CN101591377A - 氨基酰苯丙氨酰色氨酸或其衍生物、其合成方法和应用 - Google Patents
氨基酰苯丙氨酰色氨酸或其衍生物、其合成方法和应用 Download PDFInfo
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Abstract
本发明公开了具有镇痛活性的通式I化合物及其合成方法和在医学中的应用,属于生物医学领域。本发明还公开了通式I化合物的中间体化合物N-叔丁氧羰基氨基酰苯丙氨酰色氨酸甲脂和N-叔丁氧羰基氨基酰苯丙氨酰色氨酸。动物试验表明,本发明通式I化合物具有优秀的镇痛活性,是临床潜在的镇痛剂。
Description
技术领域
本发明涉及一类具有镇痛活性的化合物,尤其涉及一系列氨基酰苯丙氨酰色氨酸及它们的衍生物N-叔丁氧羰基氨基酰苯丙氨酰色氨酸甲脂和N-叔丁氧羰基氨基酰苯丙氨酰色氨酸,本发明还涉及它们的合成方法及在医学中的应用,属于生物医药领域。
背景技术
疼痛不仅是许多疾病的并合症,而且自身已经被看作是一类疾病。从疾病层面上讲,由各种各样的疼痛造成的生活质量下降波及了最大量的人群。由于有效的镇痛剂往往与依赖性相联系,所以发明新的无依赖性的镇痛剂具有重要价值。发明人在多肽研究中偶然发现发现,含色氨酸的寡肽通常具有镇痛活性。
发明内容
本发明的目的之一是提供一类氨基酰苯丙氨酰色氨酸三肽镇痛剂。
本发明的目的之二是提供一种制备这类氨基酰苯丙氨酰色氨酸三肽镇痛剂的方法。
本发明的目的是通过以下技术方案来实现的:
具有镇痛活性的通式I化合物:
其中,AA选自亮氨酸(Leu)残基、甘氨酸(Gly)残基、脯氨酸(Pro)残基、缬氨酸(Val)残基、甲硫氨酸(Met)残基、丙氨酸(Ala)残基、苯丙氨酸(Phe)残基、异亮氨酸(Ile)残基、色氨酸(Trp)残基、苏氨酸(Thr)残基、ω-叔丁氧羰基(Boc)-组氨酸(His)残基、ω-叔丁氧羰基(Boc)-赖氨酸(Lys)残基、谷氨酰胺(Gln)残基、天冬酰胺(Asn)残基、丝氨酸(Ser)残基、酪氨酸(Tyr)残基、Arg(NO2)残基、Asp(OCH3)残基或Glu(OCH3)残基;其中,所述的Arg是精氨酸,所述的Asp是天冬氨酸,所述的Glu是谷氨酸。
上述通式I化合物的中间体通式化合物II和III:
其中,AA选自亮氨酸(Leu)残基、甘氨酸(Gly)残基、脯氨酸(Pro)残基、缬氨酸(Val)残基、甲硫氨酸(Met)残基、丙氨酸(Ala)残基、苯丙氨酸(Phe)残基、异亮氨酸(Ile)残基、色氨酸(Trp)残基、苏氨酸(Thr)残基、ω-叔丁氧羰基(Boc)-组氨酸(His)残基、ω-叔丁氧羰基(Boc)-赖氨酸(Lys)残基、谷氨酰胺(Gln)残基、天冬酰胺(Asn)残基、丝氨酸(Ser)残基、酪氨酸(Tyr)残基、Arg(NO2)残基、Asp(OCH3)残基或Glu(OCH3)残基;其中,所述的Arg是精氨酸,所述的Asp是天冬氨酸,所述的Glu是谷氨酸。
其中,AA选自亮氨酸(Leu)残基、甘氨酸(Gly)残基、脯氨酸(Pro)残基、缬氨酸(Val)残基、甲硫氨酸(Met)残基、丙氨酸(Ala)残基、苯丙氨酸(Phe)残基、异亮氨酸(Ile)残基、色氨酸(Trp)残基、苏氨酸(Thr)残基、ω-叔丁氧羰基(Boc)-组氨酸(His)残基、ω-叔丁氧羰基(Boc)-赖氨酸(Lys)残基、谷氨酰胺(Gln)残基、天冬酰胺(Asn)残基、丝氨酸(Ser)残基、酪氨酸(Tyr)残基、Arg(NO2)残基、Asp(OCH3)残基或Glu(OCH3)残基;其中,所述的Arg是精氨酸,所述的Asp是天冬氨酸,所述的Glu是谷氨酸。
-种制备通式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或二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选自亮氨酸(Leu)残基、甘氨酸(Gly)残基、脯氨酸(Pro)残基、缬氨酸(Val)残基、甲硫氨酸(Met)残基、丙氨酸(Ala)残基、苯丙氨酸(Phe)残基、异亮氨酸(Ile)残基、色氨酸(Trp)残基、苏氨酸(Thr)残基、ω-叔丁氧羰基(Boc)-组氨酸(His)残基、ω-叔丁氧羰基(Boc)-赖氨酸(Lys)残基、谷氨酰胺(Gln)残基、天冬酰胺(Asn)残基、丝氨酸(Ser)残基、酪氨酸(Tyr)残基、Arg(NO2)残基、Asp(OCH3)残基或Glu(OCH3)残基;
(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选自亮氨酸(Leu)残基、甘氨酸(Gly)残基、脯氨酸(Pro)残基、缬氨酸(Val)残基、甲硫氨酸(Met)残基、丙氨酸(Ala)残基、苯丙氨酸(Phe)残基、异亮氨酸(Ile)残基、色氨酸(Trp)残基、苏氨酸(Thr)残基、ω-叔丁氧羰基(Boc)-组氨酸(His)残基、ω-叔丁氧羰基(Boc)-赖氨酸(Lys)残基、谷氨酰胺(Gln)残基、天冬酰胺(Asn)残基、丝氨酸(Ser)残基、酪氨酸(Tyr)残基、Arg(NO2)残基、Asp(OCH3)残基或Glu(OCH3)残基;
(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。
上述制备方法中,优选的,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;
优选的,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;
步骤(5)中,所述的叔丁氧羰基保护的氨基酸优选自叔丁氧羰基保护的亮氨酸、叔丁氧羰基保护的甘氨酸、叔丁氧羰基保护的脯氨酸、叔丁氧羰基保护的缬氨酸、叔丁氧羰基保护的蛋氨酸、叔丁氧羰基保护的丙氨酸、叔丁氧羰基保护的苯丙氨酸、叔丁氧羰基保护的异亮氨酸、叔丁氧羰基保护的色氨酸、叔丁氧羰基保护的苏氨酸、叔丁氧羰基保护的谷酰胺、叔丁氧羰基保护的天冬酰胺、叔丁氧羰基保护的丝氨酸、叔丁氧羰基保护的酪氨酸、叔丁氧羰基保护的硝基精氨酸、叔丁氧羰基保护的天冬氨酸单甲酯、叔丁氧羰基保护的谷氨酸单甲酯;所述的二叔丁氧羰基保护的氨基酸优选自二叔丁氧羰基保护的组氨酸或二叔丁氧羰基保护的赖氨酸。
步骤(6)中所述的碱溶液优选为2N的NaOH溶液。
本发明的又一目的是提供一种具有镇痛活性的药用组合物,该药用组合物由治疗上有效剂量的本发明通式I化合物与药学上可接受的赋型剂或者辅加剂组成,即将有效量的本发明通式I化合物与药学上可接受的载体或稀释剂配合后,按本领域常规的制剂方法将其制备成任意一种适宜的药物组合物。通常该组合物适合于口服给药和注射给药,也适合其他的给药方法。该组合物可以是片剂、胶囊剂、粉剂、颗粒剂、锭剂、栓剂,或口服液等液体制剂形式。根据不同的给药方法,本发明药物组合物可以含有0.1%-99%重量,优选10-60%重量的本发明化合物。
