CN101570558A - 2-phenyl-4-(4-[beta]-D-allopyranosyloxy-phenyl)-1,4,5,6,7,8-hexahydroquinoline-5-ketone derivatives, and preparation method and application thereof - Google Patents
2-phenyl-4-(4-[beta]-D-allopyranosyloxy-phenyl)-1,4,5,6,7,8-hexahydroquinoline-5-ketone derivatives, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a helicidum derivative named 2-phenyl-4-(4-beta-D-allopyranosyloxy-phenyl)-1,4,5,6,7,8-hexahydroquinoline-5-ketone derivative, and a preparation method and applications thereof, the structure formula thereof is shown as the drawing, wherein, R1 is hydrogen or methyl or fluorine or chlorine or bromine, R2 is hydrogen or methyl and R3 is hydrogen or methyl. The sedatives hypnotic activity of the compound is increased compared with the helicidum and drug effect duration is longer than that of the helicidum. The preparation method of the helicidum derivative comprises the steps of: (1) the preparation of E-4-beta-D-allopyranosyloxy-styryl-substituted phenyl ketone; (2) the preparation of 2-phenyl-4-(4-beta-D-allopyranosyloxy-phenyl)-1,4,5,6,7,8-hexahydroquinoline-5-ketone derivatives.
Description
Technical field
The present invention relates to the derivative of helicidum, the preparation method of helicidum derivative and the purposes of helicidum derivative.
Background technology
Helicidum is 4-formylphenyl-beta-D-allopyranosid-(4-fornylphenyl-β-D-allopyranoside), be that Chen Weixin etc. is at Liebigs.Ann.Chem., 1981, (10) reported first is from Yunnan Province of China Proteaceae radish plant tree (Helicia Nilagirica Beed in, different name Helicia Erratica Hook) effective constituent that extracts in the fruit, its structural formula is as follows:
Helicidum is a kind of active material of calming soporific that has, and somnopathy, anxiety, dysthymia disorders are had the obvious treatment effect, has been subject to the people's attention since coming out, and many people study it, have developed a series of medicines.For example, publication number is in the patent application of CN1535690, has reported helicidum soft capsule and preparation method thereof; Publication number is in the patent application of CN1535691, provide one kind Helicid powder injection and preparation method thereof; Publication number is in the patent application of CN1586494, discloses a kind of being applicable to and has alleviated neurosal headache, giddy and somnopathy, the Helicidum oral disintegation tablet of assisting therapy primary headache; Publication number is in the patent application of CN1596903, has introduced a kind of helicidum soft capsule.But,, therefore, develop more helicidum class active substance and have great significance owing to the mental disorder that with neurasthenia is main type is increasing.
Summary of the invention
The objective of the invention is with the helicidum is lead compound, and synthetic helicidum derivative is so that the calming soporific class medicine with better pharmacologically active that exploitation makes new advances.
Helicidum derivative of the present invention is 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7,8-six hydrogen quinoline-5-ketone derivatives, and its structural formula is as follows:
In the described structural formula, R
1Be hydrogen or methyl or fluorine or chlorine or bromine, R
2Be hydrogen or methyl, R
3Be hydrogen or methyl.
The present invention proves (seeing embodiment 11) by experiment, 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7,8-six hydrogen quinoline-5-ketone derivatives is compared with helicidum, the calming soporific activity is stronger, can be used as the active pharmaceutical ingredients of calming soporific medicine, develops the better new drug of drug effect.
2-phenyl-4-of the present invention (4-beta-D-allopyranosid--phenyl)-1,4,5,6,7,8-six hydrogen quinoline-5-ketone derivatives preparation method utilizes helicidum and methyl phenyl ketone or substituted acetophenone that Schmidt-claisen condensation takes place in the sodium hydroxide solution of ethanol or methyl alcohol to obtain E-4-beta-D-allopyranosid--styryl-replacement benzophenone (looking into youngster's ketone); In the presence of ammonium acetate, E-4-beta-D-allopyranosid--styryl-replacement benzophenone and hydroresorcinol (or 5,5-dimethyl-1, hydroresorcinol) solid phase reacting by heating, obtain helicidum derivative 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7,8-six hydrogen quinoline-5-ketone derivatives, its reaction formula is as follows:
In the above-mentioned reaction formula,
1: helicidum
4:1, hydroresorcinol (or 5,5-dimethyl-hydroresorcinol)
2a: methyl phenyl ketone
3a:E-4-beta-D-allopyranosid--styryl-4-benzophenone
4:1, hydroresorcinol
5a:2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline
The 2b:4-methyl acetophenone
3b:E-4-beta-D-allopyranosid--styryl-4-methyl benzophenone
4:1, hydroresorcinol
5b:2-(4-aminomethyl phenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline
The 2c:4-fluoro acetophenone
3c:E-4-beta-D-allopyranosid--styryl-4-fluorobenzene ketone
4:1, hydroresorcinol
5c:2-(4-fluorophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline
The 2d:4-chloro-acetophenone
3d:E-4-beta-D-allopyranosid--styryl-4-chlorobenzene ketone
4:1, hydroresorcinol
5d:2-(4-chloro-phenyl-)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline
The 2e:4-bromoacetophenone
3e:E-4-beta-D-allopyranosid--styryl-4-bromobenzene ketone
4:1, hydroresorcinol
5e:2-(4-bromophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline
2f: methyl phenyl ketone
3f:E-4-beta-D-allopyranosid--styryl-4-benzophenone
4:5,5-dimethyl-hydroresorcinol
5f:7,7-dimethyl-2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline
The 2g:4-methyl acetophenone
3g:E-4-beta-D-allopyranosid--styryl-4-methyl benzophenone
4:5,5-dimethyl-hydroresorcinol
5g:7,7-dimethyl-2-(4-aminomethyl phenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline
The 2h:4-fluoro acetophenone
3h:E-4-beta-D-allopyranosid--styryl-4-fluorobenzene ketone
4:5,5-dimethyl-hydroresorcinol
5h:7,7-dimethyl-2-(4-fluorophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline
The 2i:4-chloro-acetophenone
3i:E-4-beta-D-allopyranosid--styryl-4-chlorobenzene ketone
4:5,5-dimethyl-hydroresorcinol
5i:7,7-dimethyl-2-(4-chloro-phenyl-)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline
The 2j:4-bromoacetophenone
3j:E-4-beta-D-allopyranosid--styryl-4-bromobenzene ketone
4:5,5-dimethyl-hydroresorcinol
5j:7,7-dimethyl-2-(4-bromophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline
From above-mentioned reaction formula as can be seen, have following processing step:
(1) preparation of E-4-beta-D-allopyranosid--styryl-replacement benzophenone
Raw material and prescription thereof:
Helicidum is 1 with the ratio of the mole number of methyl phenyl ketone or substituted acetophenone: 1.1-1.2,
Solvent 4-6 milliliter/mmole helicidum;
Processing step:
In normal pressure, 0 ℃-25 ℃ helicidum is added in the solvent, the NaOH aqueous solution that adds mass concentration 10%-20% under magnetic agitation makes the pH=10-11 of helicidum solution, add methyl phenyl ketone or substituted acetophenone after helicidum dissolves fully, reaction is 2 hours-4 hours under agitation condition; After reaction finishes, reaction solution is transferred to pH=7 with dilute hydrochloric acid, then by concentrate, extraction, column chromatographic isolation and purification or concentrate, recrystallization obtains E-4-beta-D-allopyranosid--styryl-replacement benzophenone;
(2) 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7, the preparation of 8-six hydrogen quinoline-5-ketone derivatives
Raw material and prescription thereof:
E-4-beta-D-allopyranosid--styryl-replacement benzophenone is 1 with the ratio of the mole number of hydroresorcinol and ammonium acetate: 1-1.25: 2.5;
Processing step:
With 1, hydroresorcinol (or 5,5-dimethyl-hydroresorcinol) and ammonium acetate add in the reaction vessel, after mixing, 75-85 ℃ of following solid phase reacting by heating 30 minutes-1 hour added E-4-beta-D-allopyranosid--styryl-replacement benzophenone then, in normal pressure, 75-85 ℃ reaction 4 hours-6 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatographic isolation and purification, obtain 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7,8-six hydrogen quinoline-5-ketone derivatives.
