CN101200466A - 具有抗血栓活性的杂环化合物、其制备方法及应用 - Google Patents
具有抗血栓活性的杂环化合物、其制备方法及应用 Download PDFInfo
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Abstract
本发明公开了具有抗血栓活性的通式(I)化合物、其制备方法及在医学中的用途。本发明以六氢吡嗪并[1’,2’∶1,6]-β-咔啉为先导结构,对六氢吡嗪并[1’,2’∶1,6]-β-咔啉的3位进行修饰,获得了具有抗血栓活性的通式(I)化合物。动物模型试验表明,本发明通式(I)化合物具有优秀的抗血栓活性。在量效关系研究时发现,本发明通式(I)化合物在5nmol/kg的给药剂量下,仍然表现出明显的抗血栓活性,说明本发明化合物是优秀的抗血栓剂。
Description
技术领域
本发明涉及化合物,尤其涉及具有抗血栓活性的杂环化合物、其制备方法及它们作为抗血栓剂应用,属于生物医药领域。
背景技术
血管栓塞性疾病对心脑血管疾病的高死亡率负最重要的责任。血栓形成是血管栓塞性疾病发病的最重要的病因。寻找抗血栓药物是新药研究的热点之一。(3S)-1,2,3,4-四氢-β-咔啉-3-羧酸是中药薤白中的一种成分,具有抗血小板聚集活性(姚新生等,中国药物化学杂志,1995,5,134)。针对(3S)-1,2,3,4-四氢-β-咔啉-3-羧酸在极性溶剂和非极性溶剂中溶解度都不好带来的低生物利用度,发明人在(3S)-1,2,3,4-四氢-β-咔啉-3-羧酸中引入L-氨基酸,获得了一类(3S)-1,2,3,4-四氢-β-咔啉-3-甲酰-L-氨基酸抗血栓剂(彭师奇、赵明、王超、杨哲,咔啉羧酸衍生物、其合成方法及其应用,申请号:200410074204.6)。研究代谢时,发明人发现在大鼠的血浆中(3S)-1,2,3,4-四氢-β-咔啉-3-甲酰-L-氨基酸可转化为六氢吡嗪并[1’,2’:1,6]-β-咔啉(图1)。根据该发现,发明人将六氢吡嗪并[1’,2’:1,6]-β-咔啉看作(3S)-1,2,3,4-四氢-β-咔啉-3-甲酰-L-氨基酸的活性形态。
发明内容
本发明的目的之一是将(3S)-1,2,3,4-四氢-β-咔啉-3-甲酰-L-氨基酸进行改造,获得一类新的具有优秀抗血栓活性的杂环化合物。
本发明的目的之一是通过以下技术方案来实现的:
具有抗血栓活性的通式(I)化合物:
其中,R选自CH3,C6H5CH2,CH(CH3)2,CH2OH,CH(OH)CH3,CH2C6H4-OH-p,四氢吡咯-2-基,CH2SH,CH2CH2SCH3,CH2CH2CO2H,CH2CO2H,1,3-咪唑-4-甲基,吲哚-3-基-甲基,CH2(CH2)2NHC(NH2)=NH,氢,CH2(CH3)3NHZ,CH2CH2CONH2,CH2CONH2,CH2CH(CH3)2或CH(CH3)CH2CH3。
本发明还提供了通式(I)化合物的以下几种中间体[通式化合物(II-VI)]:
通式(II)
其中,R1是CH3或CH2C6H5;R选自CH3,CH2C6H5,CH(CH3)2,CH2OH,CH(OH)CH3,CH2C6H4-OH-p,四氢吡咯-2-基,CH2SH,CH2CH2SCH3,CH2CH2COOCH3,CH2CH2COOCH2C6H5,CH2COOCH3,CH2COOCH2C6H5,1,3-咪唑-4-甲基,吲哚-3-基-甲基,CH2(CH2)2NHC(NH2)=NH,氢,CH2(CH3)3NHZ,CH2CH2CONH2,CH2CONH2,CH2CH(CH3)2或CH(CH3)CH2CH3。
其中,R1是CH3或CH2C6H5;R选自CH3,CH2C6H5,CH(CH3)2,CH2OH,CH(OH)CH3,CH2C6H4-OH-p,四氢吡咯-2-基,CH2SH,CH2CH2SCH3,CH2CH2COOH,CH2COOH,1,3-咪唑-4-甲基,吲哚-3-基-甲基,CH2(CH2)2NHC(NH2)=NH,氢,CH2(CH3)3NHZ,CH2CH2CONH2,CH2CONH2,CH2CH(CH3)2或CH(CH3)CH2CH3。
通式(IV)
其中,R1是CH3或C6H5CH2;
其中,R1是CH3或C6H5CH2;
其中,R1是CH3或C6H5CH2;R选自CH3,CH2C6H5,CH(CH3)2,CH2OH,CH(OH)CH3,CH2C6H4-OH-p,四氢吡咯-2-基,CH2SH,CH2CH2SCH3,CH2CH2CO2CH3,CH2CH2CO2CH2C6H5,CH2CO2CH2C6H5,1,3-咪唑-4-甲基,吲哚-3-基-甲基,CH2(CH2)2NHC(NH2)=NH,氢,CH2(CH3)3NHZ,CH2CH2CONH2,CH2CONH2,CH2CH(CH3)2或CH(CH3)CH2CH3。
本发明目的之二是提供一种制备通式(I)化合物的方法。
本发明目的之二是通过以下技术方案来实现的:
一种制备通式(I)化合物的方法,包括:
(1)按照现有技术制备咔啉羧酸;
(2)在三乙胺存在下,将咔啉羧酸和Boc-N3反应,得化合物1;
(3)在DCC和NMM存在下,化合物1与氨基酸甲酯或氨基酸苄酯偶联生成化合物2;
(4)将化合物2脱去Boc保护基,生成咔啉酰氨基酸甲酯或咔啉酰氨基酸苄酯;
(5)在碱的水溶液中将咔啉酰氨基酸甲酯或咔啉酰氨基酸苄酯发生分子内环合反应,得到本发明通式(I)化合物。
上述制备方法中,步骤(1)优选按照以下方法制备咔啉羧酸:在H2SO4存在下,将甲醛和色氨酸缩合得到咔啉羧酸;步骤(4)中将化合物2脱去Boc保护基优选按照以下条件进行:在氯化氢的乙酸乙酯溶液(4mol/L)中,将化合物2脱去脱Boc保护基;步骤(5)中所述的碱的水溶液优选为2N的NaOH水溶液。
此外,本发明还提供了另外一种制备通式(I)化合物的方法,包括以下步骤:
(1)按照现有技术方法制备咔啉羧酸;
(2)在甲醇/氯化亚砜或者苄醇/PCl5存在的条件下,将咔啉羧酸转化为咔啉羧酸甲酯盐酸盐或咔啉羧酸苄酯磷酸盐;
(3)用三乙胺中和咔啉羧酸甲酯盐酸盐或咔啉羧酸苄酯磷酸盐得到化合物1;
(4)在DCC和NMM存在下,化合物1与Boc-氨基酸偶联生成化合物2;
(5)在氯化氢的乙酸乙酯溶液中,化合物2脱Boc同时发生分子内环合反应,得到本发明通式(I)化合物。
上述制备方法中,步骤(5)中所述的氯化氢的乙酸乙酯溶液的浓度优选为4mol/L。
本发明以六氢吡嗪并[1’,2’:1,6]-β-咔啉为先导结构,对六氢吡嗪并[1’,2’:1,6]-β-咔啉的3位进行修饰,获得了具有抗血栓活性的通式(I)化合物。动物溶血栓模型试验表明,本发明通式(I)化合物具有优秀的抗血栓活性。在量效关系研究时发现,即使在5nmol/kg剂量下被测定,本发明通式(I)化合物仍然具有明显的抗血栓活性,说明本发明化合物是优秀的抗血栓剂。在口服给药研究中发现,在500nmol/kg剂量下被测定,本发明通式(I)化合物的抗血栓活性与静脉给药没有差异,说明本发明化合物是优秀的口服抗血栓剂。
附图说明
图10.15mg(3S)-1,2,3,4-四氢-β-咔啉-3-甲酰-L-赖氨酸与0.5ml大鼠血浆于37℃孵育60min,LC-MS分析揭示3-(丁氨-1-基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉为代谢产物。
图2由(3S)-1,2,3,4-四氢-β-咔啉-3-甲酰-L-氨基酸酯制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉(5a-t)的路线。I)甲醛,H2SO4;II)三乙胺,Boc-N3;III)氨基酸甲酯/DCC/NMM或者氨基酸苄酯/DCC/NMM;IV)氯化氢的乙酸乙酯溶液(4mol/L);V)三乙胺;
R1=CH3或CH2C6H5;3a,3’a,4a,4’a&5a中R=CH3;3b,3’b,4b,4’b&5b中R=CH2C6H5;3c,3’c,4c,4’c&5c中R=CH(CH3)2;3d,3’d,4d,4’d&5d中R=CH2OH;3e,3’e,4e,4’e&5e中R=CH(OH)CH3;3f,3’f,4f,4’f&5f中R=CH2C6H4-OH-p;3g,3’g,4g,4’g&5g中R=四氢吡咯-2-基;3h,3’h,4h,4’h&5h中R=CH2SH;3i,3’i,4i,4’i&5i中R=CH2CH2SCH3;3j中R=CH2CH2COOCH3,3’j&5j中R=CH2CH2COOCH2C6H5;4j,4’j&5j中R=CH2CH2COOH;3k中R=CH2COOCH3,3’k&5k中R=CH2COOCH2C6H5;4k,4’k&5k中R=CH2COOH;3l,3’l,4l,4’l&5lR=1,3-咪唑-4-甲基;3m,3’m,4m,4’m&5m中R=吲哚-3-基-甲基;3n,3’n,4n,4’n&5nR=CH2(CH2)2NHC(NH2)=NH,3o,3’o,4o&5o中R=H;3p,3’p,4p&5p中R=CH2(CH3)3NH2;3q,3’q,4q,4’q&5q中R=CH2CH2CONH2;3r,3’r,4r,4’r&5r中R=CH2CONH2;3s,3’s,4s,4’s&5s中R=CH2CH(CH3)2;3t,3’t,4t,4’t&5t中R=CH(CH3)CH2CH3.
图3由N-[L-氨基酰]-(3S)-1,2,3,4-四氢-β-咔啉-3-甲酸酯制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉(5a-t)的路线.I)甲醇/氯化亚砜或者苄醇/PCl5;II)三乙胺;III)Boc-氨基酸/DCC/NMM;IV)氯化氢的乙酸乙酯溶液(4mol/L);
R1=CH3或CH2C6H5;6Me-a,6’Me-a,7Me-a,6Bzl-a,6’Bzl-a,7Bzl-a&5a中R=CH3;6Me-b,6’Me-b,7Me-b,6Bzl-b,6’Bzl-b,7Bzl-b&5b中R=CH2C6H5;6Me-c,6’Me-c,7Me-c,6Bzl-c,6’Bzl-c,7Bzl-c&5c中R=CH(CH3)2;6Me-d,6’Me-d,7Me-d,6Bzl-d,6’Bzl-d,7Bzl-d&5d中R=CH2OH;6Me-e,6’Me-e,7Me-e,6Bzl-e,6’Bzl-e,7Bzl-e&5e中R=CH(OH)CH3;6Me-f,6’Me-f,7Me-f,6Bzl-f,6’Bzl-f,7Bzl-f&5f中R=CH2C6H4-OH-p;6Me-g,6’Me-g,7Me-g,6Bzl-g,6’Bzl-g,7Bzl-g&5g中R=四氢吡咯-2-基;6Me-h,6’Me-h,7Me-h,6Bzl-h,6’Bzl-h,7Bzl-h&5h中R=CH2SH;6Me-i,6’Me-i,7Me-i,6Bzl-i,6’Bzl-i,7Bzl-i&5i中R=CH2CH2SCH3;6Me-j,6’Me-j&7Me-j中R=CH2CH2CO2CH3;6Bzl-j,6’Bzl-j&7Bzl-j R=CH2CH2CO2CH2C6H5;5j中R=CH2CH2CO2H;6Me-k,6’Me-k,7Me-k,6Bzl-k,6’Bzl-k,&7Bzl-k中R=CH2CO2CH2C6H5;5k中R=CH2CO2H;6Me-l,6’Me-l,7Me-l,6Bzl-l,6’Bzl-l,7Bzl-l&5l中R=1,3-咪唑-4-甲基;6Me-m,6’Me-m,7Me-m,6Bzl-m,6’Bzl-m,7Bzl-m&5m中R=吲哚-3-基-甲基;6Me-n,6’Me-n,7Me-n,6Bzl-n,6’Bzl-n,7Bzl-n&5n中R=CH2(CH2)2NHC(NH2)=NH;6Me-o,6’Me-o,7Me-o,6Bzl-o,6’Bzl-o,7Bzl-o&5o中R=H;6Me-p,6’Me-p,7Me-p,6Bzl-p,6’Bzl-p,7Bzl-p&5p中R=CH2(CH3)3NHZ;6Me-q,6’Me-q,7Me-q,6Bzl-q,6’Bzl-q,7Bzl-q&5q中R=CH2CH2CONH2;6Me-r,6’Me-r,7Me-r,6Bzl-r,6’Bzl-r,7Bzl-r&5r中R=CH2CONH2;6Me-s,6’Me-s,7Me-s,6Bzl-s,6’Bzl-s,7Bzl-s&5s中R=CH2CH(CH3)2;6Me-t,6’Me-t,7Me-t,6Bzl-t,6’Bzl-t,7Bzl-t&5t中R=CH(CH3)CH2CH3.
本发明中所出现的术语或缩略语的说明:
THF 四氢呋喃
DCC 二环己基酰亚胺
DCU 二环己基脲
OBzl 苄氧基
Boc 叔丁氧羰基
HOBt N-羟基苯并三唑
TLC 薄层层析
DMF 二甲基甲酰胺
NMM N-甲基吗啉
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
具体实施方式
实施例1(3S)-1,2,3,4-四氢-β-咔啉羧酸的制备
将400ml水置于500ml的圆底烧瓶中,缓慢加入0.2ml浓硫酸。往得到的稀硫酸水溶液中加入5.0g(24.5mmol)L-色氨酸并超声振荡至L-色氨酸完全溶解。往得到的溶液中加入10ml浓度为35%的甲醛溶液。反应混合物室温搅拌6小时,薄层层析监测到L-色氨酸消失,终止反应。往反应溶液中缓慢滴加浓氨水,调反应混合物至pH6,静置半小时。减压滤出的生成的沉淀用水洗,将滤出的无色固体平铺于培养皿,置于柜子中空气干燥后得S-咔啉羧酸,为无色固体5.05g(95.4%)。Mp 280-282℃;EI/MS:217[M+H]+;IR(KBr):3450,3200,3000,2950,2850,1700,1601,1452,1070,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.99(s,1H),9.89(s,1H),7.30(t,J=7.5Hz,1H),7.22(t,J=8.0Hz,1H),7.01(d,J=8.0Hz,1H),6.81(d,J=7.5Hz,1H),4.01(t,J=4.8Hz,1H),3.75(dd,J=10.5Hz,J=5.0Hz,1H),3.64(dd,J=10.5Hz,J=2.4Hz,1H),2.91(d,J=10.5Hz,2H),2.86(s,1H).元素分析C12H12N2O2理论值C66.65,H,5.59,N 12.96.实测值C 66.45,H 5.72,N 12.79。
实施例2N-Boc-(3S)-1,2,3,4-四氢-β-咔啉羧酸的制备
将4.0g(18.5mmol)(3S)-1,2,3,4-四氢-β-咔啉羧酸悬浮于40ml DMF中。冰浴搅拌下往该悬浮液中加入5.2g(23.9mmol)Boc2O。加三乙胺将反应混合物的pH值调至10,反应混合物室温搅拌48小时,薄层层析监测至(3S)-1,2,3,4-四氢-β-咔啉羧酸消失,终止反应。将反应液倒入表面皿,在风扇下吹约24小时至干。将吹干的油状物用200ml乙酸乙酯溶解,然后置于250ml分液漏斗中,用KHSO4(5%)水溶液洗涤(20ml×3)。分出合并的乙酸乙酯层,在250ml三角瓶中加入无水硫酸钠干燥0.5h,常压过滤。滤液减压浓缩至干,析出白色固体。得到的白色固体中加入氯仿,减压过滤,得到N-Boc-(3S)-1,2,3,4-四氢-β-咔啉羧酸,为无色固体4.50g(76.9%)。Mp 165-170℃;TOF/MS:317[M+H]+339[M+Na]+,355[M+K];IR(KBr):3452,3205,3001,2952,2848,1705,1645,1600,1450,1072,901cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.873(s,1H),9.862(s,1H),7.325(t,J=7.6Hz,1H),7.214(t,J=7.9Hz,1H),7.006(d,J=7.9Hz,1H),6.844(t,J=7.6Hz,1H),4.841(t,J=5.0Hz,1H),4.202(dd,J=10.2Hz,J=4.8Hz,1H),3.980(dd,J=10.2Hz,J=3.2Hz,1H),2.933(d,J=10.2Hz,2H),1.462(s,9H).元素分析C17H20N2O4理论值C 64.54,H,6.37,N 8.86.
实测值C 64.41,H 6.25,N 8.74。
实施例3(3S)-1,2,3,4-四氢-β-咔啉羧酸苄酯磷酸盐(6Bzl)的制备
60g多聚磷酸和600ml苄醇的混合物于70℃搅拌20min使成为澄清的溶液。溶液的温度升至80℃后加入30g(3S)-1,2,3,4-四氢-β-咔啉羧酸。反应混合物搅拌24h,TLC(CHCl3/MeOH,10/1)显示(3S)-1,2,3,4-四氢-β-咔啉羧酸完全消失。反应混合物冷至室温后与500ml乙醚及2100ml水混合,室温搅拌48h。滤集到的生成的沉淀用水和乙醚洗后置无水CaCl2的干燥器中干燥,得到35g(85%)(3S)-1,2,3,4-四氢-β-咔啉羧酸苄酯磷酸盐,为无色粉。Mp.192-194℃;EI/MS:307[M+H]+;1H NMR(BHSC-500,DMSO-d6):δ=8.79(s,1H),8.22(s,1H),7.48(d,J=7.5Hz,1H),7.40(d,J=7.2Hz,2H),7.33(t,J=8.0Hz,1H),7.20(t,J=7.6Hz,2H),7.08(t,J=8.0Hz,1H),7.01(t,J=7.5Hz,1H),6.99(t,J=7.5Hz,1H),4.22(d,J=4.8Hz,1H),3.69(dd,J=10.5Hz,J=5.0Hz,1H),3.56(s,2H),3.14(dd,J=10.5Hz,J=2.4Hz,1H),2.83(ddd,J=10.5Hz,J=5.0Hz,J=2.4Hz,1H)。
实施例4(3S)-1,2,3,4-四氢-β-咔啉羧酸甲酯盐酸盐(6Me)的制备
0℃下将10ml氯化亚砜滴入50ml甲醇中。之后,加入5.0g(23.1mmol)(3S)-1,2,3,4-四氢-β-咔啉羧酸。反应混合物于室温搅拌15h,TLC(乙酸乙酯/石油醚,5/12)显示(3S)-1,2,3,4-四氢-β-咔啉羧酸完全消失。减压浓缩除去反应混合物中过量的氯化亚砜和甲醇。残留物用30ml乙酸乙酯溶解,得到的溶液依次用饱和NaCO3溶液洗(30ml×3),饱和NaCl溶液洗(30ml×3),饱和KHSO4溶液洗(30ml×3),饱和NaCl溶液洗(30ml×3),水洗(30ml×3),无水MgSO4干燥,减压浓缩。残留物用闪式硅胶柱层析纯化,得到4.9g(92%)(3S)-1,2,3,4-四氢-β-咔啉羧酸苄酯盐酸盐,为无色粉。Mp 143-145℃;FAB/MS:231[M+H]+;1H NMR(BHSC-500,DMSO-d6):δ=9.79(s,1H),8.36(s,1H),7.28(t,J=7.5Hz,1H),7.18(t,J=7.5Hz,1H),7.01(t,J=7.5Hz,1H),6.99(t,J=7.5Hz,1H),4.22(d,J=4.8Hz,2H),3.69(dd,J=10.5Hz,J=5.0Hz,1H),3.56(s,3H),3.14(dd,J=10.5Hz,J=2.4Hz,1H),2.83(ddd,J=10.5Hz,J=5.0Hz,J=2.4Hz,1H).Anal.Calcd for C13H14N2O2C 67.81,H 6.13,N 12.17.Found C 67.98,H 6.04,N12.30.
