CN106045802A - 一种脂环族和芳脂族氯甲酸酯的制备方法 - Google Patents

一种脂环族和芳脂族氯甲酸酯的制备方法 Download PDF

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CN106045802A
CN106045802A CN201610444533.8A CN201610444533A CN106045802A CN 106045802 A CN106045802 A CN 106045802A CN 201610444533 A CN201610444533 A CN 201610444533A CN 106045802 A CN106045802 A CN 106045802A
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吴爱斌
秦少雄
李鹏飞
郭权京
胡宝军
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Yangtze University
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Abstract

本发明属于精细化工技术领域，具体涉及一种脂环族和芳脂族氯甲酸酯的制备方法。以脂环族醇或芳脂族醇与固体三光气为原料，以有机碱为催化剂，在有机溶剂中于一定反应温度和反应时间下得到氯甲酸脂环醇酯或氯甲酸芳脂醇酯，其中脂环族醇或芳脂族醇与三光气、有机碱催化剂的摩尔比为1:0.4～1:1.2～3；试验时间和温度分两个阶段，第一阶段的反应温度为‑10～0℃，反应时间为2～5h，第二阶段的反应温度为0～25℃，反应时间为7～13h；有机溶剂与脂环族醇或芳脂族醇的质量比为10～25:1；反应体系中的残余物进行了有效处理，反应废弃物也经回收利用。本发明具有反应稳定，反应收率和产品纯度高，生产过程环保，生产成本低，三废排放少，且制备工艺简单，易于工业化的特点。

Description

一种脂环族和芳脂族氯甲酸酯的制备方法
技术领域
本发明属于精细化工领域，具体涉及一种脂环族和芳脂族氯甲酸酯的制备方法。
背景技术
氯甲酸酯类化合物是一类重要的精细化工中间体，在有机合成、医药、农药、化妆品和食品工业等领域具有十分广泛的应用。脂环族和芳脂族氯甲酸酯作为化学试剂中间体具有很大的实用价值和经济价值。例如氯甲酸-L-薄荷醇酯和氯甲酸苄酯，因其在手性拆分、烟草业、抗生素和多肽合成中的重要应用而日益受到市场青睐。
目前脂环族和芳脂族氯甲酸酯的制备方法主要有两种：一是以脂环族醇或芳脂族醇为原料，在光气条件下反应制得，这一反应在CN101213166、CN101080380、WO2007/001757、US006696590中有详细的介绍；二是以脂环族醇或芳脂族醇为原料，在固体三光气(双三氯甲基碳酸酯，BTC)条件下反应制得，这一反应在CN1616405、CN1803758中曾有过报道。由于光气是一种极其危险的剧毒性气体，难以准确计量，在生产中易造成安全隐患，且操作工艺复杂，还有一定的副产物生成，因而采用固体三光气替代光气，不仅使反应计量容易控制，而且毒性低，操作安全，是一种极有发展前景的方法。但是文献报道中采用固体三光气的反应在产品收率和纯度方面不理想，且未见反应中过量三光气/光气后处理操作的报道，也未见反应中各种有机和无机废弃物处理方面的报道。
发明内容
本发明针对现有技术的不足之处，提供了一种操作简便、生产安全可靠、环境污染小、成本低、产率高、品质好的制备脂环族和芳脂族氯甲酸酯的方法。
本发明采用以下技术方案解决上述技术问题：一种脂环族和芳脂族氯甲酸酯的制备方法，以脂环族醇或芳脂族醇和三光气为原料，在有机碱催化剂作用下，在有机溶剂中于设定的反应温度和反应时间下反应，其特征在于：
1)所述脂环族醇或芳脂族醇与三光气、有机碱催化剂的摩尔比为1:0.4～1:1.2～3；
2)所述反应温度和反应时间分为两个阶段，第一阶段的反应温度为-10～0℃，反应时间为2～5h，第二阶段的反应温度为0～25℃，反应时间为7～13h；
3)所述有机溶剂与脂环族醇或芳脂族醇的质量比为10～25:1。
所述脂环族醇或芳脂族醇与三光气与有机碱催化剂的摩尔比为1:0.6～0.8:1.8～2.4。
所述第一阶段的反应温度为-5℃，反应时间为3h；第二阶段的反应温度为10～20℃，反应时间为10h。
所述有机溶剂与脂环族醇或芳脂族醇的质量比为15:1。
所述脂环族醇为下列之一：L-薄荷醇、环己醇、4-叔丁基环己醇、4-环己基环己醇、环戊醇、L-香芹醇、(R)-(-)-3-奎宁醇、雪松醇、(S)-(-)-1-苄基-3-吡咯烷醇、N-苄基-4-哌啶醇、4-萜烯醇、2-金刚烷醇、2-甲基异茨醇、β-托品醇、麦角固醇。
