CN105384684B - 一种2‑氰基‑6‑甲基吡啶的制备方法 - Google Patents
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/61—Halogen atoms or nitro radicals
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Abstract
本发明的目的在于克服现有技术中的缺陷，提供了一种2‑氰基‑6‑甲基吡啶的制备方法，属于医药中间体合成技术领域。本方法为，将氢溴酸和2‑氨基‑6‑甲基吡啶混合，保温；再将溶液冷却，向溶液中加入溴素Br2，然后保持该低温反应；再在该低温下向溶液中加入亚硝酸钠水溶液反应；反应结束将反应溶液降温，用碱调pH值，然后通过水汽蒸馏得2‑溴‑6‑甲基吡啶；将氰化亚铜和溴化锂加入到质量为2‑溴‑6‑甲基吡啶质量2‑5倍的DMF中，将溶液加热后，加入2‑溴‑6‑甲基吡啶后保温反应；反应结束后将溶液降温，加水，再通过水汽蒸馏得产品。本方法操作安全，低毒，收率高，适合工业化生产。
Description
技术领域
本发明属于医药中间体合成技术领域，具体涉及一种2-氰基-6-甲基吡啶的制备方法。
背景技术
2-氰基-6-甲基吡啶，结构式如下：
为一种重要的医药中间体，多用于拉唑，他汀类药物的合成。专利EP1424336A1，WO2006/21801A1，US2004/53929A1等均采用2-甲基吡啶氮氧化物为原料，经氮氧化后得到2-甲基氮氧化吡啶，再用硫酸二甲酯甲基化、氰化钠反应得到2-氰基-6-甲基吡啶。上述工艺氮氧化操作复杂，后处理麻烦，而且后期使用的硫酸二甲酯，氰化钠，毒性较大，生产安全性低，很难工业化。
发明内容
本发明的目的在于克服现有技术中的缺陷，提供了一种2-氰基-6-甲基吡啶的制备方法。本方法通过廉价的2-氨基-6-甲基吡啶，重氮化上溴得到2-溴-6-甲基吡啶，再经过低毒的氰化亚铜上氰基得到产品。本方法操作安全，低毒，收率高，适合工业化生产。
为此，本发明的技术方案如下：
一种2-氰基-6-甲基吡啶的制备方法，包括如下步骤：
(1)在搅拌条件下，将质量浓度为45-48％的氢溴酸和2-氨基-6-甲基吡啶混合，在55～65℃下保温0.1～1h；再将溶液冷却至-5～0℃后，向溶液中滴加溴素Br2，然后保温反应0.5～3h；再在该温度下向溶液中滴加质量浓度为25～30％的亚硝酸钠水溶液，接着反应1～3h，由于反应放热，反应温度会升高，无需控制反应温度；反应结束将反应溶液温度降至20℃以下，用20～30％的氢氧化钠将pH调至10～12，然后通过水汽蒸馏得2-溴-6-甲基吡啶；
其中，2-氨基-6-甲基吡啶和氢溴酸的质量比为1:5-7；2-氨基-6-甲基吡啶和Br2的摩尔比为1:2-4；2-氨基-6-甲基吡啶和亚硝酸钠的摩尔比为1:2-4；
(2)将氰化亚铜和溴化锂加入到质量为2-溴-6-甲基吡啶质量2-5倍的DMF中，再将溶液加热至115～125℃，加入2-溴-6-甲基吡啶后，保温反应10～12h；反应结束后将溶液降温至65-75℃，加水，再通过水汽蒸馏得产品；
其中，2-溴-6-甲基吡啶和氰化亚铜的摩尔比为1:1.1-1.5，氰化亚铜和溴化锂的摩尔比为1:1-1.1。
上述方法产品的收率为68～74％。
上述反应过程如下所示：
与现有技术相比，本发明的有益效果在于：
1、本发明的方法通过廉价的2-氨基-6-甲基吡啶，重氮化上溴得到2-溴-6-甲基吡啶，再经过低毒的氰化亚铜上氰基得到产品。
2、操作安全，低毒，收率高，适合工业化生产。
具体实施方式
以下实施例中所用原料均为市购。
实施例1
(1)搅拌条件下，向反应罐中投入质量浓度48％的氢溴酸600g，2-氨基-6-甲基吡啶108g，加热到55～57℃并保温0.5h，然后冷却到-2～0℃，保持该温度范围滴加420g溴素Br2，再保温1h；再在该温度范围滴加质量浓度30％的亚硝酸钠水溶液500g，滴加完毕，无需控制反应温度搅拌反应1h；反应结束，将反应溶液温度降至19℃后，用质量浓度30％的氢氧化钠水溶液调溶液pH＝10，然后通过水汽蒸馏得2-溴-6-甲基吡啶154g，气相含量99.5％，收率89.5％；
(2)向反应罐中投入540g的DMF，氰化亚铜89g和溴化锂90g，搅拌均匀使其溶解，将溶液加热到115～117℃，向溶液中滴加2-溴-6-甲基吡啶154g，再保持该温度反应10h，完全反应后，降温到70℃，再加水600g，通过水汽蒸馏，得目标产物2-氰基-6-甲基吡啶72g，含量99.7％，收率68.2％。
实施例2
(1)搅拌条件下，向反应罐中投入质量浓度48％的氢溴酸700g，2-氨基-6-甲基吡啶108g，加热到63～65℃并保温0.5h，然后冷却到-5～-3℃,保持该温度范围滴加520g溴素Br2，再保温1h；再在该温度范围滴加质量浓度27％的亚硝酸钠水溶液520g，滴加完毕，无需控制反应温度搅拌反应1h；反应结束，将反应溶液温度降至15℃后，用质量浓度20％的氢氧化钠水溶液调溶液pH＝12，然后通过水汽蒸馏得2-溴-6-甲基吡啶158g，气相含量99.6％，收率91.2％；
