CN108456209B - 一种由羟基脯氨酸及其衍生物制备吡咯里西啶骨架的方法 - Google Patents
一种由羟基脯氨酸及其衍生物制备吡咯里西啶骨架的方法 Download PDFInfo
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- CN108456209B CN108456209B CN201710090990.6A CN201710090990A CN108456209B CN 108456209 B CN108456209 B CN 108456209B CN 201710090990 A CN201710090990 A CN 201710090990A CN 108456209 B CN108456209 B CN 108456209B
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- 238000000034 method Methods 0.000 title claims abstract description 22
- ADRDEXBBJTUCND-UHFFFAOYSA-N pyrrolizidine Chemical group C1CCN2CCCC21 ADRDEXBBJTUCND-UHFFFAOYSA-N 0.000 title claims abstract description 21
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 title claims abstract description 8
- 229960002591 hydroxyproline Drugs 0.000 title claims abstract description 8
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 title abstract description 6
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 title abstract description 4
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- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 229960002429 proline Drugs 0.000 claims abstract description 7
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- 239000012429 reaction media Substances 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- -1 aliphatic cyclic ketone Chemical class 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
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- 239000003960 organic solvent Substances 0.000 claims description 5
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 5
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- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
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- PURITTXNCHNYEP-UHFFFAOYSA-N mukoenine a Chemical compound N1C2=CC=CC=C2C2=C1C(CC=C(C)C)=C(O)C(C)=C2 PURITTXNCHNYEP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明为一种由羟基脯氨酸及其衍生物制备吡咯里西啶骨架的方法，涉及一种制备吡咯里西啶衍生物的方法，其主要步骤是：在有酸性催化剂存在条件下，由酮Ⅰ与4‑取代‑L‑脯氨酸Ⅱ在反应介质中，于60℃~160℃反应，制得目标物吡咯里西啶衍生物。该方法条件温和，无需惰性气体保护，操作简便，原子利用率高，底物应用范围广阔，适宜工业放大，具有良好的工业化前景。
Description
技术领域
本发明属于化学制药和精细化工制备技术领域，即一锅法制备吡咯里西啶生物碱，尤其是过程不涉及金属催化，最重要的是参与反应的氨基酸不需要预活化或者加入活化试剂，羧酸直接参与的Clasien缩合反应，高效的生成一种多官能团取代的吡咯里西啶生物碱结构。本发明为高效制备官能化的吡咯里西啶生物碱衍生物提供了一条可行的技术路线和设计策略，在化工制药和精细化工领域有广阔的应用。
背景技术