所述芳脂族醇为下列之一：苄醇、4-氯-3-硝基苄醇、2,4-二氯苄醇、五氟苄醇、(R)-(-)-1-茚醇、胡椒醇、糠醇、1-苯氧基-2-丙醇、3-苯基-2-丙炔-1-醇、肉桂醇、茴香醇、(5-甲基异噁唑-3-基)甲醇、9-芴醇、3-吡啶-1-丙醇。
所述有机碱催化剂优选为下列之一或一种以上的任意组合：三甲胺、三乙胺、二异丙基乙基胺、吡啶、六氢吡啶、对二甲氨基吡啶、喹啉、N,N-二甲基甲酰胺、N,N-二甲基苯胺。
所述有机溶剂为下列之一或一种以上的任意组合：二氯甲烷、三氯甲烷、1,2-二氯乙烷、苯、甲苯、二甲苯、环戊烷、正己烷、乙醚、异丙醚、丁醚、丙酮、环戊酮、乙酸乙酯、四氢呋喃、1,4-二氧六环。
所述反应结束后，将反应混合物减压过滤分离出有机盐沉淀，过滤后母液依次用水、稀盐酸、碳酸钠溶液和饱和食盐水洗涤，洗涤后的母液经过干燥、旋蒸脱除溶剂、减压蒸馏得到目标化合物。
所述过滤、洗涤、干燥过程均在负压下进行；所述负压下，过滤、洗涤过程中逸出的光气和氯化氢气体经碱和水三级吸附；所述过滤分离得到的有机盐沉淀加碱中和后蒸馏出有机碱，蒸馏后残余溶液浓缩至饱和。
其反应方程式如下：
本发明所述脂环族和芳脂族氯甲酸酯的制备方法，在一定反应条件下，产品收率≥97％，产品纯度≥98％。本发明与现有技术相比，反应收率高，产品质量优。
所述过滤分离得到的有机盐沉淀，经加碱中和和蒸馏处理得到的有机碱催化剂进行循环利用，得到的盐水母液经浓缩达到饱和后进行循环利用。该工艺显著降低了生产成本和三废排放。
所述过滤、洗涤、干燥时的出料或进料操作均在负压下进行。尤其在洗涤过程中，残余的光气和产生的氯化氢气体，通过加装碱和水三级吸收在负压下进行处理，有效地将其转化为无毒的碳酸钠和氯化钠。该工艺解决了生产过程中的安全和环保问题。
具体实施例
下面对本发明的实施例作详细说明：本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和过程，但本发明的保护范围不限于下述的实施例。
脂环族和芳脂族氯甲酸酯的制备中，包括如下步骤：1)向带有尾气吸收装置的夹套反应器中加入有机溶剂、反应物脂环族醇或芳脂族醇、三光气，搅拌溶解，控温-10～0℃；2)向上述混合物中滴加有机碱的有机溶剂溶液，控温-10～0℃，约1h滴完后，保温反应2～5h；3)自然升温至0～25℃，搅拌约7～13h；4)反应结束，减压过滤分离出沉淀，母液依次用水、5％的稀盐酸、5％的碳酸钠、饱和食盐水洗涤，继而干燥；5)旋蒸脱除溶剂；6)进行减压蒸馏收集得到产品。实施例1
在装有机械搅拌器、温度计、恒压滴液漏斗和尾气吸收装置的夹套反应釜中，加入7L二氯甲烷，第一反应阶段，控温-5℃，分批加入780g(5mol)L-薄荷醇和1187g(4mol)三光气，搅拌使其充分溶解。-5℃下滴加1215g(12mol)三乙胺的二氯甲烷(1.8L)溶液，约1～2h滴完，保温反应3h后自然升温至第二反应阶段，控温25℃，搅拌约10h。反应结束后，减压条件下，反应混合物过滤分离出沉淀，母液也在负压下依次用3L水、3L稀盐酸(5％)、0.5L碳酸钠(5％)和0.5L饱和食盐水洗涤，无水硫酸钠干燥后，旋蒸脱除溶剂，进行减压蒸馏，收集108～109℃/11mmHg的馏分，得到1063g无色液体，产率97.2％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ4.742(dt,J1＝4.4Hz,J2＝10.8Hz,1H),2.141(d,J＝12Hz,1H),1.970-1.936(m,1H),1.740-1.689(m,2H),1.507-1.449(m,2H),1.188-1.050(m,2H),0.951-0.856(m,7H),0.812(d,J＝7.2Hz,3H)ppm；13C-NMR(100MHz,CDCl3):δ149.735,83.793,46.817,40.107,33.792,31.442,26.361,23.408,21.757,20.448,16.222ppm；HRMS(ES+)calcd for C11H20ClO2([M+H])+219.1152,found219.1138。经高效液相色谱(HPLC)测定，目标化合物纯度为99.5％。
实施例2
投料摩尔比改为L-薄荷醇:三光气:三乙胺为1:0.4:1.2。溶剂为二氯甲烷，用量为L-薄荷醇质量的15倍。其它条件和制备步骤均同实施例1，得氯甲酸-L-薄荷醇酯，产率90.5％，经HPLC检测纯度为99.5％。
实施例3
投料摩尔比改为L-薄荷醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为L-薄荷醇质量的15倍。第一阶段反应温度为-10℃，保温4h；第二阶段反应温度20℃，搅拌约7h，其它条件和制备步骤均同实施例1，得氯甲酸-L-薄荷醇酯，产率95.5％，经HPLC检测纯度为99.5％。
实施例4
投料摩尔比改为L-薄荷醇:三光气:三乙胺为1:1:3。溶剂为二氯甲烷，用量为L-薄荷醇质量的10倍。其它条件和制备步骤均同实施例3，得氯甲酸-L-薄荷醇酯，产率98.0％，经HPLC检测纯度为99.5％。