在小鼠甩尾模型上评价本发明化合物的镇痛活性,实验结果表明,通式I化合物具有优秀的镇痛活性,临床上可作为镇痛剂应用。
附图说明
图1本发明通式I化合物的结构图。
图2.本发明通式I化合物的合成路线图。i)1,4-二氧六环、(Boc)2O和NaOH溶液;ii)氯化亚砜和甲醇;iii)DCC、HOBt、NMM和THF溶液;iv)氯化氢/乙酸乙酯溶液;v)DCC、HOBt、NMM、THF和叔丁氧羰基保护的氨基酸;vi)甲醇、THF和NaOH水溶液、;vii)氯化氢/乙酸乙酯溶液。其中7a AA为Leu残基、7b AA为Gly残基、7c中AA为Pro残基、7d中AA为Val残基、7e中AA为Met残基、7f中AA为Ala残基、7g中AA为Phe残基、7h中AA为Ile残基、7i中AA为Trp残基、7j中AA为Thr残基、7k中AA为His(Boc)残基、7l中AA为ω-Boc-Lys残基、7m中AA为Gln残基、7n中AA为Asn残基、7o中AA为Ser残基、7p中AA为Tyr残基、7q中AA为Arg(NO2)残基、7r中AA为Asp(OCH3)残基、和7s中AA为Glu(OCH3)残基。8a AA为Leu残基、8b AA为Gly残基、8c中AA为Pro残基、8d中AA为Val残基、8e中AA为Met残基、8f中AA为Ala残基、8g中AA为Phe残基、8h中AA为Ile残基、8i中AA为Trp残基、8j中AA为Thr残基、8k中AA为His(Boc)残基、8l中AA为ω-Boc-Lys残基、8m中AA为Gln残基、8n中AA为Asn残基、8o中AA为Ser残基、8p中AA为Tyr残基、8q中AA为Arg(NO2)残基、8r中AA为Asp残基、和8s中AA为Glu残基。9a AA为Leu残基、9b AA为Gly残基、9c中AA为Pro残基、9d中AA为Val残基、9e中AA为Met残基、9f中AA为Ala残基、9g中AA为Phe残基、9h中AA为Ile残基、9i中AA为Trp残基、9j中AA为Thr残基、9k中AA为His残基、9l中AA为Lys残基、9m中AA为Gln残基、9n中AA为Asn残基、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
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
实施例1制备Boc-Phe-OH
在250ml茄形瓶中加入6610mg(40.00mmol)Phe,冰浴条件下加入40mlNaOH(1N)溶液,用40ml二氧六环溶液将9590mg(44.00mmol)(Boc)2O溶解,然后倒入茄型瓶中,室温条件下搅拌。每6h抽CO2气一次,用NaOH调节pH在8-9之间。48h后TLC(氯仿/甲醇,30∶1)显示Phe原料点完全消失,用饱和KHSO4调pH到7,减压浓缩除去二氧六环,再用饱和KHSO4调pH2,乙酸乙酯萃取三次(50mlx3),合并乙酸乙酯,再用饱和NaCl水溶液洗涤至中性,分出乙酸乙酯层,用无水Na2SO4干燥过夜,过滤,滤液减压浓缩至干,残留物用石油醚磨洗,10.32g(收率97%)目标化合物,为无色晶体。
实施例2制备HCl·Trp-OCH3
在250ml茄形瓶中加入80ml CH3OH溶液,冰盐浴条件下用衡压漏斗缓慢滴加入13mlSOCl2溶液,滴加完毕20min后加入9190mg(45.00)mmolTrp,室温搅拌24h,TLC(氯仿/甲醇,8∶1)显示原料点完全消失,用水泵减压抽干,再用甲醇抽洗三遍,再用乙醚溶液抽洗三次,最后用甲醇-乙醚进行重结晶,得10.55g(收率92%)目标化合物,为白色晶体。
实施例3制备Boc-Phe-Trp-OCH3
50ml茄形瓶中加入930mg(3.50mmol)Boc-Phe-OH,用30ml无水THF溶解,向反应液中加入500mg(3.70mmol)HOBt,800g(3.90mmol)DCC,冰浴条件下搅拌1h后加入980mg(3.90mol)HCl·TrpOCH3,再用NMM调pH8-9之间,室温搅拌,12h后TLC(氯仿/甲醇,30∶1)显示Boc-Phe-OH原料点消失,过滤反应液,滤除DCU,滤液减压浓缩至干,用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%)。Mp:165-166℃;ESI-MS(m/e)466[M+H]+;1HNMR(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);13C-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.
实施例4制备H-Phe-Trp-OCH3
在100ml茄形瓶中,用少量EtOAc溶液将1200mg(2.60mmol)Boc-Phe-Trp-OCH3完全溶解,冰浴条件下加入4N的HCl/EtOAc溶液15ml,2h后TLC(氯仿/甲醇/冰醋酸,150∶5∶1)显示原料点完全消失,用水泵减压抽干,再用乙酸乙酯抽洗三遍,再用乙醚溶液抽洗三次,得灰色固体1040mg(收率99%).Mp:176-178℃;ESI-MS(m/e)366[M+H]+;1HNMR(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=7.5Hz,J=14.0Hz,1H);13C-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..
实施例5制备Boc-Leu-Phe-Trp-OCH3(7a)
按照实施例3的操作,以1206mg(3.00mmol)H-Phe-Trp-OCH3盐酸盐及693mg(3.00mmol)Boc-Leu-OH为原料,得1056mg(收率61%)标题化合物,类白色固体。Mp:154-156℃;ESI-MS(m/e)579[M+H]+;IR(KBr)υ:3309cm-1,3059cm-1,2954cm-1,2870cm-1,1743cm-1,1697cm-1,1651cm-1,1512cm-1,1454cm-1,1438cm-1,1392cm-1,1365cm-1,1165cm-1,740cm-1,698cm-1;1HNMR(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),0.79(d,J=7.0Hz,3H);13C-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.
