CN108752178B - 一种2,7-二甲基-2,4,6-辛三烯-1,8-二醛的制备方法 - Google Patents
一种2,7-二甲基-2,4,6-辛三烯-1,8-二醛的制备方法 Download PDFInfo
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- CN108752178B CN108752178B CN201810551744.0A CN201810551744A CN108752178B CN 108752178 B CN108752178 B CN 108752178B CN 201810551744 A CN201810551744 A CN 201810551744A CN 108752178 B CN108752178 B CN 108752178B
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Abstract
本发明公开了一种2,7‑二甲基‑2,4,6‑辛三烯‑1,8‑二醛的制备方法,包括:a)式Ⅱ的1,4‑二溴‑2‑丁烯与镁反应得到式Ⅲ的格氏试剂,b)式Ⅲ的格氏试剂与式Ⅳ的环氧乙烷反应,酸解得到化合物Ⅴ,c)化合物Ⅴ经过氧化反应得到化合物Ⅵ,d)化合物Ⅵ与甲醛发生羟醛缩合反应得到化合物Ⅶ,e)化合物Ⅶ经过临氢异构反应得到式Ⅰ的2,7‑二甲基‑2,4,6‑辛三烯‑1,8‑二醛;反应方程式如下:
Description
技术领域
本发明涉及一种2,7-二甲基-2,4,6-辛三烯-1,8-二醛的制备方法,属于有机合成领域。
背景技术
2,7-二甲基-2,4,6-辛三烯-1,8-二醛,简称为“十碳烯醛”,分子式为C10H12O2,分子量为164.2,CAS:5056-17-7,十碳烯醛通常为淡黄色粉末状固体,熔点157.0-159.0℃,易溶于甲醇、二氯甲烷,溶于石油醚、乙酸乙酯,微溶于水,是合成类胡萝卜素的关键中间体,在β-胡萝卜素、角黄素、虾青素、番茄红素的合成中有重要的应用。
目前文献报道的2,7-二甲基-2,4,6-辛三烯-1,8-二醛合成方法主要有以下几种:
上述路线为专利US20020128520、US6673972、US5300658、US5382732等报道的工艺路线,以呋喃为起始原料,与甲醇经过两步加成得到1,1,4,4-四甲氧基-2-丁烯,1,1,4,4-四甲氧基-2-丁烯在路易斯酸催化下与丙烯基甲醚缩合反应得到十碳烯醛骨架,再经碱处理消除甲醇形成双键得到产物。此路线使用到溴素,其价格高、毒性大、且化学性质活泼不稳定,此外缩醛的加成反应中副反应较多,加成的产物仍然是双缩醛结构,可以进一步与丙烯基甲醚缩合发生调聚反应形成多聚物。
上述路线为专利US5276209工艺路线,以1-乙氧基-1-丙烯为起始原料,与原甲酸三乙酯在路易斯酸催化下加成得到1,1,3,3-四乙氧基-2-甲基丙烷,在酸作用下消除一分子乙醇形成2-甲基-3-乙氧基-2-丁烯醛化合物,与乙炔双格氏试剂加成,再脱水形成烯键,三键部分氢化形成双键,最后缩醛脱保护,经七步反应合成十碳烯醛,该工艺反应步骤长,前三步反应控制较难,十碳烯醛总收率只有21%。
专利US6297416B1及US6403838报道了上述以合成维生素A的原料4-乙酰氧基-2-甲基-2-丁烯-1-醛为起始原料,首先用新戊二醇形成缩醛保护物,再碱水解,得到的羟基化合物卤代,与硫化钠反应形成硫醚化合物,硫醚经氧化变成亚砜,再与连二亚硫酸钠反应脱硫双聚缩合得到十碳烯醛的方法。该条路线共有七步反应,反应中涉及保护与脱保护,反应工艺繁琐,不利于工业化生产。
