CN101602705A - Hexahydroisoindole-1-keto compound and synthetic method thereof - Google Patents
Hexahydroisoindole-1-keto compound and synthetic method thereof Download PDFInfo
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- CN101602705A CN101602705A CNA2009101007577A CN200910100757A CN101602705A CN 101602705 A CN101602705 A CN 101602705A CN A2009101007577 A CNA2009101007577 A CN A2009101007577A CN 200910100757 A CN200910100757 A CN 200910100757A CN 101602705 A CN101602705 A CN 101602705A
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- phenyl
- ketone
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 26
- 239000002585 base Substances 0.000 claims abstract description 95
- -1 methoxybenzyl Chemical group 0.000 claims abstract description 68
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 63
- 239000001257 hydrogen Substances 0.000 claims abstract description 63
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 33
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical class CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims abstract description 27
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 19
- 150000001299 aldehydes Chemical class 0.000 claims abstract description 17
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 12
- 239000011707 mineral Substances 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 5
- 150000001242 acetic acid derivatives Chemical class 0.000 claims abstract description 4
- 238000009833 condensation Methods 0.000 claims abstract description 4
- 230000005494 condensation Effects 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 66
- 150000005171 halobenzenes Chemical group 0.000 claims description 54
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000012046 mixed solvent Substances 0.000 claims description 12
- 235000010755 mineral Nutrition 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 9
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- 235000015320 potassium carbonate Nutrition 0.000 claims description 9
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 150000002081 enamines Chemical class 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- HSFHMJJDUVEWRQ-UHFFFAOYSA-N penta-2,4-dien-1-amine Chemical compound NCC=CC=C HSFHMJJDUVEWRQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000009509 drug development Methods 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 238000012216 screening Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 19
- 238000000034 method Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 150000001993 dienes Chemical group 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000005698 Diels-Alder reaction Methods 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- 239000012230 colorless oil Substances 0.000 description 6
- JVHIPYJQMFNCEK-UHFFFAOYSA-N cytochalasin Natural products N1C(=O)C2(C(C=CC(C)CC(C)CC=C3)OC(C)=O)C3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 JVHIPYJQMFNCEK-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- ZMAODHOXRBLOQO-UHFFFAOYSA-N cytochalasin-A Natural products N1C(=O)C23OC(=O)C=CC(=O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 ZMAODHOXRBLOQO-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XXSPGBOGLXKMDU-UHFFFAOYSA-N 2-bromo-2-methylpropanoic acid Chemical class CC(C)(Br)C(O)=O XXSPGBOGLXKMDU-UHFFFAOYSA-N 0.000 description 1
- ASCFNMCAHFUBCO-UHFFFAOYSA-N 2-phosphoglycolic acid Chemical compound OC(=O)COP(O)(O)=O ASCFNMCAHFUBCO-UHFFFAOYSA-N 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- NAEWXXDGBKTIMN-OWTACEMYSA-N 53760-19-3 Chemical class C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@H]\3[C@]2([C@@H](/C=C/[C@](C)(O)C[C@@H](C)C/C=C/3)OC(C)=O)C(=O)N1)=C)C)C1=CC=CC=C1 NAEWXXDGBKTIMN-OWTACEMYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 1
- 108010016183 Human immunodeficiency virus 1 p16 protease Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 150000003869 acetamides Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000739 chaotic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- JVHIPYJQMFNCEK-ZPSJVCBQSA-N l-696,474 Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@H]\3[C@]2([C@@H](/C=C/[C@@H](C)C[C@@H](C)C/C=C/3)OC(C)=O)C(=O)N1)=C)C)C1=CC=CC=C1 JVHIPYJQMFNCEK-ZPSJVCBQSA-N 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000003632 microfilament Anatomy 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical class CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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- Indole Compounds (AREA)
Abstract
The invention discloses a kind of Hexahydroisoindole-1-keto compound and synthetic method thereof.The structure of this six hydrogen isoindole-1-ketone is suc as formula (I) or formula (II), or the enantiomer of formula (I), formula (II), in the formula, and R
1Be hydrogen, methyl or aromatic base; R
2Be hydrogen or methyl; R
3For benzyl or to methoxybenzyl; R
4Be hydrogen, methyl, carbalkoxy, benzoyl or aromatic base.The synthetic method of this six hydrogen isoindole-1-ketone is with 2, and 4-pentadiene amine generates corresponding alpha-brominated ethanamide with alpha-brominated acetate condensation earlier, in the presence of triphenylphosphine and mineral alkali, obtains with aldehyde reaction under appropriate solvent and temperature condition then.Hexahydroisoindole-1-keto compound of the present invention and synthetic method thereof can be used for bioactivity screening or drug development.
Description
Technical field
The present invention relates to nitrogenous dicyclic compound and their synthetic method, be specifically related to utilize by alpha-brominated ethanamide that contains the diene structure and aldehyde and carry out " one kettle way " Wei Tixi-Di Si-Alder (Wittig-Diels-Alder) reaction carrying out synthetic method and product thereof.
Background technology
Six hydrogen isoindole unit are present in many natural compounds molecules and the drug molecule as a kind of dominance structure.Six hydrogen isoindole more are that the structural unit form with six hydrogen isoindole-1-ketone appears at natural compounds, particularly in the Cytochalasin compounds.This compounds belongs to the secondary metabolite of mushroom, can separate to obtain from many different mushrooms, has reached more than 80 compound that structure is different at present.They have numerous biological activitys, can stop the division of cell as some and cause apoptosis (Carter, S.B.Effects of Cytochalasins on Mammalian Cells Nature 1967,213, the 261-264 of cell; Rubtsova, S.N.; Kondratov, R.V.; Et al.Disruption of Actin Microfilaments by cCytochalasinD Leads to Activation of p53 FEBS Lett.1998,430,353-357), some can stop HIV-proteolytic enzyme (Lingham, R.B.; Hsu, A.; Et al.L-696,474, a Novel Cytochalasin as anInhibitor of HIV-1 Protease.3.Biological-Activity J.Antibiot.1992,45,686-691; Hungate, R.W.; Chen, J.L.; Et al.New Cytochalasins:Synthetic Studies of a NovelHIV-1 Protease Inhibitor Tetrahedron Lett.1996,37,4113-4116); What have can suppress plant-growth (Cox, R.H.; Cutler, H.G.; Et al.Proton and C-13 Nuclear Magnetic-Resonance Studies of The Conformation of Cytochalasin-H Derivatives andPlant-Growth Regulating effects of Cytochalasins J. Agric.Food Chem.1983,31,405-408).The six hydrogen isoindolone skeletons that comprised in these compounds are just like the structure of formula V, formula (VI), formula (VII), wherein have more than ten compound to have skeleton structure as formula V.