实施例6制备Boc-Gly-Phe-Trp-OCH3(7b)
按照实施例3的操作,以1608mg(4.00mol)H-Phe-Trp-OCH3盐酸盐及700mg(3.00mol)Boc-Gly-OH为原料,得1740mg(收率83%)标题化合物,类白色固体。Mp:84-86℃;ESI-MS(m/e)523[M+H]+;IR(KBr)υ:3305cm-1,3062cm-1,2978cm-1,2927cm-1,1743cm-1,1651cm-1,1521cm-1,1454cm-1,1438cm-1,1392cm-1,1365cm-1,1246cm-1,1165cm-1,740cm-1,702cm-1,1HNMR(BHSC-500Hz,DMSO-d6)δ/ppm=10.89(s,1H),8.54(d,J=7.5Hz,1H),7.90(d,J=8.5Hz,1H),7.50(d,J=8.0Hz,1H),7.36(d,J=8.0Hz,1H),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,1H),2.68(dd,J=7.5Hz,J=11.0Hz,1H),1.38(s,9H);13C-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.
实施例7制备Boc-Pro-Phe-Trp-OCH3(7c)
按照实施例3的操作,以602.8mg(1.50mmol)H-Phe-Trp-OCH3盐酸盐及323mg(1.50mmol)Boc-Pro-OH为原料,得667mg(收率79%)标题化合物,类白色固体。Mp:102-103℃;ESI-MS(m/e)562[M+H]+;IR(KBr)υ:3317cm-1,3059cm-1,2978cm-1,2924cm-1,2850cm-1,1743cm-1,1652cm-1,1512cm-1,1454cm-1,1438cm-1,1392cm-1’1365cm-1,1249cm-1,1168cm-1,744cm-1,702cm-1;1HNMR(BHSC-500Hz,DMSO-d6),δ/ppm=10.91(s,1H),8.53(d,J=7.0Hz,1H),7.82(d,J=8.5Hz,1H),7.49(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),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,3H),1.13(s,9H);13C-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.
实施例8制备Boc-Val-Phe-Trp-OCH3(7d)
按照实施例3的操作,以1004mg(2.50mmol)H-Phe-Trp-OCH3盐酸盐及543mg(2.50mmol)Boc-Val-OH为原料,得1184mg(收率84%)标题化合物,类白色固体。Mp:179-180℃;ESI-MS(m/e)565[M+H]+;IR(KBr)υ:3298cm-1,3059cm-1,2966cm-1,2870cm-1,1732cm-1,1685cm-1,1651cm-1,1519cm-1,1454cm-1,1392cm-1,1365cm-1,1168cm-1,740cm-1,698cm-1,1HNMR(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);13C-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.
实施例9制备Boc-Met-he-Trp-OCH3(7e)
按照实施例3的操作,以1206mg(3.00mol)H-Phe-Trp-OCH3盐酸盐及747mg(3.00mol)Boc-Met-OH为原料,得1377mg(收率77%)标题化合物,类白色固体。Mp:134-135℃;ESI-MS(m/e)597[M+H]+;IR(KBr)υ:3298cm-1,2978cm-1,2924cm-1,1743cm-1,1651cm-1,1512cm-1,1454cm-1,1438cm-1,1392cm-1,1354cm-1,1165cm-1,740cm-1,698cm-1;1HNMR(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,3H),1.69(m,2H),1.37(s,9H);13C-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.
实施例10制备Boc-Ala-Phe-Trp-OCH3(7f)
按照实施例3的操作,以1608mg(4.00mol)H-Phe-Trp-OCH3盐酸盐及756mg(4.00mol)Boc-Ala-OH为原料,得2073mg(收率97%)标题化合物,类白色固体。Mp:96-98℃;ESI-MS(m/e)537[M+H]+;IR(KBr)υ:3302cm-1,2978cm-1,2927cm-1,1651cm-1,1496cm-1,1442cm-1,1392cm-1,1365cm-1,1165cm-1,744cm-1,698cm-1;1HNMR(BHSC-500Hz,DMSO-d6)),δ/ppm=11.45(s,1H),8.54(d,J=7.0Hz,1H),7.91(d,J=8.0Hz,1H),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,9H),1.25(d,J=10.0Hz,3H);13C-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.
实施例11制备Boc-Phe-Phe-Trp-OCH3(7g)
按照实施例3的操作,以1608mg(4.00mol)H-Phe-Trp-OCH3盐酸盐及1061mg(4.00mol)Boc-Phe-OH为原料,得2156mg(收率94%)标题化合物,淡黄色固体。Mp:90-91℃;ESI-MS(m/e)613[M+H]+;IR(KBr):3298cm-1,2927cm-1,1743cm-1,1689cm-1,1651cm-1,1512cm-1,1454cm-1,1438cm-1,1392cm-1,1365cm-1,1168cm-1,744cm-1,698cm-1;1HNMR(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),2.62(dd,J=10.5Hz,J=14.0Hz,1H),1.30(s,9H);13C-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.
实施例12制备Boc-Ile-Phe-Trp-OCH3(7h)
按照实施例3的操作,以1800mg(4.50mmol)H-Phe-Trp-OCH3盐酸盐及1040mg(4.50mmol)Boc-Ile-OH为原料,得2234mg(收率88%)标题化合物,类白色固体。Mp:189-190℃;ESI-MS(m/e)576[M+H]+;IR(KBr)υ:3348cm-1,3317cm-1,2974cm-1,2927cm-1,2870cm-1,1735cm-1,1647cm-1,1535cm-1,1512cm-1,1454cm-1,1435cm-1,1392cm-1,1365cm-1,1168cm-1,736cm-1,702cm-1;1HNMR(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=7.5Hz,3H),0.60(d,J=7.0Hz,3H);13C-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.
实施例13制备Boc-Trp-Phe-Trp-OCH3(7i)
按照实施例3的操作,以1608mg(3.00mol)H-Phe-Trp-OCH3盐酸盐及1217mg(4.00mol)Boc-Trp-OH为原料,得2156mg(收率83%v标题化合物,淡黄色固体。Mp:101-104℃;ESI-MS(m/e)465[M+H]+;IR(KBr)υ:3402cm-1,3309cm-1,3059cm-1,2978cm-1,1735cm-1,1651cm-1,1504cm-1,1454cm-1,1435cm-1,1392cm-1,1365cm-1,1338cm-1,1165cm-1,740cm-1,702cm-1;1HNMR(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),1.29(s,9H);13C-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.
实施例14制备Boc-Thr-Phe-Trp-OCH3(7j)
按照实施例3的操作,以1600mg(4.00mol)H-Phe-Trp-OCH3盐酸盐及876mg(4.00mol)Boc-Thr-OH为原料,得1867mg(收率82%)标题化合物,类白色固体。Mp:95-97℃;ESI-MS(m/e)567[M+H]+;IR(KBr)υ:3309cm-1,2978cm-1,2931cm-1,1743cm-1,1651cm-1,1519cm-1,1496cm-1,1454cm-1,1438cm-1,1392cm-1,1365cm-1,1165cm-1,744cm-1,702cm-1;1HNMR(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,J=9.0Hz,J=13.5Hz,1H),1.37(s,9H),0.91(d,J=6.0Hz,3H);13C-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.
