CN103172503B - 番茄红素中间体3-甲基-4,4-二烷氧基-1-丁醛的制备方法 - Google Patents
番茄红素中间体3-甲基-4,4-二烷氧基-1-丁醛的制备方法 Download PDFInfo
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- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
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- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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Abstract
本发明涉及一种番茄红素的中间体3-甲基-4,4-二烷氧基-1-丁醛的制备方法,所述制备方法包括如下步骤:(1)在惰性气体保护下,2-甲基-3,3-二烷氧基-1-卤代丙烷和镁粉,在无水四氢呋喃溶剂中于45~65℃温度下生成格氏试剂混合物;(2)再向所述格氏试剂混合物中加入N,N-二取代甲酰胺于10℃~35℃温度下反应得到3-甲基-4,4-二烷氧基-1-丁醛。本发明的工艺路线简捷,操作简单,条件温和,收率良好,极具工业价值。
Description
技术领域
本发明涉及医药化工中间体,特别是一种作为番茄红素中间体的3-甲基-4,4-二烷氧基-1-丁醛的制备方法。
背景技术
3-甲基-4,4-二烷氧基-1-丁醛作为医药化工中间体,有良好的应用前景,其分子结构独特,存在醛和缩醛两种基团,特别适合构建双键体系。近期沈润溥等人在CN201010189861.0中报道了一种以3-甲基-4,4-二烷氧基-1-丁醛为原料制备番茄红素的新方法,是此类化合物作为医药中间体应用的典型实例,该工艺路线简捷,操作简单,成本低,极具工业价值。
目前3-甲基-4,4-二烷氧基-1-丁醛的合成方法报道较少,主要有2种:
A:以2-甲基-丙烯缩二甲醛(3)为原料,在高压、催化剂催化下与氢气和一氧化碳缩合得到目标产物(1),反应方程式如下:
B:Schmid等报道以2-甲基-4-(N,N-二乙基)-2-丁烯缩二甲醛(4)为原料,在钌磷配合物催化剂催化下重排为2-甲基-4-(N,N-二乙基)-3-丁烯缩二甲醛(5),再水解得到3-甲基-4,4-二甲氧基-1-丁醛(1A)。反应方程式如下:
以上两条工艺路线都较简洁,但是方法A需使用氢气和一氧化碳在高压催化下进行,合成所用的设备制造难度大,危险性高;方法B的原料2-甲基-4-(N,N-二乙基)-2-丁烯缩二甲醇(4)来源困难,合成难度大;并且两方法都要用到昂贵复杂的催化剂,较难工业化。
发明内容
本发明所要解决的技术问题是克服上述现有技术存在的缺陷,提供一种工艺路线简捷、原料易得的3-甲基-4,4-二烷氧基-1-丁醛的制备方法。
为此,本发明采用的制备方法包括如下步骤::(1)在惰性气体保护下,式(2)所示的2-甲基-3,3-二烷氧基-1-卤代丙烷和镁粉,在无水四氢呋喃溶剂中于45~65℃温度(格氏反应的温度)下生成其格氏试剂;(2)然后再加入N,N-二取代甲酰胺于10℃~35℃温度(缩合及水解反应的温度)下反应“一锅法”制备得到目标产物式(1)所示的3-甲基-4,4-二烷氧基-1-丁醛,反应方程式如下:
其中R为烷基,优选甲基或乙基。所述2-甲基-3,3-二烷氧基-1-卤代丙烷为2-甲基-3,3-二甲氧基-1-氯代丙烷、2-甲基-3,3-二甲氧基-1-溴代丙烷、2-甲基-3,3-二乙氧基-1-氯代丙烷、和2-甲基-3,3-二乙氧基-1-溴代丙烷。所述N,N-二取代甲酰胺为N,N-二甲基甲酰胺或N-甲酰基哌啶。
上述反应中,式(2)的2-甲基-3,3-二烷氧基-1-卤代丙烷用量与镁粉用量的摩尔比优选为1∶1.0~1.5;式(2)的2-甲基-3,3-二烷氧基-1-卤代丙烷用量和N,N-二取代甲酰胺用量的摩尔比优选为1∶1.0~1.5。此外,在步骤(1)中的反应物还可以加入碘以作为格氏反应的引发剂。
本发明的工艺路线简捷,操作简单,条件温和,收率良好,极具工业价值。
具体实施方式
现结合所附较佳实施例详细说明如下,所说明的较佳实施例仅用于说明本发明的技术方案,并非限定本发明。
本发明的各个实施例中所使用的分析仪器与设备为:气质联用仪,MS5973N-GC6890N(美国安捷伦公司);核磁共振仪,AVANCE DMX II I 400M(TMS内标,Bruker公司);红外光谱仪,NICOLET360FT-IR;气相色谱,科晓GC1690。
实施例1:3-甲基-4,4-二甲氧基-1-丁醛的制备