Formula V formula (VI) formula (VII)
Rudd, (Rudd, J.A. such as J.A.; Ngan, M.P.; Wai, M.K.Eur.J.Pharmacol.1999,366,243), Jiang, (Jiang, J. such as J.; Devita, R.J.; Kumar, S.; Mills, S.G.; Tschirret-Guth, R.A WO 2007002457,2007), and Cardenas, (Cardenas, A. such as A.; Lowe, R.; Oh, S.; 1, Bodkin, S.; Kenney, T.; Lamorte, W.W.; Afdhal, N.H.; Scan.J.Gastroenterol.2008,43, research work 328-333) shows hydrogenation isoindoles compound, can be used as tachykinin NK1 acceptor suc as formula the compound shown in (VIII) and the formula (IX) and ties anti-agent, is used for
Formula (VIII) formula (IX)
The chaotic disease of the health that treatment causes because of tachykinines is excessive is as vomiting, urinary incontinence, melancholy, anxiety, hypertension etc.
Utilize combinatorial chemistry synthetic compound storehouse to become very important instrument in the drug development, yet the report that comes synthesizing hydrogenated isoindole-1-ketone compounds storehouse with combinatorial chemistry seldom.Recently, (ZhangL. such as Zhang L.; Lushington, G.H.; Neuenswander, B.; Hershberger, J.C.; Malinakova, H.C.J.Comb.Chem.2008,10,285-302) reported that the coupling of Cu catalyzed three-component and Di Si-Alder (Diels-Alder) react the method in synthesizing hydrogenated isoindole-1-ketone compounds storehouse.
The triolefin that utilizes amido linkage to connect carries out the synthetic six hydrogen isoindole of intramolecularly Di Si-Alder (Diels-Alder) reaction-1-ketone compounds as precursor, its method is very easy, only need single step reaction just can set up and encircle twin nuclei, and establish ring simultaneously and go up a plurality of substituent stereochemistry.But this method need be introduced diene segment and close diene segment step by step, and various close diene segment (α, beta-unsaturated acyl base) (α, beta-unsaturated carboxylic acid) before introducing will be synthesized in advance.The synthetic method of carboxylic acid comprises Doebner (Doebner) condensation reaction of aldehyde and propanedioic acid, pendant gold (Perkin) condensation reaction with diacetyl oxide, react the alpha, beta-unsaturated esters hydrolysis again that obtains with Wei Tixi (Wittig) reaction of ethoxycarbonyl methylene radical phosphonium ylide or the Hall Na-Wo Zi Butterworth-Ai Mengsi (Horner-Wadsworth-Emmons) of triethyl carboxymethyl phosphoric acid ester.From aldehyde and two enamines, utilize this route (shown in reaction formula 1) to synthesize six hydrogen isoindole-1-ketone compounds, need three-step reaction at least.As the synthetic method of compound library, combined coefficient is restricted.
Reaction formula 1
Summary of the invention
The purpose of this invention is to provide the method for a kind of more effective synthetic six hydrogen isoindole-1-ketone compounds, and utilize this synthetic method by containing the diene structure alpha-brominated acetamides and the substituting group of aldehyde compound change the various six hydrogen isoindole of synthetic-1-ketone new compound.
The method that the inventive method is utilized above-mentioned synthetic unsaturated acyl aminated compounds binding molecule Nei Disi-Alder (Diels-Alder) reaction is again carried out " one kettle way " synthetic six hydrogen isoindole-1-ketone compounds; promptly on the amine that contains the diene structure, insert the group that can produce close diene structure in advance: alpha-brominated ethanoyl; in the presence of triphenylphosphine and mineral alkali, at room temperature carry out Wei Tixi (Wittig) reaction then and produce close diene structure with aldehyde; and under the uniform temp condition; or be higher than under 25 ℃ of temperature condition or intramolecularly Di Si-Alder (Diels-Alder) reaction is carried out in microwave-assisted heating down, " one kettle way " finishes synthesize (shown in the reaction formula 2) of six hydrogen isoindole-1-ketone compounds.The aminated compounds that contains the diene structure can directly obtain corresponding alpha-brominated ethanamide with alpha-brominated acetate condensation.Aldehyde compound has a lot of commodity raw materials available, or is obtained through simple reaction conversion by the commodity raw material.From aldehyde and two enamines, utilize the route shown in this reaction formula 2 to synthesize six hydrogen isoindole-1-ketone compounds, only need the reaction of two steps, lack single step reaction than existing route shown in reaction formula 1, improved combined coefficient.Through the combination of two olefinic amine compounds and aldehyde compound, can produce the six hydrogen isoindole-1-ketone compounds of many different substituents.Therefore should can also be used for the synthetic of six hydrogen isoindole-1-ketone compounds storehouse by " one kettle way " Wei Tixi-Di Si-Alder (Wittig-Diels-Alder) reaction method.
