CN101570505B - Indole-2, 3-diformic ester compound and derivatives and synthetic method - Google Patents
Indole-2, 3-diformic ester compound and derivatives and synthetic method Download PDFInfo
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- CN101570505B CN101570505B CN 200910082281 CN200910082281A CN101570505B CN 101570505 B CN101570505 B CN 101570505B CN 200910082281 CN200910082281 CN 200910082281 CN 200910082281 A CN200910082281 A CN 200910082281A CN 101570505 B CN101570505 B CN 101570505B
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Abstract
The invention discloses an indole-2,3-diformic ester compound and derivatives and a synthetic method. The synthetic method includes: under the action of oxidizer, aromatic amine compound, alkynes compound and organic component solvent are mixed together for indole ring formation reaction by taking palladium as catalyst, wherein the organic component solvent is composed of DMA, DMF or DMSO and alkyl acid or benzoic acid compounds belonging to aromatic acid. In the invention, palladium is taken as catalyst for the first time, the aromatic amine compound and the alkynes compound react to generateindole under the condition that air or oxygen is taken as oxidant, the method keeps atom economy to the utmost and has the advantages of high yield, simple condition, available raw materials, simple reaction equipment and easy industrialized production, etc.
Description
Technical field
The present invention relates to a kind of Benzazole compounds and synthetic method thereof, relate in particular to a kind of indoles-2,3-diformic ester compound and derivative thereof the invention still further relates to the synthetic method of these compounds, belong to the Benzazole compounds field.
Background technology
It is bioactive that indoles is that a class has, and extensively is present in medicine, and important molecule fragment in the middle of organism.The structure of indole ring is the more interested research directions of people always, a large amount of bibliographical informations has the been arranged construction process of multiple indole ring.But indoles-2, the synthetic method report of this class benzazolyl compounds of 3-diformic ester is not also a lot, although document J.Heterocycl.Chem.2003,40,121-127; Heterocycles.2000,53 (12), 2809-2819; Heterocycles.1999,51 (7), 1585-1591; J.Am.Chem.Soc.1941,63,2762-2766 have done play-by-play to the synthetic method of this compounds, but these methods have significant limitation: 1. starting raw material is somewhat expensive, and synthetic cost is very high; 2. expect that by former the synthesis step of product is too complicated, some methods even needed for 5 steps; 3. existing method yield is all lower.
Summary of the invention
One of purpose of the present invention is to provide a class new indoles-2,3-diformic ester compound and their derivative;
Two of purpose of the present invention is to provide a kind of synthetic above-mentioned indoles-2, the method for 3-diformic ester compound and their derivative;
The objective of the invention is to be achieved through the following technical solutions:
One class indoles-2,3-diformic ester compound and derivative thereof, shown in following general formula I or general formula I I:
General formula I
Wherein R is selected from hydrogen atom, C
1-10Alkyl, halogen, carbonyl, hydroxyl, itrile group, ester group, alkoxyl group or trifluoromethoxy; E
1Or E
2Be selected from C
1-1The manthanoate of alkyl, phenyl or itrile group; Described halogen is preferably F, Cl or Br;
General formula I I
Wherein, R is selected from hydrogen atom, C
1-10Alkyl, halogen, carbonyl, hydroxyl, itrile group, ester group, alkoxyl group or trifluoromethoxy; E
1Or E
2Be selected from C
1-1The manthanoate of alkyl, phenyl or itrile group, n are the positive integer of 1-4;
Above-mentioned general formula I or general formula I I compound are as a kind of important molecule stripping and slicing, itself has certain physiologically active, also can contain the fragment of the compound of indole structure by the conversion of functional group is further synthesized some, these compounds that contain indole structure have very Johnson ﹠ Johnson's reason and pharmacologically active, such as 5-HT3 receptor antagonist 1, PDE-IV and TXA2 enzyme inhibitors 2 etc.The experiment report, the hydrochloride of compound 1 has reached IC to the effect that presses down of PDE-IV
50=118uM (J.Med.Chem.1991,34,3023-3029); Compound 2 is GR65 with the keying action of 5-HT3 acceptor, 630 3.7 times (.J.Med.Chem.1991,36,3693-3699).
