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CN101684077B - N-酰基联苯丙氨酸的制备方法 - Google Patents

N-酰基联苯丙氨酸的制备方法 Download PDF

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CN101684077B
CN101684077B CN200810200404.XA CN200810200404A CN101684077B CN 101684077 B CN101684077 B CN 101684077B CN 200810200404 A CN200810200404 A CN 200810200404A CN 101684077 B CN101684077 B CN 101684077B
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diphenylalanine
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acid
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CN101684077A (zh
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朱国良
石德送
位军辉
陶峰峰
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Ruibo Suzhou Pharmaceutical Co Ltd
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Priority to PCT/CN2009/074125 priority patent/WO2010034236A1/en
Priority to PT108182635T priority patent/PT2480523T/pt
Priority to PL10818263T priority patent/PL2480523T3/pl
Priority to MX2012003488A priority patent/MX2012003488A/es
Priority to US13/497,544 priority patent/US20130172572A1/en
Priority to ES10818263.5T priority patent/ES2627060T3/es
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5

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Abstract

本发明提供了一种N-酰基联苯丙氨酸的制备方法，以联苯甲醛、N-酰基甘氨酸和酸酐为原料在碱存在条件下在合适的有机溶剂中加热回流进行反应，获得产物1；产物1在水和/或有机溶剂中加热回流进行反应，获得产物2；产物2在有机溶剂中在氢气压力和钯碳作用下形成产物3，其合成路线具体见下，本发明工艺设计合理、原料辅料易得、成本低廉，适于大规模生产。

