CN101016290A - Method of synthesizing 3-methyl-7-,8-dihydroxyisochromanone-4 - Google Patents
Method of synthesizing 3-methyl-7-,8-dihydroxyisochromanone-4 Download PDFInfo
- Publication number
- CN101016290A CN101016290A CN 200710020464 CN200710020464A CN101016290A CN 101016290 A CN101016290 A CN 101016290A CN 200710020464 CN200710020464 CN 200710020464 CN 200710020464 A CN200710020464 A CN 200710020464A CN 101016290 A CN101016290 A CN 101016290A
- Authority
- CN
- China
- Prior art keywords
- reaction
- methyl
- dimethoxybenzyloxy
- ethyl
- dihydroxyisochromanone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000002194 synthesizing effect Effects 0.000 title 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical class CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims abstract description 16
- -1 2-(2,3-dimethoxybenzyloxy) ethyl Chemical group 0.000 claims abstract description 13
- AGDAABFRSMTRLT-UHFFFAOYSA-N 2-[(2,3-dimethoxyphenyl)methoxy]propanoic acid Chemical compound COC1=C(COC(C(=O)O)C)C=CC=C1OC AGDAABFRSMTRLT-UHFFFAOYSA-N 0.000 claims abstract description 12
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006266 etherification reaction Methods 0.000 claims abstract description 9
- BUOYAJGUTDIENY-UHFFFAOYSA-N 2-[(2,3-dimethoxyphenyl)methoxy]propanoyl chloride Chemical compound COC1=C(COC(C(=O)Cl)C)C=CC=C1OC BUOYAJGUTDIENY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- MKQQWYFVXVSJTH-UHFFFAOYSA-N 1-(bromomethyl)-2,3-dimethoxybenzene Chemical compound COC1=CC=CC(CBr)=C1OC MKQQWYFVXVSJTH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000005917 acylation reaction Methods 0.000 claims abstract description 5
- 229940116333 ethyl lactate Drugs 0.000 claims abstract description 5
- CRLBBOBKCLYCJK-UHFFFAOYSA-N (2,3-dimethoxyphenyl)methanol Chemical compound COC1=CC=CC(CO)=C1OC CRLBBOBKCLYCJK-UHFFFAOYSA-N 0.000 claims abstract 3
- 230000017858 demethylation Effects 0.000 claims abstract 2
- 238000010520 demethylation reaction Methods 0.000 claims abstract 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 238000009835 boiling Methods 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000010189 synthetic method Methods 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- MJRVJLUCLPUZER-UHFFFAOYSA-N 1-(chloromethyl)-2,3-dimethoxybenzene Chemical compound COC1=CC=CC(CCl)=C1OC MJRVJLUCLPUZER-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 235000010755 mineral Nutrition 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 5
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims 2
- 238000005658 halogenation reaction Methods 0.000 claims 2
- LQNUZADURLCDLV-IDEBNGHGSA-N nitrobenzene Chemical group [O-][N+](=O)[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 LQNUZADURLCDLV-IDEBNGHGSA-N 0.000 claims 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 1
- OAAGDVLVOKMRCQ-UHFFFAOYSA-N 5-piperidin-4-yl-3-pyridin-4-yl-1,2,4-oxadiazole Chemical compound C1CNCCC1C1=NC(C=2C=CN=CC=2)=NO1 OAAGDVLVOKMRCQ-UHFFFAOYSA-N 0.000 claims 1
- JYXVFFDYMJVWCP-UHFFFAOYSA-N 7,8-dimethoxy-3-methyl-3,4-dihydroisochromen-1-one Chemical compound C1C(C)OC(=O)C2=C(OC)C(OC)=CC=C21 JYXVFFDYMJVWCP-UHFFFAOYSA-N 0.000 claims 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 230000026030 halogenation Effects 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 238000007171 acid catalysis Methods 0.000 abstract description 2
- 229930014626 natural product Natural products 0.000 abstract description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 abstract 1
- 229940073608 benzyl chloride Drugs 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 239000012044 organic layer Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- GAWAYYRQGQZKCR-UHFFFAOYSA-N 2-chloropropionic acid Chemical compound CC(Cl)C(O)=O GAWAYYRQGQZKCR-UHFFFAOYSA-N 0.000 description 1
