CN109232448A - (e)-氯丙基烯酮/烯醛三唑化合物及其合成方法 - Google Patents
(e)-氯丙基烯酮/烯醛三唑化合物及其合成方法 Download PDFInfo
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- -1 triazole compounds Chemical class 0.000 title claims abstract description 100
- 150000002561 ketenes Chemical class 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title claims abstract description 9
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- KTHXBEHDVMTNOH-UHFFFAOYSA-N cyclobutanol Chemical compound OC1CCC1 KTHXBEHDVMTNOH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000002240 furans Chemical class 0.000 claims abstract description 9
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 17
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 7
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 1
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- 239000000460 chlorine Substances 0.000 abstract description 9
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
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- KOFFFKMEMKRWMT-UHFFFAOYSA-N 1-azidoethylbenzene Chemical compound [N-]=[N+]=NC(C)C1=CC=CC=C1 KOFFFKMEMKRWMT-UHFFFAOYSA-N 0.000 description 1
- FJSKXQVRKZTKSI-UHFFFAOYSA-N 2,3-dimethylfuran Chemical compound CC=1C=COC=1C FJSKXQVRKZTKSI-UHFFFAOYSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
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- 229910020323 ClF3 Inorganic materials 0.000 description 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
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- 229910052786 argon Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- UDLLFLQFQMACJB-UHFFFAOYSA-N azidomethylbenzene Chemical compound [N-]=[N+]=NCC1=CC=CC=C1 UDLLFLQFQMACJB-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epoxy Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种(E)‑氯丙基烯酮/烯醛三唑化合物及其合成方法,该化合物的结构式为
Description
技术领域
本发明涉及一类(E)-氯丙基烯酮/烯醛三唑化合物及其合成方法。
背景技术
烯酮三唑骨架结构代表着一类重要的小分子化合物。这类骨架由于具有较高的生物活性,引起科学家的广泛关注。研究表明,该类化合物对组蛋白去乙酰化酶(HDAC)具有很好的抑制作用,从而抑制肿瘤细胞迁移、侵袭、转移。
含氯化合物是天然产物和药物合成过程中常用的合成砌块和中间体,大量含有氯结构单元的天然产物表现出显著的生物活性。此外,超过70%的药物含有氯结构单元或者通过氯化反应来合成。传统的氯代反应是将底物中活泼的官能团,例如羟基、羧基、重氮基或者不饱和键(烯/炔)等转化为氯。因此,发展一种具有原子经济性和步骤经济性,且能直接将惰性的烷烃C(sp3)-C(sp3)键转化为C(sp3)-Cl键的氯代方法显得尤为重要。
发明内容