实施例5(3S)-1,2,3,4-四氢-β-咔啉羧酸苄酯(6’Bzl)的制备
0℃和搅拌下往402mg(1.0mmol)(3S)-1,2,3,4-四氢-β-咔啉羧酸苄酯磷酸盐与30ml乙酸乙酯的悬浮液中加入303mg(3.0mmol)三乙胺,混合物室温搅拌至澄清。溶液用饱和NaHCO3溶液洗(5%,50ml×6),饱和NaCl溶液洗(50ml×3),无水MgSO4干燥,减压浓缩,得到272mg(89%)(3S)-1,2,3,4-四氢-β-咔啉羧酸苄酯,为浅黄色粉。Mp.133-135℃;EI/MS:307[M+H]+;1H NMR(BHSC-500,DMSO-d6):δ=8.74(s,1H)7.45(d,J=7.4Hz,1H),7.37(d,J=7.2Hz,2H),7.30(t,J=8.1Hz,1H),7.17(t,J=7.4Hz,2H),7.03(t,J=8.1Hz,1H),7.00(t,J=7.3Hz,1H),6.95(t,J=7.3Hz,1H),4.24(d,J=4.7Hz,1H),3.67(dd,J=10.1Hz,J=5.2Hz,1H),3.55(s,2H),3.15(dd,J=10.1Hz,J=2.4Hz,1H),2.84(ddd,J=10.1Hz,J=5.2Hz,J=2.4Hz,1H),2.81(s,1H).
实施例6(3S)-1,2,3,4-四氢-β-咔啉羧酸甲酯(6’Me)的制备
0℃和搅拌下往267mg(1.0mmol)(3S)-1,2,3,4-四氢-β-咔啉羧酸甲酯盐酸盐与30ml乙酸乙酯的悬浮液中加入202mg(2.0mmol)三乙胺,混合物室温搅拌至澄清。溶液用饱和NaHCO3溶液洗(5%,50ml×6),饱和NaCl溶液洗(50ml×3),无水MgSO4干燥,减压浓缩,得到272mg(89%)(3S)-1,2,3,4-四氢-β-咔啉羧酸甲酯,为浅黄色粉。Mp 143-145℃;FAB/MS:231[M+H]+;1H NMR(BHSC-500,DMSO-d6):δ=9.74(s,1H),8.36(s,1H),7.26(t,J=7.3Hz,1H),7.16(t,J=7.4Hz,1H),7.00(t,J=7.4Hz,1H),6.95(t,J=7.3Hz,1H),4.20(d,J=4.7Hz,2H),3.64(dd,J=10.1Hz,J=5.2Hz,1H),3.54(s,3H),3.12(dd,J=10.1Hz,J=2.4Hz,1H),2.80(ddd,J=10.1Hz,J=5.2Hz,J=2.4Hz,1H).Anal.Calcd for C13H14N2O2C 67.81,H 6.13,N 12.17.Found C 67.98,H 6.04,N12.30。
实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作
0℃下往2.0g(6.33mmol)N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-羧酸与30ml无水四氢呋喃的溶液中加入1.2g(8.9mmol)HOBt,10min后再加入1.75g(8.5mmol)DCC(称溶液A)。6.96mmol L-氨基酸甲酯盐酸盐与3ml无水四氢呋喃的悬浮液用N-甲基吗啉调pH至8-9,室温搅拌20min.将该悬浮液加到溶液A中,0℃搅拌2h,室温搅拌16h,减压浓缩。残留物溶入30ml乙酸乙酯中,得到的溶液依次用NaHCO3溶液洗(5%,50ml×6),柠檬酸溶液洗(5%,50ml×3),饱和NaCl溶液洗(50ml×3),无水MgSO4干燥,减压浓缩,得到粉末状标题化合物。
实施例8N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-丙氨酸甲酯(3a)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由960mg(6.96mmol)HCl·L-Ala-OMe得到2679mg(96%)标题化合物,为浅黄色粉末。Mp 144-146℃;ESI/MS 402[M+H]+;IR(KBr):3451,3011,2949,2847,1730,1604,1450,1392,1370,1066,897cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.89(s,1H),7.98(s,1H),7.32(t,J=7.5Hz,1H),7.23(t,J=7.8Hz,1H),6.97(d,J=7.8Hz,1H),6.81(d,J=7.5Hz,1H),4.88(d,J=5.2Hz,1H),4.59(m,J=5.5Hz,1H),4.25(dd,J=10.0Hz,J=4.7Hz,1H),4.17(dd,J=10.1Hz,J=3.5Hz,1H),3.64(s,3H),2.94(d,J=10.1Hz,2H),1.55(d,J=5.2Hz,3H),1.43(s,9H).Anal.Calcd for C21H27N3O5C62.83,H,6.78,N 10.47.Found C 62.92,H 6.74,N 10.30.
实施例9N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-苯丙氨酸甲酯(3b)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1489mg(6.96mmol)HCl·L-Phe-OMe得到3254mg(98%)标题化合物,为浅黄色粉末。Mp 150-152℃;ESI/MS 478[M+H]+;IR(KBr):3446,3205,3006,2948,2847,1731,1645,1603,1451,1392,1370,1069,904cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.92(s,1H),7.97(s,1H),7.31(t,J=7.5Hz,1H),7.28(t,J=7.9Hz,2H),7.19(t,J=7.6Hz,1H),7.14(d,J=7.6Hz,2H),7.02(t,J=7.6Hz,1H),6.96(d,J=7.8Hz,1H),6.80(d,J=7.6Hz,1H),4.93(d,J=5.4Hz,1H),4.82(t,J=5.4Hz,1H),4.27(dd,J=10.2Hz,J=4.5Hz,1H),4.18(dd,J=10.2Hz,J=3.4Hz,1H),3.62(s,3H),3.17(d,J=5.4Hz,2H),2.93(d,J=10.2Hz,2H),1.48(s,9H).Anal.Calcd for C27H31N3O5C67.91,H 6.54,N 8.80.Found C 67.72,H 6.62,N 8.67.
实施例10N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-缬氨酸甲酯(3c)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1155mg(6.96mmol)HCl·L-Val-OMe得到2837mg(95%)标题化合物,为浅黄色粉末。Mp 138-140℃;ESI/MS 430[M+H]+.IR(KBr):3443,3202,3001,2951,2845,1729,1648,1602,1450,1392,1370,1067,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.04(s,1H),7.96(s,1H),7.29(t,J=7.4Hz,1H),7.21(t,J=7.7Hz,1H),7.00(d,J=7.7Hz,1H),6.89(d,J=7.4Hz,1H),4.84(t,J=5.4Hz,1H),4.42(d,J=5.4Hz,1H),4.22(dd,J=10.2Hz,J=4.5Hz,1H),4.03(dd,J=10.2Hz,J=3.7Hz,1H),3.62(s,3H),3.10(m,J=5.4Hz,1H),2.95(d,J=6.7Hz,2H),1.47(s,9H),1.05(d,J=5.4Hz,6H).Anal.Calcd for C23H31N3O5C 64.32,H 7.27,N 9.78.Found C 64.43,H 7.09,N 9.67.
实施例11N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-丝氨酸甲酯(3d)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1072mg(6.96mmol)HCl·L-Ser-OMe得到2670mg(92%)标题化合物,为浅黄色粉末。Mp 139-141℃;ESI/MS 418[M+H]+.IR(KBr):3442,3200,3001,2952,2845,1730,1644,1606,1455,1392,1370,1067,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.95(s,1H),7.97(s,1H),7.29(t,J=7.6Hz,1H),7.22(t,J=7.9Hz,1H),6.99(d,J=7.9Hz,1H),6.83(t,J=7.6Hz,1H),4.87(d,J=5.4Hz,1H),4.52(t,J=5.6Hz,1H),4.19(d,J=5.2Hz,2H),4.13(d,J=5.6Hz,2H),3.63(s,3H),2.95(d,J=5.6Hz,1H),2.92(d,J=5.6Hz,1H),2.28(s,1H),1.45(s,9H).Anal.Calcd for C21H27N3O6C60.42,H 6.52,N 10.07.Found C 60.31,H 6.36,N 10.24.
实施例12N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-苏氨酸甲酯(3e)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1169mg(6.96mmol)HCl·L-Thr-OMe得到2760mg(92%)标题化合物,为浅黄色粉末。Mp 140-142℃;ESI/MS 432[M+H]+;IR(KBr):3437,3200,3002,2951,2844,1735,1649,1600,1450,1392,1370,1065,901cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.98(s,1H),7.87(s,1H),7.34(t,J=7.4Hz,1H),7.25(t,J=7.6Hz,1H),6.95(d,J=7.6Hz,1H),6.72(d,J=7.4Hz,1H),4.87(t,J=5.4Hz,1H),4.67(m,J=5.6Hz,1H),4.48(t,J=5.6Hz,1H),3.99(m,J=5.2Hz,2H),3.65(s,3H),2.97(d,J=5.7Hz,2H),2.19(d,J=3.7Hz,1H),1.47(s,9H),1.19(d,J=5.6Hz,3H).Anal.Calcd forC22H29N3O6C 61.24,H 6.77,N 9.74.Found C 61.40,H 6.91,N 9.55.
实施例13N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-酪氨酸甲酯(3f)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1601mg(6.96mmol)HCl·L-Tyr-OMe得到3191mg(93%)标题化合物,为浅黄色粉末。Mp 143-145℃;ESI/MS 494[M+H]+;IR(KBr):3439,3203,3001,2955,2847,1732,1644,1601,1453,1391,1372,1062,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.99(s,1H),8.02(s,1H),7.37(t,J=7.6Hz,1H),7.22(t,J=7.7Hz,1H),7.15(d,J=7.5Hz,2H),7.02(d,J=7.5Hz,1H),6.96(d,J=7.7Hz,1H),6.91(d,J=7.5Hz,2H),4.98(s,1H),4.93(d,J=5.4Hz,1H),4.80(t,J=5.6Hz,1H),4.29(m,J=5.2Hz,2H),3.64(s,3H),3.15(d,J=5.2Hz,2H),2.97(d,J=5.0Hz,2H),1.49(s,9H).Anal.Calcd for C27H31N3O6C 65.71,H 6.33,N 8.51.Found C 65.67,H 6.50,N 8.67.
实施例14N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-脯氨酸甲酯(3g)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1141mg(6.96mmol)HCl·L-Pro-OMe得到2883mg(97%)标题化合物,为浅黄色粉末。Mp 139-141℃;ESI/MS 428[M+H]+;IR(KBr):3435,3202,3000,2950,2846,1732,1645,1602,1454,1390,1371,1063,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),7.35(t,J=7.4Hz,1H),7.20(t,J=7.7Hz,1H),7.07(d,J=7.7Hz,1H),6.91(d,J=7.4Hz,1H),4.88(t,J=5.4Hz,1H),4.35(t,J=5.6Hz,1H),4.22(d,J=5.3Hz,2H),3.59(s,3H),3.47(t,J=5.6Hz,2H),2.95(d,J=5.6Hz,2H),2.29(d,J=5.6Hz,2H),1.97(t,J=4.9Hz,2H),1.45(s,9H).Anal.Calcd for C23H29N3O5C64.62,H 6.84,N 9.83.Found C 64.57,H 6.90,N 9.67.
实施例15N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-半胱氨酸甲酯(3h)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1183mg(6.96mmol)HCl·L-Cys-OMe得到2683mg(92%)标题化合物,为浅黄色粉末。Mp 151-153℃;ESI/MS 434[M+H]+;IR(KBr):3445,3203,3000,2944,2840,1731,1643,1601,1453,1390,1372,1061,898cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.93(s,1H),7.97(s,1H),7.32(t,J=7.5Hz,1H),7.22(t,J=7.8Hz,1H),7.00(d,J=7.8Hz,1H),6.88(d,J=7.5Hz,1H),4.93(t,J=5.3Hz,1H),4.72(t,J=5.5Hz,1H),4.21(d,J=5.3Hz,2H),3.68(s,3H),3.16(d,J=5.5Hz,2H),3.01(d,J=5.6Hz,2H),1.45(s,9H),1.62(s,1H).Anal.Calcd for C21H27N3O5S C 58.18,H 6.28,N 9.69.Found C 58.27,H 6.33,N 9.57.
实施例16N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-甲硫氨酸甲酯(3i)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1378mg(6.96mmol)ofHCl·L-Met-OMe得到3112mg(97%)标题化合物,为浅黄色粉末。Mp 159-161℃;ESI/MS 462[M+H]+;IR(KBr):3441,3203,3004,2953,2847,1732,1641,1603,1454,1390,1372,1061,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.04(s,1H),7.97(s,1H),7.32(t,J=7.5Hz,1H),7.22(t,J=7.8Hz,1H),6.99(d,J=7.8Hz,1H),6.81(d,J=7.5Hz,1H),4.86(t,J=5.3Hz,1H),4.45(t,J=5.5Hz,1H),4.28(d,J=5.1Hz,2H),3.68(s,3H),2.93(d,J=5.3Hz,2H),2.42(t,J=5.4Hz,2H),2.28(d,J=5.6Hz,2H),2.10(s,3H),1.44(s,9H).Anal.Calcd for C23H31N3O5S C59.85,H 6.77,N 9.10.Found C 59.67,H 6.59,N 9.04.
实施例17N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-谷氨酸甲酯(3j)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1462mg(6.96mmol)of HCl·L-Glu-(OMe)2得到3062mg(93%)标题化合物,为浅黄色粉末。Mp 154-156℃;ESI/MS 474[M+H]+;IR(KBr):3441,3203,3000,2944,2831,1731,1645,1604,1455,1390,1372,1067,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.89(s,1H),8.04(s,1H),7.39(t,J=7.6Hz,1H),7.28(t,J=7.6Hz,1H),7.01(d,J=7.7Hz,1H),6.84(d,J=7.6Hz,1H),4.90(d,J=5.4Hz,1H),4.43(t,J=5.6Hz,1H),4.22(d,J=5.5Hz,2H),3.66(s,3H),3.64(s,3H),2.96(d,J=5.4Hz,2H),2.28(t,J=5.6Hz,2H),2.24(t,J=5.7Hz,2H),1.43(s,9H).Anal.Calcd for C24H31N3O7C60.88,H 6.60,N 8.87.Found C 60.73,H 6.49,N 8.69.
实施例18N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-天冬氨酸甲酯(3k)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1364mg(6.96mmol)HCl·L-Asp-(OMe)2得到2875mg(90%)标题化合物,为浅黄色粉末。Mp 158-160℃;ESI/MS 460[M+H]+;IR(KBr):3441,3210,3004,2955,2841,1732,1643,1604,1453,1390,1371,1061,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.05(s,1H),8.05(s,1H),7.37(t,J=7.4Hz,1H),7.25(t,J=7.4Hz,1H),7.00(d,J=7.6Hz,1H),6.95(d,J=7.4Hz,1H),4.92(d,J=5.5Hz,1H),4.77(t,J=5.5Hz,1H),4.24(d,J=5.6Hz,2H),3.62(s,3H),3.58(s,3H),2.91(d,J=5.2Hz,2H),2.85(d,J=5.4Hz,2H),1.49(s,9H).Anal.Calcd for C23H29N3O7C 60.12,H 6.36,N 9.14.Found C 60.03,H 6.49,N 8.99.
实施例19N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-组氨酸甲酯(3l)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1420mg(6.96mmol)HCl·L-His-OMe得到2939mg(93%)标题化合物,为浅黄色粉末。Mp 162-164℃;ESI/MS 468[M+H]+;IR(KBr):3442,3206,3004,2949,2839,1730,1643,1601,1454,1391,1368,1062,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=12.98(s,1H),9.96(s,1H),8.05(s,1H),7.47(s,1H),7.36(t,J=7.4Hz,1H),7.20(t,J=7.7Hz,1H),7.16(d,J=7.7Hz,1H),6.98(t,J=7.4Hz,1H),6.85(s,1H),4.93(t,J=5.3Hz,1H),4.83(t,J=5.4Hz,1H),4.26(d,J=5.2Hz,2H),3.64(s,3H),3.19(d,J=5.4Hz,2H),2.92(d,J=5.2Hz,2H),1.49(s,9H).Anal.Calcd for C24H29N5O5C61.66,H 6.25,N 14.98.Found C 61.52,H 6.38,N 14.79.
实施例20N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-色氨酸甲酯(3m)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1761mg(6.96mmol)HCl·L-Trp-OMe得到3340mg(93%)标题化合物,为浅黄色粉末。Mp 161-163℃;ESI/MS 517[M+H]+;IR(KBr):3442,3204,3000,2948,2839,1729,1642,1604,1448,1391,1372,1062,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.87(s,1H),9.86(s,1H),8.09(s,1H),7.32(t,J=7.5Hz,1H),7.30(t,J=7.4Hz,1H),7.12(d,J=7.8Hz,1H),7.11(t,J=7.8Hz,1H),7.10(d,J=7.6Hz,1H),7.09(t,J=7.8Hz,1H),7.04(d,J=7.6Hz,1H),6.98(d,J=7.5Hz,1H),6.83(s,1H),4.94(d,J=5.4Hz,1H),4.76(t,J=5.3Hz,1H),4.29(d,J=5.2Hz,2H),3.64(s,3H),3.19(d,J=5.4Hz,2H),2.95(d,J=6.4Hz,2H),1.49(s,9H).Anal.Calcd for C29H32N4O5 C 67.43,H 6.24,N 10.85.Found C 67.55,H 6.34,N 10.72.
实施例21N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-精氨酸甲酯(3n)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1552mg(6.96mmol)HCl·L-Arg-OMe得到2977mg(88%)标题化合物,为浅黄色粉末。Mp 168-170℃;ESI/MS 487[M+H]+;IR(KBr):3443,3207,3001,2948,2842,1731,1645,1602,1453,1390,1372,1061,904cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.22(s,1H),8.45(s,2H),8.27(s,1H),8.22(s,1H),8.01(s,1H),7.29(t,J=7.6Hz,1H),7.18(t,J=7.7Hz,1H),7.04(d,J=7.7Hz,1H),6.96(d,J=7.6Hz,1H),4.90(d,J=5.3Hz,1H),4.42(t,J=4.2Hz,1H),4.25(d,J=5.0Hz,2H),3.65(s,3H),2.94(d,J=4.1Hz,2H),2.68(t.J=5.4Hz,2H),1.92(m,J=5.5Hz,2H),1.58(m,J=5.5Hz,2H),1.57(s,9H).Anal.Calcd for C24H34N6O5C 59.24,H 7.04,N 17.27.Found C59.38,H 7.19,N 17.31.
实施例22N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-甘氨酸甲酯(3o)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由863mg(6.96mmol)HCl·L-Gly-OMe得到2613mg(97%)标题化合物,为浅黄色粉末。Mp 133-135℃;ESI/MS 388[M+H]+.IR(KBr):3448,3010,2945,2843,1732,1600,1453,1390,1371,1062,899cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.93(s,1H),8.02(s,1H),7.30(t,J=7.5Hz,1H),7.20(t,J=7.6Hz,1H),6.95(d,J=7.6Hz,1H),6.83(d,J=7.6Hz,1H),4.89(d,J=5.4Hz,1H),4.22(dd,J=10.2Hz,J=4.5Hz,1H),4.18(s,2H),4.19(dd,J=10.2Hz,J=3.7Hz,1H),3.66(s,3H),2.95(d,J=10.1Hz,2H),1.45(s,9H).[α]D 20=-101°(c=0.36,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC20H25N3O5 C 62.00,H,6.50,N 10.85.Found C 62.15,H 6.68,N 10.68.
