2-n-取代氨基甲基苯酚的合成与表征

2-n-取代氨基甲基苯酚的合成与表征

1-取代苯酚苯衍生物是一种广泛用于医药、染料、农业和化学品等合成的重要有机化合物。因此，它引起了人们的注意。Stokker合成了一系列2-(氨基甲基)苯酚,并测试了其对老鼠和狗的促尿排泄和利尿活性,发现了较好的利尿和抗炎作用。Kragler合成了一系列N-取代氨基甲基苯酚,研究了它们对鼠类GABA的运输组织的抑制作用,发现在mGAT3中含量为3μM时即可达到很好的抑制作用。此外,2-(氨基甲基)苯酚为苯并噁嗪类物质的主要合成原料,很多研究发现苯并噁嗪类化合物对结核分枝杆菌有较好的抑制作用,被视为潜在的抗结核药物。考虑到“一锅法”步骤少、中间分离过程少、操作简单、废物少、符合绿色化学与环境保护的要求,笔者拟以氨基酸酯盐酸盐和水杨醛为原料,采用“一锅法”合成一系列2-(N-取代氨基甲基)苯酚。2实验部分2.1核磁共振检测仪器仪器:PE-2000型傅立叶变换红外光谱仪(美国PE公司)、WRS-1B数字熔点仪(上海物理光学仪器厂)、BrukerAVANCE500核磁共振仪(氘代氯仿为溶剂,四甲基硅烷为内标,德国Bruker公司)。试剂:L-苯丙氨酸、DL-丙氨酸、甘氨酸[吉尔生化(上海)有限公司]、水杨醛、硼氢化钠、三乙胺、二氯亚砜、无水乙醇、无水甲醇,无水乙醚、二氯甲烷、乙酸乙酯、石油醚(所用试剂均为AR),溶剂均采用常规法干燥。2.3实验步骤2.3.1l-苯丙氨酸甲酯盐酸盐模型反应:在250mL三口瓶中加入150mL无水甲醇(无水乙醇),16.5g(0.1mol)L-苯丙氨酸,冰盐水浴下,滴加25mL(0.2mol)重蒸的二氯亚砜,保持温度在0℃以下,滴毕,常温下搅拌10h,减压蒸出过量的二氯亚砜和甲醇(乙醇)残余物固化,用无水甲醇-乙醚重结晶,得白色固体产物2a。2a:L-苯丙氨酸甲酯盐酸盐,收率96%,m.p.152.8~154.2℃;IR(KBr,v/cm-1):3438,2963,2856,2695,2616,1747,1578,1496,1446,1398,1290,1241,1214,1139,1083,987,933,810,741,701。2b:L-苯丙氨酸乙酯盐酸盐,收率98.2%,m.p.149.9~151.0℃;IR(KBr,v/cm-1):3456,3087,2991,2858,2622,1981,1739,1596,1494,1474,1454,1441,1365,1351,1283,1234,1212,1080,1048,1016,745,703。2c:DL-丙氨酸甲酯盐酸盐,收率93.6%,m.p.148.5~150.2℃;IR(KBr,v/cm-1):3428,2956,2720,2652,2599,2526,2279,2225,2032,1747,1593,1520,1459,1437,1388,1369,1329,1254,1214,1142,1117,1004,980,906,838,754,619,524,481。2d:甘氨酸甲酯盐酸盐,收率94.2%,m.p.172.6~172.7℃;IR(KBr,v/cm-1):3484,2969,2679,2624,2481,2453,2399,2273,2186,2117,1750,1575,1557,1490,1458,1439,1421,1398,1302,1259,1136,1056,956,901,879,675,585,458。2.3.2收率lg11)水杨醛氨基酸酯席夫碱(3)的合成模型反应:将6.45g(0.03mol)L-苯丙氨酸甲酯盐酸盐加入到250mL三口瓶中,加入100mL无水甲醇搅拌至完全溶解,再加入3.36g(0.03mol)三乙醇胺(TEA)后继续搅拌,将溶有3.66g(0.03mol)水杨醛的无水甲醇溶液缓慢加入其中,于常温下反应4h,反应完后减压脱溶,得暗红色油状物,二氯甲烷-石油醚重结晶得到黄色固体产物3a。3a:收率76.6%,m.p.48.1~48.5℃;1HNMR(CDCl3,500MHz),δ:3.14(q,J=4.5Hz,1H),3.39(q,J=4.5Hz,1H),3.79(s,3H,CH3),4.17(q,J=4.5Hz,1H),6.85~6.88(m,1H),6.99(d,J=8.5Hz,1H),7.12(dd,J1=1.5Hz,J2=1.5Hz,1H),7.17~7.19(m,2H),7.21~7.24(m,1H),7.28~7.30(m,2H),7.33~7.36(m,1H),7.99(s,1H,CH=N),13.01(s,1H,OH);IR(KBr,v/cm-1):3477,3027,3005,2952,2892,1959,1748,1633,1578,1493,1456,1434,1402,1341,1281,1267,1166,1116,1088,978,895,826,764,747,699。