本发明目的是提供一种(E)-氯丙基烯酮三唑化合物和(E)-氯丙基烯醛三唑化合物,并提供一种以呋喃环丁醇和叠氮化合物为底物,TiCl4作为碳正离子引发剂,通过环加成/双开环/氯化串联反应合成(E)-氯丙基烯酮三唑化合物和(E)-氯丙基烯醛三唑化合物的方法。
解决上述技术问题所采用的(E)-氯丙基烯酮/烯醛三唑化合物的结构式如下所示:
式中R代表H或C1~C5烷基,优选R代表H或甲基;R1代表H、C1~C5烷基、苯基、卤代苯基、C1~C4烷基取代的苯基、三氟甲基取代苯基、萘基中任意一种,具体如:H、甲基、戊基、苯基、4-溴苯基、4-甲基苯基、4-三氟甲基苯基、萘基等;R2代表C1~C5烷基、C4~C6环烷基、C2~C4烯基、苯基、苄基、C1~C4烷基取代的苯基、卤代苯基、肉桂基、卤代苄基、C1~C4烷氧基取代的苄基中任意一种,具体如:丁基、环己基、环戊基、烯丙基、苯基、苄基、4-甲基苯基、4-溴代苯基、α-苯基乙基、肉桂基、4-溴代苄基、4-甲氧基苄基等。
上述(E)-氯丙基烯酮/烯醛三唑化合物的合成方法为:将式Ⅰ所示的呋喃环丁醇与式Ⅱ所示的叠氮化物加入有机溶剂中,在TiCl4作用下-20℃~常温反应,反应完全后分离纯化,其中R代表H时,得到(E)-氯丙基烯醛三唑化合物;R代表C1~C5烷基时,得到(E)-氯丙基烯酮三唑化合物;具体反应方程式如下:
上述制备方法中,优选呋喃环丁醇与叠氮化物的摩尔比为1:1~1:1.3,TiCl4的加入量为呋喃环丁醇摩尔量的1~1.3倍。
上述的有机溶剂为二氯甲烷、1,2-二氯乙烷、甲苯、苯中任意一种。
本发明的有益效果如下:
本发明可以从简单易得的原料呋喃环丁醇和叠氮化合物出发,以TiCl4作为反应的碳正离子引发剂和氯化反应的氯源,通过一锅反应实现了C-N键和C-Cl键构筑的同时,C-C键和C-O键发生断裂,即通过一锅反应完成了串联环加成/双开环/氯代反应,实现了(E)-氯丙基烯酮三唑化合物和(E)-氯丙基烯醛三唑化合物简捷高效合成,该反应方法学具有很高的步骤经济性。
本发明所公开的(E)-氯丙基烯酮三唑化合物和(E)-氯丙基烯醛三唑化合物具有特殊的结构骨架,该类化合物在含有(E)-烯酮/醛三唑骨架的同时,还含有氯丙烷结构骨架,氯代烷是很好的反应前体,可以通过取代反应、自由基反应等化学反应来进一步修饰三唑骨架结构,可以进一步提高三唑类化合物的可溶性、生物活性等性质,具有很好的应用前景。
具体实施方式
下面结合实施例对本发明进一步详细说明,但本发明的保护范围不仅限于这些实施例。
实施例1
合成结构式如下的(E)-4-(5-(3-氯丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
将152mg(1.0mmol)1-(5-甲基呋喃-2-基)环丁烷-1-醇、138mg(1.1mmol)环己基叠氮和10mL无水二氯甲烷加入50mL干燥的圆底烧瓶中,然后将混合物用氩气冲洗1分钟后置于-20℃冰/盐浴中并开始搅拌,加入1.1mL 1mol/L(1.1mmol)TiCl4的二氯甲烷溶液,然后将所得混合物恢复至常温,搅拌并通过薄层色谱检测监测。反应完全后,加入饱和碳酸氢钠水溶液将反应混合物淬灭,然后用乙酸乙酯(3×20mL)萃取,将混合物用饱和食盐水(2×10mL)洗涤,合并有机相,用硫酸钠干燥并过滤,减压蒸馏得到残余物,使用柱色谱法用石油醚/乙酸乙酯(v:v=3:1)作为洗脱液纯化,得到(E)-4-(5-(3-氯丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为68%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.46(d,J=15.9Hz,1H),7.10(d,J=15.9Hz,1H),4.15(ddd,J=11.8,7.7,3.5Hz,1H),3.58-3.53(m,2H),3.01-2.95(m,2H),2.36(s,3H),2.13(dd,J=22.1,12.0Hz,2H),2.05-1.95(m,6H),1.39(tt,J=28.3,7.8Hz,4H);13C NMR(100MHz,CDCl3)δ198.22,140.05,135.28,129.86,126.63,58.29,43.53,33.43,32.02,28.71,25.65,25.01,19.52;HRMS(ESI)C15H22ClN3NaO[M+Na]+,[M+2+Na]+:理论值318.1344,320.1314,实测值:318.1332,320.1307。
实施例2