实施例23N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-(Z)赖氨酸甲酯(3p)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由2255mg(6.96mmol)HCl·L-Lys(Z)-OMe得到3708mg(90%)标题化合物,为浅黄色粉末。Mp 134-136℃;ESI/MS:593[M+H]+.IR(KBr):3442,3007,2940,2848,1730,1605,1455,1391,1370,1066,897cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.95(s,1H),8.03(s,1H),7.96(s,1H),7.28(t,J=7.6Hz,1H),7.22(t,J=7.2Hz,1H),7.19(t,J=7.6Hz,1H),7.17(d,J=7.2Hz,2H),7.15(t,J=7.2Hz,2H),6.96(d,J=7.6Hz,1H),6.85(d,J=7.6Hz,1H),5.36(s,2H),4.90(d,J=5.5Hz,1H),4.41(t,J=4.4Hz,1H),4.20(dd,J=10.0Hz,J=4.5Hz,1H),4.18(dd,J=10.0Hz,J=3.7Hz,1H),3.64(s,3H),2.98(t,J=4.4Hz,2H),2.93(d,J=10.0Hz,2H),1.91(m,J=4.4Hz,2H),1.55(m,J=4.4Hz,2H),1.46(s,9H),1.29(m,J=4.4Hz,2H).[α]D 20=-22°(c=0.39,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C32H40N4O7C 64.85,H,6.80,N 9.45.Found C 64.98,H 6.69,N9.62.
实施例24N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-谷氨酰胺甲酯(3q)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1357mg(6.96mmol)HCl·L-Gln-OMe得到2869mg(90%)标题化合物,为浅黄色粉末。Mp 122-124℃;ESI/MS:459[M+H]+.IR(KBr):3445,3200,3001,2940,2835,1733,1640,1602,1452,1391,1370,1065,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.91(s,1H),8.00(s,1H),7.29(t,J=7.4Hz,1H),7.20(t,J=7.4Hz,1H),7.00(d,J=7.4Hz,1H),6.80(d,J=7.4Hz,1H),6.05(s,2H),4.92(d,J=5.5Hz,1H),4.41(t,J=5.5Hz,1H),4.24(d,J=5.6Hz,2H),3.67(s,3H),2.94(d,J=5.4Hz,2H),2.18(t,J=5.5Hz,2H),2.14(t,J=5.5Hz,2H),1.46(s,9H).[α]D 20=-56°(c=0.38,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C23H30N4O6C 60.25,H 6.59,N 12.22.FoundC 60.73,H 6.49,N 8.69.
实施例25N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-天冬酰胺甲酯(3r)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1371mg(6.96mmol)HCl·L-Asn-OMe得到2843mg(92%)标题化合物,为浅黄色粉末。Mp 129-131℃;ESI/MS:445[M+H]+.IR(KBr):3440,3203,3005,2936,2830,1730,1632,1600,1455,1394,1372,1062,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.94(s,1H),8.03(s,1H),7.25(t,J=7.2Hz,1H),7.17(t,J=7.2Hz,1H),7.04(d,J=7.2Hz,1H),6.82(d,J=7.2Hz,1H),6.01(s,2H),4.95(d,J=5.4Hz,1H),4.43(t,J=5.4Hz,1H),4.26(d,J=5.4Hz,2H),3.63(s,3H),2.90(d,J=5.2Hz,2H),2.15(t,J=5.3Hz,2H),1.49(s,9H).[α]D 20=-50°(c=0.30,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C22H28N4O6C 59.45,H 6.35,N 12.60.Found C 59.28,H 6.26,N 12.77.
实施例26N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-亮氨酸甲酯(3s)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1250mg(6.96mmol)HCl·L-Leu-OMe得到2929mg(95%)标题化合物,为浅黄色粉末。Mp 131-133℃;ESI/MS:444[M+H]+.IR(KBr):3442,3203,3001,2955,2840,1731,1640,1600,1451,1390,1375,1063,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.90(s,1H),8.03(s,1H),7.25(t,J=7.2Hz,1H),7.19(t,J=7.2Hz,1H),7.00(d,J=7.2Hz,1H),6.84(d,J=7.2Hz,1H),4.95(t,J=5.3Hz,1H),4.44(t,J=5.3Hz,1H),4.25(dd,J=10.1Hz,J=4.4Hz,1H),4.06(dd,J=10.1Hz,J=3.6Hz,1H),3.64(s,3H),2.93(d,J=6.4Hz,2H),2.85(d,J=5.0Hz,2H),1.51(s,9H),1.36(m,J=5.0Hz,1H),1.09(d,J=5.2Hz,6H).[α]D 20=-41°(c=0.31,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcdfor C24H33N3O5 C 64.99,H 7.50,N 9.47.Found C 65.16,H 7.61,N 9.30.
实施例27N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-异亮氨酸甲酯(3t)的制备
采用实施例7制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸甲酯(3a-t)的一般操作,由1250mg(6.96mmol)HCl·L-Ile-OMe得到2870mg(92%)标题化合物,为浅黄色粉末。Mp 122-125℃;ESI/MS:444[M+H]+.IR(KBr):3440,3205,3006,2952,2844,1736,1645,1603,1454,1380,1390,1060,905cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.93(s,1H),8.02(s,1H),7.29(t,J=7.3Hz,1H),7.22(t,J=7.3Hz,1H),7.02(d,J=7.3Hz,1H),6.89(d,J=7.3Hz,1H),4.97(t,J=5.2Hz,1H),4.40(t,J=5.2Hz,1H),4.22(dd,J=10.0Hz,J=4.2Hz,1H),4.01(dd,J=10.0Hz,J=3.4Hz,1H),3.69(s,3H),2.96(d,J=6.2Hz,2H),2.93(m,J=5.4Hz,1H),1.49(s,9H),1.33(m,J=5.5Hz,2H),1.07(d,J=5.1Hz,3H),0.97(t,J=5.5Hz,3H).[α]D 20=-49°(c=0.37,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C24H33N3O5 C 64.99,H 7.50,N 9.47.Found C 64.80,H 7.39,N 9.62.
实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3’a-t)的一般操作
0℃下往2.0g(6.33mmol)N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-羧酸与30ml无水四氢呋喃的溶液中加入1.2g(8.9mmol)HOBt,10min后再加入1.75g(8.5mmol)DCC(称溶液A)。6.96mmol L-氨基酸苄酯盐酸盐与3ml无水四氢呋喃的悬浮液用N-甲基吗啉调pH至8-9,室温搅拌20min.将该悬浮液加到溶液A中,0℃搅拌2h,室温搅拌16h,减压浓缩。残留物溶入30ml乙酸乙酯中,得到的溶液依次用NaHCO3溶液洗(5%,50ml×6),柠檬酸溶液洗(5%,50ml×3),饱和NaCl溶液洗(50ml×3),无水MgSO4干燥,减压浓缩,得到粉末状标题化合物。
实施例29N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-丙氨酸苄酯(3,a)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1496mg(6.96mmol)HCl·L-Ala-OBzl得到2868mg(95%)标题化合物,为浅黄色粉末。Mp 110-112℃;ESI/MS:478[M+H]+.IR(KBr):3447,3342,3001,2945,2842,1761,1733,1602,1455,1391,1373,1062,899cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.93(s,1H),8.04(s,1H),7.30(t,J=7.3Hz,1H),7.24(t,J=7.3Hz,1H),7.22(t,J=7.2Hz,2H),7.14(d,J=7.2Hz,2H),7.11(t,J=7.2Hz,1H),6.95(d,J=7.3Hz,1H),6.83(d,J=7.3Hz,1H),5.35(s,2H),4.86(d,J=5.4Hz,1H),4.56(m,J=5.2Hz,1H),4.22(dd,J=10.1Hz,J=4.5Hz,1H),4.15(dd,J=10.0Hz,J=3.7Hz,1H),2.92(d,J=10.0Hz,2H),1.57(d,J=5.0Hz,3H),1.46(s,9H).[α]D 20=-100°(c=0.38,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C27H31N3O5 C 67.91,H,6.54,N 8.80.Found C67.72,H 6.40,N 8.90.
实施例30N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-苯丙氨酸苄酯(3’b)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1914mg(6.96mmol)HCl·L-Phe-OBzl得到3360mg(96%)标题化合物,为浅黄色粉末。Mp 144-146℃;ESI/MS:554[M+H]+.IR(KBr):3442,3350,3202,3009,2944,2842,1758,1734,1642,1601,1455,1390,1371,1065,902cm-1;1HNMR(BHSC-500,DMSO-d6):δ=9.95(s,1H),7.99(s,1H),7.28(t,J=7.3Hz,1H),7.25(t,J=7.6Hz,2H),7.22(t,J=7.3Hz,2H),7.17(t,J=7.3Hz,1H),7.15(d,J=7.4Hz,2H),7.13(d,J=7.3Hz,2H),7.11(t,J=7.3Hz,1H),7.03(t,J=7.3Hz,1H),6.98(d,J=7.6Hz,1H),6.82(d,J=7.2Hz,1H),5.34(s,2H),4.95(d,J=5.2Hz,1H),4.84(t,J=5.2Hz,1H),4.25(dd,J=10.0Hz,J=4.1Hz,1H),4.15(dd,J=10.0Hz,J=3.5Hz,1H),3.19(d,J=5.2Hz,2H),2.92(d,J=10.0Hz,2H),1.49(s,9H).[α]D 20=-52°(c=0.38,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C33H35N3O5 C 71.59,H 6.37,N 7.59.Found C 71.74,H 6.22,N 7.77.
实施例31N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-缬氨酸苄酯(3’c)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1691mg(6.96mmol)HCl·L-Val-OBzl得到3005mg(94%)标题化合物,为浅黄色粉末。Mp 169-171℃;ESI/MS 506[M+H]+.IR(KBr):3441,3336,3205,3004,2953,2843,1757,1732,1645,1600,1453,1390,1372,1064,900cm-1;1HNMR(BHSC-500,DMSO-d6):δ=10.00(s,1H),7.98(s,1H),7.27(t,J=7.4Hz,1H),7.23(t,J=7.0Hz,2H),7.20(t,J=7.4Hz,1H),7.02(d,J=7.4Hz,1H),7.13(d,J=7.0Hz,2H),7.10(t,J=7.0Hz,1H),6.87(d,J=7.4Hz,1H),5.34(s,2H),4.86(t,J=5.2Hz,1H),4.40(d,J=5.1Hz,1H),4.24(dd,J=10.0Hz,J=4.3Hz,1H),4.05(dd,J=10.0Hz,J=3.5Hz,1H),3.12(m,J=5.2Hz,1H),2.93(d,J=6.4Hz,2H),1.49(s,9H),1.03(d,J=5.1Hz,6H).Anal.Calcd forC29H35N3O5C 68.89,H 6.98,N 8.31.Found C 68.74,H 7.08,N 8.48.
实施例32N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-丝氨酸苄酯(3’d)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1608mg(6.96mmol)HCl·L-Ser-OBzl得到2902mg(93%)标题化合物,为浅黄色粉末。Mp 125-127℃;ESI/MS:494[M+H]+.IR(KBr):3445,3338,3207,3005,2956,2843,1762,1733,1642,1601,1457,1390,1371,1062,903cm-1;1HNMR(BHSC-500,DMSO-d6):δ=9.97(s,1H),7.99(s,1H),7.27(t,J=7.2Hz,1H),7.23(t,J=7.3Hz,1H),7.21(t,J=7.0Hz,2H),7.13(d,J=7.0Hz,2H),7.10(t,J=7.0Hz,1H),6.99(d,J=7.3Hz,1H),6.85(t,J=7.2Hz,1H),5.33(s,2H),4.89(d,J=5.2Hz,1H),4.50(t,J=5.0Hz,1H),4.17(d,J=5.0Hz,2H),4.15(d,J=5.2Hz,2H),2.94(d,J=5.3Hz,1H),2.90(d,J=5.3Hz,1H),2.25(s,1H),1.47(s,9H).[α]D 20=-51°(c=0.35,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C27H31N3O6C 65.71,H 6.33,N 8.51.Found C 65.58,H 6.39,N8.70.
实施例33N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-苏氨酸苄酯(3’e)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1639mg(6.96mmol)HCl·L-Thr-OBzl得到3176mg(90%)标题化合物,为浅黄色粉末。Mp 145-147℃;ESI/MS 508[M+H]+;IR(KBr):3440,3334,3201,3002,2951,2845,1760,1731,1640,1600,1452,1395,1375,1060,900cm-1;1HNMR(BHSC-500,DMSO-d6):δ=9.95(s,1H),7.84(s,1H),7.30(t,J=7.2Hz,1H),7.24(t,J=7.2Hz,1H),7.19(t,J=7.0Hz,2H),7.10(d,J=7.0Hz,2H),7.07(t,J=7.0Hz,1H),6.97(d,J=7.2Hz,1H),6.85(t,J=7.2Hz,1H),5.33(s,2H),4.85(t,J=5.5Hz,1H),4.63(m,J=5.5Hz,1H),4.45(t,J=5.5Hz,1H),3.95(m,J=5.3Hz,2H),2.94(d,J=5.6Hz,2H),2.20(s,1H),1.49(s,9H),1.22(d,J=5.5Hz,3H).Anal.Calcd for C28H33N3O6C 66.26,H6.55,N 8.28.Found C 66.11,H 6.38,N 8.44.
实施例34N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-酪氨酸苄酯(3’f)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由2137mg(6.96mmol)HCl·L-Tyr-OBzl得到3564mg(90%)标题化合物,为浅黄色粉末。Mp 155-157℃;ESI/MS 570[M+H]+;IR(KBr):3444,3200,3006,2950,2842,1730,1647,1600,1456,1395,1370,1060,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.95(s,1H),8.04(s,1H),7.37(t,J=7.4Hz,1H),7.23(t,J=7.6Hz,1H),7.16(d,J=7.4Hz,2H),7.14(t,J=7.1Hz,2H),7.12(d,J=7.1Hz,2H),7.09(t,J=7.1Hz,1H),7.05(d,J=7.4Hz,1H),6.93(d,J=7.6Hz,1H),6.90(d,J=7.4Hz,2H),5.40(s,2H),4.99(s,1H),4.91(d,J=5.5Hz,1H),4.82(t,J=5.7Hz,1H),4.26(m,J=5.3Hz,2H),3.17(d,J=5.3Hz,2H),2.95(d,J=5.1Hz,2H),1.47(s,9H).Anal.Calcd forC33H35N3O6C 69.58,H 6.19,N 7.38.Found C 69.41,H 6.10,N 7.53.
实施例35N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-脯氨酸苄酯(3’g)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1677mg(6.96mmol)HCl·L-Pro-OBzl得到3256mg(93%)标题化合物,为浅黄色粉末。Mp 133-135℃;ESI/MS 504[M+H]+;IR(KBr):3439,3206,3005,2952,2843,1730,1641,1600,1452,1395,1373,1060,905cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.04(s,1H),7.33(t,J=7.3Hz,1H),7.22(t,J=7.6Hz,1H),7.20(t,J=7.2Hz,2H),7.13(d,J=7.2Hz,2H),7.09(t,J=7.2Hz,1H),7.05(d,J=7.6Hz,1H),6.93(d,J=7.3Hz,1H),5.30(s,2H),4.86(t,J=5.3Hz,1H),4.33(t,J=5.5Hz,1H),4.24(d,J=5.2Hz,2H),3.49(t,J=5.5Hz,2H),2.93(d,J=5.5Hz,2H),2.27(d,J=5.5Hz,2H),1.96(t,J=4.8Hz,2H),1.45(s,9H).Anal.Calcd for C29H33N3O5C 69.17,H 6.60,N8.34.Found C 69.02,H 6.50,N 8.51.
实施例36N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-半胱氨酸苄酯(3’h)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1719mg(6.96mmol)of HCl·L-Cys-OBzl得到3170mg(90%)标题化合物,为浅黄色粉末。Mp 151-153℃;ESI/MS 510[M+H]+;IR(KBr):3441,3205,3003,2940,2842,1735,1640,1603,1450,1392,1375,1062,899cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.96(s,1H),7.95(s,1H),7.30(t,J=7.4Hz,1H),7.24(t,J=7.6Hz,1H),7.22(t,J=7.5Hz,2H),7.15(d,J=7.5Hz,2H),7.11(t,J=7.5Hz,1H),7.07(d,J=7.6Hz,1H),6.86(d,J=7.4Hz,1H),5.32(s,2H),4.95(t,J=5.4Hz,1H),4.74(t,J=5.6Hz,1H),4.23(d,J=5.4Hz,2H),3.14(d,J=5.4Hz,2H),3.02(d,J=5.5Hz,2H),1.47(s,9H),1.65(s,1H).Anal.Calcd for C27H31N3O5S C 63.63,H 6.13,N 8.25.Found C 63.45,H 6.02,N 8.10.
实施例37N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-甲硫氨酸苄酯(3’i)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1914mg(6.96mmol)of HCl·L-Met-OBzl得到3401mg(91%)标题化合物,为浅黄色粉末。Mp 167-169℃;ESI/MS 538[M+H]+;IR(KBr):3445,3200,3007,2956,2849,1730,1645,1600,1452,1395,1370,1064,905cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.07(s,1H),7.94(s,1H),7.33(t,J=7.4Hz,1H),7.23(t,J=7.6Hz,1H),7.20(t,J=7.5Hz,2H),7.17(d,J=7.5Hz,2H),7.12(t,J=7.5Hz,1H),6.95(d,J=7.4Hz,1H),6.83(d,J=7.4Hz,1H),5.32(s,2H),4.87(t,J=5.1Hz,1H),4.46(t,J=5.4Hz,1H),4.26(d,J=5.2Hz,2H),2.95(d,J=5.1Hz,2H),2.44(t,J=5.3Hz,2H),2.25(d,J=5.4Hz,2H),2.13(s,3H),1.49(s,9H).Anal.Calcd for C29H35N3O5S C 64.78,H 6.56,N7.82.Found C 64.62,H 6.45,N 7.99.
实施例38N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-谷氨酰胺苄酯(3’j)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由2526mg(6.96mmol)HCl·L-Glu-(OBzl)2得到3915mg(90%)标题化合物,为浅黄色粉末。Mp 144-146℃;ESI/MS 626[M+H]+;IR(KBr):3445,3204,3007,2948,2826,1735,1640,1600,1452,1391,1375,1062,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.92(s,1H),8.03(s,1H),7.36(t,J=7.5Hz,1H),7.27(t,J=7.5Hz,1H),7.24(t,J=7.3Hz,2H),7.22(t,J=7.4Hz,2H),7.21(d,J=7.3Hz,2H),7.19(d,J=7.4Hz,2H),7.16(t,J=7.3Hz,1H),7.14(t,J=7.4Hz,1H),7.04(d,J=7.5Hz,1H),6.86(d,J=7.5Hz,1H),5.36(s,2H),5.33(s,2H),4.93(d,J=5.3Hz,1H),4.46(t,J=5.5Hz,1H),4.25(d,J=5.4Hz,2H),2.95(d,J=5.2Hz,2H),2.25(t,J=5.5Hz,2H),2.22(t,J=5.6Hz,2H),1.48(s,9H).Anal.Calcd for C36H39N3O7C 69.10,H 6.28,N 6.72.Found C 69.27,H 6.18,N 6.89.
实施例39N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-天冬酰胺苄酯(3’k)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由2429mg(6.96mmol)of HCl·L-Asp-(OBzl)2得到3558mg(92%)标题化合物,为浅黄色粉末。Mp 132-134℃;ESI/MS 612[M+H]+;IR(KBr):3445,3340,3214,3002,2952,2843,1758,1730,1646,1602,1455,1388,1369,1064,901cm-1;1HNMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),8.02(s,1H),7.30(t,J=7.2Hz,1H),7.24(t,J=7.2Hz,1H),7.22(t,J=7.0Hz,2H),7.20(t,J=7.0Hz,2H),7.15(d,J=7.0Hz,2H),7.13(d,J=7.0Hz,2H),7.11(t,J=7.0Hz,1H),7.10(t,J=7.0Hz,1H),7.02(d,J=7.2Hz,1H),6.98(d,J=7.2Hz,1H),5.36(s,2H),5.34(s,2H),4.94(d,J=5.2Hz,1H),4.79(t,J=5.2Hz,1H),4.27(d,J=5.2Hz,2H),2.94(d,J=5.0Hz,2H),2.87(d,J=5.2Hz,2H),1.47(s,9H).Anal.Calcd for C35H37N3O7C 68.72,H 6.10,N 6.87.Found C 68.54,H 6.19,N 7.00.
