CN114853711A - 一种铜催化一锅法制备大麻酚的方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/584—Recycling of catalysts
Abstract
本发明提供了以铜作为催化剂合成CBN的新方法,以大麻二酚为原料,在溶剂中,铜催化剂和氧化剂作用下反应,即可制得大麻酚;本发明是一锅法反应,简单高效、成本低廉,具有商业化大规模生产大麻酚的潜力。
Description
技术领域
本发明属于化学合成领域,具体涉及一种铜催化一锅法制备大麻酚的方法。
背景技术
众所周知,医用大麻对人类有诸多医疗益处,其根本原因是人类体内存在着调节各个生理系统的总指挥——内源性大麻素系统(Nature 1993,365,61–65;J.Med.Chem.2005,48,7166–7171)。Anu Mahadevan和Atmaram D.等人研究发现,大麻酚(CBN)及其衍生物可以选择性地与人体受体作用,具有高效的抗菌、镇静等作用(J.Med.Chem.2000,43,3778-3785)。除大麻酚外,大麻二酚(CBD)也展现出诸多药理活性,对癫痫、抑郁症等疾病的疗效也有相关报道(徐雯,张敬军.大麻二酚治疗癫痫的研究进展[J].山东第一医科大学(山东省医学科学院)学报,2022,43(01):74-77;黄淑芸,等.大麻二酚在抑郁症中的作用[J].生命的化学,2021,41(10):2191-2195.)。然而,尽管大麻二酚(CBD)不存在致幻作用,但在后续转化中存在生成四氢大麻酚(THC)的可能,而THC是大麻中的主要精神活性物质,被列入第一类精神药品品种目录管制。
因此,若能对大麻二酚(CBD)进行进一步转化,以规避使用过程中产生四氢大麻酚(THC)的可能,同时合成更高附加值的,具备不同于CBD医药用途的大麻酚(CBN),将有利于进一步拓宽CBD和CBN的价值。
目前,由于大麻酚(CBN)具有重要的潜在医用价值,关于全合成或半合成CBN的有机合成策略相继被报道,主要涉及以下几种策略:1.分子间芳香亲核取代构建苯并吡喃酮基本骨架并进行后续甲基化(Bull.Chem.Soc.Jpn.1993,66,3034-3040;Adv.Synth.Catal.2014,356,1337–1342);2.分子内环化反应构筑苯并吡喃酮基本骨架并进行后续甲基化(Org.Lett.2013,15,2574-2577);3.大麻酚酸脱羧基(Planta Med.2007,73,273-275);4.由[2+2+2]环加成反应构筑(Org.Lett.2008,10,2195-2198);5.通过大麻二酚(CBD)的衍生化反应(J.Nat.Prod,2018,81,630-633;Free Radical Bio.Med.2021,164,258-270、专利申请WO2020031179(A1))。
然而,目前CBN的合成方法中,全合成步骤繁琐;而由大麻二酚(CBD)合成大麻酚(CBN)的策略通常需要添加计量(大过量)的碘单质来促进反应。因此,目前已知的大麻酚(CBN)的合成方法由于流程复杂、成本高等原因尚未见商业化生产,因此,亟需开发一种简单高效、成本低廉,具有商业化大规模生产潜力的制备高纯度大麻酚(CBN)的方法,以满足市场对于CBN的需求。
发明内容
本发明的目的在于提供一种简单高效、成本低廉,具有商业化大规模生产潜力的制备高纯度大麻酚(CBN)的方法。
本发明提供了一种大麻酚的制备方法,包括如下步骤:
以式I所示大麻二酚为原料,在反应试剂:铜催化剂、氧化剂作用下,于溶剂中反应,得到式II所示大麻酚;
反应式如下:
