CN107954888B - 一种凉味剂n,2,3-三甲基-2-异丙基丁酰胺的合成方法 - Google Patents

一种凉味剂n,2,3-三甲基-2-异丙基丁酰胺的合成方法 Download PDF

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CN107954888B
CN107954888B CN201711205511.7A CN201711205511A CN107954888B CN 107954888 B CN107954888 B CN 107954888B CN 201711205511 A CN201711205511 A CN 201711205511A CN 107954888 B CN107954888 B CN 107954888B
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周军学
陈清
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    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

本发明公开了一种凉味剂N,2,3‑三甲基‑2‑异丙基丁酰胺的合成方法，包括如下步骤：(1)乙酰乙酸甲酯在强碱条件下与2‑溴丙烷反应得到3，3‑二异丙基乙酰乙酸甲酯；(2)将得到的3，3‑二异丙基乙酰乙酸甲酯与乙二醇反应使酮羰基得到保护，然后在还原剂的作用下将酯水解成羟基，再与对甲基苯磺酰氯反应，然后脱除对基苯磺酸酯，而得到3‑异丙基‑4‑甲基‑2‑戊酮；(3)将3‑异丙基‑4‑甲基‑2‑戊酮与盐酸羟胺反应，然后在酸条件下经贝克曼重排而得到N,2,3‑三甲基‑2‑异丙基丁酰胺。该方法通过酯基甲基化与贝克曼重排而成功得到了N,2,3‑三甲基‑2‑异丙基丁酰胺，为合成WS‑3提供了一种新的合成方法，且该方法收率较高，适合大规模生产。

Description

一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法
技术领域
本发明涉及凉味剂合成领域，尤其涉及一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法。
背景技术
凉味剂WS-23是WS系列常用的凉味剂，具有较高的凉味活性而没有灼烧、麻木和刺激等副作用，作为致凉剂主要用于如糖果、口腔护理、医药中。已知的WS-23的合成方法是利用丙腈在ɑ碳位上与2-溴丙烷反应，而腈基醇解或者酰氢化与一甲基胺反应，而得到N,2,3-三甲基-2-异丙基丁酰胺。
发明内容
为了避开上述专利保护的合成线路，本发明提供了一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法，该方法通过多步高收率的反应，使得综合收率达到50％，可适用于工业化生产。
为达此目的，本发明采用以下技术方案：凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法，其特征在于，
反应方程式如下：
Figure BDA0001483592670000021
包括以下步骤：
(1)乙酰乙酸甲酯在强碱条件下与2-溴丙烷反应得到3，3-二异丙基乙酰乙酸甲酯；
(2)将得到的3，3-二异丙基乙酰乙酸甲酯与乙二醇反应使酮羰基得到保护，然后在还原剂的作用下将酯水解成羟基，再与对甲基苯磺酰氯反应而得到3，3-二异丙基甲基缩乙二醇(对甲基)苯磺酸甲酯，然后脱除对基苯磺酸酯，而得到3-异丙基-4-甲基-2-戊酮；
(3)将3-异丙基-4-甲基-2-戊酮与盐酸羟胺反应，然后在酸条件下经贝克曼重排而得到N,2,3-三甲基-2-异丙基丁酰胺。
优选地，在所述步骤(1)中，所述强碱选自钠氢、二异丙基氨基锂和正丁基锂中的一种。
优选地，所述步骤(1)中，所述乙酰乙酸甲酯、强碱和2-溴丙烷反应的摩尔比为1:2～2.5:2～3。
优选地，所述步骤(1)中，反应温度为-78～0℃。
优选地，所述步骤(2)中，所述乙二醇是在对苯磺甲酸催化下与羰基进行缩合反应的。
优选地，所述步骤(2)中，所述还原剂选自硼氢化钠、氢化铝锂及三乙基硼氢化锂中的一种。
优选地，所述步骤(2)中，脱除对基苯磺酸酯的工艺方法为钯碳加氢脱除或在碱性条件下脱除。
优选地，所述步骤(3)中，所述酸选自硫酸、多聚磷酸、五氯化磷、三氯化磷、苯磺酰氯及亚硫酰氯中的一种。
本发明的有益效果为：本发明一种N,2,3-三甲基-2-异丙基丁酰胺的方法，通过多步骤高收率的合成，成功研究出了一种新的N,2,3-三甲基-2-异丙基丁酰胺合成方法，解决了以单一的腈基合成路线的限制，从根本上开辟了一条可行性极高的合成方法，可适用于大规模的工业化生产。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。
实施例1，本实施方式的一种N,2,3-三甲基-2-异丙基丁酰胺的方法，按下列反应过程进行：
Figure BDA0001483592670000031
步骤一、取116g乙酰乙酸甲酯(1mol,1eq)置入3L的反应瓶中，加入1L THF，将温度降至-40～-78℃滴入4mol/L的LDA THF溶液500ml(2mol 2eq),滴加完毕后，加入2-溴丙烷245g(2mol,2eq),滴加反应完毕后，处理得180g 3，3-二异丙基乙酰乙酸甲酯(0.9mol纯度95％)。
步骤二、将上述180g 3，3-二异丙基乙酰乙酸甲酯(0.9mol)置入到反应瓶中，加入500mol甲苯溶解，加入乙二醇(0.95mol),然后加入催化量的对甲基苯磺酸，反应2～3小时后，反应完成后，加入10％碳酸氢钠水洗，将有机层干燥后蒸馏，得到残留物185g；将该残留物用乙醇溶解，然后加入硼氢化钠(1mol)反应2～4小时，反应完毕，加入水淬灭，用乙酸乙酯萃取，将有机层蒸馏，得到165g残留物。将上述165g残留物用甲苯溶解，然后加入三乙胺，和对甲基苯磺酰氯，反应完毕后，蒸除掉甲苯，乙酸乙酯溶解后，用水洗二次，再次蒸除乙酸乙酯，得到3，3-二异丙基甲基缩乙二醇(对甲基)苯磺酸甲酯168g；然后在将168g 3，3-二异丙基甲基缩乙二醇(对甲基)苯磺酸甲酯加入乙醇在钯碳催化下加氢得到136g残留物，将残留物用乙醇溶解，加入5-10％盐酸水溶液，反应2小时，然后加入碳中和，萃取，蒸馏，得到3-异丙基-4-甲基-2-戊酮128g(0.82mol纯度93.8％)。
步骤三，将上述得到的3-异丙基-4-甲基-2-戊酮128g(0.82mol)用四氢呋喃溶解，然后加入盐酸羟胺(1.2eq)，加入碳酸钾，反应2小时，确认反应完全后，将反应中加入水，用乙酸乙酯提取，得到135g残留物，将该135残留物用多聚膦酸溶解，加热至100℃反应3～8小时，确认反应完毕后，加入碱中和，萃取，干燥、蒸馏及重结晶，得到N,2,3-三甲基-2-异丙基丁酰胺85g纯度99％，综合收率49.7％。
以上结合具体实施例描述了本发明的技术原理。这些描述只是为了解释本发明的原理，而不能以任何方式解释为对本发明保护范围的限制。基于此处的解释，本领域的技术人员不需要付出创造性的劳动即可联想到本发明的其它具体实施方式，这些方式都将落入本发明的保护范围之内。