In the aforesaid method, described substituted acetophenone is a kind of in methyl phenyl ketone, 4-methyl acetophenone, 4-fluoro acetophenone, 4-chloro-acetophenone, the 4-bromoacetophenone.
In the aforesaid method, during preparation E-4-beta-D-allopyranosid--styryl-replacement benzophenone, solvent for use is ethanol or methyl alcohol.
In the aforesaid method, when preparation 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7,8-six hydrogen quinoline-5-ketone derivatives, adopt the solvent-free heating of solid phase.
The present invention has following beneficial effect:
1,2-phenyl-4-of the present invention (4-beta-D-allopyranosid--phenyl)-1,4,5,6,7,8-six hydrogen quinoline-5-ketone derivatives is compared with helicidum, the calming soporific activity is stronger, thereby be active pharmaceutical ingredients with it, can develop the multiple calming soporific medicine of better efficacy, have obvious social and economic benefit.
2, the method for the invention operational path is very simple, and cost is lower, and the yield of product is higher, can be suitable for industrialization and enlarge the needs of producing.
Embodiment
To 2-phenyl-4-of the present invention (4-beta-D-allopyranosid--phenyl)-1,4,5,6,7,8-six hydrogen quinoline-5-ketone derivatives and preparation method thereof is described further below by embodiment.
Embodiment 1: present embodiment prepares 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5a), and its structural formula is as follows:
The processing step of present embodiment is as follows:
(1) E-4-beta-D-allopyranosid--styryl-4-benzophenone (being called for short 3a) preparation
Reaction vessel is placed in the ice-water bath, add 30mL ethanol and 5.0mmol helicidum to reaction vessel, the NaOH aqueous solution with mass concentration 15% under magnetic agitation is added dropwise to reaction vessel, make the pH=11 of helicidum solution, after helicidum dissolves fully, the methyl phenyl ketone of 6.0mmol is added reaction vessel, reacted 4 hours in ice-water bath under magnetic agitation, TLC (thin-layer chromatography) monitoring reaction is after reaction finishes, with dilute hydrochloric acid reaction solution is transferred to pH=7, use the rotatory evaporator concentrating under reduced pressure then, continue after add 20mL water, ethyl acetate 3 * 10mL extraction, merge organic layer, the 5g anhydrous Na
2SO
4Drying steams ethyl acetate, and product is through silica gel column chromatography separating purification (CHCl
3: CH
3OH=8: 1v/v) get E-4-beta-D-allopyranosid--styryl-4-benzophenone (light yellow solid), productive rate 61%, m.p.79-81 ℃,
1H NMR (CD3COCD3,400MHz) δ (ppm): 3.61-4.20 (m, 6H), 5.31 (d, J=8.0Hz, 1H, 1-H), 7.11 (d, J=16.0Hz, 1H, CH=CH), 7.15-7.78 (m, 7H, PhH), 7.82 (d, J=16.0Hz, 1H, CH=CHCO), 8.13-8.16 (m, 2H, PhH), and 3.60-4.40 (br, 4H, 4OH); IR (KBr) v (cm
-1): 3400,3070,2894,1657,1599,1508,1423,1174,1080,1035,980,831; HRMS (ESI) calcd for C
21H
22O
7Na[M+Na]
+409.1258 found 409.1258.
(2) 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5a) preparation
1mmol 1, hydroresorcinol and 2.1mmol ammonium acetate add in the reaction vessel, after mixing, and 80 ℃ of following solid phase reacting by heating 35 minutes, add 1mmol E-4-beta-D-allopyranosid--styryl-benzophenone then, in normal pressure, 80 ℃ of reactions 4 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatography (CH
2Cl
2: MeOH=6: 1v/v) separation and purification, obtain 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (yellow solid), productive rate: 83%, m.p.145-146 ℃,
1HNMR (CD3COCD3,400MHz) δ (ppm): 1.04-1.07 (m, 2H, C
7-H), 2.09-2.20 (m, 2H, C
8-H), 2.49-2.51 (m, 2H, C
6-H) 3.43-3.90 (m, 6H), 5.20 (d, J=8.0Hz, 1H, 1-H), 4.53 (d, J=5.6Hz, 1H, C
4-H), 5.06 (d, J=5.6Hz, 1H, C
3-H), 6.87-6.90 (m, 4H, ArH), 7.08-7.50 (m, 5H, ArH), 8.67 (s, 1H, NH); IR (KBr) v (cm
-1): 3399,2951,2926,2887,1666,1590,1485,1389,1227,916,847,696; HRMS (ESI) calcd for C
27H
28O
7N[M-H]
-478.1866 found 478.1858.