Description

N-酰基联苯丙氨酸的制备方法
技术领域
本发明涉及化合物制备技术领域，更具体地，涉及联苯丙氨酸衍生物制备技术领域，特别是指一种N-酰基联苯丙氨酸的制备方法。 
背景技术
联苯丙氨酸的N-酰基衍生物通过化学拆分可以得到手性的联苯丙氨酸，而S-联苯丙氨酸是合成一些新药的关键中间体。 
目前合成N-酰基联苯丙氨酸的方法还没有文献报道。而联苯丙氨酸的衍生物也很少有报道，合成方法主要是采用昂贵的、非天然的D-酪氨酸为原料，还使用了价格高昂的三氟甲磺酸酐活化酚羟基，再进行偶联得到(Journal of Medicinal Chemistry 1995，Vol.38NO.10)。反应式如下式： 
该方法存在成本高等缺点，而且在大量生产时原料不易得到。 
发明内容
本发明的主要目的就是针对以上存在的问题与不足，提供一种N-酰基联苯丙氨酸的制备方法，该制备方法的工艺合理、原料辅料易得、成本低廉，适于大规模生产。 
为了实现上述目的，本发明采用的技术方案如下： 
一种N-酰基联苯丙氨酸的制备方法，其特点是，包括以下步骤： 
Figure G200810200404XD00021
其中，R1为直链或含支链的烷基、芳基；R2为甲基或乙基。 
较佳地，在步骤a中，所述联苯甲醛：所述N-酰基甘氨酸：所述酸酐：所述碱的投料摩尔比为1.0:(0.7～5.0):(1.0～6.0):(0.05～2.00)，所述溶剂I的用量为所述联苯甲醛的投料质量的0～20倍。 
较佳地，在步骤a中，所述溶剂I为苯、甲苯、二甲苯、氯苯、二氯苯、硝基苯、庚烷、乙酸、丙酸、异丁酸、正丁酸、乙酸酐或丙酸酐；所述酸酐为乙酸酐或丙酸酐；所述碱是三乙胺、吡啶、N-甲基吡咯、N-甲基吗啉、碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、乙酸钠、乙酸钾、丙酸钠或丙酸钾。 
较佳地，步骤a中的反应温度是80℃至回流，反应时间是0.5～48小时。 
较佳地，在步骤b中，所述溶剂II为水、乙醇、甲醇、异丙醇、丙醇、乙酸乙酯、乙酸异丙酯、丙酸乙酯、丙酮、丁酮、甲基异丁基酮、四氢呋喃、1，4-二氧六环、N，N-二甲基甲酰胺或N-甲基吡咯。 
较佳地，在步骤b中，所述溶剂II的投料量是步骤a中所述产物1的2～50倍，所述水的投料质量为步骤a中产物1的质量的0.5～20倍。 
较佳地，步骤b中的反应温度为室温至回流。 
较佳地，在步骤c中，所述溶剂III为乙醇、甲醇、乙酸乙酯、N，N-二甲基甲酰胺、N-甲基吡咯或四氢呋喃；所述钯碳含1％～20％钯。 
较佳地，在步骤c中，所述溶剂III的投料量是步骤a中所述产物1的5～50倍，所述钯碳的质量为步骤b中产物2的0.1％～20％。
较佳地，步骤c中还加入冰乙酸调节pH值，使反应保持在酸性条件中，反应温度为20～150℃，所述氢气的压力为0.2MPa～10.0MPa。 
本发明的有益效果具体为：本发明以联苯甲醛、N-酰基甘氨酸和酸酐为原料在碱存在条件下在合适的有机溶剂中加热回流进行反应，获得产物1；所述产物1在水和/或有机溶剂中加热回流进行反应，获得产物2；所述产物2在有机溶剂中在氢气压力和钯碳作用下形成产物3，工艺设计合理、原料辅料易得、成本低廉，适于大规模生产。 
具体实施方式
为更好的理解本发明的内容，下面结合具体实施例作进一步说明。 
实施例1：4-(4-联苯基亚甲基)-2-甲基-噁唑-5(4H)-酮(产物1)的合成 
在干净干燥的反应瓶中，投入36.4g联苯甲醛(日本三菱化学株式会社，工业，含量>98％)，28g乙酰甘氨酸(南通大鸿化工有限公司，工业)，56g醋酐(中国石油吉林石化公司电化厂，工业)以及6g无水乙酸钠(上海长征第二化工厂，无水)，加热，到回流0.5小时，保温结束，冷却至80℃。加入水200ml，搅拌30min。过滤，滤饼用100ml水洗涤两次。湿品于30～40℃真空干燥，得42～45g产物1，收率80.0～85.6％。 
实施例2：2-乙酰氨基-3-联苯基丙烯酸(产物2)的合成 
向1000ml反应瓶中，加入40g的4-(4-联苯基亚甲基)-2-甲基-噁唑-5(4H)-酮(产物1)，450ml丙酮(中国石油化工股份有限公司，工业)和60ml自来水，加热，回流8小时，保温结束。加入3g活性炭脱色1小时，过滤并用50ml丙酮洗涤，蒸丙酮约300ml后加入水200ml，冷却到20℃，过滤。湿品于60℃干燥，烘干后得36～38g，收率：84.2～88.9％。 
实施例3：3-联苯基-2-乙酰氨基丙氨酸(产物3)的合成 
在1L的高压釜(大连通产高压釜容器制造有限公司，FYX)中投入20g的2-乙酰氨基-3-联苯基丙烯酸(产物2)、300ml无水乙醇、2ml冰乙酸和1g含5％Pd的Pd/C(钯碳)(大连通用化工有限公司)。密封反应釜用氮气置换，加热至内温70～80℃，调节氢气压力在6MPa，保温反应20h，冷却反应釜60℃，放气，过滤、用约10ml乙醇洗涤。滤液浓缩到约60ml，冷却于0-5℃，过滤。湿品在60℃烘料，得干品18.5～19g，收率：91.9～94.3％。
实施例4：4-(4-联苯基亚甲基)-2-苯基-噁唑-5(4H)-酮(产物1)的合成 
在干净干燥的反应瓶中，投入36.4g联苯甲醛(日本三菱化学株式会社，工业，含量>98％)，33gN-苯甲酰甘氨酸(合肥博美生物科技有限公司，工业)，52g丙酸酐(成都科龙化工试剂厂，试剂)以及20gN-甲基吗啉(常州宇平化工有限公司，工业)和182g的氯苯加热，到100℃，保温24小时，冷却至80℃。加入水200ml，搅拌30min。过滤，滤饼用100ml水洗涤两次。湿品于30～40℃真空干燥，得60g产物1，收率92.5％。 
实施例5：2-苯甲酰氨基-3-联苯基丙烯酸(产物2)的合成 
向1000ml反应瓶中，加入60g的4-(4-联苯基亚甲基)-2-苯基-噁唑-5(4H)-酮(产物1)，1000ml四氢呋喃(台湾台尼公司，工业)和150ml自来水，加热至室温，保温24小时。加入3g活性炭脱色1小时，过滤并用50ml四氢呋喃洗涤，蒸四氢呋喃约600ml后，冷却到20℃，过滤。湿品于60℃干燥，烘干后得53g，收率：83.7％。 
实施例6：3-联苯基-2-苯甲酰氨基丙氨酸(产物3)的合成 
在1L的高压釜(大连通产高压釜容器制造有限公司，FYX)中投入10g的2-苯甲酰氨基-3-联苯基丙烯酸(产物2)、350ml甲醇、1ml冰乙酸和2g含5％Pd的Pd/C(钯碳)(大连通用化工有限公司)。密封反应釜用氮气置换，加热至内温140～150℃，调节氢气压力在0.2MPa，保温反应20h，冷却反应釜60℃，放气，过滤、用约10ml乙醇洗涤。滤液浓缩到约60ml，冷却于0-5℃，过滤。湿品在60℃烘料，得干品8g，收率：80％。 
实施例7：4-(4-联苯基亚甲基)-2-苯基-噁唑-5(4H)-酮(产物1)的合成 
在干净干燥的反应瓶中，投入36.4g联苯甲醛(日本三菱化学株式会社，工业，含量>98％)，33gN-苯甲酰甘氨酸(合肥博美生物科技有限公司，工业)，52g丙酸酐(成都科龙化工试剂厂，试剂)以及10g无水丙酸钠(上海长征第二化工厂，无水)和200g的二氯苯加热，到80℃，保温48小时，冷却至80℃。加入水200ml，搅拌30min。过滤，滤饼用100ml水洗涤两次。湿品于30～40℃真空干燥，得58g产物1，收率90.5％。 
实施例8：2-苯甲酰氨基-3-联苯基丙烯酸(产物2)的合成
向1000ml反应瓶中，加入50g的4-(4-联苯基亚甲基)-2-苯基-噁唑-5(4H)-酮(产物1)，550ml丁酮(中国石油化工股份有限公司，工业)和120ml自来水，加热至40℃，保温24小时。加入3g活性炭脱色1小时，过滤并用50ml四氢呋喃洗涤，蒸四氢呋喃约600ml后，冷却到20℃，过滤。湿品于60℃干燥，烘干后得48g，收率：80.2％。 
实施例9：3-联苯基-2-苯甲酰氨基丙氨酸(产物3)的合成 
在1L的高压釜(大连通产高压釜容器制造有限公司，FYX)中投入15g的2-苯甲酰氨基-3-联苯基丙烯酸(产物2)、300ml四氢呋喃、1.5ml冰乙酸和4g含5％Pd的Pd/C(钯碳)(大连通用化工有限公司)。密封反应釜用氮气置换，加热至内温100～110℃，调节氢气压力在10.0MPa，保温反应20h，冷却反应釜60℃，放气，过滤、用约10ml乙醇洗涤。滤液浓缩到约60ml，冷却于0-5℃，过滤。湿品在60℃烘料，得干品8.7g，收率：81.5％。 
综上所述，本发明的N-酰基联苯丙氨酸的制备方法的工艺合理、原料辅料易得、成本低廉，适于大规模生产。 
需要说明的是，在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，以上所述的是本发明的具体实施例及所运用的技术原理，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改而不背离本发明的精神与范围，这些等价形式同样落在本发明的范围内。