实施例5
投料物质和摩尔比改为L-薄荷醇:三光气:吡啶为1:0.8:2.4。溶剂为二氯甲烷，用量为L-薄荷醇质量的10倍。其它条件和制备步骤均同实施例3，得氯甲酸-L-薄荷醇酯，产率99％，经HPLC检测纯度为99.5％。
实施例6
投料物质和摩尔比改为L-薄荷醇:三光气:N,N-二甲基苯胺为1:0.8:2.4。溶剂为二氯甲烷，用量为L-薄荷醇质量的20倍。第一阶段反应温度为0℃，保温5h，第二阶段反应温度15℃，搅拌约13h，其它条件和制备步骤均同实施例1，得氯甲酸-L-薄荷醇酯，产率92.6％，经HPLC检测纯度为99.5％。
实施例7
投料摩尔比为L-薄荷醇:三光气:三乙胺为1:0.8:2.4。溶剂改为甲苯，用量为L-薄荷醇质量的20倍。其它条件和制备步骤均同实施例6，得氯甲酸-L-薄荷醇酯，产率95.1％，经HPLC检测纯度为99.5％。
实施例8
投料摩尔比为L-薄荷醇:三光气:三乙胺为1:0.8:2.4。溶剂改为乙酸乙酯，用量为L-薄荷醇质量的25倍。其它条件和制备步骤均同实施例6，得氯甲酸-L-薄荷醇酯，产率94.8％，经HPLC检测纯度为99.5％。
实施例9
投料物质和摩尔比改为环己醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为环己醇质量的15倍。其它条件和制备步骤均同实施例1，进行减压蒸馏，收集87～88℃/27mmHg的馏分，得氯甲酸环己醇酯，产率98.2％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ4.605(m,1H),1.897-1.723(m,2H),1.624-1.417(m,8H)ppm；13C-NMR(100MHz,CDCl3):δ149.886,74.596,32.718,28.170,26.924ppm；HRMS(ES+)calcd for C7H12ClO2([M+H])+163.0526,found 163.0488。经HPLC检测纯度为99.0％。
实施例10
投料物质和摩尔比改为4-叔丁基环己醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为4-叔丁基环己醇质量的15倍。其它条件和制备步骤均同实施例1，进行蒸馏，收集254～255℃/760mmHg的馏分，得氯甲酸-4-叔丁基环己醇酯，产率98.2％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ4.762(t,J＝9.8Hz,1H),1.852-1.381(m,8H),1.150(t,J＝9.2Hz,1H),0.845(s,9H)ppm；13C-NMR(100MHz,CDCl3):δ149.517,75.039,50.271,34.507,33.022,29.624,26.116ppm；HRMS(ES+)calcd for C11H20ClO2([M+H])+219.1152,found 219.1158。经HPLC检测纯度为99.0％。
实施例11
投料物质和摩尔比改为环戊醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为环戊醇质量的12倍。第一阶段反应温度为-5℃，保温3h，第二阶段反应温度20℃，搅拌约10h，其它条件和制备步骤均同实施例1，进行蒸馏，收集173～174℃/760mmHg的馏分，得氯甲酸环戊醇酯，产率97.4％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ4.727(dt,J1＝4.0Hz,J2＝9.8Hz,1H),1.952-1.564(m,8H)ppm；13C-NMR(100MHz,CDCl3):δ149.838,82.927,32.991,26.420ppm；HRMS(ES+)calcdfor C6H10ClO2([M+H])+149.0369,found 149.0361。经HPLC检测纯度为99.0％。
实施例12
投料物质和摩尔比改为L-香芹醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为L-香芹醇质量的12倍。其它条件和制备步骤均同实施例11，进行减压蒸馏得氯甲酸-L-香芹醇酯，产率98％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ5.374(m,1H),5.131-5.112(m,2H),4.922(s,1H),2.352-2.298(m,1H),2.195-1.856(m,10H)ppm；13C-NMR(100MHz,CDCl3):δ150.824,149.138,132.182,123.327,107.532,73.199,36.263,31.145,21.526,18.420ppm；HRMS(ES+)calcd forC11H16ClO2([M+H])+215.0839,found 215.0671。经HPLC检测纯度为99.0％。
