氨基酰苯丙氨酰色氨酸或其衍生物、其合成方法和应用转让专利
申请号 : CN200810113859.8
文献号 : CN101591377B
文献日 : 2012-08-15
发明人 : 彭师奇 , 赵明 , 王桥 , 王滨
申请人 : 首都医科大学
摘要 :
权利要求 :
1.具有镇痛活性的通式I化合物:
其中,AA选自脯氨酸残基、缬氨酸残基、甲硫氨酸残基、异亮氨酸残基、苏氨酸残基、谷氨酰胺残基、丝氨酸残基、酪氨酸残基或Glu残基。
2.权利要求1所述的通式I化合物的中间体化合物:其中,AA选自亮氨酸残基、脯氨酸残基、缬氨酸残基、甲硫氨酸残基、丙氨酸残基、异亮氨酸残基、色氨酸残基、苏氨酸残基、ω-叔丁氧羰基-组氨酸残基、ω-叔丁氧羰基-赖氨酸残基、谷氨酰胺残基、天冬酰胺残基、丝氨酸残基、酪氨酸残基、Arg(NO2)残基、Asp残基或Glu残基。
3.一种制备权利要求1所述通式I化合物的方法,包括:(1)、制备色氨酸甲酯;
(2)、制备叔丁氧羰基保护的苯丙氨酸;
(3)、在DCC、HOBt、NMM和THF存在下将叔丁氧羰基保护的苯丙氨酸和色氨酸甲酯耦联,合成叔丁氧羰基苯丙酰基色氨酸甲酯;
(4)、在氯化氢/乙酸乙酯溶液中加入叔丁氧羰基苯丙酰基色氨酸甲酯,脱去叔丁氧羰基,制备得到苯丙酰基色氨酸甲酯;
(5)、在DCC、HOBt、NMM和THF存在下将苯丙酰基色氨酸甲酯与叔丁氧羰基保护的氨基酸进行耦联,得到通式II化合物:其中,AA的定义与权利要求1中相同;
(6)、在冰浴条件下用碱溶液将通式II化合物进行皂化,得到通式III化合物:其中,AA的定义与权利要求1中相同;
(7)、在氯化氢/乙酸乙酯溶液中加入通式III化合物,脱去叔丁氧羰基,得到通式I化合物。
4.按照权利要求3所述的方法,其特征在于:步骤(1)中所述的色氨酸甲酯按照以下方法制备得到:在冰盐浴条件下向甲醇中逐滴加入氯化亚砜,搅拌后加入色氨酸,得到色氨酸甲酯。
5.按照权利要求3所述的方法,其特征在于:步骤(2)中所述的叔丁氧羰基保护的苯丙氨酸按照以下方法制备得到:在冰浴条件下用1N NaOH溶液将苯丙氨酸溶解,加入二氧六环溶解的(Boc)2O,制备得到叔丁氧羰基保护的苯丙氨酸。
6.按照权利要求3所述的方法,其特征在于:步骤(6)中所述的碱溶液为2N的NaOH溶液。
7.一种治疗疼痛的药物组合物,由治疗上有效量的权利要求1所述的通式I化合物和药学上可接受的辅料组成。
8.权利要求1所述的通式I化合物在制备镇痛药物中的用途。
说明书 :
氨基酰苯丙氨酰色氨酸或其衍生物、其合成方法和应用
技术领域
背景技术
发明内容
附图说明
9o中AA为Ser残基、9p中AA为Tyr残基、9q中AA为Arg残基、9r中AA为Asp残基、和9s中AA为Glu残基。
具体实施方式
50ml乙酸乙酯溶解残留物,过滤再次除去不溶的DCU,乙酸乙酯层依次用饱和碳酸氢钠水溶液(10ml×3)、5%硫酸氢钾水溶液(10ml×3)、饱和碳酸氢钠水溶液(10ml×3)、饱和氯化钠水溶液(10ml×3)各萃洗三遍,分出乙酸乙酯层用无水Na2SO4干燥过夜,过滤,滤液减压浓缩至于,然后用200-300目硅胶柱层析分离,得到淡黄色固体1500mg(收率92%)。
+ 1
Mp:165-166 ℃;ESI-MS(m/e)466[M+H] ;HNMR(BHSC-500Hz,CDCl3),δ/ppm = 10.78(s,
1H),8.15(s,1H),7.40(d,J = 7.0Hz,1H),7.35(d,J = 8.0Hz,1H),7.30-7.23(m,5H),
7.20(t,J = 7.5Hz,1H),7.09(t,J = 7.5Hz,1H),6.90(s,1H),6.38(d,J = 5.5Hz,1H),
4.90(m,1H),4.36(m,1H),3.65(s,3H),3.28-3.28(m,2H),3.06-3.04(m,2H),1.39(s,9H);
13
C-NMR(BHSC-125Hz,CDCl3),δ/ppm = 171.75,170.77,155.25,136.59,136.08,129.43,
128.62,127.53,126.93,122.26,119.69,118.49,111.30,109.79,80.09,55.68,52.99,
52.31,38.36,28.21,27.70.
溶液抽洗三次,得灰色固体1040mg(收率99%).Mp:176-178℃;ESI-MS(m/e)366[M+H] ;
1
HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=11.02(s,1H),9.25(d,J=7.5Hz,1H),8.33(s,2H),
7.50(d,J=8.0Hz,1H),7.37(d,J=8.0Hz,1H),7.33-7.25(m,6H),7.07(t,J=7.5Hz,
1H),7.01(t,J = 7.5Hz,1H),4.59(m,1H),4.13(m,1H),3.25-3.19(m,3H),3.02(dd,J =
13
7.5Hz,J=14.0Hz,1H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=171.39,170.41,155.41,
136.71,136.28,129.32,128.71,127.02,122.79,122.23,119.65,118.66,111.27,56.29,
52.08,38.73,26.30..
+ -1 -1 -1 -1
Mp:154-156℃;ESI-MS(m/e)579[M+H] ;IR(KBr)υ:3309cm ,3059cm ,2954cm ,2870cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1743cm ,1697cm ,1651cm ,1512cm ,1454cm ,1438cm ,1392cm ,1365cm ,1165cm ,-1 -1 1
740cm ,698cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=10.88(s,1H),8.52(d,J=7.5Hz,
1H),7.74(d,J=8.5Hz,1H),7.49(d,J=8.0Hz,1H)7.35(d,J=8.0Hz,1H),7.25-7.18(m,
5H),7.16(s,1H),7.08(t,J=7.5Hz,1H),7.00(t,J=4.5Hz,1H),6.90(d,J=9.0Hz,1H),
4.63(m,1H),4.53(m,1H),3.88(m,1H),3.56(s,3H),3.16(dd,J=6.5Hz,J=14.5Hz,1H),
3.09(dd,J=7.5Hz,J=14.5Hz,1H),3.00(dd,J=4.5Hz,J=13.5Hz,1H),2.79(dd,J=
4.5Hz,J=13.5Hz,1H),1.46(m,1H),1.37(s,9H),1.30(m,2H),0.825(d,J=7.0Hz,3H),
13
0.79(d,J=7.0Hz,3H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=172.54,172.45,171.52,
155.63,137.87,136.55,129.79,128.36,127.53,126.65,124.16,121.44,118.89,118.41,
111.90,109.55,78.57,53.62,53.49,52.26,41.33,38.26,28.63,27.54,24.64,23.34,
21.98.