Embodiment 2: present embodiment prepares 2-amino-4-(4-beta-D-allopyranosid--phenyl)-6-(4-aminomethyl phenyl)-pyrimidine (being called for short 5b), and its structural formula is as follows:
The processing step of present embodiment is as follows:
(1) E-4-beta-D-allopyranosid--styryl-4-methyl benzophenone (being called for short 3b) preparation
Reaction vessel is placed in the ice-water bath, add 25mL methyl alcohol and 5.0mmol helicidum to reaction vessel, the NaOH aqueous solution with mass concentration 20% under magnetic agitation is added dropwise to reaction vessel, make the pH=10 of helicidum solution, after helicidum dissolves fully, the 4-methyl acetophenone of 5.5mmol is added reaction vessel, reacted 2.5 hours in ice-water bath under magnetic agitation, TLC (thin-layer chromatography) monitoring reaction is after reaction finishes, with dilute hydrochloric acid reaction solution is transferred to pH=7, use the rotatory evaporator concentrating under reduced pressure then, continue after add 20mL water, ethyl acetate 3 * 10mL extraction, merge organic layer, the 5g anhydrous Na
2SO
4Drying steams ethyl acetate, and product is through silica gel column chromatography separating purification (CHCl
3: CH
3OH=8: 1v/v) get E-4-beta-D-allopyranosid--styryl-4-methyl benzophenone (light yellow solid), productive rate 72%, m.p.87-89 ℃,
1H NMR (CD3COCD3,400MHz) δ (ppm): 3.57-4.20 (m, 6H), 5.31 (d, J=8.0Hz, 1H, 1-H), 7.11 (d, J=16.0Hz, 1H, CH=CH), 7.50-7.78 (m, 6H, PhH), 7.82 (d, J=16.0Hz, 1H, CH=CHCO), 8.13-8.15 (m, 2H, PhH), and 3.57-4.41 (br, 4H, 4OH); IR (KBr) v (cm
-1): 3410,3070,2919,1656,1593,1508,1423,1224,1175,1080,1036,981,812; HRMS (ESI) calcd for C
22H
24O
7Na[M+Na]
+423.1403 found 423.1414.
(2) 2-(4-aminomethyl phenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5b) preparation
1mmol 1, hydroresorcinol and 2.0mmol ammonium acetate add in the reaction vessel, after mixing, and 80 ℃ of following solid phase reacting by heating 40 minutes, add 1mmol E-4-beta-D-allopyranosid--styryl-4-methyl benzophenone then, in normal pressure, 80 ℃ of reactions 4.5 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatography (CH
2Cl
2: MeOH=6: 1v/v) separation and purification, obtain 2-(4-aminomethyl phenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (yellow solid), productive rate: 85%, m.p.139-140 ℃,
1H NMR (CD3COCD3,400MHz) δ (ppm): 1.03-1.23 (m, 2H, C
7-H), 2.31-2.40 (m, 2H, C
8-H), 2.50-2.51 (m, 2H, C
6-H), 3.35-3.91 (m, 6H), 5.17 (d, J=8.0Hz, 1H, 1-H), 4.50 (d, J=5.6Hz, 1H, C
4-H), 5.05 (d, J=5.6Hz, 1H, C
3-H), 6.87-7.12 (m, 4H, ArH), 7.13-7.39 (m, 4H, ArH), 8.62 (s, 1H, NH); IR (KBr) v (cm
-1): 3387,2953,2926,2887,1660,1597,1485,1391,1232,1036,835,696; HRMS (ESI) calcd for C
28H
31O
7NNa[M+Na]
+516.1998 found 516.1970.
Embodiment 3: present embodiment prepares 2-(4-fluorophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5c), and its structural formula is as follows:
The processing step of present embodiment is as follows:
(1) E-4-beta-D-allopyranosid--styryl-4-fluorobenzene ketone (being called for short 3c) preparation
Reaction vessel is placed in the ice-water bath, add 25mL ethanol and 5.0mmol helicidum to reaction vessel, the NaOH aqueous solution with mass concentration 20% under magnetic agitation is added dropwise to reaction vessel, make the pH=11 of helicidum solution, after helicidum dissolves fully, the 4-fluoro acetophenone of 5.5mmol is added reaction vessel, reacted 2.5 hours in ice-water bath under magnetic agitation, TLC (thin-layer chromatography) monitoring reaction is after reaction finishes, with dilute hydrochloric acid reaction solution is transferred to pH=7, use the rotatory evaporator concentrating under reduced pressure then, continue after add 20mL water, ethyl acetate 3 * 10mL extraction, merge organic layer, the 5g anhydrous Na
2SO
4Drying steams ethyl acetate, and product is through silica gel column chromatography separating purification (CHCl
3: CH
3OH=8: 1v/v) get E-4-beta-D-allopyranosid--styryl-4-fluorobenzene ketone (yellow solid), productive rate: 65%, m.p.108-110 ℃,
1H NMR (CD3COCD3,400MHz) δ (ppm): 3.45-3.95 (m, 6H), 5.20 (d, J=8.0Hz, 1H, 1-H), 7.73 (d, J=16.0Hz, 1H, CH=CH), 7.07-7.88 (d, 6H, PhH), 7.83 (d, J=16.0Hz, 1H, CH=CHCO), 8.23-8.26 (d, 2H, PhH), and 4.51-5.11 (4H, br, 4OH); IR (KBr) v (cm
-1): 3400,3072,2900,1655,1598,1509,1426,1333,1180,1084,1030,870,824; HRMS (ESI) calcd for C
21H
23O
7F[M+H]
+405.1344, found405.1362.
(2) 2-(4-fluorophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5c) preparation
1.2mmol 1, hydroresorcinol and 2.2mmol ammonium acetate add in the reaction vessel, after mixing, and 80 ℃ of following solid phase reacting by heating 45 minutes, add 1mmol E-4-beta-D-allopyranosid--styryl-4-fluorobenzene ketone then, in normal pressure, 80 ℃ of reactions 3 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatography (CH
2Cl
2: MeOH=6: 1v/v) separation and purification, obtain 2-(4-fluorophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (yellow solid), productive rate: 85%, m.p.130-132 ℃,
1H NMR (400MHz, DMSO-d
6) δ (ppm): 1.03-1.07 (m, 2H, C
7-H), 1.23-1.90 (m, 2H, C
8-H), 2.20-2.50 (m, 2H, C
6-H), 3.32-3.90 (m, 6H), 5.17 (d, J=8.0Hz, 1H, 1-H), 4.70 (d, J=5.6Hz, 1H, C
4-H), 5.06 (d, J=5.6Hz, 1H, C
3-H), 6.88-7.10 (m, 4H, ArH), 7.13-7.54 (m, 4H, ArH), 8.69 (s, 1H, NH); IR (KBr) v (cm
-1): 3332,2958,2926,2887,1660,1595,1486,1391,1229,1037,832,615; HRMS (ESI) calcd for C
27H
28O
7FNNa[M+Na]
+520.1748, found 520.1669.