The structure of six hydrogen isoindole of the present invention-1-ketone compounds is suc as formula (I) or formula (II), or is the enantiomer of formula (I), formula (II),
Formula (I) formula (II)
In the formula: R
1Be hydrogen, methyl or aromatic base; R
2Be hydrogen or methyl; R
3For benzyl or to methoxybenzyl; R
4Be hydrogen, methyl, carbalkoxy, benzoyl or aromatic base.Work as R
1During for aromatic base, described R
1For phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, ortho-nitrophenyl base, m-nitro base, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent halobenzene base, a halobenzene base or to the halobenzene base, described adjacent halobenzene base, a halobenzene base, be fluorine, chlorine or bromine to the halogen atom in the halobenzene base; Work as R
4During for aromatic base, described R
4Be phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, ortho-nitrophenyl base, m-nitro base, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent halobenzene base, a halobenzene base or to the halobenzene base, are fluorine, chlorine or bromine to the halogen atom in the halobenzene base at described adjacent halobenzene base, a halobenzene base; As described R
4During for carbalkoxy, the alkoxyl group in the described carbalkoxy is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy or benzyloxy.
In the synthetic method of six hydrogen isoindole of the present invention-1-ketone compounds, comprise the steps:
Step 1: with 2,4-pentadiene-1-amine generates corresponding alpha-brominated ethanamide with alpha-brominated acetate condensation earlier, and the structure of described alpha-brominated ethanamide is suc as formula shown in (III);
Step 2: described alpha-brominated ethanamide, triphenylphosphine, structure are blended in organic solvent or the organic solvent-water mixed solvent suc as formula the aldehyde and the mineral alkali of (IV), at ambient temperature, generate the product that contains six hydrogen isoindole-1-ketone compounds by following reaction formula reaction;
Reaction formula 2
Perhaps described alpha-brominated ethanamide, triphenylphosphine, structure are blended in organic solvent or the organic solvent-water mixed solvent suc as formula the aldehyde and the mineral alkali of (IV), reaction at room temperature earlier, reaction under the microwave-assisted heating generates the product that contains six hydrogen isoindole-1-ketone compounds then.
More than the product of reaction generation is based on formula (I) and enantiomer thereof.
Six hydrogen isoindole of the present invention-1-ketone compounds can for:
(3aS, 6R, 7R, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-benzoyl-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aS)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6,7-phenylbenzene-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7S, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6,7-phenylbenzene-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aS)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-chloro-phenyl-)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7S, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-chloro-phenyl-)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aS)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-bromophenyl)-1H-isoindole-1-ketone or enantiomer;
Or (3aS, 6R, 7S, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-bromophenyl)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aS)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-methoxyphenyl)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7S, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-methoxyphenyl)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aS)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-nitrophenyl)-1H-isoindole-1-ketone itself or enantiomer;
Or (3aS, 6R, 7S, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-nitrophenyl)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-ethoxycarbonyl-1H-isoindole-1-ketone or its enantiomer.
In the synthetic method of six hydrogen isoindole of the present invention-1-ketone compounds, it is characterized in that describedly 2,4-pentadiene-1-amine is meant that structure is two enamines of formula V, in the formula, and R
1Be hydrogen, methyl or aromatic base; R
2Be hydrogen or methyl; R
3For benzyl or to methoxybenzyl; As described R
1During for aromatic base, described R
1Being phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, ortho-nitrophenyl base, m-nitro base, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent halobenzene base, a halobenzene base or to the halobenzene base, described adjacent halobenzene base, a halobenzene base, is fluorine, chlorine or bromine to the halogen atom in the halobenzene base.
Formula V
In the synthetic method of six hydrogen isoindole of the present invention-1-ketone compounds, it is characterized in that in the substituting group formula in the described alpha-brominated ethanamide (formula (III)) R
1Be hydrogen, methyl or aromatic base; R
2Be hydrogen or methyl; R
3For benzyl or to methoxybenzyl; As described R
1During for aromatic base, described R
1Being phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, ortho-nitrophenyl base, m-nitro base, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent halobenzene base, a halobenzene base or to the halobenzene base, described adjacent halobenzene base, a halobenzene base, is fluorine, chlorine or bromine to the halogen atom in the halobenzene base.
In the synthetic method of six hydrogen isoindole of the present invention-1-ketone compounds, it is characterized in that the R in the described aldehyde
4Be hydrogen, methyl, carbalkoxy, benzoyl or aromatic base; As described R
4During for aromatic base, described R
4Being phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, ortho-nitrophenyl base, m-nitro base, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent halobenzene base, a halobenzene base or to the halobenzene base, described adjacent halobenzene base, a halobenzene base, is fluorine, chlorine or bromine to the halogen atom in the halobenzene base; As described R
4During for carbalkoxy, the alkoxyl group in the described carbalkoxy is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy or benzyloxy.
Further, in the synthetic method of six hydrogen isoindole of the present invention-1-ketone compounds, described mineral alkali is meant Quilonum Retard, yellow soda ash, salt of wormwood, cesium carbonate, sodium bicarbonate or saleratus.
Further, in the synthetic method of six hydrogen isoindole of the present invention-1-ketone compounds, the equivalence ratio of described alpha-brominated ethanamide, aldehyde, triphenylphosphine and mineral alkali is 1: 1～3: 1～1.5: 1～1.5.
Further, in the synthetic method of the present invention's six hydrogen isoindole-1-ketone compounds, described organic solvent is meant acetonitrile, tetrahydrofuran (THF), toluene or dioxane, described organic solvent-water mixed solvent is meant the mixed solvent system that acetonitrile, tetrahydrofuran (THF), toluene or dioxane are mixed with water, the volume ratio of acetonitrile, tetrahydrofuran (THF), toluene or dioxane and water is 1: 2～10: 1, and described alpha-brominated ethanamide is 0.05-0.15M with respect to organic solvent or with respect to the concentration of organic solvent-water mixed solvent.
Further, in the synthetic method of the present invention's six hydrogen isoindole-1-ketone compounds, described step 2 is that described alpha-brominated ethanamide, triphenylphosphine, aldehyde and mineral alkali are blended in organic solvent or the organic solvent-water mixed solvent, at room temperature reacts to generate the product that contains six hydrogen isoindole-1-ketone compounds in 6～50 hours; Or at room temperature reacted 6～15 hours earlier, continue under the microwave-assisted heating, to react generating the product that contains six hydrogen isoindole-1-ketone compounds in 0.5～1 hour again.
