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CN101367761B - 6,7- substituted-2,2,4-trimethyl-tetrahydroquinoline-1-carboxylic acid aryl amide, synthesis and uses thereof - Google Patents

6,7- substituted-2,2,4-trimethyl-tetrahydroquinoline-1-carboxylic acid aryl amide, synthesis and uses thereof Download PDF

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CN101367761B
CN101367761B CN2008102003935A CN200810200393A CN101367761B CN 101367761 B CN101367761 B CN 101367761B CN 2008102003935 A CN2008102003935 A CN 2008102003935A CN 200810200393 A CN200810200393 A CN 200810200393A CN 101367761 B CN101367761 B CN 101367761B
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carboxylic acid
trimethylammonium
aryl amide
acid aryl
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CN101367761A (en
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郑卫红
袁钧瑛
袁承业
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention relates to a 6, 7-substituted-2, 2, 4-trimethyl-tetrahydro quinoline-1-carboxylic aryl amide compound, a preparation method thereof and usage for preparing a medicine which can prevent cell procedural necrosis. And the compound has a structural formula as below, wherein, R1 is hydrogen, C1-4 linear chain alkyl or C1-4 alkoxyl; R2 is hydrogen or C1-4 linear chain alkyl; R3 is hydrogen, single substituted or double substituted C1-4 alkyl, C1-4 alkoxyl, halogen, acetyl or nitryl.

Description

6,7-replaces-2,2,4-trimethylammonium-tetrahydroquinoline-1-carboxylic acid aryl amide, synthetic method and purposes
Technical field
The present invention relates to a kind of organic compound 6,7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide, simple synthesis and purposes.
Background technology
6,7-replaces-2,2, and 4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide might be that a class potential suppresses the downright bad active lead compound structure of programmed cell, can develop into useful medicine, and its structural formula is as follows:
Figure G2008102003935D00011
But the synthetic method of target compound finds no reported in literature through SciFinder system and other literature searches.
Have 6 in the document, 7-replaces-2,2, the report of 4-trimethyldihydroquinoline-1-carboxylic acid aryl amide ([1] Cliffe, W.H.J.Chem.Soc.19331327.): with 2,2,4-trimethylammonium-dihydroquinoline and aromatic isocyanate reflux to react in 4 hours in dry diethyl ether and obtain.Because the condition of aether backflow has been used in this reaction, there is certain danger when enlarging reaction, so people also wish to obtain more gentle reaction, obtain 6 simultaneously, 7-replaces-2,2, the 4-trimethylammonium tetrahydroquinoline-useful medicine of 1-carboxylic acid aryl amide one class.
Summary of the invention
The purpose of this invention is to provide a kind ofly 6,7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide compound.
It is a kind of above-mentioned 6 that purpose of the present invention also provides, and 7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide simple synthesis.
Another object of the present invention provides a kind of last 6, and 7-replaces-2,2, the purposes of 4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide.
Of the present invention 6,7-replaces-2,2, and 4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide compound has following structural formula:
Figure G2008102003935D00021
R wherein 1=hydrogen, C 1-4Straight chained alkyl or C 1-4Alkoxyl group; R 2=hydrogen or C 1-4Straight chained alkyl; R 3=hydrogen, the single replacement or disubstituted C 1-4Alkyl, C 1-4Alkoxyl group, halogen, ethanoyl or nitro etc.
Method of the present invention is under room temperature (rt), 6,7-replaces-2,2, in the organic solvent (solvent) of 4-trimethylammonium tetrahydrochysene (or dihydro) quinoline (1) and aromatic isocyanate, every mole 6,7-replaces-2,2,4-dimethylamino pyridine (DMAP) that 4-trimethylammonium tetrahydrochysene (or dihydro) quinoline (1) adds the 0.05-0.2 mole is as promptly generating target product 6 in catalyst reaction 1-5 hour, 7-replaces-2,2,4-trimethylammonium tetrahydrochysene (or dihydro) quinoline-1-carboxylic acid aryl amide (2).Reaction formula is as follows:
Figure G2008102003935D00022
Method one
R wherein 1And R 2As previously mentioned;---be singly-bound or do not have key.When---when being singly-bound, reaction formula is by 6, and 7-replaces-2,2, and 4-trimethyldihydroquinoline (1) and aromatic isocyanate reaction generate product 6, and 7-replaces-2,2,4-trimethyldihydroquinoline-1-carboxylic acid aryl amide; When---when being no key, be by 6,7-replaces-2,2, and 4-trimethylammonium tetrahydroquinoline (1) and aromatic isocyanate reaction generate product 6, and 7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide.