专利EP523534A2以苯亚磺酸钠作连接剂,与两分子的2-(3-氯-1-甲基-1-丙烯基)-5,5-二甲基-1,3-二噁烷反应得到砜化合物,再通过强碱消除苯磺基得到十碳烯醛。该条路线使用的原料2-(3-氯-1-甲基-1-丙烯基)-5,5-二甲基-1,3-二噁烷是由合成维生素A的原料4-乙酰氧基-2-甲基-2-丁烯-1-醛经过缩醛保护、碱水解、卤代三步反应得到,反应路线繁琐,难以工艺化。此路线反应收率较低,总收率只有15%。
专利US5471005A报道丙醛与甲酸甲酯进行Claisen缩合反应,再酯化,得到2-甲基-3-烷氧基-2-丙烯醛,而后与乙炔双格氏试剂加成,还原三键成双键,再脱水形成共轭双键得到十碳烯醛。该条工艺路线繁琐,反应步骤长,难以进行工业化生产。
专利US5107030A以1,4-二卤-2-丁烯为原料,经Abrozov重排反应得到双膦酸酯化合物,再与丙酮醛缩二甲醇进行Wittig-Horner反应、脱保护基得到十碳烯醛,总收率报道有39%,该条路线的主要原料丙酮醛缩二甲醇未有工业化产品供应,难以用于工业化合成十碳烯醛。
专利CN101234957A对十碳烯醛的合成方法做出了改进,反式-1,4-二氯-2-丁烯为起始原料,经格氏反应、缩合反应与酸性水解反应合成2,7-二甲基-2,4,6-辛三烯-1,8-二醛,该条路线的难点同样是在于丙酮醛缩二甲醇未见大规模生产报道。
综上可以看出,目前制备2,7-二甲基-2,4,6-辛三烯-1,8-二醛的方法存在原料难以购买,反应收率低,选择性差,反应路线长,三废较高等难题,因此需要寻求一种新的2,7-二甲基-2,4,6-辛三烯-1,8-二醛的合成方法解决上述技术问题。
发明内容
本发明的目的是提供一种新的2,7-二甲基-2,4,6-辛三烯-1,8-二醛制备方法。该方法使用到的原料易得,反应收率高,操作简便,易于工业化生产。
为达到以上目的,本发明的技术方案如下:
一种2,7-二甲基-2,4,6-辛三烯-1,8-二醛的制备方法,包括以下步骤:
a)式Ⅱ的1,4-二溴-2-丁烯与镁反应得到式Ⅲ的格氏试剂,
b)式Ⅲ的格氏试剂与式Ⅳ的环氧乙烷反应,酸解得到化合物Ⅴ,
c)化合物Ⅴ经过氧化反应得到化合物Ⅵ,
d)化合物Ⅵ与甲醛发生羟醛缩合反应得到化合物Ⅶ,
e)化合物Ⅶ经过临氢异构反应得到式Ⅰ的2,7-二甲基-2,4,6-辛三烯-1,8-二醛;
其反应方程式如下:
本发明方法中,步骤a)中式Ⅱ的1,4-二溴-2-丁烯与镁反应得到式Ⅲ的格氏试剂。反应的溶剂选自四氢呋喃、甲苯、无水乙醚中的一种或多种,优选溶剂为四氢呋喃;溶剂用量为1,4-二溴-2-丁烯质量的1-10倍,优选4-6倍;镁与1,4-二溴-2-丁烯的摩尔比为1.9-2.2,优选2.0-2.1;1,4-二溴-2-丁烯的加料方式可以一次性加入,也可滴加加入,优选滴加加入,滴加时间为1-5h、优选2-3h,滴加完成后继续反应0.5-2h、优选1-1.5h,若一次性加入,其与镁的反应时间为1-5h,优选2-3h;格氏反应温度为20-80℃,优选温度为50-60℃;格氏反应的引发剂选自碘单质、溴乙烷、溴丁烷中的一种或多种,优选引发剂为碘单质;引发剂用量为1,4-二溴-2-丁烯的摩尔量的0.01%-10%,优选0.1%-5%。
本发明方法中,步骤b)中,式Ⅲ的格氏试剂与式Ⅳ的环氧乙烷反应,反应完成后进一步酸解得到化合物Ⅴ。环氧乙烷的加料方式可以一次性加入,也可滴加加入,优选滴加加入,滴加时间为1-5h、优选2-3h,滴加完成后继续反应0.5-2h、优选1-1.5h,若采用一次性加入,则环氧乙烷与格氏试剂Ⅲ的反应时间为1-5h、优选2-3h;加入环氧乙烷的反应温度为0-100℃,优选30-60℃;环氧乙烷与初始加入的1,4-二溴-2-丁烯的摩尔比例为2.0-2.2,优选为2.05-2.1;反应结束后采用酸溶液进行酸解,所述酸溶液选自硫酸、盐酸、醋酸、磷酸水溶液,优选盐酸水溶液,所述酸溶液浓度为2-20wt%、优选5-10wt%;所述酸溶液用量与初始加入的镁的质量比例为5-50、优选10-15;酸解温度为0-60℃,优选10-30℃;酸解反应时间为10-90min,优选30-60min。反应完成后可以通过减压蒸馏方式脱除溶剂,减压蒸馏绝对压力为100-5000Pa,优选为500-2000Pa;减压蒸馏温度为30-60℃,优选40-50℃;然后采用真空油泵进行烘干,真空绝对压力为10-100pa,优选20-50pa,烘干温度为30-100℃,优选50-60℃。