- NDPXEUWHGBATNN-UHFFFAOYSA-N COC1=CC=CC(=C1OC)COCCC(=O)Cl Chemical compound COC1=CC=CC(=C1OC)COCCC(=O)Cl NDPXEUWHGBATNN-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种新颖天然产物3－甲基－7，8－二羟基异色满酮－4的合成方法。本发明以2，3－二甲氧基苯甲醇，与2位卤代的丙酸乙酯发生醚化反应，或者以2，3－二甲氧基苄溴或2，3－二甲氧基苄氯与乳酸乙酯发生醚化反应得到2－(2，3－二甲氧基苄氧基)丙酸乙酯。将2－(2，3－二甲氧基苄氧基)丙酸乙酯水解得到2－(2，3－二甲氧基苄氧基)丙酸，再将其制备成2－(2，3－二甲氧基苄氧基)丙酰氯，在路易斯酸催化条件下发生分子内付克酰化反应，得到3－甲基－7，8－二甲氧基异色满酮－4，最后脱甲基得到目标化合物3－甲基－7，8－二羟基异色满酮－4。The invention relates to a synthesis method of a novel natural product 3-methyl-7,8-dihydroxyisochromanone-4. In the present invention, 2,3-dimethoxybenzyl alcohol is used for etherification reaction with 2-halogenated ethyl propionate, or 2,3-dimethoxybenzyl bromide or 2,3-dimethoxy The etherification reaction between benzyl chloride and ethyl lactate gives 2-(2,3-dimethoxybenzyloxy) ethyl propionate. Hydrolyze ethyl 2-(2,3-dimethoxybenzyloxy)propionate to obtain 2-(2,3-dimethoxybenzyloxy)propanoic acid, which is then prepared into 2-(2, 3-dimethoxybenzyloxy)propionyl chloride, under the conditions of Lewis acid catalysis, intramolecular Fuke acylation reaction, to obtain 3-methyl-7,8-dimethoxyisochromanone-4, and finally Demethylation yields the target compound 3-methyl-7,8-dihydroxyisochromanone-4.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate to a kind of novel natural product 3-methyl-7, the synthetic method of 8-dihydroxyl isochromanome-4.
Background technology
The inventor finds in the research to Pericarpium Musae that in early stage it extracts efficient part and has antihypertensive activity, sees patent CN1857530A.
The inventor is extraction separation to a new effective constituent 3-methyl-7 in to the further research of Pericarpium Musae medicinal part, 8-dihydroxyl isochromanome-4, and structural formula is as follows:
To compound 3-methyl-7, find in the pharmacological testing of 8-dihydroxyl isochromanome-4 that it has good antihypertensive active, antihypertensive effect and captopril are suitable, see patent (application number) 200710019203.5.
Summary of the invention
The object of the present invention is to provide a kind of 3-methyl-7, the chemical synthesis process of 8-dihydroxyl isochromanome-4.
Synthetic method of the present invention is with 2,3-3,5-dimethoxybenzoic alcohol and 2 halogenated ethyl propionate generation etherification reactions, perhaps with 2,3-dimethoxy benzyl bromine or 2,3-dimethoxy benzyl chlorine and ethyl lactate generation etherification reaction obtain 2-(2,3-dimethoxy benzyloxy) ethyl propionate (I).Again with 2-(2; 3-dimethoxy benzyloxy) ethyl propionate (I) hydrolysis obtains 2-(2; 3-dimethoxy benzyloxy) propionic acid (II); then Compound I I is prepared into 2-(2,3-dimethoxy benzyloxy) propionyl chloride (III), issues living intramolecularly in the Louis acid catalysis condition and pay the gram acylation reaction; obtain 3-methyl-7; 8 dimethoxy isochromanomes-4 (IV) remove methyl at last and obtain target compound 3-methyl-7,8-dihydroxyl isochromanome-4 (V).
2-of the present invention (2,3-dimethoxy benzyloxy) ethyl propionate (I) is with 2,3-3,5-dimethoxybenzoic alcohol and 2 halogenated ethyl propionate generation etherification reactions, perhaps by 2,3-dimethoxy benzyl bromine or 2,3-dimethoxy benzyl chlorine and ethyl lactate generation etherification reaction and prepare.2 halogenated ethyl propionates can be 2 bromopropionic acid ethyl ester or 2-chloropropionate, the solvent that reaction is used can be ether, tetrahydrofuran (THF), acetonitrile, acetone, benzene, toluene, DMF, DMSO, HMPT, liquefied ammonia, the reaction reagent that uses can be Anhydrous potassium carbonate, anhydrous potassium fluoride, sodium methylate, sodium ethylate, sodium, sodium hydride or sodium amide, temperature of reaction can be selected suitable temperature, reaction times between the boiling temperature of room temperature and solvent for use be 2 hours to 24 hours.