Described solvent as acetone, ether, tetrahydrofuran (THF), methylene dichloride or toluene etc., is recommended as methylene dichloride for organic solvent commonly used;
Described 6,7-replaces-2,2, and the molar ratio of 4-trimethylammonium tetrahydrochysene (dihydro) quinoline and isocyanic ester is 1:1～3, is recommended as 1:2.
Adopt method of the present invention to synthesize 15 compounds 6,7-replaces-2,2, and 4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide (2) typical consequence sees Table 1.
Sequence number Compound Substituting group (R 1) Substituting group (R 2) Productive rate (%)
1 2a 6-Me 4-OMe 58
2 2b 6-Me 4-F 77
3 2c 6-Me 4-Cl 84
4 2d 6-Me 2-OMe 93
5 2e 6-Me 2，4-Cl 2 67
6 2f 6-Me 3-F 80
7 2g 6，7-Me 2 4-Cl 65
8 2h 6，7-Me 2 4-OMe 65
9 2i 6，7-Me 2 2，4-Cl 2 79
10 2j 6-F 4-OMe 85
11 2k 6-H 4-Cl 80
12 21 6-H 4-Me 70
13 2m 6-H 4-NO 2 90
14 2n 6-H 4-OMe 78
15 2o 6-OMe 4-H 75
Experimental technique reaction conditions gentleness of the present invention, the reaction times is short, and productive rate is higher, and for 2,2,4-trimethyldihydroquinoline substrate can prepare by method two.Wherein, 6,7-replaces-2,2,4-trimethyldihydroquinoline-1-carboxylic acid aryl amide obtains 6 by the Pd/C hydrogenation, and 7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide is under room temperature and hydrogen, with Pd/C catalyst 6,7-replaces-2,2,4-trimethyldihydroquinoline-1-carboxylic acid aryl amide reaction obtained 6 in 1～5 hour, 7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide; Described 6,7-replaces-2,2, and the mol ratio of 4-trimethyldihydroquinoline-1-carboxylic acid aryl amide and Pd/C catalyzer is 1:0.05-1:0.2.
Method two
Compound of the present invention can be used to prepare the medicine of the procedural necrosis of anti-cell, can be used for the treatment of the medicine of apoplexy, cancer.The for example 2a of following structural formula of the present invention and 2c
Figure G2008102003935D00041
To N-(p-methoxyphenyl)-2,2,4,6-tetramethyl--3,4-dihydroquinoline-1 (2H))-and acid amides and N-(rubigan)-2,2,4,6-tetramethyl--3,4-dihydroquinoline-1 (2H))-the amide compound measurement result, the activity (necroptosis) of their the procedural necrosis of anti-cell is respectively EC 50=1.40 μ M and 1.36 μ M.
Embodiment
Following embodiment will help further to understand the present invention, but can not limit content of the present invention.
Embodiment 16, and 7-replaces-2,2, the preparation of 4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide compound
Figure G2008102003935D00042
The ordinary test operation:
In the single port bottle of dry 25mL, add 2mmol phenylcarbimide and 6mg4-dimethylamino pyridine (DMAP) in the 5mL dichloromethane solution of 1mmol tetrahydroquinoline substrate 1 successively.System stirring at room reaction under nitrogen protection finished in 1 hour, had small amount of solid to produce in the system.Remove on Rotary Evaporators and desolvate, resistates adds the 15mL anhydrous diethyl ether, and vibration is filtered, and solid is washed with the 5mL anhydrous diethyl ether.Rapid column chromatography purifying after the filtrate that merges is removed on Rotary Evaporators and desolvated (eluent: methylene dichloride/sherwood oil=1:1)
N-(p-methoxyphenyl)-2,2,4,6-tetramethyl--3,4-dihydroquinoline-1 (2H))-acid amides (2a)
Productive rate 58%, white solid, m.p.115-116 ℃
1H?NMR(300MHz?CDCl 3)：δ1.33(m，4H)，1.57(s，3H)，1.65(s，3H)，1.87(dd，1H，J 1＝3.0Hz，J 2＝12.9Hz)，2.34(s，3H)，2.73-2.79(m，1H)，3.77(s，3H)，6.99(brs，1H，-NH-)，6.82(d，2H，J＝8.7Hz)，6.94-6.97(m，1H)，7.02(d，2H，J＝8.7Hz)，7.24-7.27(m，2H)；ESIMS：393([M+MeOH+Na] +)，361([M+Na] +)，339([M+H]+)，190；
Ultimate analysis theoretical value C 21H 26N 2O 2: C, 74.53; H, 7.74; N, 8.28. measured value: C, 74.09; H, 7.68; N, 8.15.
