CN102250048A - 2-phenylselenomethyl-2,3-dihydrobenzofuran and preparation and application thereof - Google Patents
2-phenylselenomethyl-2,3-dihydrobenzofuran and preparation and application thereof Download PDFInfo
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- phenylseleno
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- dihydrobenzofuranes
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- BDXKISVTHDWTFF-UHFFFAOYSA-N 2-(phenylselanylmethyl)-2,3-dihydro-1-benzofuran Chemical compound C1C2=CC=CC=C2OC1C[Se]C1=CC=CC=C1 BDXKISVTHDWTFF-UHFFFAOYSA-N 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 102000010909 Monoamine Oxidase Human genes 0.000 claims abstract description 31
- 108010062431 Monoamine oxidase Proteins 0.000 claims abstract description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000000694 effects Effects 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 5
- QIRNGVVZBINFMX-UHFFFAOYSA-N 2-allylphenol Chemical class OC1=CC=CC=C1CC=C QIRNGVVZBINFMX-UHFFFAOYSA-N 0.000 claims abstract description 5
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims abstract description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000005826 halohydrocarbons Chemical class 0.000 claims abstract description 3
- 150000002825 nitriles Chemical class 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- LSCKCSMWTLIWQE-UHFFFAOYSA-N [Br].C1(=CC=CC=C1)[Se] Chemical compound [Br].C1(=CC=CC=C1)[Se] LSCKCSMWTLIWQE-UHFFFAOYSA-N 0.000 claims description 15
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 14
- VQZFHIZLAPNTIB-UHFFFAOYSA-N 2-methyl-2-phenylselanyl-3H-1-benzofuran Chemical class C1(=CC=CC=C1)[Se]C1(OC2=C(C1)C=CC=C2)C VQZFHIZLAPNTIB-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 9
- 239000012141 concentrate Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- -1 nitro, methyl Chemical group 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 229960001701 chloroform Drugs 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 235000021050 feed intake Nutrition 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical class C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 10
- 239000003112 inhibitor Substances 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000012216 screening Methods 0.000 abstract description 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract 3
- 239000003054 catalyst Substances 0.000 abstract 2
- 229940079593 drug Drugs 0.000 abstract 2
- 125000000468 ketone group Chemical group 0.000 abstract 1
- LCEFEIBEOBPPSJ-UHFFFAOYSA-N phenyl selenohypobromite Chemical compound Br[Se]C1=CC=CC=C1 LCEFEIBEOBPPSJ-UHFFFAOYSA-N 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 230000001430 anti-depressive effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 0 *c(cccc1)c1SCC(Cc1c2)Oc1ccc2Cl Chemical compound *c(cccc1)c1SCC(Cc1c2)Oc1ccc2Cl 0.000 description 4
- BWCJVGMZEQDOMY-UHFFFAOYSA-N 2-methyl-2,3-dihydro-1-benzofuran Chemical class C1=CC=C2OC(C)CC2=C1 BWCJVGMZEQDOMY-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 150000002240 furans Chemical class 0.000 description 3
- 150000002429 hydrazines Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- URCIQYBNPPENHX-UHFFFAOYSA-N CC(C1)(OC(C=C2)=C1C=C2Cl)[Se]C1=CC=CC=C1 Chemical class CC(C1)(OC(C=C2)=C1C=C2Cl)[Se]C1=CC=CC=C1 URCIQYBNPPENHX-UHFFFAOYSA-N 0.000 description 2
- 229940087098 Oxidase inhibitor Drugs 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- 230000000648 anti-parkinson Effects 0.000 description 2
- 239000000939 antiparkinson agent Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000003943 catecholamines Chemical class 0.000 description 2
- 238000007337 electrophilic addition reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 1
