CN103288711A - Preparation method of 3-hydroxy-2-alkoxy-3-phenyl-isoindol-1(2H)-ketone derivatives - Google Patents
Preparation method of 3-hydroxy-2-alkoxy-3-phenyl-isoindol-1(2H)-ketone derivatives Download PDFInfo
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- CN103288711A CN103288711A CN2013102117068A CN201310211706A CN103288711A CN 103288711 A CN103288711 A CN 103288711A CN 2013102117068 A CN2013102117068 A CN 2013102117068A CN 201310211706 A CN201310211706 A CN 201310211706A CN 103288711 A CN103288711 A CN 103288711A
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- 0 *NC(C1=CCC=CCCCC1)=O Chemical compound *NC(C1=CCC=CCCCC1)=O 0.000 description 2
- NQFJNCRFKLWAJT-UHFFFAOYSA-N CC(C)C(c1ccccc1C1=O)(N1OC)O Chemical compound CC(C)C(c1ccccc1C1=O)(N1OC)O NQFJNCRFKLWAJT-UHFFFAOYSA-N 0.000 description 1
- QYDQFMMAAAJBOU-UHFFFAOYSA-N CC(C)OC(c1cc(Br)ccc1C1=O)(c2ccccc2)N1OC Chemical compound CC(C)OC(c1cc(Br)ccc1C1=O)(c2ccccc2)N1OC QYDQFMMAAAJBOU-UHFFFAOYSA-N 0.000 description 1
- MDHGALFBIQJLLE-UHFFFAOYSA-N CON(C(c1c2c(Cl)ccc1)(c1ccccc1)O)C2=O Chemical compound CON(C(c1c2c(Cl)ccc1)(c1ccccc1)O)C2=O MDHGALFBIQJLLE-UHFFFAOYSA-N 0.000 description 1
- HRGLSXQVDIZLPP-UHFFFAOYSA-N COc1cc(C(N(C2(c3ccccc3)O)OC)=O)c2cc1 Chemical compound COc1cc(C(N(C2(c3ccccc3)O)OC)=O)c2cc1 HRGLSXQVDIZLPP-UHFFFAOYSA-N 0.000 description 1
- XZAFEMICQVOTAE-UHFFFAOYSA-N COc1ccc(C(c2ccccc2C2=O)(N2OC)O)cc1 Chemical compound COc1ccc(C(c2ccccc2C2=O)(N2OC)O)cc1 XZAFEMICQVOTAE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of 3-hydroxy-2-alkoxy-3-phenyl-isoindol-1(2H)-ketone derivatives. The preparation method comprises the following steps of: dissolving N-alkoxy amide (I) and aldehyde (II) into a solvent; adding a palladium catalyst and an oxidant in sequence; reacting for 10-60 minutes at 80-120 DEG C; adding a saturated sodium thiosulfate aqueous solution; extracting with acetic ether; and purifying through column chromatographic separation to obtain the 3-hydroxy-2-alkoxy-3-phenyl-isoindol-1(2H)-ketone derivatives (III), wherein an equation is shown in the specification. The preparation method has the advantages that operation is simple, reaction raw materials and reactive reagents are easily available, types of product substituting groups are diverse, reaction innovation is high, the yield is high, etc.
Description
Technical field
The present invention relates to the preparation method of 3-hydroxyl-2-alkoxyl group-3-substituting group isoindole-1 (2H)-ketones derivant.
Background technology
Isoindolone extensively is present in many natural products and the bioactive molecules as a kind of effective heterocycle molecule, has been found it and has had diuresis, and is antibiotic, biological activitys such as hypertension.
Because it has the unique biological activity, paid close attention to by chemists about the research of the synthetic method of isoindolone always.Nearest 2 years, the chemist hankered after making up by the method for hydrocarbon activation the strategy of isoindolone structural unit, had reported by the synthetic isoindolone of the method for trivalent rhodium catalysis and derivative thereof.Specifically referring to following document:
[1]W.S.McKenzie?and?M.Rosenbery,J.Mass.Dent.Soc?2007,56,44-45.
[2]J.E.Wright,D.W.Reynolds?and?M.E.Edwards,J.Am.Med.Assoc.2002,288,2981-2986.
[3]F.G.Fang?and?S.J.Danishefsky,Tetrahedron?Lett.1989,30,2747-2752.
