CN103193794B - A kind of isoindolone Bing isoxazole fused ring compound and synthetic method thereof - Google Patents
A kind of isoindolone Bing isoxazole fused ring compound and synthetic method thereof Download PDFInfo
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- CN103193794B CN103193794B CN201310124394.7A CN201310124394A CN103193794B CN 103193794 B CN103193794 B CN 103193794B CN 201310124394 A CN201310124394 A CN 201310124394A CN 103193794 B CN103193794 B CN 103193794B
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- MJUYYZFZJVFSDO-UHFFFAOYSA-N COc1ccc(COC(C(C2(c3ccccc33)O)=CON2C3=O)=O)cc1 Chemical compound COc1ccc(COC(C(C2(c3ccccc33)O)=CON2C3=O)=O)cc1 MJUYYZFZJVFSDO-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to technical field of organic chemistry, be specially a kind of isoindolone Bing isoxazole fused ring compound and synthetic method thereof.The present invention uses electron-deficient acetylene compound and HP to be raw material, under triphenyl phosphorus catalysis by the synthesis of [3+2] cycloaddition reaction a kind of enrich active function groups isoindolone and isoxazole fused ring compound, this compounds has potential pharmaceutical application and is worth.The reaction times of this reaction is short, and yield reaches more than 90%, has good actual application value.
Description
Technical field
The present invention relates to technical field of organic chemistry, be specially a kind of isoindolone Bing isoxazole fused ring compound and synthetic method thereof.
Background technology
Isoindolone Bing isoxazole fused ring compound is the important heterogeneous ring compound of a class, extensively be present in the middle of natural product and active constituents of medicine, the indolone structure that this structure has has good antibacterial, anti-inflammatory activity, and isoxazole derivant is also that a class has good desinsection, antibacterial, the bioactive heterocyclic organic compounds of anti-inflammatory to Er.Such as, Sutent containing indolone structure is a multiple receptor tyrosine kinases inhibitor, there is good anti-tumor activity, can be used for treating and occurred to shift to cancer cells or to the gastrointestinal stromal tumor (GIST) of imatinib mesylate tolerance and the invalid metastatic renal cell cancer (MRCC) of employing cytokine therapy.Also more than 10 agricultural chemicals and medical kind has been developed, as herbicide of clomazone, antimicrobial drug sulfamethoxazole and Oxazacillin etc. in isoxazole derivant.Isoindolone Bing isoxazole fused ring compound gets more and more people's extensive concerning as a kind of important medicinal activity intermediate.Along with the development of heterocyclic synthesis chemistry, the one-step method for synthesizing of the Hete rocyclic derivatives such as azepine, oxa-is found in succession, but the rarely seen report of simple synthesis of isoindolone Bing isoxazole fused ring compound.Therefore, develop the starting raw material with simple structure, the method for one-step synthesis isoindolone Bing isoxazole fused-ring derivatives has important actual application value.The invention provides a kind of simple, the new technology that convenient, the isoindolone Bing isoxazole fused-ring derivatives of active function groups is enriched in novel preparation.
Summary of the invention
The present invention uses electron-deficient alkynes analog derivative 1 and HP 2 that [3+2] cyclization occurs under triphenyl phosphorus catalysis, and obtain isoindolone and isoxazole fused ring compound 3, its reaction formula is as follows:
Wherein compound 1 is electron-deficient alkynes analog derivative, R
1for H or CH
3, n-Pr, CH
3(CH
2)
5etc. all kinds of direct-connected alkyl, also can be the substituting group such as phenyl or substituted-phenyl, non-benzene aryl radical and ester group, R
2for Ph or 4-Me-C
6h
4, 4-MeOC
6h
4, 3,4-MeOC
6h
3, 4-Cl-C
6h
4, 3-Cl-C
6h
4, 2-Cl-C
6h
4, 4-F-C
6h
4etc. various substituted-phenyl and OCH
3, OC
2h
5, OCH
2ph, OCH
2ar, OCH
2-1-naphthyl, OCH
2the groups such as-2-furanyl, compound 2 is HP.
According to the present invention, pharmacy acceptable salt comprises the acid salt that general formula 3 compound and following acid are formed: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, toxilic acid or succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid, tussol.Comprise the acid salt of mineral alkali in addition, as: containing alkali metal cations, alkaline earth metal cation, ammonium cation salt.