吡咯里西啶类生物碱(PyrrolizidineAlkaloids，PAs，1)是一类具有吡咯双烷结构的重要生物碱，存在于多种植物中，用于抵御昆虫、植物病菌等侵害,目前发现了近660多种PAs，其中大部分对人和动物有毒性[Smith L,Culvenor C.Plant sources ofhepatotoxic pyrrolizidine alkaloids[J].J.Nat.Prod.,1981,44(2):129-152]，FDA于2012年发布了PAs的毒性警示(Bad Bug Book，BBB)[http://www.fda.gov/Food/FoodborneIllnessContaminants/CausesOfIllnessBadBugB ook/ucm070710.htm]。另一方面，吡咯里西啶结构骨架也广泛存在于许多具有重要生理活性的天然产物中，例如吡咯里西啶糖苷化合物2，有研究表明其具有抑制BEL-7402人肝癌细胞和HL-60人早幼粒白血病细胞增长的活性[Liu C M,Wang H X,Wei S L,Gao K.Pyrrolizidine alkaloids andbisabolane sesquiterpenes from the roots ofligularia cymbulifera[J].Helv.Chim.Acta.,2008,91(2):308-316]；化合物3和4具有抑制L1210细胞复制的活性[4]；化合5是一种极具潜力的FLT3-ITD激酶抑制剂[Lisowski V,Léonce S,Kraus-Berthier L,Sopková-De Oliveira Santos J,PierréA,Atassi G,Caignard D-H,Renard P,RaultS.Design,synthesis,and evaluation of novel thienopyrrolizinones asantitubulin agents[J].J.Med.Chem.,2004,47(6):1448-1464]等。
文献主要采用多步合成法，从吡咯环出发，经多次官能团引入和转化，得到最终化合物。例如化合物6的合成，从异香兰素出发，经过五步反应，完成对其的合成,收率65％[Lisowski V,Léonce S,Kraus-Berthier L,Sopková-De Oliveira Santos J,PierréA,Atassi G,Caignard D-H,Renard P,Rault S.Design,synthesis,and evaluation ofnovel thienopyrrolizinones as antitubulin agents[J].J.Med.Chem.,2004,47(6):1448-1464]。
2008年Batra课题组报道了三步合成吡咯里西啶衍生物的方法，丙烯酸甲酯7和吡咯通过Baylis-Hillman反应得到关键中间体8，然后碱解、多聚磷酸催化的分子内酰基化生成吡咯里西啶环，收率42％-74％[Nag S,Madapa S,Batra S.Application ofprimaryallylamine derivatives ofBaylis-Hillman adducts to heterocyclic synthesis:generation of5-benzyl-4(3H)-pyrimidinones and
2-benzylidene-2,3-dihydropyrrolizin-1-ones1[J].Synthesis,2008,2008(1):101-109]。
2013年Yang研究组报道了钯-铜催化β-羰基酰胺二烯化合物9的分子内C-H胺化串联C-C偶联反应，在甲苯和DMSO混合溶剂中，80℃下反应高效合成多取代氢化吡咯里西啶化合物，收率76％[Xing D,Yang D.Pd(II)-catalyzed intramolecular 1,2-aminoalkylation of conjugated 1,3-dienes for the synthesis of pyrrolizidines[J].Org.Lett.,2013,15(17):4370-4373]。
同年Sansano等也报道了醋酸银催化脯氨酸酯、芳香醛和缺电子烯烃的三组分1,3-偶极环加成反应，合成了一系列多取代的吡咯里西啶衍生物，收率62％-83％[Mancebo-Aracil J,Nájera C,Sansano J M.Multicomponent synthesis of unnaturalpyrrolizidines using 1,3-dipolar cycloaddition of proline esters[J].Chem.Commun.,2013,49(95):11218-11220]。
综合相关文献可以看出，吡咯里西啶的合成方法研究十分有限，往往采用多步合成方法或者涉及昂贵的金属作为催化剂，适用范围也极其有限。因此亟需发展一种高效、原料易得、成本低廉、易于工业放大即经济可行的制备吡咯里西啶衍生物的合成方法。
发明内容
本发明在现有技术科研成果的基础上，发现了一种采用成本低廉的4-羟基脯氨酸及其衍生物与酮直接Clasien缩合芳构化，一锅法制备多取代多功能化的吡咯里西啶衍生物。该方法无需惰性气体保护和金属催化，重要的是参与反应的氨基酸不需要预活化或加入活化试剂，操作简便，原子利用率高，底物应用范围广阔，适宜工业放大，具有良好的工业化前景，克服现有技术的不足。
所述方法的主要步骤是：在酸催化剂存在条件下，由酮(其结构式如式Ⅰ所示)与4-羟基脯氨酸或其衍生物(其结构式如式Ⅱ所示)在反应介质中，于0℃～200℃(优选60℃～160℃)反应，制得目标物吡咯里西啶衍生物(其结构如式Ⅲ所示)。
其中，式Ⅰ的R1 ,R2各自为C1～C6的烃基，C5～C10的芳香环或含有O、N、S的芳香杂环；R1,R2也可以是由C2～C6碳链构成的环烃基。
式Ⅱ的R3为H，C5～C10的芳基和含O、S、N的芳杂环，苄基
C1～C6的烃基，酯基，以及含有硝基，氰基，卤素，酯基，氨基，烷氧基取代的上述基团；R4为含C1～C6的酰基，C5～C11的芳(杂)酰基，C1～C6的烃基；R5为C1～C6的烷氧基，苄氧基或羟基；R6为H,叔丁氧羰基,苄基，烯丙基。
由于酮、羟基脯氨酸等原料和催化剂均为大宗商业产品，可以预见该方法能够有效控制成本，适宜工业生产。
具体实施方案
在本发明一个优选的技术方案中，式Ⅰ所示化合物和式Ⅱ所示化合物的摩尔比为1：0.8～10，更有选的技术方案是：式Ⅰ所示化合物和式Ⅱ所示化合物的摩尔比为1：1.0～6。
