CN115181082B - 一种天然分子Moracin M的合成方法 - Google Patents
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- LHPRYOJTASOZGJ-UHFFFAOYSA-N Moracin M Chemical compound O1C2=CC(O)=CC=C2C=C1C1=CC(O)=CC(O)=C1 LHPRYOJTASOZGJ-UHFFFAOYSA-N 0.000 title claims abstract description 44
- RTDFYRPWAYCBQQ-AZRHEHLBSA-N moracin M Natural products OC[C@H]1O[C@@H](Oc2ccc3C[C@H](Oc3c2)c4cc(O)cc(O)c4)[C@H](O)[C@@H](O)[C@@H]1O RTDFYRPWAYCBQQ-AZRHEHLBSA-N 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- -1 (2-methoxyethoxy) methoxy Chemical group 0.000 claims abstract description 47
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims abstract description 28
- AITKMKMBEMYOFF-UHFFFAOYSA-N COCCOCOC(C=C1)=CC(OCOCCOC)=C1Br Chemical compound COCCOCOC(C=C1)=CC(OCOCCOC)=C1Br AITKMKMBEMYOFF-UHFFFAOYSA-N 0.000 claims abstract description 14
- WQXWIKCZNIGMAP-UHFFFAOYSA-N 3',5'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC(O)=CC(O)=C1 WQXWIKCZNIGMAP-UHFFFAOYSA-N 0.000 claims abstract description 11
- MPCCNXGZCOXPMG-UHFFFAOYSA-N 4-bromobenzene-1,3-diol Chemical compound OC1=CC=C(Br)C(O)=C1 MPCCNXGZCOXPMG-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000012074 organic phase Substances 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- BIAAQBNMRITRDV-UHFFFAOYSA-N 1-(chloromethoxy)-2-methoxyethane Chemical compound COCCOCCl BIAAQBNMRITRDV-UHFFFAOYSA-N 0.000 claims description 14
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
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- UKNZIQFPZSCIPW-UHFFFAOYSA-N dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane methanesulfonic acid Chemical group CS(O)(=O)=O.CC(C)c1cc(C(C)C)c(c(c1)C(C)C)-c1ccccc1P(C1CCCCC1)C1CCCCC1 UKNZIQFPZSCIPW-UHFFFAOYSA-N 0.000 claims description 7
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
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- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- DYIKUAMKHXANMT-UHFFFAOYSA-N 2-(2-bromo-4-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1Br DYIKUAMKHXANMT-UHFFFAOYSA-N 0.000 description 2
- PBFDZGFZHSRZNX-UHFFFAOYSA-N 2-(3,5-dimethoxyphenyl)-1-benzofuran-6-ol Chemical compound COC1=CC(OC)=CC(C=2OC3=CC(O)=CC=C3C=2)=C1 PBFDZGFZHSRZNX-UHFFFAOYSA-N 0.000 description 2
