CN102786463B - Method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester - Google Patents
Method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester Download PDFInfo
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- CN102786463B CN102786463B CN2012102229482A CN201210222948A CN102786463B CN 102786463 B CN102786463 B CN 102786463B CN 2012102229482 A CN2012102229482 A CN 2012102229482A CN 201210222948 A CN201210222948 A CN 201210222948A CN 102786463 B CN102786463 B CN 102786463B
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- QBMDEJWOANTTST-UHFFFAOYSA-N ethyl 5-acetyloxy-1h-indole-3-carboxylate Chemical compound C1=C(OC(C)=O)C=C2C(C(=O)OCC)=CNC2=C1 QBMDEJWOANTTST-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- 238000003756 stirring Methods 0.000 claims description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 59
- 239000012043 crude product Substances 0.000 claims description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 40
- 238000002360 preparation method Methods 0.000 claims description 37
- 238000010792 warming Methods 0.000 claims description 36
- 239000007787 solid Substances 0.000 claims description 31
- BOFRXDMCQRTGII-UHFFFAOYSA-N 619-08-9 Chemical class OC1=CC=C([N+]([O-])=O)C=C1Cl BOFRXDMCQRTGII-UHFFFAOYSA-N 0.000 claims description 29
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 23
- 238000001953 recrystallisation Methods 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 14
- 239000012346 acetyl chloride Substances 0.000 claims description 14
- 239000011259 mixed solution Substances 0.000 claims description 14
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 13
- 235000015320 potassium carbonate Nutrition 0.000 claims description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- 239000012312 sodium hydride Substances 0.000 claims description 12
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 238000005984 hydrogenation reaction Methods 0.000 claims description 11
- 230000006837 decompression Effects 0.000 claims description 10
- 229960004756 ethanol Drugs 0.000 claims description 10
- 235000019441 ethanol Nutrition 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 9
- HBHKWFIMCSJFLW-UHFFFAOYSA-N CCOC(=O)C1=C(NC2=CC=CC=C21)OC(=O)C Chemical compound CCOC(=O)C1=C(NC2=CC=CC=C21)OC(=O)C HBHKWFIMCSJFLW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 238000013019 agitation Methods 0.000 claims description 4
- 238000004886 process control Methods 0.000 claims description 4
- OEXNQFWEJRSZBW-UHFFFAOYSA-N ethyl indole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OCC)C=CC2=C1 OEXNQFWEJRSZBW-UHFFFAOYSA-N 0.000 claims 3
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 claims 2
- XOUHVMVYFOXTMN-UHFFFAOYSA-N ethyl 1h-indole-3-carboxylate Chemical compound C1=CC=C2C(C(=O)OCC)=CNC2=C1 XOUHVMVYFOXTMN-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 9
- OMZHXQXQJGCSKN-UHFFFAOYSA-N ethyl 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)-1h-indol-1-ium-3-carboxylate;chloride Chemical compound Cl.CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 OMZHXQXQJGCSKN-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 abstract 1
- 230000021736 acetylation Effects 0.000 abstract 1
- 238000006640 acetylation reaction Methods 0.000 abstract 1
- 239000003443 antiviral agent Substances 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract 1
- 159000000000 sodium salts Chemical class 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 4
- 238000005893 bromination reaction Methods 0.000 description 4
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010062106 Respiratory tract infection viral Diseases 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 208000020017 viral respiratory tract infection Diseases 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Indole Compounds (AREA)
Abstract
A method for preparing 5-acetoxyl-3-indole carboxylic acid ethyl ester. The invention relates to a method for preparing the 5-acetoxyl-3-indole carboxylic acid ethyl ester which is a key intermediate of a widely-used antiviral drug Arbidol Hydrochloride. The method successively comprises the following steps that, by using 3-chlorine-4-nitrophenol as raw materials, phenolic hydroxyl groups are reacted with an acetylation reagent, then products obtained are subjected to a substitution reaction with sodium salt of malonate, and at last a hydrogenated cyclization reaction is carried out under pressurized conditions to get the 5-acetoxyl-3-indole carboxylic acid ethyl ester. The method provides a novel synthesizing route, and has advantages of concise steps, simple technology and cheap and easily-available raw materials. Each reaction step is relatively conventional operations and production cost can be effectively reduced.
Description
Technical field
The present invention relates to a kind of preparation method of intermediate of antiviral Arbidol Hydrochloride, be specifically related to the method for a kind of 5-of preparation acetoxy-3-indole-carboxylic acid ethyl ester.
Background technology
Arbidol Hydrochloride (Arbidol Hydrochloride) is the class broad-spectrum antiviral medicament by the research and development of USSR (Union of Soviet Socialist Republics) pharmaceutical chemistry research centre, the chemistry bromo-4-dimethylamino methyl of 6-by name-5-hydroxyl-1-methyl-2-(benzene thiomethyl)-1H-Indole-3-Carboxylic Acid carbethoxy hydrochloride, this medicine is Russian Initial Public Offering again in 1993, medicinal is monohydrate, this medicine is except having immunoregulation effect and interferon-induced effect, also have good antiviral activity, clinical in preventing and treating influenza and other acute viral respiratory tract infection.