实施例15制备Boc-His(Boc)-Phe-Trp-OCH3(7k)
按照实施例3的操作,以1610mg(4.00mol)H-Phe-Trp-OCH3盐酸盐及1420mg(4.00mol)Boc-His(Boc)-OH为原料,得2144mg(收率76%)标题化合物,淡黄色固体。Mp:147-148℃;ESI-MS(m/e)703[M+H]+;IR(KBr)υ:3294cm-1,2978cm-1,2931cm-1,1759cm-1,1651cm-1,1519cm-1,1454cm-1,1435cm-1,1392cm-1,1369cm-1,1249cm-1,1157cm-1,1010cm-1,740cm-1,698cm-1;1HNMR(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=15.0Hz,1H),1.54(s,9H),1.33(s,9H);13C-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.
实施例16制备Boc-Lys(Boc)-Phe-Trp-OCH3(7l)
按照实施例3的操作,以2200mg(5.0mmol)H-Phe-Trp-OCH3盐酸盐及1730mg(5.00mol)Boc-Lys(Boc)-OH为原料,得3599mg(收率99%)标题化合物,淡黄色固体。Mp:132-134℃;ESI-MS(m/e)694[M+H]+;IR(KBr)υ:3321cm-1,2970cm-1,2931cm-1,1735cm-1,1685cm-1,1647cm-1,1535cm-1,1516cm-1,1454cm-1,1435cm-1,1392cm-1,1365cm-1,1172cm-1,736cm-1,702cm-1;1HNMR(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),1.37(s,9H),1.31-1.25(m,2H),1.21-1.18(m,4H);13C-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.
实施例17制备Boc-Gln-Phe-Trp-OCH3(7m)
按照实施例3的操作,以1607mg(4.00mol)H-Phe-Trp-OCH3盐酸盐及984mg(4.00mmol)Boc-Gln-OH为原料,制得1580mg(收率69%)标题化合物,淡黄色固体。Mp:193-194℃;ESI-MS(m/e)594[M+H]+;IR(KBr)υ:3348cm-1,3302cm-1,2978cm-1,2924cm-1,1732cm-1,1670cm-1,1519cm-1,1454cm-1,1388cm-1,1365cm-1,1168cm-1,748cm-1,698cm-1,624cm-1;1HNMR(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);13C-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.
实施例18制备Boc-Asn-Phe-Trp-OCH3(7n)
将700mg(3.00mmol)Boc-Asn-OH溶解于无水DMF溶液中,冰浴条件下加入400mg(3.00mmol)HOBt,740mg(3.60mmol)DCC,1h后加入1200mg(3.00mmol)H-Phe-Trp-OCH3,用NMM调pH8-9,12h后TLC显示原料点消失,过滤除去DCU,吹干DMF溶液,用乙酸乙酯溶解残留物,再分别用饱和NaHCO3、5%KHSO4,饱和NaHCO3和饱和NaCl洗有机相,,无水Na2SO4干燥有机层过夜,过滤,减压旋干,用CHCl3-CH3OH体系柱层析分离,得1620mg(收率92.73%)淡黄色固体。Mp:184-185℃;ESI-MS(m/e)580[M+H]+;IR(KBr)υ:3302cm-1,3059cm-1,2978cm-1,2927cm-1,1743cm-1,1651cm-1,1512cm-1,1456cm-1,1438cm-1,1392cm-1,1365cm-1,1168cm-1,740cm-1,702cm-1;1HNMR(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,1H),2.32(dd,J=8.0Hz,J=15.0Hz,1H),1.37(s,9H);13C-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.
实施例19制备Boc-Ser-Phe-Trp-OCH3(7o)
按照实施例3的操作,以1667mg(4.00mol)H-Phe-Trp-OCH3盐酸盐及820mg(4.00mol)Boc-Ser-OH为原料,得1128mg(收率51%)标题化合物,类白色固体。Mp:177-178℃;ESI-MS(m/e)553[M+H]+;IR(KBr)υ:3309cm-1,2978cm-1,2931cm-1,1735cm-1,1651cm-1,1519cm-1,1438cm-1,1392cm-1,1365cm-1,1165cm-1,744cm-1,702cm-1;1HNMR(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=14.0Hz,1H),2.79(dd,J=9.0Hz,J=13.5Hz,1H),1.38(s,9H);13C-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.
实施例20制备Boc-Tyr-Phe-Trp-OCH3(7p)
按照实施例3的操作,以1600mg(4.00mol)H-Phe-Trp-OCH3盐酸盐及1120mg(4.00mol)Boc-Tyr-OH为原料,得2114mg(收率84%)标题化合物,类白色固体。Mp:105-107℃;ESI-MS(m/e)629[M+H]+;IR(KBr)υ:3305cm-1,3059cm-1,2978cm-1,2927cm-1,1735cm-1,1651cm-1,1515cm-1,1438cm-1,1392cm-1,1365cm-1,1165cm-1,744cm-1,702cm-1;1HNMR(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,4H),2.85-2.68(m,2H),1.29(s,9H);13C-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.
实施例21制备Boc-Arg(NO2)-Phe-Trp-OCH3(7q)
按照实施例3的操作,以1200mg(3.00mol)H-Phe-Trp-OCH3盐酸盐及960mg(3.00mol)Boc-Arg(NO2)-OH为原料,得1600mg(收率80%)标题化合物,类白色固体。Mp:150-151℃;ESI-MS(m/e)667[M+H]+;IR(KBr)υ:3304cm-1,2976cm-1,2949cm-1,2927cm-1,1739cm-1,1647cm-1,1600cm-1,1523cm-1,1454cm-1,1438cm-1,1392cm-1,1365cm-1,1255cm-1,1163cm-1,742cm-1,700cm-1;1HNMR(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=5.0Hz,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);13C-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.
实施例22制备Boc-Asp(OCH3)Phe-Trp-OCH3(7r)
按照实施例3的操作,以800mg(2.00mol)H-Phe-Trp-OCH3盐酸盐及500mg(2.20mmol)Boc-Asp(OCH3)-OH为原料,得1040mg(收率88%)标题化合物,白色固体。Mp:161-162℃;ESI-MS(m/e)595[M+H]+;IR(KBr)υ:3371cm-1,3298cm-1,3059cm-1,2978cm-1,1947cm-1,1720cm-1,1643cm-1,1527cm-1,1435cm-1,1392cm-1,1365cm-1,1303cm-1,1215cm-1,1165cm-1,991cm-1,732cm-1,698cm-1,636cm-1;1HNMR(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=16.0Hz,1H),2.45(dd,J=9.0Hz,J=16.0Hz,1H),1.37(s,9H);13C-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.
实施例23制备Boc-Glu(OCH3)Phe-Trp-OCH3(7s)
按照实施例3的操作,以1800mg(4.00mmol)H-Phe-Trp-OCH3盐酸盐及1200mg(4.40mmol)Boc-Glu(OCH3)-OH为原料,得1300mg(收率54%)标题化合物,类白色固体。Mp:156-157℃;ESI-MS(m/e)609[M+H]+;IR(KBr)υ:3307cm-1,2978cm-1,2951cm-1,1735cm-1,1716cm-1,1647cm-1,1514cm-1,1456cm-1,1436cm-1,1390cm-1,1367cm-1,1168cm-1,742cm-1,700cm-1;1HNMR(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),1.37(s,9H);13C-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.