3b:收率77.4%,m.p.37.4~39.2℃;1HNMR(CDCl3,500MHz),δ:1.28(t,J=7.5Hz,3H),3.13~3.18(m,1H),3.37~3.41(m,1H),4.16~4.18(m,1H),4.22~4.26(m,2H),6.85(r,J=7.5Hz,1H),6.99(d,J=8.5Hz,1H),7.12(d,J=7.5Hz,1H),7.18(d,J=7.5Hz,2H),7.21(t,J=7.0Hz,1H),7.28(d,J=6.5Hz,2H),7.32(t,J=7.5Hz,1H),7.99(s,1H,CH=N),13.03(s,1H,OH);13CNMR(CDCl3,125MHz),δ:14.06,39.92,61.41,73.12,117.01,118.39,118.62,126.79,128.44(2C),129.53(2C),131.65,132.69,136.68,160.87,166.70,170.79;IR(KBr,v/cm-1):3452,2982,1734,1632,1580,1496,1460,1405,1280,1192,1153,1118,1091,1031,861,758,699。3c:收率80.2%,m.p.38.3~40.0℃;1HNMR(CDCl3,500MHz),δ:1.56(d,J=7.0Hz,3H,CH3),3.76(s,3H,CH3),4.13~4.18(m,1H),6.89~6.91(m,1H),6.97(d,J=8.0Hz,1H),7.26~7.29(m,1H),7.32~7.34(m,1H),8.39(s,1H),13.02(s,1H,OH);IR(KBr,v/cm-1):3453,2991,2969,2952,1737,1630,1576,1489,1455,1434,1381,1322,1269,1215,1136,1111,1053,1033,988,978,926,870,857,765,738。3d:收率83.1%,m.p.42.1~43.1℃;1HNMR(CDCl3,500MHz),δ:3.78(s,3H,CH3),4.40(s,2H),6.88~6.91(m,1H),6.97(d,J=8.0Hz,1H),7.26~7.29(m,1H),7.32~7.36(m,1H),8.37(s,1H),12.94(s,1H,OH);IR(KBr,v/cm-1):3480,3055,3013,2955,2898,2849,2557,1921,1748,1637,1613,1582,1530,1502,1458,1440,1412,1347,1274,1215,1200,1182,1150,1121,1088,1014,960,905,880,782,762,739,704。2)2-(氨基甲基)苯酚(4)的合成模型反应:将8.49g(0.03mol)席夫碱3a溶于100mL无水甲醇中,在冰水浴下搅拌10min后,分批数次加入1.29g(0.033mol)硼氢化钠,约30min后反应完全(TLC检测),减压脱溶,加入200mL乙酸乙酯溶解,再分别用水(100mL×2次)与氯化钠的饱和溶液(100mL×2次)洗涤有机相,有机相用无水硫酸钠干燥,减压脱溶得粗产品,再用乙酸乙酯-石油醚重结晶得产物4a。4a:白色液体,收率85.2%;1HNMR(CDCl3,500MHz),δ:2.92~2.97(m,1H),3.04~3.08(m,1H),3.61~3.64(m,1H),3.68(d,J=13.5Hz,1H),3.74(s,3H,CH3),3.99(d,J=13.5Hz,1H),6.76(dd,J1=1.0Hz,J2=1.0Hz,1H),6.81(dd,J1=1.0Hz,J2=1.0Hz,1H),6.92(dd,J1=1.0Hz,J2=1.0Hz,1H),7.13~7.16(m,3H),7.25~7.28(m,1H),7.30~7.33(m,2H);13CNMR(CDCl3,125MHz),δ:39.27,50.98,52.00,61.02,116.42,119.08,121.95,127.06,128.52,128.61(2C),128.89,128.99(2C),136.03,157.65,173.60;IR(KBr,v/cm-1):3317,3057,3027,2926,2856,1736,1606,1595,1491,1457,1352,1272,1242,1203,1178,1122,1107,1050,1035,968,933,891,853,803,747,699。