The current main production technique of this medicine is similar, and the key distinction is the preparation method of its key intermediate 1-methyl-2-brooethyl-bromo-3-indole-carboxylic acid of 5-acetoxyl group-6-ethyl ester, mainly contains following two kinds:
One, paper " synthesizing of Arbidol Hydrochloride " (Chinese Journal of Pharmaceuticals, 2004, 35(8), mentioning 457-458) and adopting benzoquinone and the amino ethyl crotonate of 3-is raw material, through cyclisation, protection, the reaction such as hydrocarbylation and bromination prepares the key intermediate 1-methyl-2-brooethyl-bromo-3-indole-carboxylic acid of 5-acetoxyl group-6-ethyl ester, the method operation relative simple, yield is also better, but the pungency of the amino ethyl crotonate of the raw material 3-of its use is larger, production safety and workers ' health are had to certain hidden danger, and domestic price is comparatively expensive, the three wastes that technique produces are more, processing cost is large, directly cause the production cost of product higher.
Two, paper " the 1-methyl-2-brooethyl-bromo-1H-Indole-3-Carboxylic Acid of 5-acetoxyl group-6-ethyl ester " (meticulous and specialty chemicals, 2007, 15(13), mention 14-16) and also can adopt 3-methylamino--2-butylene acetoacetic ester and para benzoquinone as the cyclisation of raw material process, protection and bromination three-step reaction obtain the key intermediate 1-methyl-2-brooethyl-bromo-3-indole-carboxylic acid of 5-acetoxyl group-6-ethyl ester, the previously prepared 3-of the obtaining methylamino-of raw material that the method use is easy to get-2-butylene acetoacetic ester, can effectively reduce cost, but wherein the cyclisation step yield is too low, be only 52%, cause by product more, aftertreatment and separation and purification be difficulty comparatively, also affected quality product when having improved cost.
Summary of the invention
The object of the present invention is to provide the preparation method of the antiviral arbidol HCl intermediate 5-acetoxy-3 that a kind of equipment is simple, reaction conditions is comparatively gentle, convenient operation also can't harm environment-indole-carboxylic acid ethyl ester.
The technical solution adopted for the present invention to solve the technical problems is:
The preparation method of a kind of 5-acetoxy-3-indole-carboxylic acid ethyl ester is characterized in that: the 5-acetoxy-3 meaned with formula (I)-indole-carboxylic acid ethyl ester obtains in accordance with the following steps:
As preferably, described alkaline environment by adding sodium carbonate or salt of wormwood to realize in reaction system.
As preferably, the method comprises the steps:
A.2-the preparation of chloro-4-acetoxyl group oil of mirbane:
Weight ratio according to 1:2-10 in reactor adds the chloro-4-nitrophenols of 3-(II) and acetone, adding sodium carbonate or salt of wormwood, being warming up to 40 ℃ stirs 10 minutes, then drip Acetyl Chloride 98Min. at this temperature, the 0.45-0.50 that the add-on of Acetyl Chloride 98Min. is the chloro-4-nitrophenols of 3-(II) weight doubly, drip the process control mixture temperature and be no more than 50 ℃, remove heating unit after dropwising, continue stirring reaction 4-6 hour, after reaction finishes, reaction mixture is poured in frozen water, filter and collect the solid of separating out, obtain crude product after drying, the crude product recrystallizing methanol, the 1-2 that the consumption of methyl alcohol is the chloro-4-nitrophenols of 3-(II) weight doubly, obtain the chloro-4-acetoxyl group of 2-oil of mirbane (III),
B.2-(5-acetoxyl group-2-nitrophenyl) the preparation of diethyl malonate:
The chloro-4-acetoxyl group of 2-oil of mirbane (III) and diethyl malonate are dissolved in respectively to organic solvent, the 0.74-0.90 that the consumption of diethyl malonate is the chloro-4-acetoxyl group of 2-oil of mirbane (III) weight doubly, adding content in the mixture of diethyl malonate and organic solvent is 80%(weight) sodium hydride, the 0.13-0.17 that the add-on of sodium hydride is the chloro-4-acetoxyl group of 2-oil of mirbane (III) weight doubly, finish rear stirring at room 2 hours, and then add the mixed solution of the chloro-4-acetoxyl group of the 2-before prepared oil of mirbane (III) and organic solvent, the mixture obtained under agitation is warming up to 90-100 ℃ of reaction 6-8 hour, after reaction finishes, mixed solution is poured into water, the solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) diethyl malonate (IV) crude product, dry by ethyl alcohol recrystallization, obtain elaboration 2-(5-acetoxyl group-2-nitrophenyl) diethyl malonate (IV),
C.5-the preparation of acetoxy-3-indole-carboxylic acid ethyl ester:
Add 2-(5-acetoxyl group-2-nitrophenyl to the weight ratio according to 1:10-20 in middle pressure hydrogenation reactor) diethyl malonate (IV) and organic solvent, adding content is 10%(weight again) palladium-carbon catalyst, after stirring, closed reactor, be warming up to 50-55 ℃, then pass into hydrogen, making reactor pressure is 3-5MPa, keep being warming up to 70-75 ℃ under this pressure, stirring reaction 6-8 hour at this temperature, after reaction finishes, the emptying reactor, making it pressure is the 0.1MPa left and right, open reactor, filtering recovering catalyst, filtrate decompression is concentrated obtains the product crude product except after desolventizing, it is 5-acetoxy-3-indole-carboxylic acid ethyl ester (I).
