CN115894396B - 一种手性1,5-二取代四氮唑化合物及其制备方法 - Google Patents
一种手性1,5-二取代四氮唑化合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种手性1,5‑二取代四氮唑化合物及其制备方法，其中，所述制备方法包括在金属中心手性钴(III)配阴离子催化条件下，醛、胺、叠氮酸或叠氮基三甲基硅烷、异氰发生四组分Ugi‑azide反应。本发明提供的制备方法操作简便、反应条件温和、原料经济易得，且制备得到的1,5‑二取代四氮唑化合物光学纯度高，有望在不对称合成以及医药、农药等研发领域得到广泛应用。
Description
技术领域
本发明涉及有机化学领域，具体地，涉及一种手性1,5-二取代四氮唑化合物及其制备方法。
背景技术
自1885年Bladin制备四氮唑以来，这种富氮杂环及其衍生物已在许多学科中得到广泛应用。1,5-二取代四氮唑类化合物具有多种生物活性，是FDA 批准的药物中最常见的十种杂环化合物之一。许多文献公开报道了各种1,5- 二取代四氮唑类化合物的生物活性，例如：文献Org.Process Res.Dev.2012, 16,682；J.Med.Chem.2004,47,5597报道了该类化合物具有抗高血压活性；文献Jpn.J.Pharmacol.1988,48,91报道了该类化合物具有抗哮喘活性；文献Thromb.Haemost.1999,82,435报道了该类化合物具有PDE3抑制活性；文献J.Pharmacol.Exp.Ther.2001,298,986；Neurosci.Biobehav.Rev.2002,26,429报道了该类化合物广泛应用于焦虑症的治疗；文献Bioorg.Med.Chem. Lett.2008,18,3899；ExpertOpin.Ther.Pat.2012,22,223；Eur.J.Med.Chem. 2016,122,55等报道了该类化合物具有抗癌活性；文献Chem.Pharm.Bull. 2004,52,1422；Eur.J.Med.Chem.2014,80,447等还记载了该类化合物具有抗菌和抗病毒活性。
1,5-二取代四氮唑类化合物在生命科学、药物化学、农业、炸药和摄影等工业领域有着广泛的应用前景，同时由于药物分子中起生物活性作用的往往是消旋体中的一种対映异构体，人们迫切地需要发展高效的合成该类化合物的方法，尤其是合成手性的1,5-二取代四氮唑类化合物的方法。因此，合成结构新颖的手性1,5-二取代四氮唑化合物以及发展其高效的不对称催化合成方法，对发现具有重要生物活性的药物先导化合物是非常必要的。
发明内容
本发明的目的是提供一种手性1,5-二取代四氮唑化合物及其制备方法，该制备方法不仅收率和ee值较高，且反应中的催化剂经济易得，底物对映选择性较高。
为了实现上述目的，本发明提供了一种手性1,5-二取代四氮唑化合物，所述手性1,5-二取代四氮唑化合物的结构通式如下：
其中，
R1为氢、C1-6的直链或带有支链的烷基、C3-6的环烷基、C6-14的芳基或取代芳基中的一种；
R2为氢、C1-6的直链或带有支链的烷基、C6-14的芳基或取代芳基中的一种；
R3为氢、C1-10的直链或带有支链的烷基、C3-6的环烷基中的一种。
优选地，R1为C6-14的取代芳基，取代芳基为C1-6的烷基取代的芳基、 C1-3的烷氧基取代的芳基、氰基或硝基取代的芳基或卤代芳基；
优选地，R2为C6-14的取代芳基，取代芳基为C1-6的烷基取代的芳基、 C1-3的烷氧基取代的芳基、硝基取代的芳基或卤代芳基。
优选地，烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、正庚基、异庚基、正辛基或异辛基中的一种。
优选地，环烷基为环丙基、环丁基、环戊基或环己基中的一种。
本发明还提供了一种如上述的手性1,5-二取代四氮唑化合物的制备方法，所述制备方法包括：
在金属中心手性钴(III)配阴离子催化条件下，醛、胺、叠氮酸或叠氮基三甲基硅烷、异氰发生四组分Ugi-azide反应。
优选地，所述制备方法包括：
(1)将醛、胺、叠氮化钠、金属中心手性钴(III)配阴离子、活化的分子筛、有机溶剂和乙酸在第一条件下混合；
(2)加入异氰化物在第二条件下混合；得到手性1,5-二取代四氮唑化合物；反应线路如下：
具体地，将将醛、胺、叠氮化钠、金属中心手性钴(III)配阴离子、活化的分子筛和甲苯装入干燥的小瓶中，将所得溶液在室温下搅拌10-15分钟，然后将乙酸加入混合物中。在-20℃～-40℃下搅拌10-15分钟后，将异氰化物(0.30mmol)加入混合物中。然后将混合物在-20℃～-40℃继续搅拌 24～48h小时。反应混合物直接通过快速柱层析法纯化，最后分离出手性1,5- 二取代四氮唑化合物。
优选地，所述制备方法包括：
(1)将醛、胺、金属中心手性钴(III)配阴离子、活化的分子筛、有机溶剂、异氰化物在第一条件下混合；
(2)加入叠氮基三甲基硅烷在第二条件下混合；得到手性1,5-二取代四氮唑化合物；反应线路如下：
具体地，在室温下，将醛、胺、金属中心手性钴(III)配阴离子、活化的分子筛和甲苯装入干燥的小瓶中，将所得溶液在室温下搅拌10-15分钟，然后将异氰化物加入混合物中。在-20℃～-40℃下搅拌10-15分钟后，将叠氮基三甲基硅烷(TMSN3)加入混合物中。然后将混合物在-20℃～-40℃继续搅拌24～48h小时。反应混合物直接通过快速柱层析法纯化，最后分离出手性1,5-二取代四氮唑化合物。
