CN109232399B - 一种5-溴-2-甲基-3-(三氟甲基)吡啶的合成方法 - Google Patents
一种5-溴-2-甲基-3-(三氟甲基)吡啶的合成方法 Download PDFInfo
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Abstract
本发明公开了一种5‑溴‑2‑甲基‑3‑(三氟甲基)吡啶的合成方法，包括：将丙二酸二乙酯与2‑氯‑3‑三氟甲基‑5‑硝基吡啶在碱性条件下生成2‑(5‑硝基‑3‑(三氟甲基)吡啶‑2‑基)丙二酸二甲酯，再在酸性条件下生成2‑甲基‑5‑硝基‑3‑(三氟甲基)吡啶，还原得6‑甲基‑5‑(三氟甲基)吡啶‑3‑胺，重氮化得5‑溴‑2‑甲基‑3‑(三氟甲基)吡啶，首次提出5‑溴‑2‑甲基‑3‑(三氟甲基)吡啶的合成方案，原料易得、反应条件温和，选择性高，后处理具有很好的可操作性，收率较高，并且容易放大生产，环保。
Description
技术领域
本发明属于药物合成中间体制备技术领域，涉及一种5-溴-2-甲基-3-(三氟甲基)吡啶的合成方法，所得5-溴-2-甲基-3-(三氟甲基)吡啶在制备治疗疼痛、呼吸系统疾病以及抑制瞬时受体电位Al离子通道(TRPAI)的药物中的用途。
背景技术
瞬时受体电位Al(TRPA1)是与人类疼痛感相关的非选择性阳离子通道，存在于感觉神经元和功能检测器中，有助于检测有害化学物质，组织损伤和炎症TRPAT的激活被认为通过诱导脊髓中的伤害性神经驱动中枢致敏引起疼痛。TRPA1刺激还可以增加感觉神经元，导致致炎神经肽如NK物质P和CGRP(其诱导血管舒张并帮助募集免疫细胞)的释放。在炎症过程中产生的内源性反应性化合物激活TRPA1(包括在脂质体过氧化过程中释放的羟基壬烯醛、COX酶产生的环戊烷前列腺素和氧化应激产生的过氧化氢)，TRPA1的激活使TRPA1对寒冷敏感；此外，功能获得性突变在TRPA1中引起发作性疼痛综合征，患有这种病症的患者由于感冒而引发阵发性疼痛。因此，TRPA1被认为在与神经冷异常性疼痛和炎性疼痛相关的疼痛中发挥作用。
发明内容
本发明的目的在于提供一种用于制备治疗疼痛、呼吸系统疾病以及抑制瞬时受体电位Al离子通道(TRPAI)的药物中间体5-溴-2-甲基-3-(三氟甲基)吡啶的合成方法，本发明首次提出5-溴-2-甲基-3-(三氟甲基)吡啶的合成方法，为5-溴-2-甲基-3-(三氟甲基)吡啶的制备提供了合成路线。
本发明的上述目的通过以下技术方案来实现：
5-溴-2-甲基-3-(三氟甲基)吡啶的合成方法，合成路线如式(Ⅰ)所示：
具体地，包括以下步骤：
(1)将丙二酸二乙酯加到有机溶剂Ⅰ中，冷却至0度，加入钠氢，搅拌30～60分钟，滴加化合物1(2-氯-3-三氟甲基-5-硝基吡啶)的有机溶剂Ⅰ，10～25℃反应16～24h；冲水，EA萃取，反洗，干燥，旋干，得化合物2(2-(5-硝基-3-(三氟甲基)吡啶-2-基)丙二酸二甲酯)；其中，
所述2-氯-3-三氟甲基-5-硝基吡啶、丙二酸二乙酯和钠氢的摩尔比为1：1～1.41：1～2；
所述2-氯-3-三氟甲基-5-硝基吡啶和所述有机溶剂Ⅰ的用量比为1000：5～10(g/L)；
(2)将化合物2加到摩尔浓度为2～8N的盐酸溶液中，80～100℃过夜，冲冰水，EA萃取，饱和碳酸氢钠溶液反洗，饱和氯化钠溶液反洗，干燥，旋干，得化合物3；
(3)将化合物3加到有机酸中，升温至40～50℃，分批加入铁粉，加热到50～100℃反应1h，冲水，过滤，EA萃取，饱和碳酸氢钠溶液反洗，饱和氯化钠溶液反洗，干燥，旋干，得化合物4；其中，