The preferred following structural compounds of general formula (3) compound:
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid, ethyl ester (3a)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-benzyl carboxylate (3b)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-methylthiobenzyl ester (3c)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-methoxy-benzyl ester (3d)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-methyl-benzyl ester (3e)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-luorobenzyl ester (3f)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-nitrobenzyl ester (3g)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-1-menaphthyl ester (3h)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-furfuryl ester (3i)
3a-hydroxy-2-methyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid, ethyl ester (3j)
3a-hydroxyl-8-oxo-2-phenyl-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid, ethyl ester (3k)
3-ethanoyl-3a-hydroxyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (31)
3-benzoyl-3-ethanoyl-3a-hydroxyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3m)
3-ethanoyl-3a-hydroxyl-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3n)
3-benzoyl-3a-hydroxyl-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3o)
3a-hydroxyl-2-phenyl-3-(pyridine-3-carbonyl)-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3p)
3-benzoyl-3a-hydroxyl-2-propyl group-1-oxa--3aH-8a-azepine-cyclopenta [a] indenes-8-ketone (3q)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-2,3-dimethyl dicarboxylate (3r)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a) indenes-3-carboxylate methyl ester (3s)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-nitrobenzyl ester (3t)
2-hexyl-3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid, ethyl ester (3u)
3-(4-fluoro benzoyl)-3a-hydroxyl-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3v)
3-(4-chlorobenzene formacyl)-3a-hydroxyl-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3w)
3a-hydroxyl-3-(4-anisoyl)-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3x)
3-(3,4-Dimethoxybenzoyl)-3a-hydroxyl-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3y)
Concrete operation step is:
Electron-deficient alkynes analog derivative 1, HP 2 is dissolved in organic solvent, add organophosphorus reagent, substantially complete to reaction in room temperature reaction, the cancellation that adds water is reacted, with dichloromethane extraction, after concentrated, obtain corresponding isoindolone and isoxazole fused ring compound 3 through column chromatography for separation.
This reaction not only starting raw material is easy to get, mild condition, and synthetic route is brief, easy to operate, and cost is lower.And the reaction times only needs 1h, reaction yield reaches more than 90%, and when reaction scale is amplified to gram level, productive rate still can reach more than 80%, can be good be applied in industrial production, there is good practicality.The isoindolone Bing isoxazole fused ring compound 3 synthesized by this method has potential biological activity, has good application prospect in new drug development field.
Better reaction conditions of the present invention is:
(1) catalyzer is PPh
3;
(2) HP 2, PPh
3be 1: 0.2: 1.2 with the molar ratio of electron-deficient alkynes analog derivative 1;
(2) solvent is dry DMF;
(3) temperature of reaction is room temperature.
Embodiment
The following examples further illustrate of the present invention, instead of limit the scope of the invention.
The synthesis of embodiment 1 compound 3a
HP (0.5mmol), ethyl propiolate (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3a, yield 99% after concentrated through column chromatography for separation.White solid; M.p.74-75 DEG C of .IR (KBr): ν=3417,3086,2983,1791,1741,1707,1683,1649,1614,1467,1371,1182,1087,1057,879,696cm
-1.
1hNMR (500MHz, CDCl
3) δ 8.01 (d, J=7.7Hz, 1H), 7.77 (d, J=7.6Hz, 1H), 7.72 (td, J=7.6,1.0Hz, 1H), 7.61 (s, 1H), 7.54 (td, J=7.6,0.8Hz, 1H), 4.53 (brs, 1H), 4.25-4.19 (m, 1H), 4.19-4.13 (m, 1H), 1.28 (t, J=7.1Hz, 3H) .HRMS (ESI): calcd.forC
13h
12nO
5[M+H]
+262.0710; Found262.0711.
The synthesis of embodiment 2 compound 3b
HP (0.5mmol), propine acid benzyl ester (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3b, yield 95% after concentrated through column chromatography for separation.White solid; M.p.123-124 DEG C of .IR (KBr): ν=3389,3068,1728,1718,1620,1595,1467,1398,1336,1253,1095,1074,883,761,736cm
-1.
1hNMR (300MHz, DMSO) δ 8.34 (s, 1H), (7.89-7.75 m, 4H), 7.63 (td, J=7.5,0.9Hz, 1H), (7.39-7.31 m, 5H), 5.23 (d, J=12.5Hz, 1H), 5.16 (d, J=12.5Hz, 1H) .HRMS (ESI): calcd.forC
18h
14nO
5[M+H]
+324.0866; Found324.0867.
