CN106279182B - A kind of pyrrolo- [2,1-a] iso-indole ketone compounds and its synthetic method - Google Patents

A kind of pyrrolo- [2,1-a] iso-indole ketone compounds and its synthetic method Download PDF

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CN106279182B
CN106279182B CN201610624390.9A CN201610624390A CN106279182B CN 106279182 B CN106279182 B CN 106279182B CN 201610624390 A CN201610624390 A CN 201610624390A CN 106279182 B CN106279182 B CN 106279182B
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hydroxyl
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pyrrolo
indoles
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周庆发
张立
张北辰
陆涛
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China Pharmaceutical University
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    • 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
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Abstract

The invention belongs to organic chemistry fileds, and in particular to a kind of pyrrolo- [2, the 1-a] iso-indole ketone compounds and its synthetic method of such as formula III.This method is with 2- (1, bis- iso-indoles ketone group of 3-)-diethyl malonate and active electron deficient alkynes is raw material, reaction obtains the pyrrolo- as shown in formula III [2.1-a] iso-indole ketone compounds under triethylamine catalysis, such compound is worth with potential pharmaceutical applications.Synthetic method of the present invention has many advantages, such as wide substrate applicability, easy to operate, reaction is mild, convenient post-treatment, raw material and catalyst are simple and easy to get.

Description

A kind of pyrrolo- [2,1-a] iso-indole ketone compounds and its synthetic method
(1) technical field
The present invention relates to a kind of new methods of synthesis pyrrolo- [2,1-a] iso-indole ketone compounds, belong to organic chemistry Synthesis methodology field.
(2) background technique
Pyrrolo- [2,1-a] iso-indole ketone compounds are a kind of important heterocyclic compounds, are widely present in more In the natural products and synthetic drug of kind bioactivity, the isoindolone structure in the structure has good anti-hypertension and resists Tumor promotion.The chlorthalidone of such as ketone group containing iso-indoles is the drug for hypertension being widely used, and the class formation is also wide It is general apply in CDK kinase inhibitor for treat tumour (Honma, T, Anyu.Co.Jp, et al.J.Med.Chem 2001, 44,4628).Therefore, the synthesis of pyrrolo- [2,1-a] iso-indole ketone compounds causes the interest of vast chemist. But the method reported in the literature for using organic base to synthesize the structure as catalyst or promotor is less at present, makes mostly Make catalyst or promotor with organophosphorus reagent, but such reaction has some limitations.Such as Yavari group with 2- (1, Bis- iso-indoles ketone group of 3-)-diester malonate is raw material, the triphenylphosphine of equivalent is that promotor synthesizes pyrrolo- [2,1-a] different Yin Diindyl ketone (Yavari, l.；Esmaili, A.A.J.Chem.Res.1998,714), the reaction condition is acutely and triphenylphosphine makes Dosage is big, and does not have to connect the group that hydroxyl etc. easily performs the derivatization on the compound parent nucleus obtained with the method, in new drug Applicability is relatively narrow in research and development.Using organic base catalytic containing N more cheap and easy to get or promote such reaction so far there are no document report Road.Therefore, developing synthetic method easy, general, that raw material and catalyst are cheap and easy to get just seems particularly significant.
(3) summary of the invention
The present invention provides a kind of new method for synthesizing pyrrolo- [2.1-a] iso-indole ketone compounds.With 2- (2- (1,3- Two iso-indoles ketone groups))-diester malonate and active electron deficient alkynes is raw material, using triethylamine cheap and easy to get as catalyst, Pyrrolo- [2.1-a] Isoindolone compounds III is obtained in acetonitrile solvent, reaction equation is as follows:
Wherein compound I is 2- (2- (1,3- bis- iso-indoles ketone group))-diester malonate, R1For the straight of 1-6 carbon atom Chain or branch saturated alkyl.Compound II is electron deficient acetylenic derivative, R2For phenylpropyl, fatty alkoxy, substituted aroma first Oxygroup, alkyl etc..
According to the present invention, pharmaceutically acceptable salt includes the acid-addition salts that 3 compound of general formula and following acid are formed: salt Acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, acetone Acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, tussol.It additionally include the acid of inorganic base Salt, such as: containing alkali metal cations, alkaline earth metal cation, ammonium cation salt.