优选地，为了提高产物的对映异构选择性以及提高产率，第一条件包括温度为-20℃～-40℃；时间为10～15min；
优选地，第二条件包括温度为-20℃～-40℃；时间为24～48h。
优选地，有机溶剂为甲苯或乙醇中的一种或多种。为了提高产物的对映异构选择性以及提高产率，优选地，有机溶剂为甲苯或体积比为10/1的甲苯与甲醇的混合溶剂。
在上述的制备方法中，金属中心手性钴(III)配阴离子催化剂可采用文献Angew.Chem.Int.Ed.2015,54,11209；Angew.Chem.Int.Ed.2017,56,11931；ZL 201510426983.X报道的方法制备。
有益效果：本发明制备的手性1,5-二取代四氮唑化合物，其潜在用途是作为一种生物活性分子骨架。此外，本发明对该类化合物进行了初步的抑菌生物活性测试，结果显示其对植物病原真菌具有一定的抑菌活性。
本发明制备手性1,5-二取代四氮唑合物的方法，是一类金属中心手性配合物催化下的不对称多组分反应，从非手性的原料出发，一步构建出手性的 1,5-二取代四氮唑结构，操作简便、反应条件温和、原料经济易得，且制备得到的4-SO2MeC6H4和4-CF3C6H4等取代的1,5-二取代四氮唑化合物光学纯度高(ee值高达98％)。本发明制备得到的手性1,5-二取代四氮唑化合物，有望在不对称合成以及医药、农药等研发领域得到广泛应用。
本发明的其他特征和优点将在随后的具体实施方式部分予以详细说明。
附图说明
附图是用来提供对本发明的进一步理解，并且构成说明书的一部分，与下面的具体实施方式一起用于解释本发明，但并不构成对本发明的限制。在附图中：
图1是实施例1制得的化合物的晶体衍射结构图。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。实施例中，反应的产率指的是分离收率，ee指的是反应的对映异构体过量的百分比。
在实施例中使用的试剂，如无另外指出，均购自安耐吉、阿拉丁、上海国药公司。在实施例中使用的溶剂，如无另外指出，均购自优普特股份有限公司。在实施例中使用的薄层层析硅胶H，如无另外指出，均购自青岛海洋化工公司。
实施例1
在室温下，将4-溴苯甲醛(0.15mmol)、4-三氟甲基苯胺(0.10mmol)、叠氮化钠(0.30mmol)、金属中心手性钴(III)配阴离子(0.01mmol)、活化的分子筛(100.0mg，购自天津阿法埃莎公司)和甲苯(2.0mL)装入 10.0mL干燥的小瓶中，将所得溶液在室温下搅拌10-15分钟，然后将乙酸 (0.40mmol)加入混合物中。在-30℃下搅拌10-15分钟后，将叔丁基异氰 (0.30mmol，购自上海安耐吉公司)加入混合物中。然后将混合物在-30℃继续搅拌36小时。然后，向装有反应混合物的试管中加入预先冷冻好的三乙胺(1.0mmol)淬灭反应，用1.0mL二氯甲烷溶解稀释反应混合物。在普通玻璃柱中加入薄层层析硅胶H，将上述溶解的混合物用氮气加压柱层析 (柱长15厘米，流速3滴/秒)，洗脱剂为石油醚：乙酸乙酯：二氯甲烷＝6： 1：1(体积比)，直接通过快速柱层析法纯化，最后分离出手性1,5-二取代四氮唑化合物5a，产率82％，ee＝91％。其绝对构型通过重结晶后晶体 (ee>99％)的单晶X射线衍射(用牛津衍射公司的Gemimi S Ultra四圆单晶衍射仪在120K下测定)确定为(R)-型，下述实施例中的化合物5b-5an的绝对构型以此类推。
化合物5a的表征数据：
(R)-N-((4-bromophenyl)(1-(tert-butyl)-1H-tetrazol-5-yl)methyl)-4-(triflu oromethyl)aniline:白色固体；m.p.:143.5–145.1℃；[α]D 25＝-80.8(c 0.38,MeOH)；1H-NMR(600MHz,CDCl3)δ7.50(d,J＝8.2Hz,2H),7.40(d,J＝8.3 Hz,2H),7.25(d,J＝10.0Hz,2H),6.66(d,J＝8.4Hz,2H),6.12(d,J＝8.6Hz,1H),5.30(d,J＝8.6Hz,1H),1.73(s,9H)；13C-NMR (151MHz,CDCl3)δ154.3, 147.9,136.5,132.4,129.29,129.27,126.9(q,J＝3.8Hz),124.5(q,J＝270.4 Hz),123.1,121.0(q,J＝32.8Hz),114.2,113.13,113.10,62.0,53.3,30.2；19F-NMR(564MHz,CDCl3)δ-61.5；HRMS(ESI)calculated for C19H20 79BrF3N5[M+H]+:454.0854,found:454.0860；HRMS(ESI)calculated for C19H20 81BrF3N5[M+H]+:456.0834,found:456.0843；Enantiomeric ratio: 95.5:4.5,determined by HPLC(Daicel Chirapak IF,isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝5.26min(major),tR＝ 6.45min(minor).