合成结构式如下的(E)-4-(5-(3-氯丙基)-1-环戊基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的环戊基叠氮替换实施例1中的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯丙基)-1-环戊基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为63%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.46(dd,J=15.9,1.4Hz,1H),7.09(dd,J=15.9,2.0Hz,1H),4.75-4.66(m,1H),3.57(t,J=5.9Hz,2H),3.03-2.98(m,2H),2.37(d,J=1.6Hz,3H),2.21-2.16(m,4H),2.08-2.02(m,4H),1.80-1.73(m,2H);13C NMR(100MHz,CDCl3):δ198.23,140.34,135.87,129.92,126.66,59.30,43.52,33.65,31.83,28.57,24.81,19.68;HRMS(ESI)C14H21ClN3O[M+H]+,[M+2+H]+:理论值282.1368,284.1338,实测值284.1342.284.1342。
实施例3
合成结构式如下的(E)-4-(1-丁基-5-(3-氯丙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的正丁基叠氮替换实施例1的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(1-丁基-5-(3-氯丙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为79%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.45(d,J=15.9Hz,1H),7.09(d,J=15.9Hz,1H),4.30(dd,J=9.3,5.6Hz,2H),3.60-3.55(m,2H),2.99(dd,J=8.2,7.1Hz,2H),2.36(s,3H),2.08-2.02(m,2H),1.95-1.87(m,2H),1.44-1.36(m,2H),0.98(t,J=7.4Hz,3H);13C NMR(100MHz,CDCl3):δ198.16,140.48,136.02,129.70,126.75,48.00,43.55,32.28,31.72,28.71,19.91,19.60,13.60;HRMS(ESI)C13H20ClN3NaO[M+Na]+,[M+2+Na]+:理论值292.1187,294.1158,实测值92.1177,294.1146。
实施例4
合成结构式如下的(E)-4-(5-(3-氯丙基)-1-苯基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的苯基叠氮替换实施例1的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯丙基)-1-苯基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为40%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.61-7.57(m,3H),7.51(d,J=15.9Hz,1H),7.47-7.43(m,2H),7.22(d,J=15.9Hz,1H),3.43(t,J=6.0Hz,2H),3.02(dd,J=8.4,7.0Hz,2H),2.40(s,3H),1.93-1.87(m,2H);13C NMR(100MHz,CDCl3):δ198.04,141.97,137.00,135.77,130.36,129.94,129.25,127.42,125.52,43.38,31.33,28.90,20.11;HRMS(ESI)C15H16ClN3NaO[M+Na]+,[M+2+Na]+:理论值312.0874,314.0845,实测值312.0872,314.0850。
实施例5
合成结构式如下的(E)-4-(5-(3-氯丙基)-1-(对甲苯基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的对甲苯基叠氮替换实施例1的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯丙基)-1-(对甲苯基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为40%,结构表征数据为:1H NMR(400MHz,CDCl3)δ7.52(d,J=15.9Hz,1H),7.37(d,J=8.3Hz,2H),7.34-7.29(m,2H),7.20(d,J=15.9Hz,1H),3.43(t,J=6.0Hz,2H),3.00(dd,J=8.4,7.0Hz,2H),2.47(s,3H),2.39(s,3H),1.89(ddd,J=12.3,9.3,6.1Hz,2H);13CNMR(100MHz,CDCl3):δ198.09,140.83,140.67,137.04,133.22,130.46,129.44,127.30,125.30,43.44,31.29,28.83,21.41,20.10;HRMS(ESI)C16H18ClN3NaO[M+Na]+,[M+2+Na]+:理论值326.1031,328.1001,实测值326.1025,328.0999。
实施例6