在本发明另一个优选技术方案中，所说的酸性催化剂为有机羧酸、有机磺酸或硫酸，所说的有机羧酸或有机硫酸如(但不限于)：甲酸、乙酸、丙酸、异丁酸、环己基甲酸、苯甲酸、苯乙酸、脯氨酸、4-羟基-L-脯氨酸、三氟乙酸、甲磺酸、苯磺酸或对甲苯磺酸等；
更优选的酸性催化剂是乙酸、丙酸、三氟乙酸或者脯氨酸；
所述的酸性催化剂的用量为式Ⅰ所示化合物(直链或者支链酮、环状酮)用量的1.0equiv～5.0equiv为宜。
在本发明又一个优选的技术方案中，所述的反应介质是有机溶剂或者离子液体，如(但不限于)：甲苯、二甲苯、乙酸、1，4-二氧六环、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺、二甲亚砜(DMSO)、环丁砜、溴化1-丁基-3-甲基咪唑盐、1-丁基-3-甲基咪唑四氟硼酸盐或1-丁基-3-甲基咪唑六氟磷酸盐等；
本发明推荐使用的溶剂是：甲苯、N，N-二甲基甲酰胺(DMF)和二甲基亚砜(DMSO)；
所述有机溶剂的建议用量为10mL～20mL/g˙酮，即每克酮(式Ⅰ所示化合物)需用10mL～20mL所述的有机溶剂。
在本发明的优点：
1、该反应操作简便，只需一锅反应就可以高效的制备吡咯里西啶衍生物，易于放大工业生产。
2、该反应无需昂贵的金属催化，所用的脯氨酸无需预热或者添加其他活化试剂，一步合成吡咯里西啶，该反应的产品结构新颖。
3、该反应的产物某些表现出动物毒性和在天然产物中广泛存在，可为进一步研究其毒性和生物活性提供支持。
下面通过实施例对本发明作进一步说明，其目的仅在于更好的理解本发明的内容。因此，本发明的保护范围不受所举之例的限制。
实施例操作通法：
将酮Ⅰa-r(0.5当量)和相应的氨基酸Ⅱa-c(3.0当量)混合于甲苯(2mL)与丙酸(1mL)的混合溶剂中，140℃反应12小时。反应结束后冷却至室温，加入30mL的乙酸乙酯稀释，再用饱和碳酸氢钠中和，乙酸乙酯萃取三次，合并有机相，依次用水和饱和氯化钠各洗一次，无水硫酸钠干燥。抽滤，滤液浓缩后柱层析得相应的产物Ⅲ(石油醚/乙酸乙酯洗脱体系)。
将1.5mmol的Ⅱd-f溶解于2mL的二氯甲烷中，搅拌下加入2mL的三氟乙酸，TLC跟踪至Ⅱ完全转化(约15分钟)。完全脱Boc保护基后将溶剂减压除掉，加入相应的酮Ⅰ以及甲苯和丙酸，于140℃反应12小时。反应结束后冷却至室温，加入30mL的乙酸乙酯稀释，再用饱和碳酸氢钠中和，乙酸乙酯萃取三次，合并有机相，依次用水和饱和氯化钠各洗一次，无水硫酸钠干燥。抽滤，滤液浓缩后柱层析得相应的产物Ⅲ石油醚/乙酸乙酯洗脱体系)。
实例1：
cis-6,7,8,8a-tetrahydro-4aH-pyrrolo[1,2-a]indol-9(5H)-one,Ⅲaa,ab,ac.
1H NMR(400MHz,CDCl3)δ7.06–7.00(m,1H),6.70(d,J＝3.9Hz,1H),6.49(dd,J＝3.9,2.3Hz,1H),4.59(dd,J＝12.8,7.0Hz,1H),3.12(dd,J＝11.9,6.9Hz,1H),2.24–2.04(m,2H),1.86–1.73(m,1H),1.53(m,2H),1.48–1.31(m,3H).13C NMR(101MHz,CDCl3)δ191.9,131.8,121.7,116.1,107.5,54.1,50.2,30.1,22.5,20.8,19.5.HRMS(ESI)m/z Calcd forC11H13NO(M+H+):175.0997,found:175.0995.Light yellow oil.
实例2：
cis-5,6,7,8,9,9a-hexahydrocyclohepta[b]pyrrolizin-10(4H)-one,Ⅲba.
1H NMR(400MHz,CDCl3)δ7.01(s,1H),6.71(d,J＝3.9Hz,1H),6.53(dd,J＝3.6,2.4Hz,1H),4.69(td,J＝8.7,3.6Hz,1H),3.34–3.19(m,1H),2.18(m,1H),2.13–1.82(m,3H),1.70(m,2H),1.46(d,J＝9.8Hz,4H).13C NMR(101MHz,CDCl3)δ192.05,132.63,121.24,116.78,107.11,59.42,55.76,32.93,30.80,27.77,27.63,24.89.HRMS(ESI)m/z Calcdfor C12H15NO(M+H+):190.1232,found:190.1228.Light yellow oil.
实例3：
cis-ethyl10-oxo-4a,5,6,7,8,9,9a,10-octahydrocyclohepta[b]pyrrolizine-7-carboxylate,Ⅲca.
1H NMR(400MHz,CDCl3)δ7.04(s,1H),6.72(d,J＝3.8Hz,1H),6.53(d,J＝14.5Hz,1H),4.71–4.61(m,1H),4.19–4.10(q,J＝7.1Hz,2H),3.31–3.20(m,1H),2.47–2.28(m,3H),2.25–2.15(m,1H),2.11–2.00(m,1H),1.81(m,2H),1.72–1.63(m,2H),1.27(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ191.05,175.14,132.08,121.40,117.07,107.56,60.55,59.34,55.81,46.90,30.78,30.60,27.69,25.49,14.22.HRMS(ESI)m/z Calcd forC15H19NO3(M+H+):262.1443,found:262.1439.Light yellow solid.
实例4：
cis-6,7,8,9,10,10a-hexahydro-4aH-cycloocta[b]pyrrolizin-11(5H)-one,Ⅲda.
