CN105439966B - 化合物及其制备方法和应用 - Google Patents
化合物及其制备方法和应用 Download PDFInfo
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- CN105439966B CN105439966B CN201410476573.1A CN201410476573A CN105439966B CN 105439966 B CN105439966 B CN 105439966B CN 201410476573 A CN201410476573 A CN 201410476573A CN 105439966 B CN105439966 B CN 105439966B
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- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
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Abstract
本发明提供了化合物及其制备方法和应用,特别是式I所示化合物或其对映异构体、非对映异构体、外消旋体、药学上可接受的盐、结晶水合物、酮‑烯醇互变异构化合物或溶剂合物,R1、R2和R3分别独立地为至少一个卤素、氢、任选取代的烷基或任选取代的烷氧基;m和n分别独立地为选自0~5的整数;X为0、(CH2)s1、(CH2)s2N(R3)(CH2)s3,其中,s1、s2和s3分别独立地为1~5的整数。该化合物能够用于治疗癌症相关疾病。
Description
技术领域
本发明涉及医药领域,具体的,本发明涉及化合物及其制备方法和应用,更具体的,本发明涉及式Ι所示化合物以及衍生物及其制备方法、药物组合物、式Ι所示化合物在制备药物中的用途。
背景技术
肿瘤是机体在各种致癌因素作用下,局部组织的某一个细胞在基因水平上失去对其生长的正常调控,导致其克隆性异常增生而形成的异常病变。学界一般将肿瘤分为良性和恶性两大类。
然而,现有肿瘤的治疗手段仍有待改进。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此,本发明的一个目的在于提出一种能够用于制备治疗癌症的药物的化合物。
在本发明的第一方面,提供了一种化合物,根据本发明的实施例,该化合物为式I所示化合物或式I所示化合物的对映异构体、非对映异构体、外消旋体、药学上可接受的盐、结晶水合物、酮-烯醇互变异构化合物或溶剂合物,
其中,R1、R2和R3分别独立地为至少一个卤素、氢、任选取代的烷基或任选取代的烷氧基;m和n分别独立地为选自0~5的整数;X为0、(CH2)s1、(CH2)s2N(R3)(CH2)s3,其中, s1、s2和s3分别独立地为1~5的整数。
发明人惊奇地发现,根据本发明实施例的化合物具有有效地抗肿瘤活性。尤其是,针对癌症,例如口腔底癌、乳腺癌或鼻咽癌。
根据本发明的实施例,上述化合物还可以具有下列附加技术特征:
在本发明的一个实施例中,所述卤素为F、Cl或Br;
在本发明的一个实施例中,所述烷基和所述烷氧基分别独列地含有1~10个碳原子;
在本发明的一个实施例中,R1和R2分别独立地为至少一个H、含有1~3个碳原子的烷氧基、含有1~3碳原子的全氟烷基或Cl,任选地,所述R1和R2分别独立地为至少一个H、 -OCH3、-F、-Cl或者-CF3,任选地,所述R1和R2分别独立地代表两个卤素,任选地,所述两个卤素呈间位关系,任选地,所述两个卤素均为Cl;
在本发明的一个实施例中,s1、s2和s3分别独立地为1~3的整数,任选地s1为2或3, s2和s3分别为1;
在本发明的一个实施例中,R3为选自含有1~3个碳原子的直链或支链烷基、-R4Ar、 -Q-R5,其中,R4为含有1~3个碳原子的直链或支链烷基,Ar表示芳基,任选地,所述芳基为苯基,Q为R5为含有1~4个碳原子的直链或支链烷基。
在本发明的一个实施例中,所述化合物为下列化合物或者所述下列化合物的对映异构体、非对映异构体、外消旋体、药学上可接受的盐、结晶水合物、酮-烯醇互变异构化合物或溶剂合物:
在本发明的第二方面,本发明提供了一种制备前面所述化合物的方法,根据本发明的实施例,该方法包括:
(1)使式A所示化合物与丙炔醇进行接触,以便获得式B所示化合物;
(2)使所述式B所示化合物与二氧化锰进行接触,以便获得式C所示化合物;
(3)使所述式C所示化合物与对称的酮进行接触,以便获得式Ⅰ所示化合物;
其中,R1、R2、R3、s1、s2、s3、m、n是如前面所描述的。
根据本发明的实施例的方法,能够有效地制备前面所描述的化合物,关于该化合物的特征和优点,前面进行了详细描述,同样适用本方法,在此不再赘述。
由此,根据本发明的实施例,本发明提出了一条合成路线,可以用于制备式I所示化合物
。根据本发明的实施例,A化合物与丙炔醇摩尔比为1:1~1:3,直接采用叔丁醇/水为溶剂,催化剂抗坏血酸钠和硫酸铜或碘(氯)化亚铜,反应得到中间体B,B再用氧化剂二氧化锰氧化得C,中间体C再与对称的酮以摩尔比为2:1~4:1,有机溶剂为乙醇、乙腈、二氧六环或二氯甲烷等极性溶剂,碱催化下在20℃-100℃反应2-12小时,即可以较好的收率合成得到通式I的产物。
在本发明的第三方面,本发明提供了一种药物组合物,其包括前面所描述的化合物。发明人发现,该药物组合物能够有效地用于抗肿瘤,尤其是,针对癌症,例如口腔底癌、乳腺癌或鼻咽癌。关于该化合物的特征和优点,前面进行了详细描述,同样适用于本药物组合物,在此不再赘述。
在本发明的第四方面,本发明提供了前面所述的化合物或药物组合物在制备药物中的用途,所述药物用于治疗癌症,任选地,所述癌症为口腔底癌、乳腺癌或鼻咽癌。
具体实施方式
下面详细描述本发明的实施例。下面通过参考描述的实施例是示例性的,仅用于解释本发明,而不能理解为对本发明的限制。
实施例1
化合物1
1,5-二(1-苯甲基-1H-1,2,3-***)-1,4-戊二烯-3-酮
将0.10mol(12.7g 98%)氯化苄加入250mL三颈圆底烧瓶,150mlDMF溶解,再加入0.11mol的叠氮化钠,70℃搅拌反应3h,反应液冷却至室温,加入200ml水将不溶物溶解,转移至分液漏斗中,乙酸乙酯萃取3次(30ml×3),收集有机相,无水硫酸钠干燥2h,减压过滤,脱溶得浅黄色油状物苯甲基叠氮10.37g,粗收率78%,未提纯直接用于下一步反应。
在100mL三口瓶中加入2.67g(0.01mol)苯甲基叠氮与1.12g(0.01mol)丙炔醇。用叔丁醇与水的混合溶剂30ml溶解,搅拌下加入8mol%的抗坏血酸钠和2mol%的五水合硫酸铜,室温下搅拌反应,TLC监测,大约3h.反应完毕,向该反应体系中加入100ml水以溶解固体沉淀,转移至分液漏斗,乙酸乙酯萃取3次,每次30ml。合并有机相,无水硫酸钠干燥过夜,减压过滤脱溶得棕黄色固体。硅胶柱层析提纯,溶剂为石油醚/丙酮(体积比2∶ 1),得白色固体1-苯甲基-1H-1,2,3-***-4-甲醇2.72g,收率72%,熔点72-73℃(文献值: 73~75℃)。
将1.89g(0.01mol)1-苯甲基-1H-1,2,3-***-4-甲醇加入到100ml的单颈圆底烧瓶中,用50ml干燥的二氯甲烷溶解,再加入17.4g(0.20mol)活性二氧化锰,室温下搅拌反应, TLC监测至反应完毕。硅藻土过滤,脱溶得白色固体1-苯甲基-1H-1,2,3-***-4-甲醛1.50g,收率80%,熔点:85~86℃(文献值:88~90℃)。
向50ml的三颈瓶中加入0.38g(2mmol)1-苯甲基-1H-1,2,3-***-4-甲醛,20ml乙醇,搅拌均匀后加入0.058g(1mmol)丙酮和催化量的甲醇钠。室温搅拌至析出黄色固体。继续搅拌1h,过滤,水洗,乙醇洗。红外干燥箱干燥得0.32g黄色固体,收率80%,熔点241~243℃。
分子式:C23H20N6O:
元素分析(%),计算值:C,69.68;H,5.08;N,21.20;实测值:C,69.46;H,5.02;N,21.07;
IR(KBr,υ/cm-1):3127,3105,2924,1673(C=O),1635,1595,1466,1093,725cm-1;
1H NMR(δ,CDCl3,TMS,400MHz):5.56(s,4H,CH2Ar),7.25-7.41(m,10H,Ar-H;2H,-CH=), 7.62-7.67(m,2H,=CH-),7.62-7.67(m,2H,triazole-H)。
13C NMR(DMSO,100MHz)δ(ppm):53.0,125.9,128.0,128.3,128.9,131.6,135.6,143.4, 188.1.
EI-MS(70ev)m/z(%):396(M+).
以下化合物按照化合物11的方法制备,其结构鉴定数据如下:
化合物2
1,5-二[1-(4-甲氧基)苯甲基-1H-1,2,3-***]-1,4-戊二烯-3-酮
所得纯品为黄色固体,收率80%,熔点219-221℃。
分子式:C25H25N6O3(%)
元素分析(%),计算值:C,65.78;H,5.30;N,18.41;实测值:C,65.74;H,5.26;N,18.2.
IR(KBr)υ:3130,2953,1674(C=O),1641,1514,1250,1178,1094,816,770cm-1.
1H NMR(DMSO,400MHz)δ(ppm):3.74(s,6H,OCH3),5.57(s,4H,ArCH2),6.95(d,4H,J= 8.4Hz,H-Ar),7.27-7.33(m,4H,H-Ar;2H,=CHCO-),7.67(s,2H,=CH-),8.57(d,2H,J=16.0 Hz,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):δ52.6,55.1,114.2,125.5,125.8,127.5,129.7,131.6, 143.4,159.2,188.0.
EI-MS(70ev)m/z(%):456(M+).
化合物3
1,5-二[1-(4-甲基)苯甲基-1H-1,2,3-***]-1,4-戊二烯-3-酮
所得纯品为黄色固体,收率70%,熔点220-222℃。
分子式:C25H24N6O(%)
元素分析(%),计算值:C,70.73;H,5.70;N;19.80;实测值:C,70.64;H,5.61;N,19.57。 IR(KBr)υ:3128,3048,1674(C=O),1640,1593,1465,1093,793cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.28(s,6H,CH3),5.60(s,4H,-CH2Ar),7.19(d,4H,J= 8.0Hz,H-Ar),7.23(d,4H,J=8.0Hz,H-Ar),7.66(s,1H,triazole-H),7.70(s,1H,triazole-H), 8.58(s,2H,=CH-).
13C NMR(100MHz,dmso)δ20.8,52.9,125.9,128.1,129.4,131.7,132.7,137.7,143.4,186.9. EI-MS(70ev)m/z(%):424(M+).
化合物4
1,5-二[1-(4-氟)苯甲基-1H-1,2,3-***]-1,4-戊二烯-3-酮
所得纯品为黄色固体,收率47%,熔点244-246℃。
分子式:C23H18F2N6O(%)
元素分析(%),计算值:C,63.88;H,4.20;N,19.43;实测值:C,64.38;H,4.38;N,19.08。 IR(KBr)υ:3132,3048,1675(C=O),1642,1598,1462,1239,1093,818,772cm-1.