合成结构式如下的(E)-4-(1-(4-溴苯基)-5-(3-氯丙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的对溴苯基叠氮替换实施例1的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(1-(4-溴苯基)-5-(3-氯丙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为43%,结构表征数据为:1H NMR(400MHz,CDCl3)δ7.72(d,J=8.6Hz,2H),7.49(d,J=15.9Hz,1H),7.35(d,J=8.6Hz,2H),7.18(d,J=15.9Hz,1H),3.45(t,J=5.9Hz,2H),3.06-2.97(m,2H),2.39(s,3H),1.97-1.87(m,2H);13C NMR(100MHz,CDCl3):δ197.76,140.88,136.71,134.45,132.93,128.82,127.39,126.69,124.24,43.17,31.04,28.55,19.79;HRMS(ESI)C15H15BrClN3NaO[M+Na]+,[M+2+Na]+:理论值389.9979,391.9958,实测值389.9975,391.9952。
实施例7
合成结构式如下的(E)-4-(5-(3-氯丙基)-1-(4-甲氧基苄基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的对甲氧基苄基叠氮替换实施例1的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯丙基)-1-(4-甲氧基苄基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为58%,结构表征数据为:1H NMR(600MHz,CDCl3)δ7.42(d,J=15.9Hz,1H),7.17(d,J=8.5Hz,2H),7.09(d,J=15.9Hz,1H),6.87(d,J=8.5Hz,2H),5.50(s,2H),3.79(s,3H),3.46(t,J=5.8Hz,2H),2.91-2.86(m,2H),2.35(s,3H),1.78(td,J=12.5,6.2Hz,2H);13C NMR(150MHz,CDCl3):δ197.90,159.72,141.04,136.09,129.40,128.66,126.81,126.35,114.39,55.24,51.67,43.47,31.01,28.47,19.63;HRMS(ESI)C17H20ClN3NaO2[M+Na]+,[M+2+Na]+:理论值356.1136,358.1108,实测值356.1135,358.1119。
实施例8
合成结构式如下的(E)-4-(1-苄基-5-(3-氯丙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的苄基叠氮替换实施例1的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(1-苄基-5-(3-氯丙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为63%,结构表征数据为:1H NMR(400MHz,CDCl3)δ7.43(d,J=16Hz,1H),7.35(d,J=7.0Hz,2H),7.20(dd,J=7.3,1.8Hz,2H),7.10(d,J=16.0Hz,1H),5.57(s,2H),3.46-3.41(m,2H),2.91-2.85(m,2H),2.35(s,3H),1.77(ddd,J=12.1,9.2,6.1Hz,2H);13C NMR(100MHz,CDCl3):δ197.93,141.03,136.24,134.38,129.35,129.05,128.59,127.11,126.87,52.05,43.39,30.95,28.44,19.58;HRMS(ESI)C16H18ClN3NaO[M+Na]+,[M+2+Na]+:理论值326.1031,328.1002,实测值326.1029,328.1007。
实施例9
合成结构式如下的(E)-4-(1-(4-溴苄基)-5-(3-氯丙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的对溴苄基叠氮替换实施例1的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(1-(4-溴苄基)-5-(3-氯丙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为43%,结构表征数据为:1H NMR(600MHz,CDCl3)δ7.49(d,J=8.0Hz,2H),7.41(d,J=15.9Hz,1H),7.16-7.06(m,3H),5.52(s,2H),3.53-3.46(m,2H),2.88(t,J=7.6Hz,2H),2.36(s,3H),1.91-1.78(m,2H;13C NMR(150MHz,CDCl3):δ197.84,141.14,136.14,133.41,132.26,129.10,128.84,127.05,122.76,51.33,43.43,31.12,28.58,19.54;HRMS(ESI)C16H18BrClN3O[M+H]+,[M+2+H]+:理论值382.0316,384.0295,实测值382.0321,384.0296。