Claims (8)

1.一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法，其特征在于，
反应方程式如下：
Figure FDA0001483592660000011
包括以下步骤：
(1)乙酰乙酸甲酯在强碱条件下与2-溴丙烷反应得到3，3-二异丙基乙酰乙酸甲酯；
(2)将得到的3，3-二异丙基乙酰乙酸甲酯与乙二醇反应使酮羰基得到保护，然后在还原剂的作用下将酯水解成羟基，再与对甲基苯磺酰氯反应而得到3，3-二异丙基甲基缩乙二醇(对甲基)苯磺酸甲酯，然后脱除对基苯磺酸酯，而得到3-异丙基-4-甲基-2-戊酮；
(3)将3-异丙基-4-甲基-2-戊酮与盐酸羟胺反应，然后在酸条件下经贝克曼重排而得到N,2,3-三甲基-2-异丙基丁酰胺。
2.如权利要求1所述的一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法，其特征在于，在所述步骤(1)中，所述强碱选自钠氢、二异丙基氨基锂和正丁基锂中的一种。
3.如权利要求1所述的一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法，其特征在于，所述步骤(1)中，所述乙酰乙酸甲酯、强碱和2-溴丙烷反应的摩尔比为1:2～2.5:2～3。
4.如权利要求1所述的一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法，其特征在于，所述步骤(1)中，反应温度为-78～0℃。
5.如权利要求1所述的一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法，其特征在于，所述步骤(2)中，所述乙二醇是在对苯磺甲酸催化下与羰基进行缩合反应的。
6.如权利要求1所述的一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法，其特征在于，所述步骤(2)中，所述还原剂选自硼氢化钠、氢化铝锂及三乙基硼氢化锂中的一种。
7.如权利要求1所述的一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法，其特征在于，所述步骤(2)中，脱除对基苯磺酸酯的工艺方法为钯碳加氢脱除或在碱性条件下脱除。
8.如权利要求1所述的一种凉味剂N,2,3-三甲基-2-异丙基丁酰胺的合成方法，其特征在于，所述步骤(3)中，所述酸选自硫酸、多聚磷酸、五氯化磷、三氯化磷、苯磺酰氯及亚硫酰氯中的一种。
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