CN108440271A - 一种6-甲氧基萘嵌苯酮类化合物的制备方法 - Google Patents
一种6-甲氧基萘嵌苯酮类化合物的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- -1 methoxyl group perinaphthenone class compound Chemical class 0.000 claims abstract description 17
- 238000006254 arylation reaction Methods 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 8
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 8
- 238000006735 epoxidation reaction Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- WWBGWPHHLRSTFI-UHFFFAOYSA-N phenalen-1-one Chemical compound C1=CC(C(=O)C=C2)=C3C2=CC=CC3=C1 WWBGWPHHLRSTFI-UHFFFAOYSA-N 0.000 claims description 9
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 4
- XJIPTTLNJAQLLR-UHFFFAOYSA-N 2-bromonaphthalene-1-carbaldehyde Chemical class C1=CC=CC2=C(C=O)C(Br)=CC=C21 XJIPTTLNJAQLLR-UHFFFAOYSA-N 0.000 claims description 3
- KZDNSNCCYBKKCC-UHFFFAOYSA-N [N]=O.C1(=CC=CC=C1)C1=CC=NC=C1 Chemical class [N]=O.C1(=CC=CC=C1)C1=CC=NC=C1 KZDNSNCCYBKKCC-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
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- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 125000006015 bromomethoxy group Chemical group 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 3
- 229910052794 bromium Inorganic materials 0.000 abstract 3
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 abstract 1
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 abstract 1
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- 241000196324 Embryophyta Species 0.000 description 4
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- 229930000044 secondary metabolite Natural products 0.000 description 2