(2)向反应罐中投入310g的DMF，氰化亚铜98g，溴化锂96g，搅拌均匀使其溶解，将溶液加热到123～125℃，向溶液中滴加2-溴-6-甲基吡啶154g，再保持该温度反应12h，完全反应后，降温到70℃，再加水600g，通过水汽蒸馏，得目标产物2-氰基-6-甲基吡啶74.2g，含量99.6％，收率70.3％。
实施例3
(1)搅拌条件下，向反应罐中投入质量浓度45％的氢溴酸540g，2-氨基-6-甲基吡啶108g，加热到58～60℃并保温0.1h，然后冷却到-3～-1℃，保持该温度范围滴加320g溴素Br2，再保温0.5h；再在该温度范围滴加质量浓度25％的亚硝酸钠水溶液550g，滴加完毕，无需控制反应温度搅拌反应2h；反应结束，将反应溶液温度降至18℃后，用25％的氢氧化钠调溶液pH＝11，然后通过水汽蒸馏得2-溴-6-甲基吡啶150g，气相含量99.1％，收率87.2％；
(2)向反应罐中投入DMF400g，氰化亚铜79g和溴化锂84g，搅拌均匀使其溶解，将溶液加热到118～120℃，向溶液中滴加2-溴-6-甲基吡啶137.6g，再保持该温度反应11h，完全反应后，降温到65℃，再加水600g，通过水汽蒸馏，得目标产物2-氰基-6-甲基吡啶68.3g，含量99.5％，收率72.4％。
实施例4
(1)搅拌条件下，向反应罐中投入质量浓度46％的氢溴酸756g，2-氨基-6-甲基吡啶108g，加热到60～62℃并保温1h，然后冷却到-5～-3℃，保持该温度范围滴加640g溴素Br2，再保温3h；再在该温度范围滴加质量浓度30％的亚硝酸钠水溶液920g，滴加完毕，无需控制反应温度搅拌反应3h；反应结束，将反应溶液温度降至15℃后，用质量浓度30％的氢氧化钠水溶液调溶液pH＝11，然后通过水汽蒸馏得2-溴-6-甲基吡啶150g，气相含量99.4％，收率93.1％；
(2)向反应罐中投入DMF690g，氰化亚铜108g和溴化锂104g，搅拌均匀使其溶解，将溶液加热到120～122℃，向溶液中滴加2-溴-6-甲基吡啶137.6g，再保持该温度反应11h，完全反应后，降温到75℃，再加水700g，通过水汽蒸馏，得目标产物2-氰基-6-甲基吡啶69.9g，含量99.7％，收率74.1％。
Claims (7)
1.一种2-氰基-6-甲基吡啶的制备方法，其特征在于，包括如下步骤：
(1)在搅拌条件下，将氢溴酸和2-氨基-6-甲基吡啶混合，保温；再将溶液冷却至-5～0℃，向溶液中加入溴素Br2，然后保持-5～0℃低温反应；再在该低温下向溶液中加入亚硝酸钠水溶液，然后反应；反应结束将反应溶液降温，用碱调pH值，然后通过水汽蒸馏得2-溴-6-甲基吡啶；
(2)将氰化亚铜和溴化锂加入到质量为2-溴-6-甲基吡啶质量2-5倍的DMF中，再将溶液加热，加入2-溴-6-甲基吡啶后，保温反应；反应结束后将溶液降温，加水，再通过水汽蒸馏得产品；其中，所述再将溶液加热为加热至115～125℃；保温反应时间为10～12h；所述将溶液降温为降温至65～75℃；2-溴-6-甲基吡啶和氰化亚铜的摩尔比为1∶1.1-1.5；氰化亚铜和溴化锂的摩尔比为1∶1-1.1。
2.根据权利要求1所述的一种2-氰基-6-甲基吡啶的制备方法，其特征在于，所述步骤(1)中，2-氨基-6-甲基吡啶和氢溴酸的质量比为1∶5-7；2-氨基-6-甲基吡啶和Br2的摩尔比为1∶2-4；2-氨基-6-甲基吡啶和亚硝酸钠的摩尔比为1∶2-4。
3.根据权利要求1所述的一种2-氰基-6-甲基吡啶的制备方法，其特征在于，步骤(1)中，所述氢溴酸的质量浓度为45-48％；所述亚硝酸钠水溶液的质量浓度为25～30％。
4.根据权利要求1所述的一种2-氰基-6-甲基吡啶的制备方法，其特征在于，步骤(1)中，所述保温为在55～65℃下保持0.1～1h。
5.根据权利要求1所述的一种2-氰基-6-甲基吡啶的制备方法，其特征在于，步骤(1)中，所述的将溶液冷却为冷却至-5～0℃；所述低温反应的时间为0.5～3h。
6.根据权利要求1所述的一种2-氰基-6-甲基吡啶的制备方法，其特征在于，步骤(1)中，加入亚硝酸钠水溶液后反应的时间为1～3h；所述将反应溶液降温为降温至20℃以下。
7.根据权利要求1所述的一种2-氰基-6-甲基吡啶的制备方法，其特征在于，所述步骤(1)中，将pH调至10～12。
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Effective date of registration: 20181211 Address after: 123129 Fuxin Fumeng County Fuxin City, Liaoning Province, Fuxingdi Village (Fluorine Chemical Industry Base) Patentee after: Liaoning Fluto New Energy Materials Co., Ltd. Address before: No. 47, Zhonghua Road, Xihe District, Fuxin, Liaoning Province Patentee before: Liaoning Technical University |