1H NMR(DMSO,400MHz)δ(ppm):5.66(s,4H,CH2Ar),7.21-7.25(m,4H,Ar-H),7.30(m,2H, J=15.6Hz,=CH),7.40-7.43(m,4H,Ar-H),7.68(m,2H,J=15.6Hz,=CH),8.61(s,2H, triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):52.3,115.7(d,J=21.6Hz),125.8(d,J=8.7Hz),130.4 (d,J=8.4Hz),131.7(d,J=28.0Hz),143.4,188.0.
EI-MS(70ev)m/z(%):432(M+).
实施例2
化合物5
2,6-二(1-苯甲基-1H-1,2,3-***-4-甲烯基)环己酮
将0.10mol(12.7g 98%)氯化苄加入250mL三颈圆底烧瓶,150mlDMF溶解,再加入0.11mol的叠氮化钠,70℃搅拌反应3h,反应液冷却至室温,加入200ml水将不溶物溶解,转移至分液漏斗中,乙酸乙酯萃取3次(30ml×3),收集有机相,无水硫酸钠干燥2h,减压过滤,脱溶得浅黄色油状物苯甲基叠氮10.37g,粗收率78%,未提纯直接用于下一步反应。
在100mL三口瓶中加入2.67g(0.01mol)苯甲基叠氮与2.24g(0.02mol)丙炔醇。用叔丁醇与水的混合溶剂30ml溶解,搅拌下加入5mol%的抗坏血酸钠和2mol%的五水合硫酸铜,室温下搅拌反应,TLC监测,大约3h。反应完毕,向该反应体系中加入100ml水以溶解固体沉淀,转移至分液漏斗,乙酸乙酯萃取3次,每次30ml。合并有机相,无水硫酸钠干燥过夜,减压过滤脱溶得棕黄色固体。硅胶柱层析提纯,溶剂为石油醚/丙酮(体积比 2∶1),得白色固体1-苯甲基-1H-1,2,3-***-4-甲醇2.72g,收率72%,熔点72-73℃(文献值:73~75℃)。
将1.89g(0.01mol)1-苯甲基-1H-1,2,3-***-4-甲醇加入到100ml的单颈圆底烧瓶中,用50ml干燥的三氯甲烷溶解,再加入8.7g(0.10mol)活性二氧化锰,50℃下搅拌反应,TLC监测至反应完毕。硅藻土过滤,脱溶得白色固体1-苯甲基-1H-1,2,3-***-4-甲醛1.50g,收率80%,熔点:85~86℃(文献值:88~90℃)。
向50ml的三颈瓶中加入0.57g(3mmol)1-苯甲基-1H-1,2,3-***-4-甲醛,20ml甲醇,搅拌均匀后加入0.098g(1mmol)环己酮和催化量的乙醇钠。50~60℃搅拌至析出黄色固体。继续搅拌1h,过滤,水洗,乙醇洗。红外干燥箱干燥得0.32g黄色固体,收率91%,熔点216-218℃。
分子式:C26H24N6O(%)
元素分析(%),计算值:C,71.54;H,5.54;N,19.25;实测值:C,71.27;H,5.49;N,19.07。 IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,600MHz)δ(ppm):1.88(m,2H,CH2),3.07(t,4H,CH2),5.58(s,4H,CH2), 7.29-7.61(m,10H,Ar-H),7.61(s,2H,=CH),7.69(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):21.1,28.0,52.9,124.4,126.8,127.9,128.2,128.8,135.5, 135.8,143.1,187.8.
EI-MS(70ev)m/z(%):436(M+).
化合物6
2,5-二(1-苯甲基-1H-1,2,3-***-4-甲烯基)环戊酮
所得纯品为黄色固体,收率98%,熔点233-235℃。
分子式:C25H22N6O(%)
元素分析(%),计算值:C,71.07;H,5.25;N,19.89;实测值:C,70.93;H,5.15;N,19.69。 IR(KBr)υ:3127,2933,1695(C=O),1640,1614,1174,1124,1050,717cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):3.11(s,4H,CH2),5.59(s,4H,ArCH2),7.29(d,4H,J=6.0 Hz,Ar-H),7.39(d,4H,J=7.2Hz,Ar-H),7.52(s,2H,triazole-H),7.65(s,2H,=CH-).
13C NMR(100MHz,DMSO)δ(ppm):21.1,28.0,52.9,124.4,126.8,127.9,128.2,128.8,135.5, 135.9,143.1,187.8(CO).
EI-MS(70ev)m/z(%):422(M+).
化合物7
2,6-二(1-(4-甲基)苯甲基-1H-1,2,3-***-4-甲烯基)环己酮
所得纯品为黄色固体,收率89%,熔点202-204℃。
分子式:C28H28N6O(%)
元素分析(%),计算值:C,72.39;H,6.08;N,18.09;实测值:C,72.20;H,6.05;N,18.02。 IR(KBr)υ:3124,2934,1674(C=O),1626,1589,1144,1052,785cm-1.
1H NMR(DMSO,600MHz)δ(ppm):1.82(s,2H,CH2),2.28(s,6H,CH3),2.97(s,4H,CH2), 5.61(s,4H,ArCH2),7.19(d,4H,J=7.8Hz,H-Ar),7.25(d,4H,J=7.8Hz,H-Ar),7.58(s,2H, triazole-H),8.60(s,2H,=CH-).
EI-MS(70ev)m/z(%):464(M+).
化合物8
2,6-二(1-(4-氟)苯甲基-1H-1,2,3-***-4-甲烯基)环己酮
所得纯品为黄色固体,收率83%,熔点226-227℃。
分子式:C26H22F2N6O(%)
元素分析(%),计算值:C,66.09;H,4.69;N,17.79;实测值:C,65.87;H,4.68;N,17.51。IR(KBr)υ:3126,2950,1673(C=O),1625,1511,1231,1144,1051,860,787cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.81(s,2H,CH2),2.97(s,4H,CH2),5.65(s,4H,ArCH2), 7.18-7.22(t,4H,H-Ar),7.42(t,4H,H-Ar),7.59(s,2H,triazole-H),8.60(s,2H,=CH-).
13C NMR(100MHz DMSO)δ(ppm):δ21.1,28.0,52.2,115.67(d,J=21.6Hz),124.4,126.7, 130.3(d,J=8.1Hz),132.1,135.6,143.2,160.7,163.2,187.8.
EI-MS(70ev)m/z(%):472(M+)。
实施例3
化合物9
3,5-二(1-苯甲基-1H-1,2,3-***4-甲烯基)-1-甲基哌啶-4-酮
将0.10mol(12.7g 98%)氯化苄加入250mL三颈圆底烧瓶,150mlDMF溶解,再加入0.11mol的叠氮化钠,70℃搅拌反应3h,反应液冷却至室温,加入200ml水将不溶物溶解,转移至分液漏斗中,乙酸乙酯萃取3次(30ml×3),收集有机相,无水硫酸钠干燥2h,减压过滤,脱溶得浅黄色油状物苯甲基叠氮10.37g,粗收率78%,未提纯直接用于下一步反应。
在100mL三口瓶中加入2.67g(0.01mol)苯甲基叠氮与3.36g(0.03mol)丙炔醇。用叔丁醇与水的混合溶剂50ml溶解,搅拌下加入8mol%的抗坏血酸钠和2mol%的五水合硫酸铜,室温下搅拌反应,TLC监测,大约3h。反应完毕,向该反应体系中加入100ml水以溶解固体沉淀,转移至分液漏斗,乙酸乙酯萃取3次,每次30ml。合并有机相,无水硫酸钠干燥过夜,减压过滤脱溶得棕黄色固体。硅胶柱层析提纯,溶剂为石油醚/丙酮(体积比 2∶1),得白色固体1-苯甲基-1H-1,2,3-***-4-甲醇2.72g,收率72%,熔点72-73℃(文献值:73~75℃)。
将1.89g(0.01mol)1-苯甲基-1H-1,2,3-***-4-甲醇加入到100ml的单颈圆底烧瓶中,用50ml干燥的三氯甲烷溶解,再加入26.1g(0.30mol)活性二氧化锰,80℃下搅拌反应, TLC监测至反应完毕。硅藻土过滤,脱溶得白色固体1-苯甲基-1H-1,2,3-***-4-甲醛1.50g,收率80%,熔点:85~86℃(文献值:88~90℃)。
向50ml的三颈瓶中加入0.76g(4mmol)1-苯甲基-1H-1,2,3-***-4-甲醛,20ml乙腈,搅拌均匀后加入0.11g(1mmol)1-甲基哌啶酮和催化量的氢氧化钠。室温搅拌至析出黄色固体。继续搅拌1h,过滤,水洗,乙醇洗。红外干燥箱干燥得黄色固体,收率76%,熔点 189~191℃。
化合物9
3,5-二(1-苯甲基-1H-1,2,3-***4-甲烯基)-1-甲基哌啶-4-酮
所得纯品为黄色固体,收率76%,熔点189-191℃。
分子式:C26H25N7O(%)
元素分析(%),计算值:C,69.16;H,5.58;N,21.71;实测值:C,68.88;H,5.43;N,21.56。 IR(KBr)υ:3129,2940,1680(C=O),1633,1595,1455,1298,1172,1051,717cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.45(s,3H,N-CH3),3.07(t,4H,CH2),5.58(s,4H,CH2), 7.29~7.60(m,10H,Ar-H),7.61(s,2H,=CH-),7.69(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):45.5,52.9,56.8,109.4,122.3,127.5,127.8,128.2,128.8, 133.1,135.7,142.6,185.8.
EI-MS(70ev)m/z(%):451(M+).
化合物10
3,5-二(1-苯甲基-1H-1,2,3-***4-甲烯基)-1-乙基哌啶-4-酮
所得纯品为黄色固体,收率93%,熔点200-202℃。
分子式:C27H27N7O(%)
元素分析(%),计算值:C,69.66;H,5.85;N,21.06;实测值:C,69.53;H,5.85;N,20.93。 IR(KBr)υ:3128,2970,1680(C=O),1633,1595,1170,1120,1051,714cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.08(t,CH3),2.63(q,2H,N-CH2),3.92(s,4H,CH2),5.67 (s,4H,CH2Ar),7.33-7.40(m,10H,Ar-H),7.52(s,2H,=CH),8.62(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):δ12.3,50.7,53.0,54.2,127.5,127.9,128.2,128.8,133.3, 135.8,142.7,186.3.
EI-MS(70ev)m/z(%):465(M+).
化合物11
3,5-二(1-苯甲基-1H-1,2,3-***4-甲烯基)-1-丙基哌啶-4-酮
所得纯品为黄色固体,收率92%,熔点177-179℃。
分子式:C28H29N7O(%)
元素分析(%),计算值:C,70.12;H,6.10;N,20.44;实测值:C,70.01;H,6.00;N,20.28。 IR(KBr)υ:3128,2960,1680(C=O),1633,1594,1207,1168,1051,713cm-1.
1H NMR(DMSO,600MHz)δ(ppm):0.87(t,CH3),1.52(q,CH2),2.54(t,2H,N-CH2),3.92(s, 4H,CH2),5.68(s,4H,CH2Ar),7.33-7.41(m,10H,Ar-H),7.52(s,2H,=CH),8.63(s,2H, triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):11.7,19.8,52.9,54.5,58.6,122.4,127.5,127.9,128.2, 128.8,133.2,135.7,142.6,186.2.
EI-MS(70ev)m/z(%):479(M+).