[4]V.Fajardo,V.Elango,B.K.Cassels?and?M.Shamma,Tetrahedron?Lett.1982,23,39-42.
[5]E.C.Izgu?and?T.R.Hoye,Chem.Sci.2013,4,2262-2266.
[6]E.Fuse,T.Kuwabara,A.Sparreboom,E.A.Sausville?and?W.D.Figg,J.Clin.Pharmacol.,2005,45,394-403.
[7]S.Sharma,E.Park,J.Park?and?I.S.Kim,Org.Lett.2012,14,906-909.
Yet the method that catalyzes and synthesizes isoindolone by the divalence palladium also is not in the news.
Summary of the invention
The object of the present invention is to provide the preparation method of 3-hydroxyl-2-alkoxyl group-3-phenyl isoindole-1 (2H)-ketones derivant (III).
Technical scheme of the present invention is summarized as follows:
The preparation method of a kind of 3-hydroxyl-2-alkoxyl group-3-phenyl isoindole-1 (2H)-ketones derivant, comprise the steps: N-alkoxyl group acid amides (I) and aldehyde (II) are dissolved in the solvent, add palladium catalyst successively, oxygenant in 80-120 ℃ of reaction 10-60min, adds saturated aqueous sodium thiosulfate, use ethyl acetate extraction, through column chromatography separating purification, obtain 3-hydroxyl-2-alkoxyl group-3-phenyl isoindole-1 (2H)-ketones derivant (III), reaction formula is:
R wherein
1Be methoxyl group, benzyloxy or isopropoxy;
R
2Be phenyl, propyl group, sec.-propyl, rubigan or p-methoxyphenyl;
Ar is phenyl or substituted-phenyl.
Described substituted-phenyl is: 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-p-methoxy-phenyl, 2-chloro-phenyl-, 2-aminomethyl phenyl, 3-chloro-phenyl-, 3-p-methoxy-phenyl or 2,3-Dimethoxyphenyl.
Described palladium catalyst is palladium, Palladous chloride, palladium trifluoroacetate or three (dibenzalacetone) two palladiums.
Described oxygenant is peroxy tert-butyl alcohol, hydrogen peroxide, benzoquinones, ammonium persulphate or Potassium Persulphate.
Described solvent is 1,4-dioxane, tetrahydrofuran (THF), toluene, p-Xylol, ethanol, butanols, the trimethyl carbinol, dimethyl formamide, dimethyl methyl sulfone, acetonitrile, acetic acid or ethyl acetate.
Preferably 100 ℃ of temperature of reaction, the reaction times is 15min preferably.
Oxygenant is preferably selected peroxy tert-butyl alcohol for use.
The present invention has simple to operate, and reaction raw materials and reaction reagent are easy to get, and product substituting group type is various, the reaction strong innovation, and yield is than advantages such as height.
Embodiment
The synthetic method total reaction equation of 3-hydroxyl of the present invention-2-alkoxyl group-3-phenyl isoindole-1 (2H)-ketones derivant (III) is:
Needed reaction raw materials N-alkoxyl group acid amides (I) among the embodiment, be the preparation of reference literature method ([1] N.Guilmond, C.Gouliaras, K.Fagnou, J.Am.Chem.Soc.2010,132,6908-6909.[2] L.Ackermann, A.V.Lygin, N.Hofmann, Angew.Chem.Int.Ed.2011,50,6379-6382.)
The present invention is further illustrated below in conjunction with specific embodiment.
Embodiment 1
The preparation of 3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-a)
With N-methoxy benzamide (I-a) (45mg, 0.3mmol) and phenyl aldehyde (II-a) (160mg 1.5mmol) is dissolved in 1, the 4-dioxane (0.2M, 1.5mL) in, add palladium (6.7mg subsequently successively, 10mol%), peroxy tert-butyl alcohol (40%in H
2O, 2.5mmol), mixture reacts 10min down at 100 ℃, after reaction finishes, add saturated aqueous sodium thiosulfate (20mL), with ethyl acetate (20mL x3) extraction, organic phase is through the anhydrous sodium sulfate drying after-filtration, revolve and desolventize, crude product gets 3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketones derivant (III-a) 116mg through column chromatography separating purification, is white solid, productive rate: 91%, fusing point: 162-163 ℃.
