CN106366105A - 一种二氟烯丙基硼酸酯的制备方法及其应用 - Google Patents
一种二氟烯丙基硼酸酯的制备方法及其应用 Download PDFInfo
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- CN106366105A CN106366105A CN201610635012.0A CN201610635012A CN106366105A CN 106366105 A CN106366105 A CN 106366105A CN 201610635012 A CN201610635012 A CN 201610635012A CN 106366105 A CN106366105 A CN 106366105A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 title abstract description 7
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- 238000000034 method Methods 0.000 claims abstract description 47
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 18
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 229910052742 iron Inorganic materials 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- -1 alcohol ester Chemical class 0.000 claims description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- 239000000463 material Substances 0.000 claims description 27
- 239000002585 base Substances 0.000 claims description 26
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 14
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- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 13
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- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 claims description 9
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
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- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
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- 229910052744 lithium Inorganic materials 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
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- 125000003545 alkoxy group Chemical group 0.000 claims description 5
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000003477 4 aminobutyric acid receptor stimulating agent Substances 0.000 claims description 4
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- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims description 3
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- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical group Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 3
- GYCHYNMREWYSKH-UHFFFAOYSA-L iron(ii) bromide Chemical compound [Fe+2].[Br-].[Br-] GYCHYNMREWYSKH-UHFFFAOYSA-L 0.000 claims description 3
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
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- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 claims description 3
- 238000007171 acid catalysis Methods 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