1H NMR(400MHz,CDCl3)δ7.03(d,J＝7.8Hz,1H),6.69(d,J＝3.6Hz,1H),6.54–6.50(m,1H),4.38–4.28(m,1H),2.99–2.87(m,1H),2.49(m,1H),2.40–2.25(m,1H),1.92–1.82(m,3H),1.68(m,2H),1.61–1.39(m,5H).13C NMR(101MHz,CDCl3)δ191.7,131.8,120.9,116.6,107.3,60.7,56.5,35.7,30.0,27.2,26.8,23.6(2C).HRMS(ESI)m/z Calcd forC13H17NO(M+H+):204.1388,found:204.1385.Light yellow oil.
实例5：
cis-7-methyl-6,7,8,8a-tetrahydro-4aH-pyrrolo[1,2-a]indol-9(5H)-one,Ⅲea.
1H NMR(400MHz,CDCl3)δ6.95(d,J＝1.4Hz,1H),6.58(d,J＝3.9Hz,1H),6.37(dd,J＝3.8,2.3Hz,1H),4.48(dd,J＝15.2,6.8Hz,1H),3.10(td,J＝6.9,2.2Hz,1H),2.27(dd,J＝18.2,6.1Hz,1H),2.23–2.10(m,1H),1.40(M,1H),1.33–1.07(m,3H),0.99–0.86(m,1H),0.84(d,J＝6.3Hz,3H).13C NMR(101MHz,CDCl3)δ192.9,131.9,121.1,116.0,108.2,53.3,50.6,33.0,28.6,27.95,26.5,22.34.HRMS(ESI)m/z Calcd for C12H15NO(M+H+):190.1232,found:190.1225.Colorless solid.
实例6：
cis-7-ethyl-6,7,8,8a-tetrahydro-4aH-pyrrolo[1,2-a]indol-9(5H)-one,Ⅲfa.
1H NMR(400MHz,CDCl3)δ7.03(d,J＝1.3Hz,1H),6.70(d,J＝3.9Hz,1H),6.48(dd,J＝3.9,2.3Hz,1H),4.59(dd,J＝13.9,7.5Hz,1H),3.21(td,J＝7.0,2.6Hz,1H),2.38(d,J＝13.8Hz,1H),2.25(m,1H),1.61–1.48(m,1H),1.40–1.15(m,5H),1.08–0.96(m,1H),0.88(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ191.6,131.6,121.9,116.0,107.4,54.4,50.5,34.0,31.3,29.6,28.5,26.5,11.3.HRMS(EI)m/z Calcd for C13H17NO(M+):203.1310,found:203.1311.Colorless solid.
实例7：
cis-7-phenyl-6,7,8,8a-tetrahydro-4aH-pyrrolo[1,2-a]indol-9(5H)-one,Ⅲga.
1H NMR(400MHz,CDCl3)δ7.32–7.26(m,2H),7.23–7.16(m,3H),7.06(d,J＝1.3Hz,1H),6.74(d,J＝3.7Hz,1H),6.50(dd,J＝3.8,2.3Hz,1H),4.66(dd,J＝15.3,6.9Hz,1H),3.31(td,J＝7.0,1.5Hz,1H),2.66–2.59(m,1H),2.53–2.47(m,1H),2.45–2.38(m,1H),1.84–1.69(m,2H),1.64–1.54(m,1H),1.44–1.33(m,1H).13C NMR(101MHz,CDCl3)δ190.9,146.2,131.4,128.5(2C),126.8(2C),126.4,122.2,116.2,107.7,53.9,51.0,39.2,32.8,30.5,28.4.HRMS(ESI)m/z Calcd for C17H17NO(M+H+):252.1388,found:252.1382.Colorless solid.
实例8：
cis-ethyl 9-oxo-5,6,7,8,8a,9-hexahydro-4aH-pyrrolo[1,2-a]indole-7-carboxylate,Ⅲha.
1H NMR(400MHz,CDCl3)δ7.07(d,J＝1.2Hz,1H),6.72–6.67(m,1H),6.50(dd,J＝3.9,2.3Hz,1H),4.68(dd,J＝13.0,7.2Hz,1H),4.12(q,J＝7.1Hz,2H),3.27(m,1H),2.52–2.44(m,1H),2.42–2.33(m,1H),2.32–2.23(m,1H),1.92(m,1H),1.64(dt,J＝12.1,4.5Hz,2H),1.53–1.42(m,1H),1.25(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ190.5,175.2,131.6,122.0,116.5,107.8,60.6,53.5,49.1,37.1,29.3,24.2,22.1,14.2.HRMS(ESI)m/zCalcd for C14H17NO3(M+H+):248.1287,found:248.1284.
实例9：
cis-7-(trifluoromethyl)-6,7,8,8a-tetrahydro-4aH-pyrrolo[1,2-a]indol-9(5H)-one,Ⅲia.