化合物12
3,5-二(1-苯甲基-1H-1,2,3-***4-甲烯基)-1-异丙基哌啶-4-酮
所得纯品为黄色固体,收率90%,熔点162-163℃。
分子式:C28H29N7O(%)
元素分析(%),计算值:C,70.12;H,6.10;N,20.44;实测值:C,70.00;H,5.82;N,20.21。 IR(KBr)υ:3128,2968,1675(C=O),1633,1587,1222,1144,1054,716cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.09(d,J=9.6Hz,CH3),2.99(m,1H,NCH),3.96(s,4H, CH2),5.68(s,4H,CH2Ar),7.33-7.40(m,10H,Ar-H),7.50(s,2H,=CH),8.60(s,2H,triazole-H). 13C NMR(DMSO,100MHz)δ(ppm):18.1,50.2,52.9,53.1,122.0,127.4,127.8,128.2,128.7, 133.9,135.7,142.7,186.7.
EI-MS(70ev)m/z(%):479(M+).
化合物13
3,5-二(1-苯甲基-1H-1,2,3-***4-甲烯基)-1-乙氧羰基哌啶-4-酮
所得纯品为黄色固体,收率88%,熔点185-185℃。
分子式:C28H27N7O3(%)
元素分析(%),计算值:C,66.00;H,5.34;N,19.24;实测值:C,65.81;H,5.18;N,19.12。IR(KBr)υ:3113,1695(C=O),1674,1631,1590,1238,1147,1056,723cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.03(t,CH3),3.98(q,COOCH2),4.96(s,4H,CH2),5.69(s, 4H,CH2Ar),7.33-7.39(m,10H,Ar-H),7.58(s,2H,=CH),8.66(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):14.3,45.3,52.9,61.2,123.3,127.9,128.1,128.2,128.8, 131.8,135.6,142.6,154.7,185.3.
EI-MS(70ev)m/z(%):509(M+).
化合物14
3,5-二(1-苯甲基-1H-1,2,3-***4-甲烯基)-1-苯甲基哌啶-4-酮
所得纯品为黄色固体,收率89%,熔点193-195℃。
分子式:C32H29N7O(%)
元素分析(%),计算值:C,72.84;H,5.54;N,18.58;实测值:C,72.65;H,5.26;N,18.34。 IR(KBr)υ:3130,2954,1680(C=O),1632,1594,1200,1123,1052,699cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.025(t,CH3),3.98(q,COOCH2),4.96(s,4H,CH2),5.69 (s,4H,CH2Ar),7.33-7.39(m,10H,Ar-H),7.58(s,2H,=CH-),8.66(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):δ52.8,54.4,60.7,122.6,127.1,127.4,127.9,128.2,128.8, 133.2,135.7,137.7,142.6,186.2.
EI-MS(70ev)m/z(%):527(M+).
化合物15
3,5-二(1-苯甲基-1H-1,2,3-***4-甲烯基)-1-苯乙基哌啶-4-酮
所得纯品为黄色固体,收率85%,熔点171-172℃。
分子式:C33H31N7O(%)
元素分析(%),计算值:C,73.18;H,5.77;N,18.10;实测值:C,73.02;H,5.64;N,17.99。IR(KBr)υ:3138,2939,1679(C=O),1631,1594,1455,1125,1052,721cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.83(t,2CH2),4.00(s,4H,CH2),5.68(s,4H,CH2Ar), 7.15-7.38(m,15H,Ar-H),7.54(s,2H,=CH),8.62(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):33.0,52.9,54.3,58.2,122.7,125.9,127.5,127.8,128.2, 128.6,128.8,133.1,135.7,140.0,142.6,186.1.
EI-MS(70ev)m/z(%):541(M+).
化合物16
3,5-二(1-苯甲基-1H-1,2,3-***4-甲烯基)-1-叔丁氧羰基哌啶-4-酮
所得纯品为黄色固体,收率76%,熔点171-172℃。
分子式:C30H31N7O3(%)
元素分析(%),计算值:C,67.02;H,5.81;N,18.24;实测值:C,66.84;H,5.55;N,18.06。 IR(KBr)υ:3126,2972,1707(C=O),1678(C=O),1631,1592,1456,1168,1144,711cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.20(s,9H,CH3),4.90(s,4H,CH2),5.68(s,4H,CH2Ar), 7.33-7.38(m,10H,Ar-H),7.57(s,2H,=CH),8.65(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):27.7,45.4,52.9,68.1,79.4,122.1,132.1,132.9,135.7, 142.5,154.0,184.9.
EI-MS(70ev)m/z(%):537.2(M+).
化合物17
3,5-二(1-苯甲基-1H-1,2,3-***4-甲烯基)-1-乙酰基哌啶-4-酮
所得纯品为黄色固体,收率88%,熔点203-205℃。
分子式:C27H25N7O2(%)
元素分析(%),计算值:C,67.63;H,5.25;N,20.45;实测值:C,67.60;H,5.15;N,20.40。 IR(KBr)υ:3130,2977,1670(C=O),1640,1585,1455,1178,1051,712cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.02(s,3H,CH3),4.99(s,2H,CH2),5.10(s,2H,CH2), 5.69(s,4H,CH2Ar),7.34-7.39(m,10H,Ar-H),7.59(d,2H,J=8.4Hz,=CH),8.68(d,2H,J=8.0Hz,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):δ21.1,43.3,46.9,53.0,122.7,123.8,127.9,128.2,128.4, 128.8,131.5,132.0,135.7,142.6,168.7,185.5.
EI-MS(70ev)m/z(%):479(M+).
化合物18
3,5-二[1-(4-甲氧基)苯甲基-1H-1,2,3-***4-甲烯基]-1-苯乙基哌啶-4-酮
所得纯品为黄色固体,收率88%,熔点150-152℃。
分子式:C35H35N7O3(%)
元素分析(%),计算值:C,69.86;H,5.86;N,16.30;实测值:C,69.56;H,5.64;N,16.07。IR(KBr)υ:3125,2954,1681(C=O),1634,1515,1251,1176,1052,850,800cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.82(t,4H,CH2),3.72(s,6H,OCH3),3.99(s,4H,CH2), 5.59(s,4H,ArCH2),6.93(d,4H,J=6.6Hz,H-Ar),7.21-7.33(m,9H,H-Ar),7.52(s,2H,=CH), 8.57(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):33.0,52.5,54.3,55.1,58.2,127.1,127.6,128.2,128.6, 129.5,133.1,140.0,142.6,159.2,186.2.
EI-MS(70ev)m/z(%):601(M+).
化合物19
3,5-二[1-(4-甲氧基)苯甲基-1H-1,2,3-***4-甲烯基]-1-叔丁氧羰基哌啶-4-酮
所得纯品为黄色固体,收率77%,熔点214-215℃。
分子式:C32H35N7O5(%)
元素分析(%),计算值:C,64.31;H,5.90;N,16.41;实测值:C,64.13;H,5.73;N,16.30。IR(KBr)υ:3113,2969,1697(C=O),1677(C=O),1633,1515,1254,1178,1051,797,767 cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.21(s,9H,CH3),3.73(s,6H,OCH3),4.88(s,4H,CH2), 5.60(s,4H,ArCH2),6.93(d,4H,J=6.8Hz,H-Ar),7.32(d,4H,J=7.2Hz,H-Ar),7.56(s,2H, =CH-),8.61(s,2H,triazole-H).
13C NMR(100MHz DMSO)δ(ppm):δ27.7,45.4,51.3,52.5,55.1,79.4,114.1,127.6,129.6, 132.0,142.5,154.0,159.2,185.5.
EI-MS(70ev)m/z(%):597(M+).
化合物20
3,5-二[1-(4-甲氧基)苯甲基-1H-1,2,3-***4-甲烯基]-1-乙氧羰基哌啶-4-酮
所得纯品为黄色固体,收率82%,熔点190-192℃。
分子式:C30H31N7O5(%)
元素分析(%),计算值:C,63.26;H,5.49;N,17.21;实测值:C,63.18;H,5.20;N,17.18.。 IR(KBr)υ:3113,2969,1698(C=O),1679(C=O),1636,1516,1253,1179,1053,790,768 cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.02(t,3H,CH3),3.73(s,6H,OCH3),3.97(q,2H,CH2), 4.95(s,4H,CH2),5.60(s,4H,ArCH2),6.94(d,4H,J=8.4Hz,H-Ar),7.32(d,4H,J=8.4Hz, H-Ar),7.56(s,2H,=CH-),8.61(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):δ(ppm)14.3,45.3,52.5,55.1,61.2,114.1,127.5,127.8, 129.6,131.7,142.5,154.7,159.2,185.3.
EI-MS(70ev)m/z(%):569(M+).
化合物21
3,5-二[1-(4-甲氧基)苯甲基-1H-1,2,3-***4-甲烯基]-1-甲基哌啶-4-酮
所得纯品为黄色固体,收率81%,熔点166-168℃。
分子式:C28H29N7O3(%)
元素分析(%),计算值:C,65.74;H,5.71;N,19.17;实测值:C,65.48;H,5.51;N,18.91。 IR(KBr)υ:3128,2937,1679(C=O),1633,1515,1253,1177,1051,796,768cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.46(s,3H,CH3),3.73(s,6H,OCH3),3.85(s,4H,CH2), 5.58(s,4H,ArCH2),6.94(d,4H,J=8.8Hz,H-Ar),7.32(d,4H,J=8.4Hz,H-Ar),7.50(s,2H, =CH-),8.57(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):δ44.6,52.4,55.1,56.9,114.1,122.4,127.3,127.6,129.6, 133.0,142.6,159.1,185.8.
EI-MS(70ev)m/z(%):511(M+).
化合物22
3,5-二[1-(4-甲氧基)苯甲基-1H-1,2,3-***4-甲烯基]-1-苯甲基哌啶-4-酮
所得纯品为黄色固体,收率83%,熔点181-183℃。
分子式:C34H33N7O3(%)
元素分析(%),计算值:C,69.49;H,5.66;N,16.68;实测值:C,69.27;H,5.38;N,16.56。 IR(KBr)υ:3129,2935,1679(C=O),1631,1515,1252,1176,1051,792,767cm-1.
1H NMR(DMSO,400MHz)δ(ppm):3.74(s,6H,OCH3),3.75(s,2H,PhCH2),3.94(s,4H,CH2), 5.55(s,4H,ArCH2),6.93(d,4H,J=8.4Hz,H-Ar),7.20-7.32(m,9H,H-Ar),7.51(s,2H,=CH-), 8.46(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):52.4,54.4,55.1,60.8,114.1,122.6,127.1,127.5,128.2, 128.8,129.6,133.1,137.7,142.5,159.1,186.2.
EI-MS(70ev)m/z(%):587(M+).
化合物23
3,5-二[1-(4-甲氧基)苯甲基-1H-1,2,3-***4-甲烯基]-1-丙基哌啶-4-酮
所得纯品为黄色固体,收率89%,熔点181-183℃。
分子式:C30H33N7O3(%)
元素分析(%),计算值:C,66.77;H,6.16;N,18.17;实测值:C,66.60;H,5.91;N,17.90。 IR(KBr)υ:3125,2959,1681(C=O),1634,1516,1255,1121,1052,825,799,517cm-1.