- VFZRZRDOXPRTSC-UHFFFAOYSA-N 3,5-Dimethoxybenzaldehyde Chemical compound COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
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- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HTVPLYLPPDPIGE-UHFFFAOYSA-N 2-(2-bromo-4-hydroxyphenyl)-3-(3,5-dimethoxyphenyl)prop-2-enoic acid Chemical compound BrC1=C(C=CC(=C1)O)C(C(=O)O)=CC1=CC(=CC(=C1)OC)OC HTVPLYLPPDPIGE-UHFFFAOYSA-N 0.000 description 1
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 1
- 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
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- 229910052802 copper Inorganic materials 0.000 description 1
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- YCIMNLLNPGFGHC-UHFFFAOYSA-N o-dihydroxy-benzene Natural products OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于有机合成技术领域,具体涉及一种天然分子Moracin M的合成方法,其包括制备步骤如下:以4‑溴间苯二酚和3,5‑二羟基苯乙酮为起始原料,分别经过2‑甲氧基乙氧基甲基保护反应制备1‑溴‑2,4‑双((2‑甲氧基乙氧基)甲氧基)苯和3,5‑双((2‑甲氧基乙氧基)甲氧基)苯乙酮,然后在钯催化作用下发生酮的α‑芳基化偶联反应生成2‑(2,4‑双((2‑甲氧基乙氧基)甲氧基)苯基)‑1‑(3,5‑双((2‑甲氧基乙氧基)甲氧基)苯基)乙烷‑1‑酮,最后经过脱保护/环合串联反应生成天然分子Moracin M。本发明合成路线简洁,起始原料4‑溴间苯二酚和3,5‑二羟基苯乙酮廉价易得,反应操作简便,无需微波高温加热等苛刻条件,总收率高,利于工业化生产。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种天然分子Moracin M的合成方法。
背景技术
Moracin M,是一种从中药桑白皮中分离出的重要生物活性天然分子,其英文名为:5-(6-hydroxybenzofuran-2-yl)benzene-1,3-diol,其结构通式如I所示:
;
其活性包括抗肿瘤、抗菌、抗哮喘等,是一种有效的磷酸二酯酶 4(PDE4)抑制剂,对于PDE4D2,PDE4B2,PDE5A1和PDE9A2的IC50分别为2.9 μM,4.5 μM,> 40 μM和> 100 μM。然而,仅仅通过从植物中提取的方法获得该天然分子效率低、成本高。因此迫切需要发展高效简洁的方法来规模化地合成Moracin M,从而促进其在生物医药领域的开发和应用。
目前合成Moracin M的方法主要有三种:
1. 美国Matthias Selke课题组开发的[4+2]环加成及重排法,利用反式白藜芦醇与单线态氧在光激发下发生反应生成环加成内过氧化物中间体,然后加热条件下重排得到Moracin M,然而总收率只有38%(Org. Lett. 2011, 13, 4846–4849)。
2. 西班牙Fernando P. Cossío课题组开发的关苯并呋喃环、脱保护法,利用间苯二酚与2-溴-1-(3,5-二甲氧基苯基)乙-1-酮在中性氧化铝的作用下反应生成2-(3,5-二甲氧基苯基)- 6-羟基-苯并呋喃,再通过三溴化硼脱除两个甲基得到Moracin M,两步总收率只有6.5%(J. Org. Chem. 2012, 77, 266-275),并且该路线中的涉及的原料2-溴-1-(3,5-二甲氧基苯基)乙-1-酮价格昂贵。
3. 中国专利CN104447646 A提供了一种四步线性步骤合成Moracin M的方法,利用原料2-溴-4-羟基苯乙酸和3,5-二甲氧基苯甲醛经过Perkin缩合生成2-(2-溴-4羟基苯基)-3-(3,5-二甲氧基苯基)丙烯酸,然后通过两步高温条件下铜催化的反应先后经历关环和脱羧得到2-(3,5-二甲氧基苯基)- 6-羟基-苯并呋喃,最后脱除甲基得到Moracin M。然而该路线的起始原料2-溴-4-羟基苯乙酸昂贵不易获得,而且其中两步铜催化的反应都需要微波加热,尤其是脱羧反应的温度要达到160℃~200℃,不易工业化生产。
发明内容
本发明的目的是提供一种活性天然分子Moracin M的新合成方法。该方法所需原料廉价易得,方法简便,反应条件温和,总收率高,便于工业化制备。
实现本发明目的而采用的技术方案为:一种天然分子Moracin M的合成方法,包括如下步骤:
以4-溴间苯二酚和3,5-二羟基苯乙酮为起始原料,分别经过2-甲氧基乙氧基甲基保护反应制备1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯和3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮,二者在钯催化作用下发生酮的α-芳基化偶联反应生成2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮,其经过脱保护/环合串联反应生成天然分子Moracin M。
所述方法具体步骤如下:
1)4-溴间苯二酚溶解于溶剂A中,加入碱A和2-甲氧基乙氧基甲基氯进行反应;反应完毕后加水淬灭反应,分液,水相采用有机溶剂萃取后合并有机相旋干溶剂,经过硅胶柱纯化得到1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯;
2)3,5-二羟基苯乙酮溶解于溶剂B中,加入碱B和2-甲氧基乙氧基甲基氯进行反应;反应完毕后加水淬灭反应,分液,水相采用有机溶剂萃取后合并有机相旋干溶剂,经过硅胶柱纯化得到3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮;
3)在甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)和叔丁醇钠存在下,将1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯和3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮溶解于1,4-二氧六环中,加热后进行反应;反应完毕后加水淬灭反应,加入有机溶剂,分液,水相采用有机溶剂萃取后合并有机相旋干溶剂,经过硅胶柱纯化得到2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮;
4)2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮溶解于甲醇中,加入对甲苯磺酸,加热后进行反应;反应完毕后加饱和碳酸氢钠溶液淬灭反应,加入有机溶剂,分液,水相采用有机溶剂萃取后合并有机相旋干溶剂,经过硅胶柱纯化得到天然分子Moracin M;
优选的,步骤1)所述的碱A为N,N-二异丙基乙胺,氢化钠或三乙胺;所述溶剂A是二氯甲烷或四氢呋喃,所述反应的温度是室温,反应的时间是6~12h;所述4-溴间苯二酚、碱A、2-甲氧基乙氧基甲基氯的摩尔比为1:2.5~3:2.2~3;
优选的,步骤2)所述的碱B为N,N-二异丙基乙胺,氢化钠或三乙胺;所述溶剂B是二氯甲烷或四氢呋喃,所述反应的温度是室温,反应的时间是6~12h;所述3,5-二羟基苯乙酮、碱B、2-甲氧基乙氧基甲基氯的摩尔比为1:2.5~3:2.2~3;
优选的,步骤3)所述反应的温度是80℃~90℃,反应的时间2~4h;所述1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯、3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮、甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)、叔丁醇钠的摩尔比为1:1.2~1.6:0.05~0.2:2~3;
优选的,步骤4)所述反应的温度是45℃~60℃,反应的时间2~4h;所述2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮、对甲苯磺酸的摩尔比为1:3~5。
与现有技术相比,本发明的技术优点在于:
1)本发明基于1,2-二芳基乙酮类结构发生新颖的串联脱保护/关苯并呋喃环的方法高效制备天然分子Moracin M,只需要用到温和的对甲苯磺酸作为促进剂,最优收率达到90%以上。其中1,2-二芳基乙酮中间体则只需要通过简单的芳基乙酮和芳基卤代物发生钯催化偶联反应获得,本发明克服了常规大位阻卤代物不容易发生酮的α-芳基化偶联反应的问题。此外,本发明选用的2-甲氧基乙氧基甲基(MEM)保护基,容易脱除,避免使用常规难脱的甲基作为保护基。
2)本发明合成路线简洁,起始原料4-溴间苯二酚和3,5-二羟基苯乙酮廉价易得,反应操作简便,无需微波高温加热等苛刻条件,总收率高,利于工业化生产。
附图说明
图1为本发明涉及的化学反应式。
图2为本发明制备的Moracin M的1H-NMR图。
图3为本发明制备的Moracin M的13C-NMR图。
具体实施方式
下面结合实施例和附图对本发明做进一步地描述。
实施例一:
(1)向反应瓶中依次加入4-溴间苯二酚(5.0 g,26.4 mmol), 二氯甲烷(50 mL)和N,N-二异丙基乙胺(9.55 g,73.9 mmol),搅拌5min,冰浴下加入2-甲氧基乙氧基甲基氯(8.22 g,66.0 mmol),升至室温下反应12h;反应完毕后加入80 mL水,分液,水相用二氯甲烷萃取(80 mL×2),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=2:1)纯化,得到白色油状的1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯(8.87 g,产率92%)。1HNMR (400 MHz, Chloroform-d): δ 7.38 (d, J = 10.5 Hz, 1H), 6.88 (s, 1H), 6.67– 6.59 (m, 1H), 5.29 (s, 2H), 5.21 (s, 2H), 3.86 (d, J = 4.8 Hz, 2H), 3.79(d, J = 4.8 Hz, 2H), 3.57 – 3.52 (m, 4H), 3.36 (s, 6H); ESI-MS m/z = 387 [M+Na]+;
(2)向反应瓶中依次加入3,5-二羟基苯乙酮(5.0 g,32.9 mmol),二氯甲烷(50mL)和N,N-二异丙基乙胺(11.9 g,92.1 mmol),搅拌5min,冰浴下加入2-甲氧基乙氧基甲基氯(10.2 g,82.25 mmol),升至室温下反应12h;反应完毕后加入50 mL水,分液,水相用二氯甲烷萃取(80 mL×2),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=3:1)纯化,得到淡黄色油状的3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮(8.97 g,产率83%)。 1H NMR (400 MHz, Chloroform-d): δ 7.27 (s, 2H), 6.94 (s, 1H), 5.27 (s,4H), 3.82 (d, J = 4.7 Hz, 4H), 3.55 (d, J = 4.9 Hz, 4H), 3.37 (s, 6H), 2.55(s, 3H);ESI-MS m/z = 351 [M+Na]+;
(3)向反应瓶中依次加入甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II) (914 mg,1.08 mmol),叔丁醇钠(2.1 g, 21.6mmol),1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯(4.0 g,10.8 mmol),3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮(4.96 g,15.12 mmol)和1,4-二氧六环(80 mL),氮气保护下搅拌升温至80oC,反应3h;反应完毕后冷却至室温,加入100 mL水,反应液用乙酸乙酯萃取(100 mL×3),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=1:1)纯化,得到棕色油状的2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮(5.3 g,产率80%)。1H NMR (400 MHz, Chloroform-d):δ 7.33 (s,2H), 7.04 (d, J = 8.8 Hz, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 6.69 (d, J = 10.7Hz, 1H), 5.26 (s, 4H), 5.23 (s, 2H), 5.20 (s, 2H), 4.15 (s, 2H), 3.81 (s,6H), 3.71 (s, 2H), 3.55 (s, 6H), 3.50 (s, 2H), 3.37 (s, 9H), 3.34 (s, 3H);ESI-MS m/z =635 [M+Na]+;
(4)向2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮(5.0 g,8.16 mmol)的甲醇(60 mL)溶液中加入对甲苯磺酸一水合物(6.2 g,32.64 mmol),搅拌下升温至50 oC,反应3 h;反应完毕后冰浴下加入80 mL饱和碳酸氢钠溶液,反应液用乙酸乙酯萃取(80 mL×3),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=2:1)纯化,得到白色Moracin M固体(1.8 g,产率91%)。1HNMR (400 MHz, DMSO-d6):δ 9.58 (s, 1H), 9.43 (s, 2H), 7.38 (d, J = 8.4 Hz,1H), 7.08 (d, J = 1.0 Hz, 1H), 6.92 (d, J = 1.7 Hz, 1H), 6.73 (dd, J = 8.4,2.1 Hz, 1H), 6.67 (d, J = 2.2 Hz, 2H), 6.20 (t, J = 2.2 Hz, 1H); 13C NMR (101MHz, DMSO-d6): δ 159.3 , 156.3 , 155.8 , 154.5 , 132.2 , 121.7 , 121.3 ,112.9 , 103.1, 102.8 , 102.1 , 98.0;HRMS(ESI-TOF):m/z[M+H]+calcd forC14H10O4: 243.0652, found: 243.0686。