With respect to prior art, beneficial effect of the present invention is:
(1) among the present invention, the amine that contains the diene structure can obtain by existing method is synthetic, and used aldehyde compound can be the commodity raw material or be obtained through simple reaction is synthetic by the commodity raw material; (2) since two enamines and aldehyde, can obtain hydrogenated iso-indoles-1-ketone through two-step reaction, lack single step reaction than existing method, this provides new, more efficient methods for hydrogenated iso-indoles-1-ketone compounds synthetic; (3) utilize the inventive method to synthesize some new hydrogenated iso-indoles-1-ketone compounds.Combination by two olefinic amine compounds and aldehyde compound, can produce the hydrogenated iso-indoles-1-ketone compounds of many different substituents, therefore should can be used for the synthetic of six hydrogen isoindole-1-ketone compounds storehouse by " one kettle way " Wei Tixi-Di Si-Alder (Wittig-Diels-Alder) reaction method, will provide material base for the bioactivity screening and the drug development of this compounds.
Embodiment
Embodiment 1:
(3aS
*, 6R
*, 7R
*, 7aR
*)-2,3,3a, 6,7, the synthesis step of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-benzoyl-1H-isoindole-1-ketone is as follows:
(2E, 4E)-N-(4-methoxybenzyl)-5-phenyl penta-2, the alpha-brominated ethanamide of 4-dialkylene (114 milligrams, tetrahydrofuran (THF)-water mixed solution (H 0.28mmol)
2O: THF=1: 10, add in 3ml) triphenylphosphine (88 milligrams, 0.34mmol), salt of wormwood (58 milligrams, 0.42mmol) and hydration methyl phenyl ketone aldehyde (51 milligrams, 0.34mmol), with this mixture stirring reaction 6 hours at room temperature.Reaction mixture dilutes with ethyl acetate 10mL, and uses saturated aqueous ammonium chloride and saturated common salt water washing (each 5mL) successively, and the water after the merging is with ethyl acetate extraction (3 * 5ml).Organic phase is used anhydrous Na after merging
2SO
4Drying is filtered, and removal of solvent under reduced pressure gets crude product, this crude product with the petroleum ether solution that contains 20% ethyl acetate carry out silica gel column chromatography separate purify product (3aS
*, 6R
*, 7R
*, 7aR
*)-2,3,3a, 6,7,107 milligrams of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-benzoyl-1H-isoindole-1-ketone, productive rate is 88%.White solid; Mp 176-178 ℃;
1H NMR (400MHz, CDCl
3) δ 7.85 (d, J=7.2Hz, 2H), 7.52 (dd, J=8.0,8.0Hz, 1H), 7.42 (dd, J=8.0,8.0Hz, 2H), and 7.18-7.11 (m, 5H), 6.87-6.83 (m, 4H), 6.07 (d, J=9.6Hz, 1H), 5.73 (ddd, J=9.6,3.2,3.2Hz, 1H), 4.39 and 4.34 (ABq, J=14.4Hz, 2H), 4.21 (dd, J=12.0,8.4Hz, 1H), 4.09-4.06 (m, 1H), 3.80 (s, 3H), 3.35 (dd, J=8.8,6.8Hz, 1H), 3.16 (dd, J=10.8,10.8Hz, 1H), 3.02 (dd, J=12.8,12.8Hz, 1H), and 2.77-2.70 (m, 1H).
Embodiment 2:
(3aS
*, 6R
*, 7R
*, 7aR
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-ethoxycarbonyl-1H-isoindole-1-ketone synthetic
(2E, 4E)-N-(4-methoxybenzyl)-5-phenyl penta-2, the alpha-brominated ethanamide of 4-dialkylene (60 milligrams, tetrahydrofuran (THF)-water mixed solution (H 0.15mmol)
2O: THF=2: 1, add in 2ml) triphenylphosphine (59 milligrams, 0.22mmol), salt of wormwood (22 milligrams, 0.16mmol) and glyoxylic acid ethyl ester (46 milligrams, 0.45mmol), with this mixture stirring reaction 48 hours at room temperature.Method by embodiment 1 is carried out aftertreatment, gets product (3aS
*, 6R
*, 7R
*, 7aR
*)-2,3,3a, 6,7,29 milligrams of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-ethoxycarbonyl-1H-isoindole-1-ketone, productive rate is 48%.Colorless oil;
1H NMR (400MHz, CDCl
3) δ 7.32-7.21 (m, 3H), 7.20-7.12 (m, 4H), 6.86 (d, J=8.4Hz, 2H), 6.02 (d, J=9.6Hz, 1H), 5.71 (ddd, J=9.6,3.2,3.2Hz, 1H), 4.49 and 4.25 (ABq, J=14.4Hz, 2H), 4.02-3.96 (m, 1H), 3.80 (s, 3H), 3.78-3.64 (m, 2H), 3.31 (dd, J=9.2,7.2Hz, 1H), 3.15 (dd, J=11.6,8.0Hz, 1H), 3.10 (dd, J=10.0,10.0Hz, 1H), 2.67 (dd, J=13.2,13.2Hz, 1H), 2.62-2.53 (m, 1H), 0.90 (t, J=7.2Hz, 3H).
