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      N-(l-氨基酰)-1,2,3,4-四氫咔啉酰氨基酸芐酯及其合成方法及應(yīng)用的制作方法

      文檔序號:3572613閱讀:504來源:國知局

      專利名稱::N-(l-氨基酰)-1,2,3,4-四氫咔啉酰氨基酸芐酯及其合成方法及應(yīng)用的制作方法
      技術(shù)領(lǐng)域
      :本發(fā)明涉及具有抗腫瘤活性的化合物,尤其涉及具有抗腫瘤活性的^(1^氨基酰)-1,2,3,4-四氫昨啉酰氨基酸芐酯類化合物及其制備方法,本發(fā)明還涉及該化合物在制備抗腫瘤藥物中的應(yīng)用,屬于生物醫(yī)藥領(lǐng)域。
      背景技術(shù)
      :惡性腫瘤是一種嚴重威脅人類健康的常見病和多發(fā)病,人類因惡性腫瘤而引起的死亡率是所有疾病死亡率的第二位,僅次于心腦血管疾病。腫瘤的治療方法有手術(shù)治療,放射治療和藥物治療(化學(xué)治療)。目前,化學(xué)治療仍然是臨床治療腫瘤的主要手段。尋找抗腫瘤藥物是新藥研究的熱點之一。發(fā)明人認識到,在(3-咔啉-3-羧酸的2位N引入氨基酸及3位羧基引入氨基酸芐基可能產(chǎn)生抗腫瘤作用。
      發(fā)明內(nèi)容本發(fā)明目的之一是提供一類新的具有抗腫瘤活性的化合物。本發(fā)明目的之二是提供一種制備上述具有抗腫瘤活性的化合物的方法。本發(fā)明目的之三是提供一種具有抗腫瘤功效的藥物組合物。本發(fā)明上述目的是通過以下技術(shù)方案來實現(xiàn)的具有抗腫瘤活性的化合物,該化合物的結(jié)構(gòu)式為通式I或通式II所示通式I其中,AA!選自丙氨酸(Ala)殘基、甘氨酸(Gly)殘基、脯氨酸(Pro)、谷氨酰胺(Gln)殘基、亮氨酸(Leu)殘基、苯丙氨酸(Phe)殘基、異亮氨酸(Ile)殘基、甲硫氨酸(Met)殘基、酪氨酸(Tyr)殘基、色氨酸(Trp)殘基、纈氨酸(Val)殘基、賴氨酸(Lys)殘基、Arg(N02)、Thr(Bzl)、Se《Bzl)或Cys(CH2-C6H4-OCH3);AA2選自丙氨酸(Ala)殘基、甘氨酸(Gly)殘基、脯氨酸(Pro)殘基、谷氨酰胺(Gln)殘基、亮氨酸(Leu)殘基、苯丙氨酸(Phe)殘基、異亮氨酸(Ile)殘基、甲硫氨酸(Met)殘基、酪氨酸(Tyr)殘基、色氨酸(Trp)殘基、纈氨酸(Val)殘基、賴氨酸Lys(Z)、Arg(N02)、Thr(Bzl)、Ser(Bzl)或Cys(But);其中,AA!選自Asp(OBZl)或Glu(0BZ1);AA2選自Asp(OBZl)或Glu(0BZ1);一種制備上述通式I化合物的方法,該方法包括(1)將L-色氨酸轉(zhuǎn)變?yōu)?,2,3,4-四氫咔啉羧酸;(2)將1,2,3,4-四氫咔啉羧酸轉(zhuǎn)變?yōu)檫沁人崞S酯;(3)在對甲苯磺酸和芐醇存在下將氨基酸轉(zhuǎn)化成氨基酸芐酯(2;);(4)在(Boc)20和NaOH存在下氨基酸轉(zhuǎn)化成N-叔丁氧羰基氨基酸(l);(5)將N-叔丁氧羰基氨基酸和1,2,3,4-四氫咔啉羧酸芐酯縮合,生成N-叔丁氧羰基氨基酰-1,2,3,4-四氫咔啉羧酸芐酯;(6)將N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉羧酸芐酯氫解,生成N-叔丁氧羰基氨基酰-1,2,3,4-四氫咔啉羧酸;(7)將N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉羧酸芐酯水解,生成N-叔丁氧羰基氨基酰-1,2,3,4-四氫咔啉羧酸;(8)將N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉羧酸和氨基酸芐酯縮合,生成N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉酰氨基酸芐酯;(9)將N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉酰氨基酸芐酯酸解,即得。上述制備方法中,步驟(3)中所述的氨基酸芐酯選自Ala-OBzl、Gly-OBzl、Pro-OBzl、Gln-OBzl、Leu國OBzl、Phe-OBzl、Ile-OBzl、Met-OBzl、Tyr-OBzl、Trp-OBzl、Val-OBz、Lys(Z)-OBzl、Arg(N02)-OBzl、Thr(Bzl)-OBzl、Ser(Bzl)-OBzl、Cys(But)-OBzl、Asp(OBzl)^Obzl或通式nGlu(OBzl)-OBzl;步驟(4)中所述的N-叔丁氧羰基氨基酸選自N-Boc-Ala、N-Boc-Gly、N-Boc-Pro、N-Boc陽Gln、N-Boc-Leu、N-Boc-Phe、N-Boc-Ile、N-Boc-Met、N-Boc-Tyr、N-Boc-Trp、N-Boc隱Val、N隱Boc隱Lys、N-Boc-Arg(N02)、N-Boc-Thr(Bzl)、N-Boc-Ser(Bzl)、N-Boc-Cys(CH2-C6H4-OCH3)、N陽Boc-Asp(OBzl)或N-Boc-Glu(OBzl);一種制備上述通式II化合物的方法,該方法包括(1)將L-色氨酸轉(zhuǎn)變?yōu)?,2,3,4-四氫咔啉羧酸;(2)將1,2,3,4-四氫咔啉羧酸轉(zhuǎn)變成N-叔丁氧羰基-l,2,3,4-四氫咔啉羧酸;(3)將N-N-叔丁氧羰基-l,2,3,4-四氫咔啉羧酸和氨基酸芐酯縮合,生成N-N-叔丁氧羰基-1,2,3,4-四氫咔啉酰氨基酸芐酯;(4)將N-N-叔丁氧羰基-l,2,3,4-四氫咔啉酰氨基酸芐酯酸解,生成1,2,3,4-四氫咔啉酰氨基酸芐酯;(5)將N-叔丁氧羰基氨基酸和1,2,3,4-四氫咔啉酰氨基酸芐酯縮合,生成N-N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉酰氨基酸芐酯;(6)將N-N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉酰氨基酸芐酯酸解,即得。其中,步驟(3)中所述的氨基酸芐酯選自Asp(OBZl)-OBzl或Glu(OBZl)-OBzl;步驟(5)中所述的N-叔丁氧羰基氨基酸選自N-Boc-Asp(OBZl)或N-Boc-Glu(OBZ1)本發(fā)明的又一目的是提供一種具有抗腫瘤活性的藥用組合物,該藥用組合物由治療上有效劑量的本發(fā)明通式I或通式II化合物與藥學(xué)上可接受的載體組成,即將有效量的本發(fā)明通式i或通式n化合物與藥學(xué)上可接受的載體或稀釋劑配合后,按本領(lǐng)域常規(guī)的制劑方法將其制備成任意一種適宜的藥物組合物。通常該組合物適合于口服給藥和注射給藥,也適合其他的給藥方法。該組合物可以是片劑、膠囊劑、粉劑、顆粒劑、錠劑、栓劑,或口服液等液體制劑形式。根據(jù)不同的給藥方法,本發(fā)明藥物組合物可以含有0.1%-99%重量,優(yōu)選10-60%重量的本發(fā)明化合物。本發(fā)明在小鼠S,8Q肉瘤模型上評價本發(fā)明通式I和通式II化合物的抗腫瘤活性,試驗結(jié)果表明,本發(fā)明通式i和通式n化合物具有確切的抗腫瘤活性。圖l本發(fā)明通式化合物的結(jié)構(gòu)圖。圖2通式I化合物的合成路線圖;i)甲醛和濃硫酸、室溫攪拌;ii)芐醇、多聚磷酸、油浴90。C;iii)Boc-AA!、DCC、HoBt、NMM;iv-l)Pd/C,H2,乙醇AA,選自AIa、Gly、Pro、Gln、Leu、Phe、Ile、Tyr、Trp、Val、Lys(Boc);iv-2)2NNaOH、甲醇AAi選自Met、Arg(N02)、Thr(Bzl)、Ser(Bzl)、Cys(CH2-C6H4-OCH3);v)L-AA2-OBzl、DCC、HoBt、雨M;vi)4N氯化氫-乙酸乙酯溶液;7a-p中AA!選自Ala、Gly、Pro、Gln、Leu、Phe、Ile、Met、Tyr、Trp、Val、Lys(Boc)、Arg(N02)、Thr(Bzl)、Ser(BzI)、Cys(CH2-C6H4-OCH3);AA2選自Ala、Gly、Pro、Gln、Leu、Phe、Ile、Met、Tyr、Trp、Val、Lys(Z)、Arg(N02)、Thr(Bzl)、Ser(Bz)、Cys(But);8a-p中AA!選自Ala、Gly、Pro、Gln、Leu、Phe、Ile、Met、Tyr、Trp、Val、Lys、Arg(N02)、Thr(Bzl)、Ser(Bzl)、Cys(CH2-C6H4-OCH3);AA2選自AIa、GIy、Pro、Gln、Leu、Phe、Ile、Met、Tyr、Trp、Val、Lys(Z)、Arg(N02)、Thr(Bzl)、Ser(Bzl)、Cys(But)。圖3通式II化合物的合成路線圖;i)甲醛和濃硫酸,室溫攪拌;ii)(Boc)20,三乙胺,DMF;iii)DCC、HOBt、AAOBzl、無水THF;iv)4NHCl-EtoAC;v)DCC,HOBt,Boc-AA-OH,無水THF;vi)4NHCl-EtoAC;5q,r中AA選自Asp(OBz喊Glu(OBzl);6q,r中AA選自Asp(OBzl)或Glu(OBzl);7q,r中AAi選自Asp(OBzl)或Glu(OBZl),AA2選自Asp(OBzl)或Glu(OBZ1);8q,r中AA,選自Asp(OBZl)或Glu(0BZ1),AA2選自Asp(OBZl)或Glu(0BZ1)。具體實施例方式為了進一步闡述本發(fā)明,下面給出一系列實例。這些實例完全是例證性的,它們僅用來對本發(fā)明進行具體描述,不應(yīng)當理解為對本發(fā)明的限制。實施例11,2,3,4-四氫咔啉-3-羧酸(2)將400ml水置于500ml的圓底燒瓶中,緩慢加入0.2ml濃硫酸搖勻.往得到的稀硫酸溶液中加入5.0g(24.5mmo1)L-色氨酸.用超聲振蕩至L-色氨酸完全溶解,往得到的溶液中加入10ml濃度為35。/。的甲醛,攪袢,TLC板檢測L-色氨酸原料點消失終止反應(yīng).往反應(yīng)液中緩慢滴加氨水調(diào)PH值到6,靜止半個小時,減壓濾出生成的沉淀,用水沖洗濾出的無色固體干燥稱重5.01g,產(chǎn)率:95%。M.p.229國231。C,ESI-MS(m/z):[M+H]十217。實施例22-Boc-l,2,3,4-四氫咔啉-3-羧酸(3)冰浴下將lg(4.63mmo1)1,2,3,4-四氫咔啉-3-羧酸懸浮于含1.2g(Boc)2O(5.50mmol)的10mlDMF溶液中,然后加三乙胺調(diào)PH8-9反應(yīng),隨著反應(yīng)的進行混懸的溶液逐漸變澄清,溶液顏色為黃色,TLC板檢測反應(yīng)(氯仿:甲醇-10:1)原料點消失停止反應(yīng),電風(fēng)扇吹干DMF,用乙酸乙酯將吹干后的殘留物溶解,5%的KHS04洗滌3次,飽和的NaCl洗滌3次,無水Na2S04干燥,過濾,蒸干殘留物用氯仿洗滌得到目標化合物958mg,無色固體,產(chǎn)率65.5%,Mp:241-243°C;025=64.43((:1;甲醇).ESI-MS(m/z)317[M+H]+;'HNMR(500畫z,DMSO-d6):S/ppn^12.794(s,1H),10.887(d,J=23.5Hz,1H),7.293-7.440(m,J=8Hz,J=7.5Hz,2H),6.969-7.077(m,J=7Hz,J=7.5Hz,2H),5.1245(dd,J=5.5Hz,1H),4.742(t,J=17Hz,J=19Hz,H),4.4195(dd,J=20Hz,1H),3.323(m,J=7.5Hz,1H),2.985(m,J=6.5Hz,1H),1.460(s,9H).13CNMR(DMSO-d6):S/ppm=173.28,155.56,136.66,130.81,126.76,121.41,119.01,118.03,111.47,104.99,80.27,60.20,53.86,28.49,23.34.實施例31,2,3,4-四氫咔啉-3-羧酸芐酯(4)取20ml芐醇和2g多聚磷酸使之互溶,油浴7(TC,加入咔啉羧酸lg開始不溶,反應(yīng)液為黃綠色升溫至90。