CN1817863A - 3-substituted 1,2,3.4-tetrahydro-quinazine derivative, its synthesis and use - Google Patents
3-substituted 1,2,3.4-tetrahydro-quinazine derivative, its synthesis and use Download PDFInfo
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Abstract
A 3-substituted 1, 2, 3, 4-tetrahydro-quinoline derivative, its synthesis and use are disclosed. The procedure is carried out by condensing substituted-o-nitrobenzaldehyde or o-aminobenzaldehyde with aryl-acetonitrile derivative, reducing by double bond and obtaining 3-substituted 1, 2, 3, 4-tetraquinazine derivate by loop closing under the condition of catalytic hydrogenation. It can be used for cerebral local ischemia, suppressive vasorelaxation, antiarrhythmic and antineoplastic activities. It is simple, has gentle reactive condition and more output.
Description
Technical field
The present invention relates to 1,2,3 of 3-replacement, 4-tetrahydroquinoline derivative and preparation method and use thereof, more specifically, relating to 3 is 1,2,3 of aryl replacement, 4-tetrahydroquinoline derivative and preparation method and use thereof.
Background technology
Tetrahydroquinoline and tetrahydroisoquinoline extensively are present in nature, and 1,2,3, the 4-Tetrahydroquinolinesas has vasorelaxation, anti-arrhythmia and the antitumor isoreactivity of inhibition, also has the effect of immunosuppressor, also is the dyestuff intermediate that has more characteristic.
A lot of tetrahydroquinoline derivatives are considered to very strong affinity ligands on the DMAD acceptor glycine position, it also is the convenience factor of norepinephrine transmission, still do not influence the myotility sensitive agent of metabolic defect in cellular calcium ion running simultaneously, therefore be potential drug (the Alan R.Katritzky et al. that treats diseases such as cerebral ischemia, Tetrahedron.52,48,15031-15070,1996).
The synthetic method that this compounds is commonly used has: the three component condensations that the aniline of replacement, aldehyde and electron rich alkene participate in obtain quinolines, and the quinolines that obtains is reduced or catalytic hydrogenating reduction with the active metal.These method of reducing condition harshnesses, not easy to operate, and also the diversity of quinoline is subjected to the considerable restraint of synthesis condition, is difficult for making by known method as the 3-aryl quinoline, and then just more is difficult to prepare 3-aryl-1,2,3,4-tetrahydroquinoline derivative.
Summary of the invention
Therefore, the objective of the invention is to, provide that the 3-of a class novelty replaces 1,2,3, the 4-tetrahydroquinoline derivative.
Another object of the present invention is to, provide 1,2,3 of above-mentioned 3-replacement, the synthetic method of 4-tetrahydroquinoline derivative.
An also purpose of the present invention is, 1,2,3 of above-mentioned 3-replacement is provided, the purposes of 4-tetrahydroquinoline derivative in the medicine of preparation treatment cerebral ischemia disease.
The invention provides that 3-with following general structure I replaces 1,2,3, the 4-tetrahydroquinoline derivative:
Wherein, R
1, R
2, R
3And R
4H, C respectively do for oneself
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen or adjacent R
1With R
2, R
2With R
3, or R
3With R
4Link to each other and constitute alkylene dioxo base;
Ar is an aryl, for example phenyl of various replacements, fused ring aryl, heterocyclic aryl, and described Ar can be selected from H, phenyl, C
1-C
6Alkyl, C
1-C
6One or more substituting groups in alkoxyl group or adjacent alkylene dioxo base, amido, halogen, cyano group and the trihalogenmethyl replace.
The invention provides that the 3-of said structure general formula I replaces 1,2,3,4-tetrahydroquinoline derivative synthetic method, synthetic route is as follows:
Or
This synthetic method comprises: under alkaline condition, the Ortho Nitro Benzaldehyde of replacement or o-Aminobenzaldehyde and aryl acetonitrile derivative are condensed into the acrylonitrile compound of structural formula A; The acrylonitrile compound of this structural formula A is reduced into the propionitrile compounds of structural formula B through double bond reduction reaction; Then generate 1,2,3 of 3-replacement, 4-tetrahydroquinoline derivative at catalytic hydrogenation condition ShiShimonoseki ring.
1,2,3 of 3-replacement provided by the invention, the 4-tetrahydroquinoline derivative has the treatment cerebral ischemia, suppresses vasorelaxation, anti-arrhythmia and antitumor isoreactivity, also has the effect of immunosuppressor.
1,2,3 of 3-replacement provided by the invention, the synthetic method of 4-tetrahydroquinoline derivative, this method simple possible, next step has synthesized tetrahydroquinoline derivative at the room temperature catalytic condition by nitro or amino and cyano group, has avoided the quinolines hydrogenation reduction of condition harshness; And the intermediate productive rate of reaction is very high, uses purifying hardly, the annulation mild condition, and aftertreatment is simple, and productive rate is medium.
Embodiment
3-provided by the invention replace 1,2,3,4-tetrahydroquinoline derivative, wherein preferred compound as shown in Table:
| Numbering | Compound number | R 1 | R 2 | R 3 | R 4 | Ar |
| 1 | I-1 | H | H | H | H | Phenyl |
| 2 | I-2 | H | H | H | H | The 4-p-methoxy-phenyl |
| 3 | I-3 | H | H | OCH 3 | H | The 4-p-methoxy-phenyl |
| 4 | I-4 | H | OCH 3 | OCH 3 | H | The 4-p-methoxy-phenyl |
| 5 | I-5 | H | H | OCH 3 | H | The 4-fluorophenyl |
| 6 | I-6 | H | H | OCH 3 | H | 3-amino-4-p-methoxy-phenyl |
| 7 | I-7 | OCH 3 | OCH 3 | OCH 3 | H | The 4-p-methoxy-phenyl |
| 8 | I-8 | H | OCH 3 | OCH 3 | H | 3, the 4-methylenedioxyphenyl |
| 9 | I-9 | H | 3, the 4-methylene-dioxy | H | 3, the 4-Dimethoxyphenyl | |
| 10 | I-10 | H | OCH 3 | H | H | The 4-p-methoxy-phenyl |
| 11 | I-11 | H | H | H | OCH 3 | The 4-p-methoxy-phenyl |
| 12 | I-12 | H | F | H | H | The 4-p-methoxy-phenyl |
| 13 | I-13 | H | H | OCH 3 | H | 3-fluoro-4-p-methoxy-phenyl |
| 14 | I-14 | H | CH 3 | H | CH 3 | The 4-p-methoxy-phenyl |
| 15 | I-15 | H | H | H | H | The 4-aminomethyl phenyl |
| 16 | I-16 | H | H | H | H | The 3-trifluoromethyl |
| 17 | I-17 | H | H | H | H | The 2-cyano-phenyl |
| 18 | I-18 | H | H | H | H | The 4-xenyl |
| 19 | I-19 | H | H | H | H | The 1-naphthyl |
| 20 | I-20 | H | H | H | H | The 2-pyridyl |
1,2,3 of 3-replacement provided by the invention, 4-tetrahydroquinoline derivative synthetic method, synthetic route is as follows:
Or
This synthetic method comprises: under alkaline condition, the Ortho Nitro Benzaldehyde of replacement or o-Aminobenzaldehyde and aryl acetonitrile derivative are condensed into the acrylonitrile compound of structural formula A; The acrylonitrile compound of this structural formula A is reduced into the propionitrile compounds of structural formula B through double bond reduction reaction; Then generate 1,2,3 of 3-replacement, 4-tetrahydroquinoline derivative at catalytic hydrogenation condition ShiShimonoseki ring.