N-(to fluorophenyl)-2,2,4,6-tetramethyl--3,4-dihydroquinoline-1 (2H))-acid amides (2b)
Productive rate 77%
1H?NMR(300MHz?CDCl 3)：δ1.31-1.35(m，4H)，1.58(s，3H)，1.66(s，3H)，1.88(dd，1H，J 1＝2.7Hz，J 2＝12.9Hz)，2.35(s，3H)，2.73-2.79(m，1H)，6.99(brs，1H，-NH-)，6.93-7.02(m，5H)，7.26-7.31(m，2H)；
ESIMS：381([M+MeOH+Na] +)，349([M+Na] +)，327([M+H] +)，190；
IR(KBr，cm -1)：3293，2956，2928，1656，1510，1499，1314，1211，833，808；
Ultimate analysis theoretical value C 20H 23N 2O:C, 73.59; H, 7.10; N, 8.58. measured value: C, 73.63; H, 7.32; N, 8.56.
N-(rubigan)-2,2,4,6-tetramethyl--3,4-dihydroquinoline-1 (2H))-acid amides (2c)
Productive rate 84%, white solid, m.p.144-145 ℃
1HNMR(300MHz?CDCl 3)：δ1.31-1.35(m，4H)，1.56(s，3H)，1.66(s，3H)，1.88(dd，1H，J 1＝2.7Hz，J 2＝12.9Hz)，2.34(s，3H)，2.73-2.79(m，1H)，6.59(brs，1H，-NH-)，6.98-7.02(m，3H)，7.20-7.30(m，4H)；
ESIMS：397([M+MeOH+Na] +)，365([M+Na] +)，343([M+H] +)，190；
IR(KBr，cm -1)：3280，2966，2930，1681，1654，1520，1492，1314，1240，1098，830，808；
Ultimate analysis theoretical value C 20H 23ClN 2O:C, 70.06; H, 6.76; N, 8.17. measured value: C, 69.77; H, 6.60; N, 7.87.
N-(guaiacyl)-2,2,4,6-tetramethyl--3,4-dihydroquinoline-1 (2H))-acid amides (2d)
Productive rate 93%,
1HNMR(300MHz?CDCl 3)：δ1.33-1.35(m，4H)，1.58(s，3H)，1.68(s，3H)，1.87(dd，1H，J 1＝2.7Hz，J 2＝12.9Hz)，2.34(s，3H)，2.76-2.82(m，1H)，3.67(s，3H)，6.77-6.80(m，1H)，6.91-6.96(m，3H)，6.98(m，1H)，7.07-7.10(m，1H)，7.40(brs，1H，-NH-)，8.22-8.26(m，1H)；
ESIMS：361([M+Na] +)，339([M+H] +)；
IR(KBr，cm -1)：3417，2962，2932，1683，1601，1518，1459，1305，1029，822，806；
Ultimate analysis theoretical value C 21H 26N 2O 2: C, 74.53; H, 7.74; N, 8.28. measured value: C, 74.60; H, 7.83; N, 8.20.
N-(2,4 dichloro benzene base)-2,2,4,6-tetramethyl--3,4-dihydroquinoline-1 (2H))-acid amides (2e)
Productive rate 67%,
1H?NMR(300MHz?CDCl 3)：δ1.22-1.26(m，4H)，1.48(s，3H)，1.61(s，3H)，1.79(dd，1H，J 1＝2.7Hz，J 2＝12.9Hz)，2.26(s，3H)，2.68-2.74(m，1H)，3.78(s，3H)，6.87-6.90(m，1H)，6.94(s，1H，-NH-)，7.01(d，1H，J＝7.5Hz)，7.11(dd，1H，J 1＝2.4Hz，J 2＝8.7Hz)，7.16-7.19(m，2H)，8.24(d，1H，J＝9.0Hz)；
13C?NMR(400MHz?CDCl 3)：δ17.1，21.1，26.1，28.5，28.8，52.2，58.3，120.9，122.4，123.7，124.4，127.0，127.6，128.4，134.0，134.6，135.8，140.1，153.8
EIMS：378(12.60)，377(3.21)，376(M +，17.10)，189(18.90)，174(100，base)，159(16.09)，160(61.13)，142(16.80)；
HRMS (EI): theoretical value C 20H 22N 2OCl 2: 376.1109; Measured value: 376.1106;
IR(KBr，cm -1)：3403，2964，2929，1687，1508，1307，1246，1223，810.