实施例10
合成结构式如下的(E)-4-(5-(3-氯丙基)-1-(1-苯乙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的(1-叠氮基乙基)苯替换实施例1的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯丙基)-1-(1-苯乙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为52%,结构表征数据为:1H NMR(400MHz,CDCl3)δ7.43(d,J=15.9Hz,1H),7.36-7.29(m,2H),7.25-7.18(m,2H),7.11(d,J=15.9Hz,1H),5.59(q,J=7.0Hz,1H),3.43(t,J=5.8Hz,2H),2.86(dd,J=11.5,4.5Hz,2H),2.36(s,3H),2.08(d,J=7.0Hz,3H),1.81-1.65(m,2H);13C NMR(150MHz,CDCl3):δ198.04,140.89,140.48,136.13,129.54,129.08,128.35,126.82,125.95,58.93,43.52,31.15,28.50,22.3,19.67;HRMS(ESI)C17H20ClN3NaO[M+Na]+,[M+2+Na]+:理论值340.1187,342.1159,实测值340.1187,342.1161。
实施例11
合成结构式如下的(E)-4-(5-(3-氯丙基)-1-肉桂基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的肉桂基叠氮替换实施例1的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯丙基)-1-肉桂基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为66%,结构表征数据为:1H NMR(400MHz,CDCl3)δ7.45(d,J=16.0Hz,1H),7.38-7.27(m,5H),7.11(d,J=16Hz,1H),6.57(d,J=15.9Hz,1H),6.31(dt,J=15.9,6.2Hz,1H),5.14(d,J=6.2Hz,2H),3.58-3.52(m,2H),3.07-2.97(m,2H),2.36(s,3H),2.10-1.98(m,2H);13CNMR(150MHz,CDCl3):δ197.97,140.83,136.27,135.19,134.49,129.33,128.66,128.49,126.81,126.55,121.87,50.34,43.51,31.33,28.57,19.52;HRMS(ESI)C18H20ClN3NaO[M+Na]+,[M+2+Na]+:理论值352.1187,354.1159,实测值352.1179,354.1159。
实施例12
合成结构式如下的(E)-4-(1-烯丙基-5-(3-氯丙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的烯丙基叠氮替换实施例1的环己基叠氮,其他步骤与实施例1相同,得到(E)-4-(1-烯丙基-5-(3-氯丙基)-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为74%,结构表征数据为:1H NMR(400MHz,CDCl3)δ7.45(d,J=16.0Hz,1H),7.10(d,J=16Hz,1H),6.07-5.94(m,1H),5.37-5.31(m,1H),5.16(d,J=16.9Hz,1H),4.99(dt,J=5.5,1.5Hz,2H),3.60-3.54(m,2H),2.98(dd,J=8.3,7.0Hz,2H),2.37(s,3H),2.05(ddd,J=12.1,8.4,6.1Hz,2H);13C NMR(100MHz,CDCl3):δ197.90,140.69,136.23,131.21,129.35,126.81,119.13,50.51,43.40,31.26,28.48,19.41;HRMS(ESI)C12H16ClN3NaO[M+Na]+,[M+2+Na]+:理论值276.0874,278.0845,实测值276.0862,278.0833。
实施例13
合成结构式如下的(E)-3-(5-(3-氯丙基)-1-环己基-1H-1,2,3-三唑-4-基)丙烯醛