实施例40N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-组氨酸苄酯(3’l)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1956mg(6.96mmol)of HCl·L-His-OBzl得到3439mg(91%)标题化合物,为浅黄色粉末。Mp 153-155℃;ESI/MS 544[M+H]+;IR(KBr):3445,3202,3007,2943,2832,1735,1640,1600,1452,1395,1371,1060,905cm-1;1H NMR(BHSC-500,DMSO-d6):δ=12.95(s,1H),9.98(s,1H),8.01(s,1H),7.45(s,1H),7.35(t,J=7.2Hz,1H),7.22(t,J=7.3Hz,2H),7.17(t,J=7.4Hz,1H),7.15(d,J=7.3Hz,2H),7.13(d,J=7.4Hz,1H),7.11(t,J=7.3Hz,1H),6.95(t,J=7.2Hz,1H),6.88(s,1H),5.38(s,2H),4.91(t,J=5.2Hz,1H),4.80(t,J=5.1Hz,1H),4.22(d,J=5.1Hz,2H),3.21(d,J=5.2Hz,2H),2.90(d,J=5.1Hz,2H),1.47(s,9H).Anal.Calcd for C30H33N5O5C 66.28,H6.12,N 12.88.Found C 66.11,H 6.00,N 13.07.
实施例41N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-酪氨酸苄酯(3’m)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由2297mg(6.96mmol)of HCl·L-Trp-OBzl得到3453mg(92%)标题化合物,为浅黄色粉末。Mp 136-138℃;ESI/MS:593[M+H]+.IR(KBr):3444,3337,3208,3005,2945,2835,1758,1736,1645,1602,1449,1390,1370,1067,903cm-1;1HNMR(BHSC-500,DMSO-d6):δ=9.96(s,1H),9.89(s,1H),8.03(s,1H),7.29(t,J=7.3Hz,1H),7.27(t,J=7.2Hz,1H),7.22(t,J=7.0Hz,2H),7.14(d,J=7.0Hz,2H),7.12(d,J=7.5Hz,1H),7.11(t,J=7.0Hz,1H),7.10(t,J=7.5Hz,1H),7.09(d,J=7.3Hz,1H),7.07(t,J=7.5Hz,1H),7.02(d,J=7.3Hz,1H),6.97(d,J=7.2Hz,1H),6.85(s,1H),5.36(s,2H),4.96(d,J=5.2Hz,1H),4.73(t,J=5.1Hz,1H),4.27(d,J=5.0Hz,2H),3.17(d,J=5.2Hz,2H),2.97(d,J=6.2Hz,2H),1.47(s,9H).[α]D 20=-77°(c=0.36,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C35H36N4O5 C 70.93,H 6.12,N 9.45.Found C 70.80,H 6.01,N9.60.
实施例42N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-精氨酸苄酯(3’n)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由2088mg(6.96mmol)HCl·L-Arg-OBzl得到3325mg(85%)标题化合物,为浅黄色粉末。Mp 152-154℃;ESI/MS 563[M+H]+;IR(KBr):3446,3203,3005,2944,2846,1725,1642,1603,1450,1395,1370,1064,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.20(s,1H),8.42(s,2H),8.25(s,1H),8.20(s,1H),8.00(s,1H),7.27(t,J=7.4Hz,1H),7.24(t,J=7.2Hz,2H),7.17(d,J=7.2Hz,2H),7.15(t,J=7.5Hz,1H),7.13(t,J=7.2Hz,1H),7.01(d,J=7.5Hz,1H),6.93(d,J=7.4Hz,1H),5.34(s,2H),4.92(d,J=5.2Hz,1H),4.40(t,J=4.4Hz,1H),4.27(d,J=5.2Hz,2H),2.90(d,J=4.4Hz,2H),2.67(t,J=5.2Hz,2H),1.95(m,J=5.3Hz,2H),1.56(m,J=5.3Hz,2H),1.55(s,9H).Anal.Calcd for C30H38N6O5C 64.04,H 6.81,N 14.94.Found C 64.21,H 6.69,N 14.78.
实施例43N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-甘氨酸苄酯(3’o)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1399mg(6.96mmol)HCl·L-Gly-OBzl得到2784mg(95%)标题化合物,为浅黄色粉末。Mp 139-141℃;ESI/MS:464[M+H]+.IR(KBr):3444,3336,3004,2940,2845,1761,1730,1602,1455,1392,1375,1060,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.96(s,1H),8.05(s,1H),7.27(t,J=7.4Hz,1H),7.23(t,J=7.2Hz,2H),7.18(t,J=7.4Hz,1H),7.15(d,J=7.2Hz,2H),7.11(t,J=7.2Hz,1H),6.93(d,J=7.4Hz,1H),6.85(d,J=7.4Hz,1H),5.36(s,2H),4.86(d,J=5.2Hz,1H),4.25(dd,J=10.0Hz,J=4.3Hz,1H),4.17(dd,J=10.0Hz,J=3.4Hz,1H),4.15(s,2H),2.93(d,J=10.0Hz,2H),1.48(s,9H).[α]D 20=-84°(c=0.36,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcdfor C26H29N3O5C 67.37,H,6.31,N 9.07.Found C 67.25,H 6.18,N 9.19.
实施例44N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-(Z)赖氨酸苄酯(3’p)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由2826mg(6.96mmol)of HCl·L-Lys(Z)-OBzl得到3890mg(92%)标题化合物,为浅黄色粉末。Mp 123-125℃;ESI/MS:669[M+H]+.IR(KBr):3445,3339,3002,2942,2845,1761,1735,1602,1459,1392,1371,1063,899cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.98(s,1H),8.02(s,1H),7.99(s,1H),7.27(t,J=7.3Hz,1H),7.22(t,J=7.2Hz,2H),7.20(t,J=7.0Hz,1H),7.17(t,J=7.3Hz,1H),7.14(d,J=7.0Hz,2H),7.13(d,J=7.2Hz,2H),7.12(t,J=7.0Hz,2H),7.10(t,J=7.2Hz,1H),6.98(d,J=7.3Hz,1H),6.88(d,J=7.3Hz,1H),5.35(s,2H),5.33(s,2H),4.93(d,J=5.2Hz,1H),4.45(t,J=4.2Hz,1H),4.25(dd,J=10.2Hz,J=4.3Hz,1H),4.15(dd,J=10.2Hz,J=3.4Hz,1H),2.96(t,J=4.2Hz,2H),2.94(d,J=10.2Hz,2H),1.93(m,J=4.2Hz,2H),1.55(m,J=4.4Hz,2H),1.48(s,9H),1.27(m,J=4.2Hz,2H).[α]D 20=-41°(c=0.39,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcdfor C38H44N4O7C 68.24,H,6.63,N 8.38.Found C 68.08,H 6.77,N 8.53.
实施例45N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-谷氨酰胺苄酯(3’q)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1893mg(6.96mmol)HCl·L-Gln-OBzl得到3233mg(87%)标题化合物,为浅黄色粉末。Mp 130-132℃;ESI/MS:535[M+H]+.IR(KBr):3441,3207,3004,2942,2830,1736,1642,1600,1455,1390,1375,1062,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.95(s,1H),8.04(s,1H),7.27(t,J=7.3Hz,1H),7.24(t,J=7.2Hz,2H),7.18(t,J=7.3Hz,1H),7.16(d,J=7.2Hz,2H),7.13(t,J=7.2Hz,1H),7.04(d,J=7.3Hz,1H),6.85(d,J=7.3Hz,1H),6.08(s,2H),5.35(s,2H),4.94(d,J=5.4Hz,1H),4.43(t,J=5.4Hz,1H),4.27(d,J=5.5Hz,2H),2.90(d,J=5.2Hz,2H),2.15(t,J=5.4Hz,2H),2.16(t,J=5.4Hz,2H),1.49(s,9H).[α]D 20=-50°(c=0.38,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C29H34N4O6C 65.15,H 6.41,N 10.48.Found C 65.32,H 6.52,N 10.31.
实施例46N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-天冬酰胺苄酯(3’r)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1796mg(6.96mmol)HCl·L-Asn-OBzl得到3257mg(90%)标题化合物,为浅黄色粉末。Mp 142-144℃;ESI/MS:521[M+H]+.IR(KBr):3443,3207,3004,2932,2833,1735,1630,1604,1451,1392,1375,1064,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.96(s,1H),8.05(s,1H),7.28(t,J=7.3Hz,1H),7.23(t,J=7.4Hz,2H),7.19(t,J=7.3Hz,1H),7.17(d,J=7.4Hz,2H),7.15(t,J=7.4Hz,1H),7.06(d,J=7.3Hz,1H),6.87(d,J=7.3Hz,1H),6.05(s,2H),5.33(s,2H),4.97(d,J=5.3Hz,1H),4.45(t,J=5.3Hz,1H),4.24(d,J=5.3Hz,2H),2.92(d,J=5.1Hz,2H),2.17(t,J=5.1Hz,2H),1.47(s,9H).[α]D 20=-42°(c=0.30,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC28H32N4O6C 64.60,H 6.20,N 10.76.Found C 64.78,H 6.29,N 10.57.
实施例47N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-亮氨酸苄酯(3’s)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1789mg(6.96mmol)HCl·L-Leu-OBzl得到3323mg(92%)标题化合物,为浅黄色粉末。Mp 140-142℃;ESI/MS:520[M+H]+.IR(KBr):3440,3207,3005,2951,2842,1735,1644,1603,1452,1393,1370,1060,904cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.95(s,1H),8.06(s,1H),7.27(t,J=7.3Hz,1H),7.24(t,J=7.1Hz,2H),7.21(t,J=7.3Hz,1H),7.15(d,J=7.1Hz,2H),7.11(t,J=7.1Hz,1H),7.06(d,J=7.3Hz,1H),6.82(d,J=7.3Hz,1H),5.33(s,2H),4.93(t,J=5.2Hz,1H),4.41(t,J=5.2Hz,1H),4.26(dd,J=10.0Hz,J=4.5Hz,1H),4.09(dd,J=10.0Hz,J=3.8Hz,1H),2.91(d,J=6.2Hz,2H),2.83(d,J=5.1Hz,2H),1.53(s,9H),1.34(m,J=5.1Hz,1H),1.07(d,J=5.3Hz,6H).[α]D 20=-33°(c=0.31,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C30H37N3O5C69.34,H 7.18,N 8.09.Found C 69.25,H 7.08,N 8.26.
实施例48N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-异亮氨酸苄酯(3’t)的制备
采用实施例28制备N-(N-Boc-3S-1,2,3,4-四氢-β-咔啉-3-甲酰)-L-氨基酸苄酯(3a-t)的一般操作,由1789mg(6.96mmol)HCl·L-Ile-OBzl得到2957mg(90%)标题化合物,为浅黄色粉末。Mp 134-136℃;ESI/MS:520[M+H]+.IR(KBr):3445,3339,3210,3010,2955,2840,1758,1732,1645,1600,1452,1390,1371,1064,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.96(s,1H),8.00(s,1H),7.27(t,J=7.1Hz,1H),7.22(t,J=7.0Hz,2H),7.20(t,J=7.1Hz,1H),7.00(d,J=7.1Hz,1H),7.13(d,J=7.0Hz,2H),7.10(t,J=7.0Hz,1H),6.88(d,J=7.1Hz,1H),5.35(s,2H),4.95(t,J=5.0Hz,1H),4.42(t,J=5.0Hz,1H),4.25(dd,J=10.2Hz,J=4.0Hz,1H),4.05(dd,J=10.2Hz,J=3.5Hz,1H),2.94(d,J=6.0Hz.2H),2.91(m,J=5.1Hz,1H),1.47(s,9H),1.30(m,J=5.2Hz,2H),1.05(d,J=5.2Hz,3H),0.95(t,J=5.2Hz,3H).[α]D 20=-36°(c=0.37,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcdfor C30H37N3O5C 69.34,H 7.18,N 8.09.Found C 69.50,H 7.29,N 8.24。
实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作0℃和搅拌下往2.50mmol of Boc-L-氨基酸,350mg(2.59mmol)HOBt,600mg(2.90mmol)DCC与15ml无水二氯甲烷的溶液中加入500mg(2.17mmol)3S-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(6’Me)。反应混合物0℃搅拌30min,室温搅拌40min,TLC(乙酸乙酯∶石油醚,5∶12)显示反应完成。滤除生成的DCU沉淀,滤液减压浓缩,残留物溶入30ml乙酸乙酯。得到的溶液得到的溶液依次用饱和NaCO3溶液洗(30ml×3),饱和NaCl溶液洗(30ml×3),饱和KHSO4溶液洗(30ml×3),饱和NaCl溶液洗(30ml×3),水洗(30ml×3),无水MgSO4干燥,减压浓缩。残留物用闪式硅胶柱层析(CHCl3/CH3OH,30∶1)纯化,得到无色粉末状产物。
实施例50(3S)-N-(Boc-L-丙氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-a)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由470mg(2.50mmol)Boc-L-Ala-OH得到811mg(93%)标题化合物,为无色粉末。Mp 148-150℃;FAB/MS:403[M+H]+;IR(KBr):3340,3006,2953,2840,1748,1642,1605,1450,1391,1072,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.93(s,1H),8.03(s,1H),7.28(t,J=7.5Hz,1H),7.18(t,J=7.5Hz,1H),6.97(t,J=7.5Hz,1H),6.94(t,J=7.5Hz,1H),4.76(t,J=5.8Hz,1H),4.66(m,J=5.3Hz,1H),3.84(s,2H),3.62(dd,J=10.2Hz,J=5.2Hz,1H),3.61(s,3H),3.20(dd,J=10.2Hz,J=2.8Hz,1H),1.48(d,J=5.3Hz,3H),1.45(s,9H).[α]D 20=-131°(c=0.38,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C21H27N3O5C 62.83,H 6.78,N 10.47.Found C 62.66,H 6.61,N10.29.
实施例51(3S)-N-(Boc-L-苯丙氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-b)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由660mg(2.50mmol)Boc-L-Phe-OH得到963mg(93%)标题化合物,为无色粉末。Mp 147-149℃;FAB/MS:478[M+H]+;IR(KBr):3338,3010,2943,2840,1752,1640,1602,1458,1390,1070,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.97(s,1H),7.89(s,1H),7.27(t,J=7.4Hz,1H),7.20(t,J=7.8Hz,2H),7.16(t,J=7.4Hz,1H),7.11(d,J=7.8Hz,2H),7.07(t,J=7.8Hz,1H),6.99(t,J=7.4Hz,1H),6.95(t,J=7.4Hz,1H),5.01(t,J=5.6Hz,1H),4.79(t,J=5.6Hz,1H),3.88(s,2H),3.64(dd,J=10.0Hz,J=5.1Hz,1H),3.63(s,3H),3.26(dd,J=10.0Hz,J=2.9Hz,1H),3.06(d,J=5.6Hz,2H),1.46(s,9H).[α]D 20=-89°(c=0.37,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C27H31N3O5C 67.91,H 6.54,N 8.80.Found C 67.73,H 6.70,N 9.00.
实施例52(3S)-N-(Boc-L-缬氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-c)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由540mg(2.50mmol)Boc-L-Val-OH得到810mg(87%)标题化合物,为无色粉末。Mp 137-139℃;FAB/MS:430[M+H]+;IR(KBr):3343,3000,2952,2845,1743,1640,1605,1455,1391,1375,1070,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.92(s,1H),8.00(s,1H),7.25(t,J=7.2Hz,1H),7.13(t,J=7.2Hz,1H),6.95(t,J=7.2Hz,1H),6.91(t,J=7.2Hz,1H),4.73(t,J=5.6Hz,1H),4.52(d,J=5.2Hz,1H),3.86(s,2H),3.62(dd,J=10.3Hz,J=5.1Hz,1H),3.64(s,3H),3.22(dd,J=10.3Hz,J=3.2Hz,1H),2.66(m,J=5.2Hz,1H),1.45(s,9H),1.03(d,J=5.4Hz,6H).[α]D 20=-46°(c=0.35,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C23H31N3O5 C 64.32,H 7.27,N 9.78.Found C64.16,H 7.20,N 9.92.
实施例53(3S)-N-(Boc-L-丝氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-d)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由510mg(2.50mmol)Boc-L-Ser-OH得到842mg(93%)标题化合物,为无色粉末。Mp 155-157℃;FAB/MS:418[M+H]+;IR(KBr):3339,3006,2945,2842,1750,1643,1605,1459,1391,1072,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),8.03(s,1H),7.29(t,J=7.6Hz,1H),7.19(t,J=7.6Hz,1H),7.02(t,J=7.6Hz,1H),6.90(t,J=7.6Hz,1H),4.78(t,J=5.7Hz,1H),4.65(t,J=5.5Hz,1H),4.05(d,J=5.5Hz,1H),3.91(s,2H),3.62(dd,J=10.1Hz,J=5.0Hz,1H),3.60(s,3H),3.28(dd,J=10.1Hz,J=2.7Hz,1H),3.08(d,J=5.5Hz,2H),1.48(s,9H).[α]D 20=-77°(c=0.39,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C21H27N3O6C 60.42,H 6.52,N 10.07.Found C 60.60,H 6.71,N 9.88.
实施例54(3S)-N-(Boc-L-苏氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-e)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由545mg(2.50mmol)Boc-L-Thr-OH得到970mg(90%)标题化合物,为无色粉末。Mp 128-130℃;ESI/MS 432[M+H]+;IR(KBr):3433,3205,3000,2955,2841,1730,1643,1605,1452,1390,1372,1060,904cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.02(s,1H),7.89(s,1H),7.30(t,J=7.3Hz,1H),7.22(t,J=7.3Hz,1H),6.90(d,J=7.4Hz,1H),6.70(d,J=7.3Hz,1H),4.82(t,J=5.3Hz,1H),4.63(m,J=5.3Hz,1H),4.44(t,J=5.3Hz,1H),4.03(m,J=5.2Hz,2H),3.62(s,3H),2.95(d,J=5.4Hz,2H),2.21(d,J=3.6Hz,1H),1.45(s,9H),1.21(d,J=5.6Hz,3H).Anal.Calcd forC22H29N3O6C 61.24,H 6.77,N 9.74.Found C 61.11,H 6.65,N 9.89.
实施例55(3S)-N-(Boc-L-酪氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-f)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由700mg(2.50mmol)of Boc-L-Tyr-OH得到1072mg(87%)标题化合物,为无色粉末。Mp 145-147℃;FAB/MS:494[M+H]+;IR(KBr):3337,3004,2945,2845,1752,1641,1600,1452,1390,1070,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.02(s,1H),8.00(s,1H),7.27(t,J=7.5Hz,1H),7.19(t,J=7.5Hz,1H),6.96(d,J=7.6Hz,2H),6.89(d,J=7.5Hz,1H),6.88(d,J=7.5Hz,1H),6.68(d,J=7.6Hz,2H),5.02(s,1H),4.94(t,J=5.4Hz,1H),4.83(t,J=5.4Hz,1H),3.93(s,2H),3.64(dd,J=10.0Hz,J=5.1Hz,1H),3.63(s,3H),3.31(dd,J=10.0Hz,J=2.7Hz,1H),3.07(d,J=5.4Hz,2H),1.46(s,9H).[α]D 20=-26°(c=0.36,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC27H31N3O6 C 65.71,H 6.33,N 8.51.Found C 65.54,H 6.46,N 8.70.
实施例56(3S)-N-(Boc-L-脯氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-g)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由535mg(2.50mmol)of Boc-L-Pro-OH得到982mg(92%)标题化合物,为无色粉末。Mp 118-120℃;ESI/MS 428[M+H]+;IR(KBr):3431,3206,3003,2954,2842,1730,1643,1605,1456,1394,1370,1065,904cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.97(s,1H),7.32(t,J=7.2Hz,1H),7.22(t,J=7.4Hz,1H),7.03(d,J=7.4Hz,1H),6.93(d,J=7.2Hz,1H),4.85(t,J=5.3Hz,1H),4.31(t,J=5.5Hz,1H),4.25(d,J=5.4Hz,2H),3.62(s,3H),3.44(t,J=5.5Hz,2H),2.97(d,J=5.5Hz,2H),2.25(d,J=5.4Hz,2H),1.95(t,J=5.1Hz,2H),1.47(s,9H).Anal.Calcd for C23H29N3O5C64.62,H 6.84,N 9.83.Found C 64.75,H 6.92,N 9.97.