1H NMR(DMSO,400MHz)δ(ppm):0.86(t,3H,CH3),1.48-1.52(m,2H,CH2),2.53(t,2H, CH2),3.73(s,6H,OCH3),3.90(s,4H,CH2),5.58(s,4H,ArCH2),6.94(d,4H,J=8.4Hz,H-Ar), 7.32(d,4H,J=8.4Hz,H-Ar),7.50(s,2H,=CH-),8.57(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):δ11.6,19.8,52.4,54.5,55.1,58.6,114.1,122.5,127.2, 127.6,129.5,133.2,142.6,159.1,186.2.
EI-MS(70ev)m/z(%):539(M+).
化合物24
3,5-二[1-(4-甲基)苯甲基-1H-1,2,3-***4-甲烯基]-1-叔丁氧羰基哌啶-4-酮
所得纯品为黄色固体,收率91%,熔点220-222℃。
分子式:C32H35N7O3(%)
元素分析(%),计算值:C,67.95;H,6.24;N,17.33;实测值:C,67.84;H,6.00;N,17.05。 IR(KBr)υ:3132,2977,1705(C=O),1677(C=O),1629,1167,1141,1053,794cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.13(s,9H,-CH3),2.27(s,6H,CH3),4.67(s,4H,CH2), 5.62(s,4H,ArCH2),7.21(d,8H,J=14.8Hz,Ar-H),7.56(s,2H,triazole-H),8.62(s,2H,=CH-). 13C NMR(100MHz,DMSO)δ(ppm):20.7,27.7,45.4,52.7,79.4,109.3,127.2,127.9,129.3, 132.1,132.7,137.6,142.5,160.3,181.1,185.5.
EI-MS(70ev)m/z(%):565(M+).
化合物25
3,5-二[1-(4-甲基)苯甲基-1H-1,2,3-***4-甲烯基]-1-乙氧羰基哌啶-4-酮
所得纯品为黄色固体,收率68%,熔点213-215℃。
分子式:C30H31N7O3(%)
元素分析(%),计算值:C,67.02;H,5.81;N,18.24;实测值:C,66.79;H,5.75;N,18.10。IR(KBr)υ:3132,2977,1705(C=O),1677(C=O),1629,11673,1141,1053,794cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.02-1.05(t,3H,CH3),2.28(s,6H,CH3),3.97-3.40(q,2H, CH2),4.97(s,4H,CH2),5.64(s,4H,ArCH2),7.19(d,4H,J=6.8Hz,Ar-H),7.25(d,4H,J=7.2 Hz,Ar-H),7.58(s,2H,triazole-H),8.63(s,2H,=CH-).
13C NMR(100MHz,DMSO)δ(ppm):14.3,20.7,45.4,52.8,61.2,128.0,129.3,131.8,132.7, 137.6,142.6,154.7,185.4.
EI-MS(70ev)m/z(%):537(M+).
化合物26
3,5-二[1-(4-甲基)苯甲基-1H-1,2,3-***4-甲烯基]-1-乙酰基哌啶-4-酮
所得纯品为黄色固体,收率72%,熔点216-218℃。
分子式:C29H29N7O2(%)
元素分析(%),计算值:C,68.62;H,5.76;N,19.32;实测值:C,68.42;H,5.50;N,19.16。 IR(KBr)υ:3101,1681(C=O),1641(C=O),1597,1457,1151,1056,787cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.02(s 3H,CH3),2.27(s,6H,CH3),4.98(s,2H,CH2), 5.09(s,2H,CH2),5.63(s,4H,ArCH2),7.21(d,4H,J=7.2Hz,Ar-H),7.24(d,4H,J=7.2Hz, Ar-H),7.58(d,2H,J=6.4Hz,triazole-H),8.64(d,2H,J=5.9Hz,=CH-).
13C NMR(100MHz,DMSO)δ(ppm):20.7,21.1,43.3,46.9,52.8,122.8,123.9,127.8,128.0, 128.3,129.3,131.5,132.0,132.6,132.7,137.6,142.5,142.6,168.7,185.5.
EI-MS(70ev)m/z(%):507(M+).
化合物27
3,5-二[1-(4-甲基)苯甲基-1H-1,2,3-***4-甲烯基]-1-苯乙基哌啶-4-酮
所得纯品为黄色固体,收率88%,熔点149-151℃。
分子式:C35H35N7O(%)
元素分析(%),计算值:C,73.79;H,6.19;N,17.21;实测值:C,73.63;H,5.87;N,16.98. IR(KBr)υ:3101,1681(C=O),1641,1597,1457,1151,1056,787cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.26(s,6H,CH3),2.82(s,4H,CH2),3.99(s,4H,CH2), 5.61(s,4H,ArCH2),7.16-7.25(m,13H,Ar-H),7.54(s,2H,triazole-H),8.58(s,2H,=CH-).
13C NMR(100MHz,DMSO)δ(ppm):20.7,33.0,52.7,54.3,58.2,122.7,125.9,127.3,127.9, 128.2,128.6,129.3,132.7,133.1,137.5,140.0,142.6,186.1.
EI-MS(70ev)m/z(%):569(M+).
化合物28
3,5-二[1-(4-甲基)苯甲基-1H-1,2,3-***4-甲烯基]-1-异丙基哌啶-4-酮
所得纯品为黄色固体,收率79%,熔点181-183℃。
分子式:C30H33N7O(%)
元素分析(%),计算值:C,70.98;H,6.55;N,19.31;实测值:C,70.79;H,6.49;N,19.07。 IR(KBr)υ:3133,2966,1635(C=O),1575,1597,1459,1123,1072,758cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.08(d,6H,J=6.4Hz,CH3),2.27(s,6H,CH3),2.96(m, 1H,CH),3.95(s,4H,CH2),5.61(s,4H,ArCH2),7.18(d,4H,J=7.6Hz,Ar-H),7.23(d,4H,J=7.6Hz,Ar-H),7.49(s,2H,triazole-H),8.58(s,2H,=CH-).
13C NMR(100MHz,DMSO)δ(ppm):18.1,20.7,50.3,52.7,53.1,122.0,127.3,127.9,129.3, 132.8,133.9,137.6,142.7,186.7.
EI-MS(70ev)m/z(%):508(M++1).
化合物29
3,5-二[1-(4-氟苯甲基)-1H-1,2,3-***4-甲烯基]-1-异丙基哌啶-4-酮
所得纯品为黄色固体,收率90%,熔点172-174℃。
分子式:C28H27F2N7O(%)
元素分析(%),计算值:C,65.23;H,5.28;N,19.02;实测值:C,65.19;H,4.85;N,18.96。 IR(KBr)υ:3131,2971,1681(C=O),1634,1603,1513,1231,1051,844,772cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.14(d,J=6.4Hz,6H,CH3),3.02(s,1H,CH)4.00(s,4H, CH2),5.72(s,4H,ArCH2),7.25-7.29(t,4H,H-Ar),7.45-7.48(t,4H,Ar-H),7.54(s,2H,=CH), 8.66(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):18.0,50.2,52.1,53.1,115.6(d,J=21.6Hz),121.9,127.3, 130.2(d,J=8.5Hz),133.9,142.7,160.6,163.1,186.7.
EI-MS(70ev)m/z(%):515(M+).
化合物30
3,5-二[1-(4-氟苯甲基)-1H-1,2,3-***4-甲烯基]-1-叔丁氧羰基哌啶-4-酮
所得纯品为黄色固体,收率90%,熔点239-241℃。
分子式:C30H29F2N7O3(%)
元素分析(%),计算值:C,62.82;H,5.10;N,17.09;实测值:C,62.69;H,5.07;N,16.85。 IR(KBr)υ:3125,2975,1703(C=O),1677(C=O),1632,1608,1513,1236,1051,801,773cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.19(s,9H,CH3),4.88(s,4H,CH2),5.66(s,4H,ArCH2), 7.20-7.24(m,4H,H-Ar),7.41-7.42(m,4H,Ar-H),7.57(s,2H,=CH),8.66(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):27.6,45.3,52.1,79.4,115.6(d,J=21.8Hz),127.7,130.3 (d,J=8.4Hz),132.0(d,J=18.6Hz).
EI-MS(70ev)m/z(%):574(M++1).
化合物31
3,5-二[1-(4-氟苯甲基)-1H-1,2,3-***4-甲烯基]-1-苯甲基哌啶-4-酮
所得纯品为黄色固体,收率93%,熔点196-198℃。
分子式:C32H27F2N7O(%)
元素分析(%),计算值:C,68.19;H,4.83;N,17.40;实测值:C,68.14;H,4.80;N,17.25。 IR(KBr)υ:3134,2936,1679(C=O),1631,1595,1513,1233,1052,817,773cm-1.
1H NMR(DMSO,400MHz)δ(ppm):3.75(s,2H,CH2),3.94(s,4H,CH2),5.63(s,4H,ArCH2), 7.20-7.40(m,13H,H-Ar),7.51(s,2H,=CH-),8.50(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):52.1,54.4,60.8,115.6(d,J=21.7Hz),122.6,127.2(d,J =28.4Hz),128.1,128.8,130.2(d,J=8.4Hz),131.9,133.2,137.7,142.6,160.7,163.1,186.2. EI-MS(70ev)m/z(%):563(M+).
化合物32
3,5-二[1-(4-氟苯甲基)-1H-1,2,3-***4-甲烯基]-1-苯乙基哌啶-4-酮
所得纯品为黄色固体,收率93%,熔点167-169℃。
分子式:C33H29F2N7O(%)
元素分析(%),计算值:C,68.62;H,5.06;N,16.97;实测值:C,68.36;H,4.93;N,16.78。 IR(KBr)υ:3137,2956,1683(C=O),1632,1595,1513,1235,1052,804,536cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.82(s,4H,CH2),3.99(s,4H,CH2),5.67(s,4H,ArCH2), 7.15-7.26(m,9H,H-Ar),7.40-7.43(m,4H,H-Ar),7.53(s,2H,=CH-),8.61(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):δ47.7,52.1,54.3,64.3,115.6(d,J=21.5Hz),122.6, 127.4,128.4(d,J=37.3Hz),130.2(d,J=8.5Hz),131.9,133.1,139.9,142.6,160.6,163.1, 186.1.
EI-MS(70ev)m/z(%):577(M+).
化合物33
3,5-二[1-(4-氟苯甲基)-1H-1,2,3-***4-甲烯基]-1-乙氧羰基哌啶-4-酮
所得纯品为黄色固体,收率67%,熔点220-222℃。
分子式:C28H25F2N7O3(%)
元素分析(%),计算值:C,61.65;H,4.62;N,17.97;实测值:C,61.48;H,4.37;N,17.70。 IR(KBr)υ:3125,2980,1706(C=O),1678(C=O),1631,1588,1513,1240,1050,798,773cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.02(d,3H,J=6.8Hz,CH3),3.98(q,2H,OCH2),4.97(s, 4H,CH2),5.69(s,4H,ArCH2),7.20-7.24(t,4H,H-Ar),7.43(t,4H,H-Ar),7.59(s,2H,triazole-H),8.66(s,2H,=CH).
13C NMR(DMSO,100MHz)δ(ppm):14.3,45.3,52.1,61.2,115.6(d,J=21.7Hz),128.0, 130.35(d,J=8.4Hz),131.8(d,J=7.9Hz),142.6,154.7,160.7,163.1,185.3.
EI-MS(70ev)m/z(%):545(M+).