The preferably following structural compounds of compound of formula III:
1- benzyl -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -1, 3,3- tricarboxylic esters (III-1)
3,3- diethyl -1- (4- methylbenzyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] is different Indoles -1,3,3- tricarboxylic ester (III-2)
3,3- diethyl -1- (4- methoxy-benzyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] Iso-indoles -1,3,3- tricarboxylic ester (III-3)
1- (4- bromobenzyl) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] different Yin Diindyl 1,3,3- tricarboxylic ester (III-4)
1- (the chloro- benzyl of 4-) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] is different Indoles 1,3,3- tricarboxylic ester (III-5)
1- (the fluoro- benzyl of 4-) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] is different Indoles 1,3,3- tricarboxylic ester (III-6)
1- (4- romethyl-benzy) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2, 1-a] iso-indoles 1,3,3- tricarboxylic ester (III-7)
1- (4- Nitro-benzyl) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] Iso-indoles 1,3,3- tricarboxylic ester (III-8)
3,3 '-diethyl -1- (naphthalene -2- ylmethyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] Iso-indoles -1,3,3- tricarboxylic ester (III-9)
3,3 '-diethyl -1- (furans -2- ylmethyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1- A] iso-indoles -1,3,3-- tricarboxylic ester (III-10)
3,3 '-diethyl -1- (thiophene -2- ylmethyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1- A] iso-indoles -1,3,3-- tricarboxylic ester (III-11)
3,3- diethyl -1- methyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -1, 3,3- tricarboxylic esters (III-12)
Triethyl group -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -1,3,3- tricarboxylic ester (III-13)
1- tert-butyl -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles - 1,3,3- tricarboxylic ester (III-14)
1- acetyl group -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -3,3- dicarboxylic acids two Ethyl ester (III-15)
1- caproyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -3,3- dicarboxylic acids two Ethyl ester (III-16)
1- cyclohexanoyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -3,3- dicarboxylic acids Diethylester (III-17)
1- (3- hydrocinnamoyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -3,3- bis- Carboxylic acid diethylester (III-18)
1- benzyl -3,3- dimethyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -1, 3,3- tricarboxylic esters (III-19)
1- benzyl -3,3- diisopropyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles - 1,3,3- tricarboxylic ester (III-20)
Concrete operation step are as follows:
2- (2- (1,3- bis- iso-indoles ketone group))-diethyl malonate and active electron deficient alkynes are dissolved in organic solvent In, triethylamine is added, substantially completely in 0 DEG C of reaction to reaction, reaction solution is concentrated, through with petroleum ether: ethyl acetate volume ratio It is eluted for 8: 1 to 4: 1 mixed solvent as eluant, eluent column chromatographic grade, collects the eluent part of all products detected, Revolving obtains pyrrolo- as shown in Equation 3 [2.1-a] iso-indole ketone compounds III after removing solvent.
Not only starting material is easy to get for the reaction, and mild condition, synthetic route is brief, easy to operate, and cost is relatively low.And work as When reaction scale is amplified to gram-grade, yield remains to be maintained, and good can be applied in industrial production, has good reality The property used.Pyrrolo- [2.1-a] the iso-indole ketone compounds III synthesized by this method has potential bioactivity, and hydroxyl can To carry out a variety of derivatizations, there is preferable application prospect in new drug development field.
Preferable reaction condition of the invention are as follows:
(1) catalyst is triethylamine；
(2) 2- (2- (1,3- bis- iso-indoles ketone group))-diethyl malonate, active electron deficient alkynes, triethylamine dosage Molar ratio is 1: 2.0: 0.2；
Solvent is acetonitrile；
Reaction temperature is 0 DEG C.
Compound III in the present invention can be prepared with above-mentioned or similar above-mentioned preparation method, according to substituent group Difference and the differences of substituting group position select corresponding raw materials.
(4) specific embodiment
The invention will now be further described with reference to specific embodiments, the advantages and features of the present invention will be with description and It is apparent.But examples are merely exemplary for these, and it is not intended to limit the scope of the present invention in any way.Those skilled in the art Member it should be understood that without departing from the spirit and scope of the invention can details to technical solution of the present invention and form into Row modifications or substitutions, but these modifications and replacement are fallen within the protection scope of the present invention.
Hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] of embodiment 1:1- benzyl -3,3- diethyl -9b Iso-indoles 1,3,3- tricarboxylic ester (III-1)
Acetonitrile (5mL), 2- (2- (1,3- bis- iso-indoles ketone group))-diethyl malonate are added in 25mL round-bottomed flask bottle (122mg, 0.4mmol), propine acid benzyl ester (128mg, 0.8mmol) and triethylamine (8mg, 0.08mmol).0 DEG C is stirred to react 100h.Reaction solution is concentrated, through using petroleum ether: the mixed solvent of ethyl acetate volume ratio 4: 1 is washed as eluant, eluent column chromatography It is de-, isolated white solid III-1 102mg, yield 55%.
1H NMR (DMSO) δ 7.95 (d, J=7.5Hz, 1H), 7.73-7.55 (m, 3H), 7.55-7.30 (m, 6H), 7.16 (s, 1H), 5.41-5.25 (m, 2H), 4.47-4.01 (m, 4H), 1.27 (t, J=7.1Hz, 3H), 1.10 (t, J=7.1Hz, 3H)；HRMS(ESI+)m/z 488.1326[M+Na]+。
Embodiment 2:3,3- diethyl -1- (4- methylbenzyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -1,3,3- tricarboxylic ester (III-2)
With II-2 4- Methyl-benzvl propiolate (139mg, 0.8mmol) for raw material, the same III-1 of operating method is obtained white Color solid III-2 75mg, yield 39%.
1H NMR (DMSO) δ 7.97 (dt, J=7.7,0.9Hz, 1H), 7.70 (td, J=7.4,6.0Hz, 2H), 7.61 (td, J=7.5,1.1Hz, 1H), 7.43-7.35 (m, 3H), 7.25 (d, J=7.8Hz, 2H), 7.15 (s, 1H), 5.35-5.25 (m, 2H), 4.40-4.07 (m, 4H), 2.34 (s, 3H), 1.30 (t, J=7.1Hz, 3H), 1.12 (t, J=7.1Hz, 3H)； HRMS(ESI+)m/z 502.1473[M+Na]+。
Embodiment 3:3,3- diethyl -1- (4- methoxy-benzyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrroles And [2,1-a] iso-indoles -1,3,3- tricarboxylic ester (III-3)
With II-3 4- methyoxy-benzyl propiolate (152mg, 0.8mmol) for raw material, the same III-1 of operating method is obtained White solid III-3 48mg, yield 24%.
1H NMR (DMSO): δ 7.94 (dd, J=7.4,1.7Hz, 1H), 7.73-7.62 (m, 2H), 7.62-7.53 (m, 1H), 7.49-7.32 (m, 3H), 7.11 (s, 1H), 7.02-6.89 (m, 2H), 5.33-5.16 (m, 2H), 4.38-4.03 (m, 4H), 3.76 (s, 3H), 1.26 (t, J=7.1Hz, 3H), 1.08 (t, J=7.1Hz, 3H)；HRMS(ESI+)m/z 518.1436 [M+Na]+。
Embodiment 4:1- (4- bromobenzyl) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2, 1-a] iso-indoles 1,3,3- tricarboxylic ester (III-4)
With the bromo- benzyl propiolate (191mg, 0.8mmol) of II-4 4- for raw material, the same III-1 of operating method is obtained white Solid III-4 131mg, yield 60%.
1H NMR (DMSO): δ 7.95 (d, J=6.9Hz, 1H), 7.75-7.54 (m, 5H), 7.52-7.38 (m, 3H), 7.19 (s, 1H), 5.30 (s, 2H), 4.40-4.01 (m, 4H), 1.26 (t, J=7.1Hz, 3H), 1.09 (t, J=7.1Hz, 3H)；HRMS(ESI+)m/z 566.0438[M+Na]+。
Embodiment 5:1- (the chloro- benzyl of 4-) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] iso-indoles 1,3,3- tricarboxylic ester (III-5)
With the chloro- benzyl propiolate (156mg, 0.8mmol) of II-5 4- for raw material, the same III-1 of operating method is obtained white Solid III-5 94mg, yield 47%.