+ -1 -1 -1 -1
Mp:84-86 ℃;ESI-MS(m/e)523[M+H] ;IR(KBr)υ:3305cm ,3062cm ,2978cm ,2927cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1743cm ,1651cm ,1521cm ,1454cm ,1438cm ,1392cm ,1365cm ,1246cm ,1165cm ,-1 -1 1
740cm ,702cm ,HNMR(BHSC-500Hz,DMSO-d6)δ/ppm = 10.89(s,1H),8.54(d,J =
7.5Hz,1H),7.90(d,J = 8.5Hz,lH),7.50(d,J = 8.0Hz,1H),7.36(d,J = 8.0Hz,lH),
7.29-7.20(m,5H),7.19(s,1H),7.10(t,J=7.0Hz,1H),7.07(t,J=7.0Hz,1H),6.92(t,J=6.0Hz,1H),4.60(m,1H),4.54(m,1H),3.55(s,1H),3.39(s,2H),3.24(dd,J=7.5Hz,J=15.0Hz,1H),3.09(dd,J=7.5Hz,J=15.0Hz,1H),2.95(dd,J=4.5Hz,J=11.0Hz,
13
1H),2.68(dd,J=7.5Hz,J=11.0Hz,lH),1.38(s,9H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.50,171.50,169.47,156.21,137.99,136.55,129.70,128.46,127.52,126.71,
124.23,121.45,118.91,118.42,111.91,109.63,78.56,53.82,53.56,52.28,43.55,
38.16,28.65,27.51.
+ -1 -1 -1 -1
Mp:102-103℃;ESI-MS(m/e)562[M+H] ;IR(KBr)υ:3317cm ,3059cm ,2978cm ,2924cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
2850cm ,1743cm ,1652cm ,1512cm ,1454cm ,1438cm ,1392cm ,1365cm ,1249cm ,-1 -1 -1 1
1168cm ,744cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=10.91(s,1H),8.53(d,J=7.0Hz,lH),7.82(d,J=8.5Hz,1H),7.49(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,lH),
7.28-7.23(m,5H),7.19(s,1H),7.08(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),4.64(m,
1H),4.57(m,1H),4.00(m,1H),3.56(s,3H),3.41-3.32(m,2H),3.24-3.16(m,2H),3.10(dd,J=8.0Hz,J =15.0Hz,1H),3.00(dd,J =8.0Hz,15Hz,1H),2.00(m,1H),1.67-1.60(m,
13
3H),1.13(s,9H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.54,172.25,153.80,
138.19,136.57,129.63,128.40,127.53,126.67,124.10,121.44,118.88,118.41,111.90,
109.62,78.82,60.07,53.94,53.57,52.27,46.92,38.06,29.87,29.47,28.61,23.37.[0049] 实施例8制备Boc-Val-Phe-Trp-OCH3(7d)
+ -1 -1 -1 -1
Mp:179-180℃;ESI-MS(m/e)565[M+H] ;IR(KBr)υ:3298cm ,3059cm ,2966cm ,2870cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1732cm ,1685cm ,1651cm ,1519cm ,1454cm ,1392cm ,1365cm ,1168cm ,740cm ,-1 1
698cm ,HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 10.59(s,1H),8.51(d,J = 7.0Hz,1H),
7.90(d,J=8.5Hz,1H),7.48(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),7.24-7.16(m,
6H),7.07(t,J=7.5Hz,1H),7.00(t,J=5.0Hz,1H),6.65(d,J=9.0Hz,1H),4.66(m,1H),
4.53(m,1H),3.73(m,1H),3.55(s,3H),3.15(dd,J= 6.0Hz,J= 14.5Hz,1H),3.09(dd,J=7.5Hz,J=14.5Hz,1H),2.99(dd,J=4.5Hz,J=13.5Hz,1H),2.77(dd,J=9.5Hz,J = 13.5Hz,1H),1.80(m,1H),1.38(s,9H),0.68(dd,J = 6.5Hz,J = 17.5Hz,6H);
13
C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=172.44,171.66,171.45,155.74,138.01,136.55,
129.69,128.42,127.52,126.67,124.16,121.43,118.88,118.41,111.89,109.53,78.53,
60.37,53.70,53.57,52.26,38.24,31.00,28.63,27.52,19.55,18.52.
+ -1 -1 -1 -1
Mp:134-135℃;ESI-MS(m/e)597[M+H] ;IR(KBr)υ:3298cm ,2978cm ,2924cm ,1743cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1651cm ,1512cm ,1454cm ,1438cm ,1392cm ,1354cm ,1165cm ,740cm ,698cm ;
1
HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=10.89(s,1H),8.55(d,J=7.5Hz,1H),7.82(d,J=
8.0Hz,1H),7.49(d,J=7.5Hz,1H),7.48(d,J=8.0Hz,1H),7.25-7.16(m,6H),7.08(t,J=7.5Hz,1H),7.0(t,J=7.5Hz,2H),4.62(m,1H),4.54(m,1H),3.95(m,1H),3.56(s,3H),
3.17(dd,J=6.5Hz,J=14.5Hz,1H),3.09(dd,J=7.5Hz,J=4.5Hz,1H),3.00(dd,J=4.5Hz,J= 14.0Hz,1H),2.78(dd,J=9.0Hz,J= 14.0Hz,1H),2.33(m,2H),1.98(s,
13
3H),1.69(m,2H),1.37(s,9H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm= 172.45,171.73,
171.50,155.69,137.87,136.54,129.77,128.40,127.54,126.70,124.17,121.44,118.90,
118.42,111.90,109.56,78.72,54.19,53.64,52.27,38.20,32.25,30.06,28.62,27.54,
15.05.
+ -1 -1 -1 -1
Mp:96-98 ℃;ESI-MS(m/e)537[M+H] ;IR(KBr)υ:3302cm ,2978cm ,2927cm ,1651cm ,-1 -1 -1 -1 -1 -1 -1 1
1496cm ,1442cm ,1392cm ,1365cm ,1165cm ,744cm ,698cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 11.45(s,1H),8.54(d,J = 7.0Hz,1H),7.91(d,J = 8.0Hz,lH),
7.50(d,J=8.0Hz,1H),7.35(d,J=8.5Hz,1H),7.26-7.17(m,6H),7.08(t,J=7.5Hz,
1H),7.00(t,J = 7.5Hz,1H),6.92(t,J = 6.5Hz,1H),4.60(m,1H),4.54(m,1H),3.57(s,
3H),3.46(m,1H),3.18(dd,J=6.0Hz,J=14.5Hz,1H),3.09(dd,J=7.5Hz,J=14.5Hz,
1H),2.99(dd,J=4.5Hz,J=4Hz,1H),2.77(dd,J=9.5Hz,J =14.0Hz,1H),1.38(s,
13
9H),1.25(d,J=10.0Hz,3H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=712.51,171.52,
169.47,156.21,137.99,136.54,129.71,128.46,127.51,126.71,124.23,121.45,118.91,
118.42,111.91,109.62,78.54,53.81,53.56,52.29,43.52,38.16,28.65,27.50,18.88.[0055] 实施例11制备Boc-Phe-Phe-Trp-OCH3(7g)
+ -1 -1 -1 -1
Mp:90-91 ℃;ESI-MS(m/e)613[M+H] ;IR(KBr):3298cm ,2927cm ,1743cm ,1689cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1651cm ,1512cm ,1454cm ,1438cm ,1392cm ,1365cm ,1168cm ,744cm ,698cm ;
1
HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=10.90(s,1H),8.57(d,J=7.5Hz,1H),8.27(d,J=
8.5Hz,1H),7.55(d,J=7.5Hz,1H),7.35(d,J=8.5Hz,1H),7.24-7.12(m,11H),7.08(t,J=7.5Hz,1H),7.0(t,J=7.5Hz,1H),6.87(d,J=8.0Hz,1H),4.65(m,1H),4.55(m,1H),
4.12(m,1H),3.58(s,3H),3.18(dd,J=6.0Hz,J=15.0Hz,1H),3.10(dd,J=7.5Hz,J=
15.0Hz,1H),3.03(dd,J=5.0Hz,J=14.0Hz,1H),2.82(dd,J=9.5Hz,J=14.0Hz,2H),
13
2.62(dd,J=10.5Hz,J=14.0Hz,1H),1.30(s,9H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.47,171.79,171.53,155.51,138.56,137.90,136.54,129.72,129.59,128.46,
128.41,127.53,126.74,126.56,124.23,121.44,118.90,118.42,111.90,109.56,78.57,
56.24,53.79,53.61,52.29,38.29,37.98,28.56,27.54.