实施例13
投料物质和摩尔比改为(R)-(-)-3-奎宁醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为(R)-(-)-3-奎宁醇质量的10倍。其它条件和制备步骤均同实施例11，进行减压蒸馏得氯甲酸-(R)-(-)-3-奎宁醇酯，产率98％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ4.671-4.574(m,1H),2.815-2.450(m,2H),2.310-2.214(m,4H),2.081-1.925(m,1H),1.561-1.315(m,4H)ppm；13C-NMR(100MHz,CDCl3):δ150.819,72.314,60.513,50.012,27.733,20.910ppm；HRMS(ES+)calcdfor C8H13ClNO2([M+H])+190.0635,found 190.0617。经HPLC检测纯度为99.0％。
实施例14
投料物质和摩尔比改为4-萜烯醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为4-萜烯醇质量的10倍。其它条件和制备步骤均同实施例11，进行减压蒸馏得氯甲酸-4-萜烯醇酯，产率98％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物为目标化合物结构。1H-NMR(400MHz,CDCl3):δ5.285-5.264(m,1H),2.308-1.662(m,13H),1.651(s,3H)ppm；13C-NMR(100MHz,CDCl3):δ151.391,134.120,118.626,83.772,31.931,29.344,27.360,26.251,22.035,17.468ppm；HRMS(ES+)calcd for C11H18ClO2([M+H])+216.0917,found216.0889。经HPLC检测纯度为99.0％。
实施例15
投料物质和摩尔比改为(S)-(-)-1-苄基-3-吡咯烷醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为(S)-(-)-1-苄基-3-吡咯烷醇质量的15倍。其它条件和制备步骤均同实施例1，进行减压蒸馏得氯甲酸-(S)-(-)-1-苄基-3-吡咯烷醇酯，产率97.5％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ7.359-7.210(m,5H),4.965-4.826(m,1H),3.681(s,2H),2.922-2.254(m,4H),2.057-1.712-1.564(m,2H)ppm；13C-NMR(100MHz,CDCl3):δ152.849,140.683,130.811,129.435,129.280,74.173,67.828,66.492,55.373,36.021ppm；HRMS(ES+)calcd for C12H15ClNO2([M+H])+240.0791,found 240.0699。经HPLC检测纯度为99.0％。
实施例16
投料物质和摩尔比改为N-苄基-4-哌啶醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为N-苄基-4-哌啶醇质量的15倍。其它条件和制备步骤均同实施例1，进行减压蒸馏得氯甲酸-N-苄基-4-哌啶醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ7.384-7.229(m,5H),5.425-5.226(m,1H),3.821(s,2H),2.650-2.518(m,4H),1.966-1.728(m,4H)ppm；13C-NMR(100MHz,CDCl3):δ151.984,139.836,130.112,129.874,128.250,71.052,66.730,51.782,29.442ppm；HRMS(ES+)calcd for C13H17ClNO2([M+H])+254.0948,found 254.0920。经HPLC检测纯度为99.0％。
实施例17
投料物质和摩尔比改为2-金刚烷醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为2-金刚烷醇质量的20倍。其它条件和制备步骤均同实施例1，进行减压蒸馏得氯甲酸-2-金刚烷醇酯，产率98.2％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ4.985(t,J＝7.8Hz,1H),2.652-2.407(m,2H),1.938-1.7521(m,12H)ppm；13C-NMR(100MHz,CDCl3):δ152.548,74.019,38.012,37.899,35.551,28.178ppm；HRMS(ES+)calcd for C11H16ClO2([M+H])+215.0839,found 215.0817。经HPLC检测纯度为99.0％。