Embodiment 26, and 7-replaces-2,2, the preparation of 4-trimethyldihydroquinoline-1-carboxylic acid aryl amide compound:
Method only replaces the tetrahydroquinoline substrate with corresponding dihydroquinoline substrate with embodiment 1, and reaction product and analytical results are as follows:
N-(adjacent fluorophenyl)-2,2,4,6-tetramethyl--3,4-dihydroquinoline-1 (2H))-acid amides (2f)
1H?NMR(DMSO-d6，300MHz)δ：9.15(s，1H)，
6.73-7.30(m，8H)，2.62-2.78(m，1H)，2.27(s，3H)，1.93(dd，J＝3.9，12.9Hz，1H)，1.46(d，J＝8.4Hz，1H)，1.21-1.36(m，4H)；
MS(EI)m/z(％)：326(M +，91)，327(22)，311(8)，189(11)，174(100)，160(45)；
IR(KBr)v：3428，3339，2964，2931，1685，1616，1600，1524，1492，1439，1309；
HRMS (MALDI) theoretical value C 20H 24NO 2F +(M+H +): 327.1867, measured value 327.1881
N-(rubigan)-2,2,4,6,7-pentamethyl--3,4-dihydroquinoline-1 (2H))-acid amides (2g)
Productive rate 65%, white solid, m.p.151-152 ℃
1H?NMR(300MHz?CDCl 3)：δ1.30-1.34(m，4H)，1.56(s，3H)，1.65(s，3H)，1.87(dd，1H，J 1＝3.0Hz，J 2＝12.9Hz)，2.18(s，3H)，2.26(s，3H)，2.72-2.77(m，1H)，6.62(brs，1H，-NH-)，6.88(s，1H)，6.97(s，1H)，7.22(d，2H，J＝8.7Hz)，7.29(d，2H，J＝8.7Hz)；
EIMS：357([M] +，1.46)，356(4.45)，203(22.54)，188(100，base)，189(15.03)，174(23.52)，153(23.42)；
IR(KBr，cm -1)：3290，2964，2928，1682，1654，1525，1492，1396，1313，1239，830；
Ultimate analysis theoretical value C 21H 25ClN 2O:C, 70.67; H, 7.06; N, 7.85. measured value: C, 70.65; H, 7.09; N, 7.82.
N-(p-methoxyphenyl)-2,2,4,6,7-pentamethyl--3,4-dihydroquinoline-1 (2H))-acid amides (2h)
Productive rate 65%, white solid, m.p.130-131 ℃
1HNMR(300MHz?CDCl 3)：δ1.31-1.33(m，4H)，1.57(s，3H)，1.64(s，3H)，1.86(dd，1H，J 1＝3.0Hz，J 2＝12.9Hz)，2.19(s，3H)，2.25(s，3H)，2.72-2.77(m，1H)，3.78(s，3H)，6.55(brs，1H，-NH-)，6.83(d，2H，J＝9.0Hz)，6.94(d，2H，J＝8.7Hz)，7.25(s，1H)，7.27(s，1H)；
EIMS：352([M] +，33.12)，203(27.40)，188(100，base)，189(15.10)，174(27.00)，149(25.80)，134(14.33)；
IR(KBr，cm -1)：3308，2931，1677，1657，1532，1510，1248，1238，838；
Ultimate analysis theoretical value C 22H 28N 2O 2: C, 74.97; H, 8.01; N, 7.95. measured value: C, 75.25; H, 8.00; N, 7.86.
N-(2,4 dichloro benzene base)-2,2,4,6,7-pentamethyl--3,4-dihydroquinoline-1 (2H))-acid amides (2i)
Productive rate 79%, white solid, m.p.128-129 ℃
1H?NMR(300MHz?CDCl 3)：δ1.29-1.33(m，4H)，1.57(s，3H)，1.70(s，3H)，1.86(dd，1H，J 1＝2.7Hz，J 2＝12.9Hz)，2.19，(s，3H)，2.26(s，3H)，2.73-2.81(m，1H)，6.97(s，1H)，7.01(s，1H)，7.21(dd，1H，J1＝2.7Hz，J2＝8.7Hz)，7.26-7.28(m，1H)，7.40(brs，1H，-NH-)，8.35(d，1H，J＝9.0Hz)；
EIMS：392([M+H] +，12.42)，391(M +，6.95)，390(20.20)，189(20.12)，188(100，base)，174(74.37)，172(17.52)，156(16.34)，41(13.53)，
IR (KBr, cm -1): 3403,2958,2921,1685,1574,1507,1314,1304,1245,1230,811; Anal.Caled for C 21H 24Cl 2N 2O:C, 64.45; H, 6.18; N, 7.16. measured value: C, 64.36; H, 6.25; N, 6.91.