+ -1 -1 -1 -1
Mp:189-190℃;ESI-MS(m/e)576[M+H] ;IR(KBr)υ:3348cm ,3317cm ,2974cm ,2927cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
2870cm ,1735cm ,1647cm ,1535cm ,1512cm ,1454cm ,1435cm ,1392cm ,1365cm ,-1 -1 -1 1
1168cm ,736cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 10.88(s,1H),8.48(d,J=7.5Hz,1H),7.89(d,J=8.5Hz,1H),7.48(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),
7.24-7.16(m,6H),7.08(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),6.69(d,J=9.0Hz,
1H),4.66(m,1H),4.53(m,1H),3.76(m,1H),3.54(s,3H),3.15(dd,J=6.5Hz,J=14.5Hz,
1H),3.09(dd,J=7.5Hz,J=14.5Hz,1H),2.99(dd,J=4.5hz,J=14.0Hz,1H),2.78(dd,J = 10.0Hz,J = 14.0Hz,1H),1.55(m,1H),1.38(s,9H),1.28-1.21(m,2H),0.73(t,J =
13
7.5Hz,3H),0.60(d,J = 7.0Hz,3H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.42,
171.62,171.49,155.66,138.00,136.56,129.69,128.39,127.53,126.65,124.15,121.43,
118.41,118.41,111.89,78.54,59.46,53.67,53.59,52.24,38.24,37.05,28.64,27.55,
24.69,15.59,11.31.
体。Mp:101-104 ℃;ESI-MS(m/e)465[M+H] ;IR(KBr)υ:3402cm ,3309cm ,3059cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
2978cm ,1735cm ,1651cm ,1504cm ,1454cm ,1435cm ,1392cm ,1365cm ,1338cm ,-1 -1 -1 1
1165cm ,740cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 10.90(s,1H),10.78,(s,1H),8.57(d,J=7.0Hz,1H),7.94(d,J=8.5Hz,1H),7.54(d,J=8.0Hz,1H),7.50(d,J = 8.0Hz,1H),7.35(d,J = 8.0Hz,1H),7.32(d,J = 8.0Hz,1H),7.30-7.18(m,6H),
7.01-6.96(m,5H),6.79(d,J=8.0Hz,1H),4.67(m,1H),4.57(m,1H),4.16(m,1H),3.57(s,
1H),3.17(dd,J=8.5Hz,J=14.5Hz,1H),3.11(dd,J=7.5Hz,J=14.5Hz,1H),3.03(dd,J =5.0Hz,J =14.0Hz,1H),2.93(dd,J =4.5Hz,J= 15.0Hz,1H),2.86-2.78(m,2H),
13
1.29(s,9H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.47,172.05,171.55,155.53,
137.92,136.56,136.50,129.85,128.43,127.85,127.56,126.72,124.21,123.92,121.45,
121.26,118.91,118.87,118.62,118.44,111.91,111.71,110.76,109.57,78.59,55.86,
53.73,53.66,52.28,38.32,28.56,28.24,27.56.
+ -1 -1 -1 -1
Mp:95-97 ℃;ESI-MS(m/e)567[M+H] ;IR(KBr)υ:3309cm ,2978cm ,2931cm ,1743cm ,- -1 -1 -1 -1 -1 -1 -1 -1
1651cm1,1519cm ,1496cm ,1454cm ,1438cm ,1392cm ,1365cm ,1165cm ,744cm ,-1 1
702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 10.87(s,1H),8.50(d,J = 7.0Hz,1H),
7.91(d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),7.35(d,J=8.5Hz,1H),7.24-7.16(m,
6H),7.08(t,J = 7.5Hz,1H),7.00(t,J = 7.5Hz,1H),6.38(d,J = 8.0Hz,1H),4.61(m,
1H),4.51(m,1H),3.86-3.79(m,2H),3.55(s,3H),3.16(dd,J = 6.5Hz,J = 14.5Hz,1H),
3.07(dd,J=8.0Hz,J=14.5Hz,1H),3.01(dd,J=4.5Hz,J= 14.0Hz,1H),2.79(dd,
13
J=9.0Hz,J=13.5Hz,1H),1.37(s,9H),0.91(d,J=6.0Hz,3H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.45,171.44,170.47,155.73,137.87,136.55,129.71,128.45,
126.72,124.01,121.49,118.94,118.39,111.93,109.55,78.85,67.22,60.50,53.79,
53.68,52.27,37.94,28.57,27.50,19.84.
固 体。Mp:147-148 ℃;ESI-MS(m/e)703[M+H] ;IR(KBr)υ:3294cm ,2978cm ,2931cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1759cm ,1651cm ,1519cm ,1454cm ,1435cm ,1392cm ,1369cm ,1249cm ,1157cm ,-1 -1 -1 1
1010cm ,740cm ,698cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 10.90(s,1H),
8.58(d,J = 7.5Hz,1H),8.10(s,1H),7.91(d,J = 8.0Hz,1H),7.48(d,J = 8.0Hz,1H),
7.25-7.16(m,6H),7.07(t,J=7.5Hz,1H),6.99(t,J=7.5Hz,1H),6.88(d,J=8.5Hz,
1H),4.61-4.53(m,2H),4.16(m,1H),3.56(s,3H),3.17(dd,J = 5.5Hz,J = 14.5Hz,1H),
3.08(dd,J=7.5Hz,J=14.5Hz,1H),3.00(dd,J=4.5Hz,J=14.0Hz,1H),2.80(dd,J=
9.5Hz,J=14.0Hz,1H),2.74(dd,J=4.0Hz,J=15.0Hz,1H),2.63(dd,J=9.5Hz,J=
13
15.0Hz,1H),1.54(s,9H),1.33(s,9H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm= 172.48,
171.45,155.54,147.15,137.94,137.07,136.54,129.77,128.41,127.54,126.68,124.16,
121.43,118.89,118.42,114.61,111.88,109.56,85.53,78.71,54.26,53.85,53.57,
52.28,38.01,31.10,28.54,27.82,27.51.
固 体。Mp:132-134 ℃;ESI-MS(m/e)694[M+H] ;IR(KBr)υ:3321cm ,2970cm ,2931cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1735cm ,1685cm ,1647cm ,1535cm ,1516cm ,1454cm ,1435cm ,1392cm ,1365cm ,-1 -1 -1 1
1172cm ,736cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 10.88(s,1H),8.50(d,J=7.5Hz,1H),7.77(d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),7.34(d,J=8.0Hz,1H),
7.25-7.16(m,6H),7.08(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),6.83(d,J=8.0Hz,
1H),6.75(t,J=5.0Hz,1H),4.62(m,1H),4.54(m,1H),3.80(m,1H),3.56(s,3H),3.16(dd,J=6.5Hz,J=15.0Hz,1H),3.09(dd,J=7.5Hz,J=14.5Hz,1H),2.99(dd,J=4.5Hz,J= 13.5Hz,1H),2.89-2.82(m,2H),2.78(dd,J= 4.0Hz,J= 13.5Hz,1H),1.38(s,9H),
13
1.37(s,9H),1.31-1.25(m,2H),1.21-1.18(m,4H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.45,172.27,171.53,156.03,155.68,137.89,136.54,129.77,128.38,127.54,
126.67,124.16,121.43,118.89,118.41,111.89,109.55,78.58,77.79,55.06,53.58,
52.26,38.22,32.16,29.65,28.75,27.53,23.22.