实施例18
投料物质和摩尔比改为β-托品醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为β-托品醇质量的20倍。其它条件和制备步骤均同实施例1，进行减压蒸馏得氯甲酸-β-托品醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ5.342-5.208(m,1H),2.365(s,3H),1.938-1.415(m,10H)ppm；13C-NMR(100MHz,CDCl3):δ151.845,68.820,66.742,40.265,35.891,27.124ppm；HRMS(ES+)calcd for C9H15ClNO2([M+H])+204.0791,found 204.0779。经HPLC检测纯度为99.0％。
实施例19
投料物质和摩尔比改为麦角固醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为麦角固醇质量的15倍。第一阶段反应温度为0℃，保温5h,第二阶段反应温度10℃，搅拌约13h，其它条件和制备步骤均同实施例1，进行减压蒸馏得氯甲酸麦角固醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ5.682(s,2H),5.485(d,J＝9.8Hz,2H),4.718-4.580(m,1H),2.469-1.018(m,26H),0.886(t,J＝7.8Hz,12H)ppm；13C-NMR(100MHz,CDCl3):δ152.126,141.168,139.820,134.166,131.089,119.972,116.402,71.365,56.808,55.240,50.213,46.351,43.609,39.624,38.105,37.027,36.358,33.791,30.804,27.720,27.518,23.910,21.355,21.150,16.848,16.336,15.523,14.307ppm；HRMS(ES+)calcd for C29H44ClO2([M+H])+459.3030,found 459.3002。经HPLC检测纯度为99.0％。
实施例20
在装有机械搅拌器、温度计、恒压滴液漏斗和尾气吸收装置的夹套反应釜中，加入5L二氯甲烷，控温-5℃，分批加入540g(5mol)苯甲醇和890g(3mol)三光气，搅拌使其充分溶解。-5℃下滴加910g(9mol)三乙胺的二氯甲烷(1.2L)溶液，约1～2h滴完。保温反应3h后自然升温至10℃，搅拌约10h。反应结束后，反应混合物经负压过滤分离出沉淀，母液也在减压条件下依次用2.5L水、2.5L稀盐酸(5％)、0.4L碳酸钠(5％)和0.4L饱和食盐水洗涤，无水硫酸钠干燥后，旋蒸脱除溶剂，进行减压蒸馏，收集102～103℃/20mmHg的馏分，得到837g无色液体，产率98.1％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ7.415-7.260(s,5H),5.312(s,2H)ppm；13C-NMR(100MHz,CDCl3):δ150.185,136.325,127.468,127.401,126.337,64.361ppm；HRMS(ES+)calcd for C8H8ClO2([M+H])+171.0213,found 171.0207。经HPLC检测纯度为99.5％。
实施例21
投料摩尔比改为苯甲醇:三光气:三乙胺为1:0.4:1.2。溶剂为二氯甲烷，用量为苯甲醇质量的25倍。其它条件和制备步骤均同实施例20，得氯甲酸苄酯，产率94.5％，经HPLC检测纯度为99.5％。
实施例22
投料摩尔比改为苯甲醇:三光气:三乙胺为1:0.8:2.4。溶剂为二氯甲烷，用量为苯甲醇质量的25倍。其它条件和制备步骤均同实施例20，得氯甲酸苄酯，产率98.5％，经HPLC检测纯度为99.5％。
实施例23
投料物质和摩尔比改为苯甲醇:三光气:吡啶为1:0.6:1.8。溶剂为二氯甲烷，用量为苯甲醇质量的20倍。其它条件和制备步骤均同实施例20，得氯甲酸苄酯，产率99％，经HPLC检测纯度为99.5％。
实施例24
投料物质和摩尔比改为苯甲醇:三光气:N,N-二甲基苯胺为1:0.6:1.8。溶剂为二氯甲烷，用量为苯甲醇质量的18倍。第一阶段反应温度为-10℃，保温3h,第二阶段反应温度25℃，搅拌约10h,其它条件和制备步骤均同实施例20，得氯甲酸苄酯，产率93.5％，经HPLC检测纯度为99.5％。