1H NMR (DMSO) δ 7.98 (d, J=5.0Hz, 1H), 7.74-7.67 (m, 2H), 7.62 (t, J=7.5Hz, 1H), 7.57-7.48 (m, 4H), 7.40 (d, J=1.9Hz, 1H), 7.20 (d, J=1.7Hz, 1H), 5.40-5.30 (m, 2H), 4.41- 4.07 (m, 4H), 1.30 (td, J=7.1,1.2Hz, 3H), 1.13 (td, J=7.1,1.2Hz, 3H)；HRMS(ESI+)m/z 522.0941[M+Na]+。
Embodiment 6:1- (the fluoro- benzyl of 4-) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] iso-indoles 1,3,3- tricarboxylic ester (III-6)
With the fluoro- benzyl propiolate (142mg, 0.8mmol) of II-6 4- for raw material, the same III-1 of operating method is obtained white Solid III-6 77mg, yield 40%.
1H NMR (DMSO): δ 7.95 (d, J=7.5Hz, 1H), 7.68 (t, J=7.4Hz, 2H), 7.64-7.49 (m, 3H), 7.42 (s, 1H), 7.25 (dd, J=8.7,8.6Hz, 2H), 7.18 (s, 1H), 5.31 (s, 2H), 4.41-4.00 (m, 4H), 1.26 (t, J=7.1Hz, 3H), 1.09 (t, J=7.1Hz, 3H)；HRMS(ESI+)m/z 506.1222[M+Na]+。
Embodiment 7:1- (4- romethyl-benzy) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrole Cough up simultaneously [2,1-a] iso-indoles 1,3,3- tricarboxylic ester (III-7)
With III-7 4- romethyl-benzy propiolate (142mg, 0.8mmol) for raw material, the same III-1 of operating method, Obtain white solid III-7 149mg, yield 70%.
1H NMR (DMSO): δ 7.97 (d, J=7.2Hz, 1H), 7.79 (d, J=8.2Hz, 2H), 7.76-7.65 (m, 4H), 7.60 (ddd, J=8.4,6.4,1.1Hz, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 5.43 (s, 2H), 4.41-4.02 (m, 4H), 1.27 (t, J=7.1Hz, 3H), 1.10 (t, J=7.1Hz, 3H)；HRMS(ESI+)m/z556.120[M+Na]+。
Embodiment 8:1- (4- Nitro-benzyl) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] iso-indoles 1,3,3- tricarboxylic ester (III-8)
With II-8 4- Nitro-benzyl propiolate (164mg, 0.8mmol) for raw material, the same III-1 of operating method is obtained white Color solid III-8 92mg, yield 45%.
1H NMR (DMSO) δ 8.27 (d, J=8.7Hz, 2H), 7.97 (d, J=8.1Hz, 1H), 7.76 (d, J=8.7Hz, 2H), 7.70 (d, J=6.9Hz, 2H), 7.60 (t, J=6.6Hz, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 5.48 (s, 2H), 4.37-4.07 (m, 4H), 1.27 (t, J=7.1Hz, 3H), 1.10 (t, J=7.1Hz, 3H)；HRMS(ESI+)m/z 533.1180[M+Na]+。
Embodiment 9:3,3 '-diethyl -1- (naphthalene -2- ylmethyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrroles And [2,1-a] iso-indoles -1,3,3- tricarboxylic ester (III-9)
With II-9 (naphthalene -2- ylmethyl)-propiolate (168mg, 0.8mmol) for raw material, the same III-1 of operating method is obtained White solid III-9 111mg, yield 54%.
1H NMR (DMSO) δ 8.33-7.88 (m, 6H), 7.75-7.54 (m, 5H), 7.41 (s, 1H), 7.22 (s, 1H), 5.59-5.47 (m, 2H), 4.73-3.78 (m, 4H), 1.30 (t, J=4.5Hz, 3H), 1.11 (t, J=4.6Hz, 3H)；HRMS (ESI+)m/z 538.1488[M+Na]+。
Embodiment 10:3,3 '-diethyl -1- (furans -2- ylmethyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrole Cough up simultaneously [2,1-a] iso-indoles -1,3,3-- tricarboxylic ester (III-10)
With II-10 (furans -2- base-methyl)-propiolate (120mg, 0.8mmol) for raw material, the same III- of operating method 1, obtain white solid I-10 100mg, yield 55%.