Wherein, be condensed in the acrylonitrile compound of structural formula A at the Ortho Nitro Benzaldehyde that replaces or o-Aminobenzaldehyde and aryl acetonitrile derivative, used alkali can be mineral alkali, as salt of wormwood; Also can be organic bases, as organic amine, sodium alkoxide or potassium alcoholate.The consumption of alkali is the mol ratio of the 10%-100% of arbitrary reactant.
The acrylonitrile compound of structural formula A is reduced into the propionitrile compounds of structural formula B, and available also original reagent has sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride or zinc powder/ammonium formate, and its consumption is the mol ratio of the 50%-150% of structural formula A compound amount.Reaction solvent can be methyl alcohol, ethanol, tetrahydrofuran (THF) or acetonitrile etc.
The catalyzer of described catalytic hydrogenation can be Pd/C, Pd (OH)
2/ C, Rh/C, Ni or Pt etc., catalyst consumption is the 5%-30% mass ratio of structural formula B compound.Temperature of reaction is at 20～120 ℃.
In synthetic method provided by the present invention, the raw material that is adopted is the conventional chemical preparation, can commercially obtain.
Below in conjunction with specific embodiment compound of the present invention and synthetic method thereof are further elaborated, but the present invention is not limited to this.
Embodiment 1
The preparation of the acrylonitrile compound of structural formula A
(1) (Z)-preparation of 3-(2-nitrophenyl)-2-phenyl vinyl cyanide (A-1)
0.23g (10mmol) sodium is dissolved in the 50mL dehydrated alcohol fully, stir and add 15.12g (100mmol) 2-nitrobenzaldehyde and 11.71g (100mmol) benzyl cyanide down, stirring at room 4h, filtration, absolute ethanol washing gets glassy yellow solid 23.00g, productive rate 92.0%.
1HNMR(300MHz，CDCl
3)δ7.42-7.53(m，3H)，7.64(t，J＝8.2，1H)，7.73(dd，J＝1.7，8.1，2H)，7.80(t，J＝7.6，1H)，7.95(d，J＝7.6，1H)，8.06(s，1H)，8.26(d，J＝8.3，1H)；MS(EI)：m/e(％)250(16M
+)，119(100)，92(84)。
(2) (Z)-preparation of 2-(4-p-methoxy-phenyl)-3-(2-nitrophenyl)-vinyl cyanide (A-2)
2-nitrobenzaldehyde and 4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-2, productive rate 74.2%.
1HNMR(300MHz，CDCl
3)δ3.87(s，3H)，6.99(d，J＝8.8，2H)，7.61(t，J＝8.0，1H)，7.66(d，J＝9.2，2H)，7.77(t，J＝7.6，1H)，7.92(s，1H)，7.95(s，1H)，8.23(dd，J＝1.3，8.3，1H)；MS(EI)：m/e(％)280(50M
+)，119(88)，92(100)。
(3) (Z)-preparation of 3-(4-methoxyl group-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-3)
2-nitro-4-methoxybenzaldehyde and 4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-3, productive rate 80.6%.
1HNMR(300MHz，CDCl
3)δ3.86(s，3H)，3.94(s，3H)，6.97(d，J＝8.8，2H)，7.28(m，1H)，7.64(d，J＝8.8，2H)，7.85(s，1H)，7.91(d，J＝8.5，1H)；MS(EI)：m/e(％)310(80M
+)，293(100)，149(65)，122(70)。
(4) (Z)-preparation of 3-(4,5-dimethoxy-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-4)
2-nitro-4,5-dimethoxy benzaldehyde and 4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-4, productive rate 84.3%.
1HNMR(300MHz，CDCl
3)δ3.87(s，3H)，4.01(s，3H)，4.07(s，3H)，6.99(d，J＝8.9，2H)，7.40(s，1H)，7.66(d，J＝9.0，2H)，7.78(s，1H)，7.92(s，1H)，7.99(s，1H)；MS(EI)：m/e(％)340(25M
+)，164(100)，136(60)。
(5) (Z)-preparation of 2-(4-fluorophenyl)-3-(4-methoxyl group-2-nitrophenyl)-vinyl cyanide (A-5)
2-nitro-4-methoxybenzaldehyde and 4-fluorophenyl acetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-5, productive rate 67.0%.
1HNMR(300MHz，CDCl
3)δ3.94(s，3H)，7.16(t，J＝8.6，2H)，7.29(dd，J＝2.5，8.8，1H)，7.66-7.73(m，3H)，7.88(s，1H)，7.90-7.91(m，1H)；MS(EI)：m/e(％)298(80M
+)，281(85)，208(70)，149(100)，122(85)。
(6) (Z)-preparation of 3-(4-methoxyl group-2-nitrophenyl)-2-(4-methoxyl group-3-nitrophenyl)-vinyl cyanide (A-6)
2-nitro-4-methoxybenzaldehyde and 3-nitro-4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-6, productive rate 83.4%.
1HNMR(300MHz，CDCl
3)δ3.96(s，3H)，4.03(s，3H)，7.19(d，J＝9.1，1H)，7.30(dd，J＝2.7，8.7，1H)，7.74(d，J＝2.4，1H)，7.85-7.87(m，1H)，7.88-7.90(m，1H)，7.94(s，1H)，8.16(d，J＝2.5，1H)；MS(EI)：m/e(％)355(50M
+)，338(45)，149(100)，122(70)。
(7) (Z)-preparation of 2-(4-p-methoxy-phenyl)-3-(2,3,4-trimethoxy-6-nitrophenyl)-vinyl cyanide (A-7)
2,3,4-trimethoxy-6-nitrobenzaldehyde and 4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-7, productive rate 63.5%.
1HNMR(300MHz，CDCl
3)δ3.86(s，3H)，3.88(s，3H)，3.98(s，3H)，4.01(s，3H)，6.97(d，J＝9.0，2H)，7.56(s，1H)，7.59(s，1H)，7.64(d，J＝8.9，2H)；MS(EI)：m/e(％)370(20M
+)，353(40)，194(100)，166(35)。
(8) (Z)-preparation of 2-(5-benzo [1,3] dioxy base)-3-(4,5-dimethoxy-2-nitrophenyl)-vinyl cyanide (A-8)
2-nitro-4,5-dimethoxy benzaldehyde and 3,4-methylene-dioxy benzyl cyanide is undertaken by embodiment 1. (1) described methods, makes compd A-8, productive rate 62.4%.
1HNMR(300MHz，CDCl
3)δ4.01(s，3H)，4.06(s，3H)，6.05(s，2H)，6.88(d，J＝7.8，1H)，7.17(d，J＝1.6，1H)，7.22(d，J＝1.8，1H)，7.37(s，1H)，7.78(s，1H)7.95(s，1H)；MS(EI)：m/e(％)354(37M
+)，164(100)，136(60)。
(9) (Z)-preparation of 2-(3, the 4-Dimethoxyphenyl)-3-(6-nitro-5-benzo [1,3] dioxy base)-vinyl cyanide (A-9)
3,4-methylene-dioxy-6-nitrobenzaldehyde and 3, the 4-dimethoxybenzeneacetonitrile is undertaken by embodiment 1. (1) described methods, makes compd A-9, productive rate 79.6%.