本发明方法中,步骤c)中化合物Ⅴ经过氧化反应得到化合物Ⅵ,氧化反应的溶剂选自四氢呋喃、甲苯、无水乙醚、二氯甲烷中的一种或多种,优选溶剂为二氯甲烷;溶剂用量为化合物Ⅴ质量的1-20倍,优选5-10倍;氧化反应温度为0-100℃,优选20-30℃;氧化反应时间为2-20h,优选4-6h;氧化剂选自空气、氧气、二氧化锰、双氧水、次氯酸钠中的一种或多种,优选氧气;氧化剂用量为化合物Ⅴ的摩尔量的3-30倍,优选为5-10倍;催化剂选自2,2,6,6-四甲基哌啶氧化物(TEMPO)、分子筛、沸石中的一种或多种,优选2,2,6,6-四甲基哌啶氧化物(TEMPO),催化剂用量为化合物Ⅴ的摩尔量的0.1-10%,优选为0.5-2%。反应完成后可以通过减压蒸馏方式脱除溶剂,减压蒸馏绝对压力为100-5000pa,优选为500-2000pa;蒸馏温度为20-50℃,优选25-35℃;然后采用真空油泵进行烘干,真空绝对压力为10-100pa,优选20-50pa,烘干温度为30-100℃,优选50-60℃条。
本发明方法中,步骤d)中:化合物Ⅵ与甲醛发生羟醛缩合反应得到化合物Ⅶ。羟醛缩合反应的反应溶剂选自四氢呋喃、甲苯、无水乙醚、石油醚、乙酸乙酯、水中的一种或多种,优选水和/或四氢呋喃;溶剂用量为化合物Ⅵ质量的1-10倍,优选3-6倍;甲醛与化合物Ⅵ的摩尔比例为2-4,优选为2.1-2.5;通常的,甲醛溶液的质量分数可以是35-45wt%,优选40wt%;反应温度为20-100℃,优选40-60℃;反应时间为2-10h,优选3-5h;羟醛缩合反应的催化剂为碱,所述碱选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾中的一种或多种,优选为氢氧化钠;催化剂碱的用量与化合物Ⅵ的摩尔比例为0.01-10,优选0.1-1。反应完成后,抽滤即得化合物Ⅶ,然后在30-100℃、优选50-60℃条件下将化合物Ⅶ烘干。
本发明方法中,步骤e)中,化合物Ⅶ经过临氢异构反应得到式Ⅰ的2,7-二甲基-2,4,6-辛三烯-1,8-二醛;反应溶剂选自四氢呋喃、甲苯、无水乙醚、乙酸乙酯、二氯甲烷、石油醚、正己烷中的一种或多种,优选溶剂为四氢呋喃和/或甲苯;溶剂用量为化合物Ⅶ质量的1-20倍,优选5-10倍;反应温度为0-200℃,优选80-100℃;反应时间为2-20h,优选4-6h;反应绝压为0.1-20MPa,优选1-5MPa;临氢异构反应的催化剂选自镍、钯、钌、铑、铂中的一种或多种,优选钯;催化剂用量为化合物Ⅶ摩尔量的0.01-1%,优选为0.05-0.1%;催化剂以负载形式使用,载体可为活性炭、分子筛、沸石,优选为活性炭,催化剂活性组分含量范围为0.5-10wt%,优选1-5wt%。
反应完成后可以通过减压蒸馏方式脱除溶剂,减压蒸馏绝对压力为100-5000Pa,优选为500-2000Pa;蒸馏温度为30-60℃,优选40-50℃;然后采用真空油泵进行烘干,真空绝对压力为10-100Pa,优选20-50Pa,烘干温度为30-100℃,优选50-60℃。
本发明的积极效果:本发明提供了一种新的制备2,7-二甲基-2,4,6-辛三烯-1,8-二醛的方法,该条路线原料易得,经过五步反应得到2,7-二甲基-2,4,6-辛三烯-1,8-二醛,反应收率可以达到78-84%,工艺简单,便于工业化生产。