实施例2
采用与实施例1相同的方法，其中：采用的醛为4-氟苯甲醛。最后分离得到产品5b，产率78％，ee＝90％。
化合物5b的表征数据：
(R)-N-((1-(tert-butyl)-1H-tetrazol-5-yl)(4-fluorophenyl)methyl)-4-(triflu oromethyl)aniline:白色泡沫状；[α]D 25＝-108.4(c 0.31,MeOH)；1H-NMR(600MHz,CDCl3)δ7.40(d,J＝8.3Hz,2H),7.37–7.32(m,2H),7.06(t,J＝ 8.4Hz,2H),6.66(d,J＝8.3Hz,2H),6.15(d,J＝8.6Hz,1H),5.24(d,J＝8.4Hz,1H),1.72(s,9H)；13C-NMR(151MHz,CDCl3)δ163.6,162.0,154.6,148.0, 133.3,129.5(d,J＝8.4Hz),126.8(q,J＝3.8Hz),124.5(q,J＝270.9Hz),120.9(q,J＝32.3Hz),116.3(d,J＝21.9Hz),113.1,61.9,53.2,30.1；19F-NMR(564 MHz,CDCl3)δ-112.2,-61.5；HRMS(ESI)calculated for C19H20F4N5[M+H]+: 394.1655,found:394.1658；Enantiomeric ratio:95:5,determined by HPLC(Daicel Chirapak IF,isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30 ℃,λ＝254nm):tR＝4.83min(major),tR＝5.97min(minor).
实施例3
采用与实施例1相同的方法，其中：采用的醛为4-氯苯甲醛。最后分离得到产品5c，产率69％，ee＝90％。
化合物5c的表征数据：
(R)-N-((1-(tert-butyl)-1H-tetrazol-5-yl)(4-chlorophenyl)methyl)-4-(triflu oromethyl)aniline:淡黄色泡沫状；[α]D 25＝-92.8(c 0.28,MeOH)；1H-NMR(600MHz,CDCl3)δ7.40(d,J＝8.4Hz,2H),7.37–7.33(m,2H),7.32–7.29 (m,2H),6.65(d,J＝8.4Hz,2H),6.14(d,J＝8.6Hz,1H),5.25(d,J＝8.6Hz,1H),1.73(s,9H)；13C-NMR(151MHz,CDCl3)δ154.3,147.9,136.0,135.0, 129.5,129.0,126.8(q,J＝3.6Hz),124.5(q,J＝270.5Hz),121.0(q,J＝33.8Hz),113.1,62.0,53.2,30.1；19F-NMR(564MHz,CDCl3)δ-61.5；HRMS(ESI) calculated for C19H20 35ClF3N5[M+H]+:410.1354,found:410.1362；HRMS(ESI)calculated for C19H20 37ClF3N5[M+H]+:412.1324,found:412.1304； Enantiomeric ratio:95:5,determined by HPLC(Daicel Chirapak IF, isopropanol/hexanel＝30/70,flowrate 1.0mL/min,T＝30℃,λ＝254nm):tR＝5.10min(major),tR＝6.18min(minor).
实施例4
采用与实施例1相同的方法，其中：采用的醛为4-硝基苯甲醛。最后分离得到产品5e，产率82％，ee＝94％。
化合物5e的表征数据：
(R)-N-((1-(tert-butyl)-1H-tetrazol-5-yl)(4-nitrophenyl)methyl)-4-(trifluoromethyl)aniline:淡黄色泡沫状；[α]D 25＝-70.1(c 0.28,MeOH)；1H-NMR(600MHz,CDCl3)δ8.24(d,J＝8.7Hz,2H),7.60(d,J＝8.6Hz,2H),7.42(d,J＝8.4 Hz,2H),6.67(d,J＝8.4Hz,2H),6.26(d,J＝8.7Hz,1H),5.28(d,J＝8.6Hz,1H),1.78(s,9H)；13C-NMR(151MHz,CDCl3)δ153.7,148.1,147.4,144.4, 128.5,127.0(q,J＝3.8Hz),125.3(q,J＝276.0Hz),124.4,121.6(q,J＝37.1Hz),113.1,62.2,53.0,30.2；19F-NMR(564MHz,CDCl3)δ-61.6；HRMS(ESI) calculated for C19H20F3N6O2[M+H]+:421.1594,found:421.1597；Enantiomeric ratio:97:3,determined by HPLC(Daicel Chirapak IF,isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝9.20min(major),tR＝6.77min(minor).