Embodiment 3:
(3aS
*, 6R
*, 7R
*, 7aS
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6,7-phenylbenzene-1H-isoindole-1-ketone and (3aS
*, 6R
*, 7S
*, 7aR
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6,7-phenylbenzene-1H-isoindole-1-ketone synthetic
To fill (2E, 4E)-N-(4-methoxybenzyl)-5-phenyl penta-2, (32 milligrams of the alpha-brominated ethanamides of 4-dialkylene, 0.08mmol), (26 milligrams of triphenylphosphines, 0.10mmol), salt of wormwood (17 milligrams, 0.12mmo1) and phenyl aldehyde (17 milligrams, tetrahydrofuran (THF)-water mixed solution (H 0.16mmol)
2O: THF=1: 1, after microwave reaction pipe 1ml) sealed, at room temperature stirring reaction was 15 hours, and 180 ℃ of reactions of microwave heating are 0.5 hour then.Method by embodiment 1 is carried out aftertreatment, gets product (3aS
*, 6R
*, 7R
*, 7aS
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6,23 milligrams of 7-phenylbenzene-1H-isoindole-1-ketone, productive rate is 70%.Colorless oil;
1H NMR (400MHz, CDCl
3) δ 7.17 (d, J=8.4Hz, 2H), 7.10-7.03 (m, 6H), 6.87 (d, J=8.8Hz, 2H), 6.73-6.69 (m, 4H), 6.09 (d, J=9.6Hz, 1H), 5.82 (ddd, J=9.2,2.8,2.8Hz, 1H), 4.51 and 4.16 (ab, J=14.4Hz, 2H), 3.81 (s, 3H), 3.81-3.77 (m, 1H), 3.57 (dd, J=10.8,6.8Hz, 1H), 3.35 (dd, J=8.8,6.0Hz, 1H), 3.11 (dd, J=10.0,10.0Hz, 1H), 2.87-2.74 (m, 2H).
Get product (3aS
*, 6R
*, 7S
*, 7aR
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6,9 milligrams of 7-phenylbenzene-1H-isoindole-1-ketone, productive rate 27%.Colorless oil;
1H NMR (400MHz, CDCl
3) δ 7.20 (dd, J=7.2,7.2Hz, 2H), 7.16-7.11 (m, 6H), 7.03 (d, J=7.6Hz, 2H), 6.89-6.85 (m, 4H), 5.96 (d, J=10.0Hz, 1H), 5.88 (d, J=9.6Hz, 1H), 4.34 and 4.29 (ab, J=14.8Hz, 2H), 3.81 (s, 3H), 3.54 (d, J=8.4Hz, 1H), 3.44 (dd, J=8.8,8.4Hz, 1H), 3.14 (dd, J=8.4,8.4Hz, 1H), and 3.09-3.03 (m, 1H), 2.99 (dd, J=10.0,7.6Hz, 1H), 2.88 (dd, J=8.8,8.8Hz, 1H).
Embodiment 4:
(3aS
*, 6R
*, 7R
*, 7aS
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-chloro-phenyl-)-1H-isoindole-1-ketone and (3aS
*, 6R
*, 7S
*, 7aR
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-chloro-phenyl-)-1H-isoindole-1-ketone synthetic
To fill (2E, 4E)-N-(4-methoxybenzyl)-5-phenyl penta-2, (132 milligrams of the alpha-brominated ethanamides of 4-dialkylene, 0.33mmol), triphenylphosphine (104 milligrams, 0.39mmol), (68 milligrams in salt of wormwood, 0.49mmol) and the 4-chlorobenzaldehyde (55 milligrams, tetrahydrofuran (THF)-water mixed solution (H 0.39mmol)
2O: THF=1: 1, after microwave reaction pipe 3.5ml) sealed, at room temperature stirring reaction was 6 hours, and 180 ℃ of reactions of microwave heating are 0.5 hour then.Method by embodiment 1 is carried out aftertreatment, gets product (3aS
*, 6R
*, 7R
*, 7aS
*)-2,3,3a, 6,7,102 milligrams of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-chloro-phenyl-)-1H-isoindole-1-ketone, productive rate is 70%.White solid; Mp 142-144 ℃;
1H NMR (400MHz, CDCl
3) δ 7.16 (d, J=8.4Hz, 2H), 7.12-7.06 (m, 3H), 7.03 (d, J=8.0Hz, 2H), 6.86 (d, J=8.4Hz, 2H), 6.71 (d, J=6.8Hz, 2H), 6.64 (d, J=7.6Hz, 2H), 6.09 (d, J=9.6Hz, 1H), 5.81 (ddd, J=9.6,3.6,2.8Hz, 1H), 4.49 and 4.17 (ab, J=14.4Hz, 2H), 3.80 (s, 3H), 3.77 (br s, 1H), 3.53 (dd, J=11.2,6.8Hz, 1H), 3.35 (dd, J=8.8,6.0Hz, 1H), 3.11 (dd, J=10.0,10.0Hz, 1H), 2.85-2.78 (m, 1H), 2.73 (dd, J=11.6,11.6Hz, 1H).
Get product (3aS
*, 6R
*, 7S
*, 7aR
*)-2,3,3a, 6,7,25 milligrams of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-chloro-phenyl-)-1H-isoindole-1-ketone, productive rate is 17%.Colorless oil;
1H NMR (400MHz, CDCl
3) δ 7.17-7.11 (m, 7H), 6.92 (d, J=8.8Hz, 2H), 6.87-6.83 (m, 4H), 5.93 (d, J=10.0Hz, 1H), 5.87 (ddd, J=10.0,3.2,2.8Hz, 1H), 4.33 and 4.29 (ab, J=15.2Hz, 2H), 3.81 (s, 3H), 3.45 (dd, J=8.8,8.4Hz, 2H), 3.13 (dd, J=9.2,8.4Hz, 1H), and 3.10-3.00 (m, 1H), 2.96 (dd, J=10.8,7.6Hz, 1H), 2.78 (dd, J=11.2,9.2Hz, 1H).
