【摘要】：為解決富馬酸合成路線需要硫代和格氏反應(yīng)在環(huán)保、安全上面臨的挑戰(zhàn),尋找更加綠色的合成工藝,本論文對(duì)目前公開(kāi)的以L-半胱氨酸鹽酸鹽為起始原料合成生物素中間體(5Z)-5-[(3aS,6aR)]-1,3-二芐基-2-酮基-六氫-4H-噻吩并[3,4-d]咪唑-4-烯基]-戊酸(4)的工藝路線進(jìn)行了優(yōu)化研究,主要研究了投料比、反應(yīng)溫度、反應(yīng)時(shí)間、攪拌速度等參數(shù)對(duì)反應(yīng)的影響;同時(shí)將一些輔料進(jìn)行了常規(guī)試劑的替換,對(duì)原工藝進(jìn)行了簡(jiǎn)化,使反應(yīng)變得更加簡(jiǎn)單穩(wěn)定。實(shí)驗(yàn)結(jié)果表明,采取分步氧化法的最佳合成工藝是:用40%的過(guò)氧乙酸作為氧化劑在NaOH甲醇溶液中,反應(yīng)溫度為-10℃,氧化(3S,7S,7aR)-3-苯基-7-(2-酮基環(huán)己基)-咪唑并[1,5-c]噻唑-5(1H,3H,6H)-酮(1),得到6-[(3S,7S,7aR)-3-苯基-5-酮基-6-芐基-四氫咪唑并[1,5-c]噻唑-7-基]-6-羥基己酸(2),然后用3.7%wt 6-[(3S,7S,7aR)-3-苯基-5-酮基-6-芐基-四氫咪唑并[1,5-c]噻唑-7-基]-6-羥基己酸(2)量的N-羥基鄰苯二甲酰亞胺在乙腈溶劑中使用純氧氣常壓進(jìn)行氧化得到6-[(3S,7S,7aR)-3-苯基-5-酮基-6-芐基-四氫咪唑并[1,5-c]噻唑-7-基]-6-酮基己酸(3),再用3倍摩爾量的鋅粉,10倍乙酸和哌啶混合溶劑,在100℃條件下反應(yīng)16 h,一步反應(yīng)得到(5Z)-5-[(3aS,6aR)]-1,3-二芐基-2-酮基-六氫-4H-噻吩并[3,4-d]咪唑-4-烯基]-戊酸(4),總收率可以達(dá)到58.4%。優(yōu)化后的合成工藝能為生物素的工業(yè)化合成提供新的方法,通過(guò)改進(jìn),氧化試劑可以使用較為常規(guī)的40%過(guò)氧乙酸代替過(guò)氧苯甲酸;真正實(shí)現(xiàn)了從6-[(3S,7aR)-3-苯基-5-酮基-6-芐基-四氫-1H-咪唑并[1,5-c]噻唑-7基]-6-酮基己酸(3)到(5Z)-5-[(3aS,6aR)-1,3-二芐基-2-酮基-六氫-4H-噻吩并[3,4-d]咪唑-4-烯基]-戊酸(4)的一步合成,并省去了酯化和皂化反應(yīng)以及后處理,簡(jiǎn)化了操作過(guò)程。
[Abstract]:In order to solve the challenge of thio- and Grignard reaction in environmental protection and safety in order to solve the synthesis route of fumaric acid, a greener synthetic process is sought. In this paper, the process of synthesizing biotin intermediate (5Z) -5- [(3aSh 6aR)] -1o 3-dibenzyl-2-keto-hexahydro-4H-thiopheno [34-d] imidazole-4-enyl] -pentanoic acid (4) from L- cysteine salt was studied. The effects of reaction temperature, reaction time and stirring speed on the reaction were also discussed, and some excipients were replaced by conventional reagents, the original process was simplified to make the reaction more simple and stable. The experimental results show that the optimum synthesis process is that 40% peracetic acid is used as oxidant in NaOH methanol solution, and the reaction temperature is -10 鈩，

本文編號(hào)：2144346