2-(2 of the present invention, 3-dimethoxy benzyloxy) propionic acid (II), be with 2-(2,3-dimethoxy benzyloxy) ethyl propionate (I) is a raw material, adopt conventional method for hydrolysis preparation, the alkali that uses can be NaOH, KOH or LiOH, and solvent is the mixing solutions of methyl alcohol, ethanol, water or former three.Temperature of reaction can be selected suitable temperature, reaction times between the boiling temperature of room temperature and solvent for use be 1 hour to 24 hours.
2-of the present invention (2,3-dimethoxy benzyloxy) propionyl chloride (III) is to prepare with 2-(2,3-dimethoxy benzyloxy) propionic acid (II) chlorination.The chlorizating agent that uses is oxalyl chloride, sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride, with benzene or directly use chlorizating agent as reaction solvent.Temperature of reaction can be selected suitable temperature between the boiling temperature of 0 ℃ and solvent for use, the reaction times is 15 minutes to 12 hours.
3-methyl-7 of the present invention, 8-dimethoxy isochromanome-4 (IV) is to pay the gram acylation reaction by 2-(2,3-dimethoxy benzyloxy) propionyl chloride (III) generation intramolecularly to obtain.The catalyzer that uses is Lewis acid, as aluminum chloride, iron trichloride, boron trifluoride ethyl ether complex, anhydrous stannic chloride, Zinc Chloride Anhydrous, solvent can be oil of mirbane, dithiocarbonic anhydride, benzene, methylene dichloride, chloroform, ether, tetrahydrofuran (THF), temperature of reaction can be selected suitable temperature, 1 hour to 6 hours reaction times between the boiling temperature of-4 ℃ and solvent for use.
3-methyl-7 of the present invention, 8-dihydroxyl isochromanome-4 (V) is by 3-methyl-7,8-dimethoxy isochromanome-4 (IV) removes methyl and obtains.The reagent that uses can be mineral acid such as Hydrogen bromide, hydrochloric acid, phosphoric acid or polyphosphoric acid, perhaps be Lewis acid such as aluminum chloride, boron tribromide or boron trifluoride, solvent can be oil of mirbane, dithiocarbonic anhydride, benzene, methylene dichloride, chloroform, ether, tetrahydrofuran (THF), or directly be solvent with the mineral acid, temperature of reaction can be selected suitable temperature between the boiling temperature of 0 ℃ and solvent for use, the reaction times is 1 hour to 12 hours.
Embodiment
Following specific embodiment can be described in more detail the present invention, but does not limit the present invention in any form.
Embodiment 1
The preparation of 2-(2,3-dimethoxy benzyloxy) ethyl propionate (I)
16.8g 2, the 3-3,5-dimethoxybenzoic alcohol is dissolved in 200mL DMF, adds 15.0g K
2CO
3The back drips 2 bromopropionic acid ethyl ester 18.1g, and stirring at room 6 hours after reaction finishes, is filtered, and 130～150 ℃ of cuts are collected in the filtrate decompression distillation.Get colorless oil 2-(2,3-dimethoxy benzyloxy) ethyl propionate 24.4g, yield 91.0%.
1H-NMR(CDCl
3，300MHz)δ，ppm：1.27(d，3H，J＝6.9Hz，-CH
3)，1.34(t，3H，J＝7.2Hz，-CH
3)，3.88(s，3H，-OCH
3)，3.93(s，3H，-OCH
3)，4.12(q，1H，J＝6.9Hz，-CH-)，4.25(q，2H，J＝7.2Hz，-CH
2-)，4.57(d，1H，J＝10.5Hz，-CH
2-)，4.67(d，1H，J＝10.5Hz，-CH
2-)，6.96～7.13(m，3H，Ar-H)
MS(ESI?m/z)：[M+H]
+269
Embodiment 2
The preparation of 2-(2,3-dimethoxy benzyloxy) propionic acid (II)
20.1g 2-(2,3-dimethoxy benzyloxy) ethyl propionate adds 50% ethanolic soln that 200mL contains 20gKOH, refluxed 3 hours, and be evaporated to no ethanol again, with the hydrochloric acid adjust pH to 1 of 2N, extracted with diethyl ether, each 100mL extracts 3 times, merges ether solution, anhydrous sodium sulfate drying, concentrate white solid 2-(2,3-dimethoxy benzyloxy) propionic acid 14.1g, yield 78.3%.