实施例57(3S)-N-(Boc-L-半胱氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-h)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由550mg(2.50mmol)Boc-L-Cys-OH得到974mg(93%)标题化合物,为无色粉末。Mp 133-135℃;ESI/MS 434[M+H]+;IR(KBr):3441,3205,3004,2940,2842,1734,1640,1605,1450,1392,1370,1064,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.02(s,1H),7.99(s,1H),7.30(t,J=7.3Hz,1H),7.20(t,J=7.5Hz,1H),7.03(d,J=7.5Hz,1H),6.85(d,J=7.3Hz,1H),4.90(t,J=5.1Hz,1H),4.73(t,J=5.3Hz,1H),4.23(d,J=5.4Hz,2H),3.63(s,3H),3.13(d,J=5.2Hz,2H),2.99(d,J=5.3Hz,2H),1.47(s,9H),1.64(s,1H).Anal.Calcd for C21H27N3O5S C 58.18,H 6.28,N 9.69.Found C 58.25,H 6.38,N 9.86.
实施例58(3S)-N-(Boc-L-甲硫氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-i)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由620mg(2.50mmol)of Boc-L-Met-OH得到1049mg(91%)标题化合物,为无色粉末。Mp 133-135℃;ESI/MS 462[M+H]+;IR(KBr):3443,3205,3007,2950,2844,1730,1645,1602,1455,1392,1375,1064,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),7.99(s,1H),7.30(t,J=7.3Hz,1H),7.20(t,J=7.5Hz,1H),6.97(d,J=7.5Hz,1H),6.83(d,J=7.3Hz,1H),4.83(t,J=5.2Hz,1H),4.47(t,J=5.3Hz,1H),4.27(d,J=5.3Hz,2H),3.66(s,3H),2.95(d,J=5.4Hz,2H),2.45(t,J=5.3Hz,2H),2.25(d,J=5.3Hz,2H),2.11(s,3H),1.47(s,9H).Anal.Calcd for C23H31N3O5S C59.85,H 6.77,N 9.10.Found C 59.69,H 6.85,N 9.26.
实施例59(3S)-N-[Boc-L-(γ-甲酯)-谷氨酰]-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-j)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由650mg(2.50mmol)Boc-L-Glu-(OMe)-OH得到1049mg(91%)标题化合物,为无色粉末。Mp 122-124℃;ESI/MS 474[M+H]+;IR(KBr):3443,3205,3004,2940,2834,1735,1642,1601,1452,1395,1370,1063,901cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.92(s,1H),8.01(s,1H),7.35(t,J=7.2Hz,1H),7.26(t,J=7.2Hz,1H),7.00(d,J=7.5Hz,1H),6.86(d,J=7.3Hz,1H),4.87(d,J=5.3Hz,1H),4.45(t,J=5.5Hz,1H),4.24(d,J=5.4Hz,2H),3.67(s,3H),3.65(s,3H),2.97(d,J=5.3Hz,2H),2.29(t,J=5.4Hz,2H),2.23(t,J=5.5Hz,2H),1.47(s,9H).Anal.Calcd for C24H31N3O7C60.88,H 6.60,N 8.87.Found C 60.75,H 6.47,N 9.05.
实施例60(3S)-N-[Boc-L-(β-甲酯)-天冬酰]-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-k)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由808mg(2.50mmol)Boc-L-Asp(OBzl)-OH得到1231mg(92%)标题化合物,为无色粉末。Mp 144-146℃;FAB/MS:536[M+H]+;IR(KBr):3340,3004,2948,2845,1748,1642,1600,1455,1391,1072,904cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.95(s,1H),8.02(s,1H),7.29(t,J=7.6Hz,1H),7.22(t,J=7.2Hz,2H),7.20(d,J=7.2Hz,2H),7.18(t,J=7.5Hz,1H),7.16(t,J=7.2Hz,1H),6.97(t,J=7.5Hz,1H),6.93(t,J=7.5Hz,1H),5.36(s,2H),5.14(t,J=5.5Hz,1H),4.77(t,J=5.7Hz,1H),3.62(dd,J=10.2Hz,J=5.1Hz,1H),3.64(s,3H),3.24(dd,J=10.2Hz,J=2.7Hz,1H),3.06(d,J=5.6Hz,2H),2.75(d,J=5.5Hz,2H),1.46(s,9H).[α]D 20=-61°(c=0.39,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C29H33N3O7C 65.03,H 6.21,N 7.85.Found C65.18,H 6.06,N 7.99.
实施例61(3S)-N-(Boc-L-组氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-l)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由635mg(2.50mmol)Boc-L-His-OH得到1074mg(92%)标题化合物,为无色粉末。Mp 140-142℃;ESI/MS 468[M+H]+;IR(KBr):3445,3203,3005,2944,2837,1731,1645,1602,1451,1393,1370,1060,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=12.95(s,1H),9.98(s,1H),8.02(s,1H),7.45(s,1H),7.32(t,J=7.2Hz,1H),7.18(t,J=7.5Hz,1H),7.18(d,J=7.5Hz,1H),6.99(t,J=7.2Hz,1H),6.87(s,1H),4.94(t,J=5.1Hz,1H),4.81(t,J=5.3Hz,1H),4.23(d,J=5.1Hz,2H),3.67(s,3H),3.17(d,J=5.2Hz,2H),2.95(d,J=5.1Hz,2H),1.47(s,9H).Anal.Calcd for C24H29N5O5C61.66,H 6.25,N 14.98.Found C 61.79,H6.34,N 14.82.
实施例62(3S)-N-(Boc-L-色氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-m)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由756mg(2.50mmol)of Boc-L-Trp-OH得到997mg(89%)标题化合物,为无色粉末。Mp 126-128℃;FAB/MS:517[M+H]+;IR(KBr):3335,3009,2942,2842,1750,1643,1604,1453,1391,1072,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.99(s,1H),9.96(s,1H),8.02(s,1H),7.29(t,J=7.6Hz,1H),7.21(t,J=7.4Hz,1H),7.19(t,J=7.4Hz,1H),7.18(t,J=7.4Hz,1H),7.17(t,J=7.4Hz,1H),7.16(t,J=7.6Hz,1H),7.01(t,J=7.6Hz,1H),6.89(t,J=7.6Hz,1H),6.82(s,1H),4.90(t,J=5.5Hz,1H),4.85(t,J=5.4Hz,1H),3.92(s,2H),3.62(dd,J=10.1Hz,J=5.0Hz,1H),3.65(s,3H),3.32(dd,J=10.1Hz,J=2.9Hz,1H),2.92(t,J=5.5Hz,2H),1.48(s,9H).[α]D 20=-97°(c=0.38,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C29H32N4O5C 67.43,H 6.24,N 10.85.Found C 67.59,H 6.40,N 10.72.
实施例63(3S)-N-(Boc-L-精氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-n)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由478mg(2.50mmol)Boc-L-Arg-OH得到1069mg(88%)标题化合物,为无色粉末。Mp 137-139℃;ESI/MS 487[M+H]+;IR(KBr):3445,3209,3004,2945,2840,1733,1642,1600,1451,1392,1370,1064,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.20(s,1H),8.43(s,2H),8.25(s,1H),8.20(s,1H),8.03(s,1H),7.27(t,J=7.4Hz,1H),7.17(t,J=7.5Hz,1H),7.01(d,J=7.5Hz,1H),6.93(d,J=7.4Hz,1H),4.91(d,J=5.1Hz,1H),4.40(t,J=4.3Hz,1H),4.27(d,J=5.1Hz,2H),3.67(s,3H),2.92(d,J=4.3Hz,2H),2.66(t,J=5.5Hz,2H),1.93(m,J=5.3Hz,2H),1.57(m,J=5.4Hz,2H),1.55(s,9H).Anal.Calcd for C24H34N6O5C 59.24,H 7.04,N 17.27.Found C 59.10,H 6.95,N 17.40.
实施例64(3S)-N-(Boc-甘氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-o)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由435mg(2.50mmol)Boc-Gly-OH得到798mg(95%)标题化合物,为无色粉末。Mp 150-152℃;FAB/MS:388[M+H]+;IR(KBr):3342,3003,2950,2844,1745,1645,1603,1452,1390,1070,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.91(s,1H),8.11(s,1H),7.29(t,J=7.6Hz,1H),7.16(t,J=7.6Hz,1H),7.00(t,J=7.6Hz,1H),6.97(t,J=7.6Hz,1H),4.76(t,J=5.6Hz,2H),4.52(d,J=4.9Hz,2H),3.87(s,2H),3.65(dd,J=10.5Hz,J=5.0Hz,1H),3.58(s,3H),3.17(dd,J=10.5Hz,J=2.4Hz,1H),1.44(s,9H).[α]D 20=-100°(c=0.34,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C20H25N3O5C 62.00,H 6.50,N 10.85.Found C 62.18,H 6.34,N 10.67.
实施例65(3S)-N-[Boc-L-(Z)-赖氨酰]-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-p)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由950mg(2.50mmol)ofBoc-L-(Z)Lys-OH得到1362mg(92%)标题化合物,为无色粉末。Mp 95-97℃;FAB/MS:593[M+H]+;IR(KBr):3342,3003,2940,2845,1752,1641,1602,1456,1390,1070,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.97(s,1H),8.05(s,1H),8.00(s,1H),7.27(t,J=7.5Hz,1H),7.22(t,J=7.2Hz,1H),7.17(t,J=7.5Hz,1H),7.15(d,J=7.2Hz,2H),7.13(t,J=7.2Hz,2H),7.00(t,J=7.5Hz,1H),6.88(t,J=7.5Hz,1H),5.36(s,2H),4.76(t,J=5.6Hz,1H),4.55(t,J=5.6Hz,1H),3.63(dd,J=10.2Hz,J=5.1Hz,1H),3.64(s,3H),3.30(dd,J=10.1Hz,J=2.7Hz,1H),3.08(d,J=5.5Hz,2H),2.95(t,J=5.4Hz,2H),1.75(t,J=5.5Hz,2H),1.58(t,J=5.3Hz,2H),1.48(s,9H),1.27(m,J=5.6Hz,2H).[α]D 20=-29°(c=0.35,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C32H40N4O7C 64.85,H 6.80,N 9.45.Found C 64.69,H 6.71,N9.62.
实施例66(3S)-N-(Boc-L-谷氨酰胺酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-q)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由613mg(2.50mmol)of Boc-L-Gln-OH得到855mg(86%)标题化合物,为无色粉末。Mp 145-147℃;FAB/MS:459[M+H]+;IR(KBr):3342,3011,2949,2844,1750,1640,1603,1456,1391,1072,905cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.00(s,1H),8.02(s,1H),7.29(t,J=7.6Hz,1H),7.17(t,J=7.6Hz,1H),6.86(d,J=7.6Hz,1H),6.83(d,J=7.6Hz,1H),6.12(s,2H),4.90(t,J=5.4Hz,1H),4.55(t,J=5.4Hz,1H),3.95(s,2H),3.62(dd,J=10.2Hz,J=5.0Hz,1H),3.60(s,3H),3.32(dd,J=10.1Hz,J=2.9Hz,1H),2.19(t,J=4.9Hz,2H),2.01(m,J=4.9Hz,2H),1.42(s,9H).[α]D 20=-27°(c=0.38,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C23H30N4O6C 60.25,H6.59,N 12.22.Found C 60.38,H 6.77,N 12.37.
实施例67(3S)-N-(Boc-L-天冬酰胺酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-r)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由578mg(2.50mmol)Boc-L-Asn-OH得到1010mg(91%)标题化合物,为无色粉末。Mp 137-139℃;ESI/MS:445[M+H]+.IR(KBr):3443,3205,3001,2932,2833,1734,1630,1604,1457,1391,1370,1061,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.97(s,1H),8.01(s,1H),7.22(t,J=7.3Hz,1H),7.14(t,J=7.1Hz,1H),7.01(d,J=7.3Hz,1H),6.85(d,J=7.3Hz,1H),6.03(s,2H),4.91(d,J=5.3Hz,1H),4.41(t,J=5.3Hz,1H),4.24(d,J=5.3Hz,2H),3.65(s,3H),2.92(d,J=5.1Hz,2H),2.55(t,J=5.3Hz,2H),1.49(s,9H).[α]D 20=-38°(c=0.30,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C22H28N4O6C 59.45,H 6.35,N 12.60.Found C 59.62,H 6.44,N 12.43.
实施例68(3S)-N-(Boc-L-亮酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-s)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由575mg(2.50mmol)of Boc-L-Leu-OH得到836mg(87%)标题化合物,为无色粉末。Mp 135-137℃;FAB/MS:444[M+H]+;IR(KBr):3344,3002,2950,2842,1745,1640,1603,1452,1390,1070,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.87(s,1H),8.00(s,1H),7.27(t,J=7.4Hz,1H),7.15(t,J=7.4Hz,1H),6.99(t,J=7.4Hz,1H),6.96(t,J=7.4Hz,1H),4.75(t,J=5.9Hz,1H),4.55(d,J=5.4Hz,1H),3.88(s,2H),3.60(dd,J=10.0Hz,J=5.0Hz,1H),3.62(s,3H),3.22(dd,J=10.0Hz,J=2.9Hz,1H),1.88(m,J=5.4Hz,1H),1.78(t,J=5.0Hz,2H),1.46(s,9H),1.03(d,J=5.4Hz,6H).[α]D 20=-52°(c=0.35,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C24H33N3O5C64.99,H 7.50,N 9.47.Found C 65.16,H 7.63,N 9.32.
实施例69(3S)-N-(Boc-L-异亮酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯(7Me-t)的制备
采用实施例49制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸甲酯[7Me-(a-t)]的一般操作,由575mg(2.50mmol)Boc-L-Ile-OH得到846mg(88%)标题化合物,为无色粉末。Mp 130-132℃;FAB/MS:444[M+H]+;IR(KBr):3344,3002,2950,2842,1745,1640,1603,1452,1390,1070,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.89(s,1H),8.03(s,1H),7.27(t,J=7.4Hz,1H),7.15(t,J=7.4Hz,1H),6.99(t,J=7.4Hz,1H),6.96(t,J=7.4Hz,1H),4.75(t,J=5.9Hz,1H),4.55(d,J=5.4Hz,1H),3.88(s,2H),3.60(dd,J=10.0Hz,J=5.0Hz,1H),3.62(s,3H),3.22(dd,J=10.0Hz,J=2.9Hz,1H),2.48(m,J=5.4Hz,1H),1.33(m,J=5.0Hz,2H),1.46(s,9H),1.06(d,J=5.4Hz,3H),1.00(t,J=5.0Hz,3H).[α]D 20=-40°(c=0.35,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC24H33N3O5C 64.99,H 7.50,N 9.47.Found C 65.16,H 7.63,N 9.32.
实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作
0℃和搅拌下往2.50mmol of Boc-L-氨基酸,350mg(2.59mmol)HOBt,600mg(2.90mmol)DCC与15ml无水二氯甲烷的溶液中加入664mg(2.17mmol)3S-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(6’Bzl)。反应混合物0℃搅拌30min,室温搅拌40min,TLC(乙酸乙酯∶石油醚,5∶12)显示反应完成。滤除生成的DCU沉淀,滤液减压浓缩,残留物溶入30ml乙酸乙酯。得到的溶液得到的溶液依次用饱和NaCO3溶液洗(30ml×3),饱和NaCl溶液洗(30ml×3),饱和KHSO4溶液洗(30ml×3),饱和NaCl溶液洗(30ml×3),水洗(30ml×3),无水MgSO4干燥,减压浓缩。残留物用闪式硅胶柱层析(CHCl3/CH3OH,30∶1)纯化,得到无色粉末状产物。
实施例71(3S)-N-(Boc-L-丙氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-a)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由435mg(2.50mmol)of Boc-Ala-OH得到973mg(94%)标题化合物,为无色粉末。Mp 130-132℃;FAB/MS:478[M+H]+;IR(KBr):3347,3005,2951,2843,1745,1642,1604,1457,1391,1371,1071,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.97(s,1H),8.03(s,1H),7.24(t,J=7.2Hz,1H),7.20(t,J=7.1Hz,2H),7.13(t,J=7.2Hz,1H),7.10(d,J=7.1Hz,2H),7.07(t,J=7.1Hz,1H),6.97(t,J=7.2Hz,1H),6.93(t,J=7.2Hz,1H),5.33(s,2H),4.75(m,J=5.5Hz,1H),4.66(m,J=5.4Hz,1H),3.83(s,2H),3.64(dd,J=10.1Hz,J=5.2Hz,1H),3.25(dd,J=10.1Hz,J=2.9Hz,1H),1.49(s,9H),1.45(d,J=5.1Hz,3H).[α]D 20=-1248°(c=0.35,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C27H31N3O5C 67.91,H 6.54,N 8.80.Found C 67.76,H 6.65,N 8.97.
实施例72(3S)-N-(Boc-L-苯丙氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-b)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由660mg(2.50mmol)Boc-L-Phe-OH得到1140mg(95%)标题化合物,为无色粉末。Mp 129-131℃;FAB/MS:554[M+H]+;IR(KBr):3345,3014,2942,2833,1751,1647,1603,1452,1389,1062,901cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),7.89(s,1H),7.27(t,J=7.3Hz,1H),7.20(t,J=7.5Hz,2H),7.18(t,J=7.1Hz,2H),7.17(t,J=7.3Hz,1H),7.13(d,J=7.6Hz,2H),7.10(d,J=7.1Hz,2H),7.07(t,J=7.1Hz,1H),7.05(t,J=7.6Hz,1H),6.95(t,J=7.2Hz,1H),6.90(t,J=7.3Hz,1H),5.33(s,2H),5.01(t,J=5.3Hz,1H),4.79(t,J=5.4Hz,1H),3.91(s,2H),3.65(dd,J=10.1Hz,J=5.2Hz,1H),3.23(dd,J=10.1Hz,J=2.9Hz,1H),3.09(d,J=5.3Hz,2H),1.47(s,9H).[α]D 20=-80°(c=0.35,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C33H35N3O5C 71.59,H 6.37,N 7.59.Found C 71.74,H 6.46,N 7.73.
实施例73(3S)-N-(Boc-L-缬氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-c)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由540mg(2.50mmol)Boc-L-Val-OH得到966mg(89%)标题化合物,为无色粉末。Mp 127-129℃;FAB/MS:506[M+H]+;IR(KBr):3343,3002,2941,2844,1743,1642,1600,1453,1392,1375,1070,901cm-1;1H NMR(BHSC-500,DMSO-d6)δ=10.02(s,1H),8.03(s,1H),7.25(t,J=7.2Hz,1H),7.20(t,J=7.0Hz,2H),7.13(t,J=7.2Hz,1H),7.12(d,J=7.0Hz,2H),7.08(t,J=7.0Hz,1H),6.96(t,J=7.2Hz,1H),6.91(t,J=7.2Hz,1H),5.33(s,2H),4.72(t,J=5.7Hz,1H),4.53(d,J=5.1Hz,1H),3.87(s,2H),3.62(dd,J=10.1Hz,J=5.3Hz,1H),3.23(dd,J=10.1Hz,J=3.3Hz,1H),2.65(m,J=5.1Hz,1H),1.47(s,9H),1.07(d,J=5.3Hz,6H).[α]D 20=-58°(c=0.39,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C29H35N3O5C 68.89,H 6.98,N 8.31.Found C 68.73,H 6.87,N8.47.
实施例74(3S)-N-(Boc-L-丝氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-d)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由510mg(2.50mmol)Boc-L-Ser-OH得到1087mg(90%)标题化合物,为无色粉末。Mp 127-129℃;FAB/MS:494[M+H]+;IR(KBr):3345,3013,2940,2844,1750,1642,1600,1457,1392,1073,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),8.03(s,1H),7.25(t,J=7.2Hz,1H),7.21(t,J=7.0Hz,2H),7.15(t,J=7.2Hz,1H),7.11(d,J=7.0Hz,2H),7.08(t,J=7.0Hz,1H),7.01(t,J=7.2Hz,1H),6.90(t,J=7.1Hz,1H),5.35(s,2H),4.73(t,J=5.6Hz,1H),4.60(t,J=5.1Hz,1H),4.05(d,J=5.3Hz,1H),3.90(s,2H),3.62(dd,J=10.1Hz,J=5.3Hz,1H),3.23(dd,J=10.1Hz,J=2.9Hz,1H),3.10(d,J=5.1Hz,2H),1.45(s,9H).[α]D 20=-51°(c=0.35,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C27H31N3O6C 65.71,H 6.33,N 8.51.Found C65.50,H 6.25,N 8.68.