实施例25
投料摩尔比为苯甲醇:三光气:三乙胺为1:0.6:1.8。溶剂改为甲苯，用量为苯甲醇质量的12倍。其它条件和制备步骤均同实施例24，得氯甲酸苄酯，产率97.5％，经HPLC检测纯度为99.5％。
实施例26
投料摩尔比为苯甲醇:三光气:三乙胺为1:0.6:1.8。溶剂改为乙酸乙酯，用量为苯甲醇质量的10倍。其它条件和制备步骤均同实施例24，得氯甲酸苄酯，产率97％，经HPLC检测纯度为99.5％。
实施例27
投料物质和摩尔比改为4-氯-3-硝基苄醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为苯甲醇质量的15倍。其它条件和制备步骤均同实施例20，进行减压蒸馏得氯甲酸-4-氯-3-硝基苄酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ8.264(s,1H),7.815-7.713(m,1H),7.682-7.606(m,1H),5.238(s,2H)ppm；13C-NMR(100MHz,CDCl3):δ151.456,148.860,141.226,136.817,134.109,126.782,125.106,65.271ppm；HRMS(ES+)calcd for C8H6Cl2NO4([M+H])+249.9674,found 249.9598。经HPLC检测纯度为99.0％。
实施例28
投料物质和摩尔比改为五氟苄醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为五氟苄醇质量的25倍。其它条件和制备步骤均同实施例20，进行减压蒸馏得氯甲酸五氟苄酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ5.235(s,2H)ppm；13C-NMR(100MHz,CDCl3):δ151.826,146.214,142.713,136.693,113.989,51.825ppm；HRMS(ES+)calcd for C8H3ClF5O2([M+H])+260.9742,found 260.9788。经HPLC检测纯度为99.0％。
实施例29
投料物质和摩尔比改为(R)-(-)-1-茚醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为(R)-(-)-1-茚醇质量的15倍。第一阶段反应温度为-5℃，保温5h，第二阶段反应温度25℃，搅拌约7h，其它条件和制备步骤均同实施例20，进行减压蒸馏得氯甲酸-(R)-(-)-1-茚醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ7.275-7.022(m,4H),6.121(t,J＝8.6Hz,2H),3.315-3.052(m,2H),2.498-2.087(m,2H)ppm；13C-NMR(100MHz,CDCl3):δ151.566,144.421,142.237,129.263,126.551,126.110,76.839,31.589,30.525ppm；HRMS(ES+)calcd forC10H10ClO2([M+H])+197.0369,found 197.0377。经HPLC检测纯度为99.0％。
实施例30
投料物质和摩尔比改为糠醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为糠醇质量的10倍。其它条件和制备步骤均同实施例20，进行减压蒸馏得氯甲酸呋喃甲醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ7.595(t,J＝7.2Hz,1H),6.502-6.413(m,2H),5.212(s,2H)ppm；13C-NMR(100MHz,CDCl3):δ153.112,151.786,144.209,111.625,107.942,60.164ppm；HRMS(ES+)calcd for C6H6ClO3([M+H])+161.0005,found 160.9987。经HPLC检测纯度为99.0％。
实施例31
投料物质和摩尔比改为1-苯氧基-2-丙醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为1-苯氧基-2-丙醇质量的20倍。其它条件和制备步骤均同实施例20，进行减压蒸馏得氯甲酸-1-苯氧基-2-丙醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ7.275-7.228(m,2H),6.934-6.755(m,3H),5.282-5.248(m,1H),4.335-4.028(m,2H),1.318(d,J＝5.6Hz,3H)ppm；13C-NMR(100MHz,CDCl3):δ160.411,150.892,130.359,120.862,115.324,72.046,66.815,15.591ppm；HRMS(ES+)calcd for C10H12ClO3([M+H])+215.0475,found 215.0269。经HPLC检测纯度为99.0％。