1H-NMR(CD
3，300MHz)δ，ppm：1.50(d，3H，J＝6.9Hz，-CH
3)，3.89(s，3H，-OCH
3)，3.93(s，3H，-OCH
3)，4.12(q，1H，J＝6.9Hz，-CH-)，4.56(d，1H，J＝10.5Hz，-CH
2-)，4.64(d，1H，J＝10.5Hz，-CH
2-)，6.93～7.09(m，3H，Ar-H)
MS(ESI?m/z)：[M-H]
-239
Embodiment 3
3-methyl-7, the preparation of 8-dimethoxy isochromanome-4 (IV)
12.0g 2-(2,3-dimethoxy benzyloxy) propionic acid under the condition of ice bath, drips SOCl
220mL was warming up to stirring at room 1 hour, removed excessive SOCl under reduced pressure
2, add benzene 50mL dissolving.The benzole soln of 2-(2,3-dimethoxy benzyloxy) propionyl chloride of preparation is splashed into ice bath refrigerative 7g ZnCl
2The suspension of benzene in, stirring reaction 4 hours finishes after the reaction to tell organic layer in the dilute hydrochloric acid with reaction solution impouring 2N, sour water layer extracted with diethyl ether, each 40mL extracts 2 times, merge organic layer, use saturated sodium bicarbonate, saturated common salt water washing successively, anhydrous sodium sulfate drying.Organic layer concentrates, and silica gel column chromatography separates, and petroleum ether-ethyl acetate (10: 1) wash-out gets white solid 3-methyl-7,8-dimethoxy isochromanome-43.9g.121～122 ℃ of mp, yield 35.1%.
1H-NMR(CDCl
3，300MHz)δ，ppm：1.50(d，3H，J＝6.6Hz，-CH
3)，3.85(s，3H，-OCH
3)，3.95(s，3H，-OCH
3)，4.19(q，1H，J＝6.6Hz，-CH-)，4.79(d，1H，J＝15.9Hz，-CH
2-)，5.13(d，1H，J＝15.9Hz，-CH
2-)，6.95(d，1H，J＝8.7Hz，Ar-H)，7.83(d，1H，J＝8.7Hz，Ar-H)
MS(ESI，m/z)：[M+H]
+223，[M+Na]
+245
IR(KBr)，cm
-1：2991，2979，2963，2937，2844，2826，1693，1597，1580，1494，1454，1358，1288，1272，1126，1079
Embodiment 4
3-methyl-7, the preparation of 8-dihydroxyl isochromanome-4 (V)
2.22g 3-methyl-7,8-dimethoxy isochromanome-4 is dissolved in 25mL benzene, and gradation adds 5g AlCl
3, reflux is after 3 hours, in the ice-cold dilute hydrochloric acid with reaction solution impouring 2N, tell organic layer, water layer extracted with diethyl ether, each 10mL, extract 2 times, merge organic layer, anhydrous sodium sulfate drying, after organic layer concentrates, silica gel column chromatography, sherwood oil-acetone (4: 1) wash-out, get white solid 3-methyl-7,8-dihydroxyl isochromanome-41.07g, mp174～176 ℃ (decomposition), yield 55.1%.
1H-NMR(CD
3COCD
3)δ，ppm：1.38(d，3H，J＝6.2Hz，-CH
3)，4.22(q，1H，J＝6.2Hz，-CH-)，4.75(d，1H，J＝15.5Hz，-CH
2-)，5.03(d，1H，J＝15.5Hz，-CH
2-)，6.91(d，1H，J＝8.5Hz，Ar-H)，7.43(d，1H，J＝8.5Hz，Ar-H)
MS(ESI?m/z)：[M-H]
-193
IR(KBr)，cm
-1：3432，3428，1664，1613，2987，2844，1558，1480，1450，1394，1363，1306，1277，1256，1216，1179，1120，1074，951，908，825，788
Claims (9)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100204649A CN100475806C (en) | 2007-03-01 | 2007-03-01 | A kind of synthetic method of 3-methyl-7,8-dihydroxyisochromanone-4 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100204649A CN100475806C (en) | 2007-03-01 | 2007-03-01 | A kind of synthetic method of 3-methyl-7,8-dihydroxyisochromanone-4 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101016290A true CN101016290A (en) | 2007-08-15 |
| CN100475806C CN100475806C (en) | 2009-04-08 |
Family
ID=38725531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2007100204649A Expired - Fee Related CN100475806C (en) | 2007-03-01 | 2007-03-01 | A kind of synthetic method of 3-methyl-7,8-dihydroxyisochromanone-4 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100475806C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532087A (en) * | 2011-10-09 | 2012-07-04 | 中国药科大学 | Method for synthesizing 3-methyl-7,8-dimethoxy-chroman-4-one |
| CN103570665A (en) * | 2012-07-23 | 2014-02-12 | 中国药科大学 | Enantiomers of 3-methyl-7, 8-dihydroxy-isochroman-4-one, and applications thereof in controlling cardiovascular diseases |
| CN110105658A (en) * | 2019-04-04 | 2019-08-09 | 台州市黄岩聚丰机车有限公司 | Halogen-free polypropylene flame redardant electric bicycle exterior trimming parts raw material |
