CN104151160A - 用酯类化合物合成2-甲基丙酸酯衍生物的方法 - Google Patents
用酯类化合物合成2-甲基丙酸酯衍生物的方法 Download PDFInfo
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- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
本发明提供了一种用酯类化合物作为原料之一合成2-甲基丙酸酯衍生物的方法。本方法创造性地选择了异丁酸酯作为反应的原料之一,代替现有技术中的烯类化合物。本方法只需一步反应便可得到所需产物,反应时间短,反应可在室温进行,能耗低,成本低,而且原料异丁酸酯容易获得,对于工业化生产有极大的便利。
Description
技术领域
本发明涉及一种药物中间体的合成方法,特别涉及用酯类化合物作为原料之一合成2-甲基丙酸酯衍生物的方法。
背景技术
式I化合物(2-甲基丙酸酯衍生物)是制备一种抗组胺药物的重要中间体:
式I
现有技术合成式I的方法都不适于工业化生产。比如存在路线较长、能耗较高、费时较长、不环保等问题。如
现有技术一:CN200980105040,其原料2为1-甲氧基-1-(三甲基甲硅氧基)-2-甲基-1-丙烯,该原料不易购得,且反应温度较高(80度以上),反应时间较长(18小时以上)。
现有技术二:Synthetic Communications41(9),1394-1402,2011报道了另一种制备该化合物的方法:
该方法步骤较多(两步反应),而且原料锡化合物较难购买,且污染较大。
发明内容
本发明的目的是提供一种原料易得、能耗低(反应温度较低,反应时间较短),适于工业化生产式I的方法。
本发明要解决的技术问题是,选择另一种原料,代替CN200980105040中难以得到的1-甲氧基-1-(三甲基甲硅氧基)-2-甲基-1-丙烯,并且达到上述发明目的。
本发明创造性地找到了一种酯类化合物——异丁酸酯,作为反应的原料之一,合成出了式I:
式II 式III 式I
式中,R1为羟基保护基团,R2为醇除去羟基后的部分,X是离去基团。
更具体地说:
R1选自甲基、C1-6直链或支链烷基、环烷基、苯取代的烷基、直链或支链烷基硅基,烷酰基;优选乙基、环己基、苄基、叔丁基二甲基硅基或乙酰基;
R2选自甲基、C1-6直链或支链烷基、环烷基、烷氧基苄基、苯取代的烷基;优选甲基、对甲氧苄基、异丙基、环己基或苄基;
X是卤素,选自氯或溴。
本方法的其它说明:
1、原料用量比不需特别限定
式II取代苯衍生物与式III异丁酸酯的用量比例不需特别限定,根据不同化合物的成本、来源等,可做调整,比如式III的用量可选择式II用量的0.5-10摩尔倍。
2、反应在有机锂化合物的存在下进行
有机锂化合物是反应助剂,可以增强原料异丁酸酯的进攻活性,并阻止在苯环其他位置发生的烷基化,从而使副反应更少。
所述有机锂化合物优选胺基锂,更优选二烷基胺基锂或二硅烷基胺基锂,如双三甲硅基胺基锂、二环己基胺基锂、二异丙基胺基锂等。
虽然锂化合物用量比例不需特别限定,使用过量并不影响反应进行,但因其较昂贵,考虑成本问题,本发明选择的有机锂化合物用量是式II用量的0.5-10摩尔倍。
3、催化剂为钯化合物
反应的催化剂为钯化合物。使用催化剂可以使反应更容易进行,钯化合物用量比例亦不需特别限定,如可选择式II用量的0.00005摩尔倍以上。
钯化合物优选0价或I价的,如二溴双(三叔丁基膦)化钯(I)、四(三苯基膦)钯(0)等。
4、反应溶剂
反应溶剂为非质子极性有机溶剂,优选苯、甲苯、四氢呋喃、醚类溶剂;醚类溶剂中优选乙醚、甲基叔丁基醚或乙二醇二甲醚;
5、在较宽的温度和反应时间内进行反应,均能达到好的效果。
反应温度可以为0-100℃,但为适应工业化生产,节约能源,可采用常温(如15-30℃)反应,0.5~2小时即可完成反应。
本发明的创造性:
1、通常不会想到采用酯类化合物为原料在苯环上引入烷基
本方法属于对取代苯的烷基化反应,一般使用烯烃类化合物进行,如使用现有技术CN200980105040中使用1-甲氧基-1-(三甲基甲硅氧基)-2-甲基-1-丙烯。
因为,一般情况下,采用酯类化合物进行烷基化的效果较差。
2、苯环引入烷基通常不选用空间位阻大的叔丁基化合物,因为通常反应难度大
要在原料式II苯环的卤素位置引入一个三取代的碳原子得到式IV,这相对于一般的烷基化来说更加困难,因为三取代碳原子的空间位阻太大。
但是,发明人出乎意料地发现,用异丁酸酯可以在式II苯环上引入烷基,只需一步反应便可得到所需产物,反应时间短,反应可在室温进行,能耗低,成本低。而且原料异丁酸酯容易获得。这对于工业化生产有极大的便利。
本发明的技术效果:
1、降低了能耗。反应温度降低、反应时间缩短。
2、路线简短。一步反应即得。
3、便于工业化。原料易得,更利于大规模生产。
具体实施方式
原料式II、式III、催化剂钯化合物、助剂有机锂化合物均市购。
用于检测反应以及产物的方法为HPLC,检测条件是:
色谱柱:VP-ODS C-18,4.6×150mm,5um;
