CN115504862A - 一种大麻萜酚的制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0215—Sulfur-containing compounds
- B01J31/0222—Sulfur-containing compounds comprising sulfonyl groups
- B01J31/0224—Sulfur-containing compounds comprising sulfonyl groups being perfluorinated, i.e. comprising at least one perfluorinated moiety as substructure in case of polyfunctional compounds
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
- B01J31/0274—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 containing silicon
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
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- B01J31/0275—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 also containing elements or functional groups covered by B01J31/0201 - B01J31/0269
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
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Abstract
本发明公开了一种大麻萜酚的制备方法，以橄榄醇和香叶醇为原料，以三氟甲磺酸酯为催化剂，在溶剂中进行催化反应后得到大麻萜酚。本发明提供的大麻萜酚的制备方法条件温和、易于操作，最终获得大麻萜酚的收率较现有方法有明显提高，具有良好的应用前景。
Description
技术领域
本发明属于医药技术领域，尤其是涉及一种大麻萜酚的制备方法。
背景技术
大麻萜酚(CBG)是一种无精神活性和非成瘾性的大麻素类化合物并且具有抗炎、抗氧化、神经保护、缓解疼痛及抗肿瘤等多种药理活性。
CBG可以从工业大麻中提取获得。但是由于一般的工业大麻品种中，CBG 的含量很低，造成提取存在较大难度。再者，由于工业大麻中多种大麻素类化合物的性质非常接近，因此提取的CBG中会难以避免地存在少量大麻二酚、四氢大麻酚等，这对高纯度CBG的质量控制提出了极高的要求。
CBG也可以通过化学合成的方法获得，使用橄榄醇和香叶醇两种原料，在路易斯酸或质子酸的催化下生成CBG，技术路线如下所示：
如Baek等(Tetrahedron Lett.1985，26,1083)报道，将三氟化硼-乙醚吸附在硅胶上做催化剂，可将香叶醇和橄榄醇两种原料转化为大麻萜酚，收率是 29％。
近年来，也有一些专利文献(如WO2014134281A1，WO2017181118A1，WO2017216362A1)中使用对甲苯磺酸进行催化，大麻萜酚的收率有所提高，但仍然只能达到40％左右，且产生较多难以分离的杂质。
由此可见，现有CBG获取技术仍存在收率不高、产物难以分离的缺点，急需开发新的技术解决上述难题。
发明内容
发明目的：本发明的目的就是为了解决现有CBG制备方法收率低、产物难以分离的问题，而提供一种大麻萜酚的制备方法。
本发明的技术方案：
一种大麻萜酚的制备方法，以橄榄醇和香叶醇为原料，以三氟甲磺酸酯为催化剂，在三氟甲磺酸酯的催化下进行反应，制备得到大麻萜酚。
具体为：将橄榄醇和香叶醇溶解在溶剂中，再加入三氟甲磺酸酯进行催化反应，反应液经洗涤、浓缩后，可得大麻萜酚。
所述橄榄醇即3,5-二羟基戊苯，所述香叶醇即3,7-二甲基-2,6-辛二烯-1-醇。
进一步地，加入三氟甲磺酸酯时温度控制在-30～0℃，优选控制在 -25～-10℃。
进一步地，所述催化反应的温度为-40～60℃，反应时间为0.1～72小时；优选地，所述催化反应的温度为-20～30℃，反应时间为1～15小时；进一步优选地，所述催化反应的温度为20～25℃，反应时间为10～15小时。
进一步地，所述橄榄醇与香叶醇的摩尔比为1：0.5～10，所述三氟甲磺酸酯与橄榄醇的摩尔比为0.001～2：1。
优选地，所述橄榄醇与香叶醇的摩尔比为1：1～2，所述三氟甲磺酸酯与橄榄醇摩尔比为0.1～0.2：1。
进一步地，所述溶剂选自二氯甲烷、二氯乙烷、四氢呋喃、2-甲基四氢呋喃、丙酮、苯、甲苯、乙苯、二甲苯、氯苯、硝基苯、乙腈、N,N-二甲基甲酰胺、二甲基亚砜或乙酸乙酯中的一种或多种。
进一步地，所述三氟甲磺酸酯具有如下结构特征：CF3SO3R，其中R为 C1～C20的烃基或者-SiR1R2R3，所述R1、R2、R3各自独立地表示C1～C10的烃基，，所述C1～C20的烃基中的一个或多个-CH2-可被-O-替代；优选地，所述R 为-CH3或-Si(CH3)3。
进一步优选地，所述三氟甲磺酸酯选自三氟甲磺酸甲酯、三氟甲磺酸乙酯、三氟甲磺酸三甲基硅醇酯或叔丁基二甲硅基三氟甲磺酸酯中的一种或多种。