Another object of the present invention is to provide a kind of method of synthetic above-mentioned general formula I or general formula I I compound;
Another object of the present invention is achieved through the following technical solutions:
A kind of method of synthetic above-mentioned compound of Formula I comprises the following steps:
Under the oxygenant effect, take palladium as catalyzer, aromatic amine compounds, acetylene compound and organic mixed solvent are mixed into the indole ring reaction, and get final product.Wherein, described organic mixed solvent is comprised of the aromatic acid of DMA, DMF or DMSO and alkyl acid or benzoic acids;
Described oxygenant can be air or oxygen; Described oxygen is preferably the oxygen of 1atm;
In order to reach better synthetic effect, preferred, catalyzer, the mol ratio of aromatic amine compounds and acetylene compound is 1: (1-1000): (1-1000), more preferably 1: 10: 10;
Wherein, the volume ratio of DMA, DMF or DMSO and alkyl acid or aromatic acid is preferably (1-100): 1, and more preferably 4: 1.Described palladium can be PdCl
2, Pd (OAc)
2, Pd (OPiv)
2, Pd (OTFA)
2, Pd (OTf)
2, Pd (PhCOO)
2, Pd (CH
3CN)
2Cl
2, Pd (CH
3CN)
1(BF
1)
2Or Pd (PhCN)
2Cl
2Be preferably Pd (OAc)
2
Described amino benzenes compounds can be selected from aniline, para-totuidine, meta-aminotoluene, Ortho Toluidine, between isopropyl aniline, to cyclohexyl aniline, P-nethoxyaniline, ORTHO ANISIDINE, 2,4-dimethoxyaniline, 2,5 dimethoxyanilines, 3,4-dimethoxyaniline, the 4-trifluoro-methoxyaniline, PABA ethyl ester, 4-fluoroaniline, 4-chloroaniline or 4-hydroxyanilines, naphthylamines, diaminodiphenyl oxide;
Described acetylene compound is dimethyl butyn preferably;
Described mixed solvent preferably is comprised of the aromatic acid of DMA, DMF or DMSO and alkyl, alkyl acid or the benzoic acids volume ratio according to 4: 1; Wherein, described alkyl acid is the alkyl acid of Cl-17 preferably, as formic acid, and acetic acid, propionic acid butanic acid, isopropylformic acid, uncle's fourth formic acid (PivOH), more preferably tertiary butyl formic acid; The aromatic acid of described benzoic acids is phenylformic acid preferably;
The temperature of described one-tenth indole ring reaction is preferably 40-150 ℃;
A kind of method of synthetic above-mentioned general formula I I compound comprises the following steps:
Under the oxygenant effect, take palladium as catalyzer, aromatic amine compounds, acetylene compound and organic mixed solvent are mixed into the indole ring reaction, and get final product; Wherein, described organic mixed solvent is comprised of the aromatic acid of DMA, DMF or DMSO and alkyl acid or benzoic acids;
Wherein, described oxygenant can be air or oxygen; Described oxygen is preferably the oxygen of 1atm;
Described palladium can be PdCl
2, Pd (OAc)
2, Pd (OPiv)
2, Pd (OTFA)
2, Pd (OTf)
2, Pd (PhCOO)
2, Pd (CH
3CN)
2Cl
2, Pd (CH
3CN)
1(BF
1)
2Or Pd (PhCN)
2Cl
2Be preferably Pd (OAc)
2
Described aromatic amine compounds is selected from indoline, methyl indoline or tetrahydroquinoline;
Described acetylene compound is acetylenedicarboxylic acid two formicesters preferably, acetylenedicarboxylic acid isopropyl esters, benzyne or benzyne nitrile;
Described organic mixed solvent preferably is comprised of the aromatic acid of DMA, DMF or DMSO and alkyl, alkyl acid or the benzoic acids volume ratio according to 4: 1; Wherein, described alkyl acid is the alkyl acid of Cl-17 preferably, as formic acid, and acetic acid, propionic acid butanic acid, isopropylformic acid, tertiary butyl formic acid (PivOH), more preferably tertiary butyl formic acid; The aromatic acid of described benzoic acids is phenylformic acid preferably;
The present invention is first take palladium as catalyzer, is that under the condition of oxygenant, alkynes and amine generate indoles at air or oxygen, and the inventive method has kept Atom economy greatly, have yield high, condition is simple, and raw material is easy to get, conversion unit is simple, is easy to the plurality of advantages such as suitability for industrialized production.
Description of drawings
The synthetic route chart of Fig. 1 the compounds of this invention.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment are only exemplary, scope of the present invention are not consisted of any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can modify or replace details and the form of technical solution of the present invention, but these modifications and replacement all fall within the scope of protection of the present invention.
Method one: get a reaction tubes; add 4.5mg palladium, 22.0 μ L aniline under the oxygen protection; 24.6 μ L dimethyl butyn; 1.25mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 39.5mg, productive rate 85%.