Embodiment 4: present embodiment prepares 2-(4-chloro-phenyl-)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5d), and its structural formula is as follows:
The processing step of present embodiment is as follows:
(1) E-4-beta-D-allopyranosid--styryl-4-chlorobenzene ketone (being called for short 3d) preparation
Reaction vessel is placed in the ice-water bath, add 30mL methyl alcohol and 5.0mmol helicidum to reaction vessel, the NaOH aqueous solution with mass concentration 20% under magnetic agitation is added dropwise to reaction vessel, make the pH=11 of helicidum solution, after helicidum dissolves fully, the 4-chloro-acetophenone of 5.5mmol is added reaction vessel, reacted 2 hours in ice-water bath under magnetic agitation, TLC (thin-layer chromatography) monitoring reaction is after reaction finishes, with dilute hydrochloric acid reaction solution is transferred to pH=7, use the rotatory evaporator concentrating under reduced pressure then, continue after add 20mL water, ethyl acetate 3 * 10mL extraction, merge organic layer, the 5g anhydrous Na
2SO
4Drying steams ethyl acetate, and product is through silica gel column chromatography separating purification (CHCl
3: CH
3OH=8: 1v/v) get E-4-beta-D-allopyranosid--styryl-4-chlorobenzene ketone (light yellow solid), productive rate 74%, m.p 91-93 ℃, 1H NMR (CD3COCD3,400MHz) δ (ppm): 3.53-4.20 (m, 6H), 5.31 (d, J=8.0Hz, 1H, 1-H), 7.12 (d, J=16.0Hz, 1H, CH=CH), 7.13-7.80 (m, 6H, PhH), 7.81 (d, J=16.0Hz, 1H, CH=CHCO), 8.15-8.17 (m, 2H, PhH), and 3.54-4.40 (br, 4H, 4OH); IR (KBr) v (cm
-1): 3399,3070,2895,1655,1598,1508,1421,1216,1173,1078,1032,977,817,628; HRMS (ESI) calcd for C
21H
22O
7ClNa[M+Na]
+443.0866 found 443.0868.
(2) 2-(4-chloro-phenyl-)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5d) preparation
1.2mmol 1, hydroresorcinol and 2.2mmol ammonium acetate add in the reaction vessel, after mixing, and 80 ℃ of following solid phase reacting by heating 45 minutes, add 1mmol E-4-beta-D-allopyranosid--styryl-4-chlorobenzene ketone then, in normal pressure, 80 ℃ of reactions 3 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatography (CH
2Cl
2: MeOH=6: 1v/v) separation and purification, obtain 2-(4-chloro-phenyl-)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (yellow solid), productive rate: 80%, m.p.150-151 ℃;
1H NMR (CD3COCD3,400MHz) δ (ppm): 1.82-1.90 (m, 2H, C
7-H), 2.19-2.50 (m, 2H, C
8-H), 2.59-2.64 (m, 2H, C
6-H), 3.35-3.90 (m, 6H), 5.24 (d, J=8.0Hz, 1H, 1-H), 4.62 (d, J=5.6Hz, 1H, C
4-H), 5.06 (d, J=5.6Hz, 1H, C
3-H), 6.88-7.13 (m, 4H, ArH), 7.44-7.58 (m, 4H, ArH), 8.69 (s, 1H, NH); IR (KBr) v (cm
-1): 3375,2933,2926,2871,1660,1596,1485,1392,1230,1037,835,762; HRMS (ESI) calcd for C
27H
28O
7ClNNa[M+Na]
+536.1452 found 536.1450.
Embodiment 5: present embodiment prepares 2-(4-bromophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5e), and its structural formula is as follows:
The processing step of present embodiment is as follows:
(1) E-4-beta-D-allopyranosid--styryl-4-bromobenzene ketone (being called for short 3e) preparation
Reaction vessel is placed in the ice-water bath, add 25mL ethanol and 5.0mmol helicidum to reaction vessel, the NaOH aqueous solution with mass concentration 15% under magnetic agitation is added dropwise to reaction vessel, make the pH=11 of helicidum solution, after helicidum dissolves fully, the 4-bromoacetophenone of 5.5mmol is added reaction vessel, reacted 2.5 hours in ice-water bath under magnetic agitation, TLC (thin-layer chromatography) monitoring reaction is after reaction finishes, with dilute hydrochloric acid reaction solution is transferred to pH=7, use the rotatory evaporator concentrating under reduced pressure then, continue after add 20mL water, ethyl acetate 3 * 10mL extraction, merge organic layer, the 5g anhydrous Na
2SO
4Drying steams ethyl acetate, and product is through silica gel column chromatography separating purification (CHCl
3: CH
3OH=8: 1v/v) get E-4-beta-D-allopyranosid--styryl-4-bromobenzene ketone (light yellow solid), productive rate 65%, m.p.98-100 ℃,
1H NMR (CD3COCD3,400MHz) δ (ppm): 3.62-4.21 (m, 6H), 5.31 (d, J=8.0Hz, 1H, 1-H), 7.12 (d, J=16.0Hz, 1H, CH=CH), 7.15-7.80 (m, 6H, PhH), 7.82 (d, J=16.0Hz, 1H, CH=CHCO), 8.07-8.10 (m, 2H, PhH), and 3.62-4.41 (br, 4H, 4OH); IR (KBr) v (cm
-1): 3418,3071,2920,1657,1591,1508,1423,1215,1173,1071,1035,975,815,626; HRMS (ESI) calcd for C
21H
21O
7BrNa[M+Na]
+487.0340 found 487.0363.
(2) 2-(4-bromophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5e) preparation
1.2mmol 1, hydroresorcinol and 2.4mmol ammonium acetate add in the reaction vessel, after mixing, and 80 ℃ of following solid phase reacting by heating 50 minutes, add 1mmol E-4-beta-D-allopyranosid--styryl-4-bromobenzene ketone then, in normal pressure, 80 ℃ of reactions 3.5 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatography (CH
2Cl
2: MeOH=6: 1v/v) separation and purification, obtain 2-(4-bromophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (yellow solid), productive rate: 152-154 ℃,
1H NMR (CD3COCD3,400MHz) δ (ppm): 1.03-1.07 (m, 2H, C
7-H), 1.81-1.90 (m, 2H, C
8-H), 2.50-2.65 (m, 2H, C
6-H), 3.36-3.91 (m, 6H), 5.25 (d, J=8.0Hz, 1H, 1-H), 4.52 (d, J=5.6Hz, 1H, C
4-H), 5.04 (d, J=5.6Hz, 1H, C
3-H), 6.88-7.12 (m, 4H, ArH), 7.44-7.72 (m, 4H, ArH), 8.71 (s, 1H, NH); IR (KBr) v (cm
-1): 3361,2953,2926,2887,1654,1594,1485,1444,1391,1078,828,619; HRMS (ESI) calcd for C
27H
28O
7BrNNa[M+Na]
+580.0947 found 580.0963.