The synthesis of embodiment 3 compound 3c
HP (0.5mmol), 4-(methylthio group) benzyl propiolate (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3c, yield 92% after concentrated through column chromatography for separation.White solid; M.p.98-99 DEG C of .IR (KBr): ν=3437,3080,1745,1681,1614,1593,1506,1408,1394,1336,1107,1089,808,763,721cm
-1.
1hNMR (300MHz, DMSO) δ 8.31 (s, 1H), 8.03-7.72 (m, 4H), 7.63 (t, J=7.4Hz, 1H), 7.30 (dd, J=22.8,8.3Hz, 4H), 5.17 (d, J=12.4Hz, 1H), 5.11 (d, J=12.8Hz, 1H), 2.47 (s, 3H) .HRMS (ESI): calcd.forC
19h
16nO
5s [M+H]
+370.0744; Found370.0750.
The synthesis of embodiment 4 compound 3d
HP (0.5mmol), 4-(methoxyl group) benzyl propiolate (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3d, yield 99% after concentrated through column chromatography for separation.White solid; M.p.86-87 DEG C of .IR (KBr): ν=3321,3088,2956,2837,1757,1712,1612,1595,1516,1465,1384,1332,1303,1247,1176,1153,1111,1085,1030,877,823,763,729cm
-1.
1hNMR (300MHz, CDCl
3) δ 7.81 (d, J=7.7Hz, 1H), (7.65 d, J=7.6Hz, 1H), 7.58-7.47 (m, 2H), 7.41 (t, J=7.5Hz, 1H), 7.17 (d, J=8.6Hz, 2H), 6.76 (d, J=8.6Hz, 2H), 5.04 (d, J=11.9Hz, 1H), 4.96 (d, J=11.9Hz, 1H), 4.90 (brs, 1H), 3.68 (s, 3H) .HRMS (ESI): calcd.forC
19h
16nO
6[M+H]
+354.0972; Found354.0967.
The synthesis of embodiment 5 compound 3e
HP (0.5mmol), 4-(methyl) benzyl propiolate (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3e, yield 89% after concentrated through column chromatography for separation.White solid; M.p.70-71 DEG C of .IR (KBr): ν=3435,3034,2929,2850,1747,1714,1649,1624,1541,1508,1456,1087,1026,997,827,761,765cm
-1.
1hNMR (300MHz, DMSO) δ 8.31 (s, 1H), 7.88 (d, J=7.5Hz, 1H), 7.82-7.74 (m, 3H), 7.62 (t, J=7.5Hz, 1H), 7.27 (d, J=7.9Hz, 2H), 7.17 (d, J=7.9Hz, 2H), 5.17 (d, J=12.3Hz, 1H), 5.11 (d, J=12.3Hz, 1H), 2.28 (s, 3H) .HRMS (ESI): calcd.forC
19h
16nO
5[M+H]
+338.1023; Found338.1022.
The synthesis of embodiment 6 compound 3f
HP (0.5mmol), 4-luorobenzyl propiolate (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3f, yield 99% after concentrated through column chromatography for separation.White solid; M.p.134-136 DEG C of .IR (KBr): ν=3468,3414,2922,2850,1720,1637,1618,1512,1471,1450,1398,1384,1336,1321,1153,1097,1074,883,819,765,746cm
-1.
1hNMR (300MHz, DMSO) δ 8.35 (s, 1H), (7.88-7.75 m, 4H), 7.66-7.60 (m, 1H), 7.50-7.41 (m, 2H), (7.27-7.15 m, 2H), 5.20 (d, J=12.4Hz, 1H), 5.14 (d, J=12.4Hz, 1H) .HRMS (ESI): calcd.forC
18h
13fNO
5[M+H]
+342.0772; Found342.0772.
The synthesis of embodiment 7 compound 3g
HP (0.5mmol), 4-nitrobenzyl propiolate (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3g, yield 94% after concentrated through column chromatography for separation.White solid; M.p.140-141 DEG C of .IR (KBr): ν=3495,3416,3111,2941,2848,1749,1714,1622,1518,1433,1386,1342,1145,1128,1097,1070,877,769,734,663cm
-1.
1hNMR (300MHz, DMSO) δ 8.42 (s, 1H), 8.22 (d, J=8.6Hz, 2H), 7.90-7.79 (m, 4H), 7.69-7.61 (m, 3H), 5.34 (s, 2H) .HRMS (ESI): calcd.forC
18h
12n
2naO
7[M+Na]
+391.0537; Found391.0542.