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- 238000010189 synthetic method Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- VEUMANXWQDHAJV-UHFFFAOYSA-N 2-[2-[(2-hydroxyphenyl)methylideneamino]ethyliminomethyl]phenol Chemical compound OC1=CC=CC=C1C=NCCN=CC1=CC=CC=C1O VEUMANXWQDHAJV-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 240000003826 Eichhornia crassipes Species 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000000884 anti-protozoa Effects 0.000 description 1
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- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- MMIPFLVOWGHZQD-UHFFFAOYSA-N manganese(3+) Chemical compound [Mn+3] MMIPFLVOWGHZQD-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004506 ultrasonic cleaning Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
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- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
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Abstract
本发明公开了一种6‑甲氧基萘嵌苯酮类化合物的制备方法，包括采用廉价易得的4‑溴‑1‑萘醛为原料与魏悌锡试剂反应得到4‑溴‑1‑萘烯酸酯类化合物，再经水解、路易酸催化环化得到高产率的6‑溴‑1‑萘嵌苯酮类化合物，在此基础上进一步甲氧基化得到6‑甲氧基萘嵌苯酮类化合物；再经与格式试剂反应、氧化得到9位芳基化的6‑甲氧基萘嵌苯酮类化合物，再经环氧化反应、开环反应、烷基化反应得到9位芳基化，同时2位烷氧基取代的6‑甲氧基萘嵌苯酮类化合物。该方法无需使用过渡金属催化剂、操作简便、反应时间短、收率高，对于6‑甲氧基萘嵌苯酮类化合物的工业制备具有很高的实用价值。
Description
技术领域
本发明涉及化合物制备技术领域，更具体地，涉及一种6-甲氧基萘嵌苯酮类化合物的制备方法。
背景技术
9-苯基-2，6-二甲氧基萘嵌苯酮类化合物起初是一类由于植物受到化学、物理、微生物等胁迫作用而产生的植物类毒素。属于植物次生代谢产物，这些次生代谢产物的产生是植物预防病原菌复合系统的一部分。9-苯基-2，6-二甲氧基萘嵌苯酮化合物在抗原虫、杀菌、抗病毒、抗肿瘤等方面具有明显的作用效果。9-苯基-2，6-二甲氧基萘嵌苯酮化合物最先由发明人在中国云南产的水葫芦中分离得到（Helv. Chim. Acta. 2011, 94, 61-66），天然来源的9-苯基-2，6-二甲氧基萘嵌苯酮化合物在植物中含量较低，分离纯化困难，不利于科研人员研究及应用。至今为止未见任何文献报到它的合成方法。
发明内容
本发明的目的在于提供了一种6-甲氧基萘嵌苯酮类化合物的制备方法。
本发明的目的通过以下技术方案实现：
一种6-甲氧基萘嵌苯酮类化合物的制备方法，包括如下步骤：
S1.将4-溴-1-萘甲醛和魏悌锡试剂反应生成4-溴-1-萘丙烯酸；
S2.将4-溴-1-萘丙烯酸水解后，经过路易酸催化环化生成6-溴-1-萘嵌苯酮；
S3.将6-溴-1-萘嵌苯酮中溴基用甲氧基取代，生成6-甲氧基萘嵌苯酮；
S4.将6-甲氧基萘嵌苯酮与格氏试剂ArMgBr反应，生成9位芳基化的6-甲氧基萘嵌苯酮；
S5.将9位芳基化的6-甲氧基萘嵌苯酮进行环氧化反应、开环反应、2位烷基化反应后得
；
其中，Ar为苯基或取代苯基，取代苯基中取代基为C1~C5烷基、C1~C3烷氧基或卤基；R为C1~C5烷基。
优选地，步骤S2中采用草酰氯进行酰氯化后，使用三氯化铝进行催化环化，按物质的量摩尔比计，4-溴-1-萘丙烯酸与草酰氯的比例为1：（1~5）；三氯化铝与4-溴-1-萘丙烯酸的质量比为（1~2）：1。
优选地，步骤S3中采用甲醇钠和碘化亚铜进行甲氧基取代，6-溴-1-萘嵌苯酮、甲醇钠与碘化亚铜的摩尔比为（4~6）：（45~55）：1。