N-(p-methoxyphenyl)-6-fluoro-2,2,4-trimethylammonium-3,4-dihydroquinoline-1 (2H))-acid amides (2j)
1H?NMR(300MHz?CDCl 3)：δ1.32-1.34(m，4H)，1.56(s，3H)，1.66(s，3H)，1.86(d，1H，J 2＝13.2Hz)，2.73-2.84(m，1H)，3.77(s，3H)，6.40(s，1H)，6.83(d，2H，J＝8.7Hz)，6.87-6.94(m，2H)，7.06-7.11(m，1H)，7.24(d，2H，J＝8.7Hz).
N-(rubigan)-2,2,4 ,-trimethylammonium-3,4-dihydroquinoline-1 (2H))-acid amides (2k)
1H?NMR(DMSO-d6，300MHz)δ：9.34(s，1H)，7.47
(d，J＝7.2Hz，2H)，7.39(d，J＝9.3Hz，2H)，7.20(d，J＝7.5Hz，1H)，7.06(t，J＝7.8Hz，1H)，6.95(d，J＝7.5Hz，1H)，2.65-2.84(m，1H)，1.93(dd，J＝3.9，12.9Hz，1H)，1.43(s，6H)，1.23-1.39(m，4H)；
MS(EI)m/z：328(14)，330(5)，160(100)，146(98)；
IR(KBr)v：3420，2956，2873，1689，1590，1516，1494，1484，1313cm-1；
HRMS (MA1DI) theoretical value C 19H 22N 2OCl +(M+H +): 329.1415, measured value: 329.1441.
N-(p-methylphenyl)-2,2,4 ,-trimethylammonium-3,4-dihydroquinoline-1 (2H))-acid amides (2l)
1H?NMR(DMSO-d6，300MHz)δ：9.20(s，1H)，6.72-7.35(m，8H)，3.32(s，3H)，2.75-2.83(m，1H)，2.22(s，3H)，1.88(dd，J＝4.5，10.2Hz，1H)，1.40(d，J＝4.2Hz，6H)，1.21-1.32(m，4H)；
ESIMS?m/z：309(M+H+).
N-(p-nitrophenyl)-2,2,4-trimethylammonium-3,4-dihydroquinoline-1 (2H))-acid amides (2m)
1H?NMR(DMSO-d6，300MHz)δ：9.17(s，1H)，6.74-7.32(m，8H)，2.68-2.82(m，1H)，223(s，3H)，1.90(dd，J＝4.5，12.9Hz，1H)，1.40(d，J＝3.0Hz，1H)，1.29(d，J＝6.6Hz，3H)，1.06-1.21(m，1H).
N-(p-methoxyphenyl)-2,2,4-trimethylammonium-3,4-dihydroquinoline-1 (2H))-acid amides (2n)
1H?NMR(CDCl 3300MHz)δ1.34-1.37(m，4H)，1.59(s，3H)，1.66(s，3H)，1.90(dd，1H，J 1＝3.0Hz，J 2＝12.9Hz)，2.74-2.87(m，1H)，3.78(s，3H)，6.53(brs，1H，-NH-)，6.82(s，1H，)，6.85(s，1H)，7.04-7.10(m，1H)，7.14-7.17(m，2H)，7.21-7.28(m，3H)；
ESIMS：325([M+H] +)，347([M+Na] +)；
IR(KBr?cm -1)：3283，2966，2928，1682，1654，1513，1237，1034；
Ultimate analysis theoretical value C 20H 24N 2O 2: C, 74.04; H, 7.46; N, 8.64. measured value: C, 74.15; H, 7.57; N, 8.51.