The synthesis of embodiment 8 compound 3h
HP (0.5mmol), 1-menaphthyl propiolate (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3h, yield 96% after concentrated through column chromatography for separation.White solid; M.p.67-68 DEG C of .IR (KBr): ν=3412,3411,3068,1747,1714,1637,1618,1508,1467,1384,1115,1085,800,761,619cm
-1.
1hNMR (300MHz, DMSO) δ 8.34 (s, 1H), 8.06-7.93 (m, 3H), 7.84 (s, 1H), 7.81-7.69 (m, 2H), 7.67-7.45 (m, 6H), 5.71 (d, J=12.6Hz, 1H), 5.62 (d, J=12.6Hz, 1H) .HRMS (ESI): calcd.forC
22h
15nNaO
5[M+Na]
+396.0842; Found396.0848.
The synthesis of embodiment 9 compound 3i
HP (0.5mmol), furfuryl propiolate (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3i, yield 90% after concentrated through column chromatography for separation.White solid; M.p.162-163 DEG C of .IR (KBr): ν=3473,3412,3232,3053,1790,1739,1710,1685,1637,1616,1483,1464,1383,1186,1138,1080,976,883,700,619cm
-1.
1hNMR (300MHz, DMSO) δ 8.32 (s, 1H), 7.88-7.76 (m, 4H), 7.70-7.59 (m, 2H), 6.56 (d, J=3.1Hz, 1H), 6.46 (dd, J=2.9,1.7Hz, 1H), (5.21 d, J=13.2Hz, 1H), 5.12 (d, J=13.3Hz, 1H) .HRMS (ESI): calcd.forC
16h
11nNaO
6[M+Na]
+336.0479; Found336.0481.
The synthesis of embodiment 10 compound 3j
HP (0.5mmol), ethyl butyn (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3j, yield 99% after concentrated through column chromatography for separation.White solid; M.p.55-56 DEG C of .IR (KBr): ν=3342,3209,3080,2982,1755,1707,1645,1608,1467,1400,1379,1334,1319,1290,1244,1174,1153,1099,1058,1033,970,914,752,707cm
-1.
1hNMR (300MHz, CDCl
3) δ 7.92 (d, J=7.7Hz, 1H), 7.65 (m, 2H), 7.46 (t, J=7.5Hz, 1H), 4.84 (brs, 1H), 4.23-4.15 (m, 1H), 4.15-4.06 (m, 1H), 2.26 (s, 3H), 1.26 (t, J=7.1Hz, 3H) .HRMS (ESI): calcd.forC
14h
14nO
5[M+H]
+276.0866; Found276.0868.
The synthesis of embodiment 11 compound 3k
HP (0.5mmol), ethyl phenylpropiolate (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3k, yield 99% after concentrated through column chromatography for separation.White solid; M.p.105-106 DEG C of .IR (KBr): ν=3379,3064,2955,1714,1635,1597,1494,1448,1396,1336,1290,1184,1070,1047,912,837,761,692cm
-1.
1hNMR (500MHz, DMSO) δ 8.06-7.44 (m, 10H), 4.13-4.09 (m, 1H), 4.08-3.95 (m, 1H), 1.11 (t, J=6.9Hz, 3H) .HRMS (ESI): calcd.forC
19h
16nO
5[M+H]
+338.1023; Found338.1037.
The synthesis of embodiment 12 compound 3l
HP (0.5mmol), 3-crotonylene-one (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3l, yield 96% after concentrated through column chromatography for separation.White solid; M.p.70-71 DEG C of .IR (KBr): ν=3416,3080,2922,2852,1757,1647,1610,1510,1469,1421,1381,1342,1251,1128,1078,943,871,763,705cm
-1.
1hNMR (300MHz, DMSO) δ 8.51 (s, 1H), 8.00 (d, J=7.7Hz, 1H), 7.89-7.72 (m, 2H), 7.68-7.55 (m, 2H), 2.21 (s, 3H) .HRMS (ESI): calcd.forC
12h
9nNaO
4[M+Na]
+254.0424; Found254.0429.
The synthesis of embodiment 13 compound 3m
HP (0.5mmol), 1-phenyl third-2-acetylenic ketone (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3m, yield 99% after concentrated through column chromatography for separation.White solid; M.p.157-158 DEG C of .IR (KBr): ν=3421,3063,1764,1745,1749,1626,1587,1508,1384,1359,1122,1076,891,875,727cm
-1.