1H NMR (DMSO): δ 7.96-7.88 (m, 1H), 7.76 (dd, J=1.9,0.9Hz, 1H), 7.73-7.64 (m, 2H), 7.59 (ddd, J=8.3,6.5,1.2Hz, 1H), 7.41 (s, 1H), 7.13 (s, 1H), 6.65 (dd, J=3.2,1.9Hz, 1H), 6.51 (dd, J=3.2,1.9Hz, 1H), 5.41-5.20 (m, 2H), 4.37-4.03 (m, 4H), 1.26 (t, J=7.1Hz, 3H), 1.08 (t, J=7.1Hz)；HRMS(ESI+)m/z 478.1121[M+Na]+。
Embodiment 11:3,3 '-diethyl -1- (thiophene -2- ylmethyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrole Cough up simultaneously [2,1-a] iso-indoles -1,3,3- tricarboxylic ester (III-11)
With II-11 (thiophene -2- ylmethyl)-propiolate (120mg, 0.8mmol) for raw material, the same III-1 of operating method, Obtain colorless oil III-11 74mg, yield 39%.
1H NMR (DMSO): δ 7.97 (d, J=7.6Hz, 1H), 7.74-7.65 (m, 2H), 7.65-7.53 (m, 2H), 7.40 (s, 1H), 7.29 (d, J=3.5,1H), 7.12 (s, 1H), 7.06 (t, J=4.4Hz, 1H), 5.60-5.40 (m, 2H), 4.37-4.03 (m, 4H), 1.26 (t, J=7.0Hz, 3H), 1.08 (t, J=7.1Hz)；HRMS(ESI+)m/z 494.0878[M +Na]+。
Embodiment 12:3,3- diethyl -1- methyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] Iso-indoles -1,3,3- tricarboxylic ester (III-12)
With II-12 Methyl propiolate (67mg, 0.8mmol) for raw material, the same III-1 of operating method obtains white solid III- 12 83mg, yield 53%.
1H NMR (DMSO): δ 8.02 (d, J=7.6Hz, 1H), 7.79-7.66 (m, 2H), 7.60 (t, J=7.4,1H), 7.39 (s, 1H), 7.13 (s, 1H), 4.40-4.02 (m, 4H), 3.82 (s, 1H), 1.27 (t, J=7.1Hz, 3H), 1.08 (t, J =7.1Hz, 3H；HRMS(ESI+)m/z 412.1001[M+Na]+。
Embodiment 13: triethyl group -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -1,3, 3- tricarboxylic ester (III-13)
With II-13 ethyl propiolate (78mg, 0.8mmol) for raw material, the same III-1 of operating method obtains white solid III- 13 81mg, yield 50%.
1H NMR (DMSO): δ 8.02 (d, J=7.0Hz, 1H), 7.74 (ddd, J=7.6,7.4,1.4Hz, 1H), 7.69 (d, 7.4Hz, 1H), 7.60 (dd, 7.5,1.1Hz, 1H), 7.38 (s, 1H), 7.10 (s, 1H), 4.40-4.01 (m, 6H), 1.31 (t, J=7.1Hz, 3H), 1.27 (t, J=7.1Hz, 3H), 1.10 (t, J=7.1Hz, 3H)；HRMS(ESI+)m/z 426.1169[M+Na]+。
Embodiment 14:1- tert-butyl -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1- A] iso-indoles -1,3,3- tricarboxylic ester (III-14)
With II-14 propine tert-butyl acrylate (101mg, 0.8mmol) for raw material, the same III-1 of operating method obtains white solid III-14 28mg, yield 16%.
1H NMR (DMSO) δ 8.03 (d, J=7.6Hz, 1H), 7.75 (dd, J=7.4,7.5Hz, 1H), 7.69 (d, J= 7.4Hz, 1H), 7.60 (t, J=7.4Hz, 1H), 7.34 (s, 1H), 6.97 (s, 1H), 4.41-4.03 (m, 4H), 1.52 (s, 9H), 1.27 (t, J=7.1Hz, 3H), 1.11 (t, J=7.1Hz, 3H)；HRMS(ESI+)m/z 454.1465[M+Na]+。
Embodiment 15:1- acetyl group -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -3, 3- diethyl dicarboxylate (III-15)
With II-15 3- crotonylene -one (54mg, 0.8mmol) for raw material, the same III-1 of operating method obtains white solid III-15 130mg, yield 87%.