C反應(yīng)液逐漸溶解變澄清顏色逐漸變棕色,TLC板檢測反應(yīng),24小時原料點消失進行后處理.冷卻,加入50ml乙醚和70ml水充分攪拌出現(xiàn)結(jié)晶,過濾,乙醚水反復(fù)洗得到黃白色的咔啉羧酸芐酯磷酸鹽.將得到的咔啉羧酸芐酯磷酸鹽混旋在乙酸乙酯中,滴加三乙胺至澄清,用5%碳酸氫鈉洗滌6次,飽和氯化鈉洗滌3次,無水硫酸鈉干燥,過濾,旋干,得到黃白色的咔啉羧酸芐酯0.85g,產(chǎn)率60%;Mpl22隱124。C;+;'HNMR(500MHZ,DMSO-d6):S/ppm=7.275-7.401(m,7H),6.95l(t,J=7.5Hz,1H),7.025(t,J=10Hz,1H),5.191(s,2H),3.9885(q,片15.5Hz,2H),3.824(q,J=4.5Hz,J=8.5Hz,1H),2.9765(dd,J=4.5Hz,J=15Hz,1H),2'815(q,J=8.5Hz,J=15Hz).13CNMR(DMSO-d6):S/ppm=173.21,136.57,136.23,133.46,128.卯,128.71,128.46,128.21,127.30,120.97,118.79,117.73,111.33,105.83,66.15,55.63,41.7,25.26.實施例4N-Boc-Ala-l,2,3,4-四氫咔啉-3-羧酸芐酯(5a)冰浴下用無水THF將1.229g(6.5mmol)Boc-Ala溶解,加0.921g(6.82mmol)N-羥基苯并三氮唑(HOBt),完全溶解后加入1.741g(8.45mmol)二環(huán)己基羰二亞胺(DCC).10分鐘后,往里加入無水THF與1.53g(5.0mmoI)l,2,3,4-四氫咔啉-3-羧酸芐酯并用N-甲基嗎啉調(diào)PH值8-9之間的溶液。反應(yīng)混合物攪拌,TLC板檢測(石油謎/丙酮,3:l,Rf=0.2)。原料點消失后濾出二環(huán)己基脲(DCU),濾液減壓濃縮,殘留物用40ml乙酸乙酯溶解。得到的溶液依次用飽和NaHC03,飽禾卩NaCl、5%KHS04、飽和NaCl、飽和NaHC03、飽和NaCl各洗三次至中性,無水Na2S04干燥。過濾,濾液減壓濃縮至干,得到1.761g(74%)標題化合物(淡黃色固體)。Mp87-90°C;[a]D25=27.33(C=1.0,甲醇)。ESI-MS(m/z)478[M+H]+。實施例5N-Boc-Gly-l,2,3,4-四氫咔啉-3-羧酸芐酯(5b)按照制備5a的操作,從0.91g(5.2mmol)Boc-Gly和1.224g(4.0mmol)1,2,3,4-四氫咔啉-3-羧酸芐酯得1.48g(79.9n/。)標題化合物(淡黃色固體)。Mp102-104°C;[a]D25=19.47(C=1.0,甲醇);ESI-MS(m/z)464[M+H]+。實施例6N-Boc-Pro-l,2,3,4-四氫咔啉-3-羧酸節(jié)酯(5c)按照制備5a的操作,從1.118g(5.2mmol)Boc-Pro和1.224g(4.0mmol)1,2,3,4-四氫咔啉-3-羧酸芐酯得0.372g(19%)標題化合物(黃色固體)。Mp88-90°C;[a]D25=-2.70(C=1.0,甲醇);ESI-MS(m/z)504[M+H]+。實施例7N-Boc-Gln-l,2,3,4-四氫咔啉-3-羧酸芐酯(5d)按照制備5a的操作,從0.949g(6.5mmol)Boc-Gln和1.53g(5.0mmol)1,2,3,4-四氫咔啉-3-羧酸芐酯得l.Og(37%)標題化合物(無色固體)。Mp102-104°C;[a]D25=74(O1.0,甲醇);ESI-MS(m/z)535[M+H]+。實施例8N-Boc-Leu-l,2,3,4-四氫咔啉-3-羧酸芐酯(5e)按照制備5a的操作,從1.201g(5.2mmol)Boc-Leu和1.224g(4.0mmol)1,2,3,4-四氫咔啉-3-羧酸芐酯得1.654g(80%)標題化合物(無色固體)。Mp84-86'C;[a]D25=38.5(C=1.0;甲醇);ESI-MS(m/z)520[M+H]+。實施例9N-Boc-Phe-l,2,3,4-四氫咔啉-3-羧酸芐酯(5f)按照制備5a的操作,從1.378g(5.2mmol)Boc-Phe和1.224g(4.0mmo1)1,2,3,4-四氫昨啉陽3-羧酸芐酯得2.033g(92%)標題化合物(無色固體)。Mp74陽76。C;[a]D25=53.0(C=1.0,甲醇);ESI-MS(m/z)554[M+H]+。實施例10N-Boc-Ile-l,2,3,4-四氫咔啉-3-羧酸芐酯(5g)按照制備5a的操作,從L502g(6.5mmol)Boc-Ile和1.53g(5.0mmo1)1,2,3,4-四氫昨啉墨3-羧酸芐酯得1.90g(73%)標題化合物(無色固體)。Mp78-81°C;[a]D25=46.7(C=1.0,甲醇);ESI-MS(m/z)542[M+H]+。實施例11N-Boc-Met-l,2,3,4-四氫咔啉-3-羧酸芐酯(5h)按照制備5a的操作,從1.618g(6.5mmol)Boc-Met和1.53g(5.0mmo1)1,2,3,4-四氫咔啉-3-羧酸節(jié)酯得1.69g(63%)標題化合物(黃色固體)。Mp76-78°C;[a]D25=46.9(C=1.0,甲醇);ESI-MS(m/z)538[M+H]+。實施例12N-Boc-Tyr-l,2,3,4-四氫咔啉-3-羧酸芐酯(5i)按照制備5a的操作,從1.826g(6.5mmol)Boc-Tyr和1.53g(5.0mmo1)1,2,3,4-四氫咔啉-3-羧酸芐酯得0.747g(26%)標題化合物(黃色固體)。Mp102-103°C;[a]D25=48.1(C=1.0,甲醇);ESI-MS(m/z)592[M+H]+。實施例13N-Boc-Trp-l,2,3,4-四氫咔啉-3-羧酸芐酯(5j)按照制備5a的操作,從1.58g(5.2mmol)Boc-Trp和1.224g(4.0mmo1)1,2,3,4陽四氫咔啉-3-羧酸芐酯得1.80g(76%)標題化合物(無色固體)。Mp102-104°C;[a]D25=56.5(C=1.0,甲醇);ESI掘(m/z)593[M+H]+。實施例14N-Boc-Val-l,2,3,4-四氫咔啉-3-羧酸芐酯(5k)按照制備5a的操作,從U28g(5.2mmol)Boc-Val和1.224g(4.0mmo1)1,2,3,4-四氫咔啉-3-羧酸芐酯得1.403g(69%)標題化合物(黃色固體)。Mp72-74°C;[a]D25=80.6(C=1.0;甲醇);ESI-MS(m/z)506[M+H]+。11實施例15N-Boc-Lys(Boc)-l,2,3,4-四氫咔啉-3-羧酸芐酯(51)按照制備5a的操作,從1.799g(5.2mmol)Boc-Lys(Boc)和1.224g(4.0mmo1)1,2,3,4-四氫咔啉-3-羧酸芐酯得2.298g(91%)標題化合物(黃色固體)。Mp78-79°C;[a]D25=40.2(C=1.0,甲醇);ESI-MS(m/z)635[M+H]+。實施例16N-Boc-Arg(N02)-l,2,3,4-四氫咔啉-3-羧酸芐酯(5m)按照制備5a的操作,從0.957g(3.0mmol)Boc-Arg(N02)和0.765g(2.5mmo1)1,2,3,4隱四氫咔啉-3-羧酸芐酯得0.90g(59%)標題化合物(黃色固體)。Mp118-121°C;[a]D25=42.1(O1.0,甲醇);ESI-MS(m/z)608[M+H]+。實施例17N-Boc-Thr(Bzl)-l,2,3,4-四氫咔啉-3-羧酸芐酯(5n)按照制備5a的操作,從0.927g(3.0mmol)Boc-Thr(Bzl)和0.765g(2.5mmo1)1,2,3,4-四氫咔啉-3-羧酸芐酯得0.90g(60%)標題化合物(無色固體)。Mp148-150°C;[a]D25=46.3(C=1.0,甲醇);ESI-MS(m/z)598[M+H]+。實施例18N-Boc-Ser(Bzl)-l,2,3,4-四氫咔啉-3-羧酸芐酯(50)按照制備5a的操作,從0.885g(3.0mmol)Boc-Ser(BzI)和0.765g(2.5mmo1)1,2,3,4-四氫咔啉-3-羧酸節(jié)酯得1.075g(74%)標題化合物(無色固體)。Mp66-68°C;[a]D25=38.9(C=1.0,甲醇);ESI-MS(m/z)584[M+H〗+。實施例19N-Boc-Cys(CH2-C6H4-OCH3)-l,2,3,4-四氫咔啉-3-羧酸芐酯(5p)按照制備5a的操作,從1.228g(3.6mmol)Boc-Cys(CH2-C6H4-OCH3;^0.918g(3.0mmol)1,2,3,4-四氫咔啉-3-羧酸芐酯得1.30g(69%)標題化合物(無色固體)。Mp50-53°C;[a]D25=13.0(01.0,甲醇);ESI-MS(m/z)630[M+H]+。實施例20N-Boc-l,2,3,4-四氫咔啉-3-甲酰-Asp(OBzl)-OBzl(5q)按照制備5a的操作,從0.632g(2.0mmo1)N-Boc-l,2,3,4-四氫咔啉-3-羧酸和1.067g(2.2mmo1)Asp(OBzl)-OBz得0.657g(54%)標題化合物(無色固體)。Mp50-52°C;[a]D25=29.7(C=1.0,甲醇);ESI陽MS(m/z)612[M+H]+。實施例21N-Boc-l,2,3,4-四氫咔啉-3-甲酰-Glu(OBzl)-OBzl(5r)按照制備5a的操作,從0.632g(2.0mmo1)N-Boc-l,2,3,4-四氫咔啉-3-羧酸和1.10g(2.2mmo1)Glu(OBzl)-OBzl得0.671g(54%)標題化合物(無色固體)。Mp53-56°C;[a]D25=20.5(C=1.0,甲醇);ESI-MS(m/z)626[M+H]+。實施例22N-Boc-Ala-l,2,3,4-四氫咔啉-3-羧酸(6a)在100ml的圓底燒瓶中,用20011無水乙醇將1.6£(3.351011101:^-800八1&-1,2,3,4-四氫咔啉-3-羧酸芐酯溶解,加入0.8gPd/C,通入H2攪拌反應(yīng),TLC檢測原料點消失,終止反應(yīng);過濾Pd/C,蒸干母液得1.23g(95X)標題化合物(無色固體)。Mpl48-150。C;[a]D25=55.3(C=1.0,甲醇);ESI-MS(m/z)386[M-H]-。實施例23N-Boc-Gly-l,2,3,4-四氫咔啉-3-羧酸(6b)按照制備6a的操作,從1.2g(2.59mmol)N-Boc-Gly-l,2,3,4-四氫咔啉-3-羧酸芐酯得0.956g(99。/。)標題化合物(無色固體)。Mp142-144°C;[a]D25=63.2(O1.0,甲醇);ESl-MS(m/z)370[M-町。實施例24N-Boc-Pro-l,2,3,4-四氫咔啉-3-羧酸(6c)按照制備6a的操作,從0.370g(0.74mmol)N-Boc-Pro-l,2,3,4-四氫咔啉-3-羧酸芐酯得0.364g(97%)標題化合物(無色固體)。Mp167-169°C;[a]D25=-12.5(O1.0,甲醇);ESI-MS(m/z)412[M-町。實施例25N-Boc-Gln-l,2,3,4-四氫咔啉-3-羧酸(6d)按照制備6a的操作,從1.0g(1.873mmol)N-Boc-Gln-l,2,3,4-四氫咔啉-3-羧酸芐酯得0.80g(96%)標題化合物(無色固體)。Mp151-153°C;[a〗D25=71.7(01.0,甲醇);ESI-MS(m/z)443[M-H〗。實施例26N-Boc-Leu-l,2,3,4-四氫咔啉-3-羧酸(6e)按照制備6a的操作,從1.0g(1.93mmol)N-Boc-Leu-l,2,3,4-四氫咔啉-3-羧酸芐酯得0.786g(95%)標題化合物(無色固體)。Mp142-144°C;[a]D25=64.1(C=1.0,甲醇);ESI-MS(m/z)428[M-H]。實施例27N-Boc-Phe-l,2,3,4-四氫咔啉-3-羧酸(6f)按照制備6a的操作,從0.676g(1.222mmol)N-Boc-Phe-l,2,3,4-四氫咔啉-3-羧酸節(jié)酯得0.534g(94%)標題化合物(無色固體)。