所述化合物3与所述铁粉的摩尔比为1：2～2.6；
(4)将化合物4加到乙腈中，加入溴化铜，滴加亚硝酸叔丁酯，10～25℃反应2h，有机溶剂Ⅱ萃取，反洗，干燥，旋干，纯化，得黄色油产品；其中，
所述化合物4、溴化铜和亚硝酸叔丁酯的摩尔比为1：1～1.1：1～4。
优选地，步骤(1)中，所述2-氯-3-三氟甲基-5-硝基吡啶、丙二酸二乙酯和钠氢的摩尔比为1：1.41：2；所述有机溶剂Ⅰ为四氢呋喃或N,N-二甲基甲酰胺。
优选地，步骤(1)中，所述有机溶剂Ⅰ为四氢呋喃。
优选地，步骤(1)中，所述2-氯-3-三氟甲基-5-硝基吡啶和所述有机溶剂Ⅰ的用量比为200：1(g/L)。
优选地，步骤(2)中，所述盐酸溶液的摩尔浓度为6N。
优选地，步骤(3)中，所述有机酸为乙酸，所述化合物3与铁粉的摩尔比为1：2.6。
优选地，步骤(4)中，所述化合物4、溴化铜和亚硝酸叔丁酯的摩尔比为1：1.1：3.1。
优选地，步骤(4)中，所述有机溶剂Ⅱ为乙酸乙酯或二氯甲烷；所述的纯化方式为蒸馏或过柱。
优选地，步骤(4)中，所述有机溶剂Ⅱ为乙酸乙酯；所述的纯化方式为蒸馏。
另一方面，上述5-溴-2-甲基-3-(三氟甲基)吡啶的合成方法所得5-溴-2-甲基-3-(三氟甲基)吡啶在制备治疗疼痛、呼吸系统疾病以及抑制瞬时受体电位Al离子通道(TRPAI)的药物中的用途。
本发明的有益效果在于：
(1)本发明首次提出5-溴-2-甲基-3-(三氟甲基)吡啶的合成方案，为5-溴-2-甲基-3-(三氟甲基)吡啶的制备提供了合成路线。
(2)本发明5-溴-2-甲基-3-(三氟甲基)吡啶的合成方案为四步反应，总收率约为31.1％，且原料易得，制备工艺较为简单，成本低，可大规模生产。
附图说明
图1为5-溴-2-甲基-3-(三氟甲基)吡啶的核磁氢谱图。
具体实施方式
以下通过具体实施例来说明本发明的技术方案，但本发明的保护范围不限于此。
实施例1：制备化合物2(2-(5-硝基-3-(三氟甲基)吡啶-2-基)丙二酸二甲酯)
反应路线如式(Ⅱ)所示，将丙二酸二乙酯(1000g，约6.24mol)加到5LTHF中，冷却至0度，加入钠氢(350g，约8.75mol)，搅拌30min，滴加化合物1(2-氯-3-三氟甲基-5-硝基吡啶，1000g，约4.41mol)的1.5LTHF溶液，RT反应过夜；冲水，EA萃取，饱和食盐水反洗，硫酸钠干燥，过滤，母液旋干，得2000g化合物2(2-(5-硝基-3-(三氟甲基)吡啶-2-基)丙二酸二甲酯)，收率约为140％。
实施例2-5的制备方法同实施例1，改变反应物的摩尔比、反应温度和反应时间如表1所示，测得化合物2(2-(5-硝基-3-(三氟甲基)吡啶-2-基)丙二酸二甲酯)的收率如表1所示。
表1：2-(5-硝基-3-(三氟甲基)吡啶-2-基)丙二酸二甲酯的转化率
实施例6：制备化合物3(2-甲基-5-硝基-3-(三氟甲基)吡啶)
反应路线如式(Ⅲ)所示，将化合物2(2000g，约6.2mol)加到4L浓盐酸和4L水的混合液中，回流过夜，冲冰水，EA萃取，饱和碳酸氢钠反洗，饱和氯化钠反洗，干燥，旋干，得980g化合物3(2-甲基-5-硝基-3-(三氟甲基)吡啶)，收率约为76.6％。
实施例7-9的制备方法同实施例6，改变反应物的摩尔比、反应温度和反应时间如表2所示，测得化合物2(2-(5-硝基-3-(三氟甲基)吡啶-2-基)丙二酸二甲酯)的收率如表2所示。
表2：2-甲基-5-硝基-3-(三氟甲基)吡啶的转化率