实施例75(3S)-N-(Boc-L-苏氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-e)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由545mg(2.50mmol)of Boc-L-Thr-OH得到1153mg(91%)标题化合物,为无色粉末。Mp 131-133℃;ESI/MS 508[M+H]+;IR(KBr):3443,3336,3208,3003,2950,2841,1762,1735,1643,1602,1455,1393,1373,1062,904cm-1;1HNMR(BHSC-500,DMSO-d6):δ=10.02(s,1H),7.87(s,1H),7.27(t,J=7.3Hz,1H),7.23(t,J=7.3Hz,1H),7.17(t,J=7.1Hz,2H),7.13(d,J=7.1Hz,2H),7.05(t,J=7.1Hz,1H),6.99(d,J=7.3Hz,1H),6.87(t,J=7.3Hz,1H),5.30(s,2H),4.83(t,J=5.4Hz,1H),4.61(m,J=5.4Hz,1H),4.43(t,J=5.3Hz,1H),3.97(m,J=5.5Hz,2H),2.92(d,J=5.3Hz,2H),2.17(s,1H),1.46(s,9H),1.20(d,J=5.3Hz,3H).Anal.Calcd for C28H33N3O6C 66.26,H6.55,N 8.28.Found C 66.12,H 6.43,N 8.42.
实施例76(3S)-N-(Boc-L-酪氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-f)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由700mg(2.50mmol)Boc-L-Tyr-OH得到1266mg(89%)标题化合物,为无色粉末。Mp 133-135℃;ESI/MS 570[M+H]+;IR(KBr):3442,3206,3003,2954,2840,1734,1642,1603,1452,1391,1373,1062,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),8.03(s,1H),7.33(t,J=7.2Hz,1H),7.21(t,J=7.4Hz,1H),7.14(d,J=7.2Hz,2H),7.11(t,J=7.2Hz,2H),7.07(d,J=7.2Hz,2H),7.03(t,J=7.2Hz,1H),7.01(d,J=7.2Hz,1H),6.90(d,J=7.4Hz,1H),6.88(d,J=7.2Hz,2H),5.41(s,2H),4.95(s,1H),4.88(d,J=5.3Hz,1H),4.80(t,J=5.5Hz,1H),4.23(m,J=5.4Hz,2H),3.15(d,J=5.4Hz,2H),2.92(d,J=5.2Hz,2H),1.48(s,9H).Anal.Calcd forC33H35N3O6 C 69.58,H 6.19,N 7.38.Found C 69.43,H 6.12,N 7.55.
实施例77(3S)-N-(Boc-L-脯氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-g)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由535mg(2.50mmol)ofBoc-L-Pro-OH得到1144mg(91%)标题化合物,为无色粉末。Mp 113-115℃;ESI/MS 504[M+H]+;IR(KBr):3441,3209,3001,2954,2840,1733,1644,1603,1450,1392,1370,1062,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),7.31(t,J=7.2Hz,1H),7.19(t,J=7.4Hz,1H),7.15(t,J=7.0Hz,2H),7.10(d,J=7.0Hz,2H),7.07(t,J=7.0Hz,1H),7.03(d,J=7.4Hz,1H),6.91(d,J=7.2Hz,1H),5.33(s,2H),4.84(t,J=5.4Hz,1H),4.30(t,J=5.6Hz,1H),4.21(d,J=5.3Hz,2H),3.46(t,J=5.6Hz,2H),2.91(d,J=5.4Hz,2H),2.29(d,J=5.4Hz,2H),1.93(t,J=4.7Hz,2H),1.47(s,9H).Anal.Calcd for C29H33N3O5C 69.17,H 6.60,N8.34.Found C 69.32,H 6.68,N 8.49.
实施例78(3S)-N-(Boc-L-半胱氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-h)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由550mg(2.50mmol)ofBoc-L-Cys-OH得到1145mg(90%)标题化合物,为无色粉末。Mp 131-133℃;ESI/MS 510[M+H]+;IR(KBr):3445,3201,3000,2942,2845,1732,1643,1601,1452,1391,1373,1060,901cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.00(s,1H),8.01(s,1H),7.27(t,J=7.2Hz,1H),7.21(t,J=7.4Hz,1H),7.19(t,J=7.2Hz,2H),7.13(d,J=7.2Hz,2H),7.08(t,J=7.2Hz,1H),7.06(d,J=7.4Hz,1H),6.87(d,J=7.2Hz,1H),5.33(s,2H),4.96(t,J=5.3Hz,1H),4.75(t,J=5.5Hz,1H),4.25(d,J=5.3Hz,2H),3.12(d,J=5.3Hz,2H),3.05(d,J=5.4Hz,2H),1.48(s,9H),1.63(s,1H).Anal.Calcd for C27H31N3O5S C 63.63,H 6.13,N 8.25.Found C 63.79,H6.20,N 8.11.
实施例79(3S)-N-(Boc-L-甲硫氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-i)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由620mg(2.50mmol)ofBoc-L-Met-OH得到1208mg(90%)标题化合物,为无色粉末。Mp 144-146℃;ESI/MS 538[M+H]+;IR(KBr):3443,3205,3002,2954,2845,1733,1642,1603,1455,1392,1373,1061,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.02(s,1H),7.97(s,1H),7.30(t,J=7.2Hz,1H),7.21(t,J=7.4Hz,1H),7.17(t,J=7.4Hz,2H),7.14(d,J=7.4Hz,2H),7.10(t,J=7.4Hz,1H),6.93(d,J=7.2Hz,1H),6.85(d,J=7.2Hz,1H),5.34(s,2H),4.85(t,J=5.2Hz,1H),4.44(t,J=5.3Hz,1H),4.23(d,J=5.1Hz,2H),2.97(d,J=5.2Hz,2H),2.41(t,J=5.2Hz,2H),2.21(d,J=5.3Hz,2H),2.11(s,3H),1.47(s,9H).Anal.Calcd for C29H35N3O5S C 64.78,H 6.56,N 7.82.Found C 64.60,H 6.47,N 7.97.
实施例80(3S)-N-[Boc-L-(γ-苄酯)谷氨酰]-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-j)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由880mg(2.50mmol)of Boc-L-Glu(OBzl)-OH得到1422mg(91%)标题化合物,为无色粉末。Mp 125-127℃;ESI/MS 626[M+H]+;IR(KBr):3442,3206,3003,2945,2823,1736,1641,1604,1450,1390,1373,1060,896cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.98(s,1H),8.01(s,1H),7.34(t,J=7.3Hz,1H),7.24(t,J=7.3Hz,1H),7.21(t,J=7.1Hz,2H),7.18(t,J=7.2Hz,2H),7.17(d,J=7.1Hz,2H),7.15(d,J=7.2Hz,2H),7.14(t,J=7.1Hz,1H),7.12(t,J=7.2Hz,1H),7.00(d,J=7.3Hz,1H),6.87(d,J=7.3Hz,1H),5.36(s,2H),5.34(s,2H),4.91(d,J=5.2Hz,1H),4.44(t,J=5.4Hz,1H),4.23(d,J=5.3Hz,2H),2.97(d,J=5.1Hz,2H),2.23(t,J=5.4Hz,2H),2.20(t,J=5.4Hz,2H),1.47(s,9H).Anal.Calcd for C36H39N3O7 C 69.10,H 6.28,N 6.72.Found C 68.97,H 6.21,N 6.88.
实施例81(3S)-N-[Boc-L-(β-苄酯)天冬氨酰]-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-k)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由845mg(2.50mmol)of Boc-L-Asp(OBzl)-OH得到1375mg(90%)标题化合物,为无色粉末。Mp 139-141℃;ESI/MS 612[M+H]+;IR(KBr):3441,3342,3210,3000,2954,2841,1754,1732,1643,1600,1452,1389,1368,1061,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.97(s,1H),8.00(s,1H),7.28(t,J=7.1Hz,1H),7.22(t,J=7.1Hz,1H),7.19(t,J=6.9Hz,2H),7.17(t,J=6.9Hz,2H),7.13(d,J=6.9Hz,2H),7.11(d,J=6.9Hz,2H),7.09(t,J=6.9Hz,1H),7.06(t,J=6.9Hz,1H),7.00(d,J=7.1Hz,1H),6.96(d,J=7.1Hz,1H),5.34(s,2H),5.31(s,2H),4.92(d,J=5.1Hz,1H),4.76(t,J=5.1Hz,1H),4.25(d,J=5.1Hz,2H),2.92(d,J=5.1Hz,2H),2.85(d,J=5.1Hz,2H),1.45(s,9H).Anal.Calcd for C35H37N3O7 C 68.72,H 6.10,N 6.87.Found C 68.86,H 6.18,N 7.02.
实施例82(3S)-N-(Boc-L-组氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-l)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由635mg(2.50mmol)of Boc-L-His-OH得到1235mg(91%)标题化合物,为无色粉末。Mp 137-139℃;ESI/MS 544[M+H]+;IR(KBr):3442,3201,3004,2941,2830,1732,1643,1602,1455,1393,1374,1062,901cm-1;1H NMR(BHSC-500,DMSO-d6):δ=12.97(s,1H),10.01(s,1H),8.03(s,1H),7.47(s,1H),7.33(t,J=7.1Hz,1H),7.20(t,J=7.1Hz,2H),7.15(t,J=7.2Hz,1H),7.13(d,J=7.1Hz,2H),7.11(d,J=7.2Hz,1H),7.05(t,J=7.1Hz,1H),6.97(t,J=7.1Hz,1H),6.86(s,1H),5.35(s,2H),4.93(t,J=5.1Hz,1H),4.81(t,J=5.3Hz,1H),4.24(d,J=5.2Hz,2H),3.23(d,J=5.3Hz,2H),2.93(d,J=5.2Hz,2H),1.48(s,9H).Anal.Calcd for C30H33N5O5 C 66.28,H 6.12,N 12.88.Found C 66.13,H 6.04,N 13.04.
实施例83(3S)-N-(Boc-L-色氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-m)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由758mg(2.50mmol)ofBoc-L-Trp-OH得到1332mg(90%)标题化合物,为无色粉末。Mp 144-146℃;ESI/MS:593[M+H]+.IR(KBr):3441,3332,3211,3002,2941,2830,1755,1732,1641,1600,1443,1392,1373,1062,900cm-1;1HNMR(BHSC-500,DMSO-d6):δ=9.99(s,1H),9.97(s,1H),8.01(s,1H),7.27(t,J=7.1Hz,1H),7.25(t,J=7.0Hz,1H),7.21(t,J=6.9Hz,2H),7.15(d,J=6.9Hz,2H),7.11(d,J=7.3Hz,1H),7.07(t,J=6.9Hz,1H),7.05(t,J=7.3Hz,1H),7.03(d,J=7.1Hz,1H),7.00(t,J=7.3Hz,1H),6.99(d,J=7.1Hz,1H),6.96(d,J=7.0Hz,1H),6.83(s,1H),5.32(s,2H),4.93(d,J=5.1Hz,1H),4.75(t,J=5.2Hz,1H),4.23(d,J=5.1Hz,2H),3.15(d,J=5.1Hz,2H),2.95(d,J=6.0Hz,2H),1.48(s,9H).[α]D 20=-70°(c=0.34,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C35H36N4O5C 70.93,H 6.12,N 9.45.Found C 71.08,H 6.20,N 9.62.
实施例84(3S)-N-(Boc-L-精氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-n)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由683mg(2.50mmol)ofBoc-L-Arg-OH得到1222mg(87%)标题化合物,为无色粉末。Mp 133-135℃;ESI/MS 563[M+H]+;IR(KBr):3443,3205,3001,2946,2842,1727,1645,1600,1453,1393,1372,1061,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),8.40(s,2H),8.23(s,1H),8.15(s,1H),8.03(s,1H),7.25(t,J=7.2Hz,1H),7.22(t,J=7.0Hz,2H),7.15(d,J=7.0Hz,2H),7.13(t,J=7.2Hz,1H),7.11(t,J=7.0Hz,1H),7.00(d,J=7.2Hz,1H),6.93(d,J=7.2Hz,1H),5.36(s,2H),4.90(d,J=5.1Hz,1H),4.37(t,J=4.5Hz,1H),4.25(d,J=5.1Hz,2H),2.93(d,J=4.6Hz,2H),2.68(t,J=5.1Hz,2H),1.93(m,J=5.1Hz,2H),1.54(m,J=5.1Hz,2H),1.53(s,9H).Anal.Calcd for C30H38N6O5C 64.04,H 6.81,N 14.94.Found C 64.19,H 6.90,N 14.79.
实施例85(3S)-N-(Boc-甘氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-o)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由435mg(2.50mmol)ofBoc-L-Gly-OH得到1076mg(93%)标题化合物,为无色粉末。Mp 133-135℃;ESI/MS:464[M+H]+.IR(KBr):3441,3332,3001,2944,2843,1760,1735,1601,1459,1390,1376,1062,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.99(s,1H),8.02(s,1H),7.25(t,J=7.2Hz,1H),7.20(t,J=7.0Hz,2H),7.19(t,J=7.2Hz,1H),7.13(d,J=7.0Hz,2H),7.09(t,J=7.0Hz,1H),6.95(d,J=7.2Hz,1H),6.87(d,J=7.2Hz,1H),5.35(s,2H),4.84(d,J=5.1Hz,1H),4.23(dd,J=10.1Hz,J=4.1Hz,1H),4.15(dd,J=10.1Hz,J=3.5Hz,1H),4.11(s,2H),2.95(d,J=10.1Hz,2H),1.47(s,9H).[α]D 20=-80°(c=0.37,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC26H29N3O5C 67.37,H,6.31,N 9.07.Found C 67.49,H 6.39,N 9.23.
实施例86(3S)-N-[Boc-L-(Z)赖氨酰]-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-p)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由948mg(2.50mmol)Boc-L-Lys(Bzl)-OH得到1503mg(90%)标题化合物,为无色粉末。Mp 129-131℃;ESI/MS:669[M+H]+.IR(KBr):3441,3334,3005,2946,2847,1763,1730,1600,1454,1390,1374,1062,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),8.01(s,1H),7.97(s,1H),7.25(t,J=7.1Hz,1H),7.20(t,J=7.0Hz,2H),7.17(t,J=6.9Hz,1H),7.15(t,J=7.1Hz,1H),7.12(d,J=6.9Hz,2H),7.10(d,J=7.0Hz,2H),7.08(t,J=6.9Hz,2H),7.05(t,J=7.0Hz,1H),6.95(d,J=7.1Hz,1H),6.87(d,J=7.1Hz,1H),5.33(s,2H),5.30(s,2H),4.91(d,J=5.1Hz,1H),4.43(t,J=4.3Hz,1H),4.27(dd,J=10.1Hz,J=4.1Hz,1H),4.17(dd,J=10.1Hz,J=3.6Hz,1H),2.97(t,J=4.3Hz,2H),2.93(d,J=10.1Hz,2H),1.95(m,J=4.1Hz,2H),1.53(m,J=4.5Hz,2H),1.47(s,9H),1.25(m,J=4.3Hz,2H).[α]D 20=-36°(c=0.37,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C38H44N4O7C 68.24,H,6.63,N 8.38.Found C 68.37,H 6.71,N 8.22.
实施例87(3S)-N-(Boc-L-谷氨酰胺酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-q)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由613mg(2.50mmol)of Boc-L-Gln-OH得到1175mg(88%)标题化合物,为无色粉末。Mp 137-139℃;ESI/MS:535[M+H]+.IR(KBr):3443,3211,3007,2940,2835,1732,1644,1605,1453,1393,1372,1060,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.99(s,1H),8.01(s,1H),7.25(t,J=7.1Hz,1H),7.21(t,J=7.0Hz,2H),7.16(t,J=7.1Hz,1H),7.13(d,J=7.0Hz,2H),7.10(t,J=7.0Hz,1H),7.01(d,J=7.1Hz,1H),6.87(d,J=7.1Hz,1H),6.09(s,2H),5.37(s,2H),4.92(d,J=5.3Hz,1H),4.41(t,J=5.3Hz,1H),4.25(d,J=5.4Hz,2H),2.93(d,J=5.1Hz,2H),2.17(t,J=5.2Hz,2H),2.14(t,J=5.2Hz,2H),1.47(s,9H).[α]D 20=-47°(c=0.37,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd gor C29H34N4O6C 65.15,H 6.41,N 10.48.Found C 65.01,H 6.30,N 10.65.
实施例88(3S)-N-(Boc-L-天冬酰胺酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-r)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由578mg(2.50mmol)Boc-L-Asn-OH得到1157mg(89%)标题化合物,为无色粉末。Mp 136-138℃;ESI/MS:521[M+H]+.IR(KBr):3441,3203,3001,2935,2837,1732,1634,1601,1455,1393,1376,1062,901cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.99(s,1H),8.02(s,1H),7.26(t,J=7.1Hz,1H),7.21(t,J=7.2Hz,2H),7.17(t,J=7.1Hz,1H),7.13(d,J=7.2Hz,2H),7.10(t,J=7.2Hz,1H),7.02(d,J=7.1Hz,1H),6.89(d,J=7.1Hz,1H),6.03(s,2H),5.35(s,2H),4.95(d,J=5.1Hz,1H),4.43(t,J=5.1Hz,1H),4.20(d,J=5.1Hz,2H),2.93(d,J=5.2Hz,2H),2.15(t,J=5.2Hz,2H),1.46(s,9H).[α]D 20=-37°(c=0.32,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC28H32N4O6C 64.60,H 6.20,N 10.76.Found C 64.75,H 6.27,N 10.89.
实施例89(3S)-N-(Boc-L-亮氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-s)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由575mg(2.50mmol)Boc-L-Leu-OH得到1181mg(91%)标题化合物,为无色粉末。Mp 153-155℃;ESI/MS:520[M+H]+.IR(KBr):3443,3205,3002,2954,2846,1733,1648,1601,1455,1391,1372,1063,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.99(s,1H),8.02(s,1H),7.25(t,J=7.1Hz,1H),7.21(t,J=7.0Hz,2H),7.19(t,J=7.1Hz,1H),7.13(d,J=7.0Hz,2H),7.09(t,J=7.0Hz,1H),7.02(d,J=7.1Hz,1H),6.80(d,J=7.1Hz,1H),5.35(s,2H),4.95(t,J=5.1Hz,1H),4.43(t,J=5.0Hz,1H),4.24(dd,J=10.1Hz,J=4.3Hz,1H),4.11(dd,J=10.1Hz,J=3.7Hz,1H),2.93(d,J=6.1Hz,2H),2.80(d,J=5.2Hz,2H),1.51(s,9H),1.33(m,J=5.2Hz,1H),1.09(d,J=5.1Hz,6H).[α]D 20=-39°(c=0.33,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C30H37N3O5C69.34,H 7.18,N 8.09.Found C 69.48,H 7.29,N 7.94.
实施例90(3S)-N-(Boc-L-异亮氨酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯(7Bzl-s)的制备
采用实施例70制备(3S)-N-(Boc-L-氨基酰)-1,2,3,4-四氢-β-咔啉-3-羧酸苄酯[7Bzl-(a-t)]的一般操作,由575mg(2.50mmol)Boc-L-Ile-OH得到1155mg(89%)标题化合物,为无色粉末。Mp 143-145℃;ESI/MS:520[M+H]+.IR(KBr):3441,3335,3216,3012,2951,2844,1755,1730,1641,1603,1455,1392,1374,1060,900cm-1;1HNMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),8.03(s,1H),7.25(t,J=7.0Hz,1H),7.20(t,J=6.9Hz,2H),7.17(t,J=7.0Hz,1H),7.11(d,J=6.9Hz,2H),7.07(t,J=6.9Hz,1H),7.00(d,J=7.0Hz,1H),6.86(d,J=7.0Hz,1H),5.33(s,2H),4.93(t,J=5.2Hz,1H),4.40(t,J=5.1Hz,1H),4.23(dd,J=10.1Hz,J=4.2Hz,1H),4.03(dd,J=10.1Hz,J=3.3Hz,1H),2.95(d,J=6.1Hz,2H),2.90(m,J=5.2Hz,1H),1.45(s,9H),1.32(m,J=5.1Hz,2H),1.03(d,J=5.1Hz,3H),0.94(t,J=5.3Hz,3H).[α]D 20=-37°(c=0.35,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C30H37N3O5 C 69.34,H 7.18,N 8.09.Found C 69.21,H 7.10,N 8.26.