Method two: get a reaction tubes; add 4.5mg palladium, 22.0 μ L aniline under the oxygen protection; 24.6 μ L dimethyl butyn; 1.25mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 40 ℃ from room temperature, within 48 hours, reaction finishes.Conventional processing obtains sterling 30.0mg, produces two rates 65%.IR：(KBr)v
max?3305，1728，1690，1281，1259，1068，752cm
-1；
1HNMR：(300MHz，CDCl
3)δ9.48(brs，1H)，8.06(d，J＝7.8Hz，1H)，7.45(d，J＝8.4Hz，1H)，7.40-7.34(m，1H)，7.30-7.25(m，1H)，3.99(s，3H)，3.98(s，3H)；
13C?NMR：(75MHz，CDCl
3)δ164.6，161.4，134.8，128.0，126.8，125.9，122.7，122.6，111.9，52.7，51.8；MS(70eV)：m/z(％)：233.1(39)[M]
+，143.0(100).
Embodiment 2 5-skatole-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 4.5mg palladium, 25mg para-totuidine under the oxygen protection; 24.6 μ L dimethyl butyn; 1.25mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 46.3mg, productive rate 93%.
IR：(KBr)v
max?3298，2925，1718，1690，1256cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.35(brs，1H)，7.83(s，1H)，7.33(d，J＝8.7Hz，1H)，7.19(d，J＝8.4Hz，1H)，3.99(s，3H)，3.97(s，3H)，2.47(s，3H)；
13C?NMR：(75MHz，CDCl
3)δ164.8，161.4，133.2，132.2，127.9，127.1，121.9，121.8，111.6，111，3，52.6，51.8，21.6；MS(70eV)：m/z(％)：247.1(44)[M]
+，157.1(100).
Embodiment 3 6-skatole-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; under oxygen protection, add 4.5mg palladium, 25mg meta-aminotoluene; 24.6 μ L dimethyl butyn; 1.25mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 46.8mg, productive rate 95%.
IR：(KBr)v
max?3308，1734，1678，1261cm-1；
1H?NMR：(300MHz，CDCl3)δ9.47(brs，1H)，7.92(d，J＝8.4Hz，1H)，7.20(s，1H)，7.09(d，J＝8.4Hz，1H)，3.98(s，3H)，3.95(s，3H)，2.46(s，3H)；
13C?NMR：(75MHz，CDCl3)δ164.6，161.4，136.3，135.2，127.3，124.8，124.7，122.3，111.9，111，4，52.6，51.8，21.8；MS(70eV)：m/z(％)：247.2(24)[M]
+，157.1(100)；HRMS?m/z(ESI)calcd?for?C13H13NO4Na(M+Na)
+270.07368，found?270.07407.
Embodiment 4 7-skatole-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 4.5mg palladium, 25mg Ortho Toluidine under the oxygen protection; 24.6 μ L dimethyl butyn; 1.25mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 36.0mg, productive rate 72%.
IR：(KBr)v
max?3239，2954，2926，1741，1694，1446，1236，1100cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.16(brs，1H)，7.88(d，J＝6.9Hz，1H)，7.22-7.17(m，2H)，4.00(s，3H)，3.99(s，3H)，2.53(s，3H)；
13C?NMR：(75MHz，CDCl
3)δ164.6，161.5，134.6，127.6，126.5，126.2，122.8，121.2，120.3，112.4，52.7，51.8，165；MS(70eV)：m/z(％)：247.1(43)[M]
+，157.1(100).
Embodiment 5 6-isopropyl indole-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add isopropyl aniline between 9.0mg palladium, 66mg under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 109.6mg, productive rate 99%.
IR：(KBr)v
max?3294，2953，1726，1686，1530，1444，1263，1069cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.38(brs，1H)，7.88(d，J＝8.7Hz，1H)，7.19(s，1H)，7.10(d，J＝8.1Hz，1H)，3.91(s，3H)，3.89(s，3H)，2.98-2.89(m，1H)，1.22(d，J＝6.9Hz，6H)；
13C?NMR：(100MHz，CDCl
3)δ164.7，161.5，147.4，135.3，127.5，125.1，122.4，111.8，108.7，52.6，51.8，34.3，24.0；MS(70eV)：m/z(％)：275.2(55)[M]
+，228.2(100)；HRMS?m/z(ESI)calcd?for?C15H17NO4Na(M+Na)
+298.10498，found?298.10506.
Embodiment 6 5-cyclohexyl indole-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 84mg to cyclohexyl aniline under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 102.4mg, productive rate 81%.