进一步地,上述铜催化剂为CuCl2、CuBr2、Cu(OAc)2、CuCl、CuBr、CuI中的任意一种或多种;
和/或,所述氧化剂为氧气、碘苯二乙酸、双氧水、二氯二氰基苯醌中的一种或多种;
和/或,所述的溶剂为甲苯、二甲苯、乙腈、N,N-二甲基甲酰胺、四氢呋喃、二甲基亚砜中的任意一种或多种。
更进一步地,上述铜催化剂为CuBr2、Cu(OAc)2、CuCl或CuBr。
进一步地,上述大麻二酚、铜催化剂和氧化剂的摩尔比为1:(0.01~0.2):(0.5~5.0),优选为1:(0.05~0.2):(3.0~5.0)。
更进一步地,上述反应试剂还包括催化剂配体,优选地,所述催化剂配体为对甲苯磺酸。
更进一步地,上述大麻二酚和催化剂配体的摩尔比为1:(0.5~2.5),优选为1:(0.8~2.0)。
进一步地,上述反应温度为0~120℃。
更进一步地,上述反应温度为40~120℃。
进一步地,上述反应时间为2~48h。
更进一步地,上述反应时间为6~48h。
本发明具有以下有益效果:
(1)本发明首次报道以铜作为催化剂合成CBN的新策略,成本低廉。
(2)本发明产物收率高(高于80%)。
(3)本发明的方法可一锅法制备CBN,操作简便,反应条件温和,产物分离提纯方便,具有良好的应用前景和可期的经济效益。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
实施例1、本发明方法制备CBN
将CBD(1.0mmol)、对甲苯磺酸(0.5mmol)、Cu(OAc)2(0.05mmol)、二氯二氰基苯醌(3.0mmol)加入单口烧瓶中溶于甲苯(5mL),升温至100℃反应24小时,TLC检测,加饱和氯化铵淬灭,萃取、干燥、旋蒸,柱层析分离纯化,得到CBN,收率86%。
实施例2、本发明方法制备CBN
将CBD(1.0mmol)、Cu(OAc)2(0.1mmol)、碘苯二乙酸(4.0mmol)加入单口烧瓶中溶于二甲苯(5mL),升温至120℃反应24小时,TLC检测原料反应完全,加饱和氯化铵淬灭,萃取、干燥、旋蒸、柱层析分离纯化,得到CBN,收率84%。
实施例3、本发明方法制备CBN
将CBD(1.0mmol)、CuBr2(0.1mmol)、双氧水(3.0mmol)加入单口烧瓶中溶于乙腈(5mL),升温至80℃反应48小时,加饱和氯化铵淬灭,萃取、干燥、旋蒸、柱层析分离纯化,得到CBN,收率72%。
实施例4、本发明方法制备CBN
将CBD(1.0mmol)、Cu(OAc)2(0.2mmol)、二氯二氰基苯醌(5.0mmol)加入单口烧瓶中溶于THF(5mL),升温至100℃反应24小时,TLC检测原料反应完全,加饱和氯化铵淬灭,萃取、干燥、旋蒸、柱层析分离纯化,得到CBN,收率83%。
实施例5、本发明方法制备CBN
将CBD(1.0mmol)、对甲苯磺酸(0.8mmol)、CuCl2(0.2mmol)、溶于甲苯(5mL)加入三口烧瓶(25mL)中,利用三通玻璃阀使反应瓶中充满常压氧气(根据烧瓶容积,氧气为CBD的4~5倍当量),升温至40℃反应48小时,TLC检测原料反应完全,加饱和氯化铵淬灭,萃取、干燥、旋蒸、柱层析分离纯化,得到CBN,收率75%。
实施例6、本发明方法制备CBN
将CBD(1.0mmol)、CuCl(0.2mmol)、二氯二氰基苯醌(4.0mmol)加入单口烧瓶中溶于DMSO(3mL),升温至100℃反应36小时,TLC检测原料反应完全,加饱和氯化铵淬灭,萃取、干燥、旋蒸、柱层析分离纯化,得到CBN,收率85%。
实施例7、本发明方法制备CBN