1HNMR(300MHz，CDCl
3)δ3.94(s，3H)，3.96(s，1H)，6.21(s，2H)，6.93(d，J＝8.4，1H)，7.14(d，J＝2.2，1H)，7.28(d，J＝2.5，1H)，7.30(d，J＝2.3，1H)，7.72(s，1H)，7.87(s，1H)；MS(EI)：m/e(％)354(55M
+)，163(87)，135(100)。
(10) (Z)-preparation of 3-(5-methoxyl group-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-10)
2-nitro-5-methoxybenzaldehyde and 4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-10, productive rate 40.0%.
1HNMR(300MHz，CDCl
3)δ3.85(s，3H)，3.94(s，3H)，6.95(d，J＝8.7，2H)，7.13(d，J＝8.8，1H)，7.29(s，1H)，7.53(d，J＝8.1，1H)，7.57(d，J＝8.8，2H)，7.71(d，J＝8.0，1H)；MS(EI)：m/e(％)310(15M
+)，264(85)，187(93)，164(100)，150(70)。
(11) (Z)-preparation of 3-(3-methoxyl group-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-11)
2-nitro-3-methoxybenzaldehyde and 4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-11, productive rate 43.4%.
1HNMR(300MHz，CDCl
3)δ3.85(s，3H)，3.94(s，3H)，6.95(d，J＝8.5，2H)，7.13(d，J＝8.3，1H)，7.29(s，1H)，7.53(d，J＝8.3，1H)，7.57(d，J＝8.8，2H)，7.71(d，J＝7.7，1H)；MS(EI)：m/e(％)310(10M
+)，166(100)，149(65)。
(12) (Z)-preparation of 3-(5-fluoro-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-12)
2-nitro-5-fluorobenzaldehyde and 4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-12, productive rate 91.2%.
1HNMR(300MHz，CDCl
3)δ3.87(s，3H)，6.97-7.03(m，3H)，7.30(d，J＝2.1，1H)，7.66(d，J＝8.9，2H)，7.97(s，1H)，8.24(d，J＝9.5，1H)；MS(EI)：m/e(％)298(32M
+)，137(97)，109(100)。
(13) (Z)-preparation of 2-(3-fluoro-4-p-methoxy-phenyl)-3-(4-methoxyl group-2-nitrophenyl)-vinyl cyanide (A-13)
2-nitro-4-methoxybenzaldehyde and 3-fluoro-4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-13, productive rate 95.3%.
1HNMR(300MHz，CDCl
3)δ3.94(s，3H)，3.95(s，3H)，7.02(t，J＝8.6，1H)，7.28(dd，J＝2.5，8.6，1H)，7.41-7.44(m，1H)，7.45-7.47(m，1H)，7.71(d，J＝2.7，1H)，7.85(s，1H)，7.88(d，J＝8.7，1H)；MS(EI)：m/e(％)328(96M
+)，311(100)，149(88)，122(90)。
(14) (Z)-preparation of 3-(3,5-dimethyl-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-14)
2-nitro-3,5-dimethylbenzaldehyde and 4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-14, productive rate 85.8%.
1HNMR(300MHz，CDCl
3)δ2.37(s，3H)，2.44(s，3H)，3.85(s，3H)，6.95(d，J＝8.7，2H)，7.17(s，1H)，7.37(s，1H)，7.53(d，J＝8.1，1H)，7.57(d，J＝9.0，2H)，7.69(s，1H)；MS(EI)：m/e(％)308(17M
+)，147(65)，119(100)。
(15) (Z)-preparation of 3-(2-nitrophenyl)-2-p-tolyl propene nitrile (A-15)
2-nitrobenzaldehyde and 4-methylbenzene acetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-15, productive rate 61.0%.
1HNMR(300MHz，CDCl
3)δ2.41(s，3H)，7.28(d，J＝7.9，2H)，7.59-7.65(m，3H)，7.78(t，J＝7.9，1H)，7.93(d，J＝7.7，1H)，8.00(s，1H)，8.23(dd，J＝1.4，8.2，1H)；MS(EI)：m/e(％)264(15M
+)，119(100)，92(97)。
(16) (Z)-preparation of 3-(2-nitrophenyl)-2-(3-trifluoromethyl)-vinyl cyanide (A-16)
2-nitrobenzaldehyde and 3-trifluoromethyl benzyl cyanide are undertaken by embodiment 1. (1) described methods, make compd A-16, productive rate 85.9%.
1HNMR(300MHz，CDCl
3)δ7.61-7.73(m，3H)，7.82(t，J＝7.4，1H)，7.91-7.95(m，3H)，8.12(s，1H)，8.29(dd，J＝1.1，8.2，1H)；MS(EI)：m/e(％)318(15M
+)，119(100)，92(77)。
(17) (z)-preparation of 3-(2-nitrophenyl) 2-(2-cyano-phenyl)-vinyl cyanide (A-17)
2-nitrobenzaldehyde and 2-cyano benzyl cyanide are undertaken by embodiment 1. (1) described methods, make compd A-17, productive rate 54.2%.
1HNMR(300MHz，CDCl
3)δ7.57-7.61(m，1H)，7.67-7.76(m，3H)，7.81-7.87(m，2H)，7.97(d，J＝7.8，1H)，8.13(s，1H)，8.30(dd，J＝0.9，8.2，1H)；MS(EI)：m/e(％)275(15M
+)，119(100)，92(84)。
(18) (Z)-preparation of 2-(4-xenyl)-3-(2-nitrophenyl)-vinyl cyanide (A-18)
2-nitrobenzaldehyde and 4-biphenyl acetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-18, productive rate 94.5%.
1HNMR(300MHz，CDCl
3)δ7.37-7.53(m，3H)，7.62-7.26(m，5H)，7.79-7.83(m，3H)，7.97(d，J＝7.7，1H)，8.10(s，1H)，8.26(dd，J＝1.3，8.3，1H)；MS(EI)：m/e(％)326(40M
+)，295(54)，119(100)，92(72)。
(19) (Z)-preparation of 2-(1-naphthyl)-3-(2-nitrophenyl)-vinyl cyanide (A-19)
2-nitrobenzaldehyde and 1-naphthalene acetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-19, productive rate 56.7%.
1HNMR(300MHz，CDCl
3)δ7.53-7.71(m，4H)，7.77-7.98(m，4H)，8.08-8.10(m，1H)，8.13(s，1H)，8.19-8.31(m，2H)；MS(EI)：m/e(％)300(80M
+)，119(100)，92(80)。
(20) (Z)-preparation of 3-(2-nitrophenyl)-2-(2-pyridyl)-vinyl cyanide (A-20)
2-nitrobenzaldehyde and 2-pyridyl acetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-20, productive rate 92.4%.
1HNMR(300MHz，CDCl
3)δ7.35-7.39(m，1H)，7.66(t，J＝7.8，1H)，7.77-7.88(m，3H)，7.95(d，J＝7.7，1H)，8.25(d，J＝8.2，1H)，8.70(d，J＝4.4，1H)，8.87(s，1H)；MS(EI)：m/e(％)205(100)，105(67)。
(21) (Z)-preparation of 3-(2-aminophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-21)
2-aminobenzaldehyde and 4-p-methoxybenzeneacetonitrile are undertaken by embodiment 1. (1) described methods, make compd A-21, productive rate 74.2%.