化合物34
3,5-二[1-(4-氟苯甲基)-1H-1,2,3-***4-甲烯基]-1-乙酰基哌啶-4-酮
所得纯品为黄色固体,收率62%,熔点148-150℃。
分子式:C27H23F2N7O2(%)
元素分析(%),计算值:C,62.91;H,4.50;N,19.02;实测值:C,62.91;H,4.43;N,18.93。 IR(KBr)υ:3136,2955,1683(C=O),1635,1511,1456,1225,1054,844,790cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.02(s,3H,CH3),4.98(s,2H,CH2),5.10(s,2H,CH2), 5.69(s,4H,ArCH2),7.20-7.24(t,4H,H-Ar),7.41-7.45(m,4H,H-Ar),7.58(d,J=8.7Hz,2H, triazole-H),8.66(d,J=5.7Hz,2H,=CH-).
13C NMR(DMSO,100MHz)δ(ppm):δ21.1,43.3,46.9,52.2,115.6(d,J=21.4Hz),122.7, 123.8,127.8,128.3,130.4,131.8(dd,J=27.5,17.2Hz),142.6(d,J=9.9Hz),160.7,163.2, 168.7,185.5.
EI-MS(70ev)m/z(%):515(M+).
化合物35
3,5-二[1-(4-氟苯甲基)-1H-1,2,3-***4-甲烯基]-1-丙基哌啶-4-酮
所得纯品为黄色固体,收率96%,熔点185-187℃。
分子式:C28H27F2N7O(%)
元素分析(%),计算值:C,65.23;H,5.28;N,19.02;实测值:C,64.95;H,5.25;N,18.83。 IR(KBr)υ:3129,2964,2934,1681(C=O),1633,1596,1514,1331,1234,1051,772cm-1.
1H NMR(DMSO,400MHz)δ(ppm):0.79-0.88(t,3H,CH3),1.48-1.52(m,2H,CH2),2.43-2.55 (m,2H,CH2),3.91(s,4H,CH2),5.66(s,4H,ArCH2),7.15-7.24(m,4H,H-Ar),7.35-7.43(m,4H, H-Ar),7.51(s,2H,=CH-),8.60(s,2H,triazole-H).
13C NMR(100MHz,DMSO)δ(ppm):δ11.7,19.8,52.1,54.5,58.6,115.6(d,J=21.6Hz), 122.4,127.5,130.3(d,J=8.4Hz),132.0,133.2,142.6,160.6,163.1,186.2.
EI-MS(70ev)m/z(%):515(M+).
化合物36
3,5-二[1-(4-氟苯甲基)-1H-1,2,3-***4-甲烯基]-1-甲基哌啶-4-酮
所得纯品为黄色固体,收率96%,熔点176-178℃。
分子式:C26H23F2N7O(%)
元素分析(%),计算值:C,64.06;H,4.76;N,20.11;实测值:C,63.81;H,4.63;N,19.90。
IR(KBr)υ:3132,1682(C=O),1635,1514,1457,1122,1052,827,773cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.45(s,3H,CH3),3.86(s,4H,CH2),5.66(s,4H,ArCH2), 7.18-7.22(t,4H,H-Ar),7.40-7.43(t,4H,H-Ar),7.52(s,2H,=CH),8.61(s,2H,triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):δ45.5,52.2,56.8,115.7(d,J=21.5Hz),122.4,127.5, 130.3(d,J=8.4Hz),132.0,133.1,142.7,160.7,163.2,185.9.
EI-MS(70ev)m/z(%):487(M+).
化合物37
3,5-二[1-(4-氟苯甲基)-1H-1,2,3-***4-甲烯基]-1-乙基哌啶-4-酮
所得纯品为黄色固体,收率90%,熔点172-174℃。
分子式:C27H25F2N7O(%)
元素分析(%),计算值:C,64.66;H,5.02;N,19.55;实测值:C,64.23;H,4.93;N,19.06。 IR(KBr)υ:3129,2973,1681(C=O),1634,1598,1457,1233,1051,805,773cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.06-1.09(t,3H,CH3),2.63(q,2H,CH2),3.90(s,4H,CH2), 5.66(s,4H,ArCH2),7.22(t,4H,H-Ar),7.40-7.44(m,4H,Ar-H),7.51(s,2H,=CH-),8.61(s,2H, triazole-H).
13C NMR(DMSO,100MHz)δ(ppm):12.3,50.8,52.2,54.2,115.7(d,J=21.6Hz),122.5,127.5, 130.38(d,J=8.4Hz),132.0,133.3,142.7,160.8,163.2,186.3.
EI-MS(70ev)m/z(%):501(M+).
实施例4
化合物40
(Z)-2,6-二((1-邻甲基苯基-1H-1,2,3-***-4-甲烯基)环己酮
在250mL三口瓶内加入23mL盐酸、12mL水和10.7g(0.10mol)邻甲基苯胺。搅拌得白色固体,用冰盐水冷却至0℃,在搅拌下0~4℃范围内滴加7g(0.10mol)亚硝酸钠与12mL 水配成的溶液,得到红棕色液体,有少量白色固体析出,继续搅拌20分钟,过滤,得红色透明溶液。
称9.75g(0.15mol)叠氮化钠于250mL三颈圆底烧瓶,100mL水溶解,冰水浴控制温度在10℃以下,搅拌下缓慢滴加上述邻甲苯基重氮盐溶液,滴毕继续室温搅拌1小时。将反应液转移至分液漏斗中,并用30mL乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥。过滤,脱溶得浅黄色油状物粗品,不经提纯,直接用于下一步反应。
在100mL三口瓶中加入1.33g(0.01mol)邻甲基苯基叠氮与2.24g(0.04mol)丙炔醇,用叔丁醇与水的混合溶剂30ml溶解,搅拌下加入8mol%的抗坏血酸钠和2mol%的五水合硫酸铜,或者CuCl或CuI,50~70℃搅拌反应,TLC监控,大约3h反应完毕,向该反应体系中加入100ml水,转移至分液漏斗,乙酸乙酯萃取3次,每次30ml,合并有机相,无水硫酸钠干燥过夜,减压过滤脱溶得棕黄色固体。硅胶柱层析提纯,洗脱剂为石油醚/丙酮(体积比2∶1),得白色固体1.36g,收率72%,熔点55-56℃,文献值58-59℃。
将1.89g(0.01mol)1-邻甲基苯基-1H-1,2,3-***-4-甲醇加入到100ml的单颈圆底烧瓶中,用50ml干燥的乙腈溶解,再加入17.4g(0.20mol)活性二氧化锰,回流反应,TLC监测至反应完毕。硅藻土过滤,脱溶得白色固体1.50g,收率80%;熔点63-64,文献值71-71℃。
向50ml的三颈圆底烧瓶中加入0.38g(2mmol)1-邻甲基苯基-1H-1,2,3-***-4-甲醛, 20ml二氧六环,搅拌均匀后加入0.098g(1mmol)环己酮和催化量的甲醇钠。逐渐加热至100℃搅拌至析出黄色固体。继续搅拌1h,减压过滤,水洗,乙醇洗。红外干燥箱干燥得黄色固体。收率75%,熔点176-178℃。
分子式:C26H24N6O
元素分析(%),计算值:C,71.54;H,5.54;N,19.25;实测值:C,71.38;H,5.28;N,19.02。
IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):1.96-1.99(m,2H,-CH2-),2.25(s,6H,CH3),3.20-3.23(t, 4H,CH2),7.35~7.45(m,8H,Ar-H),7.84(s,2H,CH),7.94(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):17.8,21.5,28.7,124.0,125.8,126.4,126.8,130.0,131.5, 133.5,135.9,136.7,144.0,189.0.
EI-MS(70ev)m/z(%):436(M+).
以下化合物按化合物40类似的方法制备,其结构鉴定数据如下:
化合物38
(Z)1,5-二(1-(4-三氟甲基)苯基)-1H-1,2,3-***-1,4-戊二烯-3-酮
所得纯品为黄色固体,收率62%,熔点148-150℃。
分子式:C23H14F6N6O(%)
元素分析(%),计算值:C,54.77;H,2.80;N,16.66;实测值:C,54.51;H,2.51;N,16.60。 IR(KBr)υ:3128,2975,2316,1661(C=O),1598,1485,1144,1328,1132,799cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):1.21(d,6H,J=6.0Hz,CH3),3.07-3.13(m,1H,CH),4.25 (s,4H,CH2),7.48(d,2H,J=8.8Hz,Ar-H),7.64(d,4H,J=7.6Hz,Ar-H),7.69(s,2H,CH), 8.19(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):18.4,50.8,53.9,76.6,76.9,77.3,121.2,127.3,128.2, 128.3,129.1,130.5,132.9,135.5,136.4,143.8,187.4.
EI-MS(70ev)m/z(%):504(M+).
化合物39
(Z)1,5-二[1-(2-甲氧基)苯基-1H-1,2,3-***]-1,4-戊二烯-3-酮
所得纯品为黄色固体,收率79%,熔点274-276℃。
分子式:C23H20N6O3(%)
元素分析(%),计算值:C,64.48;H,4.71;N,19.62;实测值:64.27;H,4.54;N,19.37。
IR(KBr)υ:3120,2938,1672(C=O),1635,1503,1251,1180,1094,754cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.88(m,2H,CH2),3.11(t,4H,CH2),3.88(s,6H,OCH3), 7.17-7.19(t,2H,Ar-H),7.36(d,2H,J=8.4Hz,Ar-H),7.57-7.59(t,2H,Ar-H),7.67-7.69(m,2H, Ar-H,2H,triazole-H),8.85(s,2H,=CH-).
13C NMR(DMSO,100MHz)δ(ppm):21.2,28.1,56.1,113,120.9,124.0,125.3,125.9,128.6, 131.1,135.9,142.9,151.9,187.9.
EI-MS(70ev)m/z(%):429(M++1).
化合物41
(Z)-2,6-二(1-(2,4-二氯)苯基-1H-1,2,3-***-4-甲烯基)环己酮
所得纯品为黄色固体,收率62%,熔点220-222℃。
分子式:C24H16Cl4N6O(%)
元素分析(%),计算值:C,52.77;H,2.95;N,15.39;实测值:C,52.50;H,2.74;N,15.31。 IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):1.97-2.00(m,2H,CH2),3.22(t,4H,CH2),7.48(d,2H,J= 8.8Hz,Ar-H),7.63(d,2H,J=7.2Hz,Ar-H),7.82(s,2H,CH),8.16(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):17.8,21.6,28.7,124.0,125.8,126.4,126.8,130.0,131.5, 133.6,135.9,136.7,144.0,189.0.
EI-MS(70ev)m/z(%):544(M+).
化合物42
(Z)-2,6-二(1-(4-三氟甲基)苯基-1H-1,2,3-***-4-甲烯基)环己酮
所得纯品为黄色固体,收率89%,熔点233-235℃。
分子式:C26H18F6N6O(%)
元素分析(%),计算值:C,57.36;H,3.33;N,15.44;实测值:C,57.08;H,3.17;N,15.30。 IR(KBr)υ:3133,2974,2320,1633(C=O),1620,1484,1414,1327,1130,1070,864cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.21(d,6H,J=6.0Hz,CH3),3.07-3.13(m,1H,CH),4.25 (s,4H,CH2),7.48(d,2H,J=8.8Hz,Ar-H),7.64(d,4H,J=7.6Hz,Ar-H),7.69(s,2H,CH), 8.19(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):18.4,50.9,53.9,76.7,77.0,77.3,121.2,127.3,128.2, 128.3,129.1,130.6,132.9,135.5,136.4,143.8,187.4.
EI-MS(70ev)m/z(%):544(M+).