1H?NMR(600MHz,CDCl
3):δ7.81(d,J=7.5Hz,1H,ArH),7.53(td,J=7.5Hz,J=1.0Hz,1H,ArH),7.50-7.47(m,3H,ArH),7.38-7.34(m,3H,ArH),7.29(d,J=7.5Hz,1H,ArH),3.90(s,3H,OCH
3),3.69(br?s,1H,OH).
Embodiment 2
The preparation of 5-fluoro-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-b)
With 4-fluoro-N-methoxy benzamide (I-b) (51mg, 0.3mmol) and phenyl aldehyde (II-a) (160mg 1.5mmol) is raw material, be dissolved in tetrahydrofuran (THF) (0.2M, 1.5mL) in, add Palladous chloride (5.3mg subsequently successively, 10mol%), hydrogen peroxide (40% in H
2O, 2.5mmol), mixture reacts 10min down at 120 ℃, after reaction finishes, add saturated aqueous sodium thiosulfate (20mL), with ethyl acetate (20mL x3) extraction, organic phase is through the anhydrous sodium sulfate drying after-filtration, revolve and desolventize, crude product obtains 5-fluoro-3-hydroxyl-2 methoxyl groups-3-phenyl isoindole-1 (2H)-ketone (III-b) through column chromatography separating purification, obtains white solid, productive rate: 83%, fusing point: 146-147 ℃.
1H?NMR(600MHz,CDCl
3):δ7.70(dd,J=8.0,5.0Hz,1H,ArH),7.46(d,J=6.5Hz,2H,ArH),7.38-7.36(m,3H,ArH),7.11(t,J=8.5Hz,1H,ArH),7.97(d,J=7.5Hz,1H,ArH),4.57(s,1H,OH),3.83(s,3H,OCH
3).
Embodiment 3
The preparation of 5-chloro-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-c)
With 4-chloro-N-methoxy benzamide (I-c) (56mg, 0.3mmol) and phenyl aldehyde (II-a) (160mg 1.5mmol) is raw material, be dissolved in toluene (0.2M, 1.5mL) in, add palladium trifluoroacetate (10.0mg subsequently successively, 10mol%), benzoquinones (40%in H
2O, 2.5mmol), mixture reacts 60min down at 80 ℃, after reaction finishes, add saturated aqueous sodium thiosulfate (20mL), with ethyl acetate (20mL x3) extraction, organic phase is through the anhydrous sodium sulfate drying after-filtration, revolve and desolventize, crude product obtains 5-chloro-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-c) through column chromatography separating purification, obtains white solid, productive rate: 75%, fusing point: 165-167 ℃.
1H?NMR(600MHz,CDCl
3):δ7.64(d,J=8.0Hz,1H,ArH),7.46(d,J=8.0Hz,2H,ArH),7.40(dd,J=8.0,1.5Hz,1H,ArH),7.39-7.36(m,3H,ArH),7.26(s,1H,ArH),4.51(br?s,1H,OH),3.84(s,3H,OCH
3).
Experiment showed, and use ethanol, butanols, the trimethyl carbinol, dimethyl formamide, dimethyl methyl sulfone, acetonitrile, acetic acid or ethyl acetate substitute the toluene in the present embodiment, can prepare product 5-chloro-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-c).
Embodiment 4
The preparation of 5-bromo-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-d)
With 4-bromo-N-methoxy benzamide (I-d) (69mg, 0.3mmol) and phenyl aldehyde (II-a) (160mg, 1.5mmol) be raw material, be dissolved in p-Xylol (0.2M, 1.5mL) in, add successively subsequently three (dibenzalacetones), two palladiums (27.5mg, 10mol%), ammonium persulphate (40%in H
2O, 2.5mmol), mixture reacts 15min down at 100 ℃, after reaction finishes, add saturated aqueous sodium thiosulfate (20mL), with ethyl acetate (20mL x3) extraction, organic phase is through the anhydrous sodium sulfate drying after-filtration, revolve and desolventize, crude product obtains 5-bromo-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-d) through column chromatography separating purification, obtains white solid, productive rate: 72%, fusing point: 178-180 ℃.
1H?NMR(600MHz,CDCl
3):δ7.58(s,2H,ArH),7.46(d,J=6.5Hz,2H,ArH),7.42(s,1H,ArH),7.39-7.37(m,3H,ArH),4.35(br?s,1H,OH),3.85(s,3H,OCH
3).
With the Potassium Persulphate of the alternative present embodiment of ammonium persulphate, other same present embodiment can be prepared corresponding product.