+ -1 -1 -1 -1
Mp:193-194℃;ESI-MS(m/e)594[M+H] ;IR(KBr)υ:3348cm ,3302cm ,2978cm ,2924cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1732cm ,1670cm ,1519cm ,1454cm ,1388cm ,1365cm ,1168cm ,748cm ,698cm ,-1 1
624cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 10.89(s,1H),8.54(d,J = 7.0Hz,1H),
7.87(d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),7.34-7.16(m,
6H),7.08(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),6.89(d,J=8.0Hz,1H),6.81(s,2H),
4.60(m,1H),4.54(m,1H),3.87(m,1H),3.56(s,3H),3.17(dd,J=6.5Hz,J=15.0Hz,1H),
3.08(dd,J=7.5Hz,J=14.5Hz,1H),2.99(dd,J=5.0Hz,J =14.0Hz,1H),2.79(dd,J = 9.0Hz,J = 13.5Hz,1H),2.11-2.00(m,2H),1.74(m,1H),1.62(m,1H),1.37(s,9H);
13
C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=174.46,172.45,171.97,171.46,155.66,137.87,
136.54,129.73,128.42,127.53,126.69,124.12,121.44,118.90,118.41,111.89,109.63,
78.62,54.53,53.75,53.52,52.27,38.23,32.05,28.64,28.40,27.48.
得1620mg(收率92.73%)淡黄色固体。Mp:184-185℃;ESI-MS(m/e)580[M+H] ;IR(KBr)-1 -1 -1 -1 -1 -1 -1 -1 -1
υ:3302cm ,3059cm ,2978cm ,2927cm ,1743cm ,1651cm ,1512cm ,1456cm ,1438cm ,-1 -1 -1 -1 -1 1
1392cm ,1365cm ,1168cm ,740cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm =
10.88(s,1H),8.52(d,J=7.0Hz,1H),7.82(d,J=8.0Hz,1H),7.49(d,J=8.0Hz,1H),
7.35(d,J=8.0,1H),7-31(s,1H),7-31-7.17(m,6H),7.08(t,J=7.5Hz,1H),7.00(t,J=
7.5Hz,1H),6.92(d,J=8.0Hz,2H),4.55-4.50(m,2H),4.23(m,1H),3.56(s,3H),3.17(dd,J=6.5Hz,J=14.5Hz,1H),3.09(dd,J=7.5Hz,J=14.5Hz,1H),2.95(dd,J=4.5Hz,J=14.0Hz,1H),2.80(dd,J=8.5Hz,J=14.0Hz,1H),2.41(dd,J=5.0Hz,J=15.0Hz,
13
1H),2.32(dd,J=8.0Hz,J=15.0Hz,1H),1.37(s,9H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.46,172.14,171.65,171.30,155.52,137.90,136.54,130.18,129.74,128.45,
127.53,126.68,124.21,121.44,118.90,118.42,111.91,109.65,78.77,53.95,53.65,
52.27,51.77,37.97,37.70,28.63,27.50.
+ -1 -1 -1
体。Mp:177-178 ℃;ESI-MS(m/e)553[M+H] ;IR(KBr)υ:3309cm ,2978cm ,2931cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1735cm ,1651cm ,1519cm ,1438cm ,1392cm ,1365cm ,1165cm ,744cm ,1702cm ;
1
HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=10.89(s,1H),8.51(d,J=7.0Hz,1H),7.90(d,J=8.5Hz,1H),7.49(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),7.34-7.17(m,6H),7.10(t,J=7.5Hz,1H),7.02(t,J=7.5Hz,1H),6.69(d,J=8.0Hz,1H),4.93(t,J=5.5Hz,1H),
4.59(m,1H),4.52(m,1H),3.97(m,1H),3.56(s,3H),3.46(t,J = 6.0Hz,2H),3.16(dd,J=6.0Hz,J=14.5Hz,1H),3.07(dd,J=8.0Hz,J=15.0Hz,1H),3.02(dd,J=9.5Hz,J
13
=14.0Hz,1H),2.79(dd,J=9.0Hz,J=13.5Hz,1H),1.38(s,9H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.43,171.37,170.52,155.60,137.92,136.56,129.76,128.41,
127.51,126.68,124.19,121.45,118.91,118.41,111.20,109.59,78.72,62.37,57.30,
53.87,53.68,52.26,37.97,28.63,27.54.
体。Mp:105-107 ℃;ESI-MS(m/e)629[M+H] ;IR(KBr)υ:3305cm ,3059cm ,2978cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
2927cm ,1735cm ,1651cm ,1515cm ,1438cm ,1392cm ,1365cm ,1165cm ,744cm ,-1 1
702cm ;HNMR(BHSC-300Hz,DMSO-d6),δ/ppm = 10.89(s,1H),9.15(s,1H),8.55(d,J =
7.5Hz,1H),7.91(d,J = 8.4Hz,1H),7.49(d,J = 7.8Hz,1H),7.34(d,J = 8.1Hz,1H),
7.26-7.16(m,6H),7.07(t,J = 7.5Hz,1H),7.05-6.93(m,3H),6.80(d,J = 8.7Hz,1H),
6.61(d,J=8.4Hz,2H),4.63(m,1H),4.54(m,1H),4.02(m,1H),3.55(s,3H),3.21-2.98(m,
13
4H),2.85-2.68(m,2H),1.29(s,9H);C-NMR(BHSC-75Hz,DMSO-d6),δ/ppm = 172.44,
171.96,171.52,156.13,155.52,137.90,136.53,130.47,129.81,128.58,128.43,127.53,
126.71,124.21,121.43,118.90,118.42,115.22,111.89,109.54,103.51,78.54,56.63,
53.77,53.60,52.27,38.27,37.17,28.58,27.53.
+ -1 -1 -1 -1
Mp:150-151℃;ESI-MS(m/e)667[M+H] ;IR(KBr)υ:3304cm ,2976cm ,2949cm ,2927cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1739cm ,1647cm ,1600cm ,1523cm ,1454cm ,1438cm ,1392cm ,1365cm ,1255cm ,-1 -1 -1 1
1163cm ,742cm ,700cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 10.88(s,1H),8.54(d,J= 5.0Hz,1H),8.47(s,1H),7.80(d,J= 10.0Hz,1H),7.49(d,J= 5.0Hz,1H),7.35(d,J = 5.0Hz,1H),7.25-7.15(m,6H),7.08(t,J = 7.5Hz,1H),7.00(t,J = 7.5Hz,1H),
6.91(d,J=10.0Hz,1H),4.63(m,1H),4.54(m,1H),3.86(m,1H),3.56(s,3H),3.17(dd,J=
10.0Hz,J=15.0Hz,1H),3.11-3.07(m,4H),3.00(dd,J=50Hz,J=15.0Hz,1H),2.80(dd,J = 10.0Hz,J = 15.0Hz,1H),2.09(s,2H),1.49-1.47(m,2H),1.37(s,9H),1.19(m,2H);
13
C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=172.47,171.98,171.47,159.79,155.69,137.83,
136.55,129.78,128.40,127.53,126.69,124.18,121.45,118.91,118.42,111.91,105.57,
78.72,54.64,53.62,52.27,40.77,38.26,31.16,29.68,28.63,27.52.