本实施例中,用等摩尔的1-(呋喃-2-基)环丁烷-1-醇替换实施例1的1-(5-甲基呋喃-2-基)环丁烷-1-醇,其他步骤与实施例1相同,得到(E)-3-(5-(3-氯丙基)-1-环己基-1H-1,2,3-三唑-4-基)丙烯醛,其产率为56%,结构表征数据为:1H NMR(400MHz,CDCl3)δ9.69(d,J=7.7Hz,1H),7.45(d,J=15.9Hz,1H),6.97(dd,J=15.9,7.7Hz,1H),4.21-4.10(m,1H),3.61-3.52(m,2H),3.06-2.94(m,2),2.14(d,J=10.0Hz,2H),2.08-1.97(m,6H),1.51-1.34(m,4);13C NMR(100MHz,CDCl3):δ193.36,139.79,139.54,135.39,128.56,58.31,43.33,33.34,31.66,25.54,24.88,19.53;HRMS(ESI)C14H21ClN3O[M+H]+,[M+2+H]+:理论值282.1368,284.1338,实测值282.1355,284.1331。
实施例14
合成结构式如下的(E)-4-(5-(3-氯丙基)-1-环己基-1H-1,2,3-三唑-4-基)-3-甲基丁-3-烯-2-酮
本实施例中,用等摩尔的1-(4,5-二甲基呋喃-2-基)环丁烷-1-醇替换实施例1的1-(5-甲基呋喃-2-基)环丁烷-1-醇,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯丙基)-1-环己基-1H-1,2,3-三唑-4-基)-3-甲基丁-3-烯-2-酮,其产率为64%,结构表征数据为:1H NMR(400MHz,CDCl3)δ6.22(d,J=1.7Hz,1),4.07(ddd,J=11.7,7.6,3.6Hz,1H),3.62-3.49(m,2H),2.90-2.81(m,2H),2.36(s,3H),2.09-1.91(m,11H),1.79-1.71(m,1H),1.46-1.26(m,3);13C NMR(100MHz,CDCl3):δ207.24,140.84,140.12,131.50,115.00,57.89,43.52,33.34,31.84,29.44,25.53,24.95,21.11,19.21;HRMS(ESI)C16H24ClN3NaO[M+Na]+,[M+2+Na]+:理论值332.1500,334.1471,实测值332.1486,334.1459。
实施例15
合成结构式如下的(E)-4-(5-(3-氯-2-苯丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的1-(5-甲基呋喃-2-基)-3-苯基环丁基-1-醇替换实施例1的1-(5-甲基呋喃-2-基)环丁烷-1-醇,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯-2-苯丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为49%,结构表征数据为:1HNMR(400MHz,CDCl3)δ7.34-7.23(m,3H),7.11-7.06(m,1H),6.99(dd,J=14.0,8.7Hz,3H),3.92-3.70(m,3H),3.56(dd,J=14.2,3.2Hz,1H),3.09-3.00(m,1H),2.96(dd,J=14.2,10.1Hz,1H),2.27(s,3H),1.94(dddd,J=40.2,36.2,16.4,10.2Hz,5H),1.70(d,J=10.6Hz,1H),1.37-1.15(m,4H);13C NMR(150MHz,CDCl3):δ197.96,140.17,139.15,133.87,129.67,129.07,128.06,127.26,126.66,57.95,49.03,47.47,33.31,32.68,27.86,26.94,25.45,24.76;HRMS(ESI)C21H27ClN3O[M+H]+,[M+2+H]+:理论值372.1837,374.1809,实测值372.1825,374.1803。
实施例16
合成结构式如下的(E)-4-(5-(3-氯-2-(对甲苯基)丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的1-(5-甲基呋喃-2-基)-3-(对甲苯基)环丁烷-1-醇替换实施例1的1-(5-甲基呋喃-2-基)环丁烷-1-醇,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯-2-(对甲苯基)丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为44%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.08(dd,J=14.9,7.8Hz,3H),6.97(d,J=16.0Hz,1H),6.87(d,J=8.0Hz,2H),3.88-3.69(m,3H),3.53(dd,J=14.2,3.3Hz,1H),3.05-2.96(m,1H),2.91(dd,J=14.2,10.1Hz,1H),2.29(s,3H),2.27(s,3H),2.04-1.80(m,6H),1.39-1.21(m,4H);13C NMR(150MHz,CDCl3):δ197.97,140.33,138.00,136.18,136.18,134.00,129.78,127.21,126.72,58.03,48.74,47.63,33.39,32.82,27.85,27.14,25.50,24.86,20.93;HRMS(ESI)C22H29ClN3O[M+H]+,[M+2+H]+:理论值386.1994,388.1966,实测值386.1981,388.1954。