具体实施方式
下面的实施例将对本发明所提供的方法予以进一步的说明,但本发明不限于所列出的实施例,还应包括在本发明所要求的权利范围内其它任何公知的改变。
气相色谱分析条件:安捷伦气相色谱的聚硅氧烷柱HP-5进行在线测定,气化室温度为250℃,检测器温度250℃,柱温为程序升温:50℃,1min;80℃,1min;10℃/min至250℃,10min,进样量0.2μL。
1HNMR采用Bruker AVANCEⅢ500MHz(CDCl3作溶剂,TMS为内标)
实施例1化合物Ⅴ的制备
称取100g四氢呋喃、24g(1mol)镁片于2L三口瓶中,而后加入0.1g碘引发反应,而后向体系内滴加106.5g(0.5mol)1,4-二溴-2-丁烯与500g四氢呋喃的混合溶液,控制反应内温在55-60℃,约2h滴加完全,滴加完全后继续保温反应1h,而后向反应液中滴加44.1g环氧乙烷,控制反应温度不超过60℃,2h滴加完全,滴加完全后继续保温反应2h,将反应液缓慢倒入300g 5wt%的盐酸中进行酸解,酸解温度不超过10℃,加入完全后继续搅拌30min,分液,减压脱除四氢呋喃(绝对压力1000Pa,温度45℃),而后真空油泵烘干(真空绝对压力30Pa,烘干温度50℃)得到68.6g化合物Ⅴ,产品气相纯度99.2%,收率95.3%。
实施例2化合物Ⅴ的制备
称取100g四氢呋喃、25.2g(1.05mol)镁片于2L三口瓶中,而后加入0.1g碘引发反应,而后向体系内滴加106.5g(0.5mol)1,4-二溴-2-丁烯与500g四氢呋喃的混合溶液,控制反应内温在55-60℃,约3h滴加完全,滴加完全后继续保温反应1h,而后向反应液中滴加44.1g环氧乙烷,控制反应温度不超过60℃,约3h滴加完全,滴加完全后继续保温反应1h,将反应液缓慢倒入300g 5%的盐酸中进行酸解,酸解温度不超过10℃,加入完全后继续搅拌30min,分液,减压脱除四氢呋喃(绝对压力1000Pa,温度45℃),而后真空油泵烘干(真空绝对压力30Pa,烘干温度50℃),得到69.6g化合物Ⅴ,产品气相纯度99.2%,收率96.7%。
实施例3化合物Ⅵ的制备
称取实施例1制备的28.8g(0.2mol)化合物Ⅴ,200g二氯甲烷,0.3g(0.002mol)2,2,6,6-四甲基哌啶氧化物于500ml三口瓶中,20℃下搅拌,向体系内鼓入氧气,速度为100ml/min,气相检测反应进程,约5h化合物Ⅴ反应完全,向体系内加入100g水终止反应,分液,减压蒸馏脱除有机相溶剂(绝对压力1000Pa,温度30℃),而后真空油泵烘干(真空绝对压力20Pa,烘干温度50℃),得到25.6g化合物Ⅵ,产品气相纯度99.5%,收率91.4%。
实施例4化合物Ⅵ的制备
称取实施例2制备的28.8g(0.2mol)化合物Ⅴ,200g二氯甲烷,0.6g(0.004mol)2,2,6,6-四甲基哌啶氧化物于500ml三口瓶中,30℃下搅拌,向体系内鼓入氧气,速度为100ml/min,气相检测反应进程,约4h化合物Ⅴ反应完全,向体系内加入100g水终止反应,分液,减压蒸馏脱除有机相溶剂(绝对压力800Pa,温度25℃),而后真空油泵烘干(真空绝对压力20Pa,烘干温度50℃),得到26.5g化合物Ⅵ,产品气相纯度99.5%,收率94.6%。
实施例5化合物Ⅶ的制备
称取实施例3制备的28.0g(0.2mol)化合物Ⅵ,30g 40%的甲醛水溶液,100g5wt%的氢氧化钠水溶液于250ml三口瓶中,60℃保温搅拌4h,而后降温至5℃抽滤,滤饼为淡黄色固体,60℃烘干,得到30.2g化合物Ⅶ,产品气相纯度98.1%,收率为92.1%。