固 体。Mp:161-162 ℃;ESI-MS(m/e)595[M+H] ;IR(KBr)υ:3371cm ,3298cm ,3059cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
2978cm ,1947cm ,1720cm ,1643cm ,1527cm ,1435cm ,1392cm ,1365cm ,1303cm ,-1 -1 -1 -1 -1 -1 1
1215cm ,1165cm ,991cm ,732cm ,698cm ,636cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=10.89(s,1H),8.51(d,J=7.5Hz,1H),7.79(d,J=8.5Hz,1H),7.49(d,J=8.0Hz,1H),
7.35(d,J=8.0Hz,1H),7.27-7.17(m,6H),7.11(d,J=8.0Hz,1H),7.08(t,J=7.5Hz,
1H),7.00(t,J = 7.5Hz,1H),4.58-4.52(m,2H),4.29(m,1H),3.57(s,3H),3.56(s,3H),
3.17(dd,J=6.5Hz,J=14.5Hz,1H),3.09(dd,J=7.5Hz,J=14.5Hz,1H),2.99(dd,J=4.5Hz,J=14.0Hz,1H),2.82(dd,J=8.5Hz,J=13.5Hz,1H),2.61(dd,J=5.0Hz,J
13
=16.0Hz,1H),2.45(dd,J=9.0Hz,J=16.0Hz,1H),1.37(s,9H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.44,171.21,170.86,155.59,137.77,136.55,129.76,128.62,
128.43,127.53,126.72,124.17,121.44,118.90,118.42,111.90,109.58,78.93,53.92,
53.60,52.27,51.95,51.49,38.09,36.52,28.59,27.55.
固 体。Mp:156-157 ℃;ESI-MS(m/e)609[M+H] ;IR(KBr)υ:3307cm ,2978cm ,2951cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1735cm ,1716cm ,1647cm ,1514cm ,1456cm ,1436cm ,1390cm ,1367cm ,1168cm ,-1 -1 1
742cm ,700cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 10.88(s,1H),8.55(d,J =
5.0Hz,1H),7.85(d,J=5.0Hz,1H),7.49(d,J=10.0Hz,1H),7.35(d,J=10.0Hz,1H),
7.23-7.17(m,6H),7.08(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),6.92(d,J=10.0Hz,
1H),4.62(m,1H),4.54(m,1H),3.89(m,1H),3.57(s,3H),3.56(s,3H),3.17(dd,J=5.0Hz,J=15.0Hz,1H),3.10(dd,J=10.0Hz,J=15.0Hz,1H),3.00(dd,J=5.0Hz,J=15.0Hz,
1H),2.79(dd,J=10.0Hz,J=15.0Hz,1H),2.19(t,J=5.0Hz,2H),1.78-1.64(m,2H),
13
1.37(s,9H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 173.26,172.45,171.52,155.60,
137.88,136.55,129.75,128.39,127.54,126.68,124.16,121.43,118.89,118.43,111.89,
109.57,78.74,54.12,53.64,52.25,51.74,38.20,30.26,28.61,27.78,27.52.[0081] 实施例24制备Boc-Leu-Phe-Trp-OH(8a)
ESI-MS(m/e)563[M-1] ;IR(KBr)υ:3309cm ,2958cm ,2931cm ,1651cm ,1512cm ,-1 -1 -1 -1 -1 -1 -1
1454cm ,1438cm ,1392cm ,1365cm ,1165cm ,740cm ,698cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3313cm ,2978cm ,2931cm ,1658cm ,1512cm ,1365cm ,1246cm ,1165cm ,-1 -1
740cm ,702cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3317cm ,2978cm ,2931cm ,1670cm ,1519cm ,1454cm ,1392cm ,1238cm ,-1 -1 -1
1161cm ,740cm ,698cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3325cm ,2970cm ,2931cm ,1651cm ,1512cm ,1454cm ,1392cm ,1365cm ,-1 -1 -1 -1
1246cm ,1161cm ,740cm ,698cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3302cm ,2978cm ,2924cm ,1651cm ,1512cm ,1454cm ,1438cm ,1392cm ,-1 -1 -1 -1 -1
1365cm ,1249cm ,1165cm ,744cm ,702cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3379cm ,3321cm ,2978cm ,2931cm ,1728cm ,1685cm ,1662cm ,1535cm ,-1 -1 -1 -1 -1 -1 -1 -1 -1
1512cm ,1442cm ,1369cm ,1327cm ,1246cm ,1165cm ,1064cm ,736cm ,702cm .[0093] 实施例30制备Boc-Phe-Phe-Trp-OH(8g)
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3410cm ,3302cm ,2978cm ,2931cm ,1693cm ,1651cm ,1512cm ,1496cm ,-1 -1 -1 -1 -1 -1 -1
1454cm ,1392cm ,1365cm ,1249cm ,1168cm ,74cm ,698cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3317cm ,2966cm ,2931cm ,1647cm ,1512cm ,1454cm ,1392cm ,1365cm ,-1 -1 -1 -1
1246cm ,1165cm ,740cm ,698cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3394cm ,3325cm ,2978cm ,2931cm ,1654cm ,1512cm ,1496cm ,1454cm ,-1 -1 -1 -1 -1 -1
1392cm ,1365cm ,1249cm ,1161cm ,740cm ,70cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3410cm ,3317cm ,2927cm ,1697cm ,1651cm ,1535cm ,1454cm ,1392cm ,-1 -1 -1 -1 -1 -1 -1 -1
1369cm ,1280cm ,1246cm ,1280cm ,1246cm ,1168cm ,744cm ,702cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3286cm ,1685cm ,1504cm ,1438cm ,1392cm ,1365cm ,1253cm ,1165cm ,-1 -1
744cm ,702cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3325cm ,2978cm ,2931cm ,1658cm ,1512cm ,1454cm ,1392cm ,1365cm ,-1 -1 -1
1168cm ,740cm ,702cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3309cm ,2978cm ,2927cm ,1654cm ,1516cm ,1454cm ,1392cm ,1365cm ,-1 -1 -1 -1 -1
1338cm ,1249cm ,1168cm ,744cm ,698cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3325cm ,2974cm ,2931cm ,1647cm ,1523cm ,1458cm ,1438cm ,1392cm ,-1 -1 -1 -1
1365cm ,1168cm ,744cm ,702cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3317cm ,2978cm ,2931cm ,1654cm ,1519cm ,1454cm ,1392cm ,1365cm ,-1 -1 -1
1161cm ,744cm ,698cm .
υ:3309cm ,2974cm ,2931cm ,1654cm ,1512cm ,1454cm ,1365cm ,1246cm ,1165cm ,-1 -1
744cm ,702cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3387cm ,3325cm ,2974cm ,2931cm ,1670cm ,1523cm ,1458cm ,1396cm ,-1 -1 -1 -1 -1
1365cm ,1261cm ,1161cm ,744cm ,698cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3410cm ,3317cm ,2927cm ,2850cm ,1697cm ,1651cm ,1535cm ,1454cm ,-1 -1 -1 -1 -1
1392cm ,1369cm ,1168cm ,744cm ,702cm .