实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作
0℃下将2.0mmol of 7Bzl-(a-t)溶解在10ml氯化氢/乙酸乙酯(4mol/L)并搅拌10min。反应混合物室温搅拌20-25min,TLC(乙酸乙酯∶石油醚,5∶12)显示反应完成。反应混合物减压浓缩至干。残留物用10ml乙酸乙酯溶解,再减压浓缩至干。该操作重复3次,得到无色粉末状的产品,收率为87%-92%。
实施例923-甲基-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5a)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1005mg(2.50mmol)7Bzl-a得到599mg(89%)标题化合物,为无色粉末。Mp.233-235℃,ESI-MS(m/z)270[M+H]+,IR(KBr):3337,2926,1678,1455,1326,744cm-1;1H-NMR(DMSO-d6,300MHz):δ=10.97(s,1H),8.46(d,J=2.1Hz,1H),7.46(d,J=7.5Hz,1H),7.35(t,J=7.5Hz,1H),7.07(t,J=7.5Hz,1H),6.96(t,J=7.5Hz,1H),5.33(d,J=16.8Hz,1H),4.73(m,J=6.9Hz,1H),4.28(dd,J=4.2Hz,J=11.7Hz,1H),4.20(d,J=16.5Hz,1H),3.26(dd,J=4.2Hz,J=15.0Hz,1H),2.80(t,J=4.8Hz,1H),1.35(d,J=6.9Hz,3H).13C-NMR(DMSO-d6,300MHz)δ=167.21,166.82,136.02,134.55,131.00,126.26,121.36,120.12,119.15,111.09,59.80,52.98,42.87,24.75,17.31.[α]D 20=-150°(c=0.40,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C15H15N3O2C 66.90,H5.61,N 15.60.Found C 66.70,H 5.41,N 15.81.
实施例933-苄基-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5b)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1106mg(2.0mmol)7Bzl-b得到621mg(90%)标题化合物,为无色粉末。Mp.142-145℃;EI-MS(m/z)346[M+H]+;IR(KBr):3328,2936,1669,1455,1328,744cm-1;1H-NMR(DMSO-d6,300MHz)δ=10.81(s,1H),8.46(d,J=1.8Hz,1H),7.42(d,J=7.5Hz,1H),7.31(t,J=7.5Hz,1H),7.22(t,J=7.2Hz,2H),7.14(d,J=7.2Hz,2H),7.06(t,J=7.2Hz,1H),7.02(t,J=7.5Hz,1H),6.93(t,J=7.5Hz,1H),5.32(d,J=16.5Hz,1H),4.37(s,2H),4.07(d,J=16.8Hz,1H),3.98(dd,J=11.7Hz,J=4.5Hz,1H),3.17(dd,J=13.2Hz,J=3.3Hz,1H),2.88(dd,J=13.5Hz,J=5.1Hz,1H),2.64(dd,J=14.7Hz,J=3.6Hz,1H);[α]D 20=-53°(c=0.30,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C21H19N3O2 C73.03,H 5.54,N 12.17.Found C 73.30,H 5.76,N 12.01.
实施例943-异丙基-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5c)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1010mg(2.0mmol)7Bzl-c得到546mg(92%)标题化合物,为无色粉末。Mp.216-218℃,ESI-MS(m/z)298[M+H]+;IR(KBr):3331,2939,1662,1457,1384,1365,746cm-1;1H-NMR(DMSO-d6,300MHz):δ=10.82(s,1H),8.60(d,J=2.7Hz,1H),7.36(d,J=7.1Hz,1H),7.25(t,J=7.1Hz,1H),7.02(t,J=7.1Hz,1H),6.93(t,J=7.1Hz,1H),5.22(d,J=15.2Hz,1H),4.21(dd,J=11.3Hz,J=4.2Hz,1H),4.19(d,J=17.0Hz,1H),3.27(dd,J=14.6Hz,J=3.7Hz,1H),2.99(m,J=13.3Hz,1H),2.89(t,J=13.3Hz,1H),2.74(m,J=6.2Hz,1H),1.07(d,J=6.2Hz,6H).13C-NMR(DMSO-d6,300MHz)δ=169.05,168.48,135.09,133.71,130.93,122.59,121.47,118.99,113.44,111.27,66.99,63.10,41.72,28.75,24.38,16.82.[α]D 20=-61°(c=0.44,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC17H19N3O2C 68.67,H 6.44,N 14.13.Found C 68.50,H 6.27,N 14.00.
实施例953-羟甲基-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5d)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由986mg(2.0mmol)7Bzl-d得到513mg(90%)标题化合物,为无色粉末。Mp.264-267℃,ESI-MS(m/z)286[M+H]+,IR(KBr):3344,2926,1683,1642,1463,1334,744cm-1;1H-NMR(DMSO-d6,300MHz)δ=10.92(s,1H),8.24(d,J=2.4Hz,1H),7.43(d,J=7.5Hz,1H),7.32(t,J=7.5Hz,1H),7.04(t,J=7.5Hz,1H),6.93(t,J=7.5Hz,1H),5.42(d,J=16.5Hz,1H),5.23(t,J=4.8Hz,1H),4.25(dd,J=11.4Hz,J=4.2Hz,1H),4.15(d,J=16.5Hz,1H),4.05(d,J=4.8Hz,1H),3.94(s,1H),3.17(dd,J=15.0Hz,J=3.6Hz,1H),2.98(t,J=13.5Hz,2H);13C-NMR(DMSO-d6,300MHz)δ=166.88,163.82,135.86,129.77,126.33,120.86,118.56,117.46,110.96,105.82,62.66,57.37,55.82,27.00.[α]D 20=-141°(c=0.30,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C15H15N3O3 C63.15,H 5.30,N 14.73.Found C 63.48,H 5.52,N 14.54.
实施例963-(1’-羟乙-1’-基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5e)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1014mg(2.0mmol)7Bzl-e得到534mg(89%)标题化合物,为无色粉末。Mp 147-149℃;ESI/MS 300[M+H]+;IR(KBr):3340,2929,1686,1642,1465,1333,744cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.00(s,1H),7.98(s,1H),7.29(t,J=7.1Hz,1H),7.25(t,J=7.1Hz,1H),7.09(t,J=7.1Hz,1H),6.97(d,J=7.1Hz,1H),4.81(t,J=5.3Hz,1H),4.63(m,J=5.2Hz,1H),4.45(t,J=5.4Hz,2H),4.22(m,J=5.6Hz,1H),2.90(d,J=5.4Hz,2H),2.15(s,1H),1.22(d,J=5.6Hz,3H).Anal.Calcd for C16H17N3O3C 64.20,H 5.72,N 14.04.Found C 64.32,H 5.80,N 14.22.
实施例973-(对-羟基苯甲基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5f)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1138mg(2.0mmol)7Bzl-f得到635mg(88%)标题化合物,为无色粉末。Mp 149-151℃;ESI/MS 362[M+H]+;IR(KBr):3342,2936,1682,1643,1464,1333,743cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.02(s,1H),8.01(s,1H),7.31(t,J=7.0Hz,1H),7.23(t,J=7.2Hz,1H),7.16(d,J=7.0Hz,2H),7.13(d,J=7.0Hz,2H),7.01(t,J=7.2Hz,1H),6.89(d,J=7.0Hz,1H),4.97(s,1H),4.85(d,J=5.2Hz,1H),4.78(t,J=5.4Hz,1H),4.21(m,J=5.2Hz,2H),3.13(d,J=5.2Hz,2H),2.90(d,J=5.4Hz,2H).Anal.Calcd forC21H19N3O3C 69.79,H 5.30,N 11.63.Found C 69.61,H 5.41,N 11.47.
实施例98(5aS,14aS)-1,2,3,5,5a,6,11,12,14,14a-十氢吡咯并[1”,2”:4’5’]吡嗪并[1’,2’:1,6]-β-咔啉(5g)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1006mg(2.0mmol)7Bzl-g得到525mg(89%)标题化合物,为无色粉末。Mp 133-135℃;ESI/MS 296[M+H]+;IR(KBr):3344,2934,1684,1643,1460,1332,743cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.03(s,1H),7.21(t,J=7.2Hz,1H),7.15(t,J=7.2Hz,1H),7.05(t,J=7.2Hz,1H),6.95(d,J=7.2Hz,1H),4.86(t,J=5.5Hz,1H),4.33(t,J=5.4Hz,1H),4.24(d,J=5.5Hz,2H),3.45(t,J=5.4Hz,2H),2.93(d,J=5.3Hz,2H),2.25(d,J=5.4Hz,2H),1.95(t,J=5.4Hz,2H).Anal.C alcd for C17H17N3O2C 69.14,H 5.80,N 14.23.Found C 69.01,H 5.70,N 14.14.
实施例993-(巯甲基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5h)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1018mg(2.0mmol)7Bzl-h得到548mg(91%)标题化合物,为无色粉末。Mp 147-149℃;ESI/MS 302[M+H]+;IR(KBr):3343,2936,1647,1641,1459,1333,741cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.03(s,1H),8.00(s,1H),7.28(t,J=7.0Hz,1H),7.15(d,J=7.0Hz,1H),7.08(d,J=7.0Hz,1H),6.89(d,J=7.0Hz,1H),4.93(t,J=5.4Hz,1H),4.79(t,J=5.6Hz,1H),4.29(d,J=5.2Hz,2H),2.92(d,J=5.4Hz,2H),3.07(d,J=5.6Hz,2H),1.65(s,1H).Anal.Calcd for C15H15N3O2S C 59.78,H 5.02,N 13.94.Found C 59.92,H5.13,N 13.76.
实施例1003-(甲巯基乙基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5i)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1074mg(2.0mmol)7Bzl-i 1018mg(2.0mmol)7Bzl-h得到592mg(90%)标题化合物,为无色粉末。Mp 160-162℃;ESI/MS 330[M+H]+;IR(KBr):3341,2934,1648,1643,1458,1332,742cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.00(s,1H),7.99(s,1H),7.27(t,J=7.0Hz,1H),7.19(t,J=7.0Hz,1H),7.08(t,J=7.0Hz,1H),6.87(d,J=7.0Hz,1H),4.87(t,J=5.4Hz,1H),4.49(t,J=5.2Hz,1H),4.29(d,J=5.3Hz,2H),2.94(d,J=5.4Hz,2H),2.43(t,J=5.3Hz,2H),2.17(d,J=5.3Hz,2H),2.10(s,3H).Anal.Calcd for C17H19N3O2S C 61.98,H 5.81,N 12.76.Found C 62.14,H 5.89,N 12.90.
实施例1013-(苄氧羰基乙基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5’j)的制备
采用实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1250mg(2.0mmol)7Bzl-j得到765mg(92%)标题化合物,为无色粉末。Mp136-138℃;ESI/MS 417[M+H]+;IR(KBr):3342,3000,2940,1675,1602,1586,1457,1333,750cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.99(s,1H),8.00(s,1H),7.30(t,J=7.1Hz,1H),7.22(t,J=7.1Hz,1H),7.18(t,J=7.0Hz,2H),7.13(d,J=7.0Hz,2H),7.08(t,J=7.0Hz,1H),7.06(t,J=7.0Hz,1H),7.01(d,J=7.2Hz,1H),6.85(d,J=7.2Hz,1H),5.33(s,2H),4.92(d,J=5.0Hz,1H),4.43(t,J=5.2Hz,1H),4.21(d,J=5.1Hz,2H),2.94(d,J=5.2Hz,2H),2.25(t,J=5.5Hz,2H),2.22(t,J=5.5Hz,2H).Anal.Calcd for C24H23N3O4C 69.05,H 5.55,N 10.07.Found C 68.90,H 5.62,N 10.21.
实施例1023-(苄氧羰基甲基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5’k)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1222mg(2.0mmol)7Bzl-k得到725mg(90%)标题化合物,为无色粉末。Mp.255-257℃,ESI-MS(m/z)404[M+H]+;(KBr):3346,2923,1678,1600,1589,1507,1460,1335,747cm-1;1H-NMR(DMSO-d6,300MHz)δ=9.98(s,1H),8.20(s,1H),7.30(d,J=7.4Hz,1H),7.23(t,J=7.4Hz,1H),7.20(t,J=7.2Hz,2H),7.13(t,J=7.2Hz,2H),7.10(t,J=7.2Hz,1H),7.03(t,J=7.4Hz,1H),6.92(t,J=7.3Hz,1H),5.35(d,J=16.6Hz,1H),5.33(s,2H),4.22(dd,J=11.0Hz,J=3.6Hz,1H),4.17(d,J=16.5Hz,1H),4.12(d,J=14.3Hz,1H),3.16(dd,J=14.0Hz,J=3.6Hz,1H),2.96(t,J=13.0Hz,1H),2.81(d,J=10.0Hz,2H).[α]D 20=-70°(c=0.44,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC23H21N3O4C 68.47,H 5.25,N 10.42.Found C 68.35,H 5.09,N 10.27.
实施例1033-[1’,3’-咪唑-4’-基]甲基]-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5l)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1086mg(2.0mmol)7Bzl-l得到610mg(91%)标题化合物,为无色粉末。Mp 149-151℃;ESI/MS 336[M+H]+;IR(KBr):3344,2925,1677,1601,1587,1505,1458,1333,751cm-1;1H NMR(BHSC-500,DMSO-d6):δ=12.99(s,1H),10.03(s,1H),7.98(s,1H),7.45(s,1H),7.33(t,J=7.0Hz,1H),7.25(t,J=7.0Hz,1H),7.09(t,J=7.0Hz,1H),6.99(t,J=7.0Hz,1H),6.87(s,1H),4.92(t,J=5.2Hz,1H),4.83(t,J=5.5Hz,1H),4.27(d,J=5.5Hz,2H),3.20(d,J=5.5Hz,2H),2.92(d,J=5.1Hz,2H).Anal.Calcd forC18H17N5O2C 64.47,H 5.11,N 20.88.Found C 64.62,H 5.20,N 21.03.
实施例1043-吲哚甲基-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5m)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1184mg(2.0mmol)7Bzl-m得到668mg(87%)标题化合物,为无色粉末。Mp.176-180℃;ESI-MS(m/z)385[M+H]+;IR(KBr):3329,2938,1683,1465,1338,746cm-1;1H-NMR(DMSO-d6,300MHz):δ=10.76(s,1H),10.74(s,1H),8.43(d,1H,J=1.8Hz,1H),7.50(d,J=7.5Hz,1H),7.28(t,J=7.5Hz,1H),7.26(t,J=7.2Hz,1H),7.24(t,J=7.2Hz,1H),7.22(d,J=7.2Hz,1H),7.20(t,J=7.2Hz,1H),7.08(t,J=7.5Hz,1H),6.95(t,1H,J=7.5Hz,1H),6.82(s,1H),5.27(d,J=16.2Hz,1H),4.31(d,J=2.4Hz,1H),4.05(d,J=16.5Hz,1H),3.95(dd,J=12.0Hz,J=4.5Hz,1H),3.28(dd,J=14.1Hz,J=3.6,Hz,1H),3.07(dd,J=14.1Hz,J=4.2Hz,1H),2.93(d,J=3.5Hz,2H);13C-NMR(DMSO-d6,300MHz)δ=165.65,164.64,135.80,135.71,129.11,127.62,126.19,124.00,120.58,118.45,118.36,118.10,117.25,110.81,108.02,105.42,79.06,55.77,55.36,30.17,25.6;[α]D 20=-182°(c=0.34,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C23H20N4O2 C 71.86,H5.24,N 14.57.Found C 72.04,H 5.56,N 14.33.
实施例1053-(3’-胍基丙基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5n)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1124mg(2.0mmol)7Bzl-n得到637mg(90%)标题化合物,为无色粉末。Mp 155-157℃;ESI/MS 355[M+H]+;IR(KBr):3339,2941,1680,1456,1342,743cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.03(s,1H),8.44(s,2H),8.20(s,1H),8.16(s,1H),8.01(s,1H),7.23(t,J=7.0Hz,1H),7.15(t,J=7.0Hz,1H),7.02(d,J=7.0Hz,1H),6.95(d,J=7.0Hz,1H),4.92(d,J=5.2Hz,1H),4.35(t,J=4.6Hz,1H),4.23(d,J=5.2Hz,2H),2.91(d,J=4.7Hz,2H),2.66(t,J=5.2Hz,2H),1.95(m,J=5.2Hz,2H),1.56(m,J=5.2Hz,2H).Anal.Calcd for C18H22N6O2 C 61.00,H 6.26,N 23.71.Found C 61.18,H 6.33,N23.53.
实施例106六氢吡嗪并[1’,2’:1,6]-β-咔啉(5o)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由926mg(2.0mmol)7Bzl-o得到469mg(92%)标题化合物,为无色粉未。Mp.247-249℃;ESI-MS(m/z)256[M+H]+;IR(KBr):3307,2986,1646,1455,1328,748cm-1;1H-NMR(DMSO-d6,300MHz):δ=10.94(s,1H),8.26(s,1H),7.43(d,J=7.5Hz,1H),7.33(t,J=7.5Hz,1H),7.08(t,J=7.5Hz,1H),6.96(t,J=7.5Hz,1H),5.36(d,J=16.5Hz,1H),4.22(m,J=13.0Hz,2H),4.05(d,J=17.7Hz,1H),3.86(d,J=17.7Hz,1H),3.20(m,J=13.5Hz,1H),2.88(t,J=13.5Hz,1H).13C-NMR(DMSO-d6,300MHz)δ=168.87,167.66,136.11,134.02,130.34,124.63,121.55,120.21,119.44,111.22,59.75,52.76,42.80,24.77.[α]D 20=-135(c=0.34,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC14H13N3O2C 65.87,H 5.13,N 16.46.Found C 65.65,H 5.01,N 16.67.
实施例1073-(4’-苄氧羰基氨丁基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5’p)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1336mg(2.0mmol)7Bzl-p得到828mg(90%)标题化合物,为无色粉末。Mp 144-146℃;ESI/MS:461[M+H]+.IR(KBr):3445,3308,2985,1601,1450,1064,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.03(s,1H),8.00(s,1H),7.99(s,1H),7.27(t,J=7.2Hz,1H),7.21(t,J=7.1Hz,2H),7.19(t,J=7.1Hz,1H),7.17(t,J=7.2Hz,1H),7.16(d,J=7.1Hz,2H),7.07(t,J=7.2Hz,1H),6.89(d,J=7.2Hz,1H),5.32(s,2H),4.93(d,J=5.2Hz,1H),4.47(t,J=4.5Hz,1H),4.29(dd,J=10.0Hz,J=4.2Hz,1H),4.19(dd,J=10.0Hz,J=3.8Hz,1H),2.98(t,J=4.7Hz,2H),2.95(d,J=5.2Hz,2H),1.91(m,J=4.7Hz,2H),1.55(m,J=4.7Hz,2H),1.29(m,J=4.7Hz,2H).[α]D 20=-44°(c=0.37,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C26H28N4O4C 67.81,H 6.13,N 12.17.Found C 67.96,H 6.21,N 12.33.
实施例1083-(丙酰氨-2’-基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5q)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1068mg(2.0mmol)7Bzl-q得到600mg(92%)标题化合物,为无色粉末。Mp 151-153℃;ESI/MS:327[M+H]+.IR(KBr):3344,2939,1684,1465,1332,746cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.01(s,1H),7.98(s,1H),7.27(t,J=7.2Hz,1H),7.19(t,J=7.2Hz,1H),7.03(d,J=7.2Hz,1H),6.85(d,J=7.2Hz,1H),6.11(s,2H),4.93(d,J=5.5Hz,1H),4.44(t,J=5.4Hz,1H),4.27(d,J=5.5Hz,2H),2.92(d,J=5.2Hz,2H),2.17(t,J=5.4Hz,2H),2.11(t,J=5.4Hz,2H).[α]D 20=-62°(c=0.37,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C17H18N4O3C 62.57,H 5.56,N 17.17.Found C 62.71,H 5.64,N17.35.