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- 238000013459 approach Methods 0.000 abstract description 2
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Abstract
本发明涉及一种二氟烯丙基硼酸酯的制备方法及其应用,属于化合物制备领域。一种二氟烯丙基硼酸酯的制备方法,是于溶剂中,以通式II所示化合物和联硼酸频那醇酯为原料,在铁催化剂和碱存在下按下述反应式进行反应,得通式I所示化合物,
Description
技术领域
本发明涉及一种二氟烯丙基硼酸酯的制备方法及其应用,属于化合物制备领域。
背景技术
在有机分子中引入氟原子通常可以改变化合物的物理、化学及生物活性相关的性质,因此,在各种药物、高分子材料、液晶材料中引入氟原子是提高物质性质常用的一种手段。
1,1-二氟烯烃是一类重要的含氟基团,常常用于含氟化合物骨架的构建,1,1-二氟烯烃官能团可以脱氟形成单氟烯烃(Chem.Lett.1979,983.)、加氢生成二氟甲基(J.Chem.Soc.,Chem.Commun.1989,1437.)、加氟生成三氟甲基(J.Org.Chem.1997,62,7758.),不饱和双键还可以进行亲核加成反应、通过分子间环加成形成含氟杂环(Angew.Chem.Int.Ed.2012,51,12059.)。除此之外,1,1-二氟烯烃官能团在药物设计方面被认为是羰基的生物电子等排体(J.Chem.Soc.,Chem.Commun.1989,1437.),并且含有1,1-二氟烯烃官能团的有机分子也常常作为酶抑制剂使用(Fluorine in MedicinalChemistry and Chemical Biology;Wiley-Blackwell:West Sussex,UK,2009.),因此能够较为简易合成含有1,1-二氟烯烃官能团的有机分子显得尤为重要。
烷基硼酸酯和烷基硼酸是有机合成领域一类非常重要的中间体(Boronic Acids:Preparation and Applications in Organic Synthesis and Medicine,Wiley-VCH,Weinheim,2005),在各种药物、高分子材料、液晶材料、荧光探针材料的合成中都得到了广泛的应用。含有硼酸酯或硼酸官能团的化合物除了可以用于经典的Suzuki-Miyaura偶联之外(Angew.Chem.,Int.Ed.2011,50,6722.),而且还能较为容易地转化为相应的醇、醛、胺官能团等(Chem.Commun.2013,49,11230.)。大多数含有硼酸酯或硼酸官能团的化合物相比于其它的金属有机亲核试剂(比如格氏试剂)有着良好的稳定性,能够直接在空气氛围下进行提纯或储存,因此合成官能团多样化的硼酸酯或硼酸化合物具有十分重要的意义。
分子中同时含有1,1-二氟烯烃官能团和硼酸酯官能团的二氟烯丙基硼酸酯化合物是优异的有机合成砌块,但是二氟烯丙基硼酸酯类化合物的合成目前只有一个实例报道(Angew.Chem.Int.Ed.2011,50,7079.),该方法需要复杂的卡宾铜络合物作催化剂,并且产率也较低。
3-(4-乙酰苯基)-1-(金刚烷-1-基)-2,2-二氟-3-羟基-1-丙酮(化合物III)是一种γ-氨基丁酸受体激动剂(J.Med.Chem.2013,56,2456),已有合成路线以1-(金刚烷-1-基)-4,4,4-三氟-3-羟基-1-丁酮为原料,经Selectfluor氟化,脱三氟乙酰基并与醛加成制得,所用试剂较贵(J.Am.Chem.Soc.2011,133,5802)。
发明内容
本发明的目的是提供一种使用便宜、市售的铁盐直接作为催化剂,以联硼酸频那醇酯为硼化试剂,以三氟甲基烯(通式I所示化合物)为原料,高效、简便、经济的合成二氟烯丙基硼酸酯类化合物(通式II所示化合物)的方法,并将其用于γ-氨基丁酸受体激动剂的合成。
一种二氟烯丙基硼酸酯的制备方法,是于溶剂中,以通式II所示化合物和联硼酸频那醇酯为原料,在铁催化剂和碱存在下按下述反应式进行反应,得通式I所示化合物,
其中,
R1选自C1~C10烷基、其中,m=0~4,n=1~5;
R2选自H、C1~C6烷基;
R3选自H、C1~C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1~C4烷氧基、C2~C5酯基。
所述铁催化剂为氯化亚铁、氯化铁、溴化亚铁、溴化铁、乙酰丙酮铁、乙酰丙酮亚铁、乙酸亚铁中的至少1种。
所述碱选自叔丁醇钾、叔丁醇钠、叔丁醇锂、甲醇钠、甲醇锂、甲醇钾、碳酸铯、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、磷酸钾中的至少1种。
本发明所述溶剂优选为四氢呋喃(THF)、乙腈、N,N-二甲基甲酰胺、甲苯、二氯甲烷、1,2-二氯甲烷、苯甲醚、甲基叔丁基醚、二氧六环、乙二醇二甲醚中的至少1种。
本发明所述溶剂,其用量满足反应要求即可,优选通式Ⅱ所示化合物与溶剂的量之比为1mmol:5~15mL。
除另有说明外,本文中使用的术语具有以下含义。
本文中使用的术语“烷基”包括直链烷基和支链烷基。如提及单个烷基如“丙基”,则只特指直链烷基,如提及单个支链烷基如“异丙基”,则只特指支链烷基。例如,“C4以下烷基”包括甲基、乙基、正丙基、异丙基、正丁基和叔丁基等。类似的规则也适用于本说明书中使用的其它基团。
本文中使用术语“卤素”包括氟、氯、溴、碘。
本文中所述C2~C5酯基为具有如下结构的基团:-COOR,其中,R为C1~C4烷基。
本文中所述C1~C4烷氧基为具有如下结构的基团:-O-M1,其中,M1为C1~C4烷基,如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基。
上述技术方案中,所述(m=0~4,n=1~5),其中,(R3)n中,n=1~5指R3在苯基上的取代可为单取代或多位取代,可为1、2、3、4或5取代。n=1时为单取代,单取代的取代位可为2、3或4位;n=2、3、4或5时,为多位取代,其中,n=2为双取代,双取代的取代位为2,3-、2,4-、2,5-、2,6-、3,4-、3,5-;n=3为三取代,三取代的取代位为2,3,4-、2,3,5-、2,3,6-、3,4,5-。