实施例5
采用与实施例1相同的方法，其中：采用的醛为4-甲磺酰基苯甲醛。最后分离得到产品5h，产率70％，ee＝98％。
化合物5h的表征数据：
(R)-N-((1-(tert-butyl)-1H-tetrazol-5-yl)(4-(methylsulfonyl)phenyl)methyl )-4-(trifluoromethyl)-aniline:白色泡沫状；[α]D 25＝-67.9(c 0.32,MeOH)；1H-NMR(600MHz,CDCl3)δ7.93(d,J＝8.3Hz,2H),7.62(d,J＝8.2Hz,2H), 7.40(d,J＝8.4Hz,2H),6.68(d,J＝8.4Hz,2H),6.25(d,J＝8.6Hz,1H),5.51 (d,J＝8.4Hz,1H),3.03(s,3H),1.78(s,9H)；13C-NMR(151MHz,CDCl3)δ 153.8,147.6,143.6,141.0,128.5,128.2,127.0(q,J＝3.8Hz),124.4(q,J＝270.8Hz),121.2(q,J＝32.8Hz),113.0,62.3,53.0,44.3,30.2；19F-NMR(564 MHz,CDCl3)δ-61.5；HRMS(ESI)calculated for C20H22F3N5NaO2S[M+Na]+:476.1344,found:476.1338；Enantiomeric ratio:99:1,determined by HPLC(DaicelChirapak IF,isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30 ℃,λ＝254nm):tR＝6.07min(major),tR＝7.83min(minor).
实施例6
采用与实施例1相同的方法，其中：采用的醛为2-氯苯甲醛。最后分离得到产品5k，产率62％，ee＝88％。
化合物5k的表征数据：
(R)-N-((1-(tert-butyl)-1H-tetrazol-5-yl)(2-chlorophenyl)methyl)-4-(triflu oromethyl)aniline:无色油状物；[α]D 25＝-76.3(c 0.25,MeOH)；1H-NMR(600MHz,CDCl3)δ7.47–7.43(m,1H),7.43–7.36(m,3H),7.35–7.28(m,2H), 6.67(d,J＝8.4Hz,2H),6.53(d,J＝9.1Hz,1H),5.13(d,J＝9.1Hz,1H),1.75 (s,9H)；13C-NMR(151MHz,CDCl3)δ153.7,147.9,134.9,133.1,130.2,130.0, 128.9,127.7,126.9(q,J＝3.8Hz),122.7(q,J＝272.2Hz),121.1(q,J＝32.8Hz),113.1,62.4,50.6,29.9；19F-NMR(564MHz,CDCl3)δ-61.5；HRMS(ESI) calculated for C19H20 35ClF3N5[M+H]+:410.1359,found:410.1366；HRMS(ESI) calculated for C19H20 37ClF3N5[M+H]+:412.1324,found:412.1284； Enantiomericratio:94:6,determined by HPLC(Daicel Chirapak IA,isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝7.00min(major),tR＝5.36min(minor).
实施例7
采用与实施例1相同的方法，其中：采用的醛为2-三氟甲基苯甲醛。最后分离得到产品5l，产率78％，ee＝90％。
化合物5l的表征数据：
(R)-N-((1-(tert-butyl)-1H-tetrazol-5-yl)(2-(trifluoromethyl)phenyl)methy l)-4-(trifluoromethyl)-aniline:淡黄色油状物；[α]D 25＝-38.5(c 0.34,MeOH)；1H-NMR(600MHz,CDCl3)δ7.75(d,J＝7.9Hz,2H),7.61(t,J＝7.6Hz,1H), 7.50(t,J＝7.7Hz,1H),7.39(d,J＝8.5Hz,2H),6.64(d,J＝8.5Hz,2H),6.58(d, J＝8.9Hz,1H),5.22(d,J＝8.8Hz,1H),1.77(s,9H)；13C-NMR(151MHz, CDCl3)δ153.7,147.3,135.6,132.8,129.0,128.8,127.8(q,J＝30.7Hz),127.0 (q,J＝3.6Hz),126.6(q,J＝5.8Hz),124.4(q,J＝266.1Hz),123.5(q,J＝272.4Hz),121.2(q,J＝31.0Hz),112.9,63.0,49.3,29.8；19F-NMR(564MHz,CDCl3) δ-61.5,-59.3；HRMS(ESI)calculated for C20H19F6N5Na[M+Na]+:466.1442, found:466.1446；Enantiomeric ratio:95:5,determined by HPLC(DaicelChirapak IF,isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝4.34min(major),tR＝3.89min(minor).