1HNMR(300MHz，CDCl
3)δ3.85(s，3H)，6.81(d，J＝8.0，1H)，6.91-6.96(m，3H)，7.23(dd，J＝1.4，8.0，1H)，7.50(s，1H)，7.62(d，J＝8.9，2H)，7.80(d，J＝7.3，1H)；MS(EI)：m/e(％)250(80M
+)，249(100)。
Embodiment 2
The preparation of the propionitrile compounds of structural formula B
(1) preparation of 3-(2-nitrophenyl)-2-phenyl propionitrile (B-1)
With 5.00g (20mmol) (Z)-3-(2-nitrophenyl)-2-phenyl-vinyl cyanide is dissolved in the 20mL anhydrous tetrahydro furan, adds 1.13g (30mmol) sodium borohydride under the ice-water bath, stirring at room in batches; Behind the no raw material of TLC monitoring, the 1mol/LHCl cancellation, concentrating under reduced pressure is removed tetrahydrofuran (THF), ethyl acetate extraction then, the saturated nacl aqueous solution washing, the organic phase anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure gets yellow solid 4.80g, productive rate 92.0%.Need not purifying and directly carry out next step reaction.
1HNMR(300MHz，CDCl
3)δ3.22(dd，J＝10.3，13.3，1H)，3.54(dd，J＝5.2，13.1，1H)，4.39(dd，J＝5.1，10.8，1H)，7.32-7.53(m，7H)，7.60-7.66(m，1H)，8.08(d，J＝8.1，1H)；MS(EI)：m/e(％)217(100)，136(97)，78(100)。
(2) preparation of 2-(4-p-methoxy-phenyl)-3-(2-nitrophenyl)-propionitrile (B-2)
(Z)-2-(4-p-methoxy-phenyl)-3-(2-nitrophenyl)-vinyl cyanide (A-2) reduces by embodiment 2. (1) described methods, makes compd B-2, productive rate 84.1%.
1HNMR(300MHz，CDCl
3)δ3.22(dd，J＝10.3，13.2，1H)，3.50(dd，J＝5.4，13.5，1H)，3.82(s，3H)，4.32(dd，J＝5.4，10.2，1H)，6.92(d，J＝8.9，2H)，7.35(d，J＝8.6，2H)，7.44(d，J＝7.8，1H)，7.49-7.51(m，1H)，7.59-7.64(m，1H)，8.07(d，J＝7.9，1H)；MS(EI)：m/e(％)282(7M
+)。
(3) preparation of 3-(4-methoxyl group-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-propionitrile (B-3)
(Z)-3-(4-methoxyl group-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-3) reduces by embodiment 2. (1) described methods, makes compd B-3, productive rate 100%.
1HNMR(300MHz，CDCl
3)δ3.15(dd，J＝10.3，13.5，1H)，3.43(dd，J＝5.2，13.2，1H)，3.82(s，3H)，3.88(s，3H)，4.28(dd，J＝5.3，10.1，1H)，6.92(d，J＝8.7，2H)，7.14(dd，J＝2.9，8.6，1H)，7.33(d，J＝8.3，1H)，7.34(d，J＝8.8，2H)，7.57(d，J＝2.7，1H)；MS(EI)：m/e(％)312(7M
+)，166(100)，146(85)。
(4) preparation of 3-(4,5-dimethoxy-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-propionitrile (B-4)
(Z)-3-(4,5-dimethoxy-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-4) reduces by embodiment 2. (1) described methods, makes compd B-4, productive rate 90.4%.
1HNMR(300MHz，CDCl
3)δ3.16(dd，J＝10.1，13.1，1H)，3.57(dd，J＝5.3，13.0，1H)，3.82(s，3H)，3.94(s，3H)，3.96(s，3H)，4.29(dd，J＝5.2，10.1，1H)，6.75(s，1H)，6.93(d，J＝8.6，2H)，7.37(d，J＝8.7，2H)，7.69(s，1H)；MS(EI)：m/e(％)342(3M
+)，196(100)，146(50)。
(5) preparation of 2-(4-fluorophenyl)-3-(4-methoxyl group-2-nitrophenyl)-propionitrile (B-5)
(Z)-2-(4-fluorophenyl)-3-(4-methoxyl group-2-nitrophenyl)-vinyl cyanide (A-5) reduces by embodiment 2. (1) described methods, makes compd B-5, productive rate 91.9%.
1HNMR(300MHz，CDCl
3)δ3.15(dd，J＝10.2，13.6，1H)，3.43(dd，J＝5.3，13.6，1H)，3.89(s，3H)，4.33(dd，J＝5.1，10.4，1H)，7.09(t，J＝8.5，2H)，7.15(dd，J＝2.8，8.5，1H)，7.33(d，J＝8.5，1H)，7.40-7.44(m，2H)，7.59(d，J＝2.6，1H)；MS(EI)：m/e(％)300(10M
+)，166(100)，108(35)。
(6) preparation of 3-(4-methoxyl group-2-nitrophenyl)-2-(4-methoxyl group-3-nitrophenyl)-propionitrile (B-6)
(Z)-3-(4-methoxyl group-2-nitrophenyl)-2-(4-methoxyl group-3-nitrophenyl)-vinyl cyanide (A-6) reduces by embodiment 2. (1) described methods, makes compd B-6, productive rate 76.9%.
1HNMR(300MHz，CDCl
3)δ3.17(dd，J＝10.6，13.4，1H)，3.45(dd，J＝5.3，13.5，1H)，3.89(s，3H)，3.99(s，3H)，4.37(dd，J＝5.2，10.6，1H)，7.13-7.19(m，2H)，7.35(d，J＝8.6，1H)，7.60(d，J＝2.6，1H)，7.65(dd，J＝2.4，8.7，1H)，7.90(d，J＝2.1，1H)；MS(EI)：m/e(％)357(5M
+)，166(100)，108(37)。
(7) preparation of 2-(4-p-methoxy-phenyl)-3-(2,3,4-trimethoxy-6-nitrophenyl)-propionitrile (B-7)
(Z)-2-(4-p-methoxy-phenyl)-3-(2,3,4-trimethoxy-6-nitrophenyl)-vinyl cyanide (A-7) reduces by embodiment 2. (1) described methods, makes compd B-7, productive rate 100%.
1HNMR(300MHz，CDCl
3)δ3.30(dd，J＝6.3，13.3，1H)，3.56(dd，J＝9.7，12.9，1H)，3.81(s，3H)，3.94(s，9H)，4.25(dd，J＝6.4，9.8，1H)，6.91(d，J＝8.6，2H)，7.33(d，J＝8.6，2H)，7.42(s，1H)；MS(EI)：m/e(％)372(10M
+)。
(8) preparation of 2-(5-benzo [1,3] dioxy base)-3-(4,5-dimethoxy-2-nitrophenyl)-propionitrile (B-8)
(Z)-2-(5-benzo [1,3] dioxy base)-3-(4,5-dimethoxy-2-nitrophenyl)-vinyl cyanide (A-8) reduces by embodiment 2. (1) described methods, makes compd B-8, productive rate 88.4%.