化合物43
(Z)-2,6-二((1-邻甲氧基苯基-1H-1,2,3-***-4-甲烯基)环己酮
所得纯品为黄色固体,收率89%,熔点202-204℃。
分子式:C26H24N6O3(%)
元素分析(%),计算值:C,66.65;H,5.16;N,17.94;实测值:C,66.55;H,4.95;N,17.67。
IR(KBr)υ:3175,2939,1671(C=O),1622,1499,1474,1144,1043,749cm-1.
1H NMR(DMSO,600MHz)δ(ppm):1.88(m,2H,CH2),3.11(t,4H,CH2),3.88(s,6H,OCH3), 7.17-7.19(t,2H,J=8.4Hz,Ar-H),7.36(d,2H,J=8.4Hz,Ar-H),7.57-7.59(t,2H,Ar-H), 7.67-7.69(m,2H,Ar-H,2H,triazole-H),8.85(s,2H,=CH-).
13C NMR(DMSO,100MHz)δ(ppm):21.2,28.1,56.1,113.0,120.9,124.0,125.3,125.9,128.6, 131.1,135.9,142.9,151.8,187.9.
EI-MS(70ev)m/z(%):468(M+).
化合物44
(Z)-3,5-二(1-邻甲基苯基-1H-1,2,3-***-4-甲烯基)-1-苯甲基哌啶-4-酮
所得纯品为黄色固体,收率89%,熔点266-268℃。
分子式:C32H29N7O(%)
元素分析(%),计算值:C,72.84;H,5.54;N,18.58;实测值:C,72.75;H,5.29;N,18.34。
IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):2.23(s,6H,CH3),3.89(s,2H,CH2),4.20(s,4H,CH2), 7.23~7.49(m,13H,Ar-H),7.80(s,2H,CH),7.80(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):17.8,54.9,61.8,122.5,125.8,126.6,126.9,127.2,128.3, 129.1,130.0,131.5,133.5,134.4,135.9,137.6,143.5,187.0.
EI-MS(70ev)m/z(%):527(M+).
化合物45
(Z)-3,5-二(1-邻甲基苯基-1H-1,2,3-***-4-甲烯基)-1-叔丁氧羰基哌啶-4-酮
所得纯品为黄色固体,收率60%,熔点200-201℃。
分子式:C30H31N7O3(%)
元素分析(%),计算值:C,67.02;H,5.81;N,18.24;实测值:C,66.73;H,5.63;N,18.21。
IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,600MHz)δ(ppm):1.31(s,9H,CH3),2.15(s,6H,CH3),5.01(s,4H,CH2), 7.26~7.34(m,8H,Ar-H),7.71(s,2H,CH),7.99(s,2H,CH).
13C NMR(CDCl3,150MHz)δ(ppm):17.7,17.8,27.0,27.1,28.1,28.2,29.2,29.3,45.8,80.3, 125.7,126.9,130.0,131.5,133.0,133.4,135.8,143.1,154.5,186.1.
EI-MS(70ev)m/z(%):537(M+).
化合物46
(Z)-3,5-二(1-邻甲基苯基-1H-1,2,3-***-4-甲烯基)-1-乙酰基哌啶-4-酮
所得纯品为黄色固体,收率73%,熔点226-228℃。
分子式:C27H25N7O2(%)
元素分析(%),计算值:C,67.63;H,5.25;N,20.45;实测值:C,67.52;H,4.93;N,20.15。
IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.1H NMR(CDCl3, 600MHz)δ(ppm):2.22(s,3H,CH3),2.24(s,6H,CH3),5.11(s,2H,CH2),5.36(s,2H,CH2), 7.34~7.43(m,8H,Ar-H),7.70(s,1H,CH),7.88(s,1H,CH),8.25(d,2H,J=6.0Hz,CH).13C NMR(150MHz CDCl3-d)δ(ppm):17.8,21.4,44.0,47.4,122.0,125.0,125.6,125.8,126.8, 126.9,128.1,130.0,130.2,131.5,131.6,132.2,132.3,133.3,133.5,135.6,135.7,142.8,143.2, 169.7,186.0.
EI-MS(70ev)m/z(%):479(M+).
化合物47
(Z)-3,5-二(1-邻甲基苯基-1H-1,2,3-***-4-甲烯基)-1-乙氧羰基哌啶-4-酮
所得纯品为黄色固体,收率61%,熔点136-137℃。
分子式:C28H27N7O3(%)
元素分析(%),计算值:C,66.00;H,5.34;N,19.24;实测值:C,65.75;H,5.07;N,19.11。 IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,600MHz)δ(ppm):1.20-1.23(s,3H,CH3),2.26(s,6H,CH3),4.12-4.17(q,2H, CH2),5.16(s,4H,CH2),7.36~7.47(m,8H,Ar-H),7.80(s,2H,CH),8.04(s,2H,CH).
13C NMR(CDCl3,150MHz)δ(ppm):14.4,17.8,18.3,45.8,61.8,125.7,126.9,130.1,131.5, 132.7,133.4,133.8,135.7,143.1,155.4,186.2.
EI-MS(70ev)m/z(%):509(M+).
化合物48
(Z)-3,5-二(1-邻甲基苯基-1H-1,2,3-***-4-甲烯基)-1-甲基哌啶-4-酮
所得纯品为黄色固体,收率89%,熔点193-195℃。
分子式:C26H25N7O(%)
元素分析(%),计算值:C,69.16;H,5.58;N,21.71;实测值:C,69.03;H,5.43;N,21.44。 IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,600MHz)δ(ppm):2.25(s,6H,CH3),2.62(s,3H,CH3),4.18(s,4H,CH2), 7.36~7.45(m,8H,Ar-H),7.73(s,2H,CH),7.95(s,2H,CH).
13C NMR(CDCl3,150MHz)δ(ppm):17.8,27.8,46.0,57.4,121.8,125.7,126.9,127.1,130.0, 131.5,133.5,134.3,135.9,143.5,186.7.
EI-MS(70ev)m/z(%):509(M+).
化合物49
(Z)-3,5-二(1-邻甲基苯基-1H-1,2,3-***-4-甲烯基)-1-丙基哌啶-4-酮
所得纯品为黄色固体,收率58%,熔点101-103℃。
分子式:C28H29N7O(%)
元素分析(%),计算值:C,70.12;H,6.10;N,20.44;实测值:C,69.92;H,6.09;N,20.14。 IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,600MHz)δ(ppm):0.93-0.96(t,3H,CH3),1.65-1.70(m,2H,CH2),2.25(s, 6H,CH3),2.65-2.69(s,2H,CH2),4.22(s,4H,CH2),7.37-7.46(m,8H,Ar-H),7.74(s,2H,CH), 7.92(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):11.8,17.9,20.3,55.3,59.7,121.9,125.8,126.9,127.0, 130.0,131.5,133.5,134.6,135.8,143.6,187.2.
EI-MS(70ev)m/z(%):479(M+).
化合物50
(Z)-3,5-二(1-邻甲基苯基-1H-1,2,3-***-4-甲烯基)-1-异丙基哌啶-4-酮
所得纯品为黄色固体,收率48%,熔点127-129℃。
分子式:C28H29N7O(%)
元素分析(%),计算值:C,70.12;H,6.10;N,20.44;实测值:C,69.95;H,6.06;N,20.20。 IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):1.20-1.21(d,6H,J=2.8Hz,CH3),2.24(s,6H,CH3),3.09 (m,1H,CH),4.25(s,4H,CH2),7.35-7.39(m,8H,Ar-H),7.70(s,2H,CH),7.90(s,2H,CH).13C NMR(CDCl3,100MHz)δ(ppm):11.8,17.9,20.3,55.3,59.7,121.9,125.8,126.9,127.0,130.0, 131.5,133.5,134.6,135.8,143.6,187.2.
EI-MS(70ev)m/z(%):479(M+).
化合物51
(Z)-3,5-二(1-邻甲基苯基-1H-1,2,3-***-4-甲烯基)-1-苯乙基哌啶-4-酮
所得纯品为黄色固体,收率78%,熔点132-134℃。
分子式:C33H31N7O(%)
元素分析(%),计算值:C,73.18;H,5.77;N,18.10;实测值:C,72.94;H,5.54;N,18.02。 IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):2.25(s,6H,CH3),2.99-3.03(t,4H,CH2),4.25(s,4H,CH2), 7.07-7.47(m,13H,Ar-H),7.76(s,2H,CH),7.83(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):17.9,34.0,55.3,59.1,122.1,125.8,125.9,126.9,127.0, 128.3,128.7,130.1,131.5,133.6,134.4,135.9,136.4,137.7,140.2,143.6,187.0.
EI-MS(70ev)m/z(%):479(M+).
化合物52
(Z)-3,5-二[1-(2,4-二氯)苯基-1H-1,2,3-***-4-甲烯基]-1-苯甲基哌啶-4-酮
所得纯品为黄色固体,收率74%,熔点186-188℃。
分子式:C30H21Cl4N7O(%)
元素分析(%),计算值:C,56.53;H,3.32;N,15.38;实测值:C,56.43;H,3.19;N,15.23。 IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):3.90(s,2H,CH2),4.19(s,4H,CH2),7.25-7.66(m,11H, Ar-H),7.78(s,2H,CH),8.07(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):54.9,61.8,122.1,126.9,127.2,128.2,128.3,129.0,129.5, 130.6,132.8,133.5,134.7,136.4,137.0,137.4,140.9,143.5,186.9.
EI-MS(70ev)m/z(%):635(M+).
化合物53
(Z)-3,5-二[1-(2,4-二氯)苯基-1H-1,2,3-***-4-甲烯基]-1-叔丁氧羰基哌啶-4-酮
所得纯品为黄色固体,收率31%,熔点185-187℃。
分子式:C28H23Cl4N7O3(%)
元素分析(%),计算值:C,51.95;H,3.58;N,15.15;实测值:C,51.81;H,3.45;N,15.00。IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):1.97-2.00(m,2H,CH2),3.22(t,4H,CH2),7.48(d,2H,J= 8.8Hz,Ar-H),7.63(d,2H,J=7.2Hz,Ar-H),7.82(s,2H,CH),8.16(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):14.9,52.31,54.0,67.1,84.8,114.3,123.2,126.1,127.2, 129.9,134.1,152.2,153.0,163.3,166.9,171.9,172.6.
EI-MS(70ev)m/z(%):645(M+).
化合物54
(Z)-3,5-二[1-(2,4-二氯)苯基-1H-1,2,3-***-4-甲烯基]-1-乙氧羰基哌啶-4-酮
所得纯品为黄色固体,收率51%,熔点175-177℃。
分子式:C26H19Cl4N7O3(%)
元素分析(%),计算值:C,50.43;H,3.09;N,15.83;实测值:C,50.30;H,2.87;N,15.57。
IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):1.19-1.23(t,3H,CH3),4.11-4.17(q,2H,CH2),5.14(s,4H, CH2),7.47-7.64(m,6H,Ar-H),7.77(s,2H,CH),8.26(s,2H,CH).
EI-MS(70ev)m/z(%):617(M+).
化合物55
(Z)-3,5-二[1-(2,4-二氯)苯基-1H-1,2,3-***-4-甲烯基]-1-乙酰基哌啶-4-酮
所得纯品为黄色固体,收率63%,熔点244-246℃。
分子式:C25H17Cl4N7O2(%)
元素分析(%),计算值:C,50.96;H,2.91;N,16.64;实测值:C,50.77;H,2.91;N,16.50。
IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):2.22(s,3H,CH3),5.13(s,2H,CH2),5.34(s,2H,CH2), 7.25-7.62(m,6H,Ar-H;),7.69(s,1H,CH),7.85(s,1H,CH),8.23(s,2H,CH).
