CN103664976A - 一种顺式六氢呋喃并[2,3-b]呋喃-3-醇的制备方法 - Google Patents
一种顺式六氢呋喃并[2,3-b]呋喃-3-醇的制备方法 Download PDFInfo
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Abstract
本发明涉及一种新型的手性非金属催化剂催化合成顺式六氢呋喃并[2,3-B]呋喃-3-醇的方法，该方法以2,3-二氢呋喃及羟基乙醛二聚体为原料，在手性非金属催化剂恶唑硼烷正离子的催化下，得到顺式六氢呋喃并[2,3-B]呋喃-3-醇；该呋喃醇经过酶催化下的选择性乙酰化，可以进一步分离得到(3R,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇。本发明方法与已有方法相比，更为便捷、绿色、经济。
Description
技术领域
本发明属于有机化学合成领域，具体涉及一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法。
发明背景
对HIV蛋白酶进行抑制，已经成为了AIDS的一种治疗手段。2006年，FDA批准第二代蛋白酶抑制剂Darunavir用于治疗现有抗逆转录病毒药物疗效不佳的HIV感染成年患者，而(3R,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇作为Darunavir的重要的药理组成部分，随后也被运用到多种HIV蛋白酶抑制剂的研究中，例如Brecanavir、UIC-94003、GS-8374。
关于(3R,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇的合成方法Ghosh’ group已做了不少报导，其中三条路线如Scheme 1、Scheme 2、Scheme 3所示。该路线步骤较多，且条件控制上比较苛刻，个别路线还使用到自由基反应，臭氧氧化等，不利于放大规模的生产。
另外，Richard H 等从起始物料上做出了改进，使用2,3-二氢呋喃和羟基乙醛二聚体为原料，在手性镧系及过渡金属催化剂的作用下，一步得到六氢呋喃并[2,3-B]呋喃-3-醇，而后经过酶拆分，得到(3R,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇（见Scheme 4）。相似的路线，Will L. Canoy 等人也进行了报导。该路线直接简便，但使用了昂贵且有毒的金属催化剂，仍有较大的改进空间。
David M. Black 等人运用相似的金属催化剂，报导了另一条路线（见Scheme 5）。该路线以硅醚化的环戊酯和苄基保护的羟基乙醛进行Mukaiyama反应，经过低温DIBAL-H还原及Pd/C加氢脱保护得到(3S,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇，再氧化还原改变羟基的绝对构型，得到(3R,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇。该路线在不使用手性原料的前提下，不需要拆分就得到了手性目标产物，因而是值得肯定的路线。但是，该路线同样使用了有毒的金属催化剂，大大限制了它的实用性。
因而，开发一条更为便捷、绿色、低毒的合成路线来制备(3R,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇仍是必要的。
发明内容
为解决现有合成(3R,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇中存在的步骤过多，操作条件苛刻、使用有毒金属催化剂等一系列问题，本发明提供一种顺式六氢呋喃并[2,3-B]呋喃-3-醇得合成方法，然后经过酶拆分得到(3R,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇。
本发明所要解决的技术问题通过以下技术方案予以实现：
一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，包括以下步骤：
在氮气保护下，在含有手性恶唑硼烷正离子（7）的有机溶剂中分别加入羟基乙醛二聚体（3）和2,3-二氢呋喃（2）进行反应，反应后滴入淬灭剂后得到所述顺式六氢呋喃并[2,3-B]呋喃-3-醇；其中手性恶唑硼烷正离子（7）中的R、Ar1、Ar2为苯基、各种烷基取代的苯基。
进一步的，所述羟基乙醛二聚体（3）和手性恶唑硼烷正离子（7）的摩尔比为1:0.05~1。
进一步的，所述羟基乙醛二聚体（3）和2,3-二氢呋喃（2）的摩尔比为2~20:1。
进一步的，所述反应温度为-78℃~-10℃；反应时间为15h~48h。
进一步的，所述淬灭剂为有机弱碱溶剂、无机弱碱水溶液中的至少一种。
进一步的，所述有机溶剂为二氯甲烷、烃类溶剂中的至少一种。
进一步的，所述手性恶唑硼烷正离子（7）通过如下步骤获得：
将S-(-)-α,α-二芳基脯氨醇（5）、取代硼氧六环（8）加入至含有有机溶剂的容器中，在氮气保护下加热回流反应，反应后在氮气保护下降温，向容器滴加三氟甲磺酸后得到所述手性恶唑硼烷正离子（7），其中R、Ar1、Ar2如上所述。
进一步的，所述S-(-)-α,α-二芳基脯氨醇（5）和取代硼氧六环（8）的摩尔比为2.8~3.5:1。
进一步的，所述有机溶剂为甲苯、二氯甲烷、烃类溶剂中的至少一种。
进一步的，所述加热回流温度为135~150℃，回流时间为2.5~4h；降温为将温度降至-20~-60℃。
本发明具有如下有益效果：
（1）本发明反应步骤少，过程中不含有毒金属催化剂，采用一锅法合成手性催化剂及顺式六氢呋喃并[2,3-B]呋喃-3-醇。
（2）本发明是合成顺式六氢呋喃并[2,3-B]呋喃-3-醇的更方便和更安全有效的方法，其成本降低，更适合商业生产顺式六氢呋喃并[2,3-B]呋喃-3-醇。
具体实施方式
下面对本发明优选实施例作详细说明。本发明旨在与保护整条合成路线，以下合成实例仅为证明该合成路线可行。但发明保护内容不限于实例。
实例1：7c的制备及(±)-1的制备