Mp136-138°C;[a]D25=58.8(C=1.0,甲醇);ESI-MS(m/z)462[M-H]。實施例28N-Boc-Ile-l,2,3,4-四氫咔啉-3-羧酸(6g)按照制備6a的操作,從1.0g(1.222mmol)N-Boc-Ile-l,2,3,4-四氫咔啉-3-羧酸節(jié)酯得0.819g(99%)標題化合物(無色固體)。Mp145-146°C;[a]D25=55.0(C=1.0,甲醇);ESI-MS(m/z)428[M-H]。實施例29N-Boc-MeM,2,3,4-四氫咔啉-3-羧酸(6h)將1.2g(2.235mmol)N-Boc-Met-l,2,3,4-四氫咔啉-3-羧酸節(jié)酯溶于4ml甲醇,冰浴下向得到的溶液滴入3ml2NNaOH水溶液并攪拌至原料點消失,終止反應(yīng)。反應(yīng)化合物用飽和KHS04調(diào)pH6-7,減壓濃縮除去蒸甲醇。殘留物用飽和KHS04調(diào)pH卜2,乙酸乙酯萃取3次,合并乙酸乙酯層用飽和NaCl水溶液洗3次,乙酸乙酯層用無水Na2S04干燥,過濾,減壓濃縮至干得0.849g(85^)標題化合物(無色固體)。Mp104-106°C;[a]D25=48.7(C=1.0,甲醇);ESI-MS(m/z)446[M+H]+。實施例30N-Boc-Tyr-l,2,3,4-四氫咔啉-3-羧酸(6i)按照制備6a的操作,從0.720g(1.265mmol)N-Boc-Tyr-l,2,3,4-四氫咔啉-3-羧酸芐酯得0.569g(94%)標題化合物(無色固體)。Mp166-168°C;[a]D25=51.7(C=1.0,甲醇);ESI-MS(m/z)478[M-H]-。實施例31N-Boc-Trp-l,2,3,4-四氫咔啉-3-羧酸(6j)按照制備6a的操作,從U70g(1.976mmol)N-Boc-Trp-l,2,3,4-四氫昨啉-3-羧酸節(jié)酯得0.962g(97%)標題化合物(無色固體)。Mp168-169°C;[a]D25=72.5(C=l.0,甲醇);ESI-MS(m/z)5Ol[M-H]-。實施例32N-Boc-Val-l,2,3,4-四氫咔啉-3-羧酸(6k)按照制備6a的操作,從1.403g(2.780mmol)N-Boc-Val-l,2,3,4-四氫咔啉-3-羧酸芐酯得U30g(98%)標題化合物(無色固體)。Mp139-141°C;[a]D25=66.2(O1.0,甲醇);ESI-MS(m/z)414[M-H]。實施例33N-Boc-Lys(Boc)-l,2,3,4-四氫咔啉-3-羧酸(61)按照制備6a的操作,從1.0g(1.577mmol)N-Boc-Lys(Boc)-l,2,3,4-四氫咔啉-3-羧酸芐酯得0.849g(99%)標題化合物(無色固體)。Mp123-125°C;[a]D25=18.6(C=1.0,甲醇);ESI-MS(m/z)543[M-H]-。實施例34N-Boc-Arg(N02)-l,2,3,4-四氫咔啉-3-羧酸(6m)按照制備6h的操作,從L5g(2.479mmol)N-Boc-Arg(N02)-l,2,3,4-四氫咔啉-3-羧酸芐酯得U53g(90%)標題化合物(無色固體)。Mp170-172°C;[a]D25=27.7(C=l.0,甲醇);ESI-MS(m/z)516[M-H]-。實施例35N-Boc-Thr(Bzl)-l,2,3,4-四氫咔啉-3-羧酸(6n)按照制備6h的操作,從1.0g(1.675mmol)N-Boc-Thr(Bzl)-l,2,3,4-四氫咔啉-3-羧酸芐酯得0.789g(93%)標題化合物(無色固體)。Mp89-92°C;[a]D25=39.1(C=1.0,甲醇);ESI-MS(m/z)506[M-町。實施例36N-Boc-Ser(Bzl)-l,2,3,4-四氫咔啉-3-羧酸(60)按照制備6h的操作,從U05g(1.895mmol)N-Boc-Ser(Bzl)-l,2,3,4-四氫咔啉-3-羧酸芐酯得0.925g(99%)標題化合物(無色固體)。Mp53-55°C;[a]D25=30.9(C=1.0,甲醇);ESI-MS(m/z)492[M-H]-。實施例37N-Boc-Cys(CH2-C(;H4-OCH3)-l,2,3,4-四氫咔啉-3-羧酸(6p)按照制備6h的操作,從1.2(^(1.9080111101)^80<^^5((:&-<:必4-00&)-1,2,3,4-四氫咔啉-153-羧酸芐酯得1.0g(97%)標題化合物(無色固體)。Mp44-46°C;[a]D25=-47.4(O1.0,甲醇);ESI-MS(m/z)538[M國H]。實施例381,2,3,4-四氫咔啉-3-?;?Asp(OBzl)-OBzl(6q)在100ml的圓底燒瓶中,用lml乙酸乙酯將0.657§(1.07511111101)^8001,2,3,4-四氫昨啉-3-酰基-Asp(OBzl)-OBzl溶解,冰浴條件下,加入2ml4NHCl/乙酸乙酯攪拌反應(yīng),TLC板檢測反應(yīng),原料點消失時終止反應(yīng)。抽干母液,加入乙醚反復(fù)3次得到0.581g(98.6。/。)標題化合物(黃色固體)。M.p.93-95°C;[a]D25=-55.5(C=1.0,甲醇);ESI-MS(m/z):512.5[M+H]+。實施例391,2,3,4-四氫咔啉-3-?;?Glu(OBzl)-OBzl(6r)按照制備6q的操作,從0.671g(1.074mmol)N-Boc-l,2,3,4-四氫咔啉-3-?;?Glu(OBzl)-OBzl得到0.602g(99%)標題化合物(黃色固體)。Mp108-n0°C;[a]D25=-57.0(C=1.0,甲醇);ESI-MS(m/z):526.5[M+H]+。實施例40Boc-Ala-l,2,3,4-四氫咔啉-3-酰基-Ala-OBzl(7a)冰浴下用無水THF將0.776g(2.0mmo1)Boc-Ala-l,2,3,4-四氫咔啉羧酸溶解,加入0.284g(2.104mmol)N-羥基苯并三氮唑(HOBt),完全溶解后加入0.536g(2.60mmol)二環(huán)己基羰二亞胺(DCC).10分鐘后,往里加入無水THF與0.913g(2.60mmo1)Ala-OBzI并用N-甲基嗎啉調(diào)PH值8-9之間的溶液。反應(yīng)混合物攪拌,TLC板檢測(石油謎/丙酮,3:l,RfK).35)。原料點消失后濾出二環(huán)己基脲(DCU),濾液減壓濃縮,殘留物用40ml乙酸乙酯溶解。得到的溶液依次用飽和NaHC03,飽和NaCl、5%KHS04、飽和NaCl、飽和NaHC03、飽和NaCl各洗三次至中性,無水Na2S04干燥。過濾,濾液減壓濃縮至干,得到0.709gC64.7。/cO標題化合物(無色固體)。M.p.:113-115.80。C;[a]D25=-5.6(C=1.0,甲醇);ESI-MS(m/z):549.4[M+H]+。IR(KBr):3313,2978,2931,1739,1678,1647,1520,1452,1246,1163,1065,744,693.'HNMR(500MHz,DMSO-d6):5/ppm=10.806(s,1H),8.374(t,J=8.5Hz,1H),7.094-7.439(m,7H),7.05(t,J=7Hz,1H),6.9725(t,J=6.5Hz,1H),4.167-5.635(m,7H),3.372(q,J=15.5Hz,J=46.5Hz,1H),2.9285(m,J=6Hz,1H),1.405(s,9H),1.225-1.338(m,6H).13CNMR(DMSO-d6):5/ppm=172.58,172.43,171.10,156.22,155.50,136.34,130,17,128.79,128.35,128.07,126.93,121.26,118.90,111.43,105.03,79.00,78.63,66.22,48.63,33.81,28.62,24.92,23.41,17.15.實施例41Boc-Gly-l,2,3,4-四氫咔啉-3-?;?Gly-OBzl(7b)按照制備7a的操作,從0.590g(1.582mmol)Boc-Gly-l,2,3,4-四氫咔啉羧酸得到0.452g(54.95%)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,Rf=0.4);Mp114-116°C;[a]D25=49.9(01.0,甲醇);ESI-MS(m/z):521.6[M+H]+;543.6[M+Na]+.IR(KBr):3396,3302,2976,2931,1751:1685,1647,1521,1452,1390,1367,1161,744,690.!HNMR(300MHz,DMSO-d6):5/ppm=10.817(s,IH),8.4425(m,J=5.4Hz,J=5.7Hz1H),7.3895(d,J=7.5Hz,1H),7.258-7.377(m,6H),7.047(t,J=7.2Hz,1H),6.9655(t,J=6.9Hz,IH),4.329-5.02l(m,5H),3.739-4.164(m,4H),3.3935(m,J=2.7Hz,1H),2.9195(dd,J=5.7Hz,J=15.9Hz,1H),1.404(s,9H)."CNMR(DMSO隱d6):5/ppm=171.04,170.61,170.56,156.22,136.77,136.52,130.58,129.85,128.84,128.46,128.35,126.98,118.93,111.54,105.39,78.58,66.34,65.36,54.25,42.96,41.51,28.70,22.74.實施例42Boc-Pro-l,2,3,4-四氫咔啉-3-酰基-Pro-OBzl(7c)按照制備7a的操作,從0.174g(0.421mmo1)Boc-Pro-l,2,3,4-四氫咔啉羧酸得到O.llOg(43.5%)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,Rf=0.2);Mp100-103°C;[a]D25=-156.2(C=1.0,甲醇);ESI-MS(m/z):623.3[M+Na]+;523.4[M+Na-Boc]+。IR(KBr):3330,2938,2850,1739,1689,1647,1452,1409,1165,743,693.!HNMR(500MHz,CDC13-d6):5/ppm=7.140-7.560(m,7H),7.029-7.067(m,2H),4.489-5.410(m,7H),4J33(m,1H),4.176(q,風(fēng)5Hz,J=11.5Hz,1H),4.032(q,J=3.5Hz,J=6Hz,1H),3.9125(q,J=6.5Hz,J=10.5Hz,1H),3.430(m,J=16Hz,1H),2.827(dd,J=6Hz,J=5.5Hz,IH),1.472(s,9H),1.231-1.360(m,3H),0,979-1.223(m.3H),0,887-0.90(d,J=6.5Hz,2H).13CNMR(DMSO-d6):S/ppm=171.30,170.44,169.91,156.82,137.78,136.52,135.32,128.54,128.19,127.96,126.91,121.97,119.60,110.84,106.20,80.03,75.93,74.29,71.47,59.10,56.89,42.59,33.97,30.87,28.79,28.31,24.94,23.02,22.15.實施例43Boc-Gln-l,2,3,4-四氫咔啉-3-酰基-Gln-OBzl(7d)按照制備7a的操作,從0.707g(1.60mmol)Boc-Gln-l,2,3,4-四氫咔啉羧酸得到0.325g(30.68%)標題化合物(無色固體)。