Embodiment 5:
(3aS
*, 6R
*, 7R
*, 7aS
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-bromophenyl)-1H-isoindole-1-ketone and (3aS
*, 6R
*, 7S
*, 7aR
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-bromophenyl)-1H-isoindole-1-ketone synthetic
To fill (2E, 4E)-N-(4-methoxybenzyl)-5-phenyl penta-2, (130 milligrams of the alpha-brominated ethanamides of 4-dialkylene, 0.32mmol), triphenylphosphine (100 milligrams, 0.38mmol), (66 milligrams in salt of wormwood, 0.48mmol) and the 4-bromobenzaldehyde (71 milligrams, tetrahydrofuran (THF)-water mixed solution (H 0.38mmol)
2O: THF=1: 1, after microwave reaction pipe 3.5ml) sealed, at room temperature stirring reaction was 6 hours, and 180 ℃ of reactions of microwave heating are 0.5 hour then.Method by embodiment 1 is carried out aftertreatment, gets product (3aS
*, 6R
*, 7R
*, 7aS
*)-2,3,3a, 6,7,115 milligrams of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-bromophenyl)-1H-isoindole-1-ketone, productive rate is 74%.White solid; Mp 153-155 ℃;
1H NMR (400MHz, CDCl
3) δ 7.18-7.14 (m, 4H), 7.12-7.06 (m, 3H), 6.86 (d, J=8.0Hz, 2H), 6.70 (d, J=7.6Hz, 2H), 6.58 (d, J=7.6Hz, 2H), 6.08 (ddd, J=10.0,1.6,1.6Hz, 1H), 5.80 (ddd, J=10.0,2.8,2.8Hz, 1H), 4.48 and 4.16 (ab, J=14.8Hz, 2H), 3.80 (s, 3H), 3.78-3.74 (m, 1H), 3.51 (dd, J=11.6,6.8Hz, 1H), 3.35 (dd, J=8.8,6.4Hz, 1H), 3.10 (dd, J=10.0,10.0Hz, 1H), and 2.86-2.77 (m, 1H), 2.72 (dd, J=11.6,11.6Hz, 1H).
Get product (3aS
*, 6R
*, 7S
*, 7aR
*)-2,3,3a, 6,7,26 milligrams of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-bromophenyl)-1H-isoindole-1-ketone, productive rate is 16%.Colorless oil;
1H NMR (400MHz, CDCl
3) δ 7.30 (d, J=8.8Hz, 2H), 7.15-7.12 (m, 5H), 6.88-6.83 (m, 6H), 5.93 (d, J=10.0Hz, 1H), 5.87 (ddd, J=10.4,3.2,2.4Hz, 1H), 4.33 and 4.29 (ab, J=14.4Hz, 2H), 3.81 (s, 3H), 3.47-3.43 (m, 2H), 3.13 (dd, J=8.8,8.8Hz, 1H), and 3.09-3.03 (m, 1H), 2.96 (dd, J=10.8,7.6Hz, 1H), 2.76 (dd, J=10.8,9.6Hz, 1H).
Embodiment 6
(3aS
*, 6R
*, 7R
*, 7aS
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-methoxyphenyl)-1H-isoindole-1-ketone and (3aS
*, 6R
*, 7S
*, 7aR
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-methoxyphenyl)-1H-isoindole-1-ketone synthetic
To fill (2E, 4E)-N-(4-methoxybenzyl)-5-phenyl penta-2, (149 milligrams of the alpha-brominated ethanamides of 4-dialkylene, 0.37mmol), triphenylphosphine (116 milligrams, 0.44mmol), (66 milligrams in salt of wormwood, 0.48mmol) and the 4-methoxybenzaldehyde (101 milligrams, tetrahydrofuran (THF)-water mixed solution (H 0.74mmol)
2O: THF=1: 1, after microwave reaction pipe 4ml) sealed, at room temperature stirring reaction was 15 hours, and 180 ℃ of reactions of microwave heating are 0.8 hour then.Method by embodiment 1 is carried out aftertreatment, gets product (3aS
*, 6R
*, 7R
*, 7aS
*)-2,3,3a, 6,7,87 milligrams of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-methoxyphenyl)-1H-isoindole-1-ketone, productive rate is 54%.White solid; Mp 160-162 ℃;
1H NMR (400MHz, CDCl
3) δ 7.17 (d, J=8.0Hz, 2H), 7.12-7.05 (m, 3H), 6.86 (d, J=8.0Hz, 2H), 6.72 (d, J=7.2Hz, 2H), 6.62 (s, 4H), 6.07 (d, J=9.6Hz, 1H), 5.81 (d, J=9.6Hz, 1H), 4.52 and, 4.15 (ab, J=14.4Hz, 2H), 3.81 (s, 3H), 3.76 (br s, 1H), 3.73 (s, 3H), 3.52 (dd, J=11.6,6.8Hz, 1H), 3.33 (dd, J=7.6,7.6Hz, 1H), 3.09 (dd, J=10.4,9.2Hz, 1H), and 2.87-2.77 (m, 1H), 2.71 (dd, J=12.0,12.0Hz, 1H).
Get product (3aS
*, 6R
*, 7S
*, 7aR
*)-2,3,3a, 6,7,20 milligrams of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-methoxyphenyl)-1H-isoindole-1-ketone, productive rate is 12%.Colorless oil;
1H NMR (400MHz, CDCl
3) δ 7.16-7.10 (m, 5H), 6.93 (d, J=8.0Hz, 2H), 6.88-6.84 (m, 4H), 6.74 (d, J=9.2Hz, 2H), 5.94 (d, J=10.0Hz, 1H), 5.86 (ddd, J=10.0,3.2,2.8Hz, 1H), 4.31 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.48 (dd, J=8.8,2.4Hz, 1H), 3.43 (dd, J=8.4,8.4Hz, 1H), 3.13 (dd, J=8.8,8.8Hz, 1H), and 3.09-3.00 (m, 1H), 2.95 (dd, J=10.4,8.4Hz, 1H), 2.79 (dd, J=10.0,9.2Hz, 1H).