- XKFPYPQQHFEXRZ-UHFFFAOYSA-N 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide Chemical compound O1C(C)=CC(C(=O)NNCC=2C=CC=CC=2)=N1 XKFPYPQQHFEXRZ-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 244000080767 Areca catechu Species 0.000 description 1
- 235000006226 Areca catechu Nutrition 0.000 description 1
- LBHDPXABBANTNM-UHFFFAOYSA-N CC(C1)(OC(C=C2)=C1C=C2F)[Se]C1=CC=CC=C1 Chemical class CC(C1)(OC(C=C2)=C1C=C2F)[Se]C1=CC=CC=C1 LBHDPXABBANTNM-UHFFFAOYSA-N 0.000 description 1
- FMHMFGCGQGUGJS-UHFFFAOYSA-N CC(C1Cl)(OC2=C1C=CC=C2)[Se]C1=CC=CC=C1 Chemical class CC(C1Cl)(OC2=C1C=CC=C2)[Se]C1=CC=CC=C1 FMHMFGCGQGUGJS-UHFFFAOYSA-N 0.000 description 1
- MAFXDOPKPSDFGY-UHFFFAOYSA-N CC1=C(C=CC2=C1OC(C2)(C)[Se]C3=CC=CC=C3)O Chemical class CC1=C(C=CC2=C1OC(C2)(C)[Se]C3=CC=CC=C3)O MAFXDOPKPSDFGY-UHFFFAOYSA-N 0.000 description 1
- SUCJPQDYDPBJPS-UHFFFAOYSA-N COc1ccc2OC(CSc3ccccc3)Cc2c1 Chemical compound COc1ccc2OC(CSc3ccccc3)Cc2c1 SUCJPQDYDPBJPS-UHFFFAOYSA-N 0.000 description 1
- PGZNNKQRKUFGEY-UHFFFAOYSA-N Cc1c2OC(CSc3ccccc3)Cc2ccc1Oc(cc1)ccc1SCC(C1)Oc2c1ccc1c2ccc(-c(cc2)ccc2SCC2Oc3cc(Cl)cc(Cl)c3C2)c1 Chemical compound Cc1c2OC(CSc3ccccc3)Cc2ccc1Oc(cc1)ccc1SCC(C1)Oc2c1ccc1c2ccc(-c(cc2)ccc2SCC2Oc3cc(Cl)cc(Cl)c3C2)c1 PGZNNKQRKUFGEY-UHFFFAOYSA-N 0.000 description 1
- BZMZBTKOGQXDBX-UHFFFAOYSA-N Fc1ccc2OC(CSc3ccccc3)Cc2c1 Chemical compound Fc1ccc2OC(CSc3ccccc3)Cc2c1 BZMZBTKOGQXDBX-UHFFFAOYSA-N 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- KTZMNDDWNBCOAI-UHFFFAOYSA-N Oc(c1c(c(C(c2ccccc2)=O)c2)OC(CSc3ccccc3)C1)c2C(c1ccccc1)=O Chemical compound Oc(c1c(c(C(c2ccccc2)=O)c2)OC(CSc3ccccc3)C1)c2C(c1ccccc1)=O KTZMNDDWNBCOAI-UHFFFAOYSA-N 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 238000003705 background correction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 229960002672 isocarboxazid Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000010333 neurotransmitter inactivation Effects 0.000 description 1
- 238000007833 oxidative deamination reaction Methods 0.000 description 1
- 229960000964 phenelzine Drugs 0.000 description 1
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Abstract
The invention discloses 2-phenylselenomethyl-2,3-dihydrobenzofuran and preparation compounds shown in a formula (I), and a preparation method and application thereof. Phenylselenyl bromide shown as a formula (II) and substituted o-allylphenol shown as a formula (III), which are taken as raw materials, are reacted at the temperature of between 0 and 62DEG C for 0.5 to 5 hours in an organic solvent in the presence of a catalyst to form the 2-phenylselenomethyl-2,3-dihydrobenzofuran and preparation compounds, wherein the organic solvent is ketone with 3 to 6 carbon atoms, tetrahydrofuran, dioxane, nitrile with 2 to 4 carbon atoms or halohydrocarbon with 1 to 2 carbon atoms; and the catalyst is triethylamine, pyridine or tetramethylethylenediamine. The compounds have activity of inhibiting monoamine oxidase, are inhibitor medicines having the activity of obviously inhibiting the monoamine oxidase, and provide research basis for screening new medicines for anti-depression, antiparkinsonism and the like; and the synthesis process is simple and suitable for industrialization.
Description
(1) technical field
The present invention relates to a kind of 2-phenylseleno methyl 2,3-Dihydrobenzofuranes compounds and preparation thereof and application.
(2) background technology
Monoamine oxidase (monoamine oxidase) is the enzyme of catalysis monoamine oxidative deamination.Abbreviation MAO also has to be called to contain the flavine amine oxidase, can make the enzyme of catechu amine neurotransmitter inactivation, can be used as antidepressant and levies medicine.