TLC(氯仿/甲醇,10:1,Rf=0.2);Mp114-117°C;[a]D25=16.7(01.0,甲醇);ESI-MS(m/z):663.3[M+H]+.IR(KBr):3334,2940,2856,1750,1662,1627,1520,1450,1166,743,697.'HNMR(300MHz,CDCl3-d6):5/ppm=7.207-7.487(m,7H),7.037-7.085(m,2H),4.493(m,1H),4駕-5.120(m,4H),5.711-5.811(m,2H),3.5825(m,J=5.4Hz,1H),3.087(dd,J=5.5Hz,J=15.5Hz,1H),2.190-2.400(m,8H),1.4195(s,9H).13CNMR(DMSO-d6):5/ppm=174.56,173.97,172.83,171.87,170.34,156.72,136.77,136.56,130.19,128.80,128.36,128.12,127.96,126.84,121.26,118.90,118.03,111.49,105.00,79.64,66.25,65.37,52.74,51.43,31.68,31.04,29.44,28.67,27.62,26.79,23.04.實施例44Boc-Leu-l,2,3,4-四氫咔啉-3-?;?Leu-OBzl(7e)按照制備7a的操作,從0.387g(0.902mmo1)Boc-Leu-l,2,3,4-四氫昨啉羧酸得到0.252g(44.2%)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,Rf=0.3);Mp81.9-83.2°C;[a]D25=27.4(C=1.0,甲醇);ESI-MS(m/z):633.6[M+H]+.IR(KBr):3313,2956,2931,1739,1680,1643,1521:1435,1165,744,697.'HNMR(500MHz,DMSO-d6):5/ppm=7.233-7.710(m,7H),7.084-7.1475(m,2H),4.436-4.895(m,2H),4"0-5.230(m,4H),5.255墨5.524(m,1H),3.505(m,J=15Hz,J=15.3Hz,1H),2.8558(dd,J=4.5Hz,J=5.1Hz,1H),2.191-2.193(m,6H),L444(s,9H),0.668-1.276(m,12H).I3CNMR(DMSO-d6):5/ppm=173.30,172.54,169.20,168.26,156.83,136.31,135.56,128.64,128.57,128.32,127.86,121.卯,119.58,110.83,106.24,80.52,66.81,66.65,55.60,41.25,40.50,30.88,28.44,23.33,22.83,21.91,21.38.實施例45Boc-Phe-l,2,3,4-四氫咔啉-3-?;?Phe-OBzl(7f)按照制備7a的操作,從0.744g(1.61mmo1)Boc-Phe-l,2,3,4-四氫咔啉羧酸得到0.520g(46.14%)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,Rf=0.3);Mp94-97°C;[a]D25=-10.9(C=l.0,甲醇);ESI-MS(m/z):701.7[M+H]+.IR(KBr):3292,2952,2890,1735,1685,1642,1521,1454,1166,1030,742,697.'HNMR(500MHz,CDCl3-d6):S/卯n^7.171-7.323(m,17H),7.017-7.091(m,2H),4.652-4.754(m,2H),4.759-4.986(m,H),4.990-5.107(m,1H),5.129-5.202(m,2H),5.134-5.410(m,1H),2.894-3.502(m,6H),L4795(s,9H).13CNMR(DMSO-d6):5/ppm=172.06,171.34,168.98,156.16,154.63,136.89,136.26,135.81,129.63,128.96,128.66,127.92,126.96,126.65,122.40,122.08,119.61,110.64,106.24,80.27,67.45,66.93,53.48,52.44,38.77,37.59,36.81,28.56,21.13.實施例46Boc-Ile-l,2,3,4-四氫咔啉-3-酰基-Ile-OBzl(7g)按照制備7a的操作,從0.551g(1.284mmo1)Boc-Ile-l,2,3,4-四氫咔啉羧酸得到0.541g(66.65%)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,RfK).3);Mp96-98°C;[a]D25=-1.0(C=1.0,甲醇);ESI-MS(m/z):633.6[M+H]+.IR(KBr):3315,2964,2856,1735,1680,1624,1521,1454,1431,1165,1020,743,699.'HNMR(500MHz,DMSO-d6):5/ppm=7.488(dd,J=8Hz,1H),7.258陽7.467(m,6H),7.151(m,1H),7.1025(t,J=7.5Hz,1H),4.436-5.239(m,7H),3.4925(m,J-9.3Hz,lH),2.958(dd,J=5.7Hz,J=15HZ,lH),2.201(s,lH),1.676(s,lH),1.4395(s,9H),1.067-1.399(m,4H),0.756-0.973(m,12H)."CNMR(DMSO-d6):S/ppm=173.29,172.85,169.07,156.22,155.45,136.41,135.29,128.59,128.54,128.39,126.82,125.06,119.62,111.47,109.87,80.24,67.19,66.96,55.90,52.19,38.78,37.92,36.53,28.33,25.42,24.85,23.41,22.82,22.42,16.01,15.89.實施例47Boc-Met-l,2,3,4-四氫昨啉-3-酰基-Met-OBzl(7h)按照制備7a的操作,從0.332g(0.743mmo1)Boc-Met-l,2,3,4-四氫昨啉羧酸得到0.090g(18.15%)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,Rf=0.25);Mp73-75°C;[a]D25=-18.2(C=1.0,甲醇);ESI-MS(m/z):691.4[M+Na]+;591.1[M+Na-Boc]+.IR(KBr):3315,2985,2917,1735,1691,1648,1526,1441,1167,1042,747,693.'HNMR(500MHz,CDCl3-d6):S/ppm=7.487(dd,J=7.5Hz,J=8Hz,1H),7.251-3卯(m,6H),7.054(t,J=7.5Hz,IH),6.9815(t,J=7.5Hz,1H),5.451(m,IH),5.316(dd,J=7Hz,J=5.5Hz,IH),5.006-5.164(m,3H),4.8515(m,IH),4.5725(m,IH),3.3945(dd,J=9.3Hz,J=9.5Hz,IH),2.976(dd,J=4.5Hz,J=5.0Hz,IH),2.661(t,J=7Hz,IH),2.5815(t,J=6.5Hz,IH),2.413(m,IH),2.2775(t,J=7Hz,IH),2.136-2.200(m,4H),1.997-2.lOO(m,2H),1.889-1.967(m,4H),1.3775(s,9H).13CNMR(DMSO-d6):S/ppm=172.49,171.42,171.33,156.56,136.58,136.43,135.57,128.65,128.60,128.36,127.86,122.73,119.68,110.96,106.37,80.77,67.50,66.99,55,72,52,29,50.24,31.70,30.88,29.77,28.33,22.64,15.63,15.26.實施例48Boc-Tyr-l,2,3,4-四氫味啉-3-?;?Tyr-OBzl(7i)按照制備7a的操作,從0.586g(1.220mmol)Boc-Tyr-l,2,3,4-四氫咔啉羧酸得到0.247g(27.66%)標題化合物(無色固體)。TLC(石油醚/丙酮,2:1,Rf=0.25);Mp135-139°C;[a]D25=l.l(C=1.0,甲醇);ESI-MS(m/z):733.4[M+H]+,755.7[M+Na]+.IR(KBr):3398,2970,2855,1730,1690,1640,1520,1448,1228,1168,1020,744,699.'HNMR(500MHz,CDCl3-d6):S/ppm=7.310陽7.790(m,7H),6.620-7.206(m,10H),5.955(m,IH),5.586(m,IH),4.955-5.360(m,3H),4.410-4.80(m,2H),3.215(d,J=15Hz,IH),2.785-3.105(m,5H),1.4045(s,9H).13CNMR(DMSO-d6):S/ppm=173.39,171.69,168.94,155.88,155.35,136.11,135.60,130.57,128.64,128.55,128.08,127.34,126.51,125.25,121.43,118.97,115.77,110.90,105.94,80.81,67.09,56.20,54.23,52.52,41.37,38.75,37.84,28.42,22.64.實施例49Boc-Trp-l,2,3,4-四氫咔啉-3-?;?Trp-OBzl(7j)按照制備7a的操作,從0.461g(0.918mmol)Boc-Trp-l,2,3,4-四氫咔啉羧酸得到0.535g(74.9%)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,Rf=0.25);Mp128-130°C;[a]D25=25.2(C=19I.0,甲醇);ESI-MS(m/z):801.9[M+Na]+;701.5[M+Na-Boc]+.IR(KBr):3404,3323,2956,2856,1735,1647,1624,1496,1456,1234,1163,1010,767,693.'HNMR(500MHz,DMSO-d6):S/ppm=7.599(dd,J=7.5Hz,J=5.4Hz,IH),6.877-7.510(m,18H),5.1075(d,J=17.1Hz,IH),4.360-5.098(m,6H),3.590(m,1H),2.950-3.395(m,4H),2.892(m,IH),L3385(s,9H).13CNMR(DMSO-d6):S/ppm=172.78,171.88,169.87,156.46,155.35,136.61,136.45,130.22,129.61,128.72,128.08,127.89,127.57,124.54,123.97,121.47,118.95,111.34,110.71,109.86,79.32,78.59,66.28,55.22,54.53,41.82,38.58,28.69,21.69.實施例50Boc-Val-l,2,3,4-四氫咔啉-3-?;?Val-OBzl(7k)按照制備7a的操作,從0.550g(1.330mmol)Boc-Val-l,2,3,4-四氫咔啉羧酸得到0.40g(43.8%)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,Rf=0.3);Mp99.6-10rC;[a]D25=-4.7(01.0,甲醇);ESI-MS(m/z):627.5[M+Na]+;527.5[M+Na-Boc]+.IR(KBr):3327,2966,2933,1732,1678,1624,1500,1456,1367,1236,1166,1020,740,699.'HNMR(500MHz,DMSO-d6):5/ppm=7.033-7.510(m,7H),7.103(t,J=8.5Hz,IH),6.9645(t,J=7.5Hz,IH),5.510(m,IH),5.215(m,IH),4.876-5.098(m,3H),4.420(m,lH),4.151(m,IH),3.395(m,IH),2.987(m,IH),2.212-2.052(m,2H),L366(s,9H),0.793-0.943(m,12H).13CNMR(DMSO-d6):S/ppm=173,19,172.81,170.58,156.46,156.14,136.69,130.54,128.82,128.48,128.39,126.99,121.30,118.91,1II.42,104.74,78.91,66.29,58.51,57.64,56.65,39.18,30.57,30.15,28.63,22.99,19,77,18.90.