CN104710348B - 一种3,5‑二氰基‑4‑对氟苯基‑2,6‑哌啶二酮的制备方法 - Google Patents

一种3,5‑二氰基‑4‑对氟苯基‑2,6‑哌啶二酮的制备方法 Download PDF

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CN104710348B
CN104710348B CN201510169133.6A CN201510169133A CN104710348B CN 104710348 B CN104710348 B CN 104710348B CN 201510169133 A CN201510169133 A CN 201510169133A CN 104710348 B CN104710348 B CN 104710348B
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fluorophenyl
methyl
dicyano
water
fluorobenzaldehyde
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CN104710348A (zh
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郑土才
舒霖
潘向军
戴武俊
许彤
陈旭霞
王应祥
陈英英
姜涛
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Quzhou University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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Abstract

本发明公开了一种由对氟苯甲醛、氰乙酸甲酯、氰乙酰胺和氨水等为原料，经一锅煮的反应、酸化、过滤等步骤制备3,5‑二氰基‑4‑对氟苯基‑2,6‑哌啶二酮的方法，所得产物为抗抑郁药帕罗西汀的中间体。本发明方法具有原料价廉易得、操作简单、条件温和、收率高、成本低、节能省耗等特点，具有较好的工业化前景。

Description

一种3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的制备方法
技术领域
本发明涉及一种医药中间体3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的制备方法。
背景技术
3,5-二氰基-4-对氟苯基-2,6-哌啶二酮是重要的精细化工中间体，它经水解、脱羧可制得抗抑郁药帕罗西汀的中间体3-对氟苯基戊二酸，如Scott等（WO 2009/005647）和Chaubey等（Tetrahedron:Asymmetry 2012,23,1206- 1212），因此3,5-二氰基-4-对氟苯基-2,6-哌啶二酮是重要的有机合成目标。
3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的合成仅见于Wu等（Heterocycles 2009,78(4),977-982）的报道，对氟苯甲醛与两分子氰乙酸乙酯在无水甲醇中，氮化锂Li3N为氨源经一锅煮反应得到目标产物，收率74%。虽然反应在室温下进行，但要求无水、密闭，反应时间较长，收率偏低，特别是氮化锂与水剧烈反应，在空气中能燃烧，危险性大，价格高不易得，使用量大，难以实现工业化。
发明内容
为了克服现有工艺中氮化锂价格高不易得、反应条件较为苛刻、收率低、成本高等缺点，本发明提供了一种成本低、易操作的3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的制备方法。
本发明以仲胺或叔胺为催化剂，将对氟苯甲醛、氰乙酸甲酯、氰乙酰胺及催化剂溶于溶剂中，控制不高于15℃的条件下滴加氨水，室温搅拌反应7-10h，加水稀释、酸化、过滤、洗涤、干燥制得3,5-二氰基-4-对氟苯基-2,6-哌啶二酮。产品收率83%以上，粗品含量95%以上。
其中仲胺催化剂包括哌啶、吗啉、哌嗪、吡咯烷和二正丙胺，其中叔胺催化剂包括N-甲基哌啶、N-甲基吗啉、1-甲基哌嗪、1,4-二甲基哌嗪、N-甲基吡咯烷和三乙胺。
其中溶剂为甲醇或乙醇或异丙醇或水，或水与前述任意一种醇的混合物。
其中对氟苯甲醛:氰乙酸甲酯:氰乙酰胺的摩尔配比优选1:1.1:1至1:1:1.2之间。
本发明的一锅煮反应，包括对氟苯甲醛与氰乙酸甲酯的Knoevenagel缩合，缩合产物与氰乙酰胺的Michael加成，酯与酰胺的分子内环合，成盐，酸化等步骤，反应式如下所示。
本发明的氰乙酸甲酯也可以是氰乙酸乙酯、氰乙酸异丙酯等，但氰乙酸甲酯的消耗和价格最低，具有工业化生产前景。
本发明的后处理方法，只是在反应结束后加水稀释、盐酸酸化、过滤、洗涤、干燥，整个过程简单方便，节时省耗，反应设备包括反应釜和管道等无需干燥直接进行下一批反应，解决了现有技术中每批反应后相关设备必须进行脱水干燥的步骤，提高了生产效率。
本发明提出3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的制备方法，其重要特征是：（1）氨水替代氮化锂为氨源，价廉易得，使用方便，反应体系不需严格控制无水、密闭条件，安全性好；（2）反应时间短、产物收率高、三废污染少；（3）反应的后处理简单方便，反应体系无需干燥，节时省耗，生产效率高。
本发明以对氟苯甲醛、氰乙酸甲酯、氰乙酰胺、氨水为原料，在仲胺或叔胺催化下，于甲醇或乙醇或异丙醇或水或水与前述任意一种醇的混合物中一锅煮反应、酸化、过滤等制得3,5-二氰基-4-对氟苯基-2,6-哌啶二酮，具有原料价廉易得、操作简单、条件温和、收率高、成本低、节能省耗等优点，具有较高的工业化生产价值。
具体实施方式
以下实施例所用原料、溶剂等均为工业级产品，未经进一步纯化。含量测定使用高效液相色谱（HPLC）归一化法。红外、核磁和质谱结构表征分别使用红外光谱仪、核磁共振谱仪和质谱仪。
实施例1
3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的合成
向四口瓶中加入对氟苯甲醛24.8g(0.20mol)、氰乙酰胺20.2g(0.24mol)、氰乙酸甲酯19.8g(0.20mol)、吗啉1.0g和甲醇120mL，搅拌下滴加氨水170g(1.98mol)，滴加过程控制温度在15℃以下。滴完室温搅拌反应7h，加入水120mL、盐酸酸化至pH 5以下。过滤、水洗、干燥得到米黄色至类白色粉状产物3,5-二氰基-4-对氟苯基-2,6-哌啶二酮45.6g，收率83.2%，含量96.8%。
实施例2
3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的合成
向四口瓶中加入对氟苯甲醛24.8g(0.20mol)、氰乙酰胺17.6g(0.21mol)、氰乙酸甲酯19.8g(0.20mol)、哌啶0.85g、乙醇80mL、水20mL，搅拌下滴加氨水160g(1.65mol)，滴加过程控制温度在10℃以下。滴完室温搅拌反应9h，加入水160mL、盐酸酸化至pH 5以下。过滤、水洗、干燥得到米黄色至类白色粉状产物3,5-二氰基-4-对氟苯基-2,6-哌啶二酮47.5g，收率86.7%，含量96.2%。
实施例3
3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的合成
向四口瓶中加入对氟苯甲醛24.8g(0.20mol)、氰乙酰胺16.8g(0.20mol)、氰乙酸甲酯19.8g(0.20mol)、三乙胺1.2g和异丙醇100mL，搅拌下滴加氨水100g(1.65mol)，滴加过程控制温度在10℃以下。滴完室温搅拌反应8h，加入水300mL、盐酸酸化至pH 5以下。过滤、水洗、干燥得到米黄色至类白色粉状产物3,5-二氰基-4-对氟苯基-2,6-哌啶二酮46.9g，收率85.5%，含量97.1%。
实施例4
3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的合成
向四口瓶中加入对氟苯甲醛24.8g(0.20mol)、氰乙酰胺16.8g(0.20mol)、氰乙酸甲酯21.8g(0.22mol)、二正丙胺1.0g、乙醇100mL，搅拌下滴加氨水90g(1.48mol)，滴加过程控制温度在15℃以下。滴完室温搅拌反应10h，加入水280mL、盐酸酸化至pH 5以下。过滤、水洗、干燥得到米黄色至类白色粉状产物3,5-二氰基-4-对氟苯基-2,6-哌啶二酮47.9g，收率87.4%，含量97.5%。
实施例5
3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的合成
向四口瓶中加入对氟苯甲醛24.8g(0.20mol)、氰乙酰胺17.6g(0.21mol)、氰乙酸甲酯19.8g(0.20mol)、N-甲基吡咯烷0.9g、水100mL，搅拌下滴加氨水120g(1.98mol)，滴加过程控制温度在5℃以下。滴完室温搅拌反应8h，加入水260mL、盐酸酸化至pH 5以下。过滤、水洗、干燥得到米黄色至类白色粉状产物3,5-二氰基-4-对氟苯基-2,6-哌啶二酮46.2g，收率84.3%，含量95.4%。
实施例6
3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的合成
向四口瓶中加入对氟苯甲醛24.8g(0.20mol)、氰乙酰胺16.8g(0.20mol)、氰乙酸甲酯21.8g(0.22mol)、1-甲基哌嗪1.0g、甲醇120mL、水20mL，搅拌下滴加氨水110g(1.32mol)，滴加过程控制温度在0℃以下。滴完室温搅拌反应7h，加入水230mL、盐酸酸化至pH 5以下。过滤、水洗、干燥得到米黄色至类白色粉状产物3,5-二氰基-4-对氟苯基-2,6-哌啶二酮46.9g，收率85.6%，含量96.6%。
产品的表征数据如下：IR（KBr）/cm-1：3315（NH），2274（氰基）,1726,1702（羰基）。1HNMR(DMSO-d6,300MHz)/ppm:12.08(s,1H,NH),7.20-6.92(m,4H, ArH),4.73-4.69(m,2H,CH),4.34-4.28(m,1H,CH)。MS（m/z）：258 [M+H]+。
本行业的技术人员应该理解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是为了说明本发明的原理。在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些都落入本发明要求保护的范围内。