1H NMR (DMSO) δ 8.05 (d, J=7.6Hz, 1H), 7.77-7.62 (m, 2H), 7.57 (t, J=7.4Hz, 1H), 7.44 (s, 1H), 7.14 (s, 1H), 4.44-4.03 (m, 4H), 2.42 (s, 3H), 1.29 (t, J=7.0Hz, 3H), 1.12 (t, J =7.1Hz, 3H)；HRMS(ESI+)m/z 396.1049[M+Na]+。
Embodiment 16:1- caproyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -3, 3- diethyl dicarboxylate (III-16)
With II-16 1- octyne -3- ketone (99mg, 0.8mmol) for raw material, the same III-1 of operating method obtains white solid III-16 83mg, yield 48%.
1H NMR (DMSO) δ 8.05 (d, J=7.7Hz, 1H), 7.77-7.63 (m, 2H), 7.56 (t, J=7.4Hz, 1H), 7.44 (s, 1H), 7.15 (s, 1H), 4.41-4.22 (m, 2H), 4.20-4.06 (m, 2H), 2.80 (td, J=7.3,2.3Hz, 2H), 1.59-1.46 (m, 2H), 1.35-1.19 (m, 7H), 1.10 (t, J=7.1Hz, 3H), 0.82 (t, J=6.8Hz, 3H)； HRMS(ESI+)m/z 452.1689[M+Na]+。
Embodiment 17:1- cyclohexanoyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles - 3,3- diethyl dicarboxylates (III-17)
With II-17 1- cyclohexyl -2- propine -1- ketone (109mg, 0.8mmol) for raw material, the same III-1 of operating method is obtained White solid III-17 94mg, yield 53%.
1H NMR (DMSO) δ 8.02 (d, J=7.6Hz, 1H), 7.76-7.62 (m, 2H), 7.56 (t, J=7.4Hz, 1H), 7.48 (s, 1H), 7.15 (s, 1H), 4.42-4.19 (m, 2H), 4.19-4.06 (m, 2H), 3.26-3.06 (m, 1H), 1.84- 1.67 (m, 2H), 1.65-1.58 (m, 2H), 1.42-1.22 (m, 6H), 1.19-0.92 (m, 6H)；HRMS(ESI+)m/z 464.1677[M+Na]+。
Embodiment 18:1- (3- hydrocinnamoyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] different Yin Diindyl -3,3- diethyl dicarboxylate (III-18)
With II-18 5- phenyl -1- pentyne -3- ketone (126mg, 0.8mmol) for raw material, the same III-1 of operating method is obtained white Color solid III-18 115mg, yield 62%.
1H NMR (DMSO) δ 8.04 (d, J=7.6Hz, 1H), 7.77-7.62 (m, 2H), 7.57 (t, J=7.4Hz, 1H), 7.51 (s, 1H), 7.29-7.20 (m, 4H), 7.20-7.03 (m, 2H), 4.37-4.05 (m, 4H), 3.24-3.05 (m, 2H), 2.85 (t, J=7.6Hz), 1.27 (t, J=7.0Hz, 3H), 1.09 (t, J=7.1Hz)；HRMS(ESI+)m/z 486.1533 [M+Na]+。
Embodiment 19:1- benzyl -3,3- dimethyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] Iso-indoles -1,3,3- tricarboxylic ester (III-19)
With I-2 2- (2- (1,3- bis- iso-indoles ketone group))-dimethyl malenate (111mg, 0.4mmol) for raw material, operation The same III-1 of method obtains white solid III-19 70mg, yield 40%.
1H NMR (DMSO) δ 7.95 (d, J=7.5Hz, 2H), 7.75-7.55 (m, 3H), 7.49-7.34 (m, 5H), 7.22 (s, 1H), 5.2-5.43 (m, 2H), 3.80 (s, 3H), 3.64 (s, 1H)；HRMS(ESI+)m/z 460.1003[M+Na]+。
Embodiment 20:1- benzyl -3,3- diisopropyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1- A] iso-indoles -1,3,3- tricarboxylic ester (III-20)
With I-3 2- (2- (1,3- bis- iso-indoles ketone group))-Diisopropyl malonate (156mg, 0.4mmol) for raw material, behaviour Make the same III-1 of method, obtains white solid III-20 95mg, yield 48%.