实施例24制备Boc-Leu-Phe-Trp-OH(8a)
在100ml茄形瓶中,用5mlMeOH和2mlTHF的混合溶液将450mg(7.80mmol)Boc-Leu-Phe-Trp-OCH3完全溶解,冰浴条件下加入NaOH(2N)溶液,调节pH12,保持冰浴条件不变,2h后TLC(氯仿/甲醇/冰醋酸,150∶5∶1)显示原料点完全消失,用HCl(1N)调pH7,减压浓缩除去溶剂,加入10mlH2O,用HCl(1N)在冰浴搅拌条件下调pH至2,溶液用乙酸乙酯萃取三次(15ml×3),再用饱和NaCl洗涤酯层至中性。用无水Na2SO4干燥过夜,过滤,滤液减压浓缩至干,得273mg(收率67%)标题化合物,淡黄色固体。Mp:120-121℃;ESI-MS(m/e)563[M-1]-;IR(KBr)υ:3309cm-1,2958cm-1,2931cm-1,1651cm-1,1512cm-1,1454cm-1,1438cm-1,1392cm-1,1365cm-1,1165cm-1,740cm-1,698cm-1.
实施例25制备Boc-Gly-Phe-Trp-OH(8b)
按照实施例24的操作,以793mg(1.50mmol)Boc-Gly-Phe-Trp-OCH3为原料,得450mg(收率58%)标题化合物,淡黄色固体。Mp:119-120℃;ESI-MS(m/e)509[M+H]+;IR(KBr)υ:3313cm-1,2978cm-1,2931cm-1,1658cm-1,1512cm-1,1365cm-1,1246cm-1,1165cm-1,740cm-1,702cm-1.
实施例26制备Boc-Pro-Phe-Trp-OH(8c)
按照实施例24的操作,以700mg(0.80mmol)Boc-Pro-Phe-Trp-OCH3为原料,得503mg(收率74%)标题化合物,淡黄色固体。Mp:119-121℃;ESI-MS(m/e)549[M+H]+;IR(KBr)υ:3317cm-1,2978cm-1,2931cm-1,1670cm-1,1519cm-1,1454cm-1,1392cm-1,1238cm-1,1161cm-1,740cm-1,698cm-1.
实施例27制备Boc-Val-Phe-Trp-OH(8d)
按照实施例24的操作,以800mg(1.40mmol)Boc-Val-Phe-Trp-OCH3为原料,得620mg(收率79%)标题化合物,类白色固体。Mp:124-126℃;ESI-MS(m/e)549[M-1]-;IR(KBr)υ:3325cm-1,2970cm-1,2931cm-1,1651cm-1,1512cm-1,1454cm-1,1392cm-1,1365cm-1,1246cm-1,1161cm-1,740cm-1,698cm-1.
实施例28制备Boc-Met-Phe-Trp-OH(8e)
按照实施例24的操作,以700mg(1.20mmol)Boc-Met-Phe-Trp-OCH3为原料,得409mg(收率60%)标题化合物,类白色固体。Mp:122-124℃;ESI-MS(m/e)583[M+H]+;IR(KBr)υ:3302cm-1,2978cm-1,2924cm-1,1651cm-1,1512cm-1,1454cm-1,1438cm-1,1392cm-1,1365cm-1,1249cm-1,1165cm-1,744cm-1,702cm-1.
实施例29制备Boc-Ala-Phe-Trp-OH(8f)
按照实施例24的操作,以756mg(1.40mmol)Boc-Ala-Phe-Trp-OCH3为原料,得546mg(收率74%)标题化合物,类白色固体。Mp:188-189℃;ESI-MS(m/e)521[M-1]-;IR(KBr)υ:3379cm-1,3321cm-1,2978cm-1,2931cm-1,1728cm-1,1685cm-1,1662cm-1,1535cm-1,1512cm-1,1442cm-1,1369cm-1,1327cm-1,1246cm-1,1165cm-1,1064cm-1,736cm-1,702cm-1.
实施例30制备Boc-Phe-Phe-Trp-OH(8g)
按照实施例24的操作,以712mg(1.16mmol)Boc-Phe-Phe-Trp-OCH3为原料,得449mg(收率65%)标题化合物,类白色固体。Mp:104-105℃;ESI-MS(m/e)597[M-1]-;IR(KBr)υ:3410cm-1,3302cm-1,2978cm-1,2931cm-1,1693cm-1,1651cm-1,1512cm-1,1496cm-1,1454cm-1,1392cm-1,1365cm-1,1249cm-1,1168cm-1,74cm-1,698cm-1.
实施例31制备Boc-Ile-Phe-Trp-OH(8h)
按照实施例24的操作,以550mg(0.95mmol)Boc-Ile-Phe-Trp-OCH3为原料,得452mg(收率84%)标题化合物,淡黄色固体。Mp:126-127℃;ESI-MS(m/e)565[M+H]+;IR(KBr)υ:3317cm-1,2966cm-1,2931cm-1,1647cm-1,1512cm-1,1454cm-1,1392cm-1,1365cm-1,1246cm-1,1165cm-1,740cm-1,698cm-1.
实施例32制备Boc-Trp-Phe-Trp-OH(8i)
按照实施例24的操作,以540mg(0.82mmol)Boc-Trp-Phe-Trp-OCH3为原料,得416mg(收率79%)标题化合物,类白色固体。Mp:123-125℃;ESI-MS(m/e)636[M-1]-;IR(KBr)υ:3394cm-1,3325cm-1,2978cm-1,2931cm-1,1654cm-1,1512cm-1,1496cm-1,1454cm-1,1392cm-1,1365cm-1,1249cm-1,1161cm-1,740cm-1,70cm-1.
实施例33制备Boc-Thr-Phe-Trp-OH(8j)
按照实施例24的操作,以490mg(0.86mmol)Boc-Thr-Phe-Trp-OCH3为原料,得366mg(收率77%)标题化合物,类白色固体。Mp:119-120℃;ESI-MS(m/e)551[M-1]-;IR(KBr)υ:3410cm-1,3317cm-1,2927cm-1,1697cm-1,1651cm-1,1535cm-1,1454cm-1,1392cm-1,1369cm-1,1280cm-1,1246cm-1,1280cm-1,1246cm-1,1168cm-1,744cm-1,702cm-1.
实施例34制备Boc-His(Boc)-Phe-Trp-OH(8k)
按照实施例24的操作,以700mg(1.00mmol)Boc-His(Boc)-Phe-Trp-OCH3为原料,得340mg(收率50%)标题化合物,淡黄色固体。Mp:180-183℃;ESI-MS(m/e)587[M-1]-;IR(KBr)υ:3286cm-1,1685cm-1,1504cm-1,1438cm-1,1392cm-1,1365cm-1,1253cm-1,1165cm-1,744cm-1,702cm-1.