實施例51Boc-Lys(Boc)-l,2,3,4-四氫咔啉-3-?;?Lys(Z)-OBzl(71)按照制備7a的操作,從0.493g(0.906mmol)Boc-Lys(Boc)-l,2,3,4-四氫咔啉羧酸得到0.408g(50.24%)標題化合物(無色固體)。TLC(石油謎/丙酮,2:1,Rf=0.3);Mp82.6-84.6°C;[a]D25=l.3(01.0,甲醇);ESI-MS(m/z):898.0[M+H]+.IR(KBr):3313,2974,2935,1735,1678,1643,1517,1456,1365,1248,1168,1040,742,697.'HNMR(500MHz,DMSO-d6):5/ppm=7.210-7.580(m,12H),7.010-7.198(m,2H),5.048-5.298(m,6H),4.899(m,IH),4.398-4.750(m,2H),3.502(m,IH),3.026-3.310(m,4H),2.958(m,IH),1.650-1.910(m,4H),1.522-1.610(m,4H),1.448(s,18H),0.8-1.391(m,4H).13CNMR(DMSO-d6):5/ppm=172.92,171,91,169,94,156.57,156.21,155.77,136.64,135.16,128.64,128.56,128.07,123.01,121,78,119.75,118.21,110.90,80.35,67.36,66.84,66.32,55.83,52.42,42.22,40.89,31.86,30.89,29.88,28.40,22.59,21.85.實施例52Boc-Arg(N02)-l,2,3,4-四氫咔啉-3-酰基-Arg(N02)-OBzl(7m)按照制備7a的操作,從U4g(2.220mmol)Boc-Arg(NO2)-l,2,3,4-四氫咔啉羧酸得到0.770g2(42.9%)標題化合物(黃色固體)。TLC(氯仿/甲醇,10:1,Rf=0.2);Mpl31-133.2。C;[a]D25=4.2(C=1.0,甲醇);ESI-MS(m/z):809.3[M+H]+.IR(KBr):3304,2939,2856,1735,1624,1533,1445,1259,1161,740,693.麗MR(300MHz,DMSO-d6):S/ppm=7.137-7.405(m,7H),7.0425(t,J=7.8Hz,1H),6.9635(m,1H),4.610-5.810(m,5H),4.12陽4.528(m,2H),3.3975(q,J=7.2Hz,J=l4.1Hz,1H),3.03-3.270(m,4H),2.932(m,1H),1.374-1.980(m,8H),1.3675(s,9H).13CNMR(DMSO-d6):5/ppm=172.93,172.42,170.24,159.8,156.61,155.94,136.74,130.22,128.81,128.39,127.46,121.27,118.92,118.01,111.45,105.06,79.17,66.33,65.36,52.86,51.42,50.82,29.05,28.62,25.30,23.81,21.20.實施例53Boc-Thr(Bzl)-l,2,3,4-四氫咔啉-3-?;?Thr(Bzl)-OBzl(7n)按照制備7a的操作,從0.777g(1.53mmol)Boc-Thr(Bzl)-l,2,3,4-四氫咔啉羧酸得到0.416g(34.5%)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,Rf=0.2);Mp184-186°C;[a]D25=6.4(C=1.0,甲醇);ESI-MS(m/z):8I1.8[M+Na]+;711.6[M+Na-Boc]+.IR(KBr):3305,2974,2856,1735,1678,1647,1525,1452,1286,1163,1104,736,697,'H雨R(500MHz,CDCl3-d6):S/ppm=7.160-7.387(m,17H),7.045隱7.092(m,2H),4.767-5.128(m,9H),4.466-4,667(m,J=4.5Hz,2H),3.805-4.210(m,2H),3.310(m,lH),2.6335(m,J=15.5Hz,1H),l,541(s,9H),1.447-1.462(m,6H).13CNMR(DMSO-d6):5/ppm=172.%,171.73,169.91,156.94,153.79,137.77,136.65,135,31,129.33,128.81,128.73,128.20,127.96,126.71,123.96,121.83,119.46,110.99,104.29,79.99,79.64,74.52,71.49,67.09,66.89,59.93,33.89,28.80,24.99,23.61,22.63,16.12.實施例54Boc-Ser(Bzl)-l,2,3,4-四氫咔啉-3-?;?Ser(Bzl)-OBzl(7o)按照制備7a的操作,從0.951g(1.93mmol)Boc-Ser(Bzl)-l,2,3,4-四氫咔啉羧酸得到0.733g(49.97%)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,Rf=0.3);Mpl05-108°C;[a]D25=6.5(C=1.0,甲醇);ESI-MS(m/z):784.6[M+Na]+;684.3[M+Na-Boc]+.IR(KBr):3330,2985,2856,1736,1685,1620,1520,1452,1165,1110,744,693.^NMR(500MHz,CDCl3-d6):5/ppm=7.236-7.528(m,17H),7.086-7.lll(m,2H),5.5005(dd,J=8Hz,J=6Hz,1H),4.899-5.327(m,4H),4.54-4.890(m,2H),4.265陽4.50(m,4H),3.587-3.930(m,4H),3.433(m,1H),2.828(dd,J=4.5Hz,J=5Hz,IH),1.430(s,9H).3CNMR(DMSO-d6):5/ppm=171.72,170.17,169.78,155.71,154.68,137.53,136.47,135.33,129.78,128.52,128.33,128.13,128.00,127.91,127.83,127.65,122.70,121.86,119.73,111.47,107.62,80.35,73.63,73.08,70.95,69.72,69.25,67.88,53.04,52.83,38.98,28.79,22.59.實施例55Boc-Cys(CH2-C6H4-OCH3)-l,2,3,4-四氫咔啉-3-?;?Cys(But)-OBzl(7p)按照制備7a的操作,從1.426g(2.65mmol)Boc-Cys(CH2-C6H4-OCH3)-l,2,3,4-四氫咔啉羧酸得到0.687gC32.9。/。)標題化合物(無色固體)。TLC(石油醚/丙酮,3:1,Rf=0.3);Mp72.3-74°C;[a]D25=_14.7(C=1.0,甲醇);ESI-MS(m/z):789.4[M+H]+;811.6[M+Na]+.IR(KBr):3330,2985,2857,1735,1685,1640,1526,1450,1256,1165,1040,743,693.'HNMR(500MHz,DMSO-d6):S/ppm=7.317-7.450(m,7H),7.098-7.288(m,5H),6.992(m,IH),5.149(d,J=4Hz,2H),4.854(m,IH),4.752(m,IH),4.65l(m,IH),4.41l-4.448(m,2H),3.905(s,3H),3.7735(d,J=4.5Hz,2H),3.503(m,lH),2.935-3.215(m,4H),2.893(m,1H),L474(s,9H),U945(m,9H).13CNMR(DMSO-d6):5/ppm=172.23,171.53,170.03,168.78,158.42,154.89,136.56,130.73,130.15,128.55,128.12,127.22,126.70,122.10,121.92,119.64,114.43,110.89,107.25,80.14,67.37,67.15,55.81,55.29,55.23,50.49,42.66,36.25,34.54,33.96,28.33,24.94,21.41.實施例56Boc-Asp(OBzl)-l,2,3,4-四氫咔啉-3-酰基-Asp(OBzl)-OBzL(7q)按照制備7a的操作,從0.588§(1.07411111101)1,2,3,4-四氫咔啉-3-酰基-八5(0821)-OBzl得到0.385g(43.93%)標題化合物(無色固體)。TLC(石油醚/丙酮,2:1,Rf=0.3);Mp62-65°C;[a]D25=4.5(C=1.0,甲醇);ESI-MS(m/z):817.5[M+H]+.IR(KBr):3331,2986,2855,1735,1685,1620,1521,1452,1160,1010,744,697.'HNMR(500MHz,DMSO-d6):S/ppm=7.115-7.450(m,17H),7.106(m,IH),7.0895(m,J=8.5Hz,IH),5.610(m,IH),5.007-5.410(m,8H),4.820(d,J=12.5Hz,IH),4.630(m,IH),3.725(m,IH),2.842-3.305(m,4H),2.645(m,IH),1.401(s,9H).13CNMR(DMSO-d6):5/ppm=172.12,171.86,170.71,170.19,169.96,154.89,136.52,135.47,129.55,128.78,128.52,128.30,127.98,122.72,122.10,119.65,111.46,107.54,80.72,67.67,66.24,49.44,48.96,41.97,37.96,36.44,28.24,22.41.實施例57Boc-Glu(OBzl)-l,2,3,4-四氫咔啉-3-?;?Glu(OBzl)-OBzL(7r)按照制備7a的操作,從0.465g(1.38mmol)l,2,3,4-四氫咔啉-3-?;?Glu(OBzl)-OBzl得到0.323g(36.13%)標題化合物(無色固體)。TLC(石油醚/丙酮,2:1,Rf=0.3);Mp156-158°C;[a]D25=14.9(C=1.0,甲醇);ESI-MS(m/z):845.2[M+H]+.IR(KBr):3320,3200,1724,1680,1630,1520,1452,1230,1168,744,693.'HNMR(500MHz,DMSO-d6):S/ppm=7.230-7.502(m,17H),7.092-7.1165(m,2H),5.215-5.610(m,2H),5.110-5.205(m,2H),4.995-5.055(m,5H),5.714(m,IH),5.510(m,IH),3.510(m,IH),2.899(m,IH),2,087-2.634(m,8H),1.4105(m,9H).13CNMR(DMSO-d6):S/ppm=171.72,170.17,169.78,155.71,154.68,137.53,136.47,135.33,129.78,128.52,128.33,128.13,128.00,127.91,127.83,127.65,122.70,121.86,119.73,111.47,107.62,80.35,73.63,73.08,70.95,69.72,69.25,67.88,53.04,52.83,38.98,28.99,22.59.