流动相:甲醇:水=80:20;流速:1.0ml/min;
检测波长:210nm;
柱温:30℃
以下实施例中的反应式如下:
式II 式III 式I
实施例12-[4-[2-(乙氧基)乙基]苯基]-2-甲基丙酸对甲氧苄酯的合成
将含14.14g双三甲硅基胺基锂的甲苯溶液加入到反应瓶中,再加入70.37g异丁酸对甲氧苄酯(式III,R2为对甲氧苄基),搅拌10分钟后,加入10.4g4-[2-(乙氧基)乙基]氯苯(式II,R1为乙基,X为氯)和4.5mg二溴双(三叔丁基膦)化钯(I),在20-30度下反应40分钟,HPLC法检测到原料4-[2-(乙氧基)乙基]氯苯已消失。反应毕,向反应液中加入1mol/L盐酸,析出固体,过滤保留滤液,自滤液中分出有机层,浓缩,得2-[4-[2-(乙氧基)乙基]苯基]-2-甲基丙酸对甲氧苄酯15.85g,摩尔收率91.2%。
实施例22-[4-[2-(环己氧基)乙基]苯基]-2-甲基丙酸甲酯的合成
将含3.88g二异丙基胺基锂的四氢呋喃溶液加入到反应瓶中,再加入3.70g异丁酸甲酯(式III,R2为甲基),搅拌12分钟后,加入20.5g4-[2-(环己氧基)乙基]溴苯(式II,R1为环己基,X为溴)和0.8365g四(三苯基膦)钯(0),在15-25度下反应60分钟,HPLC法检测到原料4-[2-(环己氧基)乙基]溴苯已消失。反应毕,向反应液中加入1mol/L盐酸,析出固体,过滤保留滤液,自滤液中分出有机层,浓缩,得2-[4-[2-(环己氧基)乙基]苯基]-2-甲基丙酸甲酯21.51g,摩尔收率97.6%。
实施例32-[4-[2-(苄氧基)乙基]苯基]-2-甲基丙酸异丙酯的合成
将含55.30g二环己基胺基锂的乙二醇二甲醚溶液加入到反应瓶中,再加入7.69g异丁酸异丙酯(式III,R2为异丙基),搅拌8分钟后,加入8.6g4-[2-(苄氧基)乙基]溴苯(式II,R1为苄基,X为溴)和34.1mg四(三苯基膦)钯(0),在0-10度下反应110分钟,HPLC法检测到原料4-[2-(苄氧基)乙基]溴苯已消失。反应毕,向反应液中加入1mol/L盐酸,析出固体,过滤保留滤液,自滤液中分出有机层,浓缩,得2-[4-[2-(苄氧基)乙基]苯基]-2-甲基丙酸异丙酯9.70g,摩尔收率96.5%。
实施例42-[4-[2-(叔丁基二甲基硅氧基)乙基]苯基]-2-甲基丙酸环己酯的合成
将含339.72g二异丙基胺基锂的甲基叔丁基醚溶液加入到反应瓶中,再加入1079.86g异丁酸环己酯(式III,R2为环己基),搅拌20分钟后,加入200g4-[2-(叔丁基二甲基硅氧基)乙基]溴苯(式II,R1为叔丁基二甲基硅基,X为溴)和0.3015g二溴双(三叔丁基膦)化钯(I),在50-60度下反应30分钟,HPLC法检测到原料4-[2-(叔丁基二甲基硅氧基)乙基]溴苯已消失。反应毕,向反应液中加入1mol/L盐酸,析出固体,过滤保留滤液,自滤液中分出有机层,浓缩,得2-[4-[2-(叔丁基二甲基硅氧基)乙基]苯基]-2-甲基丙酸环己酯251.79g,摩尔收率98.1%。
实施例52-[4-[2-(乙酰氧基)乙基]苯基]-2-甲基丙酸苄酯的合成
将含166.60g二异丙基胺基锂的乙醚溶液加入到反应瓶中,再加入381.40g异丁酸苄酯(式III,R2为苄基),搅拌15分钟后,加入65g4-[2-(乙酰氧基)乙基]溴苯(式II,R1为乙酰基,X为溴)和7.2mg二溴双(三叔丁基膦)化钯(I),在90-100度下反应30分钟,HPLC法检测到原料4-[2-(乙酰氧基)乙基]溴苯已消失。反应毕,向反应液中加入1mol/L盐酸,析出固体,过滤保留滤液,自滤液中分出有机层,浓缩,得2-[4-[2-(乙酰氧基)乙基]苯基]-2-甲基丙酸苄酯74.61g,摩尔收率90.1%。
Claims (10)
1.式I化合物的制备方法,式II化合物烷基化得到式I,其特征是,反应的另一原料是式III化合物:
式II 式III 式I
式中,R1为羟基保护基团,R2选自C1-6直链或支链烷基、环烷基、烷氧基苄基、苯取代的烷基,X是离去基团。
2.权利要求1所述的方法,R1选自C1-6直链或支链烷基、环烷基、苯取代的烷基、直链或支链烷基硅基,烷酰基;X为卤素。
3.权利要求1所述的方法,R1选自乙基、环己基、苄基、叔丁基二甲基硅基或乙酰基。
4.权利要求1~3中任一所述的方法,R2选自甲基、对甲氧苄基、异丙基、环己基或苄基,X是氯或溴。
5.权利要求4所述的方法,反应在钯化合物催化下进行,所述钯化合物是0价或I价的。
6.权利要求5所述的方法,所述钯化合物是二溴双(三叔丁基膦)化钯(I)或四(三苯基膦)钯(0)。
7.权利要求1所述的方法,反应在有机锂化合物存在下进行。
8.权利要求7所述的方法,所述有机锂化合物是胺基锂。
9.权利要求7所述的方法,所述胺基锂选自二烷基胺基锂或二硅烷基胺基锂。
10.权利要求1所述的方法,反应溶剂为非质子极性有机溶剂。
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