1H NMR(400MHz,CDCl3)δ7.07(s,1H),6.74(d,J＝3.9Hz,1H),6.56–6.47(m,1H),4.73(dd,J＝12.8,6.0Hz,1H),3.37–3.25(m,1H),2.50(m,1H),2.31–2.11(m,2H),1.86–1.71(m,1H),1.63–1.43(m,3H).13C NMR(101MHz,CDCl3)δ189.8,131.7,127.7(q,J＝278.6Hz,CF3),122.2,117.0,108.0,53.3,48.3,35.7(q,J＝27.1Hz),28.5,20.3(d,J＝2.9Hz),18.0(d,J＝2.5Hz).HRMS(ESI)m/z Calcd for C12H12F3NO(M+H+):244.0949,found:244.0943.Light yellow oil.
实例10:
cis-7-(4-hydroxyphenyl)-6,7,8,8a-tetrahydro-4aH-pyrrolo[1,2-a]indol-9(5H)-one,Ⅲja.
1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),7.40(s,1H),7.01(d,J＝8.2Hz,2H),6.69(d,J＝8.2Hz,2H),6.63(d,J＝3.7Hz,1H),6.49(d,J＝1.3Hz,1H),4.76(dd,J＝15.0,7.1Hz,1H),3.37(m,1H),2.42(m,1H),2.31–2.18(m,2H),1.74(m,1H),1.49(m,2H),1.20–1.12(m,1H).13C NMR(101MHz,DMSO-d6)δ195.8,160.8,141.9,135.9,132.6(2C),128.5,120.8,120.3(2C),111.9,58.5,55.7,43.5,37.9,35.5,34.0.HRMS(ESI)m/z Calcd forC17H17NO2(M+H+):268.1338,found:268.1334.Off-white solid.
实例11：
2-(cis-9-oxo-5,6,7,8,8a,9-hexahydro-4aH-pyrrolo[1,2-a]indol-7-yl)isoindoline-1,3-dione,Ⅲka.
1H NMR(400MHz,CDCl3)δ7.71(dt,J＝7.0,3.5Hz,2H),7.65–7.60(m,2H),7.00(d,J＝1.2Hz,1H),6.65(d,J＝3.7Hz,1H),6.44(dd,J＝3.9,2.2Hz,1H),4.71(dd,J＝12.9,7.0Hz,1H),4.20–4.07(m,1H),3.34(m,1H),2.59–2.42(m,2H),2.37–2.25(m,1H),2.03–1.90(m,1H),1.60–1.41(m,2H).13C NMR(101MHz,CDCl3)δ190.0,168.0(2C),134.0(2C),131.8(2C),131.6,123.2(2C),122.2,116.7,107.9,53.2,49.8,44.4,30.1,24.7,24.1.HRMS(ESI)m/z Calcd for C19H16N2O3(M+H+):321.1239,found:321.1237.Lightyellow solid.
实例12：
cis-9-oxo-5,6,7,8,8a,9-hexahydro-4aH-pyrrolo[1,2-a]indol-7-ylpropionate,Ⅲla.
1H NMR(400MHz,CDCl3)δ7.03(t,J＝6.6Hz,1H),6.74(dd,J＝3.9,0.8Hz,1H),6.52(dd,J＝3.9,2.3Hz,1H),4.92(m,1H),4.64(m,1H),3.30(q,J＝6.9Hz,1H),2.35–2.28(m,3H),2.27–2.22(m,1H),2.01(m,1H),1.90–1.77(m,1H),1.69–1.60(m,1H),1.51(m,1H),1.14(t,J＝7.6Hz,3H).13C NMR(101MHz,CDCl3)δ190.7,173.6,131.6,121.8,116.7,108.1,67.7,53.2,48.0,27.8,27.6,26.7,25.8,9.1.HRMS(ESI)m/z Calcd for C14H17NO3(M+H+):248.1287,found:248.1287.Light yellow oil.
实例13：
N-(cis-9-oxo-5,6,7,8,8a,9-hexahydro-4aH-pyrrolo[1,2-a]indol-7-yl)acetamide,Ⅲma.
1H NMR(400MHz,CD3OD)δ7.21(s,1H),6.70(d,J＝3.9Hz,1H),6.58–6.48(m,1H),4.71(dd,J＝13.7,7.0Hz,1H),3.67(m,1H),3.36(m,1H),2.48–2.30(m,2H),1.94(s,3H),1.73(m,2H),1.47–1.34(m,2H).13C NMR(101MHz,CD3OD)δ193.0,172.5,132.3,124.6,117.9,109.4,54.8,51.1,45.3,30.8,29.0,28.2,23.2.HRMS(ESI)m/z Calcd forC13H16N2O2(M+H+):233.1290,found:233.1285.Light yellow solid.
实例14：
cis-2,3-dimethyl-2,3-dihydro-1H-pyrrolizin-1-one,Ⅲna.