本发明所述二氟烯丙基硼酸酯的制备方法优选R1选自C1~C10烷基、其中,m=0、1、2、3、4,进一步地,m=0或2;n=1、2、3、4、5;
R2选自H、C1~C6烷基,进一步地,R2优选为H、正丙基;
R3选自H、C1~C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1~C4烷氧基、C2~C5酯基;进一步地,R3优选为H、甲基、甲氧基、卤素、三氟甲基、叔丁基、三氟甲氧基、苯基;
本发明所述二氟烯丙基硼酸酯的制备方法优选所述碱的物质的量为通式II所示化合物物质的量的0.5~3倍,进一步优选所述碱的物质的量为所述通式II所示化合物物质的量的1~2倍。
本发明所述二氟烯丙基硼酸酯的制备方法优选所述联硼酸频那醇酯的物质的量为所述通式II所示化合物物质的量的1~3倍,进一步优选所述联硼酸频那醇酯的物质的量为所述通式II所示化合物物质的量的1~1.5倍。
本发明所述二氟烯丙基硼酸酯的制备方法优选所述催化剂的物质的量为所述通式II所示化合物物质的量的0.1%~10%,优选5%~10%。
本发明所述二氟烯丙基硼酸酯的制备方法优选上述反应的反应温度为25℃~溶剂回流温度,反应时间为10min~48h,优选5h~24h。
本发明一个优选的技术方案为:
一种二氟烯丙基硼酸酯的制备方法,是于溶剂中,以通式II所示化合物和联硼酸频那醇酯为原料,在铁催化剂和碱存在下按下述反应式进行反应,得通式I所示化合物,其中,反应温度为25℃~溶剂回流温度,反应时间为10min~48h,
其中,
R1选自C1~C10烷基、其中,m=0~4,n=1~5;
R2选自H、C1~C6烷基;
R3选自H、C1~C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1~C4烷氧基、C2~C5酯基;
所述铁催化剂为氯化亚铁、氯化铁、溴化亚铁、溴化铁、乙酰丙酮铁、乙酰丙酮亚铁、乙酸亚铁中的至少1种。
所述碱选自叔丁醇钾、叔丁醇钠、叔丁醇锂、甲醇钠、甲醇锂、甲醇钾、碳酸铯、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、磷酸钾中的至少1种。
所述溶剂选自四氢呋喃、乙腈、N,N-二甲基甲酰胺、甲苯、二氯甲烷、1,2-二氯甲烷、苯甲醚、甲基叔丁基醚、二氧六环、乙二醇二甲醚中的至少1种。
本发明的又一目的是提供上述合成方法制得的化合物在合成γ-氨基丁酸受体激动剂(III)中的应用。
一种以二氟烯丙基硼酸酯为原料合成γ-氨基丁酸受体激动剂(III)的制备方法,先利用上述方法合成2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯,再按下述路线进行:
包括以下两步反应:
①2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯与4-乙酰基苯甲醛在磷酸二苯酯和苯甲酸催化下,甲苯溶剂中,60℃反应10h~30h,2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯、4-乙酰基苯甲醛、磷酸二苯酯、苯甲酸的物质的量之比为1:(1~1.5):0.1:0.1;
②1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇溶于二氯甲烷/甲醇混合溶剂中,-78℃下鼓泡通入臭氧,并保持蓝色10min,之后移至室温并鼓泡鼓入氩气直至反应体系为无色清液;再次冷却至-78℃下保持氩气氛围加入二甲硫醚,自然升至室温反应10h~24h;1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇与二甲硫醚的物质的量之比为1:2;混合溶剂中二氯甲烷/甲醇的体积比为1:1~3:1。
表1中列举了上述反应式中各个原料化合物取代基的具体结构。
表1
表2列举了本发明合成的具体化合物1~23的结构、物理性质及1H NMR数据,但本发明并不仅限于这些化合物。
表2
本发明的有益效果为:铁作为地壳含量第二高的金属元素和人体不可缺少的微量元素,具有含量丰富、价廉、易得、低毒、环境友好的优点,以其为基础开发催化剂符合当前可持续发展与绿色化学的要求。本发明所述方法直接使用便宜、市售的金属铁盐作为催化剂,为二氟烯丙基硼酸酯的制备提供了一种方便、低成本的方法,而且为γ-氨基丁酸受体激动剂(III)的合成提供了一种新的有效的途径。
具体实施方式
下述非限制性实施例可以使本领域的普通技术人员更全面地理解本发明,但不以任何方式限制本发明。
下述实施例中所述试验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
实施例1
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
室温下,向氩气保护的25mLSchlenk瓶中依次加入催化剂FeCl2 6.3mg(0.05mmol,α-三氟甲基苯乙烯物质的量的5%,记为5mol%)、无水THF 8mL、α-三氟甲基苯乙烯172mg(1mmol)、α-三氟甲基苯乙烯1.1倍摩尔量的联硼酸频那醇酯279mg(1.1mmol)、α-三氟甲基苯乙烯1.1倍摩尔量的叔丁醇锂88mg(1.1mmol),反应体系为浅黄色浑浊液,置于65℃反应12小时。后处理通过旋转蒸发仪除去溶剂,再加入25mL水,用乙酸乙酯萃取(3×15mL),合并有机相用饱和食盐水洗涤(2×10mL)后用无水Na2SO4干燥,通过柱层析获得目标化合物,填充料为硅胶,洗脱剂为石油醚:乙酸乙酯(50:1),分离收率92%。
实施例2
2-(2-甲氧基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物2)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的2-甲氧基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率89%。