Existing oxidase inhibitor mainly is some hydrazine class and non-hydrazine class compound, and they suppress monoamine oxidase, show antidepressant effect, comprises Phenelzine, Isocarboxazide, the Ni Lami of hydrazine class, the Tranylcypromine of non-hydrazine class etc.Such medicine reduces the metabolism inactivation of catecholamine by suppressing monoamine oxidase, impels the changes of Catecholamine Content at cynapse position to increase, and produces antidepressant effect, and hypotensive effect is arranged.But this class medicine remove to suppress monoamine oxidase, and the drug metabolism enzyme of liver is also had restraining effect, and side effect is more, can produce central excitation, lures phrenoplegia into, and hepatotoxicity is arranged, and causes postural hypotension.Therefore be necessary to screen new oxidase inhibitor, to substitute existing antidepressant drug.
Benzofuran compounds is one of constituent common in the natural product; has multiple important physical activity; for example; exciting estrogenic receptor subtype, antagonism pth receptor and H3 acceptor, inhibition of histone deacetylase or the like; they are preventing and treating Parkinson's disease; osteoporosis, alzheimer's disease, aspects such as irregular pulse and tumour play significant effect.People set up the library of molecules of this compounds in searching all the time, thereby systematically carry out bioactive screening.Synthetic 2, the method for 3-Dihydrobenzofuranes compounds has a lot, for example, Chemistry of Heterocyclic Compounds, 2010,46 (2), 158-169., Org.Lett., 2010,12 (15), 3498-3501., Journal of Organic Chemistry, 2009,74 (7), 2850-2853.
But the most reactions steps of these methods is many, and productive rate is low, though the simple productive rate of some method condition is lower.The present invention is by phenyl selenium bromine and o-allyl compounds generation intramolecularly selenium electrophilic addition ring closure reaction, single step reaction has prepared the new 2-phenylseleno methyl 2 of a class with high yield, 3-Dihydrobenzofuranes compounds, this compounds is a kind of inhibitor medicaments with remarkable inhibition activity of monoamine oxidase, for new medicament screens such as antidepressant, anti-Parkinson provide the research basis.
(3) summary of the invention
The object of the invention provides a kind of 2-phenylseleno methyl 2,3-Dihydrobenzofuranes compounds and preparation method thereof, and the application of this compounds in monoamine oxidase (MAO) inhibitor medicaments, this compounds has significant inhibitory effect to monoamine oxidase, such compound synthesis technology is simple, is easy to industrialization.
The technical solution used in the present invention is:
2-phenylseleno methyl 2 shown in a kind of formula (I), 3-Dihydrobenzofuranes compounds:
In the formula (I):
R
1, R
2, R
3, R
4Independent separately is alkyl, benzoyl or the substituted benzoyl of H, hydroxyl, halogen, nitro, C1～C3, the alkoxyl group of C1～C2, and the substituting group of described substituted benzoyl is: the alkyl of halogen, nitro, C1～C3, the alkoxyl group of C1～C2; Described R
1, R
2, R
3, R
4Be not H simultaneously, and R
1, R
2, R
3, R
4When one of them was alkyl, other three was not H simultaneously; Perhaps described R
3, R
4Connect into phenyl ring.
Preferably, described R
1, R
2, R
3, R
4Independent separately is H, hydroxyl, F, Cl, Br, I, nitro, methyl, methoxyl group or benzoyl.
It is one of following that described 2-phenylseleno methyl 2,3-Dihydrobenzofuranes compounds are preferably:
(I-7)。
A kind of preparation 2-phenylseleno of the present invention methyl 2, the method of 3-Dihydrobenzofuranes compounds, described method is: with the replacement o-allyl phenol shown in phenyl selenium bromine shown in the formula (II) and the formula (III) is raw material, under the effect of catalyzer, in organic solvent, under nitrogen atmosphere, react 0.5～5h under 0～62 ℃ of condition, TLC follows the tracks of reaction, reaction finishes the aftertreatment of afterreaction liquid and makes described 2-phenylseleno methyl 2,3-Dihydrobenzofuranes compounds; Described organic solvent is one of following: C3～C6 ketone, tetrahydrofuran (THF), dioxane, C2～C4 nitrile or C1～C2 halohydrocarbon; Described catalyzer is one of following: triethylamine, pyridine or Tetramethyl Ethylene Diamine.
It is one of following that described organic solvent is preferably: acetone, ether, tetrahydrofuran (THF), methylene dichloride, trichloromethane, chloroform, 1,4-dioxane or acetonitrile.