实施例8
采用与实施例1相同的方法，其中：采用的醛为2-呋喃甲醛。最后分离得到产品5q，产率83％，ee＝85％。
化合物5q的表征数据：
(S)-N-((1-(tert-butyl)-1H-tetrazol-5-yl)(furan-2-yl)methyl)-4-(trifluorom ethyl)aniline:无色油状物；[α]D 25＝-26.2(c 0.30,MeOH)；1H-NMR(600MHz,CDCl3)δ7.44(d,J＝8.4Hz,2H),7.40–7.36(m,1H),6.76(d,J＝8.4Hz,2H), 6.38–6.31(m,1H),6.30–6.22(m,2H),5.36(d,J＝9.0Hz,1H),1.74(s,9H)；13C-NMR(151MHz,CDCl3)δ153.0,150.4,148.0,143.0,126.8(q,J＝3.7Hz), 124.5(q,J＝270.2Hz),121.1(q,J＝32.2Hz),113.2,111.0,109.1,62.1,48.2, 29.9；19F-NMR(564MHz,CDCl3)δ-61.5；HRMS(ESI)calculated for C17H19F3N5O[M+H]+:366.1536,found:366.1539；Enantiomericratio:92.5:7.5, determined by HPLC(Daicel Chirapak IF,isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝5.42min(major),tR＝6.75min(minor).
实施例9
采用与实施例1相同的方法，其中：采用的醛为2-吡啶甲醛。最后分离得到产品5s，产率67％，ee＝45％。
化合物5s的表征数据：
(R)-N-((1-(tert-butyl)-1H-tetrazol-5-yl)(pyridin-2-yl)methyl)-4-(trifluoro methyl)aniline:淡黄色油状物；[α]D 25＝-65.5(c 0.25,MeOH)；1H-NMR(600MHz,CDCl3)δ8.57–8.52(m,1H),7.72–7.65(m,1H),7.52(d,J＝7.9Hz, 1H),7.40(d,J＝8.5Hz,2H),7.26–7.22(m,1H),6.77(d,J＝8.5Hz,2H),6.38 (d,J＝6.8Hz,1H),5.89(d,J＝6.6Hz,1H),1.73(s,9H)；13C-NMR(151MHz, CDCl3)δ157.0,154.4,148.8,148.2,137.6,126.8(q,J＝3.7Hz),124.6(q,J＝ 270.6Hz),123.4,121.8,120.5(q,J＝32.6Hz),113.0,62.4,55.3,30.0；19F-NMR(564MHz,CDCl3)δ-61.4；HRMS(ESI)calculated for C18H20F3N6[M+H]+:377.1702,found:377.1710；Enantiomeric ratio:72.5:27.5,determined by HPLC(Daicel Chirapak IF,isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝6.48min(major),tR＝5.42min(minor).
实施例10
采用与实施例1相同的方法，其中：采用的醛为环己基甲醛，溶剂选用体积比为10/1的甲苯与甲醇的混合溶剂。最后分离得到产品5u，产率58％， ee＝71％。
化合物5u的表征数据：
(R)-N-((1-(tert-butyl)-1H-tetrazol-5-yl)(cyclohexyl)methyl)-4-(trifluorom ethyl)aniline:无色油状物；[α]D 25＝-48.9(c 0.22,MeOH)；1H-NMR(600MHz,CDCl3)δ7.40(d,J＝8.4Hz,2H),6.67(d,J＝8.4Hz,2H),4.94–4.88(m,1H), 4.56(d,J＝10.0Hz,1H),2.16–2.09(m,1H),2.04–2.00(m,1H),1.81–1.77(m,1H),1.73(s,9H),1.44–1.39(m,1H),1.34–1.07(m,7H)；13C-NMR(151 MHz,CDCl3)δ155.3,149.4,126.8(q,J＝3.7Hz),124.6(q,J＝270.5Hz), 119.8(q,J＝33.1Hz),112.5,61.5,54.4,44.8,30.7,30.5,29.2,26.1,26.0,25.9；19F-NMR(564MHz,CDCl3)δ-61.3；HRMS(ESI)calculated forC19H27F3N5[M+H]+:382.2219,found:382.2223；Enantiomeric ratio:85.5:14.5,determined by HPLC(Daicel Chirapak IF,isopropanol/hexanel＝10/90,flow rate1.0mL/min,T＝30℃,λ＝254nm):tR＝7.63min(major),tR＝8.26min(minor).