实施例35制备Boc-Lys(Boc)-Phe-Trp-OH(8l)
按照实施例24的操作,以700mg(1.00mmol)Boc-Lys(Boc)-Phe-Trp-OCH3为原料,得600mg(收率87%)标题化合物,淡黄色固体。Mp:128-129℃;ESI-MS(m/e)678[M-1]-;IR(KBr)υ:3325cm-1,2978cm-1,2931cm-1,1658cm-1,1512cm-1,1454cm-1,1392cm-1,1365cm-1,1168cm-1,740cm-1,702cm-1.
实施例36制备Boc-Gln-Phe-Trp-OH(8m)
按照实施例24的操作,以605mg(1.10mmol)Boc-Gln-Phe-Trp-OCH3为原料,得500mg(收率85%)标题化合物,淡黄色固体。Mp:184-185℃;ESI-MS(m/e)578[M-1]-;IR(KBr)υ:3309cm-1,2978cm-1,2927cm-1,1654cm-1,1516cm-1,1454cm-1,1392cm-1,1365cm-1,1338cm-1,1249cm-1,1168cm-1,744cm-1,698cm-1.
实施例37制备Boc-Asn-Phe-Trp-OH(8n)
按照实施例24的操作,以563mg(1.00mmol)Boc-Asn-Phe-Trp-OCH3为原料,得160mg(收率29%)标题化合物,淡黄色固体。Mp:126-129℃;ESI-MS(m/e)565[M-1]-;IR(KBr)υ:3325cm-1,2974cm-1,2931cm-1,1647cm-1,1523cm-1,1458cm-1,1438cm-1,1392cm-1,1365cm-1,1168cm-1,744cm-1,702cm-1.
实施例38制备Boc-Ser-Phe-Trp-OH(8o)
按照实施例24的操作,以560mg(1.01mmol)Boc-Ser-Phe-Trp-OCH3为原料,得505mg(收率93%)标题化合物,类白色固体。Mp:120-121℃;ESI-MS(m/e)537[M-1]-;IR(KBr)υ:3317cm-1,2978cm-1,2931cm-1,1654cm-1,1519cm-1,1454cm-1,1392cm-1,1365cm-1,1161cm-1,744cm-1,698cm-1.
实施例39制备Boc-Tyr-Phe-Trp-OH(8p)
按照实施例24的操作,以650mg(1.03mmol)Boc-Tyr-Phe-Trp-OCH3为原料,得397mg(收率63%)标题化合物,类白色固体。Mp:95-97℃;ESI-MS(m/e)613[M-1]-;IR(KBr)υ:3309cm-1,2974cm-1,2931cm-1,1654cm-1,1512cm-1,1454cm-1,1365cm-1,1246cm-1,1165cm-1,744cm-1,702cm-1.
实施例40制备Boc-Arg(NO2)-Trp-OH(8q)
按照实施例24的操作,以710mg(1.06mmol)Boc-Arg(NO2)-Phe-Trp-OCH3为原料,得650mg(收率93%)标题化合物,淡黄色固体。Mp:143-146℃;ESI-MS(m/e)652[M-1]-;IR(KBr)υ:3387cm-1,3325cm-1,2974cm-1,2931cm-1,1670cm-1,1523cm-1,1458cm-1,1396cm-1,1365cm-1,1261cm-1,1161cm-1,744cm-1,698cm-1.
实施例41制备Boc-Asp-Phe-Trp-OH(8r)
按照实施例24的操作,以600mg(1.00mmol)Boc-Asp(OCH3)-Phe-Trp-OCH3为原料,得500mg(收率88%)标题化合物,类白色固体Mp:121-124℃;ESI-MS(m/e)565[M-1]-;IR(KBr)υ:3410cm-1,3317cm-1,2927cm-1,2850cm-1,1697cm-1,1651cm-1,1535cm-1,1454cm-1,1392cm-1,1369cm-1,1168cm-1,744cm-1,702cm-1.
实施例42制备Boc-Glu-Phe-Trp-OH(8s)
按照实施例24的操作,以600mg(1.00mmol)Boc-Glu(OCH3)-Phe-Trp-OCH3为原料,得530mg(收率91%)标题化合物,类白色固体,Mp:174-175℃;ESI-MS(m/e)579[M-1]-;IR(KBr)υ:3305cm-1,2978cm-1,2931cm-1,1716cm-1,1658cm-1,1519cm-1,1454cm-1,1392cm-1,1365cm-1,744cm-1,702cm-1.
实施例43制备H-Leu-Phe-Trp-OH(9a)
100ml茄形瓶中,用少量EtOAc溶液将370mg(0.65mmol)Boc-Leu-Phe-Trp-OH完全溶解,冰浴条件下加入4N的HCl/EtOAc溶液3ml,2h后TLC(氯仿/甲醇/冰醋酸,30∶1∶0.2)显示原料点完全消失,用水泵减压抽干,再用乙酸乙酯抽洗三遍,再用乙醚溶液抽洗三次,得372mg(收率100%)标题化合物,淡蓝色粉末。Mp:189-192℃;ESI-MS(m/e)465[M+H]+;IR(KBr)υ:3196cm-1,3057cm-1,2956cm-1,2872cm-1,1724cm-1,1654cm-1,1516cm-1,1456cm-1,1390cm-1,1371cm-1,1228cm-1,742cm-1,700cm-1;1HNMR(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,1H),1.55-1.52(m,2H),0.861(t,J=5.0Hz,6H)13C-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.
实施例44制备H-Gly-Phe-Trp-OH(9b)
按照实施例43的操作,以300mg(0.49mmol)Boc-Gly-Phe-Trp-OH为原料,得220mg(收率86%)标题化合物,类白色粉末。Mp:193-194℃;ESI-MS(m/e)409[M+H]+;IR(KBr)υ:3232cm-1,3057cm-1,2978cm-1,2927cm-1,1728cm-1,1654cm-1,1529cm-1,1496cm-1,1456cm-1,1436cm-1,1207cm-1,742cm-1,700cm-1;1HNMR(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);13C-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.
实施例45制备H-Pro-Phe-Trp-OH(9c)
按照实施例43的操作,以300mg(0.54mmol)Boc-Pro-Phe-Trp-OH为原料,得230mg(收率87%)标题化合物,类白色粉末。Mp:204-205℃;ESI-MS(m/e)449[M+H]+;IR(KBr)υ:3259cm-1,3057cm-1,2927cm-1,1728cm-1,1662cm-1,1537cm-1,1456cm-1,1438cm-1,1394cm-1,1375cm-1,1247cm-1,1097cm-1,744cm-1,700cm-1,1HNMR(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),2.79(dd,J=10.0Hz,1H),2.25(m,1H),1.84-1.72(m,4H);13C-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.
实施例46制备H-Val-Phe-Trp-OH(9d)
按照实施例43的操作,以510mg(0.90mmol)Boc-Val-Phe-Trp-OH为原料,得414mg(收率92%)标题化合物,灰色粉末。Mp:251-252℃;ESI-MS(m/e)451[M+H]+;IR(KBr)υ:3452cm-1,3356cm-1,2970cm-1,1734cm-1,1654cm-1,1516cm-1,1440cm-1,1396cm-1,1348cm-1,1182cm-1,746cm-1,704cm-1;1HNMR(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,J=14.0Hz,1H),2.13(m,1H),0.89(dd,J=6.5Hz,J=13.5Hz,6H);13C-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.