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3305cm ,2978cm ,2931cm ,1716cm ,1658cm ,1519cm ,1454cm ,1392cm ,-1 -1 -1
1365cm ,744cm ,702cm .
e)465[M+H] ;IR(KBr)υ:3196cm ,3057cm ,2956cm ,2872cm ,1724cm ,1654cm ,-1 -1 -1 -1 -1 -1 -1 1
1516cm ,1456cm ,1390cm ,1371cm ,1228cm ,742cm ,700cm ;HNMR(BHSC-500Hz,DMSO-d6)δ/ppm = 12.36(s,1H),10.98(s,1H),8.82(d,J = 8.0Hz,1H),8.69(d,J =
7.5Hz,1H),8.22(s,2H),7.50(d,J = 7.5Hz,1H),7.35(d,J = 8.0Hz,1H),7.29-7.23(m,
5H),7.21(s,1H),7.08(t,J = 7.5Hz,1H),7.03(t,J = 7.5Hz,1H),4.64(m,1H),4.49(m,
1H),3.73(m,1H),3.18(dd,J=8.5Hz,J=15.0Hz,1H),3.09(dd,J=7.5Hz,J=15.0Hz,
1H),3.04(dd,J=4.5Hz,J=14.0Hz,1H),2.86(dd,J=9.0Hz,J=14.0Hz,1H),1.64(m,
13
1H),1.55-1.52(m,2H),0.861(t,J=5.0Hz,6H) C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=
171.98,171.21,169.40,137.98,136.56,129.68,128.56,127.54,126.8,124.31,121.39,
118.83,118.41,111.89,109.67.
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3232cm ,3057cm ,2978cm ,2927cm ,1728cm ,1654cm ,1529cm ,1496cm ,-1 -1 -1 -1 -1 1
1456cm ,1436cm ,1207cm ,742cm ,700cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm =
12.56(s,1H),11.05(s,1H),8.79(d,J=7.5Hz,1H),8.76(d,J=8.5Hz,1H),8.14(s,2H),
7.52(d,J=7.5Hz,1H),7.36(d,J=8.0Hz,1H),7.27-7.19(m,6H),7.08(t,J=7.5Hz,
1H),7.01(t,J = 7.5Hz,1H),4.67(m,1H),4.52(m,1H),3.54-3.49(m,2H),3.41-3.34(m,
2H),3.20(dd,J = 6.0Hz,J = 15.0Hz,1H),3.10(dd,J = 8.0Hz,J = 15.0Hz,1H);
13
C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=172.05,171.36,166.00,137.91,136.56,129.72,
128.54,127.49,126.85,124.37,121.40,118.86,118.42,111.93,109.68,54.28,53.71,
41.55,38.36,27.46.
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3259cm ,3057cm ,2927cm ,1728cm ,1662cm ,1537cm ,1456cm ,1438cm ,-1 -1 -1 -1 -1 -1 1
1394cm ,1375cm ,1247cm ,1097cm ,744cm ,700cm ,H NMR(BHSC-500Hz,DMSO-d6),δ/ppm=12.73(s,1H),10.97(s,1H),8.86(d,J=8.5Hz,1H),8.52(d,J=7.5Hz,1H),8.4(s,
1H),7.55(d,J = 8.0Hz,1H),7.35(d,J = 8.0Hz,1H),7.24(m,6H),7.08(t,J = 7.5Hz,
1H),6.99(t,J = 7.5Hz,1H),4.61(m,1H),4.50(m,1H),4.06(m,1H),3.24-3.06(m,4H),
13
2.79(dd,J=10.0Hz,1H),2.25(m,1H),1.84-1.72(m,4H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 173.61,171.14,168.42,138.03,136.55,129.66,128.57,127.63,126.84,
124.27,121.36,118.85,118.61,111.85,110.09,59.00,54.86,53.54,46.00,37.85,
30.10,27.45,23.88.
υ:3452cm ,3356cm ,2970cm ,1734cm ,1654cm ,1516cm ,1440cm ,1396cm ,1348cm ,-1 -1 -1 1
1182cm ,746cm ,704cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=12.69(s,1H),10.95(s,
1H),8.71(d,J=8.0Hz,1H),8.53(d,J=8.0Hz,1H),8.17(s,2H),7.54(d,J=8.0Hz,1H),
7.35(d,J=8.0Hz,1H),7.30-7.15(m,6H),7.07(t,J=7.5Hz,1H),6.98(t,J=7.5Hz,
1H),4.57(m,1H),4.50(m,1H),3.61(m,1H),3.18(dd,J=5.0Hz,J=15.0Hz,1H),3.09(dd,J=8.0Hz,J=15.0Hz,1H),3.03(dd,J=5.0Hz,J=14.0Hz,1H),2.85(dd,J=9.5Hz,
13
J=14.0Hz,1H),2.13(m,1H),0.89(dd,J=6.5Hz,J=13.5Hz,6H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 173.47,171.09,168.26,137.97,136.56,129.74,128.55,127.65,
126.77,124.15,121.31,118.79,118.59,111.82,110.04,57.52,54.61,53.44,37.92,
30.31,27.57,18.93,17.75.
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3304cm ,3057cm ,2916cm ,1720cm ,1654cm ,1525cm ,1456cm ,1436cm ,-1 -1 -1 1
1228cm ,742cm ,700cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=12.65(s,1H),10.96(s,
1H),8.77(d,J=8.0Hz,1H),8.59(d,J=7.5Hz,1H),8.31(s,2H),7.55(d,J=8.0Hz,1H),
7.35(d,J=8.0Hz,1H),7.32-7.18(m,6H),7.07(t,J=7.5Hz,1H),6.99(t,J=7.5Hz,
1H),4.64(m,1H),4.50(m,1H),3.80(m,1H),3.19(dd,J=5.5Hz,J=14.5Hz,1H),3.09(dd,J=8.0Hz,J=14.5Hz,1H),3.06(dd,J=4.0Hz,J=14.0Hz,1H),2.83(dd,J=10.0Hz,
13
J=14.0Hz,1H),2.45(m,2H),2.03-2.00(m,5H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=
173.52,171.28,168.57,138.04,136.52,129.71,128.57,127.66,126.83,124.26,121.33,
118.82,118.60,111.84,110.02,54.79,53.59,51.98,37.70,31.56,28.51,27.56,14.91.[0129] 实施例48制备H-Ala-Phe-Trp-OH(9f)
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3471cm ,3350cm ,3221cm ,3053cm ,2927cm ,1678cm ,1639cm ,1508cm ,-1 -1 -1 -1 -1 1
1456cm ,1359cm ,1342cm ,738cm ,700cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm =
10.85(s,1H),8.46(d,J = 7.5Hz,1H),8.07(d,J = 7.0Hz,1H),7.56(d,J = 7.5Hz,
1H),7.31(d,J = 8.0Hz,1H),7.24-7.13(m,6H),7.02(t,J = 7.5Hz,1H),6.95(t,J =
7.5Hz,1H),4.48(m,1H),4.33(m,1H),3.46(m,1H),3.27(dd,J = 5.0Hz,J = 14.0Hz,
1H),3.11-3.04(m,2H),2.74(dd,J = 9.5Hz,J = 14.0Hz,1H),1.15(d,J = 7.0Hz,3H);
13
C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=174.08,172.59,170.55,138.28,136.25,129.68,
128.50,128.23,126.70,123.86,121.08,119.03,118.53,111.56,111.07,54.72,49.32,
37.90,27.69,19.39.