实施例11
采用与实施例1相同的方法，其中：采用的醛为4-氰基苯甲醛，采用的胺为4-氟苯胺。最后分离得到产品5x，产率71％，ee＝96％。
化合物5x的表征数据：
(R)-4-((1-(tert-butyl)-1H-tetrazol-5-yl)((4-fluorophenyl)amino)methyl)be nzonitrile:白色泡沫状；[α]D 25＝-78.1(c 0.25,MeOH)；1H-NMR(600MHz,CDCl3)δ7.66(d,J＝8.0Hz,2H),7.50(d,J＝8.0Hz,2H),6.92–6.83(m,2H), 6.65–6.57(m,2H),6.08(d,J＝9.4Hz,1H),4.72(d,J＝9.4Hz,1H),1.73(s,9H)；13C-NMR(151MHz,CDCl3)δ157.9,156.3,154.1,143.1,141.3,132.8, 128.4,118.0,116.2(d,J＝22.7Hz),116.0(d,J＝7.7Hz),112.8,62.0,55.1,30.2；19F-NMR(564MHz,CDCl3)δ-124.2；HRMS(ESI)calculatedfor C19H20FN6[M+H]+:351.1728,found:351.1733；Enantiomeric ratio:98:2,determinedby HPLC(Daicel Chirapak IA,isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝12.70min(major),tR＝9.29min(minor).
实施例12
采用与实施例1相同的方法，其中：采用的醛为4-氰基苯甲醛，采用的胺为4-溴苯胺。最后分离得到产品5z，产率72％，ee＝94％。
化合物5z的表征数据：
(R)-4-(((4-bromophenyl)amino)(1-(tert-butyl)-1H-tetrazol-5-yl)methyl)b enzonitrile:白色泡沫状；[α]D 25＝-47.4(c 0.29,MeOH)；1H-NMR(600MHz, CDCl3)δ7.66(d,J＝8.3Hz,2H),7.51(d,J＝8.2Hz,2H),7.26(d,J＝9.7Hz, 2H),6.53(d,J＝8.7Hz,2H),6.11(d,J＝9.1Hz,1H),4.98(d,J＝9.1Hz,1H), 1.75(s,9H)；13C-NMR (151MHz,CDCl3)δ153.9,144.0,142.9,132.8,132.4, 128.3,118.0,115.7,112.8,111.7,62.1,53.9,30.2；HRMS(ESI)calculated for C19H20 79BrN6[M+H]+:411.0927,found:411.0934；HRMS(ESI)calculated for C19H20 81BrN6[M+H]+:413.0907,found:413.0912；Enantiomeric ratio:97:3, determined by HPLC(Daicel Chirapak IA,isopropanol/hexanel＝30/70,flow rate1.0mL/min,T＝30℃,λ＝254nm):tR＝9.42min(major),tR＝14.50min (minor).
实施例13
采用与实施例1相同的方法，其中：采用的醛为4-氰基苯甲醛，采用的胺为3-三氟甲基-4-氟苯胺。最后分离得到产品5ac，产率72％，ee＝90％。
化合物5ac的表征数据：
(R)-4-((1-(tert-butyl)-1H-tetrazol-5-yl)((4-fluoro-3-(trifluoromethyl)phen yl)amino)methyl)-bezonitrile:白色泡沫状；[α]D 25＝-78.3(c0.30,MeOH)；1H-NMR(600MHz,CDCl3)δ7.68(d,J＝7.8Hz,2H),7.50(d,J＝7.9Hz,2H), 7.01(t,J＝9.2Hz,1H),6.85–6.80(m,1H),6.80–6.75(m,1H),6.10(d,J＝8.4 Hz,1H),5.11(d,J＝8.8Hz,1H),1.73(s,9H)；13C-NMR(151MHz,CDCl3)δ 153.8,142.5,141.5(d,J＝2.3Hz),133.1,128.6,122.5(q,J＝272.3Hz),119.2(d,J＝7.4Hz),118.9(q,J＝13.6Hz),118.2(d,J＝22.0Hz),118.0,113.3,111.9 (q,J＝4.5Hz),62.3,54.7,30.3；19F-NMR(564MHz,CDCl3)δ-126.8,-61.7； HRMS(ESI)calculated for C20H19F4N6[M+H]+:419.1607,found:419.1601； Enantiomeric ratio:95:5,determined by HPLC(Daicel Chirapak IF,isopropanol/hexanel＝20/80,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝4.16min(major),tR＝4.67min(minor).