Embodiment 7
(3aS
*, 6R
*, 7R
*, 7aS
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-nitrophenyl)-1H-isoindole-1-ketone and (3aS
*, 6R
*, 7S
*, 7aR
*)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-nitrophenyl)-1H-isoindole-1-ketone synthetic
To fill (2E, 4E)-N-(4-methoxybenzyl)-5-phenyl penta-2, (133 milligrams of the alpha-brominated ethanamides of 4-dialkylene, 0.33mmol), triphenylphosphine (104 milligrams, 0.39mmol), (68 milligrams in salt of wormwood, 0.49mmol) and the 4-nitrobenzaldehyde (59 milligrams, tetrahydrofuran (THF)-water mixed solution (H 0.39mmol)
2O: THF=2: 1, after microwave reaction pipe 3.5ml) sealed, at room temperature stirring reaction was 6 hours, and 180 ℃ of reactions of microwave heating are 0.5 hour then.Method by embodiment 1 is carried out aftertreatment, gets product (3aS
*, 6R
*, 7R
*, 7aS
*)-2,3,3a, 6,7,82 milligrams of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-nitrophenyl)-1H-isoindole-1-ketone, productive rate is 55%.White solid; Mp 193-195 ℃;
1H NMR (400MHz, CDCl
3) δ 7.91 (d, J=8.8Hz, 2H), 7.15 (d, J=8.4Hz, 2H), and 7.12-7.04 (m, 3H), 6.88-6.85 (m, 4H), 6.69 (d, J=7.2Hz, 2H), 6.12 (d, J=10.0Hz, 1H), 5.81 (ddd, J=9.6,3.6,2.4Hz, 1H), 4.47 and, 4.17 (ab, J=14.4Hz, 2H), 3.85-3.80 (m, 1H), 3.80 (s, 3H), 3.65 (dd, J=11.2,6.8Hz, 1H), 3.38 (dd, J=8.4,5.6Hz, 1H), 3.14 (dd, J=11.2,9.6Hz, 1H), and 2.88-2.78 (m, 2H).
Get product (3aS
*, 6R
*, 7S
*, 7aR
*)-2,3,3a, 6,7,18 milligrams of 7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-nitrophenyl)-1H-isoindole-1-ketone, productive rate is 12%.Light yellow oil;
1H NMR (400MHz, CDCl
3) δ 8.05 (d, J=8.8Hz, 1H), 7.14-7.11 (m, 7H), 6.86 (d, J=8.4Hz, 2H), 6.83-6.81 (m, 2H), 5.94 (d, J=10.0Hz, 1H), 5.90 (d, J=10.0Hz, 1H), 4.33 and 4.28 (ab, J=10.4Hz, 2H), 3.81 (s, 3H), 3.50 (dd, J=6.0,5.6Hz, 2H), 3.18-3.02 (m, 3H), 2.84 (dd, J=10.4,10.4Hz, 1H).
Embodiment 8
(2E, 4E)-N-(4-methoxybenzyl)-5-phenyl penta-2, the alpha-brominated ethanamide of 4-dialkylene synthetic
(2E, 4E)-N-(4-methoxybenzyl)-5-phenyl penta-2, (335 milligrams of 4-dialkylenes-1-amine, 1.2mmol) methylene dichloride (15mL) solution in add (250 milligrams of alpha bromoisobutyric acids, 1.8 mmol), dicyclohexyl carbimide (DCC, 392 milligrams, 1.9mmol), the 4-Dimethylamino pyridine (DMAP, 12 milligrams, 0.1mmol), with this mixture 0 ℃ of stirring reaction 30 minutes, stirring reaction 2 hours at room temperature then.Reaction mixture dilutes with methylene dichloride, and uses saturated aqueous ammonium chloride successively, the saturated common salt water washing.The organic phase anhydrous Na
2SO
4Drying is filtered, and removal of solvent under reduced pressure gets crude product, this crude product with the petroleum ether solution that contains 20% ethyl acetate carry out silica gel column chromatography separate purify product (2E, 4E)-and N-(4-methoxybenzyl)-5-phenyl penta-2,394 milligrams of 4-dialkylene bromo ethanamides, productive rate is 82%.Yellow oil;
1H NMR (400MHz, CDCl
3) δ 7.41-7.37 (m, 2H), 7.35-7.29 (m, 2H), 7.26-7.23 (m, 1H), 7.20 and 7.14 (d, J=8.8Hz, 2H), 6.91 and 6.87 (d, J=8.8Hz, 2H), 6.77 and 6.74 (d, J=15.2Hz, 1H), 6.57 and 6.52 (d, J=15.2Hz, 1H), 6.31-6.23 (m, 1H), 5.77-5.67 (m, 1H), 4.58 and 4.55 (s, 2H), 4.08 and 3.99 (d, J=5.6Hz, 2H), 3.92 and 3.89 (s, 2H), 3.82 and 3.80 (s, 3H).
Claims (10)
1. six hydrogen isoindole-1-ketone compounds is characterized in that: its structure is suc as formula (I) or formula (II), or is the enantiomer of formula (I), formula (II),
Formula (I) formula (II)
In the formula, R
1Be hydrogen, methyl or aromatic base; R
2Be hydrogen or methyl; R
3For benzyl or to methoxybenzyl; R
4Be hydrogen, methyl, carbalkoxy, benzoyl or aromatic base; Work as R
1And R
4During for aromatic base, described R
1And R
4Being phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, ortho-nitrophenyl base, m-nitro base, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent halobenzene base, a halobenzene base or to the halobenzene base, described adjacent halobenzene base, a halobenzene base, is fluorine, chlorine or bromine to the halogen atom in the halobenzene base; Work as R
4During for carbalkoxy, the alkoxyl group in the described carbalkoxy is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy or benzyloxy.
2. six hydrogen isoindole according to claim 1-1-ketone compounds is characterized in that this compound is:
(3aS, 6R, 7R, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-benzoyl-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aS)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6,7-phenylbenzene-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7S, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6,7-phenylbenzene-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aS)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-chloro-phenyl-)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7S, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-chloro-phenyl-)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aS)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-bromophenyl)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7S, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-bromophenyl)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aS)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-methoxyphenyl)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7S, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-methoxyphenyl)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aS)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-nitrophenyl)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7S, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-(4-nitrophenyl)-1H-isoindole-1-ketone or its enantiomer;
Or (3aS, 6R, 7R, 7aR)-2,3,3a, 6,7,7a-six hydrogen-2-(4-methoxybenzyl)-6-phenyl-7-ethoxycarbonyl-1H-isoindole-1-ketone or its enantiomer.