EI-MS(70ev)m/z(%):587(M+).
化合物56
(Z)-3,5-二[1-(2,4-二氯)苯基-1H-1,2,3-***-4-甲烯基]-1-苯乙基哌啶-4-酮
所得纯品为黄色固体,收率72%,熔点140-142℃。
分子式:C31H23Cl4N7O(%)
元素分析(%),计算值:C,57.16;H,3.56;N,15.05;实测值:C,57.03;H,3.31;N,14.92。
IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):2.99(s,4H,CH2),4.29(s,4H,CH2),7.13-7.65(m,11H, Ar-H),7.74(s,2H,CH),8.13(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):33.9,55.1,59.0,76.7,77.0,77.3,121.8,125.9,127.3, 128.3,128.6,129.2,130.6,132.4,132.9,134.6,136.5,140.0,143.7,146.0,186.8.
EI-MS(70ev)m/z(%):649(M+).
化合物57
(Z)-3,5-二[1-(2,4-二氯)苯基-1H-1,2,3-***-4-甲烯基]-1-丙基哌啶-4-酮
所得纯品为黄色固体,收率60%,熔点187-189℃。
分子式:C26H21Cl4N7O(%)
元素分析(%),计算值:C,52.99;H,3.59;N,16.64;实测值:C,52.67;H,3.49;N,16.53。
IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):0.94-0.98(t,3H,CH3),1.65-1.70(m,2H,CH2),2.66-2.70(t, 2H,CH2),4.22(s,4H,CH2),7.49-7.66(m,6H,Ar-H),7.73(s,2H,CH),8.19(s,2H,CH).13C NMR(CDCl3,100MHz)δ(ppm):11.8,20.4,55.2,59.6,76.6,77.0,77.3,121.6,127.3,128.3, 128.4,129.2,130.6,132.9,135.0,136.5,143.8,187.0.
EI-MS(70ev)m/z(%):587(M+).
化合物58
(Z)-3,5-二[1-(2,4-二氯)苯基-1H-1,2,3-***-4-甲烯基]-1-异丙基哌啶-4-酮
所得纯品为黄色固体,收率88%,熔点179-181℃。
分子式:C26H21Cl4N7O(%)
元素分析(%),计算值:C,52.99;H,3.59;N,16.64;实测值:C,52.89;H,3.51;N,16.51。IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):1.21(d,6H,J=6.0Hz,CH3),3.07-3.13(m,1H,CH),4.25 (s,4H,CH2),7.48(d,2H,J=8.8Hz,Ar-H),7.64(d,4H,J=7.6Hz,Ar-H),7.69(s,2H,CH), 8.19(s,2H,CH).
13C NMR(CDCl3,100MHz)δ(ppm):18.4,50.8,53.9,76.6,77.0,77.3,121.2,127.3,128.2, 128.3,129.1,130.6,132.9,135.5,136.4,143.8,187.4.
EI-MS(70ev)m/z(%):587(M+).
化合物59
(Z)-3,5-二[1-(2,4-二氯)苯基-1H-1,2,3-***-4-甲烯基]-1-甲基哌啶-4-酮
所得纯品为黄色固体,收率86%,熔点206-208℃。
分子式:C24H17Cl4N7O(%)
元素分析(%),计算值:C,51.36;H,3.05;N,17.47;实测值:C,52.20;H,3.21;N,17.01。 IR(KBr)υ:3129,2933,1674(C=O),1624,1588,1168,1144,1051,711cm-1.
1H NMR(CDCl3,400MHz)δ(ppm):1.21(d,6H,J=6.0Hz,CH3),3.07-3.13(m,1H,CH),4.25 (s,4H,CH2),7.48(d,2H,J=8.8Hz,Ar-H),7.64(d,4H,J=7.6Hz,Ar-H),7.69(s,2H,CH), 8.19(s,2H,CH).
EI-MS(70ev)m/z(%):561(M+).
化合物60
(Z)-3,5-二[1-(4-三氟甲基)苯基-1H-1,2,3-***-4-甲烯基]-1-叔丁氧羰基哌啶-4-酮
所得纯品为黄色固体,收率86%,熔点235-237℃。
分子式:C30H25F6N7O3(%)
元素分析(%),计算值:C,55.82;H,3.90;N,15.19;实测值:C,56.16;H,3.90;N,14.97。 IR(KBr)υ:2973,2897,2328,1694(C=O),1624,1481,1168,1325,1130,930cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.28(s,9H,CH3),5.02(s,4H,CH2),7.65(s,2H,Ar-H), 7.89-7.92(m,4H,Ar-H),8.32-8.36(m,2H,Ar-H,2H,CH),9.40(s,2H,CH).
EI-MS(70ev)m/z(%):645(M+).
化合物61
(Z)-3,5-二[1-(4-三氟甲基)苯基-1H-1,2,3-***-4-甲烯基]-1-乙氧羰基哌啶-4-酮
所得纯品为黄色固体,收率53%,熔点258-260℃。
分子式:C28H21F6N7O3(%)
元素分析(%),计算值:C,54.46;H,3.43;N,15.88;实测值:C,54.33;H,3.23;N,15.84。 IR(KBr)υ:3149,2977,2318,1698(C=O),1629,1591,1485,1328,1136,799cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.07-1.11(s,3H,CH3),4.02-4.04(q,2H,CH2),5.06(s,4H, CH2),7.61(s,2H,Ar-H),7.87(s,4H,Ar-H),8.27(m,2H,Ar-H),9.30(s,2H,CH),9.34(s,2H, CH).
EI-MS(70ev)m/z(%):617(M+).
化合物62
(Z)-3,5-二[1-(4-三氟甲基)苯基-1H-1,2,3-***-4-甲烯基]-1-乙酰基哌啶-4-酮
所得纯品为黄色固体,收率36%,熔点246-248℃。
分子式:C27H19F6N7O2(%)
元素分析(%),计算值:C,55.20;H,3.26;N,16.69;实测值:C,55.04;H,3.21;N,16.39。 IR(KBr)υ:3109,2969,2316,1642(C=O),1484,1329,1173,1130,1071,800cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.08(s,3H,CH3),5.09(s,2H,CH2),5.17(s,2H,CH2), 7.64(d,2H,J=1.2Hz,Ar-H),7.89(d,4H,J=7.2Hz,Ar-H),8.31(d,2H,J=8.4Hz,Ar-H,2H, J=8.4Hz,CH),9.37(s,2H,CH).
EI-MS(70ev)m/z(%):587(M+).
化合物63
(Z)-3,5-二[1-(4-三氟甲基)苯基-1H-1,2,3-***-4-甲烯基]-1-甲基哌啶-4-酮
所得纯品为黄色固体,收率84%,熔点239-241℃。
分子式:C26H19F6N7O(%)
元素分析(%),计算值:C,55.82;H,3.42;N,17.53;实测值:C,55.74;H,3.16;N,17.34。 IR(KBr)υ:3130,2972,2321,1631(C=O),1595,1328,1175,1124,994cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.52(s,3H,CH3),3.98(s,4H,CH2),7.59(s,2H,Ar-H), 7.91(s,4H,Ar-H),8.33(m,2H,Ar-H;2H,CH),9.26(s,2H,CH).
EI-MS(70ev)m/z(%):559(M+).
化合物64
(Z)-3,5-二[1-(4-三氟甲基)苯基-1H-1,2,3-***-4-甲烯基]-1-丙基哌啶-4-酮
所得纯品为黄色固体,收率76%,熔点234-236℃。
分子式:C28H23F6N7O(%)
元素分析(%),计算值:C,57.24;H,3.95;N,16.69;实测值:C,57.18;H,3.73;N,16.64。 IR(KBr)υ:3127,2967,2317,1635(C=O),1597,1483,1326,1170,1134,1071,805cm-1.
1H NMR(DMSO,400MHz)δ(ppm):0.86-0.90(t,3H,CH3),1.53-1.58(m,2H,CH2),2.08(t,2H, CH2),4.05(s,4H,CH2),7.60(s,2H,Ar-H),7.91(s,4H,Ar-H),8.34(m,2H,Ar-H;2H,CH), 9.28(s,2H,CH).
EI-MS(70ev)m/z(%):587(M+).
化合物65
(Z)-3,5-二[1-(4-三氟甲基)苯基-1H-1,2,3-***-4-甲烯基]-1-异丙基哌啶-4-酮
所得纯品为黄色固体,收率80%,熔点239-241℃。
分子式:C28H23F6N7O(%)
元素分析(%),计算值:C,57.24;H,3.95;N,16.69;实测值:C,57.00;H,3.68;N,16.50。IR(KBr)υ:3146,2974,2317,1632(C=O),1595,1484,1327,1169,1123,814cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.13(d,6H,J=6.4Hz,CH3),2.99-3.04(m,1H,CH),4.08 (s,4H,CH2),7.54(s,2H,Ar-H),7.85-7.89(d,4H,J=7.2Hz,Ar-H),8.34(m,2H,J=6.0Hz, Ar-H;2H,CH),9.25(s,2H,CH).
EI-MS(70ev)m/z(%):587(M+).
化合物66
(Z)-3,5-二[1-(4-三氟甲基)苯基-1H-1,2,3-***-4-甲烯基]-1-苯甲基哌啶-4-酮
所得纯品为黄色固体,收率77%,熔点205-207℃。
分子式:C32H23F6N7O(%)
元素分析(%),计算值:C,60.47;H,3.65;N,15.43;实测值:C,60.21;H,3.56;N,15.43。IR(KBr)υ:3133,2974,2319,1633(C=O),1587,1324,1125,1070,800cm-1.
1H NMR(DMSO,400MHz)δ(ppm):3.85(m,2H,CH2),4.11(s,4H,CH2),7.18-7.22(t,1H, Ar-H),7.27-7.31(t,2H,Ar-H),7.38(d,2H,J=7.8Hz,Ar-H),7.60(s,2H,Ar-H),7.89(d,4H,J =8.0Hz,Ar-H),8.28(d,4H,J=9.2Hz,Ar-H;2H,CH),9.23(s,2H,CH).
EI-MS(70ev)m/z(%):635(M+).
化合物67
(Z)-3,5-二[1-(4-三氟甲基)苯基-1H-1,2,3-***-4-甲烯基]-1-苯乙基哌啶-4-酮
所得纯品为黄色固体,收率82%,熔点217-218℃。
分子式:C33H25F6N7O(%)
元素分析(%),计算值:C,61.02;H,3.88;N,15.09;实测值:C,60.77;H,3.76;N,14.59。 IR(KBr)υ:3149,2977,2320,1633(C=O),1597,1484,1327,1123,1070,811cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.88-2.90(t,4H,CH2),4.11(s,4H,CH2),7.12-7.15(m,1H, Ar-H),7.24(d,4H,J=4.0Hz,Ar-H),7.59(s,2H,Ar-H),7.88(d,4H,J=7.2Hz,Ar-H),8.30(d, 4H,J=9.6Hz,Ar-H;2H,CH),9.24(s,2H,CH).
EI-MS(70ev)m/z(%):649(M+).