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3257cm ,3032cm ,2924cm ,1720cm ,1651cm ,1525cm ,1496cm ,1456cm ,-1 -1 -1 -1 1
1438cm ,1215cm ,742cm ,700cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=12.62(s,1H),
11.01(s,1H),9.00(d,J=8.0Hz,1H),8.62(d,J=7.5Hz,1H),8.18(s,2H),7.59(d,J=
7.5Hz,1H),7.40(d,J=8.0Hz,1H),7.31-7.17(m,11H),7.08(t,J=7.5Hz,1H),7.01(t,J=7.5Hz,1H),4.65(m,1H),4.53(m,1H),4.03(m,1H),3.22(dd,J=5.5Hz,J=15.0Hz,1H),
3.17(dd,J=10.0Hz,J=15.0Hz,1H),3.12(dd,J=8.0Hz,J=14.5Hz,1H),3.04(dd,J=4.5Hz,J=14.0Hz,1H),2.94(dd,J=8.0Hz,J=14.0Hz,1H),2.87(dd,J=9.0Hz,J
13
=14.0Hz,1H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=173.55,171.15,168.29,137.95,
136.59,135.30,130.17,129.82,128.81,128.56,127.64,127.45,126.81,124.36,121.34,
118.83,118.60,111.87,110.04,54.74,53.69,53.56,38.09,37.16,27.62.[0133] 实施例50制备H-Ile-Phe-Trp-OH(9h)
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3383cm ,3059cm ,2978cm ,2910cm ,1734cm ,1654cm ,1516cm ,1456cm ,-1 -1 -1 -1 -1 -1 1
1440cm ,1390cm ,1346cm ,1176cm ,746cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm= 12.62(s,1H),10.98(s,1H),8.72(d,J= 8.0Hz,1H),8.53(d,J= 8.0Hz,1H),
8.23(s,2H),7.54(d,J=7.5Hz,1H),7.35(d,J=8.0Hz,1H),7.33-7.17(m,6H),7.07(t,J= 7.5Hz,1H),6.98(t,J= 7.5Hz,1H),4.66(m,1H),4.49(m,1H),3.64(m,1H),3.18(dd,J = 4.5Hz,J = 14.5Hz,1H),3.15-3.01(m,3H),2.86(dd,J = 9.0Hz,J = 14.0Hz,
1H),1.92(m,1H),1.47-1.43(m,2H),0.85(d,J = 7.0Hz,3H),0.79(t,J = 7.5Hz,3H);
13
C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=173.46,171.05,168.22,137.97,136.57,129.74,
128.54,127.64,126.75,124.20,121.30,118.77,118.56,111.84,110.02,56.90,54.58,
53.49,37.93,36.71,27.59,24.14,15.04,11.65.
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3630cm ,3371cm ,2972cm ,1708cm ,1651cm ,1514cm ,1456cm ,1431cm ,-1 -1 -1 -1 -1 1
1394cm ,1348cm ,1211cm ,740cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm =
12.71(s,1H),11.04(s,1H),11.02(s,1H),9.01(d,J = 8.0Hz,1H),8.62(d,J = 7.5Hz,
1H),8.07(d,J=6.0Hz,2H),7.76(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.36(dd,J=3.0Hz,J=7.5Hz,2H),7.30-7.18(m,8H),7.09-6.92(m,3H),4.66(m,1H),4.50(m,1H),
13
3.99(m,1H),3.25-3.02(m,5H),2.90(dd,J=8.5Hz,J=14.0Hz,1H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 173.62,171.24,168.91,137.99,136.78,136.56,129.80,128.57,
127.66,127.57,126.80,125.68,124.36,121.53,121.34,119.24,118.83,118.62,111.86,
110.05,107.28,54.78,53.60,52.90,38.00,27.83,27.59.
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3305cm ,3057cm ,2976cm ,2926cm ,1720cm ,1651cm ,1535cm ,1456cm ,-1 -1 -1 1
1230cm ,742cm ,700cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=12.62(s,1H),10.98(s,
1H),8.76(d,J=8.0Hz,1H),8.57(d,J=7.5Hz,1H),8.18(d,J=9.0Hz,2H),7.54(d,J=
8.0Hz,1H),7.35(d,J=8.0Hz,1H),7.29-7.18(m,6H),7.07(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),4.60(m,1H),4.48(m,1H),3.93(m,1H),3.63(m,1H),3.19(dd,J=5.0Hz,J=
15.0Hz,1H),3.10-3.02(m,2H),2.83(dd,J=9.0Hz,J=14.0Hz,1H),1.11(d,J=6.5Hz,
13
3H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 173.51,171.04,167.19,137.90,136.56,
129.76,128.56,127.60,126.79,124.26,121.33,118.82,118.55,111.86,110.07,66.41,
58.18,54.59,53.61,37.91,27.51,19.77.
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3030cm ,2922cm ,1689cm ,1658cm ,1527cm ,1456cm ,1438cm ,1224cm ,-1 -1 1
742cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=11.00(s,1H),9.02(d,J=7.5Hz,
1H),8.93(s,2H),8.80(d,J = 7.5Hz,1H),7.80(d,J = 7.5Hz,1H),7.55(d,J = 8.0Hz,
1H),7.39-7.43(m,4H),7.27-7.18(m,4H),7.07(t,J=7.5Hz,1H),6.99(t,J=7.5Hz,1H),
4.59(m,1H),4.53(m,1H),4.19(m,1H),3.34(dd,J=5.0Hz,J=15.0Hz,1H),3.27-3.19(m,
2H),3.12(dd,J=8.5Hz J=15.0Hz,1H),3.07(dd,J=4.0Hz,J=15.0Hz,1H),2.85(dd,
13
J=10.5Hz,J=14.0Hz,1H);C-NMR(BHSC-75Hz,DMSO-d6),δ/ppm=173.35,171.58,
167.79,137.90,136.35,134.39,129.73,128.58,127.59,127.33,126.88,124.19,121.34,
118.59,118.33,111.80,109.92,55.12,53.46,51.56,37.53,27.36,26.71.[0141] 实施例54制备H-Lys-Phe-Trp-OH(9l)
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3354cm ,3051cm ,2929cm ,1743cm ,1689cm ,1639cm ,1548cm ,1456cm ,-1 -1 -1 -1 1
1211cm ,1176cm ,742cm ,698cm ;HNMR(BHSC-300Hz,DMSO-d6),δ/ppm=12.63(s,1H),
11.03(s,1H),8.90(d,J=8.1Hz,1H),8.55(d,J=7.5Hz,1H),8.30(s,2H),8.13(s,2H),
7.55(d,J=7.5Hz,1H),7.36(d,J=8.1Hz,1H),7.29-7.15(m,6H),7.07(t,J=7.5Hz,
1H),6.99(t,J=7.5Hz,1H),4.58(m,1H),4.48(m,1H),3.73(m,1H),3.20(dd,J=5.1Hz,J=15.0Hz,1H),3.09(dd,J=8.4Hz,J=15.0Hz,1H),3.01(m,1H),2.85(dd,J=9.9Hz,
13
J=13.5Hz,1H),2.72(m,2H),1.76(m,2H),1.55(m,2H),1.36(m,2H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 173.59,171.31,168.97,138.06,136.53,129.73,128.54,127.63,
126.79,124.36,121.32,118.93,118.57,111.88,110.03,54.99,53.53,52.25,38.58,
37.75,30.67,27.48,26.56,21.30.