实施例6化合物Ⅶ的制备
称取实施例3制备的28.0g(0.2mol)化合物Ⅵ,30g 40%的甲醛水溶液,100g5%的氢氧化钠水溶液于250ml三口瓶中,40℃保温搅拌5h,而后降温至5℃抽滤,滤饼为淡黄色固体,60℃烘干,得到30.8g化合物Ⅶ,产品气相纯度98.1%,收率为93.9%。
实施例7化合物Ⅶ的制备
称取实施例4制备的28.0g(0.2mol)化合物Ⅵ,37.5g 40%的甲醛水溶液,160g5%的氢氧化钠水溶液于250ml三口瓶中,60℃保温搅拌4h,而后降温至5℃抽滤,滤饼为淡黄色固体,60℃烘干,得到30.6g化合物Ⅶ,产品气相纯度98.1%,收率为93.3%。
实施例8化合物Ⅰ的制备
称取实施例5制备的16.4g(0.1mol)化合物Ⅶ,100g四氢呋喃,0.164g活性钯含量5wt%的钯碳加入到500ml高压反应釜中,氢气置换三次后,反应压力为1MPa,反应温度为80℃,保温反应5h后,停止反应,反应液抽滤后,减压蒸馏脱除溶剂(绝对压力1000Pa,温度45℃),而后真空油泵烘干(真空绝对压力20Pa,烘干温度50℃),得到15.8g化合物Ⅰ,产品收率为96.3%,产品气相纯度为99.2%,熔点为157.5-158.6℃。产物经核磁分析,数据为:1HNMR(500MHz,CDCl3):1.92(s,6H,2CH3);7.00-7.10(m,4H,2CH=CH);9.54(s,2H,2CHO)。
实施例9化合物Ⅰ的制备
称取实施例6制备的16.4g(0.1mol)化合物Ⅶ,100g甲苯,0.164g活性钯含量1wt%的钯碳加入到500ml高压反应釜中,氢气置换三次后,反应压力为5MPa,反应温度为100℃,保温反应4h后,停止反应,反应液抽滤后,减压蒸馏脱除溶剂(绝对压力1000Pa,温度45℃),而后真空油泵烘干(真空绝对压力20Pa,烘干温度50℃),得到15.8g化合物Ⅰ,产品收率为96.3%,产品气相纯度为99.5%,熔点为157.6-158.4℃。
实施例10化合物Ⅰ的制备
称取实施例7制备的16.4g(0.1mol)化合物Ⅶ,100g四氢呋喃,0.164g活性钯含量2wt%的钯碳加入到500ml高压反应釜中,氢气置换三次后,反应压力为5MPa,反应温度为90℃,保温反应5h后,停止反应,反应液抽滤后,减压蒸馏脱除溶剂(绝对压力1000Pa,温度45℃),而后真空油泵烘干(真空绝对压力20Pa,烘干温度50℃),得到16.0g化合物Ⅰ,产品收率为97.6%,产品气相纯度为99.5%,熔点为157.9-158.6℃。
对比例1
化合物Ⅰ的制备
将179.1g(1.013摩尔)1,1,4,4-四甲氧基-2-丁烯和0.35g(2.16mmol)无水氯化铁引入2升甲苯。在4小时内送入147.6g(2.026摩尔)丙烯基甲醚。在此期间,反应温度保持在25℃。在进料结束后,混合物在+25℃下搅拌2小时。然后加入400g浓度2%的硫酸水溶液,然后将混合物加热到80℃并且在该温度下搅拌4小时。然后分离水相。再次加入400ml浓度2%的硫酸,并且在于80℃搅拌2小时后分离水相。该操作再重复一次。然后加入1000g浓度5%的碳酸氢钠水溶液,混合物在80-85℃下搅拌3小时。分离出下部的水相,上部的有机相在80℃下用80℃的500ml水洗涤。分离除去水相,并且在减压下将有机相浓缩到1升。将浓缩的有机相冷却到0℃,获得的I的悬浮液在0℃下搅拌1小时。抽滤得到黄色固体,真空油泵烘干(真空绝对压力20Pa,烘干温度50℃),得到65.8g化合物Ⅰ,收率40.1%。
以上具体实施方式,并非对本发明的技术方案作任何形式的限制。凡是依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化与修饰,均落入本发明的保护范围之内。