在氮气保护下,在装有机械搅拌和回流管的1L的四口瓶中,加入14.4g(0.6mol)镁粉、300mL的无水四氢呋喃和10mg碘,再加入2mL由98g(0.5mol)2-甲基-3,3-二甲氧基-1-溴代丙烷和100mL无水四氢呋喃组成的溶液,温和的加热使其引发,当碘颜色消失,则反应已引发。然后维持45℃于1小时内滴加入剩余的2-甲基-3,3-二甲氧基-1-溴代丙烷溶液,加完再于55℃反应5小时。再冷去至30℃,于0.5小时内滴加入67.8g(0.6mol)N-甲酰基哌啶与100mL无水四氢呋喃的溶液,滴加完继续搅拌反应0.5小时。再加入100mL10%的氯化铵水溶液搅拌0.5小时,分出水层。有机层用600mL乙醚分3 次萃取。合并有机层依次用水100mL、饱和碳酸钠100mL、10%氯化钠水溶液100mL洗涤,硫酸镁干燥,过滤,溶剂减压蒸干后得到3-甲基-4,4-二甲氧基-1-丁醛粗品64.5g,减压收集65-68℃/3mmHg馏分56.2g,为无色液体,气相含量98.2%,产率76.3%。
产品结构确认:
1HNMR(δ,ppm,400MHz,DMSO):0.875(d,J=6.8Hz,3H,CH3);2.173-2.459(m,2H,CH* 2CHO);2.274-2.339(m,1H,CH*CH3);3.268(s,6H,OCH3);4.098(d,J=6.0Hz,1H,CH*(OCH3)2);9.598(t,J=2.0Hz,1H,CHO);
13CNMR(δ,ppm,400MHz,DMSO):15.667,31.569,40.639,54.151,55.237,108.137,203.057
GC-MS:29,41,47,55,75(100%),83,85,102,115,145
IR:1067.99,1101.36,1723.71,2832.36,2937.00
实施例2:3-甲基-4,4-二乙氧基-1-丁醛的制备
在氮气保护下,在装有机械搅拌和回流管的1L的四口瓶中,加入16.8g(0.7mol)镁粉、300mL的无水四氢呋喃和10mg碘,再加入2mL由90g(0.5mol)2-甲基-3,3-二乙氧基-1-氯代丙烷和100mL无水四氢呋喃组成的溶液,温和的加热使其引发,当碘颜色消失,则反应已引发。然后维持65℃于1小时内滴加入剩余的2-甲基-3,3-二甲氧基-1-溴代丙烷溶液,加完再回流反应8小时。再冷却至30℃,于0.5小时内滴加入40.2g(0.55mol)DMF与50mL无水四氢呋喃的溶液,滴加完继续搅拌反应1小时。再加入100mL10%的氯化铵水溶液搅拌0.5小时,分出水层。有机层用600mL乙醚分3次萃取。合并有机层依次用水100mL、饱和碳酸钠100mL、10%氯化钠水溶液100mL洗涤,硫酸镁干燥,过滤,溶剂减压蒸干后得到3-甲基-4,4-二乙氧基-1-丁醛粗品114.6g,减压收集72-75℃/3mmHg馏分107.2g为无 色液体,气相含量98.6%,产率61.6%。
产品结构确认:
1HNMR(δ,ppm,400MHz,CDCl3):1.000(d,J=5.6Hz,3H,CH3);1.206(d,J=7.2Hz,6H,OCH2CH* 3);2.222-2.588(m,2H,CH* 2CHO);2.360-2.425(m,1H,CH*CH3);2.634-3.750(m,4H,OCH* 2CH3));4.220(d,J=6.0Hz,1H,CH*(OCH2CH3)2);9.735(t,J=2.4Hz,1H,CHO);
13CNMR(δ,ppm,400MHz,CDCl3):14.932,15.103,15.419,32.372,46.188,61.945,63.327,106.010,201.766
GC-MS:29,43,47,55,75,83,86,101,103(100%),129,173
IR:1051.73,1071.02,1738.70,2831.38,2937.62
实施例3-8:3-甲基-4,4-二甲氧基-1-丁醛的制备
在氮气保护下,在装有机械搅拌和回流管的500L的四口瓶中,加入一定量镁粉、100mL的无水四氢呋喃和10mg碘,再加入2mL由0.1mol的2-甲基-3,3-二甲氧基-1-卤代丙烷和20mL无水四氢呋喃组成的溶液,温和的加热使其引发,当碘颜色消失,则反应已引发。然后维持一定温度于0.5小时内滴加入剩余的2-甲基-3,3-二甲氧基-1-溴代丙烷溶液,加完再于一定温度反应5小时。再冷却至一定温度,于0.5小时内滴加入一定量的N,N-二取代甲酰胺与20mL无水四氢呋喃的溶液,滴加完继续搅拌反应0.5小时。再加入30mL10%的氯化铵水溶液搅拌0.5小时,分出水层。有机层用150mL乙醚分3次萃取。合并有机层依次用水30mL、饱和碳酸钠30mL、10%氯化钠水溶液30mL洗涤,硫酸镁干燥,过滤,减压蒸干溶剂得到3-甲基-4,4-二甲氧基-1-丁醛粗品,减压收集65-68℃/3mmHg馏分,测定气相含量,计算产率,结果如表1所示。