Embodiment 5
The preparation of 5-trifluoromethyl-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-e)
Be raw material with 4-trifluoromethyl-N-methoxy benzamide (I-e) and phenyl aldehyde (II-a), synthetic method with reference to (III-a) among the embodiment 1, preparation 5-trifluoromethyl-3-hydroxyl-2 methoxyl groups-3-phenyl isoindole-1 (2H)-ketone (III-e), obtain white solid, productive rate: 68%, fusing point: 167-168 ℃.
1H?NMR(600MHz,CDCl
3):δ7.80(d,J=7.5Hz,1H,ArH),7.69(d,J=7.5Hz,1H,ArH),7.55(s,1H,ArH),7.47(d,J?=7.0Hz,2H,ArH),7.43-7.26(m,3H,ArH),4.84(brs,1H,OH),3.84(s,3H,OCH
3).
Embodiment 6
The preparation of 5-nitro-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-f)
Be raw material with 4-nitro-N-methoxy benzamide (I-f) and phenyl aldehyde (II-a), synthetic method with reference to (III-a) among the embodiment 1, preparation 5-nitro-3-hydroxyl-2 methoxyl groups-3-phenyl isoindole-1 (2H)-ketone (III-f), obtain white solid, productive rate: 69%, fusing point: 159-161 ℃.
1H?NMR(600MHz,CDCl
3):δ8.33(d,J=8.5,1.5Hz,1H,ArH),8.12(d,J=1.5Hz,1H,ArH),7.95(d,J=8.5Hz,1H,ArH),7.50-7.49(m,2H,ArH),7.42-7.40(m,3H,ArH),4.55(brs,1H,OH),3.89(s,3H,OCH
3).
Embodiment 7
The preparation of 5-methoxyl group-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-g)
Be raw material with 4-methoxyl group-N-methoxy benzamide (I-g) and phenyl aldehyde (II-a), synthetic method with reference to (III-a) among the embodiment 1, preparation 5-methoxyl group-3-hydroxyl-2 methoxyl groups-3-phenyl isoindole-1 (2H)-ketone (III-g), obtain white solid, productive rate: 78%, fusing point: 154-157 ℃.
1H?NMR(600MHz,CDCl
3):δ7.67(d,J=8.0Hz,1H,ArH),7.48(d,J=7.0Hz,2H,ArH),7.37-7.33(m,3H,ArH),6.93(d,J=8.0Hz,1H,ArH),6.74(s,1H,ArH),4.01(brs,1H,OH),3.85(s,3H,OCH
3),3.77(s,3H,OCH
3).
Embodiment 8
The preparation of 7-chloro-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-h)
Be raw material with 2-chloro-N-methoxy benzamide (I-h) and phenyl aldehyde (II-a), synthetic method with reference to (III-a) among the embodiment 1, preparation 7-chloro-3-hydroxyl-2 methoxyl groups-3-phenyl isoindole-1 (2H)-ketone (III-h), obtain white solid, productive rate: 73%, fusing point: 172-175 ℃.
1H?NMR(400MHz,CDCl
3):δ7.48(d,J=7.5Hz,2H,ArH),7.42(t,J=7.5Hz,1H,ArH),7.36-7.34(m,4H,ArH),7.17(d,J=7.5Hz,1H,ArH),4.21(brs,1H,OH),3.86(s,3H,OCH3).
Embodiment 9
The preparation of 7-methyl-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-i)
Be raw material with 2-methyl-N-methoxy benzamide (I-i) and phenyl aldehyde (II-a), synthetic method with reference to (III-a) among the embodiment 1, preparation 7-methyl-3-hydroxyl-2 methoxyl groups-3-phenyl isoindole-1 (2H)-ketone (III-i), obtain white solid, productive rate: 93%, fusing point: 142-143 ℃.
1H?NMR(600MHz,CDCl
3):δ7.50(d,J=7.0Hz,2H,ArH),7.39-7.32(m,4H,ArH),7.21(d,J=7.5Hz,1H,ArH),7.09(d,J=7.5Hz,1H,ArH),3.89(s,3H,OCH
3),3.59(s,1H,OH),2.66(s,3H,CH
3).
Embodiment 10
The preparation of 6-chloro-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-j)
Be raw material with 3-chloro-N-methoxy benzamide (I-j) and phenyl aldehyde (II-a), synthetic method with reference to (III-a) among the embodiment 1, preparation 6-chloro-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-j), obtain white solid, productive rate: 76%, fusing point: 150-151 ℃.