1H NMR(400MHz,CDCl3)δ7.02(d,J＝1.3Hz,1H),6.71(d,J＝3.9Hz,1H),6.52(dd,J＝3.9,2.3Hz,1H),4.17–4.06(m,1H),2.69(qd,J＝7.4,4.8Hz,1H),1.62(d,J＝6.5Hz,3H),1.35(d,J＝7.4Hz,3H).13C NMR(101MHz,CDCl3)δ191.9,132.1,120.9,116.7,107.7,58.2,53.9,20.3,14.1.HRMS(ESI)m/z Calcd for C9H11NO(M+H+):150.0919,found:150.0914.Light yellow oil.
实例15：
cis-2-isopropyl-3-methyl-2,3-dihydro-1H-pyrrolizin-1-one,Ⅲoa1.
1H NMR(400MHz,CDCl3)δ7.02(d,J＝1.3Hz,1H),6.68(dd,J＝4.0,0.9Hz,1H),6.51(dd,J＝3.9,2.3Hz,1H),4.36(qd,J＝6.5,3.8Hz,1H),2.62(t,J＝3.9Hz,1H),2.48–2.37(m,1H),1.57(d,J＝6.5Hz,3H),1.08–1.06(m,3H),0.89(d,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3)δ191.4,133.0,121.1,116.7,107.3,64.7,52.2,28.9,22.8,20.7,17.7.HRMS(ESI)m/z Calcd for C11H15NO(M+H+):177.1154,found:177.1154.Light yellow oil.
实例16：
cis-2-methyl-3-propyl-2,3-dihydro-1H-pyrrolizin-1-one,Ⅲpa1.
1H NMR(400MHz,CDCl3)δ7.02(d,J＝1.4Hz,1H),6.75–6.67(m,1H),6.54–6.49(m,1H),4.26–4.03(m,1H),2.82–2.66(m,1H),2.08–1.86(m,2H),1.83–1.71(m,1H),1.57–1.43(m,1H),1.37(d,J＝7.4Hz,3H),1.01(t,J＝8.4,3H).13C NMR(101MHz,CDCl3)δ192.2,132.1,121.5,116.7,107.5,62.4,51.7,37.7,18.5,15.7,14.0.HRMS(ESI)m/z Calcd forC11H15NO(M+H+):178.1232,found:178.1128.Light yellow oil.
实例17：
cis-3-methyl-2-propyl-2,3-dihydro-1H-pyrrolizin-1-one,Ⅲqa.
1H NMR(400MHz,CDCl3)δ6.94(d,J＝1.2Hz,1H),6.62(d,J＝3.9Hz,1H),6.44(dd,J＝3.9,2.3Hz,1H),4.17(m,1H),2.57(m,1H),1.85(m,1H),1.58–1.47(m,4H),1.44–1.33(m,2H),0.90(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ191.7,132.3,121.0,116.8,107.5,58.9,56.5,32.6,21.8,20.5,14.1.HRMS(ESI)m/zCalcd for C11H15NO(M+H+):178.1232,found:178.1130.Light yellow oil.
实例18：
cis-2-butyl-3-methyl-2,3-dihydro-1H-pyrrolizin-1-one,Ⅲra.
1H NMR(400MHz,CDCl3)δ7.01(d,J＝1.3Hz,1H),6.69(dd,J＝3.9,0.8Hz,1H),6.51(m,1H),4.24(m,1H),2.67–2.60(m,1H),2.01–1.89(m,1H),1.67–1.55(m,4H),1.46–1.35(m,4H),0.95–0.89(m,3H).13C NMR(101MHz,CDCl3)δ191.6,132.3,121.0,116.7,107.5,59.0,56.4,30.1,29.4,22.74(s),21.8,13.9.HRMS(ESI)m/z Calcd for C12H17NO(M+H+):192.1388,found:192.1383.Light yellow oil.
实例19：
cis-3-methyl-2-pentyl-2,3-dihydro-1H-pyrrolizin-1-one,Ⅲsa.
1H NMR(400MHz,CDCl3)δ7.01(t,J＝3.0Hz,1H),6.69(dd,J＝4.0,0.9Hz,1H),6.51(m,1H),4.24(m,1H),2.63(m,1H),2.00–1.88(m,1H),1.67–1.54(m,4H),1.43(m,2H),1.38–1.27(m,4H),0.94–0.84(m,3H).13C NMR(101MHz,CDCl3)δ191.6,132.3,121.0,116.7,107.5,59.1,56.4,31.8,30.4,26.9,22.4,21.8,14.0.HRMS(ESI)m/z Calcd for C13H19NO(M+H+):206.1545,found:206.1540.Light yellow oil.
实例20：
cis-2-methyl-3-pentyl-2,3-dihydro-1H-pyrrolizin-1-one,Ⅲta.