實施例58HCl'NH2Ala-l,2,3,4-四氫咔啉-3-酰基-Ala-OBzl(8a)將0.10gBoc-Ala-KLSS-Ala-OBzl(0.18mmol)溶于2ml乙酸乙酯中,再往得到的溶液中加1ml的氯化氫-乙酸乙酯溶液。TLC(石油謎/丙酮,3:1,Rf^.3)檢測,原料點消失停止反應(yīng),抽干溶劑后,加入10ml乙醚抽干,重復(fù)3次后加入10ml乙醚研磨過濾得0.085g(96.14。/。標題化合物(黃色固體)。M.p.:146-148。C;[ot]D25=1.4(C=1.0,甲醇);ESI-MS(m/z):449.5[M+H]+.'HNMR(500MHz,DMSO-d6):5/ppm=10.99(m,1H),8.75(m,1H),8.40(m,2H),7.75-7.50(m,7H),7.05(m,IH),6.95(m,IH),5.65(m,J=5Hz,IH),5.15(m,IH),4.85-5.05(m,2H),4.65(m,1H),4.30(m,IH),3.70(m,IH),3.35(m,J=10Hz,IH),3.05(m,J=5Hz,IH),1.45陽1.50(m,3H),1.30-1.38(m,3H).13CNMR(DMSO-d6):5/ppm=172.48,170.75,169.76,136.79,136.30,130.18,129.67,128.78,128.11,126.88,121.41,119.15,118.01,111.62,104.48,67.42,66.29,50.92,47.98,33.80,28.64,21.54,17.42.實施例59HCl'NH2Gly-l,2,3,4-四氫昨啉-3-酰基-Gly-OBzl(8b)按照制備8a的操作,從0.089g(0.17mmol)Boc-Gly-l,2,3,4-四氫咔啉-3-?;?Gly-OBzl得到0.077g(97.8%)標題化合物(黃色固體)。Mp148-151°C;[a]D25=52.8(C=l.0,甲醇);ESI-MS(m/z):421.4[M+H]+.'HNMR(500MHz,DMSO-d6):S/ppm=11.120(s,1H),8.75(m,J=9.5Hz,IH),8.35(s,2H),7,21-7.51(m,7H),7.05(t,J=11.5Hz,IH),6.95(t,J=15.5Hz,IH),5.68(m,J=9.5Hz,IH),5.05(m,2H),4.85(s,IH),4.05-4.51(m,2H),3.75-3.98(m,3H),3.45(m,J=11.5Hz,1H),2.98(m,J=10.5Hz,IH).13CNMR(DMSO-d6):5/ppm=172.45,170.28,167.76,136.77,136.29,129.87,129.36,128.66,128.35,126.76,121.45,118.97,118.04,111.55,105.14,66.38,54.46,51.38,23.27,21,56.實施例60HCl'NH2Pro-l,2,3,4-四氫昨啉-3-?;?Pro-OBzl(8c)按照制備8a的操作,從0.13g(0.22mmol)Boc-Pro-l,2,3,4-四氫咔啉-3-?;?Pro-OBzl得到0.110g(94.63。/。)標題化合物(黃色固體)。Mp113-115°C;[a]D25=-61.4(C=1.0,甲醇);ESI-MS(m/z):501.4[M+H]+.'HNMR(500MHz,DMSO-d6):S/ppm=10.45(m,IH),8.56(s,IH),7.21-7.46(m,7H),7.05(t,IH),6.98(t,J=10Hz,IH),5.55(m,1H),5.15(tn,IH),4.15-4.95(m,2H),4.18-4.52(m,2H),4.05(m,IH),3.60-3.85(m,2H),2.89-3.35(m,4H),2.25(m,IH),1.5-2.05(m,7H).13CNMR(DMSO-d6):5/ppm=171.81,169.77,169.10,136.74,136.25,129.53,129.34,128.97,128.15,126.72,121.76,118.98,118.01,111.64,104.05,67.73,66.20,59.15,58.94,47.97,42.18,33.80,29.58,28.21,25.29,24.91,21.98.實施例61HCl'NH2Gln-l,2,3,4-四氫咔啉-3-?;?Gln-OBzl(8d)-Gln-l,2,3,4-四氫咔啉-3-?;?Gln-OBzl得到0.072g(98.92。/。)標題化合物(黃色固體)。Mp147-149°C;[a]D25=14.3(C=1.0,甲醇);ESI-MS(m/z):563.4[M+H]+.'HNMR(500MHz,DMSO-d6):S/ppm=10.99(d,J=10Hz,IH),8.75(m,J=10Hz,1H),8.45-8.55(m,4H),7.15-7.52(m,7H),7.05(t,J=10Hz,IH),6.89(t,J=5Hz,IH),5.65(m,J=5Hz,IH),5.15(m,J=15Hz,IH),4.75-4.92(m,2H),4.45-4.65(m,2H),4.20(m,IH),3.38(m,J=10Hz,J=5Hz,IH),3.05(m,J=5Hz,IH),2.05國2.30(m,8H).13CNMR(DMSO-d6):S/ppm=174.13,172.40,171.78,170.96,169.97,136.80,136.31,130.10,129.60,128.79,128.15,126.87,121.40,118.95,117.92,111.92,104.71,66.31,54.20,52.71,50.09,31.88,31.65,30.43,30.04,26.69,21.54.實施例62HC1.NH2Leu-l,2,3,4-四氫昨啉-3-?;?Leu-OBzl(8e)按照制備8a的操作,從0.155g(0.245mmol)Boc-Leu-l,2,3,4-四氫咔啉-3-?;?Leu-OBzl得到0.131g(93.95。/。)標題化合物(黃色固體)。Mp101-103°C;[a]D25=28.9(C=1.0,甲醇);ESI-MS(m/z):533.5[M+H]+.'服MR(500MHz,DMSO-d6):5/ppm=11.05(m,1H),8.30-8.89(m,3H),7.16-7.37(m,7H),6.89-7.09(m,J=5Hz,2H),5.65(m,J=5Hz,IH),4.95-5.15(m,2H),4.85(m,J=10Hz,IH),4.65(m,IH),4.33(m,IH),4.05(m,IH),3.46(m,IH),2.95(m,IH),1.25-1.71(m,6H),0.57-0.99(m,12H).13CNMR(DMSO-d6):S/ppm-172.72,172.38,170.60,136.80,136.20,129.88,128.95,128.77,128.30,126.64,121.30,118.97,117.97,111.40,104.67,66.47,51.65,51.06,50.80,49.45,42.30,33.80,28.64,25.81,24.90,24.64,22,03,21.53.實施例63HCl.NH2Phe-l,2,3,4-四氫咔啉-3-?;?Phe-OBzl(8f)按照制備8a的操作,從0.12g(0.17mmol)Boc-Phe-l,2,3,4-四氫咔啉-3-?;?Phe-OBzl得到0.108g(99.44。/o)標題化合物(黃色固體)。Mp122-124°C;[a]D25=10.5(C=1.0,甲醇);ESI-MS(m/z):601.4[M+H]+.'HNMR(500MHz,DMSO-d6):S/ppm=11.01(m,IH),8.25-8.8l(m,3H),7.16畫7.44(m,17H),6.88-7.10(m,2H),5.67(m,IH),5.21(m,J=5Hz,IH),5.05(m,J=5Hz,IH),4.89-5.01(m,2H),4.68(m,J=15Hz,IH),3.81(m,IH),2.89-3.36(m,6H).13CNMR(DMSO-d6):5/ppm=172.70,171.37,169.90,137.75,136.20,136.12,130.36,129.89,129.70,129.06,128.89,128.80,129.68,128.21,127.78,127.00,126.86,126.76,121,30,118.88,117.94,111.45,104.35,66.62,66.52,65.36,54.70,54.37,36.74,36.61,21.53.實施例64HCl.NH2-Ile-l,2,3,4-四氫咔啉-3-?;?Ile-OBzl(8g)按照制備8a的操作,從0.12g(0.19mmol)Boc-Ile-l,2,3,4-四氫咔啉-3-?;?IIe-OBzl得到0.105g(97.28。/c))標題化合物(黃色固體)。Mp94-96°C;[a]D25--0.8(C=1.0,甲醇);ESI-MS(m/z):533.5[M+H]+.'H雨R(500MHz,DMSO-d6):5/ppm=11.00(m,IH),8.70(m,IH),8.20-8.45(m,2H),7.15-7.54(m,7H),6.89-7.12(m,J-10Hz,2H),5.87(m,J=5Hz,1H),5.01陽5.29(m,J=10Hz,2H),4.81-5.00(m,J=15Hz,2H),4.15-4.4(m,J=5Hz,2H),2.89-3.45(m,J=15Hz,3H),2.05(m1H),1.25-1.40(m,4H),0.75陽0.98(m,12H).13CNMR(DMSO-d6):S/ppm=172.36,171.42,169.76,136.76,136.18,129.97,128.95,128.90,128.37,126.70,121.40,119.02,117.83,111.61,104.24,66.43,57.11,55.00,50.76,36.90,36.63,36.01,28.63,25.42,25.03,23.73,21.25,15.59,11.75.實施例65HCl.NH2-Met-l,2,3,4-四氫咔啉-3-?;?Met-OBzl(8h)按照制備8a的操作,從0.10g(0.15mmol)Boc-Met-l,2,3,4-四氫咔啉-3-酰基-Met-OBzl得到0.089g(98.91。/。)標題化合物(黃色固體)。Mp103-105°C;[a]D25=-7.5(C=1.0,甲醇);ESI-MS(m/z):569.4[M+H]+.'HNMR(500MHz,DMSO-d6):S/ppm=11.00(m,1H),8.40-8.99(m,3H),7.16-7.44(m,7H),6.97-7.05(m,J=5Hz,1H),7.08-7.11(m,IH),5.47(m,J=10Hz,1H),5.17(m,1H),4.82-5.05(m,2H),4.63(m,J=5Hz,IH),4.38(m,1H),3.58(m,1H),3.35(m,1H),3.05(m,J=5Hz,1H),2.58-2.80(m,2H),2.26-2.48(m,2H),2.11-2.20(m,2H),2.03-2.09(m,2H),1.84-2.02(m,6H).13CNMR(DMSO-d6):5/ppm=171.61,171.15,169.92,136.80,136.22,130.10,129.54,128.88,128.21,126.85,121.46,119.04,118.04,111.62,104.48,67.66,66.40,54.33,51.24,33.80,30.84,30.35,30.13,29.92,23.92,14.99.實施例66HCl.NH2-Tyr-l,2,3,4-四氫咔啉-3-?;?Tyr-OBzl(8i)按照制備8a的操作,從0.15g(0.205mmol)Boc-Tyr-l,2,3,4-四氫咔啉-3-?;?Tyr-OBzl得到0.134g(97.67%)標題化合物(黃色固體)。