进一步地，反应结束后，依次以饱和碳酸氢钠、盐酸和饱和食盐水洗涤反应液，有机层减压浓缩后柱层析，得到大麻萜酚产品。
有益效果：
与现有技术相比，本发明使用三氟甲磺酸酯为催化剂，生成大麻萜酚的收率最低在50％以上，例如以三氟甲磺酸甲酯为催化剂时，生成大麻萜酚的收率高达65％，大大提高了制备效率，且产物仅需要简单的分离即可获得，有效解决了现有CBG制备方法收率低、产物难以分离的问题，具有显著的技术进步。
具体实施方式
下面结合具体实施例对本发明进行详细说明，但绝不是对本发明的限制。以下实施例中所采用的相关试剂均可以从市场购得。
实施例1
将18g(0.1mol)橄榄醇和23g(0.15mol)香叶醇溶解于100mL无水二氯甲烷中，降温至-20℃并向其中加入1.64g(0.01mol)三氟甲磺酸甲酯。在 -20℃下搅拌2小时，然后使反应液自然升至室温并继续搅拌12小时。停止反应后，依次用饱和碳酸氢钠、1M盐酸和饱和食盐水洗涤反应液。有机层减压浓缩后进行柱层析，得到白色固体20.6g，收率为65％。Mp 50～52℃；1H NMR (400MHz,DMSO-d6):δ8.91(s,2H),6.09(s,2H),5.17(s,1H),5.04(s,1H),3.12 (d,J＝7.2Hz,2H),2.32(t,J＝8.8Hz,2H),1.98(m,2H),1.88(m,2H),1.69(s, 3H),1.60(s,3H),1.52(s,3H),1.47(m,2H),1.26(m,4H),0.85(t,J＝6.8Hz, 3H)。
实施例2
将18g(0.1mol)橄榄醇和23g(0.15mol)香叶醇溶解于100mL无水二氯甲烷中，降温至-20℃并向其中加入1.78g(0.01mol)三氟甲磺酸乙酯。在 -20℃下搅拌2小时，然后使反应液自然升至室温并继续搅拌12小时。停止反应后，依次用饱和碳酸氢钠、1M盐酸和饱和食盐水洗涤反应液。有机层减压浓缩后进行柱层析，得到白色固体18.36g，收率为58％。
实施例3
将18g(0.1mol)橄榄醇和27.77g(0.18mol)香叶醇溶解于100mL甲苯中，降温至-20℃并向其中加入4.44g(0.02mol)三氟甲磺酸三甲基硅醇酯。在-20℃下搅拌2小时，然后使反应液自然升至室温并继续搅拌20小时。停止反应后，依次用饱和碳酸氢钠、1M盐酸和饱和食盐水洗涤反应液。有机层减压浓缩后进行柱层析，得到白色固体17.41g，收率为55％。
实施例4
将18g(0.1mol)橄榄醇和27.77g(0.18mol)香叶醇溶解于100mL四氢呋喃中，降温至-20℃并向其中加入5.28g(0.02mol)叔丁基二甲硅基三氟甲磺酸酯。在-20℃下搅拌2小时，然后使反应液自然升至室温并继续搅拌12小时。停止反应后，依次以饱和碳酸氢钠、1M盐酸和饱和食盐水洗涤反应液。有机层减压浓缩后进行柱层析，得到白色固体16.46g，收率为52％。
由上述实施例可知，本发明使用三氟甲磺酸酯为催化剂，生成大麻萜酚的收率最低在52～65％以上，相比现有收率在29～40％左右，大麻萜酚的收率显著提高。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
1.一种大麻萜酚的制备方法，其特征在于，将橄榄醇和香叶醇溶解在溶剂中，再加入三氟甲磺酸酯进行催化反应，反应液经后处理后，可得大麻萜酚。
2.根据权利要求1所述的大麻萜酚的制备方法，其特征在于，加入三氟甲磺酸酯时温度控制在-30~0℃，优选控制在-25~-10℃。
3.根据权利要求1所述的大麻萜酚的制备方法，其特征在于，所述催化反应的温度为-40~60℃，所述催化反应时间为0.1~72小时；优选地，所述催化反应的温度为-20~30℃，所述反应时间为1~15小时；进一步优选地，所述催化反应的温度为20~25℃，反应时间为10~15小时。
4.根据权利要求1所述的大麻萜酚的制备方法，其特征在于，所述橄榄醇与香叶醇的摩尔比为1：0.5~10，所述三氟甲磺酸酯与橄榄醇的摩尔比为0.001~2：1。
5.根据权利要求4所述的大麻萜酚的制备方法，其特征在于，所述橄榄醇与香叶醇的摩尔比为1：1~2，所述三氟甲磺酸酯与橄榄醇的摩尔比为0.1~0.2：1。
6.根据权利要求1所述的大麻萜酚的制备方法，其特征在于，所述溶剂选自二氯甲烷、二氯乙烷、四氢呋喃、2-甲基四氢呋喃、丙酮、苯、甲苯、乙苯、二甲苯、氯苯、硝基苯、乙腈、N,N-二甲基甲酰胺、二甲基亚砜或乙酸乙酯中的一种或多种。
7.根据权利要求1所述的大麻萜酚的制备方法，其特征在于，所述三氟甲磺酸酯具有如下结构特征：CF3SO3R，其中R为C1~C20的烃基或者-SiR1R2R3，所述R1、R2和R3各自独立地表示C1~C10的烃基，所述C1~C20的烃基中的一个或多个-CH2-可被-O-替代。
8.根据权利要求7所述的大麻萜酚的制备方法，其特征在于，所述R为-CH3或-Si(CH3)3。
9.根据权利要求7所述的大麻萜酚的制备方法，其特征在于，所述三氟甲磺酸酯选自三氟甲磺酸甲酯、三氟甲磺酸乙酯、三氟甲磺酸三甲基硅醇酯或叔丁基二甲硅基三氟甲磺酸酯中的一种或多种。
10.根据权利要求1所述的大麻萜酚的制备方法，其特征在于，反应结束后，依次以饱和碳酸氢钠、盐酸和饱和食盐水洗涤反应液，有机层减压浓缩后柱层析，得到大麻萜酚产品。
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