3. a synthetic method for preparing the six hydrogen isoindole-1-ketone compounds of claim 1 is characterized in that it may further comprise the steps,
Step 1: with 2,4-pentadiene-1-amine generates corresponding alpha-brominated ethanamide with alpha-brominated acetate condensation earlier, and the structure of described alpha-brominated ethanamide is suc as formula shown in (III);
Step 2: described alpha-brominated ethanamide, triphenylphosphine, structure are blended in organic solvent or the organic solvent-water mixed solvent suc as formula the aldehyde and the mineral alkali of (IV), at ambient temperature, by following reaction formula reaction, generate the product that contains six hydrogen isoindole-1-ketone compounds;
Formula (III) formula (IV) trans (master) cis (inferior)
Formula (I) formula (II)
Perhaps described alpha-brominated ethanamide, triphenylphosphine, structure are blended in organic solvent or the organic solvent-water mixed solvent suc as formula the aldehyde and the mineral alkali of (IV), reaction at room temperature earlier, reaction under the microwave-assisted heating generates the product that contains six hydrogen isoindole-1-ketone compounds then.
4. the synthetic method of six hydrogen isoindole according to claim 3-1-ketone compounds is characterized in that: described 2,4-pentadiene-1-amine is meant that structure is two enamines of formula V,
Formula V
In the formula, R
1Be hydrogen, methyl or aromatic base; R
2Be hydrogen or methyl; R
3For benzyl or to methoxybenzyl; As described R
1During for aromatic base, described R
1Being phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, ortho-nitrophenyl base, m-nitro base, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent halobenzene base, a halobenzene base or to the halobenzene base, described adjacent halobenzene base, a halobenzene base, is fluorine, chlorine or bromine to the halogen atom in the halobenzene base.
5. the synthetic method of six hydrogen isoindole according to claim 3-1-ketone compounds is characterized in that: the substituent R in the described alpha-brominated ethanamide
1Be hydrogen, methyl or aromatic base, R
2Be hydrogen or methyl, R
3For benzyl or to methoxybenzyl; Work as R
1During for aromatic base, described R
1Being phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, ortho-nitrophenyl base, m-nitro base, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent halobenzene base, a halobenzene base or to the halobenzene base, described adjacent halobenzene base, a halobenzene base, is fluorine, chlorine or bromine to the halogen atom in the halobenzene base.
6. the synthetic method of six hydrogen isoindole according to claim 3-1-ketone compounds is characterized in that: the R in the described aldehyde
4Be hydrogen, methyl, carbalkoxy, benzoyl or aromatic base; Work as R
4During for aromatic base, described R
4Be phenyl, o-methyl-phenyl-, an aminomethyl phenyl, p-methylphenyl, ortho-nitrophenyl base, m-nitro base, p-nitrophenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, adjacent halobenzene base, a halobenzene base or to the halobenzene base, are fluorine, chlorine or bromine to the halogen atom in the halobenzene base at wherein said adjacent halobenzene base, a halobenzene base; Work as R
4During for carbalkoxy, the alkoxyl group in the described carbalkoxy is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy or benzyloxy.
7. the synthetic method of six hydrogen isoindole according to claim 3-1-ketone compounds is characterized in that: described mineral alkali is Quilonum Retard, yellow soda ash, salt of wormwood, cesium carbonate, sodium bicarbonate or saleratus.
8. the synthetic method of six hydrogen isoindole according to claim 3-1-ketone compounds is characterized in that: the equivalence ratio of described alpha-brominated ethanamide, aldehyde, triphenylphosphine and mineral alkali is 1: 1～3: 1～1.5: 1～1.5.
9. the synthetic method of six hydrogen isoindole according to claim 3-1-ketone compounds, it is characterized in that described organic solvent is meant acetonitrile, tetrahydrofuran (THF), toluene or dioxane, described organic solvent-water mixed solvent is meant the mixed solvent system that acetonitrile, tetrahydrofuran (THF), toluene or dioxane are mixed with water, the volume ratio of acetonitrile, tetrahydrofuran (THF), toluene or dioxane and water is 1: 2～10: 1, and described alpha-brominated ethanamide is 0.05-0.15M with respect to organic solvent or with respect to the concentration of organic solvent-water mixed solvent.
10. the synthetic method of six hydrogen isoindole according to claim 3-1-ketone compounds, it is characterized in that: described step 2 is that described alpha-brominated ethanamide, triphenylphosphine, aldehyde and mineral alkali are blended in organic solvent or the organic solvent-water mixed solvent, at room temperature reacts to generate the product that contains six hydrogen isoindole-1-ketone compounds in 6～50 hours; Or at room temperature reacted 6～15 hours earlier, continue under the microwave-assisted heating, to react generating the product that contains six hydrogen isoindole-1-ketone compounds in 0.5～1 hour again.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910759A (en) * | 2012-12-29 | 2014-07-09 | 安徽贝克生物制药有限公司 | Preparation method of (carbethoxyethylidene)triphenylphosphorane |
| CN109535204A (en) * | 2018-12-21 | 2019-03-29 | 中国科学院上海有机化学研究所 | Rhodium complex, preparation method, intermediate and application |
-
2009
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910759A (en) * | 2012-12-29 | 2014-07-09 | 安徽贝克生物制药有限公司 | Preparation method of (carbethoxyethylidene)triphenylphosphorane |
| CN109535204A (en) * | 2018-12-21 | 2019-03-29 | 中国科学院上海有机化学研究所 | Rhodium complex, preparation method, intermediate and application |
| CN109535204B (en) * | 2018-12-21 | 2021-02-09 | 中国科学院上海有机化学研究所 | Rhodium complex, preparation method, intermediate and application thereof |
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