(2)化合物(4)在少量AlCl3催化下进行羰基α位溴化，得到α-溴-4-氟-苯基苄基酮(5)；然后
(3)异丁酰乙酰苯胺在乙醇钠作用下与化合物(5)进行缩合。
2、α-溴-4-氟苯基苄基酮。
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101768102A (zh) * | 2009-01-05 | 2010-07-07 | 浙江华海药业股份有限公司 | 一种新的阿托伐他汀钙中间体1h-吡咯衍生物的制备方法 |
| CN101306988B (zh) * | 2007-05-15 | 2011-11-30 | 浙江京新药业股份有限公司 | α-溴-4-氟苯基苄基酮的新合成方法 |
| CN103724175A (zh) * | 2013-12-12 | 2014-04-16 | 安庆金泉药业有限公司 | 一种阿伐他汀中间体α-溴-4-氟苯基苄基酮的合成方法 |
| CN106397296A (zh) * | 2016-08-29 | 2017-02-15 | 江苏阿尔法药业有限公司 | 一种阿托伐他汀的制备工艺 |
| CN110724123A (zh) * | 2019-11-14 | 2020-01-24 | 扬州工业职业技术学院 | 一种卡格列净中间体的合成方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4536517A (en) * | 1983-04-25 | 1985-08-20 | American Cyanamid Company | Method of treating diabetes mellitus using arylglyoxals |
| US4829081A (en) * | 1986-01-07 | 1989-05-09 | Sandoz Pharm. Corp. | Analogs of mevalonolactone and derivatives thereof |
| US5155251A (en) * | 1991-10-11 | 1992-10-13 | Warner-Lambert Company | Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101306988B (zh) * | 2007-05-15 | 2011-11-30 | 浙江京新药业股份有限公司 | α-溴-4-氟苯基苄基酮的新合成方法 |
| CN101768102A (zh) * | 2009-01-05 | 2010-07-07 | 浙江华海药业股份有限公司 | 一种新的阿托伐他汀钙中间体1h-吡咯衍生物的制备方法 |
| CN101768102B (zh) * | 2009-01-05 | 2013-08-21 | 浙江华海药业股份有限公司 | 一种阿托伐他汀钙中间体1h-吡咯衍生物的制备方法 |
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| CN106397296A (zh) * | 2016-08-29 | 2017-02-15 | 江苏阿尔法药业有限公司 | 一种阿托伐他汀的制备工艺 |
| CN106397296B (zh) * | 2016-08-29 | 2019-03-19 | 江苏阿尔法药业有限公司 | 一种阿托伐他汀钙的制备工艺 |
| CN110724123A (zh) * | 2019-11-14 | 2020-01-24 | 扬州工业职业技术学院 | 一种卡格列净中间体的合成方法 |
| CN110724123B (zh) * | 2019-11-14 | 2022-03-01 | 扬州工业职业技术学院 | 一种卡格列净中间体的合成方法 |
| CN114195670A (zh) * | 2021-12-31 | 2022-03-18 | 河南豫辰药业股份有限公司 | 一种阿托伐他汀母核m4的精制方法 |
| CN114195670B (zh) * | 2021-12-31 | 2024-03-15 | 河南豫辰药业股份有限公司 | 一种阿托伐他汀母核m4的精制方法 |
| CN115260051A (zh) * | 2022-08-26 | 2022-11-01 | 江苏阿尔法药业股份有限公司 | 一种阿托伐他汀钙中间体的制备工艺 |
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