CN106632240A - 一种2‑甲基‑5‑(5‑溴吡啶‑2‑基)四氮唑的制备方法 - Google Patents

一种2‑甲基‑5‑(5‑溴吡啶‑2‑基)四氮唑的制备方法 Download PDF

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CN106632240A
CN106632240A CN201611066876.1A CN201611066876A CN106632240A CN 106632240 A CN106632240 A CN 106632240A CN 201611066876 A CN201611066876 A CN 201611066876A CN 106632240 A CN106632240 A CN 106632240A
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tetrazole
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董岩岩
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Shandong Xuan Pharmaceutical Technology Co Ltd
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Shandong Xuan Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明涉及式涉及一种2‑甲基‑5‑(5‑溴吡啶‑2‑基)四氮唑的新方法，该方法采用甲醛为原料，反应工艺简便、安全性高、收率高，并且可以量产。

Description

一种2-甲基-5-(5-溴吡啶-2-基)四氮唑的制备方法
1、技术领域
本发明属于医药技术领域，涉及一种制备2-甲基-5-(5-溴吡啶-2-基)四氮唑的方法。
2、背景技术
泰地唑利磷酸盐于2014年6月20日获美国食品药品管理局(FDA)批准上市，后又于2015年3月23日获欧洲药品管理局(EMA)批准上市，由Cubist在美国上市销售，商品名Sivextro。Sivextro被批准用于治疗由某些敏感细菌，如金黄色葡萄球菌(包括耐甲氧西林菌株和甲氧西林敏感菌株)、各种链球菌和粪肠球菌引起的急性细菌性皮肤及皮肤组织感染(ABSSSI)。Sivextro以静脉注射和口服给药。2-甲基-5-(5-溴吡啶-2-基)四氮唑是合成泰地唑利磷酸盐的关键中间体。
目前的现有技术中，如WO2010/42887 A2,2010、WO2005/58886 A1,2005中就介绍了关于泰地唑利磷酸盐及其中间体的制备方法，但是制备方法需要用到碘甲烷等剧毒物质，反应危险且后处理污染大。
3、发明内容
本发明的目的是提供一种合成简单、安全、易于放大生产的2-甲基-5-(5-溴吡啶-2-基)四氮唑的制备方法，具体技术方案如下：
将5-溴-2-(2H-四氮唑-5-基)吡啶、甲醛、反应溶剂、10％钯碳加入反应釜中，在氢气氛围下，室温搅拌，反应完毕，过滤，有机相蒸干，重结晶，即得2-甲基-5-(5-溴吡啶-2-基)四氮唑。
所述反应溶剂为甲醇、乙醇、异丙醇、四氢呋喃、二氧六环一种或多种的混合，优选为为甲醇。
所述5-溴-2-(2H-四氮唑-5-基)吡啶与甲醛的反应摩尔比为1:1～1:50，优选为1:3。
所述反应釜压力为0.2MPa。
所述搅拌时间为拌0.5-48小时，优选为3小时。
所述重结晶溶剂为DMF、乙腈、甲醇、二氧六环、四氢呋喃、乙醇、DMSO、异丙醇、乙酸乙酯、正己烷、正庚烷一种或多种的混合，优选为乙腈。
本发明具有以下优点：
1)本发明反应条件温和，易于操作和控制。
2)本发明的反应步骤的收率高。
3)本发明采用甲醛为反应原料，易得、成本低、环保、安全。
4)本发明氢化还原，使用常压氢化，更为安全。
5)本发明生产工艺可以实现工业化，可以进行百公斤级生产。
4、具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。
实施例1：2-甲基-5-(5-溴吡啶-2-基)四氮唑的制备
将1.5L甲醇，5-溴-2-(2H-四氮唑-5-基)吡啶(226g)，甲醛(90g)，10％钯碳(20g)加入反应釜中，在氢气氛围(0.2MPa)下，室温搅拌3小时，反应完毕，过滤，有机相蒸干，用乙腈重结晶，得产品2-甲基-5-(5-溴吡啶-2-基)四氮唑，217g，收率：90.4％。
1H NMR(400MHz,25℃,DMSO-d6)：
8.89(s,1H)，8.27(dd,J1＝4Hz，J2＝8Hz，1H)，8.09(d,J＝8Hz，1H)，4.46(s,3H) 。

Claims (10)

1.一种2-甲基-5-(5-溴吡啶-2-基)四氮唑的制备方法，其特征在于，包括以下步骤：
将5-溴-2-(2H-四氮唑-5-基)吡啶、甲醛、反应溶剂、10％钯碳加入反应釜中，在氢气氛围下，室温搅拌，反应完毕，过滤，有机相蒸干，重结晶，即得2-甲基-5-(5-溴吡啶-2-基)四氮唑。
2.根据权利要求1所述的制备方法，其特征在于：所述反应溶剂为甲醇、乙醇、异丙醇、四氢呋喃、二氧六环一种或多种的混合。
3.根据权利要求2所述的制备方法，其特征在于：所述反应溶剂为甲醇。
4.根据权利要求1所述的制备方法，其特征在于：所述5-溴-2-(2H-四氮唑-5-基)吡啶与甲醛的反应摩尔比为1:1～1:50。
5.根据权利要求4所述的制备方法，其特征在于：所述5-溴-2-(2H-四氮唑-5-基)吡啶与甲醛的反应摩尔比为1:3。
6.根据权利要求1所述的制备方法，其特征在于，所述反应釜压力为0.2MPa。
7.根据权利要求1所述的制备方法，其特征在于：所述搅拌时间为拌0.5-48小时。
8.根据权利要求7所述的制备方法，其特征在于：所述搅拌时间为拌3小时。
9.根据权利要求1所述的制备方法，其特征在于：所述重结晶溶剂为DMF、乙腈、甲醇、二氧六环、四氢呋喃、乙醇、DMSO、异丙醇、乙酸乙酯、正己烷、正庚烷一种或多种的混合。
10.根据权利要求9所述的制备方法，其特征在于：所述重结晶溶剂为乙腈。
CN201611066876.1A 2016-11-25 2016-11-25 一种2‑甲基‑5‑(5‑溴吡啶‑2‑基)四氮唑的制备方法 Pending CN106632240A (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1894242A (zh) * 2003-12-18 2007-01-10 东亚制药株式会社 新型噁唑烷酮衍生物
CN102177156A (zh) * 2008-10-10 2011-09-07 特留斯治疗学公司 制备噁唑烷酮类的方法及含有噁唑烷酮类的组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1894242A (zh) * 2003-12-18 2007-01-10 东亚制药株式会社 新型噁唑烷酮衍生物
CN102177156A (zh) * 2008-10-10 2011-09-07 特留斯治疗学公司 制备噁唑烷酮类的方法及含有噁唑烷酮类的组合物

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MASATOSHI ASAMI, ET AL.: "Enantioselective addition of diethylzinc to aldehydes catalyzed by (R)-1-phenylethylamine-derived 1,4-amino alcohols", 《TETRAHEDRON》 *
俞凌翀: "《有机化学中的人名反应》", 31 May 1984 *
邢其毅等: "《基础有机化学》", 30 November 1993 *

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Application publication date: 20170510