R among formula (I), (III)
1, R
2, R
3, R
4Independent separately is alkyl, benzoyl or the substituted benzoyl of H, hydroxyl, halogen, nitro, C1～C3, the alkoxyl group of C1～C2, and the substituting group of described substituted benzoyl is: the alkyl of halogen, nitro, C1～C3, the alkoxyl group of C1～C2, and R
1, R
2, R
3, R
4When one of them was alkyl, other three was not H simultaneously; Perhaps described R
3, R
4Connect into phenyl ring.
Further, 2-phenylseleno methyl 2, among the preparation method of 3-Dihydrobenzofuranes compounds, the feed intake ratio of amount of substance of replacement o-allyl phenol shown in phenyl selenium bromine shown in the described formula (II) and the formula (III) is 0.80～1.20: 1, and the feed intake ratio of amount of substance of the phenyl selenium bromine shown in the formula (II) and catalyzer is 1: 1～2.
Further, 2-phenylseleno methyl 2, among the preparation method of 3-Dihydrobenzofuranes compounds, described volume of organic solvent consumption is counted 1.5～200mL/g. with the compound quality shown in the formula (II)
Described 2-phenylseleno methyl 2, among the preparation method of 3-Dihydrobenzofuranes compounds, described post-treating method is: after reaction finishes, reaction solution extracts with methylene dichloride or saturated aqueous common salt, the organic phase washing, use anhydrous magnesium sulfate drying again, concentrate, get crude product, be that eluent carries out column chromatography or comes purification with 100: 1 sherwood oil of volume ratio and methylene dichloride mixed solution recrystallization with 30: 1 sherwood oil of volume ratio and ethyl acetate mixed solution again, get described 2-phenylseleno methyl 2,3-Dihydrobenzofuranes compounds.
Described temperature of reaction is preferably 25～62 ℃, preferred reaction 0.5～5h.
Preparation 2-phenylseleno methyl 2 of the present invention, the reaction formula of 3-Dihydrobenzofuranes compounds is:
A kind of 2-phenylseleno methyl 2 of the present invention, the application of 3-Dihydrobenzofuranes compounds in activity of monoamine oxidase suppresses.
Compared with prior art, beneficial effect of the present invention is mainly reflected in: (1) the present invention is by phenyl selenium bromine and o-allyl compounds generation intramolecularly selenium electrophilic addition ring closure reaction, one step prepared the new 2-phenylseleno methyl 2 of a class, 3-Dihydrobenzofuranes compounds with high yield; (2) the invention provides a kind of new 2-phenylseleno methyl 2,3-Dihydrobenzofuranes compounds; (3) this compounds is a kind of inhibitor medicaments with remarkable inhibition activity of monoamine oxidase, for new medicament screens such as antidepressant, anti-Parkinson provide the research basis; (4) compound of the present invention, synthesis technique is simple, and the yield height is easy to industrialization.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1:5-methoxyl group-2-phenylseleno methyl-2, the preparation of 3-Dihydrobenzofuranes (I-1)
Reaction formula is as follows:
Under nitrogen atmosphere, 0.328g (2.0mmol) 2-allyl group-4-methoxyphenol (III-1) is dissolved in the 20mL methylene dichloride, add 0.472g (2.0mmol) phenyl selenium bromine (II), add 0.237g (3.0mmol) pyridine at last, 25 ℃ were reacted 2.0 hours, TLC follows the tracks of reaction, 2-allyl group-4-methoxyphenol (III-1) point disappears, react completely, use the 20mL dichloromethane extraction, organic phase washing 20mL * 3 are used anhydrous magnesium sulfate drying again, concentrate, get crude product (I-1), cross chromatography column (is elutriant with 30: 1 sherwood oil of volume ratio and ethyl acetate mixed solution) purifying, get elaboration 5-methoxyl group-2-phenylseleno methyl-2,3-Dihydrobenzofuranes (I-1) 0.606g, productive rate is 95.0%.
1H-NMR(CDCl
3)：δ7.17-7.10(m，5H)，6.95-6.94(d，1H)，6.07-6.06(d，1H)，5.93-5.89(m，1H)，5.03-5.00(m，2H)，3.65(s，OCH
3)，3.35-3.33(d，2H)；?
13C-NMR(CDCl
3)：δ153.1，148.7，136.1，130.8，129.8，129.4，127.3，126.8，119.2，119.0，116.1，114.5，55.8，35.2.