1H NMR(400MHz,CDCl3)δ7.02(d,J＝1.5Hz,1H),6.70(dd,J＝5.1,4.5Hz,1H),6.52(dd,J＝3.9,2.3Hz,1H),4.08–4.02(m,1H),2.76(m,1H),2.08–1.96(m,1H),1.85–1.73(m,1H),1.54–1.30(m,9H),0.95–0.86(m,3H).13C NMR(101MHz,CDCl3)δ192.2,132.1,121.5,116.7,107.5,62.6,51.7,35.4,31.7,24.8,22.5,15.7,14.0.HRMS(ESI)m/z Calcd forC13H19NO(M+H+):206.1545,found:206.1544.Light yellow oil.
实例21：
(±)-3-methyl-2-(propan-2-ylidene)-2,3-dihydro-1H-pyrrolizin-1-one,Ⅲua.
1H NMR(400MHz,CDCl3)δ6.95(s,1H),6.72(s,1H),6.47(s,1H),5.04(d,J＝6.2Hz,1H),2.40(s,3H),1.95(s,3H),1.56(d,J＝6.3Hz,3H).Light yellow oil.
实例22：
cis-2-methyl-6,7,8,8a-tetrahydro-4aH-pyrrolo[1,2-a]indol-9(5H)-one,Ⅲad.
1H NMR(400MHz,CDCl3)δ6.83(s,1H),6.52(s,1H),4.53(dd,J＝12.8,6.8Hz,1H),3.08(dd,J＝12.0,6.7Hz,1H),2.17(s,3H),2.15–2.03(m,2H),1.87–1.69(m,2H),1.59–1.48(m,2H),1.44–1.38(m,2H).13C NMR(101MHz,CDCl3)δ191.8,131.5,127.4,120.8,107.9,54.1,49.7,29.9,22.6,20.7,19.4,12.5.HRMS(ESI)m/z Calcd for C12H15NO(M+H+):190.1232,found:190.1229.Light yellow oil.
实例23：
cis-2-benzyl-6,7,8,8a-tetrahydro-4aH-pyrrolo[1,2-a]indol-9(5H)-one,Ⅲae.
1H NMR(400MHz,CDCl3)δ7.27(m,2H),7.19(m,3H),6.78(s,1H),6.53(s,1H),4.48(dd,J＝12.9,6.7Hz,1H),3.86(s,2H),3.03(dd,J＝12.1,6.6Hz,1H),2.13–2.01(m,2H),1.82–1.69(m,1H),1.55–1.43(m,2H),1.41–1.30(m,3H).13C NMR(101MHz,CDCl3)δ191.9,141.1,131.6,131.5,128.6(2C),128.4(2C),126.0,120.6,107.3,54.1,49.7,33.8,29.9,22.5,20.7,19.4.HRMS(ESI)m/z Calcd for C18H19NO(M+H+):266.1545.found:266.1542.Light yellow solid.
实例24：
cis-2-phenyl-6,7,8,8a-tetrahydro-4aH-pyrrolo[1,2-a]indol-9(5H)-one,Ⅲaf.
1H NMR(400MHz,CDCl3)δ7.51(d,J＝7.5Hz,2H),7.35(t,J＝7.6Hz,2H),7.31(s,1H),7.23(dd,J＝13.5,6.2Hz,1H),6.97(s,1H),4.58(dd,J＝13.0,6.7Hz,1H),3.10(dd,J＝12.0,6.6Hz,1H),2.28–2.03(m,2H),1.87–1.70(m,1H),1.63–1.49(m,2H),1.47–1.31(m,3H).13C NMR(101MHz,CDCl3)δ192.2,134.7,132.5,132.4,128.9(2C),126.6,125.4(2C),118.8,104.3,54.5,49.9,30.1,22.6,20.8,19.6.HRMS(ESI)m/z Calcd for C17H17NO(M+H+):252.1388,found:252.1385.Light yellow solid.
实例25：
ethyl 2-(cis-9-oxo-5,6,7,8,8a,9-hexahydro-4aH-pyrrolo[1,2-a]indol-2-yl)acetate,Ⅲag.
1H NMR(400MHz,CDCl3)δ7.03(s,1H),6.63(s,1H),4.56(dd,J＝12.9,6.9Hz,1H),4.16(q,J＝7.1Hz,2H),3.54(s,2H),3.08(dd,J＝12.0,6.8Hz,1H),2.18-2.06(m,2H),1.82-1.76(m,1H),1.56-1.49(m,2H),1.45-1.33(m,3H),1.27(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ191.9,171.7,131.5,123.6,121.1,107.8,60.9,54.3,49.8,33.4,30.0,22.5,20.8,19.5,14.2.HRMS(ESI)m/z Calcd for C15H19NO3(M+H+):262.1443,found:262.1440.Light yellow oil.
实例26：
ethyl2-(cis-9-oxo-7-phenyl-5,6,7,8,8a,9-hexahydro-4aH-pyrrolo[1,2-a]indol-2-yl)acetate,Ⅲgg.