实施例二:
(1)向反应瓶中依次加入4-溴间苯二酚(5.0 g,26.4 mmol)和四氢呋喃(50 mL),冰浴下加入氢化钠(质量百分含量60%,2.64 g,66.0 mmol),搅拌5min,同样温度加入2-甲氧基乙氧基甲基氯(7.23 g,58.08 mmol),升至室温下反应6h;反应完毕后,冰浴下缓慢加入80 mL水,反应液用二氯甲烷萃取(80 mL×3),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=2:1)纯化,得到白色油状的1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯(7.91 g,产率82%)。
(2)向反应瓶中依次加入3,5-二羟基苯乙酮(5.0 g,32.9 mmol)和四氢呋喃(50mL),冰浴下加入氢化钠(质量百分含量60%,3.29 g,82.25 mmol),搅拌5min,冰浴下加入2-甲氧基乙氧基甲基氯(9.0 g,72.38 mmol),升至室温下反应6h;反应完毕后,冰浴下缓慢加入80 mL水,反应液用二氯甲烷萃取(80 mL×3),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=3:1)纯化,得到淡黄色油状的3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮(7.89 g,产率73%)。
(3)向反应瓶中依次加入甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(457 mg,0.54 mmol),叔丁醇钠(3.1 g, 32.4mmol),1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯(4.0 g,10.8 mmol),3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮(4.25 g,12.96 mmol)和1,4-二氧六环(80 mL),氮气保护下搅拌升温至80 oC,反应3h;反应完毕后冷却至室温,加入100 mL水,反应液用乙酸乙酯萃取(100 mL×3),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=1:1)纯化,得到棕色油状的2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮(5.0 g,产率75%)。
(4)向2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮(5.0 g,8.16 mmol)的甲醇(60 mL)溶液中加入对甲苯磺酸一水合物(7.8 g,40.8 mmol),搅拌下升温至45 oC,反应4 h;反应完毕后冰浴下加入80 mL饱和碳酸氢钠溶液,反应液用乙酸乙酯萃取(80 mL×3),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=2:1)纯化,得到白色Moracin M固体(1.7 g,产率86%)。
实施例三:
(1)向反应瓶中依次加入4-溴间苯二酚(5.0 g,26.4 mmol), 二氯甲烷(50 mL)和三乙胺(8.0 g,79.2 mmol),搅拌5min,冰浴下加入2-甲氧基乙氧基甲基氯(9.86 g,79.2mmol),升至室温下反应12h;反应完毕后加入80 mL水,分液,水相用二氯甲烷萃取(80 mL×2),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=2:1)纯化,得到白色油状的1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯(8.68 g,产率90%)。
(2)向反应瓶中依次加入3,5-二羟基苯乙酮(5.0 g,32.9 mmol),二氯甲烷(50mL)和三乙胺(9.99 g,98.7 mmol),搅拌5min,冰浴下加入2-甲氧基乙氧基甲基氯(12.24g,98.7 mmol),升至室温下反应12h;反应完毕后加入50 mL水,分液,水相用二氯甲烷萃取(80 mL× 2),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=3:1)纯化,得到淡黄色油状的3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮(8.53 g,产率79%)。
(3)向反应瓶中依次加入甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(1.83 g,2.16 mmol),叔丁醇钠(2.1 g,21.6mmol),1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯(4.0 g,10.8 mmol),3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮(5.67 g,17.28 mmol)和1,4-二氧六环(80 mL),氮气保护下搅拌升温至90 oC,反应2h;反应完毕后冷却至室温,加入100 mL水,反应液用乙酸乙酯萃取(100 mL×3),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=1:1)纯化,得到棕色油状的2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮(5.17 g,产率78%)。