实施例32
投料物质和摩尔比改为3-苯基-2-丙炔-1-醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为3-苯基-2-丙炔-1-醇质量的15倍。其它条件和制备步骤均同实施例29，进行减压蒸馏得氯甲酸-3-苯基-2-丙炔-1-醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ7.575-7.368(m,5H),4.934(s,2H)ppm；13C-NMR(100MHz,CDCl3):δ151.652,129.245,129.196,122.816,95.334,87.621,50.112ppm；HRMS(ES+)calcd for C10H8ClO2([M+H])+195.0213,found 195.0115。经HPLC检测纯度为99.0％。
实施例33
投料物质和摩尔比改为肉桂醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为肉桂醇质量的10倍。其它条件和制备步骤均同实施例17，进行减压蒸馏得氯甲酸肉桂醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ7.335-7.248(m,5H),6.742-6.651(m,1H),6.359-6.274(m,1H),4.974(d,J＝5.8Hz,2H)ppm；13C-NMR(100MHz,CDCl3):δ151.337,136.423,133.882,129.450,129.245,127.996,122.120,64.595ppm；HRMS(ES+)calcd for C10H10ClO2([M+H])+197.0369,found 197.0267。经HPLC检测纯度为99.0％。
实施例34
投料物质和摩尔比改为茴香醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为茴香醇质量的15倍。其它条件和制备步骤均同实施例20，进行减压蒸馏得氯甲酸茴香醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ6.957(dd,J1＝8.6Hz,J2＝4.8Hz,4H),5.236(s,2H),3.915(s,3H)ppm；13C-NMR(100MHz,CDCl3):δ151.523,129.398,128.415,114.512,65.328,56.142ppm；HRMS(ES+)calcd for C9H10ClO3([M+H])+201.0318,found 201.0196。经HPLC检测纯度为99.0％。
实施例35
投料物质和摩尔比改为(5-甲基异噁唑-3-基)甲醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为(5-甲基异噁唑-3-基)甲醇质量的25倍。其它条件和制备步骤均同实施例20，进行减压蒸馏得氯甲酸-(5-甲基异噁唑-3-基)甲醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ5.795(s,1H),5.631(s,2H),2.368(s,3H)ppm；13C-NMR(100MHz,CDCl3):δ170.694,150.338,150.122,102.472,58.3128,12.856ppm；HRMS(ES+)calcd for C6H7ClNO3([M+H])+176.0114,found 176.0086。经HPLC检测纯度为99.0％。
实施例36
投料物质和摩尔比改为9-芴醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为9-芴醇质量的15倍。其它条件和制备步骤均同实施例20，进行减压蒸馏得氯甲酸-9-芴醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ7.915-7.902(m,2H),7.592-7.579(m,2H),7.418-7.256(m,4H),7.092(s,1H)ppm；13C-NMR(100MHz,CDCl3):δ150.418,149.815,141.012,128.108,126.704,126.286,126.253,77.910ppm；HRMS(ES+)calcd for C14H10ClO2([M+H])+245.0369,found245.0339。经HPLC检测纯度为99.0％。