Claims (19)
1.一种制备2,7-二甲基-2,4,6-辛三烯-1,8-二醛的方法,其特征在于,所述方法包括:
a)式Ⅱ的1,4-二溴-2-丁烯与镁反应得到式Ⅲ的格氏试剂,
b)式Ⅲ的格氏试剂与式Ⅳ的环氧乙烷反应,酸解得到化合物Ⅴ,
c)催化剂1存在下,化合物Ⅴ经过氧化反应得到化合物Ⅵ,
d)催化剂2存在下,化合物Ⅵ与甲醛发生羟醛缩合反应得到化合物Ⅶ,
e)催化剂3存在下,化合物Ⅶ经过临氢异构反应得到式Ⅰ的2,7-二甲基-2,4,6-辛三烯-1,8-二醛;
其中,步骤c)中,用于氧化反应的氧化剂选自空气、氧气,氧化反应温度为20-30℃,催化剂1为2,2,6,6-四甲基哌啶氧化物;
步骤d)中,反应温度为20-100℃,催化剂2为碱,所述碱选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾中的一种或多种;
步骤e)中,反应温度为80-100℃,反应绝压为1-5MPa,催化剂3选自镍、钯、钌、铑、铂中的一种或多种;
反应方程式如下:
2.根据权利要求1所述的方法,其特征在于,步骤a)中,镁与1,4-二溴-2-丁烯的摩尔比为1.9-2.2。
3.根据权利要求2所述的方法,其特征在于,步骤a)中,镁与1,4-二溴-2-丁烯的摩尔比为2.0-2.1。
4.根据权利要求1所述的方法,其特征在于,步骤b)中,环氧乙烷与步骤a)初始加入的1,4-二溴-2-丁烯的摩尔比为2.0-2.2。
5.根据权利要求4所述的方法,其特征在于,步骤b)中,环氧乙烷与步骤a)初始加入的1,4-二溴-2-丁烯的摩尔比为2.05-2.1。
6.根据权利要求1或4中任一项所述的方法,其特征在于,步骤b)中酸解用的酸溶液选自硫酸、盐酸、醋酸、磷酸水溶液中的一种或多种;酸解反应温度为0-60℃;酸解反应时间为10-90min。
7.根据权利要求6所述的方法,其特征在于,步骤b)中酸解用的酸溶液为盐酸水溶液;酸解反应温度为10-30℃;酸解反应时间为30-60min。
8.根据权利要求1所述的方法,其特征在于,步骤c)中氧化剂用量为化合物Ⅴ的摩尔量的3-30倍。
9.根据权利要求8所述的方法,其特征在于,步骤c)中氧化剂用量为化合物Ⅴ的摩尔量的5-10倍。
10.根据权利要求1、8任一项所述的方法,其特征在于,步骤c)氧化反应时间为2-20h;催化剂1用量为化合物Ⅴ的摩尔量的0.1-10%。
11.根据权利要求10所述的方法,其特征在于,步骤c)氧化反应时间为4-6h;催化剂1用量为化合物Ⅴ的摩尔量的0.5-2%。
12.根据权利要求1所述的方法,其特征在于,步骤d)中,甲醛与化合物Ⅵ的摩尔比为2-4;反应温度为40-60℃;反应时间为2-10h。
13.根据权利要求12所述的方法,其特征在于,步骤d)中,甲醛与化合物Ⅵ的摩尔比为2.1-2.5;反应时间为3-5h。
14.根据权利要求1所述的方法,其特征在于,步骤d)中,碱的用量与化合物Ⅵ的摩尔比为0.01-10。
15.根据权利要求1、12、14任一项所述的方法,其特征在于,步骤d)中,羟醛缩合反应的催化剂2为碱,所述碱为氢氧化钠;碱的用量与化合物Ⅵ的摩尔比为0.1-1。
16.根据权利要求1所述的方法,其特征在于,步骤e)中反应时间为2-20h。
17.根据权利要求16所述的方法,其特征在于,步骤e)中反应时间为4-6h。
18.根据权利要求1所述的方法,其特征在于,步骤e)中,催化剂3用量为化合物Ⅶ摩尔量的0.01-1%。
19.根据权利要求1、18任一项所述的方法,其特征在于,步骤e)中,催化剂3为钯;催化剂3用量为化合物Ⅶ摩尔量的0.05-0.1%。
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