1HNMR(300MHz，CDCl
3)δ3.11(dd，J＝10.3，13.2，1H)，3.58(dd，J＝5.1，13.2，1H)，3.96(s，3H)，3.97(s，3H)，4.26(dd，J＝5.0，10.5，1H)，6.00(s，2H)，6.80-6.84(m，2H)，6.91-6.97(m，2H)，7.69(s，1H)；MS(EI)：m/e(％)356(5M
+)，196(100)。
(9) preparation of 2-(3, the 4-Dimethoxyphenyl)-3-(6-nitro-5-benzo [1,3] dioxy base)-propionitrile (B-9)
(Z)-2-(3, the 4-Dimethoxyphenyl)-3-(6-nitro-5-benzo [1,3] dioxy base)-vinyl cyanide (A-9) reduces by embodiment 2. (1) described methods, makes compd B-9, productive rate 92.7%.
1HNMR(300MHz，CDCl
3)δ3.07(dd，J＝10.5，13.2，1H)，3.57(dd，J＝5.0，13.2，1H)，3.90(s，3H)，3.93(s，3H)，4.30(dd，J＝4.9，10.4，1H)，6.15(s，2H)，6.85-6.90(m，2H)，6.95(d，J＝2.3，1H)，7.03(dd，J＝2.3，8.3，1H)，7.63(s，1H)；MS(EI)：m/e(％)356(5M
+)，176(100)。
(10) preparation of 3-(5-methoxyl group-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-propionitrile (B-10)
(Z)-3-(5-methoxyl group-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-10) reduces by embodiment 2. (1) described methods, makes compd B-10, productive rate 91.6%.
1HNMR(300MHz，CDCl
3)δ3.15(dd，J＝10.7，13.1，1H)，3.61(dd，J＝5.0，13.0，1H)，3.82(s，3H)，3.89(s，3H)，4.32(dd，J＝5.0，10.5，1H)，6.86(d，J＝2.7，1H)，690-6.92(m，1H)，6.93(d，J＝8.8，2H)，7.39(d，J＝8.7，2H)，8.18(d，J＝9.2，1H)；MS(EI)：m/e(％)312(3M
+)，146(100)。
(11) preparation of 3-(3-methoxyl group-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-propionitrile (B-11)
(Z)-3-(3-methoxyl group-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-11) reduces by embodiment 2. (1) described methods, makes compd B-11, productive rate 90.9%.
1HNMR(300MHz，CDCl
3)δ2.94(dd，J＝5.8，14.2，1H)，3.07(dd，J＝9.9，14.1，1H)，3.81(s，3H)，3.92(s，3H)，4.12(dd，J＝5.8，9.8，1H)，6.89(d，J＝8.6，2H)，6.94(d，J＝7.8，1H)，7.00(d，J＝8.2，1H)，7.24(d，J＝8.6，2H)，7.40(t，J＝8.2，1H)；MS(EI)：m/e(％)312(3M
+)，146(100)。
(12) preparation of 3-(5-fluoro-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-propionitrile (B-12)
(Z)-3-(5-fluoro-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-12) presses embodiment
2. (1) described method is reduced, and makes compd B-12, productive rate 84.0%.
1HNMR(300MHz，CDCl
3)δ3.12(dd，J＝10.4，12.8，1H)，3.62(dd，J＝4.7，13.0，1H)，3.82(s，3H)，4.33(dd，J＝4.7，10.5，1H)，6.85-6.90(m，2H)，6.93(d，J＝8.8，2H)，7.39(d，J＝8.7，2H)，8.17(d，J＝8.9，1H)；MS(EI)：m/e(％)300(10M
+)。
(13) preparation of 2-(3-fluoro-4-p-methoxy-phenyl)-3-(4-methoxyl group-2-nitrophenyl)-propionitrile (B-13)
(Z)-2-(3-fluoro-4-p-methoxy-phenyl)-3-(4-methoxyl group-2-nitrophenyl)-vinyl cyanide (A-13) reduces by embodiment 2. (1) described methods, makes compd B-13, productive rate 98.1%.
1HNMR(300MHz，CDCl
3)δ3.12(dd，J＝10.4，13.5，1H)，3.43(dd，J＝5.3，13.5，1H)，3.88(s，3H)，3.91(s，3H)，4.28(dd，J＝5.2，10.3，1H)，6.97(t，J＝8.6，1H)，7.13-7.15(m，1H)，7.16(d，J＝2.6，1H)，7.20(d，J＝2.1，1H)，7.33(d，J＝8.6，1H)，7.59(d，J＝2.7，1H)；MS(EI)：m/e(％)330(5M
+)，166(100)。
(14) preparation of 3-(3,5-dimethyl-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-propionitrile (B-14)
(Z)-3-(3,5-dimethyl-2-nitrophenyl)-2-(4-p-methoxy-phenyl)-vinyl cyanide (A-14) reduces by embodiment 2. (1) described methods, makes compd B-14, productive rate 100%.
1HNMR(300MHz，CDCl
3)δ2.33(s，3H)，2.35(s，3H)，2.94(dd，J＝5.8，14.0，1H)，3.01(dd，J＝10.1，13.9，1H)，3.82(s，3H)，4.15(dd，J＝5.7，9.7，1H)，6.91(d，J＝8.7，2H)，7.03(s，1H)，7.05(s，1H)，7.27(d，J＝8.8，2H)；MS(EI)：m/e(％)310(3M
+)，146(100)。
(15) preparation of 3-(2-nitro-phenyl)-2-p-methylphenyl propionitrile (B-15)
(Z)-3-(2-nitrophenyl)-2-p-tolyl propene nitrile (A-15) reduces by embodiment 2. (1) described methods, makes compd B-15, productive rate 91.3%.
1HNMR(300MHz，CDCl
3)δ2.39(s，3H)，3.20(dd，J＝10.5，13.2，1H)，3.52(dd，J＝4.8，13.2，1H)，4.34(dd，J＝4.9，10.5，1H)，7.21(d，J＝7.9，2H)，7.34(d，J＝8.4，2H)，7.45-7.53(m，2H)，7.63(t，J＝7.6，1H)，8.08(dd，J＝0.9，7.9，1H)；MS(EI)：m/e(％)366(3M
+)，130(100)。
(16) preparation of 3-(2-nitrophenyl)-2-(3-trifluoromethyl)-propionitrile (B-16)
(Z)-3-(2-nitrophenyl)-2-(3-trifluoromethyl)-vinyl cyanide (A-16) reduces by embodiment 2. (1) described methods, makes compd B-16, productive rate 100%.
1HNMR(300MHz，CDCl
3)δ3.24(dd，J＝10.8，13.1，1H)，3.56(dd，J＝5.0，13.2，1H)，4.49(dd，J＝5.0，10.3，1H)，7.46(d，J＝8.1，1H)，7.51-7.59(m，2H)，7.63-7.70(m，4H)，8.12(d，J＝7.9，1H)；MS(EI)：m/e(％)302(40M
+)，136(100)。
(17) preparation of 3-(2-nitrophenyl)-2-(2-cyano-phenyl)-propionitrile (B-17)
(Z)-3-(2-nitrophenyl)-2-(2-cyano-phenyl)-vinyl cyanide (A-17) reduces by embodiment 2. (1) described methods, makes compd B-17, productive rate 67.3%.