Embodiment 6: present embodiment preparation 7, and 7-dimethyl-2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5f), its structural formula is as follows:
The processing step of present embodiment is as follows:
(1) E-4-beta-D-allopyranosid--styryl-4-benzophenone (being called for short 3f) preparation
Reaction vessel is placed in the ice-water bath, add 30mL ethanol and 5.0mmol helicidum to reaction vessel, the NaOH aqueous solution with mass concentration 15% under magnetic agitation is added dropwise to reaction vessel, make the pH=11 of helicidum solution, after helicidum dissolves fully, the methyl phenyl ketone of 5.8mmol is added reaction vessel, reacted 4 hours in ice-water bath under magnetic agitation, TLC (thin-layer chromatography) monitoring reaction is after reaction finishes, with dilute hydrochloric acid reaction solution is transferred to pH=7, use the rotatory evaporator concentrating under reduced pressure then, continue after add 20mL water, ethyl acetate 3 * 10mL extraction, merge organic layer, the 5g anhydrous Na
2SO
4Drying steams ethyl acetate, and product is through silica gel column chromatography separating purification (CHCl
3: CH
3OH=8: 1v/v) get E-4-beta-D-allopyranosid--styryl-4-benzophenone (light yellow solid), productive rate 61%, m.p.79-81 ℃,
1H NMR (CD3COCD3,400MHz) δ (ppm): 3.61-4.20 (m, 6H), 5.31 (d, J=8.0Hz, 1H, 1-H), 7.11 (d, J=16.0Hz, 1H, CH=CH), 7.15-7.78 (m, 7H, PhH), 7.82 (d, J=16.0Hz, 1H, CH=CHCO), 8.13-8.16 (m, 2H, PhH), and 3.60-4.40 (br, 4H, 4OH); IR (KBr) v (cm
-1): 3400,3070,2894,1657,1599,1508,1423,1174,1080,1035,980,831; HRMS (ESI) calcd for C
21H
22O
7Na[M+Na]
+409.1258 found 409.1258.
(2) 7,7-dimethyl-2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5f) preparation
1mmol 5, and 5-dimethyl-hydroresorcinol and 2.5mmol ammonium acetate add in the reaction vessel, after mixing, 80 ℃ of following solid phase reacting by heating 46 minutes added 1mmol E-4-beta-D-allopyranosid--styryl-benzophenone then, in normal pressure, 80 ℃ of reactions 5 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatography (CH
2Cl
2: MeOH=6: 1v/v) separation and purification, obtain 7,7-dimethyl-2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (yellow solid), productive rate: 83%, m.p.172-174 ℃;
1H NMR (CD3COCD3,400MHz) δ (ppm): 0.94 (s, 3H, CH
3), 1.03 (s, 3H, CH
3), 1.98 (d, J=16.0Hz, 1H, C
8-H), 2.16 (d, J=16.0Hz, 1H, C
8-H), 2.50 (s, 2H, C
6-H), 3.34-3.90 (m, 6H), 5.20 (d, J=8.0Hz, 1H, 1-H), 4.50 (d, J=5.6Hz, 1H, C
4-H), 5.05 (d, J=5.6Hz, 1H, C
3-H), 6.87-6.90 (m, 4H, ArH), 7.11-7.50 (m, 5H, ArH), 8.60 (s, 1H, NH); IR (KBr) v (cm
-1): 3416,2925,2865,1744,1599,1652,1485,1388,1116,1094,835,618; HRMS (ESI) calcd for C
29H
33O
7NNa[M+Na]
+530.2155 found 530.2021.
Embodiment 7: present embodiment preparation 7,7-dimethyl-2-(its structural formula is as follows for 4-aminomethyl phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5g):
The processing step of present embodiment is as follows:
(1) E-4-beta-D-allopyranosid--styryl-4-methyl benzophenone (being called for short 3g) preparation
Reaction vessel is placed in the ice-water bath, add 25mL methyl alcohol and 5.0mmol helicidum to reaction vessel, the NaOH aqueous solution with mass concentration 20% under magnetic agitation is added dropwise to reaction vessel, make the pH=10 of helicidum solution, after helicidum dissolves fully, the 4-methyl acetophenone of 5.3mmol is added reaction vessel, reacted 2.5 hours in ice-water bath under magnetic agitation, TLC (thin-layer chromatography) monitoring reaction is after reaction finishes, with dilute hydrochloric acid reaction solution is transferred to pH=7, use the rotatory evaporator concentrating under reduced pressure then, continue after add 20mL water, ethyl acetate 3 * 10mL extraction, merge organic layer, the 5g anhydrous Na
2SO
4Drying steams ethyl acetate, and product is through silica gel column chromatography separating purification (CHCl
3: CH
3OH=8: 1v/v) get E-4-beta-D-allopyranosid--styryl-4-methyl benzophenone (light yellow solid), productive rate 72%, m.p.87-89 ℃, 1H NMR (CD3COCD3,400MHz) δ (ppm): 3.57-4.20 (m, 6H), 5.31 (d, J=8.0Hz, 1H, 1-H), 7.11 (d, J=16.0Hz, 1H, CH=CH), 7.50-7.78 (m, 6H, PhH), 7.82 (d, J=16.0Hz, 1H, CH=CHCO), 8.13-8.15 (m, 2H, PhH), and 3.57-4.41 (br, 4H, 4OH); IR (KBr) v (cm
-1): 3410,3070,2919,1656,1593,1508,1423,1224,1175,1080,1036,981,812; HRMS (ESI) calcd for C
22H
24O
7Na[M+Na]
+423.1403 found 423.1414.
(2) 2-(4-aminomethyl phenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5g) preparation
1mmol 5, and 5-dimethyl-hydroresorcinol and 2.0mmol ammonium acetate add in the reaction vessel, after mixing, 80 ℃ of following solid phase reacting by heating 50 minutes added 1mmol E-4-beta-D-allopyranosid--styryl-4-methyl benzophenone then, in normal pressure, 80 ℃ of reactions 5.6 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatography (CH
2Cl
2: MeOH=6: 1v/v) separation and purification, obtain 7,7-dimethyl-2-(4-aminomethyl phenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (yellow solid), productive rate: 85%, m.p.139-141 ℃;
1H NMR (CD3COCD3,400MHz) δ (ppm): 0.93 (s, 3H, CH
3), 1.07 (s, 3H, CH
3), 1.99 (d, J=16.0Hz, 1H, C
8-H), 2.14 (d, J=16.0Hz, 1H, C
8-H), 2.48 (s, 2H, C
6-H), 3.42-3.47 (m, 6H), 5.19 (d, J=8.0Hz, 1H, 1-H), 4.51 (d, J=5.6Hz, 1H, C
4-H), 5.06 (d, J=5.6Hz, 1H, C
3-H), 6.87-6.90 (m, 4H, ArH), 7.11-7.50 (m, 4H, ArH), 8.61 (s, 1H, NH); IR (KBr) v (cm
-1): 3362,2925,2882,1660,1592,1485,1390,1227,1085,830,619; HRMS (ESI) calcd for C
30H
35O
7NNa[M+Na]
+544.2311, found 544.2307.