实施例37
投料物质和摩尔比改为3-吡啶-1-丙醇:三光气:三乙胺为1:0.6:1.8。溶剂为二氯甲烷，用量为3-吡啶-1-丙醇质量的15倍。其它条件和制备步骤均同实施例20，进行减压蒸馏得氯甲酸-3-吡啶-1-丙醇酯，产率98.0％。经核磁共振氢谱、碳谱和高分辨质谱确证，产物即为目标化合物结构。1H-NMR(400MHz,CDCl3):δ8.427-8.359(m,2H),7.681-7.592(m,1H),7.259-7.240(m,1H),4.217(t,J＝7.8Hz,2H),2.634(t,J＝7.8Hz,2H),2.102-1.918(m,2H)ppm；13C-NMR(100MHz,CDCl3):δ151.526,150.291,149.218,138.532,137.109,123.764,61.924,40.012,29.466ppm；HRMS(ES+)calcd for C9H11ClNO2([M+H])+200.0478,found 200.0266。经HPLC检测纯度为99.0％。
以上所述实施例在负压条件下的过滤和洗涤过程中，逸出的光气和氯化氢气体经碱和水三级吸收，将吸收的光气和氯化氢气体转化为无毒的盐类物质，该工艺解决了生产过程中的安全和环保问题；过滤分离得到的有机盐沉淀，经加碱中和后蒸馏处理得到的有机碱催化剂可进行循环利用，蒸馏后所剩的盐水母液经浓缩达到饱和后进行循环利用，该工艺显著降低了生产成本和三废排放。
本发明所述脂环族和芳脂族氯甲酸酯的制备方法，在设置的反应条件下，其产品收率≥97％，纯度≥98％。本发明与现有技术相比，从工艺源头上消除了生产安全隐患，显著降低了三废产生量，解决了安全和环保问题，且操作简便，反应收率高，产品质量优，生产成本低，具有明显的实施价值和经济效益。

Claims (10)

1.一种脂环族和芳脂族氯甲酸酯的制备方法，以脂环族醇或芳脂族醇和三光气为原料，在有机碱催化剂作用下，在有机溶剂中于设定的反应温度和反应时间下反应，其特征在于：
1)所述脂环族醇或芳脂族醇与三光气、有机碱催化剂的摩尔比为1:0.4～1:1.2～3；
2)所述反应温度和反应时间分为两个阶段，第一阶段的反应温度为-10～0℃，反应时间为2～5h，第二阶段的反应温度为0～25℃，反应时间为7～13h；
3)所述有机溶剂与脂环族醇或芳脂族醇的质量比为10～25:1。
2.根据权利要求1所述脂环族和芳脂族氯甲酸酯的制备方法，其特征在于：所述脂环族醇或芳脂族醇与三光气与有机碱催化剂的摩尔比为1:0.6～0.8:1.8～2.4。
3.根据权利要求1所述脂环族和芳脂族氯甲酸酯的制备方法，其特征在于：所述第一阶段的反应温度为-5℃，反应时间为3h；第二阶段的反应温度为10～20℃，反应时间为10h。
4.根据权利要求1所述脂环族和芳脂族氯甲酸酯的制备方法，其特征在于：所述有机溶剂与脂环族醇或芳脂族醇的质量比为15:1。
5.根据权利要求1所述脂环族和芳脂族氯甲酸酯的制备方法，其特征在于：所述脂环族醇为下列之一：L-薄荷醇、环己醇、4-叔丁基环己醇、4-环己基环己醇、环戊醇、L-香芹醇、(R)-(-)-3-奎宁醇、雪松醇、(S)-(-)-1-苄基-3-吡咯烷醇、N-苄基-4-哌啶醇、4-萜烯醇、2-金刚烷醇、2-甲基异茨醇、β-托品醇、麦角固醇。
6.根据权利要求1所述脂环族和芳脂族氯甲酸酯的制备方法，其特征在于：所述芳脂族醇为下列之一：苄醇、4-氯-3-硝基苄醇、2,4-二氯苄醇、五氟苄醇、(R)-(-)-1-茚醇、胡椒醇、糠醇、1-苯氧基-2-丙醇、3-苯基-2-丙炔-1-醇、肉桂醇、茴香醇、(5-甲基异噁唑-3-基)甲醇、9-芴醇、3-吡啶-1-丙醇。
7.根据权利要求1所述脂环族和芳脂族氯甲酸酯的制备方法，其特征在于：所述有机碱催化剂优选为下列之一或一种以上的任意组合：三甲胺、三乙胺、二异丙基乙基胺、吡啶、六氢吡啶、对二甲氨基吡啶、喹啉、N,N-二甲基甲酰胺、N,N-二甲基苯胺。
8.根据权利要求1所述脂环族和芳脂族氯甲酸酯的制备方法，其特征在于：所述有机溶剂为下列之一或一种以上的任意组合：二氯甲烷、三氯甲烷、1,2-二氯乙烷、苯、甲苯、二甲苯、环戊烷、正己烷、乙醚、异丙醚、丁醚、丙酮、环戊酮、乙酸乙酯、四氢呋喃、1,4-二氧六环。
9.根据权利要求1所述脂环族和芳脂族氯甲酸酯的制备方法，其特征在于：所述反应结束后，将反应混合物减压过滤分离出有机盐沉淀，过滤后母液依次用水、稀盐酸、碳酸钠溶液和饱和食盐水洗涤，洗涤后的母液经过干燥、旋蒸脱除溶剂、减压蒸馏得到目标化合物。
10.根据权利要求9所述脂环族和芳脂族氯甲酸酯的制备方法，其特征在于：所述过滤、洗涤、干燥过程均在负压下进行；所述负压下，过滤、洗涤过程中逸出的光气和氯化氢气体经碱和水三级吸收；所述过滤分离得到的有机盐沉淀加碱中和后蒸馏出有机碱，蒸馏后的残余溶液浓缩至饱和。
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