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3196cm ,3057cm ,2974cm ,1728cm ,1654cm ,1525cm ,1456cm ,1226cm ,-1 -1 1
742cm ,702cm ;HNMR(BHSC-300Hz,DMSO-d6),δ/ppm = 12.72(s,1H),11.05(s,1H),
8.93(d,J = 7.8Hz,1H),8.64(d,J = 7.5Hz,1H),8.40(s,2H),7.54(d,J = 6.9Hz,1H),
7.36-7.14(m,7H),7.09-6.96(m,3H),4.59(m,1H),4.47(m,1H),3.75(m,1H),3.29-3.02(m,
3H),2.80(dd,J = 9.9Hz,J = 13.8Hz,1H),2.35-2.23(m,2H),2.00-1.96(m,2H);
13
C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm=174.49,173.61,171.32,168.75,138.02,136.52,
130.18,129.72,128.55,127.63,126.79,124.32,121.30,118.21,118.57,111.85,110.04,
54.95,53.54,52.15,37.87,31.07,27.66,27.42.
υ:3344cm ,3034cm ,2920cm ,1724cm ,1658cm ,1541cm ,1529cm ,1454cm ,1436cm ,-1 -1 -1 -1 1
1338cm ,1224cm ,742cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=10.85(s,1H),
8.25(d,J= 6.5Hz,2H),7.96(d,J =4.0Hz,1H),7.74(d,J = 1.5Hz,1H),7.55(d,J =
3.0Hz,1H),7.52(s,2H),7.33(d,J = 8.0Hz,1H),7.24-7.16(m,6H),7.07(t,J = 7.5Hz,
1H),.7.00(t,J=7.5Hz,1H),4.52(m,1H),4.41(m,1H),3.58(m,1H),3.23(dd,J=5.0Hz,J = 9.5Hz,1H),3.10-3.01(m,2H),2.74(m,1H),2.45(dd,J = 3.0Hz,J = 15.0Hz,1H),
13
2.15(dd,J=8.5Hz,J=15.0Hz,1H);C-NMR(BHSC-75Hz,DMSO-d6),δ/ppm=173.64,
173.47,172.09,171.38,136.99,136.55,129.79,129.56,127.98,126.84,126.67,124.90,
124.31,121.32,118.86,111.87,110.16;54.15,53.88,49.51,37.85,36.04,27.50.[0147] 实施例57制备H-Ser-Phe-Trp-OH(9o)
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3387cm ,3205cm ,3055cm ,1643cm ,1517cm ,1456cm ,1394cm ,742cm ,-1 1
698cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 10.85(s,1H),8.50(d,J = 8.0Hz,1H),
8.32(d,J= 8.5Hz,2H),8.04(d,J =7.0Hz,1H),7.61(d,J = 8.0Hz,1H),7.32(d,J =
7.5Hz,1H),7.25-7.13(m,6H),7.05(t,J = 7.5Hz,1H),6.97(t,J = 7.5Hz,1H),4.45(m,
1H),4.34(m,1H),3.62(m,1H),3.52-3.45(m,2H),3.25(dd,J = 5.0Hz,J = 14.5Hz,1H),
13
3.1-3.04(m,2H),2.73(dd,J=10.0Hz,J=14.5Hz,1H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 174.34,170.64,170.43,138.24,136.45,129.78,128.51,128.15,126.72,
124.02,121.15,118.93,118.86,111.68,110.89,62.76,56.01,54.84,54.62,37.83,
27.83.
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3234cm ,3059cm ,2924cm ,1720cm ,1658cm ,1516cm ,1440cm ,1226cm ,-1 -1 1
742cm ,700cm ;HNMR(BHSC-300Hz,DMSO-d6),δ/ppm = 12.71(s,1H),11.02(s,1H),
9.417(s,1H),8.99(d,J = 8.4Hz,1H),8.59(d,J = 7.5Hz,1H),8.08(s,2H),7.57(d,J = 7.5Hz,1H),7.35(d,J = 8.1Hz,1H),7.30-7.16(m,6H),7.11-7.02(m,4H),4.63(m,
13
1H),4.55(m,1H),3.90(m,1H),3.25-3.01(m,4H),2.89-2.77(m,2H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 173.50,171.17,168.52,157.03,138.00,136.56,131.15,129.79,
128.56,127.68,126.80,125.24,124.33,121.32,118.83,118.63,115.76,111.85,110.01,
54.84,54.04,53.53,38.03,36.44,27.62.
2920cm ,1651cm ,1541cm ,1456cm ,1232cm ,748cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 12.60(s,1H),10.86(s,1H),8.89(d,J = 8.0Hz,1H),8.55(d,J =
7.5Hz,1H),8.31(s,2H),8.10(s,2H),7.52(d,J = 8.0Hz,1H),7.35(d,J = 8.0Hz,1H),
7.29-7.18(m,7H),7.08(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),4.65(m,1H),4.58(m,
1H),3.64(m,1H),3.42(dd,J=5.0Hz,J=15.0Hz,1H),3.22(dd,J=8.0Hz,J=15.0Hz,
1H),3.15-3.04(m,2H),2.75-2.60(m,2H),2.04(s,1H),1.71-1.60(m,2H),1.48-1.31(m,
13
2H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 172.31,171.85,171.21,159.45,137.12,
136.43,129.43,128.10,127.32,126.49,124.03,121.35,118.87,118.31,111.75,109.23,
54.23,53.54,52.10,40.56,38.10,31.26,29.48,27.42.
-1 -1 -1 -1 -1 -1 -1 -1
IR(KBr)υ:3221cm ,3028cm ,2924cm ,1728cm ,1647cm ,1529cm ,1456cm ,1205cm ,-1 -1 1
744cm ,702cm ;HNMR(BHSC-500Hz,DMSO-d6),δ/ppm = 11.10(s,1H),8.60(d,J =
8.0Hz,1H),8.52(d,J = 7.5Hz,1H),7.54(d,J = 8.0Hz,1H),7.33(d,J = 8.0Hz,1H),
7.31-7.17(m,6H),7.07(t,J = 7.5Hz,1H),7.00(t,J = 7.5Hz,1H),4.49-4.42(m,2H),
3.57(m,1H),3.22(dd,J=5.0Hz,J=14.5Hz,1H),3.14(dd,J=8.5Hz,J=15.0Hz,1H),
3.07(dd,J=10.0Hz,J=13.5Hz,1H),2.73(dd,J=7.0Hz,J=15.0Hz,1H),2.67(dd,J
13
=10.5Hz,J=14.0Hz,1H),2.25(dd,J=6.5Hz,J=15.0Hz,1H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 173.63,172.50,171.55,171.35,138.06,136.52,129.73,128.50,
127.62,126.84,124.32,121.32,118.82,118.58,111.89,110.08,54.87,53.61,49.42,
38.68,36.12,28.63.
υ:3081cm ,2927cm ,1720cm ,1658cm ,1521cm ,1456cm ,1215cm ,744cm ,700cm ;
1
HNMR(BHSC-300Hz,DMSO-d6),δ/ppm=10.96(s,1H),8.73(d,J=7.8Hz,1H),8.58(d,J=
7.5Hz,1H),8.30(d,J=3.6Hz,2H),7.55(d,J=7.8Hz,1H),7.36-7.16(m,7H),7.07(t,J=
7.5Hz,1H),7.00(t,J = 7.5Hz,1H),4.62(m,1H),4.50(m,1H),3.77(m,1H),3.24-3.11(m,
2H),3.05(dd,J = 9.9Hz,J = 13.8Hz,1H),2.81(dd,J = 9.9Hz,J = 13.8Hz,1H),
13
2.42-1.98(m,2H),2.00-1.98(m,2H);C-NMR(BHSC-125Hz,DMSO-d6),δ/ppm = 174.07,
173.52,171.28,168.71,138.04,136.52,129.73,128.56,127.69,126.82,124.23,121.33,
118.84,118.64,111.83,110.01,54.78,53.58,51.86,37.70,29.60,27.52,26.99.[0157] 实验例1本发明化合物的镇痛作用评价实验