Embodiment 8: present embodiment preparation 7, and 7-dimethyl-2-(4-fluorophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5h), its structural formula is as follows:
The processing step of present embodiment is as follows:
(1) E-4-beta-D-allopyranosid--styryl-4-fluorobenzene ketone (being called for short 3h) preparation
Reaction vessel is placed in the ice-water bath, add 25mL ethanol and 5.0mmol helicidum to reaction vessel, the NaOH aqueous solution with mass concentration 20% under magnetic agitation is added dropwise to reaction vessel, make the pH=11 of helicidum solution, after helicidum dissolves fully, the 4-fluoro acetophenone of 5.0mmol is added reaction vessel, reacted 2.5 hours in ice-water bath under magnetic agitation, TLC (thin-layer chromatography) monitoring reaction is after reaction finishes, with dilute hydrochloric acid reaction solution is transferred to pH=7, use the rotatory evaporator concentrating under reduced pressure then, continue after add 20mL water, ethyl acetate 3 * 10mL extraction, merge organic layer, the 5g anhydrous Na
2SO
4Drying steams ethyl acetate, and product is through silica gel column chromatography separating purification (CHCl
3: CH
3OH=8: 1v/v) get E-4-beta-D-allopyranosid--styryl-4-fluorobenzene ketone (yellow solid), productive rate: 65%, m.p.108-110 ℃;
1H NMR (CD3COCD3,400MHz) δ (ppm): 3.45-3.95 (m, 6H), 5.20 (d, J=8.0Hz, 1H, 1-H), 7.73 (d, J=16.0Hz, 1H, CH=CH), 7.07-7.88 (d, 6H, PhH), 7.83 (d, J=16.0Hz, 1H, CH=CHCO), 8.23-8.26 (d, 2H, PhH), and 4.51-5.11 (4H, br, 4OH); IR (KBr) v (cm
-1): 3400,3072,2900,1655,1598,1509,1426,1333,1180,1084,1030,870,824; HRMS (ESI) calcd for C
21H
23O
7F[M+H]
+405.1344, found405.1362.
(2) 7,7-dimethyl-2-(4-fluorophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5h) preparation
1.2mmol 5,5-dimethyl-hydroresorcinol and 2.2mmol ammonium acetate add in the reaction vessel, after mixing, 80 ℃ of following solid phase reacting by heating 1 hour added 1mmol E-4-beta-D-allopyranosid--styryl-4-fluorobenzene ketone then, in normal pressure, 80 ℃ of reactions 3 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatography (CH
2Cl
2: MeOH=6: 1v/v) separation and purification, obtain 2-(4-fluorophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (yellow solid), productive rate: 85%, m.p.163-165 ℃;
1H NMR (CD3COCD3,400MHz) δ (ppm): 0.96 (s, 3H, CH
3), 1.05 (s, 3H, CH
3), 1.92 (d, J=16.0Hz, 1H, C
8-H), 2.15 (d, J=16.0Hz, 1H, C
8-H), 2.48 (s, 2H, C
6-H), 3.34-3.90 (m, 6H), 5.16 (d, J=8.0Hz, 1H, 1-H), 4.49 (d, J=5.6Hz, 1H, C
4-H), 5.03 (d, J=5.6Hz, 1H, C
3-H), 6.87-6.90 (m, 4H, ArH), 7.10-7.53 (m, 4H, ArH), 8.60 (s, 1H, NH); IR (KBr) v (cm
-1): 3352,2925,2882,1661,1595,1485,1390,1228,914,839,620; HRMS (ESI) calcdfor C
29H
31O
7FN[M-H]
-524.2085 found 524.2101.
Embodiment 9: present embodiment preparation 7, and 7-dimethyl-2-(4-chloro-phenyl-)-4-(4-β-D-mutter Azloglycoside-phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5h), its structural formula is as follows:
The processing step of present embodiment is as follows:
(1) E-4-beta-D-allopyranosid--styryl-4-chlorobenzene ketone (being called for short 3i) preparation
Reaction vessel is placed in the ice-water bath, add 25mL ethanol and 5.0mmol helicidum to reaction vessel, the NaOH aqueous solution with mass concentration 20% under magnetic agitation is added dropwise to reaction vessel, make the pH=11 of helicidum solution, after helicidum dissolves fully, the 4-chloro-acetophenone of 5.5mmol is added reaction vessel, reacted 4 hours in ice-water bath under magnetic agitation, TLC (thin-layer chromatography) monitoring reaction is after reaction finishes, with dilute hydrochloric acid reaction solution is transferred to pH=7, being evaporated to volume with rotatory evaporator then is original half, adds 30mL aqueous ethanolic solution (ethanol volume: the volume of water=5: 1), separate out solid at every turn, suction filtration, recrystallization gets E-4-beta-D-allopyranosid--styryl-4-chlorobenzene ketone (light yellow solid) 3 times,, productive rate 74%, m.p 91-93 ℃
1H NMR (CD3COCD3,400MHz) δ (ppm): 3.53-4.20 (m, 6H), 5.31 (d, J=8.0Hz, 1H, 1-H), 7.12 (d, J=16.0Hz, 1H, CH=CH), 7.13-7.80 (m, 6H, PhH), 7.81 (d, J=16.0Hz, 1H, CH=CHCO), 8.15-8.17 (m, 2H, PhH), and 3.54-4.40 (br, 4H, 4OH); IR (KBr) v (cm
-1): 3399,3070,2895,1655,1598,1508,1421,1216,1173,1078,1032,977,817,628; HRMS (ESI) calcd for C
21H
22O
7ClNa[M+Na]
+443.0866 found 443.0868.