(4)向2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮(5.0 g,8.16 mmol)的甲醇(60 mL)溶液中加入对甲苯磺酸一水合物(7.75 g,40.8 mmol),搅拌下升温至60 oC,反应2 h;反应完毕后冰浴下加入80 mL饱和碳酸氢钠溶液,反应液用乙酸乙酯萃取(80 mL×3),合并有机相,旋干溶剂。粗产品通过硅胶柱层析(石油醚:乙酸乙酯=2:1)纯化,得到白色Moracin M固体(1.76 g,产率89%)。
Claims (3)
1. 一种天然分子Moracin M的合成方法,其特征在于:具体制备步骤如下:
1)4-溴间苯二酚溶解于溶剂A中,加入碱A和2-甲氧基乙氧基甲基氯进行反应;反应完毕后加水淬灭反应,分液,水相采用有机溶剂萃取后合并有机相旋干溶剂,经过硅胶柱纯化得到1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯;
2)3,5-二羟基苯乙酮溶解于溶剂B中,加入碱B和2-甲氧基乙氧基甲基氯进行反应;反应完毕后加水淬灭反应,分液,水相采用有机溶剂萃取后合并有机相旋干溶剂,经过硅胶柱纯化得到3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮;
3)在甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)和叔丁醇钠存在下,将1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯和3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮溶解于1,4-二氧六环中,加热后进行反应;反应完毕后加水淬灭反应,加入有机溶剂,分液,水相采用有机溶剂萃取后合并有机相旋干溶剂,经过硅胶柱纯化得到2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮;
4)2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮溶解于甲醇中,加入对甲苯磺酸,加热后进行反应;反应完毕后加饱和碳酸氢钠溶液淬灭反应,加入有机溶剂,分液,水相采用有机溶剂萃取后合并有机相旋干溶剂,经过硅胶柱纯化得到天然分子Moracin M;
步骤1)所述的碱A为N,N-二异丙基乙胺,氢化钠或三乙胺;所述溶剂A是二氯甲烷或四氢呋喃,所述反应的温度是室温,反应的时间是6~12h;所述4-溴间苯二酚、碱A、2-甲氧基乙氧基甲基氯的摩尔比为1:2.5~3:2.2~3;
步骤2)所述的碱B为N,N-二异丙基乙胺,氢化钠或三乙胺;所述溶剂B是二氯甲烷或四氢呋喃,所述反应的温度是室温,反应的时间是6~12h;所述3,5-二羟基苯乙酮、碱B、2-甲氧基乙氧基甲基氯的摩尔比为1:2.5~3:2.2~3。
2. 根据权利要求1所述的一种天然分子Moracin M的合成方法,其特征在于:步骤3)所述反应的温度是80℃~90℃,反应的时间2~4h;所述1-溴-2,4-双((2-甲氧基乙氧基)甲氧基)苯、3,5-双((2-甲氧基乙氧基)甲氧基)苯乙酮、甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)、叔丁醇钠的摩尔比为1:1.2~1.6:0.05~0.2:2~3。
3. 根据权利要求1所述的一种天然分子Moracin M的合成方法,其特征在于:步骤4)所述反应的温度是45℃~60℃,反应的时间2~4h;所述2-(2,4-双((2-甲氧基乙氧基)甲氧基)苯基)-1-(3,5-双((2-甲氧基乙氧基)甲氧基)苯基)乙烷-1-酮、对甲苯磺酸的摩尔比为1:3~5。
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CN113698375A (zh) * | 2021-09-23 | 2021-11-26 | 八叶草健康产业研究院(厦门)有限公司 | 一种4-环己亚胺甲基取代苯并呋喃衍生物的合成方法 |
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CN104447646A (zh) * | 2014-11-28 | 2015-03-25 | 中科院广州化学有限公司 | 一种天然产物Moracin M全合成的方法 |
CN113698375A (zh) * | 2021-09-23 | 2021-11-26 | 八叶草健康产业研究院(厦门)有限公司 | 一种4-环己亚胺甲基取代苯并呋喃衍生物的合成方法 |
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