Claims (1)

1.一种3,5-二氰基-4-对氟苯基-2,6-哌啶二酮的制备方法，其特征在于：以仲胺或叔胺为催化剂，将对氟苯甲醛、氰乙酸甲酯、氰乙酰胺及催化剂溶于溶剂中，控制不高于15℃的条件下滴加氨水，室温搅拌反应7-10h，加水稀释、酸化、过滤、洗涤、干燥制得3,5-二氰基-4-对氟苯基-2,6-哌啶二酮；
所述仲胺催化剂为哌啶、吗啉、哌嗪、吡咯烷和二正丙胺其中的一种；
所述叔胺催化剂为N-甲基哌啶、N-甲基吗啉、1-甲基哌嗪、1,4-二甲基哌嗪、N-甲基吡咯烷和三乙胺其中的一种；
所述溶剂为甲醇或乙醇或异丙醇或水，或水与前述任意一种醇的混合物；
所述方法的对氟苯甲醛：氰乙酸甲酯：氰乙酰胺的摩尔比在1:1.1:1至1:1:1.2之间。
CN201510169133.6A 2015-04-13 2015-04-13 一种3,5‑二氰基‑4‑对氟苯基‑2,6‑哌啶二酮的制备方法 Expired - Fee Related CN104710348B (zh)

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