Embodiment 2:5-chloro-2-phenylseleno methyl-2, the preparation of 3-Dihydrobenzofuranes (I-2)
Reaction formula is as follows:
Under nitrogen atmosphere, 0.337g (2.0mmol) 2-allyl group-4-chlorophenol (III-2) is dissolved in the 25mL acetone, add 0.481g (2.04mmol) phenyl selenium bromine (II), add 0.42mL (3.0mmol) triethylamine at last.30 ℃ were reacted 1.0 hours, and TLC follows the tracks of reaction, and raw material point (III-2) disappears, react completely, use the 40mL dichloromethane extraction, organic phase washing 20mL * 3 are used anhydrous magnesium sulfate drying again, concentrate, cross post (is elutriant with 30: 1 sherwood oil of volume ratio and ethyl acetate mixed solution) purifying, get light yellow solid 5-chloro-2-phenylseleno methyl-2,3-Dihydrobenzofuranes (I-2) 0.602g, 47.7～50.3 ℃ of fusing points, productive rate are 93%.
1H-NMR(CDCl
3)：δ6.66-7.59(m，8H)，4.92-4.96(m，1H)，3.31-3.33(m，2H)，2.98-3.14(m，2H)，2.29(s，CH
3)；
13C-NMR(CDCl
3)：δ157.0，133.0，129.9，129.4，129.2，128.4，127.2，126.1，125.6，109.0，81.9，35.5，32.7，20.7；IRv
max(cm
-1)：2931，861，604，1491，1475，1347，1199，944，805，736，688.
Embodiment 3:5-fluoro-2-phenylseleno methyl-2, the preparation of 3-Dihydrobenzofuranes (I-3)
Reaction formula is as follows:
Under nitrogen atmosphere, 0.304g (2.0mmol) 2-allyl group-4-fluorophenol (III-3) is dissolved in 25mL 1, in the 4-dioxane, add 0.481g (2.04mmol) phenyl selenium bromine (II), add 0.42mL (3.0mmol) triethylamine at last, 25 ℃ were reacted 0.5 hour, TLC follows the tracks of reaction, and raw material point (III-3) disappears, and reacts completely, reaction solution 40mL dichloromethane extraction, organic phase washing 30mL * 3 are used anhydrous magnesium sulfate drying again, concentrate, cross post (is elutriant with 30: 1 sherwood oil of volume ratio and ethyl acetate mixed solution) purifying, get yellow solid 0.548g, 40～42. ℃ of fusing points, i.e. 5-fluoro-2-phenylseleno methyl-2,3-Dihydrobenzofuranes (I-3), productive rate are 89.2%.
1H-NMR(CDCl
3)：δ6.22-7.15(m，8H)，5.82-5.88(m，1H)，4.97-5.01(m，2H)，3.29-3.30(m，2H)；IRv
max(cm
-1)：3419，3074，2914，1639，1578，1455，1328，1205，1172，769，735，688.
Embodiment 4:4,6-two chloro-2-phenylseleno methyl-2, the preparation of 3-Dihydrobenzofuranes (I-4)
Reaction formula is as follows:
Under nitrogen atmosphere, with 0.406g (2.0mmol) 2-allyl group-3,5-chlorophenesic acid (III-4) is dissolved in the 20mL acetonitrile, add 0.463g (1.96mmol) phenyl selenium bromine (II), add 25 ℃ of reactions of 0.56mL (4.0mmol) triethylamine 1.0 hours at last, TLC follows the tracks of reaction, raw material point (III-4) disappears, and reacts completely reaction solution 50mL dichloromethane extraction, organic phase washing 30mL * 3, use anhydrous magnesium sulfate drying again, concentrate, cross post (is elutriant with 30: 1 sherwood oil of volume ratio and ethyl acetate mixed solution) purifying, get brown solid 0.637g, 50.8～51.8 ℃ of fusing points, promptly 4,6-two chloro-2-phenylseleno methyl-2,3-Dihydrobenzofuranes (I-4), productive rate are 89.0%.
1H-NMR(CDCl
3)：δ7.01-7.57(m，7H)，5.04-5.07(m，1H)，3.36-3.42(m，2H)，3.08-3.13(m，2H)；
13C-NMR(CDCl
3)：δ154.2，133.3，129.3，128.7，128.0，127.6，126.3，125.5，123.5，115.3，83.5，35.7，32.1，IRvmax(cm
-1)：3450，3070，2969，1582，1462，1021，987，852，691，608.