1HNMR(300MHz，CDCl
3)δ3.45(dd，J＝6.8，13.4，1H)，3.76(dd，J＝8.2，13.1，1H)，4.74(dd，J＝6.5，8.3，1H)，7.32(dd，J＝1.7，7.8，1H)，7.47-7.53(m，2H)，7.57(dd，J＝1.2，7.3，1H)，7.65-7.71(m，3H)，8.07(dd，J＝1.5，8.0，1H)；MS(EI)：m/e(％)136(100)。
(18) preparation of 2-(4-xenyl)-3-(2-nitrophenyl)-propionitrile (B-18)
(Z)-2-(4-xenyl)-3-(2-nitrophenyl)-vinyl cyanide (A-18) reduces by embodiment 2. (1) described methods, makes compd B-18, productive rate 100%.
1HNMR(300MHz，CDCl
3)δ3.25(dd，J＝10.5，13.2，1H)，3.59(dd，J＝4.9，13.2，1H)，4.44(dd，J＝4.9，10.5，1H)，7.35-7.41(m，1H)，7.44-7.56(m，6H)，7.58-7.66(m，5H)，8.10(d，J＝8.1，1H)；MS(EI)：m/e(％)328(5M
+)，192(100)。
(19) preparation of 2-(1-naphthyl)-3-(2-nitrophenyl)-propionitrile (B-19)
(Z)-2-(1-naphthyl)-3-(2-nitrophenyl)-vinyl cyanide (A-19) reduces by embodiment 2. (1) described methods, makes compd B-19, productive rate 99.0%.
1HNMR(300MHz，CDCl
3)δ3.41(dd，J＝10.0，13.2，1H)，3.73(dd，J＝6.1，13.2，1H)，5.17(dd，J＝6.1，9.7，1H)，7.26-7.44(m，1H)，7.45-7.52(m，2H)，7.54-7.64(m，3H)，7.75(dd，J＝1.1，7.0，1H)，7.90(t，J＝8.3，2H)，8.06(dd，J＝1.4，7.9，1H)，8.18(d，J＝8.7，1H)；MS(EI)：m/e(％)302(10M
+)，166(100)。
(20) preparation of 3-(2-nitrophenyl)-2-(2-pyridyl)-propionitrile (B-20)
(Z)-3-(2-nitrophenyl)-2-(2-pyridyl)-vinyl cyanide (A-20) reduces by embodiment 2. (1) described methods, makes compd B-20, productive rate 97.4%.
1HNMR(300MHz，CDCl
3)δ3.41-3.50(m，1H)，3.65-3.71(m，1H)，4.52-4.60(m，1H)，7.30-7.31(m，1H)，7.41-7.44(m，1H)，7.46-7.52(m，2H)，7.59-7.61(m，1H)，7.73-7.76(m，1H)，8.06(d，J＝7.9，1H)8.66-8.68(m，1H)；MS(EI)：m/e(％)207(100)。
(21) preparation of 3-(2-aminophenyl)-2-(4-p-methoxy-phenyl) propionitrile (B-21)
(Z)-3-(2-aminophenyl)-2-(4-p-methoxy-phenyl) vinyl cyanide (A-21) reduces by embodiment 2. (1) described methods, makes compd B-21, productive rate 100%.
1HNMR(300MHz，CDCl
3)δ2.97(dd，J＝7.0，14.2，1H)，3.17(dd，J＝7.7，14.1，1H)，3.81(s，3H)，4.10(dd，J＝7.1，12.7，1H)，6.65-6.70(m，1H)，6.72-6.78(m，1H)，6.86(d，J＝8.8，2H)，6.97(dd，J＝1.4，7.6，1H)，7.06-7.12(m，1H)，7.17(d，J＝8.3，2H)；MS(EI)：m/e(％)252(100)。
Embodiment 3: the preparation of series compound of the present invention
(1) 3-phenyl-1,2,3, the preparation of 4-tetrahydroquinoline (I-1)
0.20g (0.80mmol) 3-(2-nitrophenyl)-2-phenyl propionitrile is dissolved in the 5mL anhydrous tetrahydro furan, add 0.06g 10%Pd/C, room temperature catalytic hydrogenation 48h, filter, concentrating under reduced pressure is removed tetrahydrofuran (THF), silica gel column chromatography (ethyl acetate/petroleum ether, volume ratio 1/10) gets white solid 50mg, productive rate 30.1%.
1HNMR(300MHz，CDCl
3)δ2.99-3.03(m，2H)，3.12-3.20(m，1H)，3.35(t，J＝10.6，1H)，3.46-3.51(m，1H)，6.60(d，J＝8.3，1H)，6.65-6.70(m，1H)，7.01-7.07(m，2H)，7.23-7.29(m，3H)，7.33-7.38(m，2H)；MS(EI)：m/e(％)209(100M
+)。
(2) 3-(4-p-methoxy-phenyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-2)
Compd B-2 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-2, productive rate 36.1%.
1HNMR(300MHz，CDCl
3)δ2.96-2.99(m，2H)，3.10-3.20(m，1H)，3.30(t，J＝10.7，1H)，3.44-3.49(m，1H)，3.80(s，3H)，6.64-6.72(m，2H)，6.89(d，J＝9.0，2H)，6.91-7.03(m，2H)，7.18(d，J＝8.4，2H)；MS(EI)：m/e(％)239(100M
+)，121(75)。
(3) 7-methoxyl group-3-(4-p-methoxy-phenyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-3)
Compd B-3 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-3, productive rate 60.6%.
1HNMR(300MHz，CDCl
3)δ2.92-2.97(m，2H)，3.26-3.31(m，2H)，3.59-3.61(m，1H)，3.75(s，3H)，3.81(s，3H)，6.53(dd，J＝2.4，8.3，1H)，6.6(d，J＝2.2，1H)，6.89(d，J＝8.8，2H)，7.00(d，J＝8.5，1H)，7.19(d，J＝8.7，2H)；MS(EI)：m/e(％)269(100M
+)，148(55)。
(4) 6,7-dimethoxy-3-(4-p-methoxy-phenyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-4)
Compd B-4 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-4, productive rate 24.8%.
1HNMR(300MHz，CDCl
3)δ2.89-2.92(m，2H)，3.04-3.13(m，1H)，3.24(t，J＝10.6，1H)，3.38-3.41(m，1H)，3.80(s，3H)，3.81(s，3H)，3.85(s，3H)，6.20(s，1H)，6.57(s，1H)，6.89(d，J＝8.6，2H)，7.16(d，J＝8.9，2H)；MS(EI)：m/e(％)299(95M
+)，284(100)。
(5) 3-(4-fluorophenyl)-7-methoxyl group-1,2,3, the preparation of 4-tetrahydroquinoline (I-5)
Compd B-5 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-5, productive rate 57.1%.
1HNMR(300MHz，CDCl
3)δ2.89-2.92(m，2H)，3.07-3.17(m，1H)，3.28(t，J＝10.4，1H)，3.42-3.46(m，1H)，3.75(s，3H)，6.15-6.17(m，1H)，6.28(dd，J＝2.3，8.3，1H)，6.91(d，J＝8.2，1H)，6.99-7.05(m，2H)，7.17-7.21(m，2H)；MS(EI)：m/e(％)257(100M
+)，148(62)。
(6) preparation of 2-methoxyl group-5-(7-methoxyl group-3-(1,2,3, the 4-tetrahydric quinoline group))-aniline (I-6)
Compd B-6 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-6, productive rate 37.6%.