1H?NMR(600MHz,CDCl
3):δ7.71(d,J=1.5Hz,1H,ArH),7.50(dd,J=8.0,2.0Hz,1H,ArH),7.47(dd,J=8.0,1.5Hz,2H,ArH),7.39-7.36(m,3H,ArH),7.23(d,J=7.5Hz,1H,ArH),3.91(brs,1H,OH),3.87(s,3H,OCH
3).
Embodiment 11
The preparation of 6-methoxyl group-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-k)
Be raw material with 3-methoxyl group-N-methoxy benzamide (I-k) and phenyl aldehyde (II-a), synthetic method with reference to (III-a) among the embodiment 1, preparation 6-methoxyl group-3-hydroxyl-2-methoxyl group-3-phenyl isoindole-1 (2H)-ketone (III-k), obtain white solid, productive rate: 72%, fusing point: 146-148 ℃.
1H?NMR(600MHz,CDCl
3):δ7.46(d,J=7.0Hz,2H,ArH),7.36-7.32(m,3H,ArH),7.21(d,J=2.0Hz,1H,ArH),7.16(d,J=8.0Hz,1H,ArH),7.02(dd,J=8.0Hz,1H,ArH),4.32(br?s,1H,OH),3.85(s,3H,OCH
3),3.81(s,3H,OCH
3).
Embodiment 12
3-hydroxyl-2,6, the preparation of 7-trimethoxy-3-phenyl isoindole-1 (2H)-ketone (III-l)
With 2,3-dimethoxy-N-methoxy benzamide (I-l) and phenyl aldehyde (II-a) are raw material, synthetic method with reference to (III-a) among the embodiment 1, preparation 3-hydroxyl-2,6,7-trimethoxy-3-phenyl isoindole-1 (2H)-ketone (III-l) obtains white solid, productive rate: 61%, fusing point: 149-152 ℃.
1H?NMR(600MHz,CDCl
3):δ7.49(d,J=7.0Hz,2H,ArH),7.36-7.31(m,3H,ArH),6.98(d,J=8.0Hz,1H,ArH),6.91(d,J=8.0Hz,1H,ArH),4.01(s,3H,OCH
3),3.88(s,3H,OCH
3),3.83(s,3H,OCH
3),3.72(br?s,1H,OH).
Embodiment 13
The preparation of 3-(4-chloro-phenyl-)-3-hydroxyl-2-methoxyl group isoindole-1 (2H)-ketone (III-m)
Be raw material with N-methoxy benzamide (I-a) and 4-chloro-benzaldehyde (II-b), synthetic method with reference to (III-a) among the embodiment 1, preparation 3-(4-chloro-phenyl-)-3-hydroxyl-2-methoxyl group isoindole-1 (2H)-ketone (III-m), obtain white solid, productive rate: 79%, fusing point: 180-183 ℃.
1H?NMR(600MHz,CDCl
3):δ7.81(d,J=7.5Hz,1H,ArH),7.56(t,J=7.5Hz,1H,ArH),7.50(d,J=7.5Hz,1H,ArH),7.42(d,J=8.5Hz,2H,ArH),7.34(d,J=8.5Hz,2H,ArH),7.28(d,J=7.5Hz,1H,ArH),3.91(s,3H,OCH
3),3.57(br?s,1H,OH).
Embodiment 14
The preparation of 3-hydroxyl-2-methoxyl group-3-(4-p-methoxy-phenyl) isoindole-1 (2H)-ketone (III-n)
Be raw material with N-methoxy benzamide (I-a) and aubepine (II-c), synthetic method with reference to (III-a) among the embodiment 1, preparation 3-hydroxyl-2-methoxyl group-3-(4-p-methoxy-phenyl) isoindole-1 (2H)-ketone (III-n), obtain white solid, productive rate: 82%, fusing point: 138-140 ℃.
1HNMR(600MHz,CDCl
3):δ7.72(d,J=7.5Hz,1H,ArH),7.51(td,J=8.0,1.0Hz,1H,ArH),7.43(d,J=7.5Hz,1H,ArH),7.38(d,J=8.5Hz,2H,ArH),7.28(d,J=7.1H,OH),3.86(s,3H,OCH
3),3.78(s,3H,OCH
3).