Embodiment 5:2-phenylseleno methyl-2, the preparation of 3-dihydro (naphthalene [1,2] is also) furans (I-5)
Reaction formula is as follows:
Under nitrogen atmosphere, 0.368g (2.0mmol) 2-allyl group naphthalene-1-phenol (III-5) is dissolved in the 20mL tetrahydrofuran (THF), add 0.472g (2.0mmol) phenyl selenium bromine (II), add 0.232g (2.0mmol) Tetramethyl Ethylene Diamine at last, 50 ℃ were reacted 1.0 hours, and TLC follows the tracks of reaction, raw material point (III-5) disappears, react completely reaction solution 40mL dichloromethane extraction, organic phase washing 30mL * 3, use anhydrous magnesium sulfate drying again, concentrate, cross post (is elutriant with 30: 1 sherwood oil of volume ratio and ethyl acetate mixed solution) purifying, get brown solid 0.586g, it is 2-phenylseleno methyl-2,3-dihydro (naphthalene [1,2] also) furans (I-5), productive rate is 86.5%.
1H-NMR(CDCl
3)：δ7.91-7.79(m，2H)，7.61-7.59(m，2H)，7.44-7.38(m，3H)，7.31-7.26(m，4H)，5.23-5.16(m，1H)，3.586-3.43(m，2H)，3.25-3.16(m，2H)；
13C-NMR(CDCl
3)：δ154.5，133.9，133.3，129.4，129.1，127.8，127.3，125.6，125.3，122.8，121.4，120.5，120.3，119.1，82.8，36.3，32.9.
Embodiment 6:2-phenylseleno methyl-6-hydroxyl-7-methyl-2, the preparation of 3-Dihydrobenzofuranes (I-6)
Reaction formula is as follows:
Under nitrogen atmosphere, with 0.328g (2.0mmol) 4-allyl group-2-methyl isophthalic acid, 3-dihydroxy-benzene (III-6) is dissolved in 25mL 1, in the 4-dioxane, add 0.481g (2.04mmol) phenyl selenium bromine (II), add 0.232g (2.0mmol) Tetramethyl Ethylene Diamine at last, 25 ℃ were reacted 0.5 hour, the TLC detection reaction is complete, uses dichloromethane extraction, and organic phase washes 30mL * 3 with water, the organic phase anhydrous magnesium sulfate drying, concentrate, cross post (eluent: sherwood oil and ethyl acetate volume ratio are 1: 30.) and get 2-phenylseleno methyl-6-hydroxyl-7-methyl-2,3-Dihydrobenzofuranes (I-6) 0.563 gram productive rate is 88.2%.
1H-NMR(CDCl
3)：δ7.57-7.55(m，2H)，7.27-7.26(m，3H)，6.81-6.79(d，1H)，6.30-6.28(d，1H)，5.33(s，1H)，4.98-4.95(m，1H)，3.36-3.27(m，2H)，3.12-3.07(m，1H)，2.99-2.94(m，1H)，2.05(s，3H)；
13C-NMR(CDCl
3)：δ158.81，154.14，133.00，129.48，129.11，127.19，121.65，117.34，106.97，106.61，82.62，35.43，32.84，8.33.
Embodiment 7:2-phenylseleno methyl-4-hydroxyl-5,7-dibenzoyl-2, the preparation of 3-Dihydrobenzofuranes (I-7)
Reaction formula is as follows:
Under nitrogen atmosphere; 7.16g (20mmol) compound (III-5) is dissolved in the 100mL trichloromethane; add 4.96g (21mmol) phenyl selenium bromine (II); 2.80mL (20mmol) the triethylamine back flow reaction is 5 hours; the TLC detection reaction is complete; add 100mL saturated common salt water stratification; organic phase washes 80mL * 3 with water; add anhydrous magnesium sulfate drying, concentrate, with sherwood oil and methylene dichloride (100: 1) recrystallization; get white solid 2-phenylseleno methyl-4-hydroxyl-5; 7-dibenzoyl-2,3-Dihydrobenzofuranes (I-10) 9.234g, productive rate is 90%.
1H-NMR(CDCl
3)：δ12.70(s，1H)，7.78(s，1H)，7.66-7.64(m，2H)，7.54-7.534(m，2H)，7.44-7.414(m，4H)，7.36-7.30(m，4H)，7.15-7.14(m，3H)，5.06-5.03(m，1H)，3.34-3.33(m，1H)，3.21-3.17(m，1H)，3.05-2.96(m，2H)；?
13C-NMR(CDCl
3)：δ200.3，192.5，165.1，163.0，139.1，138.0，137.7，133.4，132.6，132.0，129.6，129.3，129.0，128.7，128.5，128.1，127.6，114.3，114.1，114.2，114.0，85.4，32.3，31.3；IRv
max(cm
-1)：3062，2977，1623，1446，1261，1135，1035，778，743，700，618.