IR：(KBr)v
max?3326，2924，2845，1684，1528，1348，1268cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.46(brs，1H)，7.85(s，1H)，7.36(d，J＝8.7Hz，1H)，7.24(d，J＝8.4Hz，1H)，3.99(s，3H)，3.96(s，3H)，2.65-2.58(m，1H)，1.93-1.74(m，4H)，1.54-1.25(m，6H)；
13CNMR：(75MHz，CDCl
3)δ164.9，161.5，142.7，133.5，127.9，127.0，125.9，119.6，111.7，111.6，52.6，51.8，44.8，34.8，27.0，26.1；MS(70eV)：m/z(％)：315.2(100)[M]
+；HRMS?m/z(ESI)calcd?forC18H21NO4Na(M+Na)
+338.13628，found?338.13570.
Embodiment 7 5-methoxy-Indole-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 60mg P-nethoxyaniline under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 104mg, productive rate 99%.
IR：(KBr)v
max?3281，1719，1688，1259，1161cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.31(s，1H)，7.48(s，1H)，7.33(d，J＝9.0Hz，1H)，7.33(d，J＝9.0Hz，1H)，7.04(d，J＝4.2Hz，1H)，3.99(s，3H)，3.98(s，3H)，3.88(s，3H)；
13C?NMR：(75MHz，CDCl
3)δ164.8，161.2，156.1，129.9，128.1，127.8，117.8，112.8，102.5，55.6，52.6，51.8；MS(70eV)：m/z(％)：263.2(45)[M]
+，173.1(100)；HRMS?m/z(ESI)calcd?for?C13H13NO5Na(M+Na)
+286.06859，found286.06815.
Embodiment 8 7-methoxy-Indole-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 60mg ORTHO ANISIDINE under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 84.6mg, productive rate 81%.
IR：(KBr)v
max?3300，1698，1443，1272，1242，1203cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.36(brs，1H)，7.61(d，J＝8.0Hz，1H)，7.18(t，J＝8.0Hz，1H)，6.76(d，J＝8.0Hz，1H)，3.98(s，6H)，3.96(s，3H)；
13C?NMR：(75MHz，CDCl
3)δ164.6，161.0，146.2，128.1，127.7，126.0，123.1，114.8，112.2，104.5，55.5，52.6，51.8；MS(70eV)：m/z(％)：263.2(63)[M]
+，230.1(100)；HRMS?m/z(ESI)calcd?for?C13H13NO5Na(M+Na)
+286.06859，found?286.06899.
Embodiment 95,7-dimethoxy indoles-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 73.4mg 2 under the oxygen protection; the 4-dimethoxyaniline; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N, N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid, both volume ratio is 4: 1); begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 116mg, productive rate 99%.
IR：(KBr)v
max?3293，1704，1682，1528，1504，1458，1295，1203，1150cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.34(brs，1H)，7.03(s，1H)，6.44(s，1H)，3.97(s，3H)，3.93(s，3H)，3.87(s，3H)；
13CNMR：(75MHz，CDCl
3)δ164.9，160.9，157.0，146.7，128.1，127.4，121.7，111.5，97.9，93.8，55.7，55.6，52.5，51.77；MS(70eV)：m/z(％)：293.2(98)[M]
+，260.2(100)；HRMS?m/z(ESI)calcd?for?C14H15NO6Na(M+Na)
+316.07916，found?316.07985.
Get a reaction tubes; add 9.0mg palladium, 73.4mg 2 under the oxygen protection; 5 dimethoxyanilines; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N, N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid, both volume ratio is 4: 1); begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 74.0mg, productive rate 63%.
IR：(KBr)v
max?3323，1746，1706，1530，1350，1268，1242cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.13(brs，1H)，6.60(d，J＝8.1Hz，1H)，6.37(d，J＝8.1Hz，1H)，3.98(s，3H)，3.92(s，3H)，3.90(s，3H)，3.85(s，3H)；
13C?NMR：(75MHz，CDCl
3)δ166.7，160.8，148.1，140.7，127.7，122.9，117.5，114.5，105.0，100.0，55.9，55.7，52.6，52.4；MS(70eV)：m/z(％)：293.0(54)[M]
+，260.7(100)；HRMS?m/z(ESI)calcd?for?C14H15NO6Na(M+Na)
+316.07916，found316.07926.
Embodiment 11 5,6-dimethoxy indoles-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 73.4mg 3 under the oxygen protection; the 4-dimethoxyaniline; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N, N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid, both volume ratio is 4: 1); begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 109mg, productive rate 93%.