Claims (10)

1.一种N-酰基联苯丙氨酸的制备方法，其特征在于，包括以下步骤：
Figure FDA00001986077300011
其中，R1为直链或含支链的烷基、芳基；R2为甲基或乙基。
2.根据权利要求1所述的N-酰基联苯丙氨酸的制备方法，其特征在于，在步骤a中，所述联苯甲醛：N-酰基甘氨酸：酸酐：碱的投料摩尔比为1.0：0.7～5.0：1.0～6.0：0.05～2.00。
3.根据权利要求1所述的N-酰基联苯丙氨酸的制备方法，其特征在于，在步骤a中，所述溶剂I为苯、甲苯、二甲苯、氯苯、二氯苯、硝基苯、庚烷、乙酸、丙酸、异丁酸、正丁酸、乙酸酐或丙酸酐；所述酸酐为乙酸酐或丙酸酐；所述碱是三乙胺、吡啶、N-甲基吡咯、N-甲基吗啉、碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、乙酸钠、乙酸钾、丙酸钠或丙酸钾。
4.根据权利要求1所述的N-酰基联苯丙氨酸的制备方法，其特征在于，步骤a中的反应温度是80℃至回流，反应时间是0.5～48小时。
5.根据权利要求1所述的N-酰基联苯丙氨酸的制备方法，其特征在于，在步骤b中，所述溶剂II为水、乙醇、甲醇、异丙醇、丙醇、乙酸乙酯、乙酸异丙酯、丙酸乙酯、丙酮、丁酮、甲基异丁基酮、四氢呋喃、1,4-二氧六环、N，N-二甲基甲酰胺或N-甲基吡咯。
6.根据权利要求1所述的N-酰基联苯丙氨酸的制备方法，其特征在于，在步骤b中，所述溶剂II的投料量是步骤a中所述产物1的2～50倍，所述水的投料质量为步骤a中所述产物1的质量的0.5～20倍。
7.根据权利要求1所述的N-酰基联苯丙氨酸的制备方法，其特征在于，步骤b中的反应温度为室温至回流。
8.根据权利要求1所述的N-酰基联苯丙氨酸的制备方法，其特征在于，在步骤c中，所述溶剂III为乙醇、甲醇、乙酸乙酯、N，N-二甲基甲酰胺、N-甲基吡咯或四氢呋喃；所述钯碳含1%～20%钯。
9.根据权利要求1所述的N-酰基联苯丙氨酸的制备方法，其特征在于，在步骤c中，所述溶剂III的投料量是步骤a中所述产物1的5～50倍，所述钯碳的质量为步骤b中所述产物2的0.1%～20%。
10.根据权利要求1所述的N-酰基联苯丙氨酸的制备方法，其特征在于，步骤c中还加入冰乙酸调节pH值，使反应保持在酸性条件中，反应温度为20～150℃，所述氢气的压力为0.2MPa～10.0MPa。
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