N-phenyl-6-methoxyl group-2,2,4-trimethylammonium-3,4-dihydroquinoline-1 (2H))-acid amides (2o)
1H?NMR(CDCl 3300MHz)δ1.29-1.33(m，4H)，1.56(s，3H)，1.67(s，3H)，1.87(dd，1H，J 1＝3.0Hz，J 2＝12.6Hz)，2.71-2.84(m，1H)，3.80(s，3H)，6.57(brs，1H，-NH-)，6.82(s，1H，)，6.70(dd，1H，J 1＝3.3Hz，J 2＝9.0Hz)，6.78(d，1H，J＝2.1Hz)，6.97-7.02(m，1H)，67.07(d，1H，J＝5.7Hz)7.22-7.34(m，4H)；
ESIMS：325([M+H] +)；347([M+Na] +)；
IR(KBr?cm -1)：3340，2962，1735，1684，1521，1438，1235，1046；
Ultimate analysis theoretical value C 20H 24N 2O 2: C, 74.04; H, 7.46; N, 8.64. measured value: C, 73.92; H, 7.42; N, 8.51.
Embodiment 3 is from 6, and 7-replaces-2,2,4-trimethyldihydroquinoline-1-carboxylic acid aryl amide compound 6, and 7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide compound
General experimental implementation: in dry 25mL single port bottle, add 1mmol6,7-replaces-2,2,4-trimethyldihydroquinoline-1-carboxylic acid aryl amide compound 2,20mg10% palladium carbon and 10mL anhydrous methanol.System is stirring reaction end in 3 hours under the room temperature in atmosphere of hydrogen, and by diatomite elimination palladium carbon, the 2mL anhydrous methanol cleans.The concentrated back of filtrate is removed on Rotary Evaporators and is desolvated, and thick product is further purified (eluent methylene dichloride: sherwood oil=1:2) get 6,7-replacement-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide compound 3 by rapid column chromatography.

Claims (4)

1. one kind 6,7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide compound, and it has following structural formula:
Figure FSB00000068271300011
Wherein, R 1=hydrogen or C 1-4Straight chained alkyl; R 2=hydrogen or C 1-4Straight chained alkyl; R 3=C 1-4Alkoxy or halogen.
One kind as claimed in claim 16,7-replaces-2,2, the preparation method of 4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide compound is characterized in that adopting following steps (1) or (2) method:
(1), at room temperature with organic solvent in, 6,7-replaces-2,2,4-trimethylammonium tetrahydrochysene (or dihydro) quinoline (1) and aromatic isocyanate generate product 6 4-dimethylamino pyridine catalyst reaction 1-5 hour, 7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide; Described 6,7-replaces-2,2,4-trimethylammonium tetrahydrochysene (dihydro) quinoline, isocyanic ester and 4-dimethylamino pyridine mol ratio 1: 1～3: 0.05～0.2;
(2), at room temperature with organic solvent in, 6,7-replaces-2,2,4-trimethyldihydroquinoline and aromatic isocyanate generate product 6 4-dimethylamino pyridine catalyst reaction 1-5 hour, 7-replaces-2,2,4-trimethyldihydroquinoline-1-carboxylic acid aryl amide; Described 6,7-replaces-2,2,4-trimethyldihydroquinoline, isocyanic ester and 4-dimethylamino pyridine mol ratio 1: 1～3: 0.05～0.2;
Under room temperature and hydrogen, with the Pd/C catalyst above-mentioned 6,7-replaces-2,2,4-trimethyldihydroquinoline-1-carboxylic acid aryl amide reaction obtained 6 in 1～5 hour, 7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide; Described 6,7-replaces-2,2, and the mol ratio of 4-trimethyldihydroquinoline-1-carboxylic acid aryl amide and Pd/C catalyzer is 1: 0.05-0.2.
3. as claimed in claim 26,7-replaces-2,2, and the preparation method of 4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide compound is characterized in that described organic solvent is acetone, ether, tetrahydrofuran (THF), methylene dichloride or toluene.
One kind as claimed in claim 16,7-replaces-2,2,4-trimethylammonium tetrahydroquinoline-1-carboxylic acid aryl amide compound is used to prepare the medicine of the procedural necrosis of anti-cell.
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Citations (2)

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US20050014786A1 (en) * 2003-07-11 2005-01-20 Chongqing Sun Tetrahydroquinoline derivatives as cannabinoid receptor modulators
US20070197512A1 (en) * 2006-01-27 2007-08-23 Japan Tobacco Inc. Carboxylic Acid Compounds and Use Thereof

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* Cited by examiner, † Cited by third party
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US20050014786A1 (en) * 2003-07-11 2005-01-20 Chongqing Sun Tetrahydroquinoline derivatives as cannabinoid receptor modulators
US20070197512A1 (en) * 2006-01-27 2007-08-23 Japan Tobacco Inc. Carboxylic Acid Compounds and Use Thereof

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