IR：(KBr)v
max?3288，1722，1679，1522，1451，1301，1275，1254，1201，1142cm
-1；
1H?NMR：(300MHz，DMSO)δ12.30(brs，1H)，7.27(s，1H)，6.92(s，1H)，3.86(s，3H)，3.83(s，3H)，3.80(s，3H)，3.79(s，3H)；
13C?NMR：(75MHz，DMSO)δ164.4，161.0，149.4，147.0，130.2，126.7，119.2，109.2，101.6，94.5，55.5，52.2，51.4；MS(70eV)：m/z(％)：293.2(66)[M]
+，261.2(100)；HRMS?m/z(ESI)calcd?for?C14H15NO6Na(M+Na)
+316.07916，found?316.07956.(100)；HRMS?m/z(ESI)calcd?for?C14H15NO6Na(M+Na)
+316.07916，found?316.07985
Embodiment 12 5-trifluoromethoxy indoles-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 85.0mg 4-trifluoro-methoxyaniline under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 58.3mg, productive rate 46%.
IR：(KBr)v
max?3302，1721，1686，1539，1462，1266，1199，1156，1067cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.63(brs，1H)，7.94(s，1H)，7.46(d，J＝9.0Hz，1H)，7.25(d，J＝9.3Hz，1H)，4.00(s，3H)，3.99(s，3H)；
13CNMR：(75MHz，CDCl
3)δ163.9，161.1，144.9，132.9，130.0，127.1，120.6(d，J＝254.6Hz)，120.2，115.2，113.0，111.9，52.9，52.0；MS(70eV)：m/z(％)：317.1(34)[M]
+，227.1(100)；HRMS?m/z(ESI)calcd?for?C13H10F3NO5Na(M+Na)
+340.04033.found?340.04082.
Embodiment 13 5-group-4 ethyl formate indoles-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 79.2mg PABA ethyl ester under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 119mg, productive rate 97%.
IR：(KBr)v
max?3308，1732，1680，1460，1263，1154cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.71(brs，1H)，8.79(s，1H)，8.06(d，J＝8.7Hz，1H)，7.48(d，J＝7.0Hz，1H)，4.42(q，J＝8.7Hz，1H)，4.02(s，3H)，3.99(s，3H)，1.43(t，J＝7.0Hz，3H)；
13CNMR：(75MHz，CDCl
3)δ166.9，164.1，161.0，137.0，129.4，126.8，126.2，125.8，125.6，125.0，111.8，61.0，52.9，52.1，14.4；MS(70eV)：m/z(％)：305.2(96)[M]
+，215.2(100)；HRMS?m/z(ESI)calcd?for?C15H15NO6Na(M+Na)
+328.07916，found?328.07930.
Embodiment 14 5-fluoro indole-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 45.4 μ L 4-fluoroanilines under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 88.6mg, productive rate 88%.
IR：(KBr)v
max?3321，3300，1745，1689，1249cm
-1；
1H?NMR：(300MHz，CDCl3)δ9.58(brs，1H)，7.73(dd，J＝9.4，2.4Hz，1H)，7.39(dd，J＝8.8，4.2Hz，1H)，7.16-7.10(m，1H)，3.98(s，6H)；
13CNMR：(75MHz，CDCl3)δ164.1，161.2，159.3(d，J＝237.4Hz)，131.3，129.7，127.4(d，J＝11.2Hz)，115.2(d，J＝26.6Hz)，113.1(d，J＝9.3Hz)，111.6，107.6(d，J＝24.2Hz)，52.8，51.9；MS(70eV)：m/z(％)：251.2(18)[M]
+，161.1(100)；HRMS?m/z(ESI)calcd?forC12H10FNO4Na(M+Na)
+274.04861，found?274.04862.
Embodiment 15 5-chloro-indole-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 61.2mg 4-chloroaniline under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 48.0mg, productive rate 45%.
IR：(KBr)v
max?3242，1700，1667，1522，1451，1422，1342，1260，1223cm
-1；
1HNMR：(300MHz，CDCl3)δ9.51(brs，1H)，8.06(s，1H)，7.39-7.30(m，2H)，3.99(s，6H)；
13C?NMR：(75MHz，DMSO)δ163.5，161.1，133.7，131.5，126.9，126.6，125.1，120.5，114.7，108.4，52.7，51.6；MS(70eV)：m/z(％)：267.1(24)[M]
+，177.0(100)；HRMS?m/z(ESI)calcd?forC12H10ClNO4Na(M+Na)
+290.01906，found?290.01923.
Embodiment 16 5-OHis-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 52.3mg 4-hydroxyanilines under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 37.5mg, productive rate 38%.