化合物68
(Z)-3,5-二[1-(2-甲氧基)苯基-1H-1,2,3-***-4-甲烯基]-1-叔丁氧羰基哌啶-4-酮
所得纯品为黄色固体,收率81%,熔点198-199℃。
分子式:C30H31N7O5(%)
元素分析(%),计算值:C,63.26;H,5.49;N,17.21;实测值:C,63.19;H,5.21;N,17.33。 IR(KBr)υ:3198,2974,1696(C=O),1674,1630,1499,1156,1048,750cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.28(s,9H,CH3),3.87(s,6H,OCH3),5.02(s,4H,CH2), 7.16-7.20(t,2H,Ar-H),7.35(d,2H,J=8.4Hz,Ar-H),7.56-7.59(t,2H,Ar-H),7.69(s,2H,Ar-H, 2H,triazole-H),8.94(s,2H,=CH-).
13C NMR(DMSO,100MHz)δ(ppm):27.8,56.2,79.6,113.1,121.0,125.2,125.9,129.9,131.3, 132.5,142.5,151.8,185.7.
EI-MS(70ev)m/z(%):569(M+).
化合物69
(Z)-3,5-二[1-(2-甲氧基)苯基-1H-1,2,3-***-4-甲烯基]-1-乙氧羰基哌啶-4-酮
所得纯品为黄色固体,收率77%,熔点178-180℃。
分子式:C28H27N7O5(%)
元素分析(%),计算值:C,62.10;H,5.03;N,18.10实测值:C,62.04;H,4.86;N,17.92。
IR(KBr)υ:3159,2976,1705(C=O),1677,1631,1501,1254,1157,1049,754cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.10(t,3H,CH3),3.88(s,6H,OCH3),4.05(q,2H,CH2), 5.09(s,4H,CH2),7.16-7.20(t,2H,Ar-H),7.35(d,2H,J=8.4Hz,Ar-H),7.55-7.59(t,2H,Ar-H), 7.70(d,J=5.2Hz,2H,Ar-H,2H,triazole-H),8.95(s,2H,=CH-).
13C NMR(DMSO,100MHz)δ(ppm):14.4,45.5,56.2,61.3,113.0,120.9,123.1,125.1,125.8, 130.0,131.2,132.1,142.4,151.7,154.8,185.4.
EI-MS(70ev)m/z(%):541(M+).
化合物70
(Z)-3,5-二[1-(2-甲氧基)苯基-1H-1,2,3-***-4-甲烯基]-1-乙酰基哌啶-4-酮
所得纯品为黄色固体,收率77%,熔点178-180℃。
分子式:C27H25N7O4(%)
元素分析(%),计算值:C,63.40;H,4.93;N,19.17;实测值:C,63.35;H,4.87;N,19.03。 IR(KBr)υ:3160,2930,1650(C=O),1634,1604,1498,1250,1155,1051,754cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.10(s,3H,CH3),3.87(s,6H,OCH3),4.11(s,2H,CH2), 5.18(s,2H,CH2),7.17(s,2H,Ar-H),7.34(d,2H,J=4.4Hz,Ar-H),7.56(s,2H,Ar-H),7.69(d, J=5.2Hz,2H,Ar-H,2H,triazole-H),8.93(s,1H,=CH-),8.99(s,1H,=CH-).
13C NMR(100MHz DMSO)δ(ppm):21.2,43.3,47.1,55.1,56.2,113.0,120.9,122.7,123.5, 125.1,125.8,129.9,130.0,131.2,131.8,132.3,142.4,151.6,151.7,168.8,185.4.
EI-MS(70ev)m/z(%):511(M+).
化合物71
(Z)-3,5-二[1-(2-甲氧基)苯基-1H-1,2,3-***-4-甲烯基]-1-苯乙基哌啶-4-酮
所得纯品为黄色固体,收率92%,熔点150-151℃。
分子式:C33H31N7O3(%)
元素分析(%),计算值:C,69.09;H,5.45;N,17.09;实测值:C,68.85;H,5.24;N,17.07。 IR(KBr)υ:3163,2943,1679(C=O),1633,1601,1501,1257,1161,1049,758cm-1.
1H NMR(DMSO,400MHz)δ(ppm):2.87(s,4H,CH2),3.86(s,6H,OCH3),4.10(s,4H,CH2), 7.17-7.24(m,5H,Ar-H),7.35(d,3H,J=8.4Hz,Ar-H),7.55-7.59(t,3H,Ar-H),7.69(m,4H, Ar-H,2H,triazole-H),8.87(s,1H,=CH-).
13C NMR(DMSO,100MHz)δ(ppm):33.0,46.8,54.5,56.2,113.0,120.9,122.5,125.3,126.0, 128.2,128.6,129.3,131.2,133.5,140.2,142.4,151.9,186.2.
EI-MS(70ev)m/z(%):573(M+).
化合物72
(Z)-3,5-二[1-(2-甲氧基)苯基-1H-1,2,3-***-4-甲烯基]-1-异丙基哌啶-4-酮
所得纯品为黄色固体,收率89%,熔点266-168℃。
分子式:C28H29N7O3(%)
元素分析(%),计算值:C,65.74;H,5.71;N,19.17;实测值:C,65.61;H,5.69;N,18.95。IR(KBr)υ:3189,2962,1681(C=O),1638,1602,1500,1249,1159,1050,753cm-1.
1H NMR(DMSO,400MHz)δ(ppm):1.12(d,6H,J=6.4Hz,CH3),3.00-3.03(m,1H,CH),3.87 (s,6H,OCH3),4.06(q,4H,CH2),7.15-7.19(t,2H,Ar-H),7.35(d,2H,J=8.4Hz,Ar-H),7.68(d, 2H,J=7.2Hz,Ar-H),8.89(s,2H,=CH-).
13C NMR(DMSO,100MHz)δ(ppm):18.1,50.4,53.2,56.2,113.0,120.9,121.7,125.3,125.9, 129.3,131.2,134.3,142.5,151.9,186.7.
EI-MS(70ev)m/z(%):539(M+).
实施例5抗肿瘤活性试验
供试靶标:口腔底癌细胞KB;人鼻咽癌细胞CNE2;人皮肤黑色素瘤细胞A875;人乳腺癌细胞MCF-7;人肝癌细胞HepG-2。
试验方法:MTT体外细胞毒试验方法
取对数生长期的人癌细胞制成2×104个细胞/mL的细胞悬液,按0.19mL/孔接种到96 孔板,于37℃、5%CO2培养24小时后,按0.01mL/孔加入不同浓度的样品溶液,另设生理盐水对照孔,每浓度设4个平行孔,加药后再培养72小时,培养结束前3小时按0.01mL/ 孔加入浓度为10mg/mL的3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT),培养结束时吸出培养液,每孔加0.1mL的二甲基亚砜(DMSO),于测量波长540nm参比波长655nm 下测量OD值。按下式计算细胞生长抑制率(IR),以简化概率单位法计算半数抑制浓度 (IC50)。IR%=(1-平均OD值加药组/平均OD值对照组)×100%。测定结果见表1。
表1部分式I化合物的抗肿瘤活性数据(IC50值)
实施例6抗肿瘤活性试验
供试靶标:口腔底癌细胞KB;人鼻咽癌细胞CNE2。
试验方法:MTT体外细胞毒试验方法。测定结果见表2。表中5-氟脲嘧啶(5-FU)作为阳性对照药。
表2部分式I化合物的抗肿瘤活性数据(IC50值)
实施例7抗肿瘤活性试验
供试靶标:人皮肤黑色素瘤细胞株A875。
试验方法:MTT体外细胞毒试验方法。测定结果见表3。表中5-氟脲嘧啶(5-FU)作为阳性对照药。
表3部分式I化合物的抗肿瘤活性数据(IC50值)
实施例8抗肿瘤活性试验
供试靶标:人乳腺癌细胞MCF-7。
试验方法:MTT体外细胞毒试验方法。测定结果见表4。表中5-氟脲嘧啶(5-FU)作为阳性对照药。
表4部分式I化合物的抗肿瘤活性数据(IC50值)
实施例7抗肿瘤活性试验
供试靶标:人肝癌细胞HepG-2。
试验方法:MTT体外细胞毒试验方法。测定结果见表5。表中5-氟脲嘧啶(5-FU)作为阳性对照药。
表5部分式I化合物的抗肿瘤活性数据(IC50值)
从表1数据可以看到:对于癌细胞KB,化合物1、2、3、4、13、16均表现出良好的抑制活性,尤其是化合物1、3、13、16,IC50值分别为0.56、1.63、1.43、0.70。
对于癌细胞CNE2,化合物1、3、4、6,13、16、46、53均表现出良好的抑制活性,IC50值分别为0.61、1.25、0.10、1.45、0.67、1.53、2.49。
从表2数据可以看到:对于癌细胞A875,化合物16和28均表现出特别的抑制活性,IC50值分别为0.67和1.79。
从表3数据可以看到:对于癌细胞MCF-7,化合物29抑制活性较为突出,IC50值4.37。
从表4数据可以看到:对于癌细胞HepG-2,化合物16、17、28抑制活性较为突出,IC50值3.60、3.77、3.48。
上述所列化合物对相应癌细胞的抑制活性均远远高于阳性对照药物5-氟尿嘧啶。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (12)
1.一种化合物,其特征在于,所述化合物为式I所示化合物,
其中,
R1和R2分别独立地为卤素、氢、烷基或烷氧基,所述烷基和所述烷氧基分别独立地具有1~10个碳原子;
m和n分别独立地为选自0~5的整数;
X不存在或为(CH2)s1、(CH2)s2N(R3)(CH2)s3,其中,s1为2或3、s2为1、s3为1;
R3为选自具有1~3个碳原子的直链或支链烷基、-R4Ar、-Q-R5,
其中,R4为具有1~3个碳原子的直链或支链烷基,Ar表示苯基,
Q为R5为具有1~4个碳原子的直链或支链烷基。
2.根据权利要求1所述的化合物,其特征在于,所述卤素为F、Cl或Br。
3.根据权利要求1所述的化合物,其特征在于,R1和R2分别独立地为H、具有1~3个碳原子的烷氧基、具有1~3碳原子的全氟烷基或Cl。
4.根据权利要求1所述的化合物,其特征在于,所述R1和R2分别独立地为H、-OCH3、-F、-Cl或者-CF3。
5.根据权利要求1所述的化合物,其特征在于,所述R1和R2分别独立地代表两个卤素。
6.根据权利要求5所述的化合物,其特征在于,所述两个卤素呈间位关系。
7.根据权利要求6所述的化合物,其特征在于,所述两个卤素均为Cl。
8.根据权利要求1所述的化合物,其特征在于,所述化合物为下列化合物:
9.一种制备权利要求1~8任一项所述化合物的方法,其特征在于,包括:
(1)使式A所示化合物与丙炔醇进行接触,以便获得式B所示化合物;
(2)使所述式B所示化合物与二氧化锰进行接触,以便获得式C所示化合物;
(3)使所述式C所示化合物与对称的酮进行接触,以便获得式Ⅰ所示化合物;
其中,R1、R2、X、m、n是如权利要求1~8任一项中所定义的。
10.一种药物组合物,其特征在于,包括:权利要求1~8任一项所述的化合物。
11.权利要求1~8任一项所述的化合物或权利要求10所述的药物组合物在制备药物中的用途,所述药物用于治疗癌症。
12.根据权利要求11所述的用途,其特征在于,所述癌症为口腔底癌、乳腺癌或鼻咽癌。
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