实施例3-8产品结构确认:同实施例1
1HNMR(δ,ppm,400MHz,DMSO):0.875(d,J=6.8Hz,3H,CH3);2.173-2.459(m,2H,CH* 2CHO);2.274-2.339(m,1H,CH*CH3);3.268(s,6H,OCH3);4.098(d,J=6.0Hz,1H,CH*(OCH3)2);9.598(t,J=2.0Hz,1H,CHO);
13CNMR(δ,ppm,400MHz,DMSO):15.667,31.569,40.639,54.151,55.237,108.137,203.057
GC-MS:29,41,47,55,75(100%),83,85,102,115,145
IR:1067.99,1101.36,1723.71,2832.36,2937.00
表1实施例3-8中反应物、反应温度和结果
实施例9-14:3-甲基-4,4-二乙氧基-1-丁醛的制备
在氮气保护下,在装有机械搅拌和回流管的500L的四口瓶中,加入一定量镁粉、100mL的无水四氢呋喃和10mg碘,再加入2mL由0.1mol的2-甲基-3,3-二乙氧基-1-卤代丙烷和20mL无水四氢呋喃组成的溶液,温和的加热使其引发,当碘颜色消失,则反应已引发。然后维持一定温度于0.5小时内滴加入剩余的2-甲基-3,3-二甲氧基-1-溴代丙烷溶液,加完再于一定温度反应5小时。再冷却至一定温度,于0.5小时内滴加入一定量的N,N-二取代甲酰胺与20mL无水四氢呋喃的溶液,滴加完继续搅拌反应0.5小时。再加入30mL10%的氯化铵水溶液搅拌0.5小时,分出水层。有机层用150mL乙醚分3次萃取。合并有机层依次用水30mL、饱和碳酸钠30mL、10%氯化钠水溶液30mL洗涤,硫酸镁干燥,过滤,减压蒸干溶剂得到3-甲基-4,4-二乙氧基-1-丁醛粗品,减压收集72-75℃/3mmHg馏分,测定气相含量,计算产率,结果如表2所示。
实施例9-14产品结构确认:同实施例2
1HNMR(δ,ppm,400MHz,CDCl3):1.000(d,J=5.6Hz,3H,CH3);1.206(d,J=7.2Hz,6H,OCH2CH* 3);2.222-2.588(m,2H,CH* 2CHO);2.360-2.425(m,1H,CH*CH3);2.634-3.750(m,4H,OCH* 2CH3));4.220(d,J=6.0Hz,1H,CH*(OCH2CH3)2);9.735(t,J=2.4Hz,1H,CHO);
13CNMR(δ,ppm,400MHz,CDCl3):14.932,15.103,15.419,32.372,46.188,61.945,63.327,106.010,201.766
GC-MS:29,43,47,55,75,83,86,101,103(100%),129,173
IR:1051.73,1071.02,1738.70,2831.38,2937.62
表2实施例9-14中反应物、反应温度和结果
需要声明的是,上述发明内容及具体实施方式意在证明本发明所提供技术方案的实际应用,不应解释为对本发明保护范围的限定。本领域技术人员在本发明的精神和原理内,当可作各种修改、等同替换、或改进。
Claims (5)
1.一种番茄红素中间体3-甲基-4,4-二烷氧基-1-丁醛的制备方法,所述制备方法包括如下步骤:
(1)在惰性气体保护下,式(2)所示的2-甲基-3,3-二烷氧基-1-卤代丙烷、镁粉和碘,在无水四氢呋喃溶剂中于45~65℃温度下生成格氏试剂混合物;
(2)再向所述格氏试剂混合物中加入N,N-二取代甲酰胺于10℃~35℃温度下反应得到式(1)所示的3-甲基-4,4-二烷氧基-1-丁醛,所述N,N-二取代甲酰胺为N-甲酰基哌啶;反应方程式如下:
其中:R为烷基。
2.根据权利要求1所述的制备方法,其中,所述烷基为甲基或乙基。
3.根据权利要求1所述的制备方法,其中,2-甲基-3,3-二烷氧基-1-卤代丙烷为2-甲基-3,3-二甲氧基-1-氯代丙烷、2-甲基-3,3-二甲氧基-1-溴代丙烷、2-甲基-3,3-二乙氧基-1-氯代丙烷、和2-甲基-3,3-二乙氧基-1-溴代丙烷。
4.根据权利要求1所述的制备方法,其中,2-甲基-3,3-二烷氧基-1-卤代丙烷用量与镁粉用量的摩尔比为1:1.0~1.5。
5.根据权利要求1所述的制备方法,其中,2-甲基-3,3-二烷氧基-1-卤代丙烷用量和N,N-二取代甲酰胺用量的摩尔比为1:1.0~1.5。
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