实施例14
采用与实施例1相同的方法，其中：采用的醛为4-氰基苯甲醛，采用的胺为4-三氟甲基-3-溴苯胺。最后分离得到产品5ad，产率68％，ee＝95％。
化合物5ad的表征数据：
(R)-4-(((3-bromo-4-(trifluoromethyl)phenyl)amino)(1-(tert-butyl)-1H-tet razol-5-yl)methyl)-benzonitrile:白色泡沫状；[α]D 25＝-47.9(c 0.33,MeOH)；1H-NMR(600MHz,CDCl3)δ7.70(d,J＝8.2Hz,2H),7.51(d,J＝8.2Hz,2H), 7.45(d,J＝8.6Hz,1H),6.95–6.89(m,1H),6.59–6.54(m,1H),6.16(d,J＝8.6Hz,1H),5.32(d,J＝8.5Hz,1H),1.76(s,9H)；13C-NMR(151MHz,CDCl3) δ153.6,148.3,142.1,133.2,129.3(q,J＝4.5Hz),128.5,123.3(q,J＝271.8Hz),119.1,117.9,113.5,111.4,62.4,53.3,30.4；19F-NMR(564MHz,CDCl3)δ-61.2； HRMS(ESI)calculated for C20H19 79BrF3N6[M+H]+:479.0807,found:479.0800； HRMS(ESI)calculated for C20H19 81BrF3N6[M+H]+:481.0786,found:481.0780； Enantiomeric ratio:97.5:2.5,determined by HPLC(Daicel Chirapak IF,isopropanol/hexanel＝20/80,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝6.72min(major),tR＝5.70min(minor).
实施例15
采用与实施例1相同的方法，其中：采用的醛为4-溴苯甲醛，采用的胺为4-三氟甲基苯胺，采用的异氰化物为环戊基异氰。最后分离得到产品5ai，产率72％，ee＝80％。
化合物5ai的表征数据：
(R)-N-((4-bromophenyl)(1-cyclopentyl-1H-tetrazol-5-yl)methyl)-4-(triflu oromethyl)aniline:白色泡沫状；[α]D 25＝-69.7(c 0.34,MeOH)；1H-NMR(600MHz,CDCl3)δ7.51(d,J＝8.4Hz,2H),7.39(d,J＝8.5Hz,2H),7.28(d,J＝8.4Hz,2H),6.67(d,J＝8.5Hz,2H),5.87(d,J＝6.7Hz,1H),5.52(d,J＝6.6Hz, 1H),4.79–4.72(m,1H),2.19–2.10(m,2H),2.05–1.91(m,2H),1.85–1.65 (m,4H).13C-NMR(151MHz,CDCl3)δ153.9,147.8,136.0,132.6,129.0,126.8 (q,J＝3.8Hz),124.5(q,J＝270.8Hz),123.3,120.9(q,J＝32.9Hz),113.0,59.6,52.6,33.3,33.3,24.6,24.5；19F-NMR(564MHz,CDCl3)δ-61.44；HRMS(ESI) calculated for C20H19 79BrF3N5Na[M+Na]+:488.0674,found:488.0677；HRMS(ESI)calculated for C20H19 81BrF3N5Na[M+Na]+:490.0653,found:490.0661；Enantiomeric ratio:90:10,determined by HPLC(Daicel Chirapak IF, isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝4,81min(major),tR＝5.22min(minor).
实施例16
采用与实施例1相同的方法，其中：采用的醛为4-氰基苯甲醛，采用的胺为4-三氟甲基苯胺，采用的异氰化物为正丁基异氰。最后分离得到产品 5ak，产率59％，ee＝68％。
化合物5ak的表征数据：
(R)-4-((1-butyl-1H-tetrazol-5-yl)((4-(trifluoromethyl)phenyl)amino)met hyl)benzonitrile:白色泡沫状；[α]D 25＝-37.1(c 0.24,MeOH)；1H-NMR(600 MHz,CDCl3)δ7.69(d,J＝8.3Hz,2H),7.56(d,J＝8.3Hz,2H),7.41(d,J＝8.5 Hz,2H),6.67(d,J＝8.5Hz,2H),5.92(d,J＝7.0Hz,1H),5.52(d,J＝6.9Hz,1H),4.31–4.25(m,2H),1.85–1.68(m,2H),1.34–1.27(m,2H),0.90(t,J＝ 7.4Hz,3H)；13C-NMR(151MHz,CDCl3)δ153.8,147.4,141.9,133.1,128.1, 126.9(q,J＝3.7Hz),124.4(q,J＝270.8Hz),121.5(q,J＝32.9Hz),113.3,113.1,52.4,47.7,31.3,19.6,13.3.；19F-NMR(564MHz,CDCl3)δ-61.6；HRMS (ESI)calculated for C20H19F3N6Na[M+Na]+:423.1521,found:423,1517； Enantiomeric ratio:84:16,determined by HPLC(Daicel Chirapak IF, isopropanol/hexanel＝10/90,flowrate 1.0mL/min,T＝30℃,λ＝254nm):tR＝17,31min(major),tR＝15,66min(minor).