Embodiment 15
The preparation of 3-hydroxyl-2-methoxyl group-3-propyl group isoindole-1 (2H)-ketone (III-o)
Be raw material with N-methoxy benzamide (I-a) and butyraldehyde (II-d), with reference to the synthetic method of (III-a) among the embodiment 1, preparation 3-hydroxyl-2-methoxyl group-3-propyl group isoindole-1 (2H)-ketone (III-o) obtains white solid, productive rate: 82%, fusing point: 72-75 ℃.
1HNMR(600MHz,CDCl
3):δ7.73(d,J=7.5Hz,1H,ArH),7.59(t,J=7.0Hz,1H,ArH),7.49-7.46(m,2H,ArH),4.05(s,3H,OCH3),3.23(s,1H,OH),2.21(td,J=12.0,5.0Hz,1H,CH
AH
B),2.07(td,J=12.0,4.0Hz,1H,CH
AH
B),1.14-1.05(m,1H,CH
AH
B),0.80(t,J=7.0Hz,3H,CH
3),0.78-0.69(m,1H,CH
AH
B).
Embodiment 16
The preparation of 5-chloro-3-hydroxyl-2-methoxyl group-3-propyl group isoindole-1 (2H)-ketone (III-p)
Be raw material with 4-chloro-N-methoxy benzamide (I-c) and butyraldehyde (II-d), synthetic method with reference to (III-a) among the embodiment 1, preparation 5-chloro-3-hydroxyl-2-methoxyl group-3-propyl group isoindole-1 (2H)-ketone (III-p), obtain white solid, productive rate: 88%, fusing point: 100-102 ℃.
1H?NMR(600MHz,CDCl
3):δ7.63(d,J=7.5Hz,1H,ArH),7.47(d,J=1.5Hz,1H,ArH),7.44(dd,J=7.5,1.5Hz,2H,ArH),4.04(s,3H,OCH
3),3.71(brs,1H,OH),2.21(td,J=13.0,4.5Hz,1H,CH
AH
B),2.06(td,J=13.0,4.5Hz,1H,CH
AH
B),1.10-1.06(m,1H,CH
AH
B),0.83(t,J=7.5Hz,3H,CH
3),0.76-0.71(m,1H,CH
AH
B).
Embodiment 17
3-hydroxyl-2, the preparation of 5-dimethoxy-3-propyl group isoindole-1 (2H)-ketone (III-q)
Be raw material with 4-methoxyl group-N-methoxy benzamide (I-g) and butyraldehyde (II-d), with reference to the synthetic method of (III-a) among the embodiment 1, preparation 3-hydroxyl-2,5-dimethoxy-3-propyl group isoindole-1 (2H)-ketone (III-q), obtain yellow oil, productive rate: 65%.
1H?NMR(600MHz,CDCl
3):δ7.60(d,J=8.5Hz,1H,ArH),6.95(s,1H,ArH),6.93(d,J=8.5Hz,1H,ArH),4.02(s,3H,OCH
3),3.86(s,3H,OCH
3),3.82(brs,1H,OH),2.20(td,J=13.5,4.5Hz,1H,CH
AH
B),2.01(td,J=13.5,4.5Hz,1H,CH
AH
B),1.10-1.04(m,1H,CH
AH
B),0.81(t,J=7.5Hz,3H,CH
3),0.75-0.68(m,1H,CH
AH
B).
Embodiment 18
The preparation of 3-hydroxyl-3-sec.-propyl-2-methoxyl group isoindole-1 (2H)-ketone (III-r)
Be raw material with N-methoxy benzamide (I-a) and isobutyric aldehyde (II-e), with reference to the synthetic method of (III-a) among the embodiment 1, preparation 3-hydroxyl-3-sec.-propyl-2-dimethoxy isoindole-1 (2H)-ketone (III-r) obtains white solid, productive rate: 84%, fusing point: 130-132 ℃.
1H?NMR(600MHz,CDCl
3):δ7.73(d,J=7.5Hz,1H,ArH),7.57(d,J=7.5Hz,1H,ArH),7.51-7.47(m,2H,ArH),4.03(s,3H,OCH
3),3.45(brs,1H,OH),2.67-2.63(m,1H,CH),1.17(d,J=7.5Hz,3H,CH
3),7.73(d,J=7.5Hz,3H,CH
3).