优选地，步骤S4中，6-甲氧基萘嵌苯酮与格氏试剂ArMgBr的摩尔比为1：（8~15）。
优选地，先将格氏试剂ArMgBr在氮气保护下，在-70℃~ -80℃温度下冷却15~30分钟，然后将溶解后的6-甲氧基萘嵌苯酮与格氏试剂混合，升高温度至-5℃，继续反应25~35分钟。
优选地，步骤S5中，采用Salen-Mn(Ⅲ)配合物作为催化剂，在4-苯基吡啶氮氧化物的氧化体系中进行环氧化反应，使用对甲苯磺酸进行开环反应。
优选地，9位芳基化的6-甲氧基萘嵌苯酮、4-苯基吡啶氮氧化物、Salen-Mn(Ⅲ)配合物的反应摩尔比为（16~25）：（4~6）：1。
优选地，将原料在冰浴条件下混合，将冰浴后的次氯酸钠溶液加入上述混合溶液，搅拌2~4h，用饱和硫代硫酸钠溶液淬灭反应。
优选地，次氯酸钠溶液的质量分数为12%~16%。
优选地，对甲苯磺酸与9位芳基化的6-甲氧基萘嵌苯酮的摩尔比为（2~5）：1。
与现有技术相比，本发明的有益效果是：
本发明所述的6-甲氧基萘嵌苯酮类化合物的合成方法具有操作简便、反应产率高（总收率达24.0%）、无需使用过渡金属催化剂的优点，对于这类化合物的工业制备具有很高的实用价值。
具体实施方式
以下结合具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
其中，本实施例中采用的试剂和仪器信息如下：
试剂:三溴化磷、witting试剂、钯碳、DMF、硝酸、硫酸、氯仿、二氯甲烷、THF、三氯化铝、碳酸钾、甲醇、石油醚、乙酸乙酯、氢氧化钠、盐酸等。
仪器: ABI Maldi-TOF和Qstar Elite高分辨质谱系统；Bruker Avance 400MHz核磁共振波谱仪（瑞士Bruker公司）；Agilent GC-MS； EYLA(SB-1200) 旋转蒸发仪（上海爱朗仪器有限公司）；IKA®C-MAG HS 7磁力搅拌器（上海爱朗仪器有限公司）；YUHUA( ZF-20DAN)暗箱式紫外分析仪（上海光豪分析仪器有限公司）；KQ5200E型超声清洗器（昆山市超声仪器有限公司），SB-1200 水浴锅（上海爱朗仪器有限公司），A-1000S水流抽气机（上海爱朗仪器有限公司）。
实施例1
1、中间体2a的合成
取干燥的250mL圆底烧瓶，放入搅拌子，加入溴代乙酸乙酯与三苯基膦的盐（12.6g，0.028mol），在N2保护下，加入120mL无水THF溶解，冷却至室温后，加入叔丁醇钾（4.6g，0.041mol），室温下搅拌1h。用无水THF溶解4-溴-1-萘甲醛（1a, 5g，0.02mol），用注射器缓慢打入反应瓶中，室温搅拌过夜。TLC监测反应完全，旋蒸干THF，用水和二氯甲烷萃取浓缩物，有机层用饱和NaCl洗涤，再用无水硫酸钠干燥，旋蒸干二氯甲烷过柱，得到5.5g产品。将5.4g产品溶于50mLTHF中，加入50mL水、7.0 g NaOH,室温搅拌过夜。旋蒸干THF，用50 mL二氯甲烷萃取未反应的原料，将浓盐酸缓慢滴加到水层中，有大量白色固体产生，抽滤白色固体，60℃烘干得中间体2a（4.42g，产率75%）。
2、中间体3a的合成
将中间体2a（4.4g，0.016mol）溶解在100mL的干燥的二氯甲烷中，室温搅拌，向其中加入草酰氯8.6mL，20分钟后向其中滴加2滴无水DMF，室温搅拌过夜，然后将溶液旋蒸干得到黄色固体，再用干燥的二氯甲烷100mL稀释酰氯产品，搅拌，用冰水冷却至0℃,缓慢向溶液中加入三氯化铝5g (分三批)，室温搅拌过夜。然后将黑色溶液缓慢倒入冰水中，用二氯甲烷（3x100mL）萃取，将有机层浓缩过柱，得中间体3a（2.2g，产率55%）。1H NMR (400 MHz,CDCl3) δ 8.64 (dd, J = 7.2, 1.2 Hz, 1H), 8.56 (dd, J = 8.4, 1.2 Hz, 1H), 7.84(t, J = 8.4 Hz, 2H), 7.67 (d, J = 9.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 6.72(d, J = 9.6 Hz, 1H) ppm。13C NMR (100 MHz, CDCl3) δ 184.9, 141.3, 134.1, 131.1,131.1, 131.1, 130.7, 129.6, 129.2, 128.7, 128.2, 128.0, 127.6 ppm。