| 实施例 | 浓盐酸的摩尔浓度 | 温度(℃) | 反应时间(h) | 收率(％) |
| 6 | 6N | 100 | 24 | 76.6 |
| 7 | 2N | 80 | 24 | 30 |
| 8 | 2N | 100 | 24 | 45 |
| 9 | 8N | 100 | 24 | 58 |
实施例10：制备化合物4(6-甲基-5-(三氟甲基)吡啶-3-胺)
反应路线如式(Ⅳ)所示，将化合物3(980g，约4.75mol)加到8L醋酸中，升至40℃，分批加入铁粉(700g，约12.5mol)，加热到80℃反应24h，冲水，过滤，EA萃取，饱和碳酸氢钠反洗，饱和氯化钠反洗，干燥，旋干，得700g化合物4，收率约为83.6％。
实施例11-13的制备方法同实施例10，改变反应物的摩尔比、反应温度和反应时间如表3所示，测得化合物2(2-(5-硝基-3-(三氟甲基)吡啶-2-基)丙二酸二甲酯)的收率如表3所示。
表3：6-甲基-5-(三氟甲基)吡啶-3-胺的转化率
实施例14：制备化合物5(5-溴-2-甲基-3-(三氟甲基)吡啶)
反应路线如式(Ⅴ)所示，将化合物4(700g，约3.97mol)加到7L乙腈中，加入溴化铜(980g，4.39mol)，滴加亚硝酸叔丁酯(1260g，12.2mol)，RT反应2h，EA萃取，反洗，干燥，旋干，蒸馏，得330g黄色油产品，即为5-溴-2-甲基-3-(三氟甲基)吡啶，收率约为34.6％。
实施例15-18的制备方法同实施例14，改变反应物的摩尔比、反应温度和反应时间如表4所示，测得化合物2(2-(5-硝基-3-(三氟甲基)吡啶-2-基)丙二酸二甲酯)的收率如表4所示。
表4：5-溴-2-甲基-3-(三氟甲基)吡啶的转化率
参见图1黄色油产品的核磁氢谱如下所示：1HNMR(600MHz，CDCl3)δ8.72(s，1H)，8.04(s，1H)，2.69(d，J＝1.1Hz，3H)。
在阅读本发明的上述讲述内容之后，本领域的技术人员可以对本发明做各种改动或修改，这些等价形式同样落于本申请权利要求书所限定的范围。
Claims (1)
1.5-溴-2-甲基-3-(三氟甲基)吡啶的合成方法，其特征在于，合成路线如式(Ⅰ)所示：
包括以下步骤：
(1)丙二酸二乙酯加到四氢呋喃中，冷却至0度，加入钠氢，搅拌30分钟，滴加化合物1(2-氯-3-三氟甲基-5-硝基吡啶)的四氢呋喃，25℃反应24h；冲水，EA萃取，反洗，干燥，旋干，得化合物2(2-(5-硝基-3-(三氟甲基)吡啶-2-基)丙二酸二甲酯)；2-氯-3-三氟甲基-5-硝基吡啶、丙二酸二乙酯和钠氢的摩尔比为1：1.41：2；2-氯-3-三氟甲基-5-硝基吡啶和四氢呋喃的用量比为200：1g/L；
(2)化合物2加到摩尔浓度为6N的盐酸溶液中，100℃过夜，冲冰水，EA萃取，饱和碳酸氢钠溶液反洗，饱和氯化钠溶液反洗，干燥，旋干，得化合物3；
(3)化合物3加到乙酸中，升温至40℃，分批加入铁粉，化合物3与所述铁粉的摩尔比为1：2.6，加热到80℃反应24h，冲水，过滤，EA萃取，饱和碳酸氢钠溶液反洗，饱和氯化钠溶液反洗，干燥，旋干，得化合物4；
(4)化合物4加到乙腈中，加入溴化铜，滴加亚硝酸叔丁酯，25℃反应2h，乙酸乙酯萃取，反洗，干燥，旋干，蒸馏，得黄色油产品5-溴-2-甲基-3-(三氟甲基)吡啶；化合物4、溴化铜和亚硝酸叔丁酯的摩尔比为1：1.1：3.1。
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