| CN111333604A (en) * | 2020-04-13 | 2020-06-26 | 合肥工业大学 | 3-oxo-isochroman-4-one derivative and synthesis method thereof |
-
2007
- 2007-03-01 CN CNB2007100204649A patent/CN100475806C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532087A (en) * | 2011-10-09 | 2012-07-04 | 中国药科大学 | Method for synthesizing 3-methyl-7,8-dimethoxy-chroman-4-one |
| CN103570665A (en) * | 2012-07-23 | 2014-02-12 | 中国药科大学 | Enantiomers of 3-methyl-7, 8-dihydroxy-isochroman-4-one, and applications thereof in controlling cardiovascular diseases |
| CN110105658A (en) * | 2019-04-04 | 2019-08-09 | 台州市黄岩聚丰机车有限公司 | Halogen-free polypropylene flame redardant electric bicycle exterior trimming parts raw material |
| CN110105658B (en) * | 2019-04-04 | 2021-08-20 | 台州市黄岩聚丰机车有限公司 | Halogen-free flame-retardant polypropylene electric bicycle exterior trim raw material |
| CN111333604A (en) * | 2020-04-13 | 2020-06-26 | 合肥工业大学 | 3-oxo-isochroman-4-one derivative and synthesis method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100475806C (en) | 2009-04-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101151257A (en) | Process for producing 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or salt thereof | |
| CN104520275B (en) | For preparation method and the intermediate product of integrase inhibitor | |
| NO148290B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE POLYENE COMPOUNDS | |
| ES2644413T3 (en) | Production of 2-amino-2- [2- (4-alkyl-phenyl) ethyl] propane-1,3-diols | |
| CN101016290A (en) | Method of synthesizing 3-methyl-7-,8-dihydroxyisochromanone-4 | |
| CN101747318A (en) | 1-(3,5-dichloro-pyridyl)-1H-5-pyrazole carboxylic acid ester compound | |
| Burckhalter et al. | Ethylene and Phenylacetyl Chloride in the Friedel-Crafts Reaction. Novel Syntheses of 2-Tetralones and Benzofuranones1 | |
| CN105566319A (en) | Preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane | |
| RO112031B1 (en) | Benzopyrane derivates and ltb4 antagonists, procedures for their preparation, pharmaceutical composition and method for inhibition of binding the receiver with ltb4 | |
| CN103030638A (en) | Preparation method of (S, S)-8H-6H-pyrrolo [3, 4-b] pyridine | |
| CN102249921A (en) | 2-(2,3-dimethyl phenyl) diester malonate, preparation method thereof, and application thereof | |
| CN106699722B (en) | A kind of fluoro- 1,3- benzo two of 2,2- bis- dislikes the synthetic method of cyclopentadienyl -4- formaldehyde | |
| CN101948455B (en) | Preparation method of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran | |
| CN101575348A (en) | Method for synthesizing beta-sodium glycero-phosphate | |
| CN106831863B (en) | Montelukast sodium intermediate and its preparation method and application | |
| CN113999164B (en) | Preparation method of halofuginone intermediate trans-N-benzyloxycarbonyl- (3-hydroxy-2-piperidinyl) -2-propanone | |
| CN101012192A (en) | Method of preparing zofenopril calcium | |
| KR101625128B1 (en) | Process for the synthesis of 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile, and application in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid | |
| CN103396304B (en) | Nervonic acid chemosynthesis method | |
| WO2015012271A1 (en) | Method for producing heterocyclic compound | |
| CN100475805C (en) | A kind of synthetic method of 3-methyl-7,8-dihydroxyisochromanone-4 | |
| CN100475807C (en) | A kind of synthetic method of 3-methyl-7,8-dihydroxyisochromanone-4 | |
| CN102675308A (en) | Method for preparing 8-benzyl-2,8-diazabicyclo(4.3.0) nonane | |
| CN107880011A (en) | The synthetic method of Shandong agate Kato key intermediate | |
| CN105130972A (en) | Emtricitabine benzoate, preparation method thereof, and method of preparing emtricitabine from emtricitabine benzoate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090408 Termination date: 20120301 |