实施例47制备H-Met-Phe-Trp-OH(9e)
按照实施例43的操作,以300mg(0.50mmol)Boc-Met-Phe-Trp-OH为原料,得261mg(收率98%)标题化合物,类褐色粉末。Mp:195-196℃;ESI-MS(m/e)483[M+H]+;IR(KBr)υ:3304cm-1,3057cm-1,2916cm-1,1720cm-1,1654cm-1,1525cm-1,1456cm-1,1436cm-1,1228cm-1,742cm-1,700cm-1;1HNMR(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,J=14.0Hz,1H),2.45(m,2H),2.03-2.00(m,5H);13C-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.
实施例48制备H-Ala-Phe-Trp-OH(9f)
按照实施例43的操作,以520mg(0.99mmol)Boc-Ala-Phe-Trp-OH为原料,得456mg(收率99%)标题化合物,类白色粉末。Mp:225-226℃;ESI-MS(m/e)423[M+H]+;IR(KBr)υ:3471cm-1,3350cm-1,3221cm-1,3053cm-1,2927cm-1,1678cm-1,1639cm-1,1508cm-1,1456cm-1,1359cm-1,1342cm-1,738cm-1,700cm-1;1HNMR(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);13C-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.
实施例49制备H-Phe-Phe-Trp-OH(9g)
按照实施例43的操作,以398mg(0.65mmol)Boc-Phe-Phe-Trp-OH为原料,得333mg(收率96%)标题化合物,类红棕色粉末。Mp:168-169℃;ESI-MS(m/e)499[M+H]+;IR(KBr)υ:3257cm-1,3032cm-1,2924cm-1,1720cm-1,1651cm-1,1525cm-1,1496cm-1,1456cm-1,1438cm-1,1215cm-1,742cm-1,700cm-1;1HNMR(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=14.0Hz,1H);13C-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.
实施例50制备H-Ile-Phe-Trp-OH(9h)
按照实施例43的操作,以432mg(0.76mmol)Boc-Ile-Phe-Trp-OH为原料,得380mg(收率100%)标题化合物,紫色粉末。Mp:228-229℃;ESI-MS(m/e)465[M+H]+;IR(KBr)υ:3383cm-1,3059cm-1,2978cm-1,2910cm-1,1734cm-1,1654cm-1,1516cm-1,1456cm-1,1440cm-1,1390cm-1,1346cm-1,1176cm-1,746cm-1,702cm-1;1HNMR(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);13C-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.
实施例51制备H-Trp-Phe-Trp-OH(9i)
按照实施例43的操作,以396mg(0.62mmol)Boc-Trp-Phe-Trp-OH为原料,得355mg(收率100%)标题化合物,红棕色粉末。Mp:207-208℃;ESI-MS(m/e)538[M+H]+;IR(KBr)υ:3630cm-1,3371cm-1,2972cm-1,1708cm-1,1651cm-1,1514cm-1,1456cm-1,1431cm-1,1394cm-1,1348cm-1,1211cm-1,740cm-1,702cm-1;1HNMR(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),3.99(m,1H),3.25-3.02(m,5H),2.90(dd,J=8.5Hz,J=14.0Hz,1H);13C-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.
实施例52制备H-Thr-Phe-Trp-OH(9j)
按照实施例43的操作,以446mg(0.63mmol)Boc-Thr-Phe-Trp-OH为原料,得307mg(收率100%)标题化合物,紫色粉末。Mp:115-117℃;ESI-MS(m/e)453[M+H]+;IR(KBr)υ:3305cm-1,3057cm-1,2976cm-1,2926cm-1,1720cm-1,1651cm-1,1535cm-1,1456cm-1,1230cm-1,742cm-1,700cm-1;1HNMR(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,3H);13C-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.
实施例53制备H-His-Phe-Trp-OH(9k)
按照实施例43的操作,以300mg(0.44mmol)Boc-His(Boc)-Phe-Trp-OH为原料,得223mg(收率98%)标题化合物,类褐色粉末。Mp:229-230℃;ESI-MS(m/e)489[M+H]+;IR(KBr)υ:3030cm-1,2922cm-1,1689cm-1,1658cm-1,1527cm-1,1456cm-1,1438cm-1,1224cm-1,742cm-1,702cm-1;1HNMR(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=8.5HzJ=15.0Hz,1H),3.07(dd,J=4.0Hz,J=15.0Hz,1H),2.85(dd,J=10.5Hz,J=14.0Hz,1H);13C-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.
实施例54制备H-Lys-Phe-Trp-OH(9l)
按照实施例43的操作,以500mg(0.63mmol)Boc-Lys(Boc)-Phe-Trp-OH为原料,得440mg(收率100%)标题化合物,褐色粉末。Mp:268-269℃;ESI-MS(m/e)480[M+H]+;IR(KBr)υ:3354cm-1,3051cm-1,2929cm-1,1743cm-1,1689cm-1,1639cm-1,1548cm-1,1456cm-1,1211cm-1,1176cm-1,742cm-1,698cm-1;1HNMR(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,J=13.5Hz,1H),2.72(m,2H),1.76(m,2H),1.55(m,2H),1.36(m,2H);13C-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.
实施例55制备H-Gln-Phe-Trp-OH(9m)
按照实施例43的操作,以500mg(0.86mmol)Boc-Gln-Phe-Trp-OH为原料,得405mg(收率91%)标题化合物,类白色粉末。Mp:211-213℃;ESI-MS(m/e)480[M+H]+;IR(KBr)υ:3196cm-1,3057cm-1,2974cm-1,1728cm-1,1654cm-1,1525cm-1,1456cm-1,1226cm-1,742cm-1,702cm-1;1HNMR(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);13C-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.
实施例56制备H-Asn-Phe-Trp-OH(9n)
按照实施例43的操作,以400mg(0.63mmol)Boc-Asn-Phe-Trp-OH为原料,得310mg(收率87%)标题化合物,灰色粉末。Mp:142-144℃;ESI-MS(m/e)466[M+H]+;IR(KBr)υ:3344cm-1,3034cm-1,2920cm-1,1724cm-1,1658cm-1,1541cm-1,1529cm-1,1454cm-1,1436cm-1,1338cm-1,1224cm-1,742cm-1,702cm-1;1HNMR(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),2.15(dd,J=8.5Hz,J=15.0Hz,1H);13C-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.
实施例57制备H-Ser-Phe-Trp-OH(9o)
按照实施例43的操作,以449mg(0.83mmol)Boc-Ser-Phe-Trp-OH为原料,得394mg(收率99%)标题化合物,类白色粉末。Mp:134-136℃;ESI-MS(m/e)439[M+H]+;IR(KBr)υ:3387cm-1,3205cm-1,3055cm-1,1643cm-1,1517cm-1,1456cm-1,1394cm-1,742cm-1,698cm-1;1HNMR(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),3.1-3.04(m,2H),2.73(dd,J=10.0Hz,J=14.5Hz,1H);13C-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.