实施例1093-(乙酰氨基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5r)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1040mg(2.0mmol)7Bzl-r得到570mg(91%)标题化合物,为无色粉末。Mp 144-146℃;ESI/MS:313[M+H]+.IR(KBr):3341,2942,1681,1463,1336,741cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.03(s,1H),8.00(s,1H),7.27(t,J=7.2Hz,1H),7.19(t,J=7.2Hz,1H),7.05(d,J=7.2Hz,1H),6.87(d,J=7.2Hz,1H),6.06(s,2H),4.93(d,J=5.3Hz,1H),4.45(t,J=5.2Hz,1H),4.23(d,J=5.3Hz,2H),2.92(d,J=5.4Hz,2H),2.65(t,J=5.3Hz,2H).[α]D 20=-55°(c=0.32,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcdfor C16H16N4O3C 61.53,H 5.16,N 17.94.Found C 61.38,H 5.08,N 17.76.
实施例1103-(2’-甲基丙基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5s)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1038mg(2.0mmol)7Bzl-s得到554mg(89%)标题化合物,为无色粉末。Mp 131-133℃;ESI/MS:312[M+H]+.IR(KBr):3343,2943,1682,1465,1335,743cm-1;1HNMR(BHSC-500,DMSO-d6):δ=10.02(s,1H),7.98(s,1H),7.27(t,J=7.2Hz,1H),7.19(t,J=7.2Hz,1H),7.03(d,J=7.2Hz,1H),6.85(d,J=7.2Hz,1H),4.93(t,J=5.3Hz,1H),4.45(t,J=5.2Hz,1H),4.26(dd,J=10.0Hz,J=4.4Hz,1H),4.15(dd,J=10.0Hz,J=3.9Hz,1H),2.92(d,J=6.2Hz,2H),2.65(t,J=5.3Hz,2H),1.83(m,J=5.3Hz,1H),1.07(d,J=5.3Hz,6H).[α]D 20=-52°(c=0.33,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC18H21N3O2C 69.43,H 6.80,N 13.49.Found C 69.60,H 6.71,N 13.66.
实施例1113-(1’-甲基丙基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5t)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1038mg(2.0mmol)7Bzl-t得到541mg(87%)标题化合物,为无色粉末。Mp.211-213℃,ESI-MS(m/z)312[M+H]+;IR(KBr):3328,2936,1669,1455,1388,1369,744cm-1;1H-NMR(DMSO-d6,300MHz):δ=11.12(s,1H),8.64(d,J=2.1Hz,1H),7.40(d,J=7.3Hz,1H),7.30(t,J=7.3Hz,1H),7.00(t,J=7.3Hz,1H),6.95(t,J=7.3Hz,1H),5.30(d,J=16.0Hz,1H),4.25(dd,J=11.0Hz,J=4.0Hz,1H),4.17(d,J=17.3Hz,1H),3.22(dd,J=15.0Hz,J=3.3Hz,1H),2.96(m,J=13.0Hz,1H),2.83(t,J=13.0Hz,1H),2.61(m,J=6.0Hz,1H),1.35(m,J=6.0Hz,2H),1.07(d,J=6.0Hz,3H),0.97(t,J=6.0Hz,6H).13C-NMR(DMSO-d6,300MHz)δ=167.00,166.48,136.13,130.37,126.51,121.44,118.96,117.40,111.20,105.81,56.30,53.11,46.12,26.75,34.34,23.30,14.82,11.77.[α]D 20=-80°(c=0.44,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C18H21N3O2 C 69.43,H6.80,N 13.49.Found C 69.22,H 6.61,N 13.68.
实施例112由3a-t制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作
0℃下将2.0mmol of 3a-t溶解在10ml氯化氢/乙酸乙酯(4mol/L)溶液中,0℃搅拌20min,室温搅拌50min,TLC(乙酸乙酯∶石油醚,5∶12)显示Boc被脱除。反应混合物减压浓缩至于。残留物用10ml乙酸乙酯溶解并减压浓缩至干。该操作重复3次。残留物用10ml乙酸乙酯溶解并用1.0ml三乙胺处理。反应混合物室温搅拌24h,TLC(乙酸乙酯∶石油醚,5∶12)显示环合完全。反应混合物减压浓缩,残留物用闪式硅胶柱层析(乙酸乙酯∶石油醚,5∶12)纯化,得到5a-t,为无色粉末。产物的物理化学常数与前面的实施例得到的产物相同,收率在84%-90%范围。
实施例113由3’a-t制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作
0℃下将2.0mmol of 3’a-t溶解在10ml氯化氢/乙酸乙酯(4mol/L)溶液中,0℃搅拌20min,室温搅拌50min,TLC(乙酸乙酯∶石油醚,5∶12)显示Boc被脱除。反应混合物减压浓缩至干。残留物用10ml乙酸乙酯溶解并减压浓缩至干。该操作重复3次。残留物用10ml乙酸乙酯溶解并用1.0ml三乙胺处理。反应混合物室温搅拌20h,TLC(乙酸乙酯∶石油醚,5∶12)显示环合完全。反应混合物减压浓缩,残留物用闪式硅胶柱层析(乙酸乙酯∶石油醚,5∶12)纯化,得到5a-t,为无色粉末。产物的物理化学常数与前面的实施例得到的产物相同,收率在85%-91%范围。
实施例114由5’j,5’k和5’p脱苄制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5j,5k和5p的一般操作
室温下将1mmol 5’j,5’k和5’p与50mg Pd/C(5%)及15ml甲酸的甲醇溶液(4.4%)通氢气24h。反应混合物过滤,滤液减压浓缩,得到标题化合物,为无色粉末,收率为95%-96%。
实施例11153-(羧基乙基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5j)的制备
采用实施例实施例114由5’j,5’k和5’p脱苄制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5j,5k和5p的一般操作,由1250mg(2.0mmol)7Bzl-j得到765mg(92%)标题化合物,为无色粉末。Mp 136-138℃;ESI/MS 417[M+H]+;IR(KBr):3342,3000,2940,1675,1602,1586,1457,1333,750cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.99(s,1H),8.00(s,1H),7.30(t,J=7.1Hz,1H),7.22(t,J=7.1Hz,1H),7.18(t,J=7.0Hz,2H),7.13(d,J=7.0Hz,2H),7.08(t,J=7.0Hz,1H),7.06(t,J=7.0Hz,1H),7.01(d,J=7.2Hz,1H),6.85(d,J=7.2Hz,1H),5.33(s,2H),4.92(d,J=5.0Hz,1H),4.43(t,J=5.2Hz,1H),4.21(d,J=5.1Hz,2H),2.94(d,J=5.2Hz,2H),2.25(t,J=5.5Hz,2H),2.22(t,J=5.5Hz,2H).Anal.Calcd for C24H23N3O4C 69.05,H 5.55,N 10.07.Found C 68.90,H 5.62,N 10.21.
实施例1163-(苄氧羰基甲基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5’k)的制备
采用实施例实施例91由7Bzl-(a-t)制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5a-t的一般操作,由1222mg(2.0mmol)7Bzl-k得到725mg(90%)标题化合物,为无色粉末。Mp.255-257℃,ESI-MS(m/z)404[M+H]+;(KBr):3346,2923,1678,1600,1589,1507,1460,1335,747cm-1;1H-NMR(DMSO-d6,300MHz)δ=9.98(s,1H),8.20(s,1H),7.30(d,J=7.4Hz,1H),7.23(t,J=7.4Hz,1H),7.20(t,J=7.2Hz,2H),7.13(t,J=7.2Hz,2H),7.10(t,J=7.2Hz,1H),7.03(t,J=7.4Hz,1H),6.92(t,J=7.3Hz,1H),5.35(d,J=16.6Hz,1H),5.33(s,2H),4.22(dd,J=11.0Hz,J=3.6Hz,1H),4.17(d,J=16.5Hz,1H),4.12(d,J=14.3Hz,1H),3.16(dd,J=14.0Hz,J=3.6Hz,1H),2.96(t,J=13.0Hz,1H),2.81(d,J=10.0Hz,2H).[α]D 20=-70°(c=0.44,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd forC23H21N3O4C 68.47,H 5.25,N 10.42.Found C 68.35,H 5.09,N 10.27.
实施例1173-(羧乙基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5j)的制备
采用实施例实施例114由5’j,5’k和5’p脱苄制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5j,5k和5p的一般操作,由1432mg(2.0mmol)5’j得到619mg(95%)标题化合物,为无色粉末。Mp 255-257℃;ESI/MS 328[M+H]+;IR(KBr):3445,3332,2940,1684,1338,746cm-1;1H NMR(BHSC-500,DMSO-d6):δ=11.02(s,1H),10.01(s,1H),8.02(s,1H),7.29(t,J=7.0Hz,1H),7.21(t,J=7.0Hz,1H),7.03(d,J=7.0Hz,1H),6.83(d,J=7.0Hz,1H),4.90(d,J=5.2Hz,1H),4.41(t,J=5.3Hz,1H),4.25(d,J=5.2Hz,2H),2.93(d,J=5.3Hz,2H),2.27(t,J=5.3Hz,2H),2.02(q,J=5.3Hz,2H).[α]D 20=-100.1°(c=1.0,CH3OH);Anal.Calcd for C17H17N3O4C 62.38,H 5.23,N 12.84.Found C 62.55,H5.32,N 12.71.
实施例1183-(羧甲基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5k)的制备
采用实施例实施例114由5’j,5’k和5’p脱苄制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5j,5k和5p的一般操作,由806mg(2.0mmol)5’k得到601mg(96%)标题化合物,为无色粉末。Mp.271-273℃,ESI-MS(m/z)314[M+H]+;(KBr):3442,3336,2943,1688,1337,743cm-1;1H-NMR(DMSO-d6,300MHz)δ=11.00(s,1H),9.99(s,1H),8.01(s,1H),7.28(d,J=7.2Hz,1H),7.20(t,J=7.2Hz,1H),7.05(t,J=7.2Hz,1H),6.90(t,J=7.2Hz,1H),5.05(t,J=6.6Hz,1H),4.85(t,J=5.3Hz,1H),4.24(d,J=5.6Hz,2H),2.96(t,J=5.6Hz,2H),2.85(d,J=5.3Hz,2H).[α]D 20=-59°(c=1.0,CH3OH);Anal.Calcd for C16H15N3O4 C 61.34,H 4.83,N 13.41.Found C 61.27,H 4.77,N 13.59.
实施例1193-(4’-氨丁基)-六氢吡嗪并[1’,2’:1,6]-β-咔啉(5p)的制备
采用实施例实施例114由5’j,5’k和5’p脱苄制备3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉5j,5k和5p的一般操作,由922mg(2.0mmol)5’p得到587mg(90%)标题化合物,为无色粉末。Mp.116-118℃,EI-MS(m/z)327[M+H]+;IR(KBr):3324,2936,1683,1463,1336,745cm-1;1H-NMR(DMSO-d6,300MHz)δ=9.92(s,1H),8.21(d,J=1.8Hz,1H),7.41(d,J=7.5Hz,1H),7.28(t,J=7.5Hz,1H),7.08(t,J=7.5Hz,1H),6.95(t,1H,J=7.5Hz,1H),5.36(d.J=16.5Hz,1H),4.60(t,J=6.8Hz,1H),4.30(dd,J=11.7Hz,J=4.5Hz,1H),4.13(dd,J=11.7Hz,J=4.5Hz,1H),3.26(dd,J=13.2Hz,J=3.3Hz,1H),2.79(dd,J=13.5Hz,J=5.1Hz,1H),2.70(t,J=4.8Hz,2H),2.01(s,2H),1.80(m,J=4.8Hz,2H),1.60(m,J=4.8Hz,2H),1.32(m,J=4.8Hz,2H).[α]D 20=-48°(c=0.30,CHCl3∶CH3OH,1∶1,v/v);Anal.Calcd for C18H22N4O2C 66.24,H 6.79,N 17.17.Found C 66.01,H 6.58,N 17.41.
试验例1本发明化合物(5a-s)的抗血栓活性试验
测定前将5a-s溶于生理盐水。雄性Wistra大鼠(220-240g)用戊巴比妥钠(5.0mg/ml,3ml/kg)麻醉后分离右颈动脉和左颈静脉。把一根6cm长的事先精密称重的丝线放在聚乙烯管中,将插管充满肝素钠的生理盐水溶液(50IU/ml)后,端插入左侧静脉,从一端加入定量肝素钠抗凝,并加入5a-s的生理盐水溶液(浓度为0.67mg/ml,剂量为0.5μmol/kg),然后插入右侧动脉。血流从右侧动脉流经聚乙烯管流入左侧静脉,15分钟后取出附有血栓的丝线并记录湿重,附有血栓的丝线在干燥器中放置两周后,称量干重。以生理盐水(NS,3ml/kg)作空白对照,以阿司匹林(剂量1组为0.2mol/kg,剂量2组为500μmol/kg)作阳性对照。结果见表1。
表1的数据表明在0.5μmol/kg剂量下5a-t具有明显的抗血栓活性。从表1的数据还可以看出,虽然5a-t在相当于1/400000阿司匹林剂量下抗血栓活性弱于阿司匹林,但是在相当于1/1000阿司匹林剂量下5a-s的抗血栓活性非常显著地强于阿司匹林。在剂量仅是5a-t1000倍的情形下,阿司匹林不显示抗血栓作用。该结果说明,5a-t是优秀的抗血栓剂。
表1.静脉用5a-t对大鼠血栓形成的影响(x±SD mg)n=11;
化合物 | 血栓湿重 | 血栓干重 | 化合物 | 血栓湿重 | 血栓干重 |
NS | 25.75±2.21 | 5.43±0.62 | 5j | 10.42±1.82d | 3.31±0.32 |
Aspirin1 | 7.56±1.31a | 2.40±0.5a | 5k | 12.26±1.83a | 3.89±0.54a |
Aspirin2 | 25.60±1.89 | 5.09±0.98 | 5l | 11.43±0.57a | 3.63±0.27a |
5a | 12.05±1.08a | 3.83±0.49a | 5m | 12.42±1.65a | 3.94±0.54a |
5b | 8.58±1.24b | 2.72±0.44b | 5n | 8.62±1.82b | 2.74±0.33b |
5c | 8.19±1.76b | 2.59±0.36b | 5o | 10.68±1.55d | 3.39±0.41d |
5d | 9.44±1.17c | 2.98±0.46c | 5p | 12.78±1.57a | 4.06±0.31a |
5e | 11.49±1.27a | 3.65±0.49 | 5q | 11.10±1.29a | 3.52±0.53a |
5f | 10.49±1.75d | 3.30±0.39d | 5r | 9.54±1.61c | 3.03±0.51c |
5g | 11.28±1.07a | 3.58±0.42a | 5s | 10.40±1.88d | 3.30±0.39d |
5h | 9.06±1.03c | 2.88±0.39c | 5t | 12.45±0.23a | 3.95±0.31a |
5i | 10.41±0.93d | 3.28±0.54d |
Aspirin1:剂量(静脉)=0.2mol/kg;Aspirin2:剂量(静脉)=500μmol/kg;5a-t:剂量(静脉)=0.5μmol/kg;a)与NS组比,P<0.001;b)与5a,m,p,t及NS组比P<0.001,与5f,i,j,o,s组比P<0.05;c)与5e,g,l,q组比P<0.05,与NS组比P<0.001;d)与5a,t,p组比P<0.05,与NS组比P<0.001.
试验例2评价静脉给予三种剂量本发明化合物(5b,c,n)的抗血栓活性
采用实施例119的模型,测定前将5b,c,n溶于生理盐水,每种化合物都制备三种浓度,对应于0.5μmol/kg,5nmol/kg和0.5nmol/kg三种剂量,静脉给药。结果见表2。表2的数据表明,即使在0.5nmol/kg剂量下5b,c,n仍然具有明显的抗血栓活性(与NS组比,p<0.001)。从表2的数据还可以看出,5b,c,n的抗血栓活性明确依赖于剂量。
表2.静脉给予三种剂量5b,c,n的抗血栓活性
n=11,a)与5nmol/kg组及NS组比,p<0.001;b)与0.5nmol/kg组比p<0.01,与NS组比p<0.01;c)与0.5nmol/kg组比p<0.05,与NS组比p<0.001;d)与NS组比,p<0.001.
试验例3评价灌胃给予5k,o,p的抗血栓活性
采用实施例119的模型,测定前将5k,o,p溶于生理盐水,每种化合物都制备对应于0.5μmol/kg剂量的溶液,口服给药。结果见表3。
表3的数据表明,在0.5nmol/kg剂量下灌胃给予5k,o,p可产生具有明显的抗血栓活性(与NS组比,p<0.001)。从表2的数据还可以看出,口服5k,o,p的抗血栓活性与静脉使用5k,o,p的抗血栓活性无明显差异。可见,本发明的3-取代六氢吡嗪并[1’,2’:1,6]-β-咔啉是口服有效的抗血栓剂。
表3.灌胃给予5k,o,p的抗血栓活性
n=11,dosage=0.5μmol/kg,a)Compare to NS group,p<0.001.
Claims (10)
1.具有抗血栓活性的通式(I)化合物:
通式(I)
其中,R选自CH3,C6H5CH2,CH(CH3)2,CH2OH,CH(OH)CH3,CH2C6H4-OH-p,四氢吡咯-2-基,CH2SH,CH2CH2SCH3,CH2CH2CO2H,CH2CO2H,1,3-咪唑-4-甲基,吲哚-3-基-甲基,CH2(CH2)2NHC(NH2)=NH,氢,CH2(CH3)3NHZ,CH2CH2CONH2,CH2CONH2,CH2CH(CH3)2或CH(CH3)CH2CH3。
2.权利要求1通式(I)化合物的中间体:
通式(II)
其中,R1选自CH3或CH2C6H5;R选自R选自CH3,CH2C6H5,CH(CH3)2,CH2OH,CH(OH)CH3,CH2C6H4-OH-p,四氢吡咯-2-基,CH2SH,CH2CH2SCH3,CH2CH2COOCH3,CH2CH2COOCH2C6H5,CH2COOCH3,CH2COOCH2C6H5,1,3-咪唑-4-甲基,吲哚-3-基-甲基,CH2(CH2)2NHC(NH2)=NH,氢,CH2(CH3)3NHZ,CH2CH2CONH2,CH2CONH2,CH2CH(CH3)2或CH(CH3)CH2CH3。
4.权利要求1通式(I)化合物的中间体:
通式(IV)
其中,R1选自CH3或C6H5CH2。
7.一种制备权利要求1通式(I)化合物的方法,包括:
(1)按照常规技术制备咔啉羧酸;
(2)在三乙胺存在下,将咔啉羧酸和Boc-N3反应,得化合物1;
(3)在DCC和NMM存在下,化合物1与氨基酸甲酯或氨基酸苄酯偶联生成化合物2;
(4)将化合物2脱去Boc保护基,生成咔啉酰氨基酸甲酯或咔啉酰氨基酸苄酯;
(5)在碱的水溶液中将咔啉酰氨基酸甲酯或咔啉酰氨基酸苄酯发生分子内环合反应,得到本发明通式(I)化合物。
8.按照权利要求7的方法,其特征在于,步骤(1)中按照以下方法制备咔啉羧酸:在H2SO4存在下,将甲醛和色氨酸缩合;步骤(4)中将化合物2脱去Boc保护基按照以下条件进行:在4mol/L的氯化氢的乙酸乙酯溶液中将化合物2脱去脱Boc保护基;步骤(5)中所述的碱的水溶液是2N的NaOH水溶液。
9.一种制备权利要求1通式(I)化合物的方法,包括:
(1)按照现有技术方法制备咔啉羧酸;
(2)在甲醇/氯化亚砜或者苄醇/PCl5存在的条件下,将咔啉羧酸转化为咔啉羧酸甲酯盐酸盐或咔啉羧酸苄酯磷酸盐;
(3)用三乙胺中和咔啉羧酸甲酯盐酸盐或咔啉羧酸苄酯磷酸盐得到化合物1;
(4)在DCC和NMM存在下,化合物1与Boc-氨基酸偶联生成化合物2;
(5)在氯化氢的乙酸乙酯溶液中,化合物2脱Boc同时发生分子内环合反应,得到本发明通式(I)化合物。
10.权利要求1所述的通式(I)化合物在制备抗血栓药物中的用途。
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