CN104860889A - 一种2,4-取代嘧啶的制备方法 - Google Patents

一种2,4-取代嘧啶的制备方法 Download PDF

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CN104860889A
CN104860889A CN201510244709.0A CN201510244709A CN104860889A CN 104860889 A CN104860889 A CN 104860889A CN 201510244709 A CN201510244709 A CN 201510244709A CN 104860889 A CN104860889 A CN 104860889A
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substituted pyrimidines
mgcl
tmp
licl
substituted pyrimidine
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王庆鹏
李莹
刘志康
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LEPU PHARMACEUTICAL Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
    • C07D239/30Halogen atoms or nitro radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
    • C07D239/32One oxygen, sulfur or nitrogen atom
    • C07D239/34One oxygen atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明属于化合物合成技术领域,具体涉及一种2,4-取代嘧啶的制备方法。该方法包括以下步骤:1)将2-取代嘧啶溶于四氢呋喃中,在-60—-78℃下滴加TMP.MgCl.LiCl,滴加1h后加入无水氯化锌,升温至室温,滴加卤素,1.5-2h后加入盐酸溶液淬灭反应;2)反应的反应液以乙酸乙酯萃取,有机层干燥浓缩,柱层析纯化即得产品。本发明与现有技术相比,以2-取代嘧啶为原料时能特异性的选择4位取代,同时不产生5位取代的副产物,具有选择性好、产物单一、易于提纯的特点,具有反应条件温和、反应速率快等优点。