IR：(KBr)v
max?3300，2956，2926，1661，1672，1523，1261，1235，1198，1176cm
-1；
1H?NMR：(300MHz，DMSO)δ12.35(brs，1H)，9.20(s，1H)，7.31(d，J＝8.8Hz，1H)，7.24(s，1H)，6.85(d，J＝8.8Hz，1H)，3.87(s，3H)，3.80(s，3H)；
13C?NMR：(75MHz，DMSO)δ164.2，161.4，153.2，129.8，127.0，116.1，113.6，107.9，104.3，52.4，51.3；MS(70eV)：m/z(％)：249.1(37)[M]
+，159.0(100)；HRMS?m/z(ESI)calcd?for?C12H11NO5Na(M+Na)
+272.05294，found272.05304.
Embodiment 17 benzos [e] indoles-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 68.6mg 2-naphthylamines under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 94mg, productive rate 83%.
IR：(KBr)v
max?3275，1734，1700，1255cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.63(brs，1H)，8.15(d，J＝8.1Hz，1H)，7.88(d，J＝7.8Hz，1H)，7.27(d，J＝9.0Hz，1H)，7.59-7.54(m，1H)，7.50-7.45(m，2H)，4.11(s，3H)，3.95(s，3H)；
13CNMR：(75MHz，CDCl
3)δ168.2，161.1，133.2，130.0，129.1，128.3，127.7，127.1，124.7，122.8，119.7，116.0，112.6，52.9，52.5；MS(70eV)：m/z(％)：283.1(69)[M]
+，193.1(100)；HRMS?m/z(ESI)calcd?for?C16H13NO4Na(M+Na)
+306.07368，found?306.07417；iso-3qa：
1H?NMR：(300MHz，CDCl
3)δ9.63(brs，1H)，8.15(d，J＝8.1Hz，1H)，7.88(d，J＝7.8Hz，1H)，7.27(d，J＝9.0Hz，1H)，7.59-7.54(m，1H)，7.50-7.45(m，2H)，4.05(s，3H)，4.01(s，3H).
Synthesizing of embodiment 18 2 (2,3-dioctyl phthalate value-5-indoles) oxide compound
Get a reaction tubes; add 9.0mg palladium, 40.0mg 4 under the oxygen protection; 4 '-diaminodiphenyl oxide; 74.0 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N, N N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid, both volume ratio is 4: 1); begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 83.0mg, productive rate 87%.
IR：(KBr)v
max?3294，2952，1740，1698，1532，1458，1247，1220，1195，1065cm
-1；
1H?NMR：(300MHz，DMSO)δ12.68(s，2H)，7.53(d，J＝8.4Hz，2H)，7.43(s，2H)，7.11(d，J＝8.4Hz，2H)，3.90(s，6H)，3.75(s，6H)；
13CNMR：(75MHz，DMSO)δ163.9`，161.2，153.1，131.7，130.9，126.1，118.1，114.4，109.3，108.6，52.6，51.4；MS(70eV)：m/z(％)：480.1(81)[M]
+，416.1(100)；HRMS?m/z(ESI)calcd?for?C24H20N2O9Na(M+Na)
+503.10610，found503.10686.
Embodiment 19 5-ethylindole-2,3-dioctyl phthalate methyl esters synthetic
Get a reaction tubes; add 9.0mg palladium, 44.0 μ L aniline under the oxygen protection; 63.8 μ L diethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 78.3mg, productive rate 75%.
IR：(KBr)v
max?3244，1740，1692，1438，1282，1249，1219，1074cm
-1；
1H?NMR：(300MHz，CDCl
3)δ9.51(brs，1H)，8.06(d，J＝7.8Hz，1H)，7.44(d，J＝8.1Hz，1H)，7.38-7.24(m，2H)，4.50-4.41(m，4H)，1.47-1.36(m，6H)；
13CNMR：(100MHz，CDCl
3)δ164.3，161.1，134.8，128.2，126.8，125.7，122.6，122.4，112.1，111.9，61.8，60.7，14.4，14.2；MS(70eV)：m/z(％)：261.1(39)[M]
+，143.1(100).
Embodiment 20 5-isopropyl indole-2,3-dioctyl phthalate methyl esters
Get a reaction tubes; add 9.0mg palladium, 44.0 μ L aniline under the oxygen protection; 79.2mg acetylenedicarboxylic acid isopropyl esters; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 69.4mg, productive rate 60%.