Embodiment 19
The preparation of 2-benzyloxy-3-hydroxyl-3-phenyl isoindole-1 (2H)-ketone (III-s)
Be raw material with N-benzyloxy benzamide (I-m) and phenyl aldehyde (II-a), with reference to the synthetic method of (III-a) among the embodiment 1, preparation 2-benzyloxy-3-hydroxyl-3-phenyl isoindole-1 (2H)-ketone (III-s) obtains white solid, productive rate: 81%, fusing point: 163-164 ℃.
1H?NMR(600MHz,CDCl
3):δ7.79(d,J=7.5Hz,1H,ArH),7.51(t,J=7.5Hz,1H,ArH),7.46-7.44(m,3H,ArH),7.37-7.35(m,3H,ArH),7.30(s,5H,ArH),7.26(d,J=7.0Hz,1H,ArH),5.16(d,J=10.5Hz,1H,CH
AH
B),4.90(d,J=10.5Hz,1H,CH
AH
B),3.28(brs,1H,OH).
Embodiment 20
The preparation of 3-hydroxyl-2-isopropoxy-3-phenyl isoindole-1 (2H)-ketone (III-t)
Be raw material with N-isopropoxy benzamide (I-n) and phenyl aldehyde (II-a), with reference to the synthetic method of (III-a) among the embodiment 1, preparation 3-hydroxyl-2-isopropoxy-3-phenyl isoindole-1 (2H)-ketone (III-t) obtains white solid, productive rate: 76%, fusing point: 151-153 ℃.
1H?NMR(600MHz,CDCl
3):δ7.85(d,J=7.5Hz,1H,ArH),7.54(t,J=7.0Hz,1H,ArH),7.50(t,J=7.0Hz,1H,ArH),7.45(dd,J=7.5,2.0Hz,2H,ArH),7.37-7.33(m,3H,ArH),7.29(d,J=7.5Hz,1H,ArH),4.26-4.22(m,1H,OCH),3.39(brs,1H,OH),1.25(d,J=6.0Hz,3H,CH
3),1.19(d,J=6.0Hz,3H,CH
3).
The above, only being part embodiment of the present invention, is not that the present invention is done any pro forma restriction, any simple modification that every foundation technical spirit of the present invention is done above-described embodiment, equivalent variations and modification all belong in the technical solution of the present invention scope.
Claims (7)
1. the preparation method of 3-hydroxyl-2-alkoxyl group-3-phenyl isoindole-1 (2H)-ketones derivant, it is characterized in that comprising the steps: N-alkoxyl group acid amides (I) and aldehyde (II) are dissolved in the solvent, add palladium catalyst successively, oxygenant in 80-120 ℃ of reaction 10-60min, adds saturated aqueous sodium thiosulfate, use ethyl acetate extraction, through column chromatography separating purification, obtain 3-hydroxyl-2-alkoxyl group-3-phenyl isoindole-1 (2H)-ketones derivant (III), reaction formula is:
R wherein
1Be methoxyl group, benzyloxy or isopropoxy;
R
2Be phenyl, propyl group, sec.-propyl, rubigan or p-methoxyphenyl;
Ar is phenyl or substituted-phenyl.
2. method according to claim 1 is characterized in that described substituted-phenyl is: 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, the 4-trifluoromethyl, 4-nitrophenyl, 4-p-methoxy-phenyl, 2-chloro-phenyl-, 2-aminomethyl phenyl, 3-chloro-phenyl-, 3-p-methoxy-phenyl or 2,3-Dimethoxyphenyl.
3. method according to claim 1 is characterized in that described palladium catalyst is palladium, Palladous chloride, palladium trifluoroacetate or three (dibenzalacetone) two palladiums.
4. method according to claim 1 is characterized in that described oxygenant is peroxy tert-butyl alcohol, hydrogen peroxide, benzoquinones, ammonium persulphate or Potassium Persulphate.
5. method according to claim 1 is characterized in that described solvent is 1,4-dioxane, tetrahydrofuran (THF), toluene, p-Xylol, ethanol, butanols, the trimethyl carbinol, dimethyl formamide, dimethyl methyl sulfone, acetonitrile, acetic acid or ethyl acetate.
6. method according to claim 1 is characterized in that temperature of reaction is 100 ℃, and the reaction times is 15min.
7. method according to claim 4 is characterized in that described oxygenant is peroxy tert-butyl alcohol.
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CN102617444A (en) * | 2012-03-12 | 2012-08-01 | 浙江大学 | Metabotropic glutamate receptor enhancer analogue and preparation method thereof |
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