1HNMR(300MHz，CDCl
3)δ2.86-2.92(m，2H)，3.01-3.12(m，1H)，3.26(t，J＝11.0，1H)，3.44-3.49(m，1H)，3.75(s，3H)，3.83(s，3H)，6.30(d，J＝2.4，1H)，6.35(dd，J＝2.2，8.2，1H)，6.60-6,64(m，2H)，6.75(d，J＝7.9，1H)6.93(d，J＝8.2，1H)；MS(EI)：m/e(％)284(100M
+)，149(62)。
(7) 5,6,7-trimethoxy-3-(4-p-methoxy-phenyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-7)
Compd B-7 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-7, productive rate 24.8%.
1HNMR(300MHz，CDCl
3)δ2.60-2.68(m，1H)，3.01-3.12(m，2H)，3.20-3.24(m，1H)，3.40-3.46(m，1H)，3.86(s，3H)，3.88(s，3H)，3.90(s，3H)，3.91(s，3H)，6.08(s，1H)，6.88(d，J＝8.5，2H)，7.17(d，J＝8.8，2H)；MS(EI)：m/e(％)329(50M
+)，314(100)。
(8) 3-(5-benzo [1,3] dioxy base)-6,7-dimethoxy-1,2,3, the preparation of 4-tetrahydroquinoline (I-8)
Compd B-8 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-8, productive rate 13.8%.
1HNMR(300MHz，CDCl
3)δ2.85-2.93(m，2H)，3.05-3.14(m，1H)，3.18-3.25(m，1H)，3.41-3.44(m，1H)，3.85(s，3H)，3.89(s，3H)，5.94(s，2H)，6.28(s，1H)，6.57(s，1H)，6.68-6.80(m，3H)；MS(EI)：m/e(％)313(93M
+)，298(100)。
(9) 7-(3, the 4-Dimethoxyphenyl)-5,6,7, the preparation of 8-tetrahydrochysene-[1,3] dioxy [4,5-g] quinoline (I-9)
Compd B-9 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-9, productive rate 16.9%.
1HNMR(300MHz，CDCl
3)δ2.88-2.90(m，2H)，3.05-3.14(m，1H)，3.25(t，J＝10.5，1H)，3.40-3.42(m，1H)，3.87(s，3H)，3.92(s，3H)，5.83(s，2H)，6.23(s，1H)，6.52(s，1H)，6.77(dd，J＝1.9，10.3，2H)，6.83(d，J＝7.8，1H)；MS(EI)：m/e(％)313(100M
+)。
(10) 6-methoxyl group-3-(4-p-methoxy-phenyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-10)
Compd B-10 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-10, productive rate 22.2%.
1HNMR(300MHz，CDCl
3)δ3.00-3.08(m，2H)，3.28-3.40(m，2H)，3.58-3.64(m，1H)，3.76(s，3H)，3.80(s，3H)，6.66-6.76(m，2H)，6.88(d，J＝8.8，2H)，7.06-7.10(m，1H)，7.18(d，J＝8.9，2H)；MS(EI)：m/e(％)269(30M
+)，149(100)，115(100)。
(11) 8-methoxyl group-3-(4-p-methoxy-phenyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-11)
Compd B-11 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-11, productive rate 47.7%.
1HNMR(300MHz，CDCl
3)δ2.96-2.99(m，2H)，3.07-3.18(m，1H)，3.29(t，J＝10.6，1H)，3.49-3.55(m，1H)，3.80(s，3H)，3.84(s，3H)，6.60-6.70(m，3H)，6.88(d，J＝8.8，2H)，7.18(d，J＝8.6，2H)；MS(EI)：m/e(％)269(100M
+)，121(85)。
(12) 6-fluoro-3-(4-p-methoxy-phenyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-12)
Compd B-12 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-12, productive rate 31.9%.
1HNMR(300MHz，CDCl
3)δ2.93-2.96(m，2H)，3.02-3.15(m，1H)，3.26(t，J＝10.5，1H)，3.40-3.45(m，1H)，3.80(s，3H)，6.47-6.55(m，1H)，6.71-6.76(m，2H)，6.88(d，J＝8.5，2H)，7.15(d，J＝8.9，2H)；MS(EI)：m/e(％)257(100M
+)，121(90)。
(13) 3-(3-fluoro-4-p-methoxy-phenyl)-7-methoxyl group-1,2,3, the preparation of 4-tetrahydroquinoline (I-13)
Compd B-13 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-13, productive rate 50.9%.
1HNMR(300MHz，CDCl
3)δ2.87-2.91(m，2H)，3.06-3.16(m，1H)，3.26(t，J＝10.7，1H)，3.43-3.48(m，1H)，3.75(s，3H)，3.88(s，3H)，6.20(d，J＝2.5，1H)，6.31(dd，J＝2.5，8.2，1H)，6.88-6.92(m，1H)，6.94-6.99(m，3H)；MS(EI)：m/e(％)287(100M
+)。
(14) 3-(4-p-methoxy-phenyl)-6,8-dimethyl-1,2,3, the preparation of 4-tetrahydroquinoline (I-14)
Compd B-14 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-14, productive rate 63.0%.
1HNMR(300MHz，CDCl
3)δ2.14(s，1H)，2.21(s，1H)，2.92-2.98(m，2H)，3.06-3.16(m，1H)，3.30(t，J＝10.8，1H)，3.52-5.56(m，1H)，3.80(s，3H)，6.74(s，1H)，6.77(s，1H)，6.89(d，J＝8.9，2H)，7.17(d，J＝8.6，2H)；MS(EI)：m/e(％)267(100M
+)。
(15) 3-p-methylphenyl-1,2,3, the preparation of 4-tetrahydroquinoline (I-15)
Compd B-15 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-15, productive rate 60.7%.
1HNMR(300MHz，CDCl
3)δ2.34(s，3H)，2.97-3.01(m，2H)，3.08-3.20(m，1H)，3.32(t，J＝10.8，1H)，3.45-3.48(m，1H)，6.60-6.71(m，2H)，6.71-7.05(m，2H)，7.15(s，4H)；MS(EI)：m/e(％)223(100M
+)。
(16) 3-(3-trifluoromethyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-16)
Compd B-16 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-16, productive rate 48.4%.
1HNMR(300MHz，CDCl
3)δ3.01-3.03(m，2H)，3.18-3.28(m，1H)，3.36(t，J＝10.6，1H)，3.47-3.51(m，1H)，6.59(d，J＝8.0，1H)，6.65-6.71(m，1H)，7.01-7.06(m，2H)，7.44-7.46(m，2H)，7.48-7.53(m，2H)；MS(EI)：m/e(％)277(100M
+)。
(17) 3-(2-cyano-phenyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-17)
Compd B-17 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-17, productive rate 7.1%.
1HNMR(300MHz，CDCl
3)δ2.98-3.12(m，2H)，3.33-3.41(m，1H)，3.50-3.56(m，1H)，3.59-3.69(m，1H)，6.60(d，J＝8.3，1H)，6.65-6.70(m，1H)，7.01-7.05(m，2H)，7.25-7.35(m，2H)，7.52-7.66(m，2H)；MS(EI)：m/e(％)234(100M
+)。
(18) 3-(4-xenyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-18)
Compd B-18 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-18, productive rate 57.0%.
1HNMR(300MHz，CDCl
3)δ3.04-3.07(m，2H)，3.18-3.29(m，1H)，3.39(t，J＝10.6，1H)，3，51-3.63(m，1H)，6.63-6.73(m，2H)，7.03-7.07(m，2H)，7.31-7.36(m，3H)，7.41-7.46(m，2H)，7.56-7.60(m，4H)；MS(EI)：m/e(％)285(43M
+)，167(100)。
(19) preparation of 3-(1-naphthyl)-tetrahydroquinoline (I-19)
Compd B-19 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-19, productive rate 20.7%.