The test of embodiment 8 monoamine oxidase inhibitory activities
(1) sample preparation
The compound (I-1)～(I-7) of embodiment 1～7 preparation is dissolved in the dimethyl sulfoxide (DMSO) (DMSO), is made into 5,15,25,35,45,60,75,90,105 respectively, the sample liquid of 120mmol/L concentration gradient, be designated as sample 1～sample 7.
(2) 2-phenylseleno methyl 2,3-Dihydrobenzofuranes compounds suppresses the active testing detection method to monoamine oxidase-A
Sample 1～the sample 7 that in 7 EP pipes (Eppendorf tube) that 386 μ L borate buffers (pH=8.4) are housed, adds 4 μ L monoamine oxidase-A (MAO-A) and the preparation of 4 μ L steps (1) respectively, mix, again mixture is reacted bovine serum albumin (BSA) that 2h. adds the probe 7-shown in the 2 μ L formulas (IV) (3-amino propoxy-)-4-methylcoumarin (10mmol/ml) and 4 μ L then respectively once more in 38 ℃ of water-baths in above-mentioned 7 EP pipes, and place it in and continue to react 2h in 38 ℃ of water-baths.With the enzyme work of the enzyme of inhibiting not is contrast, promptly in the EP pipe that 390 μ L borate buffers (pH=8.4) are housed, add 4 μ L monoamine oxidase-A (MAO-A), react 2h in 38 ℃ of water-baths, the BSA that adds 2 μ L probes (10mmol/ml) and 4 μ L more equally also reacts 2h in 38 ℃ of water-baths.
(IV)
Taking out 100 μ L at last in above-mentioned each EP pipe (Eppendorf tube) adds in 96 orifice plates also with global function spectrophotofluorometer (λ ex/ λ em=365/460nm) (spectraMax M, U.S. molecule instrument company) test sample 1～sample 7 and control sample.IC according to the fluorescent value calculation sample of being surveyed 1～7
50, compound (I-1)～(I-7) sees Table 1 to the active test result that suppresses of monoamine oxidase-A.
The inhibition effect of compound half-inhibition concentration (IC
50) represent.IC
50Be meant that " reaction " is suppressed the concentration of a half inhibitor, it is strong more that compound suppresses ability, and this numerical value is low more.
IC
50Can calculate in order to following method:
1) detects and calculates average fluorescent strength (F only enzyme-added and the probe damping fluid
M);
2) calculating contains the fluorescence intensity (wanting the background correction value) of each component enzyme of different concns gradient inhibitor;
3) do the straight-line regression of relation between the concentration (C) of inhibitor and the fluorescence intensity (F) according to the fluorescence intensity of each component enzyme of different concns gradient inhibitor, set up and obtain equation: F=aC+b (determine equation coefficient a and cut the b that crouches) by regression straight line;
4), ask F=1/2F according to equation
MUnder the inhibitor concentration of correspondence, can obtain inhibiting rate and be 50% o'clock inhibitor concentration, be IC
50
(3) 2-phenylseleno methyl 2,3-Dihydrobenzofuranes compounds suppresses active testing to monoamine oxidase-B
Change MAO-A into MAO-B, other operate same step (2), the results are shown in Table 1.
Table 1 2-phenylseleno methyl-2,3-Dihydrobenzofuranes compounds to monoamine oxidase inhibitory activity
| Compound | MAO-A?IC50(μM) | MAO-B?IC50(μM) |
| I-1 | 683.80 | 83.56 |
| I-2 | 262.46 | 492.53 |
| I-3 | 241.02 | 567.07 |
| I-4 | 438.45 | * |
[0082]?
| I-5 | 485.34 | 906.75 |
| I-6 | 68.50 | 476.35 |
| I-7 | * | 200.10 |
* expression does not suppress active or suppresses activity to be far longer than 1500 μ M.
As can be seen from Table 1, compound (I-1), (I-2), (I-3), (I-4), (I-5), (I-6) have the activity of inhibition to monoamine oxidase A, and wherein compound (I-2), (I-3), (I-6) have stronger inhibition activity; Compound (I-1), (I-2), (I-3), (I-5), (I-6), (I-7), monoamine oxidase-B had suppress active, wherein compound (I-1), (I-7) have stronger inhibition activity.