IR：(KBr)v
max?3335，2984，1718，1695，1280，1109，1068cm
-1；
1H?NMR：(400MHz，CDCl
3)δ9.28(brs，1H)，8.01(d，J＝8.4Hz，1H)，7.42(d，J＝8.4Hz，1H)，7.37-7.33(m，1H)，7.27-7.23(m，1H)，5.38-5.29(m，2H)，1.45(d，J＝6.4Hz，6H)，1.41(d，J＝6.4Hz，6H)；
13CNMR：(100MHz，CDCl
3)δ163.7，160.4，134.7，128.3，126.8，125.7，122.5，122.2，112.8，111.8，69.8，68.3，22.1，21.8；MS(70eV)：m/z(％)：289.2(28)[M]
+，187.1(100)；HRMS?m/z(ESI)calcd?for?C16H19NO4Na(M+Na)
+312.12063，found?312.12044.
Synthesizing of embodiment 21 2-phenyl-3-itrile group indoles
Get a reaction tubes; add 22.4mg palladium, 110 μ L aniline under the oxygen protection; 127mg benzyne nitrile; 10.0mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 45.0mg, productive rate 20%.
IR：(KBr)v
max?3320，3195，2219，1451，738，689cm
-1；
1H?NMR：(300MHz，CDCl
3)δ8.91(brs，1H)，7.90(d，J＝6.9Hz，2H)，7.78(d，J＝8.7Hz，1H)，7.60-7.46(m，4H)，7.35-7.30(m，2H)；
13C?NMR：(100MHz，CDCl
3)δ144.7，135.0，130.1，129.45，129.41，128.9，126.8，124.4，122.5，119.6，116.7，111.6，84.1；MS(70eV)：m/z(％)：218.0(100)[M]
+.
Embodiment 22 1,2-dihydro-pyrroles [3,2,1-hi] indoles 4,5-formic acid methyl synthetic
Get a reaction tubes; add 9.0mg palladium, 58.0mg Yin pyridine under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 47.3mg, productive rate 46%.
IR：(KBr)v
max?1738，1711，1278，1227，1110cm
-1；
1H?NMR：(300MHz，CDCl
3)δ7.62(d，J＝8.1Hz，1H)，7.18(t，J＝6.9Hz，1H)，7.06(d，J＝6.6Hz，1H)，4.75(t，J＝6.9Hz，2H)，3.98(s，3H)，3.95(s，3H)，3.75(t，J＝6.9Hz，1H)；
13C?NMR：(75MHz，CDCl
3)δ164.3，161.4，146.3，128.6，125.9，125.2，119.9，119.2，118.6，113.4，52.4，51.8，51.5，32.9；MS(70eV)：m/z(％)：259.2(23)[M]
+，261.2(100)；HRMS?m/z(ESI)calcd?for?C14H13NO4Na(M+Na)
+282.07368，found?282.07387.
Embodiment 23 1,2-dihydro-2-methyl-pyrroles [3,2,1-hi] indoles 4,5-formic acid methyl synthetic
Get a reaction tubes; add 9.0mg palladium, 62.6 μ L 2-methyl Yin pyridines under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 77.0mg, productive rate 77%.
IR：(KBr)v
max?1706，1486，1443，1410，1276，1235，1213，1118，1080cm
-1；
1H?NMR：(300MHz，CDCl
3)δ7.64(d，J＝8.1Hz，1H)，7.20(t，J＝6.9Hz，1H)，7.06(d，J＝6.6Hz，1H)，5.34-5.24(m，1H)，4.06-3.95(m，1H)，4.00(s，3H)，3.95(s，3H)，3.32(d，J＝16.2Hz，1H)，1.54(d，J＝6.3Hz，1H)；
13C?NMR：(100MHz，CDCl
3)δ164.5，161.7，145.5，128.6，125.2，124.7，119.8，119.0，118.6，113.6，61.4，52.4，51.5，41.9，22.3；MS(70eV)：m/z(％)：273.1(100)[M]
+；HRMS?m/z(ESI)calcd?for?C15H15NO4Na(M+Na)
+296.08933，found?296.08896.
Embodiment 24 5,6-dihydro-pyrroles [3,2,1-hi] quinoline 4,5-formic acid methyl synthetic
Get a reaction tubes; add 9.0mg palladium, 60.4 μ L tetrahydroquinolines under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PiOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 90.6mg, productive rate 83%.