步骤1和步骤2的反应流程如下：
3、中间体3b的合成
将3a（1.15g，4.45mmol）甲醇钠（2.4g，44.38mmol），碘化亚铜(169mg，0.89mmol)，加入到100mL单口烧瓶中，在N2保护下加入50ml的无水甲醇，80℃回流10h，TLC监测原料反应完后恢复至室温，滤掉不溶物，旋蒸干甲醇，用乙酸乙酯萃取2次，饱和氯化钠洗涤2次，再用无水硫酸钠干燥，旋蒸干有机层，过硅胶柱分离得到亮黄色固体3b（840mg，产率90%）1H NMR(400 MHz, CDCl3) δ 8.66 (d, J = 7.2 Hz, 1H), 8.61 (d, J = 8.0 Hz, 1H), 7.75(dd, J = 8.0, 7.2 Hz, 1H), 7.72 – 7.57 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H),6.62 (d, J = 8.0 Hz, 1H), 4.09 (s, 3H) ppm。13C NMR (100 MHz, CDCl3) δ 185.7,159.8, 141.8, 133.3, 130.8, 129.5, 129.2, 128.6, 126.5, 126.4, 124.9, 121.0,104.5, 56.0 ppm。
4、中间体3c的合成
将1mol/L的苯基溴化镁（26.7ml，26.7mmol），在N2保护下用注射器打入100ml的长颈烧瓶中，-78℃冷却20分钟，用干燥的四氢呋喃5ml溶解3b（560mg，2.66mmol），用注射器滴加到反应瓶中，滴完后将低温反应器的温度升高至-5℃,继续反应30分钟，最后用饱和氯化铵淬灭反应，用乙酸乙酯萃取（2 x100.0ml），水洗有机层，旋蒸浓缩有机层，将浓缩物再用干燥的二氯甲烷稀释溶解，加入DDQ（905mg，3.99mmol），加热回流30分钟，冷却至室温，用二氯甲烷/水萃取反应物，用饱和氯化钠洗涤，再用无水硫酸钠干燥，浓缩有机层，过硅胶柱，分离得到黄色固体3c（640mg，产率85%）。1H NMR (400 MHz, CDCl3) δ 8.58 (dd, J = 8.4, 1.2Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56 (ddd, J = 9.6,8.0, 1.2 Hz, 2H), 7.51– 7.39 (m, 2H), 7.37 (td, J = 6.0, 2.8 Hz, 3H), 6.88 (d, J = 8.0 Hz, 1H),6.47 (dd, J = 9.6, 1.2 Hz, 1H), 4.08 (s, 3H)。13C NMR (100 MHz, CDCl3) δ 185.8,159.5, 147.9, 143.2, 140.4, 133.1, 130.8, 129.4, 128.2, 127.9, 127.9, 127.0,126.2, 124.5, 121.6, 104.4, 56.0 ppm。
5、中间体3d的合成
将3c（300mg，1.05mmol），Mn（Ⅲ）salen (33.4mg,0.053mmol)，4-苯基吡啶氮氧化物(45mg,0.26mmol)放入含有30ml二氯甲烷的100ml单口烧瓶中，冰浴冷却到0℃。取另一个单口烧瓶，加入14.3%的次氯酸钠溶液30ml，冰浴冷却到0℃，将次氯酸钠溶液迅速加入到前面的反应瓶中，0 ℃剧烈搅拌3h，用饱和硫代硫酸钠溶液淬灭反应。反应液用二氯甲烷和水萃取，有机层用无水硫酸钠干燥，浓缩有机层，用30ml的甲苯溶解浓缩物，加入对甲苯磺酸（600mg，3.15mmol），室温搅拌过夜，用乙酸乙酯（100mlx3）萃取，有机层用饱和食盐水洗涤2次，用无水硫酸钠干燥，浓缩有机层，将粗品过硅胶柱，得到红色固体3d (250mg，产率80%）。1H NMR (400 MHz, CDCl3) δ 8.70 (dd, J = 8.4, 1.2 Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.58 (dd, J = 8.4, 1.2 Hz, 1H), 7.48 (ddd, J = 10.4, 7.2, 3.6 Hz,3H), 7.37 (dt, J = 8.0, 1.2 Hz, 2H), 7.08 (d, J = 1.2 Hz, 1H), 6.94 – 6.86(m, 2H), 4.08 (s, 3H) ppm。13C NMR (100 MHz, CDCl3) δ 179.9, 158.1, 149.2,148.4, 142.6, 132.4, 130.3, 129.6, 128.2, 127.8, 127.5, 125.8, 124.5, 123.6,121.5, 113.2, 105.1, 56.0 ppm。