1hNMR (300MHz, DMSO) δ 8.26 (s, 1H), 8.10 (d, J=7.7Hz, 1H), 7.94-7.77 (m, 3H), (7.70-7.56 m, 4H), 7.48 (t, J=7.6Hz, 2H) .HRMS (ESI): calcd.forC
17h
11nNaO
4[M+Na]
-316.0580; Found316.0587.
The synthesis of embodiment 14 compound 3n
HP (0.5mmol), 4-phenyl 3-crotonylene-one (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3n, yield 99% after concentrated through column chromatography for separation.White solid; M.p.162-163 DEG C of .IR (KBr): ν=3414,3269,3053,1753,1741,1629,1589,1469,1421,1383,1228,1087,1068,950,902,765,711cm
-1.
1hNMR (300MHz, CDCl
3) δ 8.09 (d, J=7.5Hz, 1H), (7.79 d, J=7.6Hz, 1H), (7.70 t, J=7.6Hz, 1H), 7.61-7.40 (m, 6H), 4.83 (brs, 1H), 1.87 (s, 3H) .HRMS (ESI): calcd.forC
18h
14nO
4[M+H]
+308.0917; Found308.0916.
The synthesis of embodiment 15 compound 3o
HP (0.5mmol), two phenyl-Ding-2-acetylenic ketone (0.6mmol) of 1,3-is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3o, yield 99% after concentrated through column chromatography for separation.White solid; M.p.154-155 DEG C of .IR (KBr): ν=3362,3068,2928,2843,1728,1631,1614,1593,1573,1492,1448,1350,1292,1232,1120,1074,902,765,734,696,653,605cm
-1.
1hNMR (300MHz, DMSO) δ 8.07 (d, J=2.2Hz, 1H), (7.89-7.80 m, 2H), 7.69-7.59 (m, 1H), (7.36-7.20 m, 7H), 7.10 (t, J=7.5Hz, 2H) .HRMS (ESI): calcd.forC
23h
16nO
4[M+H]
+370.1074; Found370.1073.
The synthesis of embodiment 16 compound 3p
HP (0.5mmol), 3-phenyl-1-(-3-pyridine)-Ding-2-acetylenic ketone (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3p, yield 80% after concentrated through column chromatography for separation.White solid; M.p.154-155 DEG C of .IR (KBr): ν=3421,3078,2845,1747,1635,1618,1589,1489,1419,1356,1236,1112,1082,1072,904,754,702cm
-1.
1hNMR (300MHz, DMSO) δ 8.44 (s, 1H), 8.40 (d, J=4.8Hz, 1H), 8.13 (s, 1H), 7.93-7.82 (m, 3H), (7.66 t, J=7.1Hz, 2H), (7.42-7.17 m, 5H), 7.10 (dd, J=7.8,4.9Hz, 1H) .HRMS (ESI): calcd.forC
22h
15n
2o
4[M+H]
+371.0126; Found371.0127.
The synthesis of embodiment 17 compound 3q
HP (0.5mmol), 1-phenyl-2-in heptan acetylenic ketone (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3q, yield 99% after concentrated through column chromatography for separation.White solid; M.p.111-112 DEG C of .IR (KBr): ν=3417,3066,2964,2933,2875,1755,1600,1587,1573,1465,1448,1367,1284,1236,1139,1101,927,740,700cm
-1.
1hNMR (300MHz, DMSO) δ 7.84-7.73 (m, 3H), (7.72-7.65 m, 1H), 7.65-7.43 (m, 6H), (2.18-1.99 m, 2H), 1.52-1.37 (m, 2H), 0.69 (t, J=7.4Hz, 3H) .HRMS (ESI): calcd.forC
20h
17nNaO
4[M+Na]
+358.1050; Found358.1053.
The synthesis of embodiment 18 compound 3r
HP (0.5mmol), diacetylene dimethyl phthalate (0.6mmol) is dissolved in 1mL dry DMF, adds catalyst P Ph
3(0.1mmol), the cancellation that adds water after room temperature reaction 1h is reacted, and with dichloromethane extraction, obtains corresponding isoindolone and isoxazole fused ring compound 3r, yield 99% after concentrated through column chromatography for separation.White solid; M.p.132-133 DEG C of .IR (KBr): ν=3410,3367,3026,2955,2922,2850,1759,1728,1699,1651,1616,1508,1440,1352,1338,1284,1238,1193,1151,1116,1087,898,794,758,729cm
-1.