将CBD(1.0mmol)、对甲苯磺酸(2mmol)、CuI(0.2mmol)、溶于DMF(3mL)加入三口烧瓶(25mL)中,利用三通玻璃阀使反应瓶中充满常压氧气(根据烧瓶容积,氧气为CBD的4~5倍当量),升温至60℃反应24小时,TLC检测原料反应完全,加饱和氯化铵淬灭,萃取、干燥、旋蒸、柱层析分离纯化,得到CBN,收率84%。
实施例8、本发明方法制备CBN
将CBD(1.0mmol)、CuBr(0.2mmol)、溶于THF(5mL)加入三口烧瓶(25mL)中,利用三通玻璃阀使反应瓶中充满常压氧气(根据烧瓶容积,氧气为CBD的4~5倍当量),升温至90℃反应6小时,加饱和氯化铵淬灭,萃取、干燥、旋蒸、柱层析分离纯化,得到CBN,收率88%。
实施例9、本发明方法制备CBN
将CBD(1.0mmol)、CuCl(0.2mmol)、二氯二氰基苯醌(4.0mmol)加入单口烧瓶中溶于二甲苯(5mL),升温至100℃反应36小时,TLC检测原料反应完全,加饱和氯化铵淬灭,萃取、干燥、旋蒸、柱层析分离纯化,得到CBN,收率81%。
实施例10、本发明方法制备CBN
将CBD(1.0mmol)、对甲苯磺酸(2.0mmol)、Cu(OAc)2(0.2mmol)、二氯二氰基苯醌(5.0mmol)加入单口烧瓶中溶于乙腈(5mL),升温至70℃反应12小时,TLC检测原料反应完全,加饱和氯化铵淬灭,萃取、干燥、旋蒸、柱层析分离纯化,得到CBN,收率78%。
产物CBN:1H NMR(400MHz,CDCl3)δ(ppm)8.16(dd,J=1.1,0.5Hz,1H),7.14(d,J=7.9Hz,1H),7.06(ddd,J=7.9,1.7,0.6Hz,1H),6.43(d,J=1.6Hz,1H),6.27(d,J=1.6Hz,1H),5.31(s,1H),2.48(t,J=7.9Hz,2H),2.38(s,3H),1.64–1.55(m,8H),1.36–1.27(m,4H),0.88(t,J=6.9Hz,3H).
综上,本发明首次报道以铜作为催化剂合成CBN的新策略,以大麻二酚为原料,通过一锅法反应即可制备得到大麻酚,简单高效、成本低廉,具有商业化大规模生产潜力。
Claims (10)
2.如权利要求1所述的制备方法,其特征在于,所述铜催化剂为CuCl2、CuBr2、Cu(OAc)2、CuCl、CuBr、CuI中的任意一种或多种;
和/或,所述氧化剂为氧气、碘苯二乙酸、双氧水、二氯二氰基苯醌中的一种或多种;
和/或,所述的溶剂为甲苯、二甲苯、乙腈、N,N-二甲基甲酰胺、四氢呋喃、二甲基亚砜中的任意一种或多种。
3.如权利要求2所述的制备方法,其特征在于,所述铜催化剂为CuBr2、Cu(OAc)2、CuCl或CuBr。
4.如权利要求1所述的制备方法,其特征在于,所述大麻二酚、铜催化剂和氧化剂的摩尔比为1:(0.01~0.2):(0.5~5.0),优选为1:(0.05~0.2):(3.0~5.0)。
5.如权利要求1~4任一项所述的制备方法,其特征在于,所述反应试剂还包括催化剂配体,优选地,所述催化剂配体为对甲苯磺酸。
6.如权利要求5所述的制备方法,其特征在于,所述大麻二酚和催化剂配体的摩尔比为1:(0.5~2.5),优选为1:(0.8~2.0)。
7.如权利要求1所述的制备方法,其特征在于,所述反应温度为0~120℃。
8.如权利要求7所述的制备方法,其特征在于,所述反应温度为40~120℃。
9.如权利要求1所述的制备方法,其特征在于,所述反应时间为2~48h。
10.如权利要求9所述的制备方法,其特征在于,所述反应时间为6~48h。
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