实施例3
2-(2-氯苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物3)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的2-氯-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率72%。
实施例4
2-(3-甲氧基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物4)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的3-甲氧基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率90%。
实施例5
2-(3-氯苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物5)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的3-氯-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率69%。
实施例6
2-(4-甲氧基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物6)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-甲氧基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率80%。
实施例7
2-(4-氯苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物7)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-氯-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率96%。
实施例8
2-(4-氟苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物8)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-氟-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率84%。
实施例9
2-(4-溴苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物9)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-溴-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率84%。
实施例10
2-(4-三氟甲基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物10)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-三氟甲基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率86%。
实施例11
2-(4-三氟甲氧基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物11)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-三氟甲氧基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率97%。
实施例12
2-(4-叔丁基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物12)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-叔丁基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率86%。
实施例13
2-(4-苯基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物13)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-苯基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率95%。
实施例14
2-(4-甲氧羰基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物14)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的4-甲氧羰基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率58%。
实施例15
2-(2,4-二甲基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物15)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的3,4-亚甲二氧基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率99%。
实施例16
2-(3,5-二甲基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物16)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的2,4-二甲基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率73%。
实施例17
2-(3,4-亚甲二氧基苯基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物17)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的3,5-二甲基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率80%。
实施例18
2-(苯并噻吩-2-基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物18)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的α-三氟甲基-2-苯并噻吩乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率73%。
实施例19
2-(1-萘基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物19)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的α-三氟甲基-1-萘乙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率72%。
实施例20
2-(2-苯基乙基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物20)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的2-三氟甲基-4-苯基-1-丁烯外,按与实施例1同样的方法进行,获得目标化合物分离收率94%。
实施例21
2-苯基-3-硼酸频哪醇酯-1,1-二氟-1-己烯的制备(化合物21)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的1-三氟甲基-1-苯戊烯(顺反构型的混合物,顺反比例为1:2.16)外,按与实施例1同样的方法进行,获得目标化合物分离收率67%。
实施例22
2-二氟甲叉基-1-十一烷硼酸频哪醇酯的制备(化合物22)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的2-三氟甲基-1-十一烯外,按与实施例1同样的方法进行,获得目标化合物分离收率91%。
实施例23
2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物23)
除了将实施例1中的α-三氟甲基苯乙烯换成同摩尔量的3,3,3-三氟-2-(金刚烷-1-基)丙烯外,按与实施例1同样的方法进行,获得目标化合物分离收率76%。
实施例24
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的无水THF换成无水乙腈外,按与实施例1同样的方法进行,获得目标化合物氢核磁收率18%(以1,1,2,2-四氯乙烷为内标)。
实施例25
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的无水THF换成无水乙二醇二甲醚外,按与实施例1同样的方法进行,获得目标化合物氢核磁收率93%(以1,1,2,2-四氯乙烷为内标)。
实施例26
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的叔丁醇锂换成甲醇钾外,按与实施例1同样的方法进行,获得目标化合物氢核磁收率45%(以1,1,2,2-四氯乙烷为内标)。
实施例27
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的叔丁醇锂降为0.6倍摩尔量外,按与实施例1同样的方法进行,获得目标化合物氢核磁收率60%(以1,1,2,2-四氯乙烷为内标)。
实施例28
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的联硼酸频那醇酯降为0.6倍摩尔量外,按与实施例1同样的方法进行,获得目标化合物氢核磁收率59%(以1,1,2,2-四氯乙烷为内标)。
实施例29
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的催化剂FeCl2降为1mol%外,按与实施例1同样的方法进行,获得目标化合物氢核磁收率17%(以1,1,2,2-四氯乙烷为内标)。
实施例30
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的催化剂FeCl2改为10mol%外,按与实施例1同样的方法进行,获得目标化合物氢核磁收率99%(以1,1,2,2-四氯乙烷为内标)。
实施例31
2-苯基-3,3-二氟烯丙基硼酸频哪醇酯的制备(化合物1)
除了将实施例1中的反应温度降至25℃外,按与实施例1同样的方法进行,获得目标化合物氢核磁收率34%(以1,1,2,2-四氯乙烷为内标)。
实施例32
3-(4-乙酰苯基)-1-(金刚烷-1-基)-2,2-二氟-3-羟基-1-丙酮的合成(化合物III)
①25mL Schlenk瓶中,氩气保护下,依次加入2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯85mg(0.2513mmol),甲苯3mL,4-乙酰基苯甲醛37mg(0.2513mmol),10mol%的磷酸二苯酯6mg(0.02513mmol),10mol%的苯甲酸3mg(0.02513mmol),封闭后移至油浴锅60℃反应24h。降温,后处理直接拌硅胶柱层析,洗脱剂为石油醚:乙酸乙酯(5:1),得到1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇58mg,产率64%。