6、终产物3e的合成
将3d（150mg，0.50mmol），碳酸钾（685mg，4.96mmol）溶于10ml的DMF中，室温搅拌1h，然后向反应瓶中加入碘甲烷（0.23ml，3.69mmol），室温搅拌10h，用乙酸乙酯萃取（50ml×3），有机层用饱和氯化钠洗涤再用无水硫酸钠干燥、浓缩有机层，将浓缩物过硅胶柱，得到最终产物3e（149mg，产率95%）。1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.4 Hz, 1H), 7.56(ddd, J = 8.4, 7.2, 2.0 Hz, 2H), 7.47 – 7.39 (m, 2H), 7.39 – 7.30 (m, 3H),6.87 (dd, J = 8.0, 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.06 (s, 3H), 3.84(s, 3H) ppm。13C NMR (100 MHz, CDCl3) δ 179.8, 157.5, 152.1, 148.4, 143.0,130.7, 130.7, 128.3, 128.1, 127.9, 126.9, 126.4, 125.8, 124.4, 121.5, 112.1,104.8, 55.9, 55.5 ppm。
步骤3~步骤6的反应流程如下：
。
Claims (10)
1.一种6-甲氧基萘嵌苯酮类化合物的制备方法，其特征在于，包括如下步骤：
S1.将4-溴-1-萘甲醛和魏悌锡试剂反应生成4-溴-1-萘丙烯酸；
S2.将4-溴-1-萘丙烯酸水解后，经过路易酸催化环化生成6-溴-1-萘嵌苯酮；
S3.将6-溴-1-萘嵌苯酮中溴基用甲氧基取代，生成6-甲氧基萘嵌苯酮；
S4.将6-甲氧基萘嵌苯酮与格氏试剂ArMgBr反应，生成9位芳基化的6-甲氧基萘嵌苯酮；
S5.将9位芳基化的6-甲氧基萘嵌苯酮进行环氧化反应、开环反应、2位烷基化反应后得
；
其中，Ar为苯基或取代苯基，取代苯基中取代基为C1~C5烷基、C1~C3烷氧基或卤基；R为C1~C5烷基。
2.根据权利要求1所述的制备方法，其特征在于，步骤S2中采用草酰氯进行酰氯化后，使用三氯化铝进行催化环化，按物质的量摩尔比计，4-溴-1-萘丙烯酸与草酰氯的比例为1：（1~5）；三氯化铝与4-溴-1-萘丙烯酸的质量比为（1~2）：1。
3.根据权利要求1所述的制备方法，其特征在于，步骤S3中采用甲醇钠和碘化亚铜进行甲氧基取代，6-溴-1-萘嵌苯酮、甲醇钠与碘化亚铜的摩尔比为（4~6）：（45~55）：1。
4.根据权利要求1所述的制备方法，其特征在于，步骤S4中，6-甲氧基萘嵌苯酮与格氏试剂ArMgBr的摩尔比为1：（8~15）。
5.根据权利要求4所述的制备方法，其特征在于，先将格氏试剂ArMgBr在氮气保护下，在-70 ℃~ - 80℃温度下冷却15~30分钟，然后将溶解后的6-甲氧基萘嵌苯酮与格氏试剂混合，升高温度至-5℃，继续反应25~35分钟。
6.根据权利要求1所述的制备方法，其特征在于，步骤S5中，采用Salen-Mn(Ⅲ)配合物作为催化剂，在4-苯基吡啶氮氧化物的氧化体系中进行环氧化反应，使用对甲苯磺酸进行开环反应。
7.根据权利要求6所述的制备方法，其特征在于，9位芳基化的6-甲氧基萘嵌苯酮、4-苯基吡啶氮氧化物、Salen-Mn(Ⅲ)配合物的反应摩尔比为（16~25）：（4~6）：1。
8.根据权利要求6或7所述的制备方法，其特征在于，将原料在冰浴条件下混合，将冰浴后的次氯酸钠溶液加入上述混合溶液，搅拌2~4h，用饱和硫代硫酸钠溶液淬灭反应。
9.根据权利要求6所述的制备方法，其特征在于，次氯酸钠溶液的质量分数为12%~16%。
10.根据权利要求6所述的制备方法，其特征在于，对甲苯磺酸与9位芳基化的6-甲氧基萘嵌苯酮的摩尔比为（2~5）：1。
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