Claims (10)
1. 2-phenylseleno methyl 2 shown in the formula (I), 3-Dihydrobenzofuranes compounds:
In the formula (I): R
1, R
2, R
3, R
4Independent separately is alkyl, benzoyl or the substituted benzoyl of H, hydroxyl, halogen, nitro, C1～C3, the alkoxyl group of C1～C2, and the substituting group of described substituted benzoyl is: the alkyl of halogen, nitro, C1～C3, the alkoxyl group of C1～C2, described R
1, R
2, R
3, R
4Be not H simultaneously, and R
1, R
2, R
3, R
4When one of them was alkyl, other three was not H simultaneously; Perhaps described R
3, R
4Connect into phenyl ring.
2. 2-phenylseleno methyl 2 as claimed in claim 1,3-Dihydrobenzofuranes compounds is characterized in that described R
1, R
2, R
3, R
4Independent separately is H, hydroxyl, F, Cl, Br, I, nitro, methyl, methoxyl group or benzoyl.
3. 2-phenylseleno methyl 2 as claimed in claim 1,3-Dihydrobenzofuranes compounds is characterized in that described compound is one of following:
4. one kind prepares 2-phenylseleno methyl 2 as claimed in claim 1, the method of 3-Dihydrobenzofuranes compounds, it is characterized in that described method is: with the replacement o-allyl phenol shown in phenyl selenium bromine shown in the formula (II) and the formula (III) is raw material, under the effect of catalyzer, in organic solvent, under nitrogen atmosphere, react 0.5～5h under 0～62 ℃ of condition, reaction finishes the aftertreatment of afterreaction liquid and makes described 2-phenylseleno methyl 2,3-Dihydrobenzofuranes compounds; Described organic solvent is one of following: C3～C6 ketone, tetrahydrofuran (THF), dioxane, C2～C4 nitrile or C1～C2 halohydrocarbon; Described catalyzer is triethylamine, pyridine or Tetramethyl Ethylene Diamine.
5. 2-phenylseleno methyl 2 as claimed in claim 4, the preparation method of 3-Dihydrobenzofuranes compounds, it is characterized in that described organic solvent is one of following: acetone, ether, tetrahydrofuran (THF), methylene dichloride, trichloromethane, chloroform, 1,4-dioxane or acetonitrile.
R among formula (I), (III)
1, R
2, R
3, R
4Independent separately is alkyl, benzoyl or the substituted benzoyl of H, hydroxyl, halogen, nitro, C1～C3, the alkoxyl group of C1～C2, and the substituting group of described substituted benzoyl is: the alkyl of halogen, nitro, C1～C3, the alkoxyl group of C1～C2, described R
1, R
2, R
3, R
4Be not H simultaneously, and R
1, R
2, R
3, R
4When one of them was alkyl, other three was not H simultaneously; Perhaps described R
3, R
4Connect into phenyl ring.
6. 2-phenylseleno methyl 2 as claimed in claim 4, the preparation method of 3-Dihydrobenzofuranes compounds, it is characterized in that the feed intake ratio of amount of substance of the replacement o-allyl phenol shown in phenyl selenium bromine shown in the described formula (II) and the formula (III) is 0.80～1.20: 1,, the feed intake ratio of amount of substance of the phenyl selenium bromine shown in the formula (II) and catalyzer is 1: 1～2.
7. 2-phenylseleno methyl 2 as claimed in claim 4, the preparation method of 3-Dihydrobenzofuranes compounds is characterized in that described volume of organic solvent consumption counts 1.5～200mL/g with the compound quality shown in the formula (II).
8. 2-phenylseleno methyl 2 as claimed in claim 4, the preparation method of 3-Dihydrobenzofuranes compounds, it is characterized in that described post-treating method is: after reaction finishes, reaction solution extracts with methylene dichloride or saturated aqueous common salt, the organic phase washing, use anhydrous magnesium sulfate drying again, concentrate, get crude product, be that eluent carries out column chromatography or comes purification with 100: 1 sherwood oil of volume ratio and methylene dichloride mixed solution recrystallization crude product with 30: 1 sherwood oil of volume ratio and ethyl acetate mixed solution again, make described 2-phenylseleno methyl 2,3-Dihydrobenzofuranes compounds.
9. 2-phenylseleno methyl 2 as claimed in claim 1, the application of 3-Dihydrobenzofuranes compounds in activity of monoamine oxidase suppresses.
10. 2-phenylseleno methyl 2 as claimed in claim 1, the application of 3-Dihydrobenzofuranes compounds in activity of monoamine oxidase suppresses, described compound is (I-1), (I-2), (I-3), (I-6), (I-7).
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