Description

一种2,4-取代嘧啶的制备方法
技术领域    
    本发明属于化合物合成技术领域,具体涉及一种2,4-取代嘧啶的制备方法。
背景技术    
嘧啶类衍生物作为有机化学中的一类基础中间体,近年来广泛应用于合成医药、农药、染料等领域。2-取代嘧啶具有4位和5位两个反应位点,并且较长时间以来,因其5位取代易行且5位取代原料廉价易得,较多的嘧啶类中间体合成路线均集中在2位与5位取代反应上,如2-氰基-5-溴嘧啶的合成方法在US20090253708、WO2009134392A1等专利中均有报道。由于2-取代嘧啶的5位较4位更易取代,因此4位取代嘧啶的种类较少,例如2-氰基-4-溴嘧啶的合成方法则鲜有报道。但随着原料药的细化发展,4位取代嘧啶成为许多原料药必不可少的中间体。
如何克服在2-取代嘧啶作为原料时4位较5位难于优先取代的难题,同时没有5位取代副产物是将来的一个趋势。
发明内容    
本发明提供一种以2-取代嘧啶为原料制备2,4-取代嘧啶的方法。
为实现上述目的,本发明采用以下技术方案:
一种2,4-取代嘧啶的制备方法,包括以下步骤:
1)将2-取代嘧啶溶于四氢呋喃中,在-60—-78℃下滴加TMP.MgCl.LiCl,滴加1h后加入无水氯化锌,升温至室温,滴加卤素,1.5-2h后加入盐酸溶液(1-2 mol/L)至pH为7淬灭反应;
2)反应的反应液用乙酸乙酯萃取,有机层干燥浓缩,柱层析纯化即得产品;
2-取代嘧啶的结构为                                               ,2,4-取代嘧啶的结构为,其中R为氰基、甲基或甲氧基,R1为卤素。
原料的用量比例如下:TMP.MgCl.LiCl与2-取代嘧啶的质量比为1-1.3:1,无水氯化锌与2-取代嘧啶的摩尔比为1-1.3:1,卤素与2-取代嘧啶的摩尔比为1-1.3:1。
TMP.MgCl.LiCl的配制方法为:将镁(8g,0.33mol)和无水氯化锂(15g,0.33mol)置于干燥的三口瓶中,加入2-氯丙烷 (28.5g,0.3mol) 的四氢呋喃(200ml)溶液,滴加完毕后,室温搅拌2小时,加入2,2,6,6-四甲基哌啶(60g.0.36mol),搅拌过夜,得到棕色溶液TMP.MgCl.LiCl备用。
本发明的合成路线如下:
,由于嘧啶环上氮原子的电负性较大,对环上电子云密度分布有很大影响,使π电子云向氮原子上偏移,在氮原子周围电子云密度高,而环的其他部分电子云密度降低,尤其是4位上降低显著,易于该试剂交换反应的进行。
本发明与现有技术相比,具有以下有益效果:(1)以2-取代嘧啶为原料时能特异性的选择4位取代,同时不产生5位取代的副产物,具有选择性好、产物单一、易于提纯的特点;(2)本方法以TMP.MgCl.LiCl为碱,具有反应条件温和、反应速率快等优点。
具体实施方式 
下面结合实施例对本发明做详细的说明
实施例1:R为氰基,R1为溴
配制TMP.MgCl.LiCl:将镁(8g,0.33mol)和无水氯化锂(15g,0.33mol)置于干燥的三口瓶中,加入2-氯丙烷 (28.5g,0.3mol) 的四氢呋喃(200ml)溶液,滴加完毕后,室温搅拌2小时,加入2,2,6,6-四甲基哌啶(60g.0.36mol),搅拌过夜,得到300ml棕色溶液TMP.MgCl.LiCl(1.1mol/L)备用;
将2-氰基嘧啶(27g,0.26mol)溶于四氢呋喃(200ml),在-60℃下,滴加已制好的TMP.MgCl.LiCl溶液(300ml,1.1mol/L),滴加完毕后,搅拌1小时,加入无水氯化锌 (39g,0.28mol) ,缓慢升至室温,滴加溴素(45g,0.28mol),2小时后,加入1mol/L 盐酸水溶液至pH为7淬灭反应;用乙酸乙酯(200ml*3次)萃取分离除去水层,合并有机层干燥浓缩,以柱层析纯化(PE:EA=10:1)即得产品()6g(产率:12.5%)。产品的HNMR数据:(DMSO,400M)δ7.70 (d, 1H), 8.55(d, 1H)。
实施例2:R为氰基,R1为溴
TMP.MgCl.LiCl的配制过程同实施例1。
将2-氰基嘧啶(27g,0.26mol)溶于四氢呋喃(200ml), 在-70℃下,滴加已制好的TMP.MgCl.LiCl溶液(300ml,1.1mol/L),滴加完毕后,搅拌1小时,加入无水氯化锌 (39g,0.28mol) ,缓慢升至室温,滴加溴素(45g,0.28mol),2小时后,加入1mol/L 盐酸水溶液至pH为7淬灭反应;用乙酸乙酯(200ml*3次)萃取分离除去水层,合并有机层干燥浓缩,以柱层析纯化(PE:EA=10:1)即得产品()6g(产率:12.5%)。产品HNMR数据: (DMSO,400M)δ7.70 (d, 1H), 8.55(d, 1H)。