1H NMR(400MHz,CDCl3)δ7.31–7.27(m,2H),7.21–7.17(m,3H),7.08(s,1H),6.66(s,1H),4.65(dd,J＝15.0,7.0Hz,1H),4.17(q,J＝7.1Hz,2H),3.55(s,2H),3.31-3.27(m,1H),2.64–2.59(m,1H),2.56–2.39(m,2H),1.84-1.73(m,2H),1.64-1.55(m,1H),1.46-1.37(m,1H),1.27(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ190.7,171.6,146.1,131.0,128.5(2C),126.7(2C),126.3,123.7,121.5,107.9,60.9,54.0,50.5,39.1,33.4,32.6,30.4,28.2,14.2.HRMS(ESI)m/z Calcd for C21H23NO3(M+H+):338.1756,found:338.1751.Whitesolid.
实例27：
cis-ethyl 2-methyl-9-oxo-5,6,7,8,8a,9-hexahydro-4aH-pyrrolo[1,2-a]indole-7-carboxylate,Ⅲhd.
1H NMR(400MHz,CDCl3)δ6.85(s,1H),6.53(s,1H),4.60(dd,J＝12.9,6.8Hz,1H),4.13(q,J＝7.1Hz,2H),3.23(m,1H),2.43(m,2H),2.23(m,1H),2.17(s,3H),1.91(m,1H),1.63(m,2H),1.54–1.43(m,1H),1.25(t,J＝7.1Hz,3H).13CNMR(101MHz,CDCl3)δ190.2,175.4,131.3,127.8,121.2,108.1,60.6,53.4,48.6,37.0,29.1,24.2,21.9,14.2,12.4.HRMS(ESI)m/z Calcd for C15H19NO3(M+H+):262.1443,found:262.1439.Whitesolid.
实例28：
cis-2,7-dimethyl-6,7,8,8a-tetrahydro-4aH-pyrrolo[1,2-a]indol-9(5H)-one,Ⅲgd.
1H NMR(400MHz,CDCl3)δ6.84(s,1H),6.50(s,1H),4.50(dd,J＝14.5,7.0Hz,1H),3.20–3.13(m,1H),2.35(d,J＝13.5Hz,1H),2.23(m,1H),2.16(s,3H),1.55–1.46(m,1H),1.45–1.36(m,1H),1.35–1.24(m,3H),0.93(d,J＝6.3Hz,3H).13C NMR(101MHz,CDCl3)δ191.2,131.1,127.2,121.1,107.8,54.0,50.2,31.7,30.8,29.2,27.6,22.3,12.4.HRMS(ESI)m/z Calcd for C13H17NO(M+H+):204.1388,found:204.1383.White solid。
Claims (8)
1.一种制备如式Ⅲ所示化合物的方法，其主要步骤是：在有酸性催化剂存在条件下，由结构式如式Ⅰ所示的酮与结构式如式Ⅱ所示的4-取代-L-脯氨酸在反应介质中，于0℃～200℃反应，制得目标物吡咯里西啶衍生物，其结构如式Ⅲ所示；
其中，式Ⅰ为带有取代基的C5～C10元脂肪环状酮、带有取代基的C5～C10开链脂肪酮，R1,R2各自为C1～C6的烃基，C6～C10的芳香环或含有O、N的C8芳香杂环或由C3～C6碳链构成的环烃基；
所述取代基选自Ar、
所述Ar为苯基或4-羟基苯基；
其中，式Ⅱ中所述R3选自
所述Ar包括苯基或4-羟基苯基；
所述R4为H或者
所述R5为C1～C6的烷氧基，苄氧基或羟基；R6为H,叔丁氧羰基,苄基或烯丙基。
2.如权利要求1所述的方法，其特征在于，其中式Ⅰ所示化合物与式Ⅱ所示化合物的摩尔比为1.0～5.0。
3.如权利要求1所述的方法，其特征在于，其中所说的酸性催化剂为有机羧酸、有机磺酸或硫酸。
4.如权利要求3所述的方法，其特征在于，其中所说的有机羧酸或有机磺酸是：甲酸、乙酸、丙酸、异丁酸、环己基甲酸、苯甲酸、苯乙酸、脯氨酸、4-羟基-L-脯氨酸、三氟乙酸、甲磺酸、苯磺酸或对甲苯磺酸。
5.如权利要求1所述的方法，其特征在于，其中所说的反应介质为有机溶剂或离子液体。
6.如权利要求5所述的方法，其特征在于，其中所说的有机溶剂是：甲苯、二甲苯、乙酸、1，4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜或环丁砜。
7.如权利要求5所述的方法，其特征在于，其中所说的离子液体是：溴化1-丁基-3-甲基咪唑盐、1-丁基-3-甲基咪唑四氟硼酸盐或1-丁基-3-甲基咪唑六氟磷酸盐。
8.如权利要求1～7中任意一项所述的方法，其特征在于，
式I中所述
还包括甲酯或乙酯；
式Ⅱ中所述
还包括甲基、三氟甲基、乙基或异丙基中的一种。
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