(2) 7,7-dimethyl-2-(4-chloro-phenyl-)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5i) preparation
1.1mmol 5,5-dimethyl-hydroresorcinol and 2.2mmol ammonium acetate add in the reaction vessel, after mixing, 80 ℃ of following solid phase reacting by heating 1 hour added 1.0mmol E-4-beta-D-allopyranosid--styryl-4-fluorobenzene ketone then, in normal pressure, 80 ℃ of reactions 4 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatography (CH
2Cl
2: MeOH=6: 1v/v) separation and purification, obtain 2-(4-chloro-phenyl-)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (yellow solid), productive rate: 79%, m.p.142-143 ℃,
1H NMR (CD3COCD3,400MHz) δ (ppm): 0.93 (s, 3H, CH
3), 1.06 (s, 3H, CH
3), 2.00 (d, J=16.0Hz, 1H, C
8-H), 2.16 (d, J=16.0Hz, 1H, C
8-H), 2.50 (s, 2H, C
6-H), 3.35-3.90 (m, 6H), 5.23 (d, J=8.0Hz, 1H, 1-H), 4.55 (d, J=5.6Hz, 1H, C
4-H), 5.05 (d, J=5.6Hz, 1H, C
3-H), 6.87-6.90 (m, 4H, ArH), 7.10-7.53 (m, 4H, ArH), 8.62 (s, 1H, NH); IR (KBr) v (cm
-1): 3361,2953,2826,1660,1597,1490,1390,1230,1038,838,620; HRMS (ESI) calcdfor C
29H
31O
7ClN[M-H]
-540.1789 found 540.1790.
Embodiment 10: present embodiment preparation 7, and 7-dimethyl-2-(4-bromophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5j), its structural formula is as follows:
The processing step of present embodiment is as follows:
(1) E-4-beta-D-allopyranosid--styryl-4-bromobenzene ketone (being called for short 3j) preparation
Reaction vessel is placed in the ice-water bath, add 25mL ethanol and 5.0mmol helicidum to reaction vessel, the NaOH aqueous solution with mass concentration 20% under magnetic agitation is added dropwise to reaction vessel, make the pH=11 of helicidum solution, after helicidum dissolves fully, the 4-bromoacetophenone of 5.5mmol is added reaction vessel, under magnetic agitation, in ice-water bath, reacted 4 hours, TLC (thin-layer chromatography) monitoring reaction, after reaction finishes, with dilute hydrochloric acid reaction solution is transferred to pH=7, being evaporated to volume with rotatory evaporator then is original half, each 30mL aqueous ethanolic solution (ethanol volume: the volume of water=5: 1) that adds, separate out solid, suction filtration, recrystallization gets E-4-beta-D-allopyranosid--styryl-4-bromobenzene ketone (light yellow solid) 3 times, m.p.98-100 ℃
1H NMR (CD3COCD3,400MHz) δ (ppm): 3.62-4.21 (m, 6H), 5.31 (d, J=8.0Hz, 1H, 1-H), 7.12 (d, J=16.0Hz, 1H, CH=CH), 7.15-7.80 (m, 6H, PhH), 7.82 (d, J=16.0Hz, 1H, CH=CHCO), 8.07-8.10 (m, 2H, PhH), and 3.62-4.41 (br, 4H, 4OH); IR (KBr) v (cm
-1): 3418,3071,2920,1657,1591,1508,1423,1215,1173,1071,1035,975,815,626; HRMS (ESI) calcd for C
21H
21O
7BrNa[M+Na]
+487.0340 found 487.0363.
(2) 7,7-dimethyl-2-(4-bromophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (being called for short 5j) preparation
1.0mmol 5,5-dimethyl-hydroresorcinol and 2.5mmol ammonium acetate add in the reaction vessel, after mixing, 80 ℃ of following solid phase reacting by heating 1 hour added 1mmol E-4-beta-D-allopyranosid--styryl-4-bromobenzene ketone then, in normal pressure, 80 ℃ of reactions 4.4 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatography (CH
2Cl
2: MeOH=6: 1v/v) separation and purification, obtain 7,7-dimethyl-2-(4-bromophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (yellow solid), productive rate: 77%, m.p.163-165 ℃;
1H NMR (CD3COCD3,400MHz) δ (ppm): 0.95 (s, 3H, CH
3), 1.06 (s, 3H, CH
3), 2.07 (d, J=16.0Hz, 1H, C
8-H), 2.16 (d, J=16.0Hz, 1H, C
8-H), 2.50 (s, 2H, C
6-H), 3.35-3.90 (m, 6H), 5.24 (d, J=8.0Hz, 1H, 1-H), 4.51 (d, J=5.6Hz, 1H, C
4-H), 5.05 (d, J=5.6Hz, 1H, C
3-H), 6.87-6.90 (m, 4H, ArH), 7.10-7.72 (m, 4H, ArH), 8.63 (s, 1H, NH); IR (KBr) v (cm
-1): 3353,2927,2871,1670,1589,1485,1393,1228,1035,825,618; HRMS (ESI) calcd for C
29H
32O
7BrNNa[M+Na]
+608.1260 found 608.1258.
Embodiment 11: biological activity test
1, experimental drug
Be subjected to reagent:
(1) the helicidum derivative of embodiment 1～embodiment 8 preparations: 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j.
5a:2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (embodiment 1 preparation)
5b:2-(4-aminomethyl phenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (embodiment 2 preparations)
5c:2-(4-fluorophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (embodiment 3 preparations)
5d:2-(4-chloro-phenyl-)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (embodiment 4 preparations)
5e:2-(4-bromophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (embodiment 5 preparations)
5f:7,7-dimethyl-2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (embodiment 6 preparations)
5g:7,7-dimethyl-2-(4-aminomethyl phenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (embodiment 7 preparations)
5h:7,7-dimethyl-2-(4-fluorophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (embodiment 8 preparations)
5i:7,7-dimethyl-2-(4-chloro-phenyl-)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (embodiment 9 preparations)
5j:7,7-dimethyl-2-(4-bromophenyl)-4-(4-beta-D-allopyranosid--phenyl)-5-ketone-1,4,5,6,7,8-six hydrogen quinoline (embodiment 10 preparations)
(2) helicidum: Zhejiang Hangzhou flavor chemistry company limited.
Solvent: mass concentration 0.9%NaCl injection liquid, produce specification: 500mL/4.5g/ bottle, lot identification mark: 08101047 by Xinan Pharmaceutical Co., Ltd. of Tai Ji group.
2, laboratory animal
72 of KM kind small white mouses, male and female half and half, body weight 17-22g is provided by the West China animal center.
3, laboratory apparatus
(1) the multi-functional mouse autonomic activities of YLS-1A registering instrument is produced by Shandong Province's medical science institute equipment station.
(2) electronic balance, factory produces model T1000, Max=1000g, d=0.1g by the two outstanding testing tool in Changshu; Produce model BS210S, Max=210g, d=0.1mg by Beijing Sai Duolisi balance company limited.
4, medicine preparation
Get each 0.04g of 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j and helicidum, be made into the suspension of mass concentration 1% respectively with the NaCl heating for dissolving of 4mL mass concentration 0.9%.