将S-(-)-α,α-二（3,5-二甲基苯基）脯氨醇（9.28g，30mmol），三苯基硼氧六环(3.12g, 10mmol)加入到干燥的500mL三口瓶中。其中一瓶口安装一恒压滴液漏斗（125 mL），内置棉花塞，90g 4A分子筛，顶部装上冷凝器。加入140mL甲苯，抽真空，通氮气，反复三次。体系在氮气保护下加热到剧烈回流（外温约为145℃）。保温回流3h后，降温到60℃，快速将冷凝干燥装置换成减压蒸馏装置，接着减压蒸馏除去大部分甲苯，约剩余25mL，降到室温将溶剂抽干（约3h)，得到粘稠油状物。加入46mL二氯甲烷，氮气保护下降温到-40℃。向体系缓缓滴加三氟甲磺酸（3.83g，25.5mmol）溶液（9.5mL二氯甲烷中），滴加时间为30min。滴加完毕，于该温度继续搅拌40min，得到7c的二氯甲烷溶液。
在氮气保护下，向上述含手性催化剂7c的二氯甲烷溶液中（-40℃）滴加羟基乙醛二聚体3（18.02g，150mmol）的二氯甲烷（90mL）溶液，滴加时保温-40±10℃。滴加完毕，搅拌5min后，继续滴加2,3-二氢呋喃2（21.27g, 303mmol）的二氯甲烷（67mL）溶液。滴加完毕，升温到-20℃，于该温度继续搅拌反应20h。TLC检测反应完毕，滴加三乙胺（2.58g，25.5mmol）；滴加完毕，升到室温。加入127.6mL水，剧烈搅拌10min后，分离出水层，用二氯甲烷洗涤（30mLx 3），浓缩水层，得到 (±)-1的油状粗品，经硅胶柱层析（乙酸乙酯：正己烷=2:3）得到(±)-1的浅黄色油状物（29.28g，74.1% ）。1HNMR(400M, CDCl3), δ(ppm): 1.88(m, 1H), 2.03(d,J=6Hz,1H), 2.31(m,1H), 2.86(m,1H), 3.65(dd,J=7.1,9.2Hz,1H), 3.88(m,1H), 3.99(m,2H), 4.46(m,1H), 5.70(d,J=5.2Hz,1H)；
实例2：酶拆分---(-)-1的分离
将实例1得到的(±)-1油状物溶解于混合溶剂中（甲基叔丁基醚：二氯甲烷=180mL：30mL），然后加入乙酸酐（17.40g，170mmol）。搅拌15分钟后，加入固化后的Lipase PS-C I 4.2g，于室温剧烈搅拌4h。过滤除去Lipase PS-C I，滤液浓缩除去溶剂级过量的乙酸酐。向浓缩物加入150mL水，溶解后以二氯甲烷洗涤（50mLx3），合并的有机层以水反萃（30mLx3）；合并水层，浓缩至干，加入90mL二氯甲烷溶解后，无水硫酸钠干燥；浓缩有机层得到淡黄色油状物，(3R,3AS,6AR)-六氢呋喃并[2,3-B]呋喃-3-醇 (-)-1（11.20g，97%ee，），收率38.25%。
表1为不同手性恶唑硼烷催化剂作用下的双呋喃醇的顺反式分配情况。
表1 不同催化剂下的双呋喃醇的顺反式分配情况
本技术领域中的普通技术人员应当认识到，以上实施例仅是用来说明本发明，而并非作为对本发明的限定，只要在本发明的范围内，对以上实施例的变化、变形都将落在本发明的保护范围。
Claims (10)
1.一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，其特征在于包括以下步骤：
在氮气保护下，在含有手性恶唑硼烷正离子（7）的有机溶剂中分别加入羟基乙醛二聚体（3）和2,3-二氢呋喃（2）进行反应，反应后滴入淬灭剂后得到所述顺式六氢呋喃并[2,3-B]呋喃-3-醇；其中手性恶唑硼烷正离子（7）中的R、Ar1、Ar2为苯基、各种烷基取代的苯基。
2.根据权利要求1所述的一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，其特征在于：所述羟基乙醛二聚体（3）和手性恶唑硼烷正离子（7）的摩尔比为1:0.05~1。
3.根据权利要求1所述的一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，其特征在于：所述羟基乙醛二聚体（3）和2,3-二氢呋喃（2）的摩尔比为2~20:1。
4.根据权利要求1所述的一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，其特征在于：所述反应温度为-78℃~-10℃；反应时间为15h~48h。
5.根据权利要求1所述的一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，其特征在于：所述淬灭剂为有机弱碱溶剂、无机弱碱水溶液中的至少一种。
6.根据权利要求1所述的一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，其特征在于：所述有机溶剂为二氯甲烷、烃类溶剂中的至少一种。
7.根据权利要求1所述的一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，其特征在于：所述手性恶唑硼烷正离子（7）通过如下步骤获得：
将S-(-)-α,α-二芳基脯氨醇（5）、取代硼氧六环（8）加入至含有有机溶剂的容器中，在氮气保护下加热回流反应，反应后在氮气保护下降温，向容器滴加三氟甲磺酸后得到所述手性恶唑硼烷正离子（7），其中R、Ar1、Ar2如权利要求1所述。
8.根据权力要7所述的一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，其特征在于：所述S-(-)-α,α-二芳基脯氨醇（5）和取代硼氧六环（8）的摩尔比为2.8~3.5:1。
9.根据权力要7所述的一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，其特征在于：所述有机溶剂为甲苯、二氯甲烷、烃类溶剂中的至少一种。
10.根据权力要7所述的一种顺式六氢呋喃并[2,3-B]呋喃-3-醇的制备方法，其特征在于：所述加热回流温度为135~150℃，回流时间为2.5~4h；降温为将温度降至-20~-60℃。
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