1hNMR (300MHz, DMSO) δ 8.29 (s, 1H), 7.94-7.83 (m, 3H), 7.72-7.64 (m, 1H), 3.90 (d, J=0.9Hz, 3H), 3.73 (d, J=1.0Hz, 3H) .HRMS (ESI): calcd.forC
14h
11nNaO
7[M+Na]
+328.0428; Found328.0423.
Claims (3)
1. compound and its pharmacy acceptable salt, described compound is selected from:
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid, ethyl ester (3a)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-benzyl carboxylate (3b)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-methylthiobenzyl ester (3c)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-methoxy-benzyl ester (3d)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-methyl-benzyl ester (3e)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-luorobenzyl ester (3f)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-4-nitrobenzyl ester (3g)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-1-menaphthyl ester (3h)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid-furfuryl ester (3i)
3a-hydroxy-2-methyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid, ethyl ester (3j)
3a-hydroxyl-8-oxo-2-phenyl-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid, ethyl ester (3k)
3-ethanoyl-3a-hydroxyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3l)
3-benzoyl-3-ethanoyl-3a-hydroxyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3m)
3-ethanoyl-3a-hydroxyl-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3n)
3-benzoyl-3a-hydroxyl-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3o)
3a-hydroxyl-2-phenyl-3-(pyridine-3-carbonyl)-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3p)
3-benzoyl-3a-hydroxyl-2-propyl group-1-oxa--3aH-8a-azepine-cyclopenta [a] indenes-8-ketone (3q)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-2,3-dimethyl dicarboxylate (3r)
3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a) indenes-3-carboxylate methyl ester (3s)
2-hexyl-3a-hydroxyl-8-oxo-3a, 8-dihydro-1-oxa--8a-azepine-cyclopenta [a] indenes-3-carboxylic acid, ethyl ester (3u)
3-(4-fluoro benzoyl)-3a-hydroxyl-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3v)
3-(4-chlorobenzene formacyl)-3a-hydroxyl-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3w)
3a-hydroxyl-3-(4-anisoyl)-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3x)
3-(3,4-Dimethoxybenzoyl)-3a-hydroxyl-2-phenyl-3aH-1-oxa--8a-azepine-cyclopenta [a] indenes-8-ketone (3y).
2. the compound of claim 1, wherein pharmacy acceptable salt is the acid salt that described compound and following acid are formed: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, toxilic acid, Phenylsulfonic acid, succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid or tussol.
3. the synthetic method of the compound of claim 1, comprise following steps: electron-deficient alkynes analog derivative reacts with HP in a mild condition, under triphenyl phosphine catalyst, ring-closure reaction occurs, obtain a kind of isoindolone and isoxazole fused ring compound, its reaction formula is as follows:
Wherein, R
1, R
2for the substituted radical that compound described in claim 1 is corresponding; Concrete operation step is: electron-deficient alkynes analog derivative 1, HP 2 is dissolved in DMF, add triphenylphosphine, substantially complete to reaction in room temperature reaction, the cancellation that adds water is reacted, with dichloromethane extraction, after concentrated, obtain corresponding isoindolone and isoxazole fused ring compound 3 through column chromatography for separation, HP 2, PPh
3be 1: 0.2: 1.2 with the molar ratio of electron-deficient alkynes analog derivative 1.
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| CN85101795A (en) * | 1984-03-19 | 1987-04-08 | 美国辉瑞有限公司 | With 1, the two 2-oxyindoles that replace of 3-prepare pain killer and antiphlogistic |
| WO2004074282A1 (en) * | 2003-02-24 | 2004-09-02 | Pharmacia & Upjohn Company Llc | Antibacterial indolone oxazolidinones, intermediates for their preparation and pharmaceutical compositions containing them |
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| CN101973925A (en) * | 2010-10-15 | 2011-02-16 | 中国药科大学 | 2-indolone compound with anti-inflammatory activity, preparation method and medicinal application thereof |
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| CN85101795A (en) * | 1984-03-19 | 1987-04-08 | 美国辉瑞有限公司 | With 1, the two 2-oxyindoles that replace of 3-prepare pain killer and antiphlogistic |
| CN1658869A (en) * | 2002-06-03 | 2005-08-24 | 安万特医药德国有限公司 | N- ((3-oxo2, 3-dihydro-1H-isoindol-1-yl) acetyl) guanidine derivatives as NHE-1 inhibitors for the treatment of infarction and angina pectoris |
| WO2004074282A1 (en) * | 2003-02-24 | 2004-09-02 | Pharmacia & Upjohn Company Llc | Antibacterial indolone oxazolidinones, intermediates for their preparation and pharmaceutical compositions containing them |
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