1H NMR (DMSO): δ 7.93 (d, J=7.4Hz, 1H), 7.72-7.54 (m, 3H), 7.52-7.32 (m, 6H), 7.10 (s, 1H), 5.33 (s, 2H), 5.10-4.99 (m, 1H), 4.99-4.88 (m, 1H), 1.27 (d, J=6.3Hz, 6H), 1.18 (d, J=6.2Hz, 3H), 1.11 (d, J=6.2Hz)；HRMS(ESI+)m/z 516.1650[M+Na]+。

Claims (6)

1. the synthetic method of the following general formula III compound:
R is phenylpropyl, fatty alkoxy, substituted aroma methoxyl group, alkyl；Alkyl is with 1-4 in above-mentioned fat alkoxy The linear chain or branched chain saturated hydrocarbyl of carbon atom；Aromatic rings in substituted aroma methoxyl group is phenyl ring, naphthalene nucleus, thiphene ring or furans Ring, and replaced on aromatic rings by halogen, nitro, methyl, methoxyl group or trifluoromethyl；
The method is with (2- (1,3- bis- iso-indoles ketone group))-diethyl malonate of compound 2- shown in Formulas I and Formula II shownization Conjunction object activity electron deficient alkynes is raw material, and cyclization occurs in the presence of triethylamine, and such as formula III compound represented is made, Reaction equation is as follows:
The method is further defined in that
2- (2- (1,3- bis- iso-indoles ketone group))-diethyl malonate and active electron deficient alkynes are dissolved in organic solvent, added Enter triethylamine, substantially completely in 0 DEG C of reaction to reaction, reaction solution is concentrated, through with petroleum ether: ethyl acetate volume ratio 8: 1 It is eluted to 4: 1 mixed solvents as eluant, eluent column chromatographic grade, collects the eluent part of all products detected, revolving is removed It is obtained after solvent such as formula III compound represented.
2. synthetic method according to claim 1, which is characterized in that compound of formula III specific structure is as follows:
3,3- diethyl -1- (4- methylbenzyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] different Yin Diindyl -1,3,3- tricarboxylic ester (III-2)
3,3- diethyl -1- (4- methoxy-benzyl) -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] different Yin Diindyl -1,3,3- tricarboxylic ester (III-3)
1- (4- bromobenzyl) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] iso-indoles 1, 3,3- tricarboxylic esters (III-4)
1- (the chloro- benzyl of 4-) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] iso-indoles 1,3,3- tricarboxylic ester (III-5)
1- (the fluoro- benzyl of 4-) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] iso-indoles 1,3,3- tricarboxylic ester (III-6)
1- (4- romethyl-benzy) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] Iso-indoles 1,3,3- tricarboxylic ester (III-7)
1- (4- Nitro-benzyl) -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- hydroxyl -3H- pyrrolo- [2,1-a] different Yin Diindyl 1,3,3- tricarboxylic ester (III-8)
3,3- diethyl -1- methyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -1,3,3- Tricarboxylic ester (III-12)
Triethyl group -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -1,3,3- tricarboxylic ester (III-13)
1- tert-butyl -3,3- diethyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -1,3, 3- tricarboxylic ester (III-14)
1- acetyl group -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -3,3- diethyl dicarboxylate (III-15)
1- caproyl -9b- hydroxyl -5- oxo -5,9b- dihydro -3H- pyrrolo- [2,1-a] iso-indoles -3,3- diethyl dicarboxylate (III-16)。
3. synthetic method of any of claims 1 or 2, it is characterised in that the organic solvent is acetonitrile.
4. synthetic method of any of claims 1 or 2, it is characterised in that reaction time 24-100h.
5. synthetic method of any of claims 1 or 2, it is characterised in that the raw material 2- (2- (1,3- bis- iso-indoles ketone group))- Diethyl malonate, active electron deficient alkynes, triethylamine dosage molar ratio be 1: 1.2~3.0: 0.1~0.4.
6. synthetic method according to claim 5, it is characterised in that the raw material 2- (2- (1,3- bis- iso-indoles ketone group))- Diethyl malonate, active electron deficient alkynes, triethylamine dosage molar ratio be 1: 2.0: 0.2.
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