实施例17
采用与实施例1相同的方法，其中：采用的醛为4-溴苯甲醛，采用的胺为4-三氟甲基苯胺，采用的异氰化物为异氰基乙酸甲酯。最后分离得到产品5al，产率49％，ee＝93％。
化合物5al的表征数据：
(R)-2-(5-((4-bromophenyl)((4-(trifluoromethyl)phenyl)- amino)methyl)-1H-tetrazol-1-yl)acetate:白色泡沫状；[α]D 25＝-59.8(c 0.23, MeOH)；1H-NMR(600MHz,CDCl3)δ7.53(d,J＝8.4Hz,2H),7.41(d,J＝8.6 Hz,2H),7.23(d,J＝8.4Hz,2H),6.67(d,J＝8.5Hz,2H),5.96(d,J＝6.2Hz,1H),5.31(d,J＝6.1Hz,1H),5.09(d,J＝17.6Hz,1H),4.92(d,J＝17.6Hz,1H), 3.71(s,3H)；13C-NMR (151MHz,CDCl3)δ170.1,165.7,155.0,147.8,134.9, 132.7,128.9(s),126.8(q,J＝3.8Hz),124.5(q,J＝271.0Hz),123.6,121.4(q,J＝32.9Hz),113.2(d,J＝8.6Hz),53.4,52.8,48.4；19F-NMR(564MHz,CDCl3) δ-61.5；HRMS(ESI)calculated for C18H15 79BrF3N5NaO2[M+Na]+:492.0259, found:492.0252；HRMS(ESI)calculated for C18H15 81BrF3N5NaO2[M+Na]+: 494.0238,found:494.0236；Enantiomericratio:96.5:3.5,determined by HPLC(Daicel Chirapak IF,isopropanol/hexanel＝30/70,flow rate 1.0mL/min,T＝30 ℃,λ＝254nm):tR＝8.75min(major),tR＝7.26min(minor).
实施例18
采用与实施例1相同的方法，其中：采用的醛为4-溴苯甲醛，采用的胺为4-三氟甲基苯胺，采用的异氰化物为2-异氰基-2,4,4-三甲基戊烷。最后分离得到产品5an，产率79％，ee＝82％。
化合物5an的表征数据：
(R)-N-((4-bromophenyl)(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl )methyl)-4(trifluoro-methyl)aniline:白色泡沫状；[α]D 25＝-113.6(c 0.40,MeOH)；1H-NMR(600MHz,CDCl3)δ7.50(d,J＝8.5Hz,2H),7.40(d,J＝8.4 Hz,2H),7.34(d,J＝8.4Hz,2H),6.69(d,J＝8.4Hz,2H),6.14(d,J＝8.7Hz,1H),5.34(d,J＝8.8Hz,1H),1.96(s,2H),1.86(s,3H),1.82(s,3H),0.69(s,9H)；13C-NMR(151MHz,CDCl3)δ154.6,147.9,136.5,132.3,129.4,126.8(q,J＝ 3.7Hz),124.5(q,J＝270.7Hz),123.0,121.0(q,J＝32.8Hz),113.2,65.7,54.0,53.5,31.6,30.7,30.5,30.1；19F-NMR(564MHz,CDCl3)δ-61.4；HRMS(ESI)calculated for C23H27 79BrF3N5Na[M+Na]+:532,1300,found:532,1296；HRMS (ESI)calculated for C23H27 81BrF3N5Na[M+Na]+:534,1279,found:534,1286； Enantiomericratio:91:9,determined by HPLC(Daicel Chirapak IF,isopropanol/hexanel＝20/70,flow rate 1.0mL/min,T＝30℃,λ＝254nm):tR＝7.09min(major),tR＝6.59min(minor).
检测例1
表1
表1为本发明中手性1,5-二取代四氮唑化合物的合成收率值和ee值。
检测例2
表2
采用菌丝生长速率法在体外测试了部分手性1,5-二取代四氮唑对三种植物病原真菌(梨炭疽病菌、草莓灰霉病菌和黄瓜枯萎病菌)的体外试验。如表2所示，以咪鲜胺作阳性对照，在浓度为100μg/mL时，手性1,5-二取代四氮唑5a、5b、5c、5d、5i、5q、5s、5x和5z均表现出一定的抗真菌活性，其中5s和5x对梨炭疽病菌和草莓灰霉病表现出较好的抗真菌活性，5q对三种病菌均表现出良好的抗真菌活性。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。
Claims (3)
1.一种手性1,5-二取代四氮唑化合物，其特征在于，所述手性1,5-二取代四氮唑化合物的结构式如下：
；；；；；；；；；；；；；；。
2.一种根据权利要求1所述的手性1,5-二取代四氮唑化合物的制备方法，其特征在于，所述制备方法包括：
（1）将醛式2、胺式3、叠氮化钠、金属中心手性钴(III)配阴离子、活化的4Å分子筛、甲苯和乙酸在第一条件下混合；
（2）加入异氰化物式4在第二条件下混合；得到手性1,5-二取代四氮唑化合物；反应线路图如下：
；
其中：金属中心手性钴(III)配阴离子的结构式为：；
其中：R1、R2、R3为如权利要求1所示的取代基团。
3.根据权利要求2所述的制备方法，其中，
第一条件包括温度为-20℃ ~-40℃；时间为10~15min；
第二条件包括温度为-20℃ ~-40℃；时间为24~48h。
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