5, experimental technique
72 mouse are divided into 10 groups (wherein, the negative control group of group, a group is the helicidum group, ten groups are respectively 5a group, 5b group, 5c group, 5d group, 5e group, 5f group, 5g group, 5h group, 5i group, 5j group), 6 every group, male and female half and half.Before the administration, measure earlier the autonomic activities number of times of every mouse 5min respectively, divide into groups again according to movable number of times then, make the mean activity number of times of each group even.
Again after being divided into group, the grouping administration.5a group, 5b group, 5c group, 5d group, 5e group, 5f group, 5g group, 5h group, 5i group, 5j group medication are abdominal injection, and dosage is 0.4ml/20g (the former medicine of 200mg/Kg animal), and administration number of times is for once.Helicidum group administering mode is an abdominal injection, and dosage is 0.4ml/20g (the former medicine of 200mg/Kg animal), and administration number of times is for once.A negative control group injecting normal saline (abdominal injection), injected dose 0.4ml/20g, frequency injection is for once.
30min, 60min, 90min, 120min after the administration measure the spontaneous activity number of times of respectively organizing mouse 5min, and the gained data are carried out statistical treatment, and experimental result sees Table 1.
Annotate: in the table 1,1 represents the helicidum group; A is a negative control group.
From the data of table 1 as can be seen, the calming soporific activity of the helicidum derivative 5a of embodiment 1～embodiment 10 preparations, 5b, 5c, 5d, 5e, 5f, 5g, 5h all strengthens to some extent than helicidum, and the duration of efficacy of 5b, 5f surpasses helicidum.Experimental result shows, R
1Drug effect is better during for donor residues, and helicidum derivative provided by the present invention is R especially
1During for donor residues, can develop the calming soporific medicine that makes new advances with better pharmacologically active.
Claims (6)
1,2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7,8-six hydrogen quinoline-5-ketone derivatives is characterized in that structural formula is as follows:
In the described structural formula, R
1Be halogen, R
2Be hydrogen or methyl, R
3Be hydrogen or methyl;
A kind of 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7, the preparation method of 8-six hydrogen quinoline-5-ketone derivatives is characterized in that processing step is as follows:
(1) preparation of E-4-beta-D-allopyranosid--styryl-replacement benzophenone
Raw material: helicidum, methyl phenyl ketone or substituted acetophenone,
Processing step:
In normal pressure, 0 ℃-25 ℃ helicidum is added in the solvent, the inorganic base aqueous solution that adds certain mass concentration under magnetic agitation makes the pH=10-11 of helicidum solution, add methyl phenyl ketone or substituted acetophenone after helicidum dissolves fully, reaction is 2 hours-4 hours under agitation condition; Reaction transfers to pH=7 with dilute hydrochloric acid with reaction solution after finishing, and concentrates, and obtains E-4-beta-D-allopyranosid--styryl-replacement benzophenone with ethyl alcohol recrystallization or through extraction, column chromatographic isolation and purification then;
(2) 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7, the preparation of 8-six hydrogen quinoline-5-ketone derivatives
Raw material: E-4-beta-D-allopyranosid--styryl-replacement benzophenone, hydroresorcinol, ammonium acetate,
Processing step:
With 1, hydroresorcinol (or 5,5-dimethyl-hydroresorcinol) and ammonium acetate add in the reaction vessel, after mixing, the solid phase reacting by heating is 30 minutes-1 hour under the certain temperature, adds E-4-beta-D-allopyranosid--styryl-replacement benzophenone then, in normal pressure, certain temperature reaction 4 hours-6 hours, after reaction finishes, be cooled to room temperature, add alcohol immersion, suction filtration, wash crude product, through column chromatographic isolation and purification, get the described 2-phenyl-4-of claim 1 (4-beta-D-allopyranosid--phenyl)-1,4,5,6,7,8-six hydrogen quinoline-5-ketone derivatives.
2,2-phenyl-4-according to claim 1 (4-beta-D-allopyranosid--phenyl)-1,4,5,6,7, the preparation method of 8-six hydrogen quinoline-5-ketone derivatives is characterized in that substituted acetophenone is a kind of in methyl phenyl ketone, 4-methyl acetophenone, 4-fluoro acetophenone, 4-chloro-acetophenone, the 4-bromoacetophenone.
3,2-phenyl-4-according to claim 1 (4-beta-D-allopyranosid--phenyl)-1,4,5,6,7, the R of 8-six hydrogen quinoline-5-ketone derivatives
1Be the fluorine in the halogen, chlorine, bromine.
4,2-phenyl-4-according to claim 1 and 2 (4-beta-D-allopyranosid--phenyl)-1,4,5,6,7, the preparation method of 8-six hydrogen quinoline-5-ketone derivatives is characterized in that preparing 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7, during 8-six hydrogen quinoline-5-ketone derivatives, be the reaction of solid phase heating catalyst-free.
5,2-phenyl-4-according to claim 1 (4-β beta-D-allopyranosid--phenyl)-1,4,5,6,7, the preparation method of 8-six hydrogen quinoline-5-ketone derivatives, preparation 2-phenyl-4-(4-beta-D-allopyranosid--phenyl)-1,4,5,6,7, during 8-six hydrogen quinoline-5-ketone derivatives, it is characterized in that R
1During for donor residues, react required long time productive rate height, and R
1During for electron withdrawing group, the reaction required time is short, but productive rate is relatively low.
6, the described 2-phenyl-4-of claim 1-4 (4-beta-D-allopyranosid--phenyl)-1,4,5,6,7, the application of 8-six hydrogen quinoline-5-ketone derivatives in preparation calming soporific medicine is characterized in that R
1During for donor residues, drug effect is excellent, R
1Be methyl, R
2Be hydrogen, R
32-phenyl-4-during for hydrogen (4-beta-D-allopyranosid--phenyl)-1,4,5,6,7, the application of 8-six hydrogen quinoline-5-ketone derivatives in preparation calming soporific medicine is outstanding.
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| CNA2009100595976A CN101570558A (en) | 2009-06-15 | 2009-06-15 | 2-phenyl-4-(4-[beta]-D-allopyranosyloxy-phenyl)-1,4,5,6,7,8-hexahydroquinoline-5-ketone derivatives, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558046A (en) * | 2012-01-18 | 2012-07-11 | 云南大学 | Solid-phase synthesis method of quinoline compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102558046A (en) * | 2012-01-18 | 2012-07-11 | 云南大学 | Solid-phase synthesis method of quinoline compound |
| CN102558046B (en) * | 2012-01-18 | 2014-02-19 | 云南大学 | Solid-phase synthesis method of quinoline compound |
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