实施例58制备H-Tyr-Phe-Trp-OH(9p)
按照实施例43的操作,以360mg(0.58mmol)Boc-Tyr-Phe-Trp-OH为原料,得320mg(收率99%)标题化合物,类白色粉末。Mp:185-187℃;ESI-MS(m/e)515[M+H]+;IR(KBr)υ:3234cm-1,3059cm-1,2924cm-1,1720cm-1,1658cm-1,1516cm-1,1440cm-1,1226cm-1,742cm-1,700cm-1;1HNMR(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,1H),4.55(m,1H),3.90(m,1H),3.25-3.01(m,4H),2.89-2.77(m,2H);13C-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.
实施例59制备H-Arg-Phe-Trp-OH(9q)
将300mg(0.46mmol)Boc-Arg(NO2)-Phe-Trp-OH用少量乙醇溶解,加入适量钯炭,连接氢气发生装置,反应5天,TLC(氯仿∶甲醇∶冰醋酸50∶5∶1)显示原料点消失,滤去钯炭,滤液减压浓缩除去溶剂,用1ml乙酸乙酯将残留物溶解,加入4ml氯化氢-乙酸乙酯溶液,冰浴搅拌2h后TLC(氯仿∶甲醇∶冰醋酸=25∶5∶1)显示原料点完全消失,水泵减压抽干反应液,再用乙醚5ml反复磨洗产品3次,减压抽干,制得目标化合物230mg(收率77%),Mp:221-223℃;ESI-MS(m/e)508[M+H]+;IR(KBr)υ:3296cm-1,3049cm-1,2920cm-1,1651cm-1,1541cm-1,1456cm-1,1232cm-1,748cm-1,702cm-1;1HNMR(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,2H);13C-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.
实施例60制备H-Asp-Phe-Trp-OH(9r)
按照实施例43的操作,以307mg(0.54mmol)Boc-Asp-Phe-Trp-OH为原料,得258mg(收率95%)目标化合物,淡黄色固体。Mp:144-145℃;ESI-MS(m/e)467[M+H]+;IR(KBr)υ:3221cm-1,3028cm-1,2924cm-1,1728cm-1,1647cm-1,1529cm-1,1456cm-1,1205cm-1,744cm-1,702cm-1;1HNMR(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=10.5Hz,J=14.0Hz,1H),2.25(dd,J=6.5Hz,J=15.0Hz,1H);13C-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.
实施例61制备H-Glu-Phe-Trp-OH(9s)
按照实施例43的操作,以480mg(0.83mmol)Boc-Glu-Phe-Trp-OH为原料,得406mg(收率95%)标题化合物,紫色粉末。Mp:181-182℃;ESI-MS(m/e)481[M+H]+;IR(KBr)υ:3081cm-1,2927cm-1,1720cm-1,1658cm-1,1521cm-1,1456cm-1,1215cm-1,744cm-1,700cm-1;1HNMR(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),2.42-1.98(m,2H),2.00-1.98(m,2H);13C-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.
实验例1本发明化合物的镇痛作用评价实验
1、受试化合物:本发明实施例43-61所制备的化合物9a-s。
2、实验方法:
雄性昆明小鼠体重在(22±2g),每日光照12小时,室内温度为20-24℃,湿度保持在45-65%,充足的食物和水。实验前一天开始禁食饲养,并将老鼠放入实验操作间适应环境,每只老鼠只参与一次实验。
实验时将小鼠装入特制的固定筒内,尾部暴露于外,75%酒精进行消毒,测痛阈时以特制聚光灯产生的光束照射鼠尾下三分之一处,用秒表计时,计从照射开始到甩尾反应的潜伏期(tail flick latency,TFL)作为痛阈。调节聚光灯与鼠尾距离使刺激强度较为灵敏TFL为2-6s。实验开始时先测3次,每次间隔5min,取均值作为基础痛阈。将受试化合物分别悬浮于0.5%羧甲基纤维素钠(CMC-Na)水溶液中,灌胃给药,按每次灌胃剂量为0.2ml以及0.13mmol/kg剂量调节悬浮浓度。每次试验设0.5%CMC-Na组作平行对照。为防止皮肤烫伤,光照截止时间10s,间隔30min复测TFL以观察药物镇痛时效关系。以痛阈提高率评定药物镇痛强度:PTV=AAPT/BPT(PTV=痛阈提高率,BPT=基础痛阈值,AAPT=给药后痛阈值-基础痛阈值)。得到的结果列入表1。
表1本发明化合物9a-s的镇痛活性
注:痛阈提高率用均数±SD%表示,n=10,给药剂量0.13mmol/kg;
a:与CMC-Na组比较P<0.05;
b:与CMC-Na组比较P<0.01;
c:与CMC-Na组比较P<0.001。
上述实验结果表明本发明化合物9a-s均具有明确的镇痛活性。
实验例2本发明化合物9a和9i不同剂量的镇痛活性
1、受试化合物:本发明实施例43和51所制备的化合物9a和9i;
2、实验方法:采用实验例1的小鼠光辐射热甩尾模型评价了受试化合物在0.13mmol/kg、0.08mmolmol/kg和0.05mmol/kg三种剂量下的镇痛作用。结果列入表2。
表2不同给药剂量9a和9i的镇痛作用
注:痛阈提高率用X±SD%表示,n=10,给药剂量0.13mmol/kg;
a:与0.08mmol/kg组比较P<0.05;b:与0.05mmol/kg组比较P<0.05。
实验结果表明受试化合物9a和9i都剂量依赖地显示镇痛作用。
Claims (9)
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或二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选自亮氨酸残基、甘氨酸残基、脯氨酸残基、缬氨酸残基、甲硫氨酸残基、丙氨酸残基、苯丙氨酸残基、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(OCH3)残基或Glu(OCH3)残基;
(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选自亮氨酸残基、甘氨酸残基、脯氨酸残基、缬氨酸残基、甲硫氨酸残基、丙氨酸残基、苯丙氨酸残基、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(OCH3)残基或Glu(OCH3)残基;
(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(5)中所述的叔丁氧羰基保护的氨基酸选自叔丁氧羰基保护的亮氨酸、叔丁氧羰基保护的甘氨酸、叔丁氧羰基保护的脯氨酸、叔丁氧羰基保护的缬氨酸、叔丁氧羰基保护的蛋氨酸、叔丁氧羰基保护的丙氨酸、叔丁氧羰基保护的苯丙氨酸、叔丁氧羰基保护的异亮氨酸、叔丁氧羰基保护的色氨酸、叔丁氧羰基保护的苏氨酸、叔丁氧羰基保护的谷酰胺、叔丁氧羰基保护的天冬酰胺、叔丁氧羰基保护的丝氨酸、叔丁氧羰基保护的酪氨酸、叔丁氧羰基保护的硝基精氨酸、叔丁氧羰基保护的天冬氨酸单甲酯、叔丁氧羰基保护的谷氨酸单甲酯;所述的二叔丁氧羰基保护的氨基酸选自二叔丁氧羰基保护的组氨酸或二叔丁氧羰基保护的赖氨酸。
7、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。
8、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载体或辅料组成。
9、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。
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