实施例3:R为氰基,R1为溴
TMP.MgCl.LiCl的配制过程同实施例1。
将2-氰基嘧啶(27g,0.26mol)溶于四氢呋喃(200ml), 在-78℃下,滴加已制好的TMP.MgCl.LiCl溶液(300ml,1.1mol/L),滴加完毕后,搅拌1小时,加入无水氯化锌 (39g,0.28mol) ,缓慢升至室温,滴加溴素(45g,0.28mol),2小时后,加入1mol/L 盐酸水溶液至pH为7淬灭反应;用乙酸乙酯(200ml*3次)萃取分离除去水层,合并有机层干燥浓缩,以柱层析纯化(PE:EA=10:1)即得产品6.2g(产率:12.9%)。产品HNMR数据: (DMSO,400M)δ7.70 (d, 1H), 8.55(d, 1H)。
从以上三个实施例中得出在-60℃—-78℃范围内,对反应的进行,纯化以及收率影响不大,因-60℃方便实施,优选温度可定为-60℃。
实施例4:R为氰基,R1为碘
TMP.MgCl.LiCl的配制过程同实施例1。
将2-氰基嘧啶(27g,0.26mol)溶于四氢呋喃(200ml), 在-60℃下,滴加已制好的TMP.MgCl.LiCl溶液(300ml,1.1mol/L),滴加完毕后,搅拌1小时,加入无水氯化锌 (39g,0.28mol) ,缓慢升至室温,滴加碘(70g,0.28mol)的四氢呋喃溶液,2小时后,加入1mol/L 盐酸水溶液至pH为7淬灭反应;用乙酸乙酯(200ml*3次)萃取分离除去水层,合并有机层,硫代硫酸钠溶液洗涤两次,硫酸镁干燥,减压浓缩,以柱层析纯化(PE:EA=10:1)即得产品()7.9g(产率:16%)。产品的HNMR数据:(DMSO,400M)δ7.35 (d, 1H), 7.78(d, 1H)。
实施例5:R为甲基,R1为溴
TMP.MgCl.LiCl的配制过程同实施例1。
将2-甲基嘧啶(24g,0.26mol)溶于四氢呋喃(200ml), 在-60℃下,滴加已制好的TMP.MgCl.LiCl溶液(300ml,1.1mol/L),滴加完毕后,搅拌1小时,加入无水氯化锌 (39g,0.28mol) ,缓慢升至室温,滴加溴素(45g,0.28mol),1.5小时后,加入2mol/L 盐酸水溶液至pH为7淬灭反应;用乙酸乙酯(200ml*3次)萃取分离除去水层,合并有机层干燥浓缩,以柱层析纯化(PE:EA=10:1)即得产品()9g(产率:18.8%)。产品的HNMR数据:(DMSO,400M)δ2.24(s,3H),7.35 (d, 1H), 8.30(d, 1H)。
实施例6:R为甲氧基,R1为溴
TMP.MgCl.LiCl的配制过程同实施例1。
将2-甲氧基嘧啶(28g,0.26mol)溶于四氢呋喃(200ml), 在-60℃下,滴加已制好的TMP.MgCl.LiCl溶液(300ml,1.1mol/L),滴加完毕后,搅拌1小时,加入无水氯化锌 (39g,0.28mol) ,缓慢升至室温,滴加溴素(45g,0.28mol),1.5小时后,加入2mol/L 盐酸水溶液至pH为7淬灭反应;用乙酸乙酯(200ml*3次)萃取分离除去水层,合并有机层干燥浓缩,以柱层析纯化(PE:EA=10:1)即得产品()8.3g(产率:17%)。产品的HNMR数据:(DMSO,400M)δ3.79(s,3H),7.37 (d, 1H), 8.73(d, 1H)。

Claims (2)

1.一种2,4-取代嘧啶的制备方法,其特征在于,包括以下步骤:
1)将2-取代嘧啶溶于四氢呋喃中,在-60—-78℃下滴加TMP.MgCl.LiCl,滴加1h后加入无水氯化锌,升温至室温,滴加卤素,1.5-2h后加入盐酸溶液淬灭反应;
2)反应的反应液用乙酸乙酯萃取,有机层干燥浓缩,柱层析纯化即得产品;
2-取代嘧啶的结构为                                               ,2,4-取代嘧啶的结构为,其中R为氰基、甲基或甲氧基,R1为卤素。
2. 如权利要求1所述的2,4-取代嘧啶的制备方法,其特征在于,原料的用量比例如下:TMP.MgCl.LiCl与2-取代嘧啶的质量比为1-1.3:1,无水氯化锌与2-取代嘧啶的摩尔比为1-1.3:1,卤素与2-取代嘧啶的摩尔比为1-1.3:1。
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Application publication date: 20150826