1HNMR(300MHz，CDCl
3)δ2.98-3.12(m，2H)，3.18-3.35(m，2H)，4.92-4.97(m，1H)，6.74-6.81(m，2H)，7.04-7.13(m，2H)，7.44-7.57(m，3H)，7.66(dd，J＝1.0，7.1，1H)，7.78-7.92(m，2H)，8.03-8.07(m，1H)；MS(EI)：m/e(％)259(100M
+)。
(20) 3-(2-pyridyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-20)
Compd B-20 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-20, productive rate 54.5%.
1HNMR(300MHz，CDCl
3)δ3.04-3.21(m，2H)，3.37-3.42(m，1H)，3.49-3.62(m，2H)，6.55(d，J＝7.7，1H)，6.65(t，J＝7.4，1H)，6.99-7.04(m，2H)，7.18-7.22(m，1H)，7.25-7.27(m，1H)，7.67(t，J＝7.7，1H)，7.59(d，J＝4.9，1H)；MS(EI)：m/e(％)210(100M
+)。
(21) 3-(4-p-methoxy-phenyl)-1,2,3, the preparation of 4-tetrahydroquinoline (I-2)
Compd B-21 carries out catalytic hydrogenation by embodiment 3. (1) described methods, makes Compound I-2, productive rate 52.5%.
1HNMR(300MHz，CDCl
3)δ2.96-2.99(m，2H)，3.10-3.20(m，1H)，3.30(t，J＝10.7，1H)，3.44-3.49(m，1H)，3.80(s，3H)，6.64-6.72(m，2H)，6.89(d，J＝9.0，2H)，6.91-7.03(m，2H)，7.18(d，J＝8.4，2H)；MS(EI)：m/e(％)239(100M
+)，121(75)。
Claims (9)
1, a class have that the 3-of following general structure I replaces 1,2,3, the 4-tetrahydroquinoline derivative:
Wherein, R
1, R
2, R
3And R
4H, C respectively do for oneself
1-C
6Alkyl, C
1-C
6Alkoxyl group, halogen or adjacent R
1With R
2, R
2With R
3, or R
3With R
4Link to each other and constitute alkylene dioxo base;
Ar is an aryl.
2,1,2,3 of 3-replacement according to claim 1, the 4-tetrahydroquinoline derivative is characterized in that, described aryl is phenyl, fused ring aryl or the heterocyclic aryl of various replacements, and these aryl are selected from H, phenyl, C arbitrarily
1-C
6Alkyl, C
1-C
6One or more substituting groups in alkoxyl group or adjacent alkylene dioxo base, amido, halogen, cyano group and the trihalogenmethyl replace.
3,1,2,3 of 3-replacement according to claim 1, the 4-tetrahydroquinoline derivative is characterized in that, described R
1, R
2, R
3And R
4Respectively do for oneself H, methyl, methoxyl group or fluorine.
4,1,2,3 of 3-replacement according to claim 1, the 4-tetrahydroquinoline derivative is characterized in that, 1 of described 3-replacement, 2,3, the 4-tetrahydroquinoline derivative is a 3-phenyl-1,2,3, the 4-tetrahydroquinoline, 3-(4-p-methoxy-phenyl)-1,2,3, the 4-tetrahydroquinoline, 7-methoxyl group-3-(4-p-methoxy-phenyl)-1,2,3, the 4-tetrahydroquinoline, 6,7-dimethoxy-3-(4-p-methoxy-phenyl)-1,2,3, the 4-tetrahydroquinoline, 3-(4-fluorophenyl)-7-methoxyl group-1,2,3, the 4-tetrahydroquinoline, (7-methoxyl group-3-(1,2,3 for 2-methoxyl group-5-, the 4-tetrahydric quinoline group))-aniline, 5,6,7-trimethoxy-3-(4-p-methoxy-phenyl)-1,2,3, the 4-tetrahydroquinoline, 3-(5-benzo [1,3] dioxy base)-6,7-dimethoxy-1,2,3, the 4-tetrahydroquinoline, 7-(3, the 4-Dimethoxyphenyl)-5,6,7,8-tetrahydrochysene-[1,3] dioxy [4,5-g] quinoline, 6-methoxyl group-3-(4-p-methoxy-phenyl)-1,2,3, the 4-tetrahydroquinoline, 8-methoxyl group-3-(4-p-methoxy-phenyl)-1,2,3, the 4-tetrahydroquinoline, 6-fluoro-3-(4-p-methoxy-phenyl)-1,2,3, the 4-tetrahydroquinoline, 3-(3-fluoro-4-p-methoxy-phenyl)-7-methoxyl group-1,2,3, the 4-tetrahydroquinoline, 3-(4-p-methoxy-phenyl)-6,8-dimethyl-1,2,3, the 4-tetrahydroquinoline, 3-p-methylphenyl-1,2,3, the 4-tetrahydroquinoline, 3-(3-trifluoromethyl)-1,2,3, the 4-tetrahydroquinoline, 3-(2-cyano-phenyl)-1,2,3, the 4-tetrahydroquinoline, 3-(4-xenyl)-1,2,3, the 4-tetrahydroquinoline, 3-(1-naphthyl)-tetrahydroquinoline, or 3-(2-pyridyl)-1,2,3, the 4-tetrahydroquinoline.
5,1,2,3 of any described 3-replacement of a kind of claim 1-4, the synthetic method of 4-tetrahydroquinoline derivative, synthetic route is as follows:
Or
This synthetic method comprises: under alkaline condition, the Ortho Nitro Benzaldehyde of replacement or o-Aminobenzaldehyde and aryl acetonitrile derivative are condensed into the acrylonitrile compound of structural formula A; The acrylonitrile compound of this structural formula A is reduced into the propionitrile compounds of structural formula B through double bond reduction reaction; Then generate 1,2,3 of 3-replacement, 4-tetrahydroquinoline derivative at catalytic hydrogenation condition ShiShimonoseki ring.
6, synthetic method according to claim 5, it is characterized in that, be condensed in the acrylonitrile compound of structural formula A at the Ortho Nitro Benzaldehyde that replaces or o-Aminobenzaldehyde and aryl acetonitrile derivative, used alkali is salt of wormwood, organic amine, sodium alkoxide or potassium alcoholate; The consumption of alkali is the mol ratio of the 10%-100% of arbitrary reactant.
7, synthetic method according to claim 5, it is characterized in that, the acrylonitrile compound of structural formula A is reduced into the propionitrile compounds of structural formula B, the used original reagent of going back is sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride or zinc powder/ammonium formate, and its consumption is the mol ratio of the 50%-150% of structural formula A compound amount; Reaction solvent is methyl alcohol, ethanol, tetrahydrofuran (THF) or acetonitrile.
8, synthetic method according to claim 5 is characterized in that, the catalyzer of described catalytic hydrogenation is Pd/C, Pd (OH)
2/ C, Rh/C, Ni or Pt; Catalyst consumption is the 5%-30% mass ratio of structural formula B compound; Temperature of reaction is at 20～120 ℃.
9, a kind of claim 1-4 arbitrarily-a described 3-replace 1,2,3, the purposes of 4-tetrahydroquinoline derivative in the medicine of preparation treatment cerebral ischemia disease.
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