IR：(KBr)v
max?2955，1706，1521，1441，1268，1226，1157，1123，1089cm
-1；
1H?NMR：(400MHz，CDCl
3)δ7.84(dd，J＝8.2，0.7Hz，1H)，7.18(dd，J＝8.2，7.1Hz，1H)，7.05(dd，J＝7.1，0.7Hz，1H)，4.30-4.28(m，2H)，4.00(s，3H)，3.93(s，3H)，2.99(t，J＝6.0Hz，2H)，2.27-2.21(m，2H)；
13C?NMR：(100MHz，CDCl
3)δ164.8，162.7，134.1，131.8，123.9，122.9，122.8，121.6，119.8，108.8，52.7，51.4，44.0，24.4，22.6；MS(70eV)：m/z(％)：273.2(47)[M]
+，155.2(100)；HRMS?m/z(ESI)calcd?for?C15H15NO4Na(M+Na)
+296.08933，found?296.08951.
Embodiment 25 5,6-dihydro 8-methyl-pyrroles [3,2,1-hi] quinoline 4,5-formic acid methyl synthetic
Get a reaction tubes; add 9.0mg palladium, 70.5mg 6-methyl tetrahydroquinoline under the oxygen protection; 49.2 μ L dimethyl butyn; 2.5mLDMA and PivOH mixed solvent (DMA:N; N-N,N-DIMETHYLACETAMIDE, PivOH: tertiary butyl formic acid; both volume ratio is 4: 1), begin slowly to be raised to 120 ℃ from room temperature, within 12 hours, reaction finishes.Conventional processing obtains sterling 95.6mg, productive rate 80%.
IR：(KBr)v
max?2956，1708，1515，1268，1230，1005cm
-1；
1H?NMR：(400MHz，CDCl
3)δ7.67(s，1H)，7.64(s，1H)，7.05(dd，J＝7.1，0.7Hz，1H)，4.30-4.28(m，2H)，4.00(s，3H)，3.93(s，3H)，2.99(t，J＝6.0Hz，2H)，2.40(s，3H)，2.27-2.21(m，2H)；
13C?NMR：(100MHz，CDCl
3)δ164.8，162.7，134.1，131.8，123.9，122.9，122.8，121.6，119.8，108.8，52.7，51.4，44.0，25.0，24.4，22.6；MS(70eV)：m/z(％)：287.1(40)[M]
+，167.2(100)；HRMS?m/z(ESI)calcd?forC16H17NO4Na(M+Na)
+310.10553，found?310.10563.
Claims (7)
1. the indoles shown in formula I-2, the synthetic method of 3-diformic ester compound:
Formula I
Comprise: under the oxygenant effect, with Pd (OAc)
2Or PdCl
2Be catalyzer, aromatic amine compounds, acetylene compound and organic mixed solvent mixed into the indole ring reaction, and get final product; Wherein, described organic mixed solvent is comprised of DMA, DMF or DMSO and alkyl acid;
Described aromatic amine compounds is
And be selected from aniline, para-totuidine, meta-aminotoluene, Ortho Toluidine, an isopropyl aniline is to cyclohexyl aniline, P-nethoxyaniline, ORTHO ANISIDINE, 2, the 4-dimethoxyaniline, 2,5 dimethoxyanilines, 3,4-dimethoxyaniline, the 4-trifluoro-methoxyaniline, the PABA ethyl ester, 4-fluoroaniline, 4-chloroaniline or 4-hydroxyanilines;
In general formula I, the R definition is identical with R in the raw material aromatic amine compounds; Described acetylene compound is dimethyl butyn, E
1And E
2For-COOCH3;
Described oxygenant is oxygen or air.
2. it is characterized in that in accordance with the method for claim 1: described oxygenant is the oxygen of 1atm.
3. it is characterized in that in accordance with the method for claim 1: described organic mixed solvent by DMA, DMF or DMSO and alkyl acid according to (1-100): 1 volume ratio is formed.
4. it is characterized in that in accordance with the method for claim 3: described organic mixed solvent is comprised of DMA, DMF or DMSO and the alkyl acid volume ratio according to 4:1.
5. in accordance with the method for claim 1, it is characterized in that: catalyzer, the mol ratio of aromatic amine compounds and acetylene compound are 1:(1-1000): (1-1000).
6. in accordance with the method for claim 5, it is characterized in that: catalyzer, the mol ratio of aromatic amine compounds and acetylene compound are 1:10:10.
7. it is characterized in that in accordance with the method for claim 1: the temperature of described one-tenth indole ring reaction is 40-150 ℃.
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| A.Monge,et al.New 5H-Pyridazino[ 4,5-b]indole Derivatives. Synthesis and Studies as Inhibitors of Blood Platelet Aggregation and Inotropics.《Journal of Medicinal Chemistry》.1991,第34卷(第10期),3023-3029. * |
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