白色固体,m.p.116~118℃,1H NMR:δ7.94(d,J=7.9Hz,2H,ArH),7.53(d,J=7.9Hz,2H,ArH),5.36(s,1H,1/2CCH2),5.25(s,1H,1/2CCH2),5.04(dd,J=10.0Hz,J=13.6Hz,1H,ArCH),3.61(br,4H,OH+CH3),2.02(br,3H,3CH),1.80(br,6H,3CH2),1.70(m,6H,3CH2)。
②25mL Schlenk瓶中依次加入1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇20mg(0.05553mmol),二氯甲烷3mL,甲醇1.5mL,冷却至-78℃下鼓泡鼓入臭氧,并保持蓝色10min,之后移至室温并鼓泡鼓入氩气直至反应体系为无色清液。再次冷却至-78℃下保持氩气氛围加入二甲硫醚7mg(0.1110mmol),自然升至室温反应18h。后处理直接拌硅胶柱层析,洗脱剂为石油醚:乙酸乙酯(5:1),得到化合物III 19mg,产率95%。
白色固体,m.p.97~99℃,1H NMR:δ7.94(d,J=7.4Hz,2H,ArH),7.52(d,J=7.9Hz,2H,ArH),5.32(dd,J=6.1Hz,J=18.0Hz,1H,ArCH),3.28(br,1H,OH),2.59(s,3H,CH3),2.02(br,3H,3CH),1.89(br,6H,3CH2),1.70(m,6H,3CH2)。
实施例33
3-(4-乙酰苯基)-1-(金刚烷-1-基)-2,2-二氟-3-羟基-1-丙酮的合成(化合物III)
①25mL Schlenk瓶中,氩气保护下,依次加入2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯169mg(0.5mmol),甲苯3mL,4-乙酰基苯甲醛111mg(0.75mmol),10mol%的磷酸二苯酯12mg(0.05mmol),10mol%的苯甲酸6mg(0.05mmol),封闭后移至油浴锅65℃反应13h。降温,后处理直接拌硅胶柱层析,洗脱剂为石油醚:乙酸乙酯(5:1),得到1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇166mg,产率92%。
②25mL Schlenk瓶中依次加入1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇20mg(0.05553mmol),二氯甲烷3mL,甲醇1.5mL,冷却至-78℃下鼓泡鼓入臭氧,并保持蓝色10min,之后移至室温并鼓泡鼓入氩气直至反应体系为无色清液。再次冷却至-78℃下保持氩气氛围加入二甲硫醚7mg(0.1110mmol),自然升至室温反应18h。后处理直接拌硅胶柱层析,洗脱剂为石油醚:乙酸乙酯(5:1),得到化合物III 19mg,产率95%。
Claims (10)
1.一种二氟烯丙基硼酸酯的制备方法,是于溶剂中,以通式II所示化合物和联硼酸频那醇酯为原料,在铁催化剂和碱存在下按下述反应式进行反应,得通式I所示化合物,
其中,
R1选自C1~C10烷基、其中,m=0~4,n=1~5;
R2选自H、C1~C6烷基;
R3选自H、C1~C6烷基、苯基、卤素、三氟甲基、三氟甲氧基、C1~C4烷氧基、C2~C5酯基;
所述铁催化剂为氯化亚铁、氯化铁、溴化亚铁、溴化铁、乙酰丙酮铁、乙酰丙酮亚铁、乙酸亚铁中的至少1种;
所述碱选自叔丁醇钾、叔丁醇钠、叔丁醇锂、甲醇钠、甲醇锂、甲醇钾、碳酸铯、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、磷酸钾中的至少1种。
2.根据权利要求1所述的方法,其特征在于:所述R2为H、丙基。
3.根据权利要求1所述的方法,其特征在于:所述R3为H、甲基、甲氧基、卤素、三氟甲基、叔丁基、三氟甲氧基、苯基。
4.根据权利要求1所述的方法,其特征在于:所述碱的物质的量为通式II所示化合物的0.5~3倍。
5.根据权利要求4所述的方法,其特征在于:所述碱的物质的量为所述通式II所示化合物的1~2倍。
6.根据权利要求1所述的方法,其特征在于:所述联硼酸频那醇酯的物质的量所述为通式II所示化合物的1~3倍。
7.根据权利要求6所述的方法,其特征在于:所述联硼酸频那醇酯的物质的量为所述通式II所示化合物的1~1.5倍。
8.根据权利要求1所述的方法,其特征在于:所述催化剂的物质的量为所述通式II所示化合物物质的量的0.1%~10%。
9.根据权利要求1~8任一项所述的方法,其特征在于:所述反应的反应温度为25℃~溶剂回流温度,反应时间为10min~48h。
10.权利要求1所述的方法制备所述通式I所示化合物在γ-氨基丁酸受体激动剂(III)合成中的应用,其特征在于:先按权利要求1所述方法合成2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯,再按下述路线进行:
包括以下两步反应:
①2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯与4-乙酰基苯甲醛在磷酸二苯酯和苯甲酸催化下,甲苯溶剂中,60℃反应10h~30h,2-(金刚烷-1-基)-3,3-二氟烯丙基硼酸频哪醇酯、4-乙酰基苯甲醛、磷酸二苯酯、苯甲酸的物质的量之比为1:(1~1.5):0.1:0.1;
②1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇溶于二氯甲烷/甲醇混合溶剂中,-78℃下鼓泡通入臭氧,并保持蓝色10min,之后移至室温并鼓泡鼓入氩气直至反应体系为无色清液;再次冷却至-78℃下保持氩气氛围加入二甲硫醚,自然升至室温反应10h~24h;1-(4-乙酰苯基)-3-(金刚烷-1-基)-2,2-二氟丁-3-烯-1-醇与二甲硫醚的物质的量之比为1:2;混合溶剂中二氯甲烷/甲醇的体积比为1:1~3:1。
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