Mp157-159°C;[a]D25=8.1(C=1.0,甲醇);ESI-MS(m/z):633.5[M+H]+,'H雨R(500MHz,DMSO-d6):S/ppm=10,96(m,1H),9.45(m,2H),8.25-8.65(m,3H),7.25-7.45(m,5H),7.11-7.25(m,3H),6.89-7.10(m,5H),6.65-6.78(m,4H),5.69(m,J=10Hz,1H),5.05(m,1H),4.45-4.95(m,3H),4.21-4.35(m,2H),3.30(m,J-15Hz,1H),2.89-3.15(m,5H).13CNMR(DMSO-d6):S/ppm=172.40,171.48,169.85,157.30,156.56,136.74,136.53,131.24,130.48,129.83,128.76,127.54,126.76,124.67,121.42,119.00,115.92,115.70,111.61,104.41,66.39,60.21,55.01,54.65,42.04,36.18,24.09,21.53.實施例67HCl.NH2-Trp-l,2,3,4-四氫咔啉-3-?;?Trp-OBZl(8j)按照制備8a的操作,從0.07g(0.0899mmol)Boc-Trp-l,2,3,4-四氫咔啉-3-?;?Trp-OBzl得到0.064g(98.77。/。)標題化合物(褐色固體)。Mp160-162°C;[a]D25=45.0(C=1.0,甲醇);ESI-MS(m/z):679.5[M+H]+.!H菌R(500MHz,DMSO-d6):5/ppm=10.89-11.15(m,3H),8.52-8,79(m,2H),8.25(s,lH),7.15-7.57(m,10H),6.89-7.11(m,9H),5.12(m,1H),4.99(m,1H),4.67-4.89(m,2H),4.25-4.62(m,2H),3.40(m,1H),2.89-3.35(m,6H).13CNMR(DMSO-d6):S/ppm=172.44,171.43,169.97,136.80,136.74,136.10,130.02,129.80,128.85,128.11,127.53,126.73,121.57,119.02,118.34,112.05,111.45,109.60,104.39,66.36,60.22,54.49,50.91,41.91,27.65,26.22,21.23.實施例68HCl'NH2-Val-l,2,3,4-四氫咔啉-3-?;?Val-OBzl(8k)按照制備8a的操作,從0.15g(0.25mmol)Boc-Val-l,2,3,4-四氫咔啉-3-酰基-Val-OBzl得到0.030g(96.96。/。)標題化合物(黃色固體)。Mp131-133°C;[a]D25=-1.7(C=1.0,甲醇);ESI-MS(m/z):505.5[M+H]+.)麗MR(500固z,DMSO-d6):S/ppm=lL02(m,1H),8.30-8.44(m,3H),7.15-7.35(m,7H),6.89-7.08(m,J=5Hz,2H),5.68(m,J=10Hz,IH),5.14(m,J=5Hz.J=10Hz,1H),4.84-5.01(m,3H),4.61(m,IH),4.15(m,J=5Hz,IH),3.85(m,IH),3.16-3.33(m,J=15Hz,IH),3.05-3.15(m,J=10Hz,IH),2.15(m,IH),0.81-1.19(m,12H).13CNMR(DMSO-d6):S/ppm=171.63,171.40,169.70,136.76,136.21,130.45,129.96,128.79,128.47,126.85,121.39,119.02,117.91,111.63,104.24,66.45,66.32,58.03,50.75,30,58,30.17,29.88,24.42,19.05,17.35.實施例69HCl.NH2-Lys-l,2,3,4-四氫咔啉-3-酰基-Lys(Z)-OBzl(81)按照制備8a的操作,從0.1(^(0.110111101)8001^(80(:)-1,2,3,4-四氫咔啉-3-酰基-Lys(Z)-OBzl得到0.084g(97.86。/。)標題化合物(黃色固體)。Mp118-120°C;[a]D25=7.9(C=1.0,甲醇);ESI掘(m/z):697,6[M+H]+.)H麗R(500MHz,DMSO-d6):S/ppm=11.0485(m,IH),8.35-8.75(m,3H),8.05-8.25(m,3H),7.15-7.51(m,12H),7.05(t,J=12Hz,IH),6.98(t,J=12.5Hz,IH),5.56(m,J=8.3Hz,IH),5.15(m,IH),5.0(s,2H),4.73-4.95(m,2H),4.51(m,IH),4.15(m,IH),3.35(m,IH),2.72-3.15(m,6H),1.55-1.85(m,6H),U5隱1.45(m,6H).13CNMR(DMSO-d6):5/ppm=172.357,171.235,170.020,156.551,137.767,136.244,130.243,129.722,128.937,128.147,126.668,121.394,118,967,117.869,111.584,104.334,66.389,65.593,53.883,52.907,51.036,50.616,42.213,38.699,38.373,30,909,30.597,29.422,26.796,23.184,21.159.實施例70HCl'NH2-Arg(N02)-l,2,3,4-四氫咔啉-3-?;?Arg(N02)-OBzl(8m)按照制備8a的操作,從0.12g(0.148mmol)Boc-Arg(NO2)-l,2,3,4-四氫咔啉-3-酰基-Arg(NO2)-OBzl得到0.110g(99.48%)標題化合物(黃色固體)。Mp163-165°C;[a]D25=5.4(C=1.0,甲醇);ESI-MS(m/z):709.5[M+H]+.'HNMR(500MHz,DMSO-d6):5/ppm=10.93(m,IH),7.89-8.65(m,7H),7.25-7.51(m,7H),7.05(t,J=5Hz,IH),6.89(t,J=10Hz,J=5HZ,IH),5.53-5.83(m,2H),4.85-5.25(m,3H),4.35(m,lH),3.05-3.45(m,7H),1.92(s,2H),1.45-1.85(m,8H).13CNMR(DMSO-d6):5/ppm=172.36,171.73,170.13,159.79,136.76,136.19,130.13,129.67,128.18,127.55,126.67,121.30,118.96,118.02,111.60,104.43,66.38,60.19,54.05,52.63,33.74,28.66,27.49,25.26,24.29,21.51.實施例71HCl'NH2-Thr(Bzl)-l,2,3,4-四氫咔啉-3-?;?Thr(Bzl)-OBzl(8n)按照制備8a的操作,從0.158(0.1911111101)8001^(821)-1,2,3,4-四氫咔啉-3-?;?1^(821)-OBzl得到0.130g(94.26%)標題化合物(黃色固體)。Mp98-100°C;[a]D25=-7.1(C=1.0,甲醇);ESI-MS(m/z):689.6[M+H]+.i麗MR(500MHz,DMSO-d6):5/ppm=11.00(m,1H),8.78(m,1H):8.23-8.56(m,2H),7.15隱7.409(m,17H),6.89-7.11(m,J=13Hz,IH),5.68(m,J=12Hz,IH),4.88-5.25(m,3H),4.21-4.80(m,8H),4.15(m,J=5Hz,IH),3.35(m,J=12.5Hz,IH),3.05(m,J=13Hz,IH),1.05-1.45(m,6H).13CNMR(DMSO-d6):S/ppm=171.83,170.30,168.39,138.57,136.14,136.01,129.77,128.87,128.76,128.50,128.47,128.34,128.00,127.89,126.71,123.37,119.87,119.01,112.61,109.10,74.50,72.14,70.74,70.62,66.88,64.91,63.04,57.02,33.79,25.82,16.99,16.70.實施例72HCl'NH2-Ser(Bzl)-l,2,3,4-四氫咔啉-3-?;?Ser(Bzl)-OBzl(8o)按照制備8a的操作,從0.15g(0.1974mmol)Boc-Ser(BzI)-l,2,3,4-四氫咔啉-3-?;?Ser(Bzl)-OBzl得到0.136g(98.93%)標題化合物(黃色固體)。Mp136-138°C;[a]D25=-3.6(01.0,甲醇);ESI-MS(m/z):661.5[M+H]+.'HNMR(500MHz,DMSO-d6):S/ppm=11.00(m,IH),8.45-8.98(m,3H),7.165-7.42(m,17H),7.55(m,J=10Hz,IH),6.99(m,片5Hz,IH),5.56(m,J=5Hz,1H),5.23(m,lH),4.89-5.04(m,2H),4.25-4.89(m,6H),3.48-3.91(m,5H),3,35(m,J=20Hz,IH),2.99(m,J=5Hz,IH).13CNMR(DMSO-d6):171.07,170.27,167.83,138.22,137.95,137.69,136.50,130.09,129.64,128.74,128.59,128.40,128.14,126.89,121.43,119.00,117.96,111.62,104.46,72.86,72.73,69.47,67.98,67.43,66.54,53.77,51.21,28.21,24.24.實施例73HCl.NH2-Cys(CH2-C6H4-OCH3)-l,2,3,4-四氫咔啉-3-?;?Cys(But)-OBzl(8p)按照制備8a的操作,從0.15g(0.19mmol)Boc-Cys(CH2-C6H4-OCH3)-l,2,3,4-四氫咔啉-3-?;?Cys(But)-OBzl得到0.136g(98.62。/。)標題化合物(黃色固體)。Mp1132-134°C;[a]D25=-12.2(C=1.0,甲醇);ESI-MS(m/z):689.5[M+H]+.'腦MR(500顧z,DMSO-d6):S/ppm=10.99(m,IH),8.45-8.95(m,3H),7.15-7.47(m,9H),6.55-7.15(m,4H),5.35(m,J=5Hz,IH),4.85-5.15(m,3H),4.65(m,IH),4.35(m,J=5Hz,J=10Hz,IH),3.84(m,IH),3.58-3.78(m,5H),2.75-3.35(m,6H),1.10-1.28(m,9H).13CNMR(DMSO-d6):S/ppm=170,49,169.54,169.11,158.89,136.84,136.23,130.77,129.80,129.55,128.80,128.19,126.92,121.44,118.97,117.92,114.41,111.63,104.69,66.67,66,61,55.56,55.45,53.98,49.75,42.64,35.59,31.81,31.10,30.94,21.53.實施例74HCl.NH2-Asp(OBzl)-l,2,3,4-四氫咔啉-3-酰基-Asp(OBzl)-OBzl(8q)按照制備8a的操作,從0.15g(0.184mmol)Boc-Asp(OBzl)-l,2,3,4-四氫咔啉-3-酰基-Asp(0Bzl)-OBzl得到0.137g(99.04%)標題化合物(黃色固體)。Mp90-92。