4b:白色固体,收率88.0%,m.p.34.2~35.1℃;1HNMR(CDCl3,500MHz),δ:1.25(t,J=7.0Hz,3H),2.96(dd,J1=7.5Hz,J2=7.5Hz,1H),3.07(dd,J1=6.0Hz,J2=6.0Hz,1H),3.62(t,J=6.5Hz,1H),3.72(d,J=13.5Hz,1H),4.03(d,J=13.5Hz,1H),4.20(q,J=7.0Hz,2H),6.78(t,J=7.0Hz,1H),6.85(d,J=8.5Hz,1H),6.95(d,J=7.0Hz,1H),7.18(t,J=8.0Hz,3H),7.29(d,J=8.0Hz,1H),7.33(t,J=7.0Hz,2H);13CNMR(CDCl3,125MHz),δ:14.12,39.38,51.05,61.15,61.19,116.49,119.12,122.06,127.06,128.55,128.62(2C),128.93,129.10(2C),136.17,157.75,173.21;IR(KBr,v/cm-1):3304,2981,1734,1588,1490,1256,1191,1104,1028,754,699。4c:白色固体,收率89.2%,m.p.47.4~48.6℃;1HNMR(CDCl3,500MHz),δ:1.36(d,J=7.0Hz,3H),3.44(d,J=7.0Hz,1H),3.77(d,J=15.0Hz,4H),4.07(d,J=13.5Hz,1H),6.76~6.79(m,1H),6.84(d,J=8.0Hz,1H),6.95~6.97(m,1H),7.16~7.18(m,1H);13CNMR(CDCl3,125MHz),δ:19.02,50.80,52.14,54.89,116.42,119.17,121.97,128.54,128.90,157.82,174.93;IR(KBr,v/cm-1):3429,3300,1903,1723,1616,1588,1493,1438,1405,1382,1301,1256,1207,1160,1106,1068,1043,1032,977,940,909,864,846,793,752,722。4d:白色固体,收率89.0%,m.p.84.9~85.9℃;1HNMR(CDCl3,500MHz),δ:3.46(s,2H),3.76(s,2H),4.00(s,2H),6.77~6.80(m,1H),6.85(d,J=8.0Hz,1H),6.98(d,J=7.0Hz,1H),7.17(t,J=7.5Hz,1H);13CNMR(CDCl3,125MHz),δ:48.57,51.99,52.07,116.44,119.19,121.72,128.66,129.00,157.81,171.83;IR(KBr,v/cm-1):3451,3352,2894,2857,2118,1898,1735,1616,1587,1484,1429,1369,1302,1260,1224,1206,1185,1136,1104,1037,988,929,899,866,847,756,720。2.3.3-3-甲基苯基-3-氧基-4-甲基苯磺酸酯3a4e的合成模型反应:将6.45g(0.03mol)L-苯丙氨酸甲酯盐酸盐加入到250mL三口瓶中,加入100mL无水甲醇搅拌至完全溶解,再加入3.36g(0.03mol)TEA后继续搅拌,将溶有3.66g(0.03mol)水杨醛的无水甲醇溶液缓慢加入其中,于常温下反应4h,将反应瓶移至冰水浴下搅拌10min后,分批数次加入1.29g(0.033mol)硼氢化钠,约30min后反应完全(TLC检测),减压脱溶,加入200mL乙酸乙酯溶解,再分别用水(100mL×2次)与氯化钠的饱和溶液(100mL×2次)洗涤有机相,有机相用无水硫酸钠干燥,减压脱溶得粗产品,再用乙酸乙酯-石油醚重结晶得产物4a(收率见表1)。3氨基酸甲酯盐酸盐化合物的合成文献报道氨基酸酯与醛反应生成的席夫碱不太稳定,容易水解,难以纯化且收率不高。张涑戎等在合成水杨醛甘氨酸乙酯时加人4A分子筛做脱水剂可以提高其收率。氨基酸甲酯是含有酯基和氨基的双官能团化合物,稳定性也比较差,易自身缩合而难以分离和提纯,而氨基酸甲酯盐酸盐虽具有较强的吸水性,但稳定性较高,干燥后可保存备用,非常方便。因此,笔者以氨基酸酯盐酸盐为原料,利用其和水杨醛反应来合成席夫碱。由于前述席夫碱较不稳定和较难提纯的原因,主要考察了分步法与“一锅法”合成2-(N-取代氨基甲基)苯酚(4)。分步法即先合成席夫碱(3),分离提纯后用硼氢化钠还原得到产品4,分步收率和总收率见表1。“一锅法”是将生成的席夫碱未经