实施例17
合成结构式如下的(E)-4-(5-(2-(4-溴苯基)-3-氯丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的3-(4-溴苯基)-1-(5-甲基呋喃-2-基)环丁烷-1-醇替换实施例1的1-(5-甲基呋喃-2-基)环丁烷-1-醇,其他步骤与实施例1相同,得到(E)-4-(5-(2-(4-溴苯基)-3-氯丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为52%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.43(d,J=8.2Hz,2H),7.05(d,J=15.9Hz,1H),6.98(d,J=15.9Hz,1H),6.89(d,J=8.2Hz,2H),3.87-3.73(m,3H),3.52(dd,J=14.4,3.4Hz,1H),3.03(td,J=8.7,4.3Hz,1H),2.92(dd,J=14.3,10.0Hz,1H),2.29(s,3H),2.10-1.73(m,6H),1.43-1.16(m,4H);13C NMR(150MHz,CDCl3):δ197.76,140.26,138.10,133.43,132.16,129.14,128.99,126.64,122.04,58.10,48.38,46.96,33.34,32.92,28.14,26.86,25.45,24.75;HRMS(ESI)C21H26BrClN3O[M+H]+,[M+2+H]+:理论值450.0942,452.0922,实测值450.0929,452.0910。
实施例18
合成结构式如下的(E)-4-(5-(3-氯-2-(4-(三氟甲基)苯基)丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的1-(5-甲基呋喃-2-基)-3-(4-(三氟甲基)苯基)环丁烷-1-醇替换实施例1的1-(5-甲基呋喃-2-基)环丁烷-1-醇,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯-2-(4-(三氟甲基)苯基)丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为54%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.57(d,J=8.0Hz,2H),7.14(d,J=8.0Hz,2H),7.06(d,J=15.8Hz,1H),6.98(d,J=15.8Hz,1H),3.92-3.71(m,3H),3.55(dd,J=14.7,4.0Hz,1H),3.13(dt,J=13.3,4.5Hz,1H),2.96(dd,J=14.7,9.9Hz,1H),2.27(s,3H),2.09-1.94(m,2H),1.88(s,2H),1.40-1.16(m,6H);13C NMR(150MHz,CDCl3):δ197.65,143.16,140.37,133.24,128.85,127.87,126.54,126.07,126.04,58.24,48.74,46.81,33.39,32.95,28.44,26.89,25.53,25.49,24.78;HRMS(ESI)C22H25ClF3N3NaO[M+Na]+,[M+2+Na]+:理论值462.1530,464.1503,实测值462.1518,464.1496。
实施例19
合成结构式如下的(E)-4-(5-(3-氯-2-(萘-1-基)丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的1-(5-甲基呋喃-2-基)-3-(萘-1-基)环丁烷-1-醇替换实施例1的1-(5-甲基呋喃-2-基)环丁烷-1-醇,其他步骤与实施例1相同,得到(E)-4-(5-(3-氯-2-(萘-1-基)丙基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为54%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.87-7.82(m,1H),7.79(d,J=8.2Hz,1H),7.49(ddt,J=20.5,16.8,5.9Hz,4H),7.20(d,J=16Hz,2H),6.97(d,J=16.0Hz,1),4.37-3.93(m,2H),3.92-3.84(m,1H),3.66(dd,J=14.8,3.7Hz,1H),3.46-3.36(m,1H),3.26(s,1H),2.25(s,3H),1.92-1.74(m,2H),1.71-1.53(m,4H),1.02-0.84(m,4H);13C NMR(150MHz,CDCl3):δ198.10,140.46,135.46,133.92,133.62,131.01,130.86,129.71,129.24,128.59,127.05,126.91,126.17,125.29,121.47,65.54,57.93,47.36,32.80,27.74,25.31,25.28,24.71;HRMS(ESI)C25H29ClN3O[M+H]+,[M+2+H]+:理论值422.1994,424.1996,实测值422.1982,424.1959。