C;[a]D25=-6.2(C=1.0,甲醇);ESI-MS(m/z):717.5[M+H]+」HNMR(500MHz,DMSO-d6):5/ppm=10.98(m,1H),8.35-8.39(m,3H),7.11-7.573(m,17H),7.05(t,J=11.5Hz,IH),6.99(t,J=12Hz,IH),5.565(m,J=9.5Hz,IH),5.05-5.21(m,4H),4.83-5.00(m,4H),4.65(m,J=llHz,1H),4.35(m,IH),3.45(m,J=25Hz,IH),2.67-3.25(m,5H).13CNMR(DMSO-d6):5/ppm=172.40,171.48,169.85,157.30,156.56,136.74,136.53,131.24,130.48,129.83,128.76,127.54,126.76,124.67,121.42,119.00,115.92,115.70,111.61,104.41,66.39,60.21,55.01,54.65,42.04,36.18,24.09,21.53.實施例75HCl.NH2-Glu(OBzl)-l,2,3,4-四氫咔啉-3-酰基-Glu(OBzl)-OBzl(8r)按照制備8a的操作,從0.20g(0.24mmol)Boc-Glu(OBzl)-l,2,3,4-四氫咔啉-3-?;?Glu(OBzl)-OBzl得到0.180g(97.32%)標題化合物(黃色固體)。Mp76-78°C;[a]D25=7.5(O1.0,甲醇);ESI-MS(m/z):745.5[M+H]+.'HNMR(500MHz,DMSO-d6):5/ppm=10.94(m,IH),8.35-8.90(m,3H),7.15-7.40(m,17H),6.88-7.08(m,2H),5.56(m,J=5Hz,IH),4.89-5.25(m,6H),4.85(m,1H),4.61(m,IH),4.25(m,IH),3.65(m,IH),3.38(m,J=10Hz,IH),3.05(m,J=10Hz,IH),2.55-2.79(m,6H),1.81-2.46(m,2H).13CNMR(DMSO-d6):5/ppm=172.54,172.33,171.46,171.06,169.89,136.85,136.27,130.07,129.53,128.88,128.44,126.88,121.47,119.05,118.05,111.64,104.54,66.55,54.32,52.34,50.09,42.08,30.55,30,36,30.21,29.08,26.44,26.00,25.55,23.83.實驗例1本發(fā)明化合物體內(nèi)抗腫瘤活性實驗I)實驗材料受試化合物本發(fā)明實施例58-75所制備的化合物8a-r;陽性對照品為阿糖胞苷實驗動物ICR小鼠,雄性,體重20士2g(士s);由北京大學(xué)醫(yī)學(xué)部動物實驗中心提供。每10只小鼠一組,空白及陽性對照各一組。瘤源小鼠S180肉瘤,由北京大學(xué)醫(yī)學(xué)部動物實驗中心提供,自行傳代維持。溶劑0.5XCMC-Na溶液。2)實驗方法1.劑量設(shè)置受試化合物8a-r及陽性對照設(shè)為8.9pmol/kg,均采用腹腔單次給藥。2.藥物配制受試化合物8a-r在水中難溶,實驗時加入少量的吐溫80潤濕助溶,逐漸加入0.5XCMC-Na溶液至所需要濃度即可。陽性對照品阿糖胞苷為水溶性,采用0.5XCMC-Na溶解即可。3)給藥劑量及給藥方案受試化合物8a-r均以腹腔單次給藥。按相應(yīng)的給藥劑量每天一次,0.2ml/鼠,連續(xù)給藥7天,共給藥7次。陰性對照以等體積的相應(yīng)溶液,均以腹腔給藥。按相應(yīng)的給藥劑量每天一次,0.2ml/鼠,連續(xù)給藥7天,共給藥7次。陽性對照品阿糖胞苷按8.9^riol/kg的劑量,腹腔給藥。每天一次,0.2ml/鼠,連續(xù)給藥7天,共給藥7次。4)動物模型的建立采用體內(nèi)抗腫瘤腋皮下接種模型在無菌條件下抽取接種5天后取生長旺盛S180腹水瘤瘤液,用生理鹽水稀釋成(1:2)的液體充分混合,將腫瘤細胞懸液用新鮮配制的培養(yǎng)基稀釋計數(shù)按如下公式計算細胞濃度和細胞存活率。細胞濃度=4大方格內(nèi)活細胞數(shù)/4xi0稀釋倍數(shù)-細胞數(shù)/ml細胞存活率=活細胞數(shù)/(活細胞數(shù)+死細胞數(shù))><100%將存活率大于90X的瘤液用勻漿法制備成lx107個/ml的細胞懸液,于相應(yīng)宿主腋皮下接種0.2ml/鼠,制成實體瘤動物模型。5)檢測指標及方法a體內(nèi)神經(jīng)毒性觀察每日觀察給藥各組動物的反應(yīng)小鼠的自主活動、精神狀態(tài)、毛發(fā)、呼吸、飲食,糞便性狀。b實體瘤抑瘤率和體重增長的測定各組連續(xù)給藥7d后,于第8d脫頸椎處死小鼠,稱取體重(處死體重),然后用鑷子固定小鼠右腋腫瘤生長部位,剪開皮膚,暴露腫瘤,鈍性剝離,稱重,按如下公式計算抑瘤率。抑瘤率%=[(陰性對照組平均瘤重一給藥組平均瘤重)/陰性對照組平均瘤重]"00%體重增長(g"處死體重-原始體重-瘤重C統(tǒng)計方法本實驗數(shù)據(jù)統(tǒng)計均采用t檢驗和方差分析,以(iSD)表示。6)實驗結(jié)果化合物8a-r對S180荷瘤小鼠的抑瘤率及體重的影響列入表1。表l化合物8a-r對S180荷瘤小鼠的抑瘤率及體重的影響<table>tableseeoriginaldocumentpage30</column></row><table>a)Arc(阿糖胞苷)和8a-r給藥劑量為8.9pmol/kg,NS-生理鹽水,n=10,瘤重和體重增加表示為5士SDg;抑制率表示為;士SDX;給藥后各組動物沒有觀察到出現(xiàn)文獻報道的震顫、跳躍、抽搐、強直、仰臥、呼吸加快的癥狀;b)與NS比較pO.05;c)與NS比較pO.01;d)與NS比較pO.001;e)與阿糖胞苷比較pO.05;f)與阿糖胞苷比較p<0.05.實驗結(jié)果表明,本發(fā)明化合物具有確切的抗腫瘤活性。根據(jù)顯著性檢驗的結(jié)果,選取對p〈0.001的化合物8f和8g進行量效關(guān)系研究,結(jié)果參見表2。表2不同劑量8f和8g對S180荷瘤小鼠抑瘤率、腫瘤重量及體重的影響a<table>tableseeoriginaldocumentpage31</column></row><table>a)Arc二阿糖胞苷,NS二生理鹽水,n=10,瘤重和體重增加表示為3±SDg;抑制率表示為5±SD%;b)與0.89ymol/kg組比較p〈0.05;c)與0.089umol/kg組比較pO.Ol;d)與0.89wmol/kg及0,089umol/kg組比較p<0.01。權(quán)利要求1、具有抗腫瘤活性的通式I化合物通式I其中,AA1選自丙氨酸殘基、甘氨酸殘基、脯氨酸殘基、谷氨酰胺殘基、亮氨酸殘基、苯丙氨酸殘基、異亮氨酸殘基、甲硫氨酸殘基、酪氨酸殘基、色氨酸殘基、纈氨酸殘基、賴氨酸殘基、Arg(NO2)、Thr(Bzl)、Ser(Bzl)或Cys(CH2-C6H4-OCH3);AA2選自丙氨酸殘基、甘氨酸殘基、脯氨酸殘基、谷氨酰胺殘基、亮氨酸殘基、苯丙氨酸殘基、異亮氨酸殘基、甲硫氨酸殘基、酪氨酸殘基、色氨酸殘基、纈氨酸殘基、Lys(Z)、Arg(NO2)、Thr(Bzl)、Ser(Bzl)或Cys(But)。2、具有抗腫瘤活性的通式II化合物其中,AA!選自Asp(OBZl)或Glu(0BZ1);AA2選自Asp(OBZl)或Glu(0BZ1)。3、一種制備權(quán)利要求1所述通式I化合物的方法,該方法包括(1)將L-色氨酸轉(zhuǎn)變?yōu)?,2,3,4-四氫咔啉羧酸;②將1,2,3,4-四氫咔啉羧酸轉(zhuǎn)變?yōu)檫沁人崞S酯;(3)將氨基酸轉(zhuǎn)化成氨基酸芐酯;(4)將氨基酸轉(zhuǎn)化成N-叔丁氧羰基氨基酸;(5)將N-叔丁氧羰基氨基酸和1,2,3,4-四氫咔啉羧酸芐酯縮合,生成N-叔丁氧羰基氨基酰-1,2,3,4-四氫昨啉羧酸芐酯;(6)將N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉羧酸芐酯氫解,生成N-叔丁氧羰基氨基酰-1,2,3,4-四氫咔啉羧酸;通式II(7)將N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉羧酸芐酯水解,生成N-叔丁氧羰基氨基酰-1,2,3,4-四氫咔啉羧酸;(8)將N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉羧酸和氨基酸芐酯縮合,生成N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉酰氨基酸芐酯;(9)將N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉酰氨基酸芐酯酸解,即得。4、按照權(quán)利要求2所述的方法,其特征在于步驟(3)中所述的氨基酸芐酯選自Ala-OBzl、Gly-OBzl、Pro-OBzl、Gln-OBzl、Leu-OBzl、Phe-OBzl、Ile-OBzl、Met-OBzl、Tyr-OBzl、Trp國OBzl、Val-OBzl、Lys(Z)-OBzl、Arg(N02)-OBzl、Thr(Bzl)-OBzl、Ser(Bzl)-OBzl、Cys(But)-OBzl、Asp(OBzl)~Obzl或Glu(OBzl)-OBzl。5、按照權(quán)利要求2所述的方法,其特征在于步驟(4)中所述的N-叔丁氧羰基氨基酸選自N-Boc-Ala、N-Boc-Gly、N-Boc誦Pro、N-Boc-Gln、N-Boc-Leu、N-Boc-Phe、N-Boc-Ile、N-Boc-Met、N-Boc-Tyr、N-Boc-Trp、N-Boc-Val、N-Boc-Lys、N-Boc-Arg(N02)、N-Boc-Thr(Bzl)、N-Boc-Ser(Bzl)、N-Boc-Cys(CH2-C6H4-OCH3)、N-Boc-Asp(OBzl)或N-Boc-Glu(OBzl)。6、一種制備權(quán)利要求2所述通式II化合物的方法,該方法包括(1)將L-色氨酸轉(zhuǎn)變?yōu)?,2,3,4-四氫咔啉羧酸;(2)將1,2,3,4-四氫咔啉羧酸轉(zhuǎn)變成N-叔丁氧羰基-l,2,3,4-四氫咔啉羧酸;(3)將N-N-叔丁氧羰基-l,2,3,4-四氫咔啉羧酸和氨基酸芐酯縮合,生成N-N-叔丁氧羰基-l,2,3,4-四氫咔啉酰氨基酸芐酯;(4)將N-N-叔丁氧羰基-l,2,3,4-四氫咔啉酰氨基酸芐酯酸解,生成1,2,3,4-四氫咔啉酰氨基酸芐酯;(5)將N-叔丁氧羰基氨基酸和1,2,3,4-四氫咔啉酰氨基酸芐酯縮合,生成N-N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉酰氨基酸芐酯;(6)將N-N-叔丁氧羰基氨基酰-l,2,3,4-四氫咔啉酰氨基酸節(jié)酯酸解,即得。7、按照權(quán)利要求6的方法,其特征在于步驟(3)中所述的氨基酸芐酯選自Asp(OBZl)-OBzl或Glu(OBZl)-OBzl;步驟(5)中所述的N-叔丁氧羰基氨基酸選自N-Boc-Asp(OBZl)或N-Boc-Glu(0BZ1)。8、一種治療腫瘤的藥物組合物,由治療上有效量的權(quán)利要求1所述的通式I化合物和藥學(xué)上可接受的載體或輔料組成。9、一種治療腫瘤的藥物組合物,由治療上有效量的權(quán)利要求2所述的通式n化合物和藥學(xué)上可接受的載體或輔料組成。10、權(quán)利要求1所述的通式I化合物或權(quán)利要求2所述的通式II化合物在制備抗腫瘤藥物中的用途。全文摘要本發(fā)明公開了具有抗腫瘤作用的N-(L-氨基酰)-1,2,3,4-四氫咔啉酰氨基酸芐酯化合物及其制備方法以及它們作為抗腫瘤劑的應(yīng)用。本發(fā)明采用S<sub>180</sub>小鼠模型評價了本發(fā)明化合物的抗腫瘤活性,實驗結(jié)果表明本發(fā)明的化合物具有優(yōu)秀的抗腫瘤作用,臨床上可作為抗腫瘤劑應(yīng)用。文檔編號C07K5/08GK101591335SQ20081011385公開日2009年12月2日申請日期2008年5月30日優(yōu)先權(quán)日2008年5月30日發(fā)明者周冬初,張建偉,彭師奇,明趙申請人:首都醫(yī)科大學(xué)
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