实施例20
合成结构式如下的(E)-4-(5-(2-(氯甲基)庚基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮
本实施例中,用等摩尔的1-(5-甲基呋喃-2-基)-3-戊基环丁烷-1-醇替换实施例1的1-(5-甲基呋喃-2-基)环丁烷-1-醇,其他步骤与实施例1相同,得到(E)-4-(5-(2-(氯甲基)庚基)-1-环己基-1H-1,2,3-三唑-4-基)丁-3-烯-2-酮,其产率为63%,结构表征数据为:1H NMR(400MHz,CDCl3):δ7.44(d,J=15.9Hz,1H),7.13(d,J=15.9Hz,1H),4.15(ddd,J=11.7,8.3,3.5Hz,1H),3.51(dd,J=11.4,5.2Hz,1H),3.42(dd,J=11.3,3.1Hz,1H),2.98(dd,J=15.1,8.0Hz,1H),2.75-2.67(m,1H),2.36(s,3H),2.12(ddd,J=15.8,12.5,6.5Hz,2H),1.96(t,J=14.6Hz,5H),1.39(d,J=7.3Hz,4H),1.29(dd,J=8.0,3.5Hz,6H),0.89(d,J=6.7Hz,3);13C NMR(100MHz,CDCl3):δ198.01,140.36,134.69,129.72,126.64,58.09,47.24,40.76,33.53,33.18,31.55,28.51,26.28,25.59,24.89,24.80,22.44,13.94;HRMS(ESI)C20H32ClN3NaO[M+Na]+,[M+2+Na]+:理论值388.2126,390.2098,实测值388.2129,390.2106。
发明人分别以本发明实施例1和实施例8所合成的化合物为起始原料,进行以下氯丙基烯羰三唑的衍生化实验:
化合物1可以被吗啉选择性的对氯进行亲核取代,以较高的收率得到化合物5,而亲电的烯酮部分不受影响。将化合物1和化合物2在丙酮中与两倍摩尔量的碘化钠回流就可以得到碘丙基取代的烯酮三唑3和4。3和4在三正丁基锡氢(nBu3SnH)和偶氮二异丁腈(AIBN)的条件下可以发生自由基关环反应得到相应的环己烷并三唑产物6和7。同时,化合物3和4可以与具有生物活性的天然产物,例如雌酮和香紫苏内酯衍生物发生偶联反应得到化合物8和9。
上述实验证明本发明化合物为药物和生物活性分子的多样性合成提供了更多的机会。
Claims (8)
1.一种(E)-氯丙基烯酮/烯醛三唑化合物,其特征在于该化合物的结构式如下所示:
式中R代表H或C1~C5烷基,R1代表H、C1~C5烷基、苯基、卤代苯基、C1~C4烷基取代的苯基、三氟甲基取代苯基、萘基中任意一种,R2代表C1~C5烷基、C4~C6环烷基、C2~C4烯基、苯基、苄基、C1~C4烷基取代的苯基、卤代苯基、肉桂基、卤代苄基、C1~C4烷氧基取代的苄基中任意一种。
2.根据权利要求1所述的(E)-氯丙基烯酮/烯醛三唑化合物,其特征在于:所述R代表H或甲基。
3.根据权利要求2所述的(E)-氯丙基烯酮/烯醛三唑化合物,其特征在于:所述R1代表H、C1~C5烷基、苯基、4-溴苯基、4-甲基苯基、4-三氟甲基苯基、萘基中任意一种。
4.根据权利要求2或3所述的(E)-氯丙基烯酮/烯醛三唑化合物,其特征在于:所述R2代表C1~C5烷基、环己基、环戊基、烯丙基、苯基、苄基、4-甲基苯基、4-溴代苯基、α-苯基乙基、肉桂基、4-溴代苄基、4-甲氧基苄基中的任意一种。
5.一种权利要求1所述的(E)-氯丙基烯酮/烯醛三唑化合物的合成方法,其特征在于:将式Ⅰ所示的呋喃环丁醇与式Ⅱ所示的叠氮化物加入有机溶剂中,在TiCl4作用下-20℃~常温反应,反应完全后分离纯化;
其中R代表H时,得到(E)-氯丙基烯醛三唑化合物;
R代表C1~C5烷基时,得到(E)-氯丙基烯酮三唑化合物。
6.根据权利要求5所述的(E)-氯丙基烯酮/烯醛三唑化合物的合成方法,其特征在于:所述呋喃环丁醇与叠氮化物的摩尔比为1:1~1:1.3。
7.根据权利要求5所述的(E)-氯丙基烯酮/烯醛三唑化合物的合成方法,其特征在于:所述TiCl4的加入量为呋喃环丁醇摩尔量的1~1.3倍。
8.根据权利要求5所述的(E)-氯丙基烯酮/烯醛三唑化合物的合成方法,其特征在于:所述的有机溶剂为二氯甲烷、1,2-二氯乙烷、甲苯、苯中任意一种。
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