As preferably, the organic solvent in steps A is DMF, and the organic solvent in step C is dehydrated alcohol or anhydrous methanol.
As preferably, in steps A, doubly, the 0.79-0.88 that the add-on of salt of wormwood is the chloro-4-nitrophenols of 3-(II) weight doubly for the 0.61-0.68 that the add-on of described sodium carbonate is the chloro-4-nitrophenols of 3-(II) weight.
As preferably, the method specifically comprises the steps:
A.2-the preparation of chloro-4-acetoxyl group oil of mirbane:
Weight ratio according to 1:2-10 in reactor adds the chloro-4-nitrophenols of 3-(II) and acetone, adding sodium carbonate or salt of wormwood, doubly, the 0.79-0.88 that the add-on of salt of wormwood is the chloro-4-nitrophenols of 3-(II) weight doubly for the 0.61-0.68 that the add-on of sodium carbonate is the chloro-4-nitrophenols of 3-(II) weight; Being warming up to 40 ℃ stirs 10 minutes, then drip Acetyl Chloride 98Min. at this temperature, the 0.45-0.50 that the add-on of Acetyl Chloride 98Min. is the chloro-4-nitrophenols of 3-(II) weight doubly, drip the process control mixture temperature and be no more than 50 ℃, remove heating unit after dropwising, continue stirring reaction 4-6 hour, after reaction finishes, reaction mixture is poured in frozen water, filter and collect the solid of separating out, obtain crude product after drying, the crude product recrystallizing methanol, the 1-2 that the consumption of methyl alcohol is the chloro-4-nitrophenols of 3-(II) weight doubly, obtains the chloro-4-acetoxyl group of 2-oil of mirbane (III);
B.2-(5-acetoxyl group-2-nitrophenyl) the preparation of diethyl malonate:
Weight ratio according to 1:2 in reactor adds the chloro-4-acetoxyl group of 2-oil of mirbane (III) and DMF (DMF), and stirring at room is evenly rear stand-by, add diethyl malonate and DMF in another reactor, the 0.74-0.90 that the add-on of diethyl malonate is the chloro-4-acetoxyl group of 2-oil of mirbane (III) weight doubly, the 4-8 that the add-on of DMF is the chloro-4-acetoxyl group of 2-oil of mirbane (III) weight doubly, after finishing, stir, add again the sodium hydride that content is 80%, the 0.13-0.17 that the add-on of sodium hydride is the chloro-4-acetoxyl group of 2-oil of mirbane (III) weight doubly, finish rear stirring at room 2 hours, and then add the solution of the chloro-4-acetoxyl group of the 2-before prepared oil of mirbane (III) and DMF, then mixture under agitation is warming up to 90-100 ℃ of reaction 6-8 hour, after reaction finishes, mixed solution is poured into water, the solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) diethyl malonate (IV) crude product, dry by ethyl alcohol recrystallization, the 1-2 that the consumption of ethanol is the chloro-4-acetoxyl group of 2-oil of mirbane (III) weight doubly, obtain elaboration 2-(5-acetoxyl group-2-nitrophenyl) diethyl malonate (IV),
C.5-the preparation of acetoxy-3-indole-carboxylic acid ethyl ester:
Add 2-(5-acetoxyl group-2-nitrophenyl to the weight ratio according to 1:10-20 in middle pressure hydrogenation reactor) diethyl malonate (IV) and dehydrated alcohol or anhydrous methanol, add again the palladium-carbon catalyst that content is 10%, the add-on of palladium-carbon catalyst is 2-(5-acetoxyl group-2-nitrophenyl) 0.05-0.1 of diethyl malonate (IV) weight is doubly, after stirring, closed reactor, be warming up to 50-55 ℃, then pass into hydrogen, making reactor pressure is 3-5MPa, keep being warming up to 70-75 ℃ under this pressure, stirring reaction 6-8 hour at this temperature, after reaction finishes, the emptying reactor, making it pressure is the 0.1MPa left and right, open reactor, filtering recovering catalyst, filtrate decompression is concentrated obtains the product crude product except after desolventizing, through ethyl alcohol recrystallization, the ethanol consumption is 2-(5-acetoxyl group-2-nitrophenyl) 2 times of diethyl malonate (IV) weight, obtain elaboration, it is 5-acetoxy-3-indole-carboxylic acid ethyl ester (I).
The present invention proposes synthetic its intermediate 5-acetoxy-3 of a new synthetic route-indole-carboxylic acid ethyl ester, this intermediate can obtain the key intermediate 1-methyl-2-brooethyl-bromo-3-indole-carboxylic acid of 5-acetoxyl group-6-ethyl ester through bromomethylation and bromination reaction again, and bromomethylation and bromination step have comparatively ripe technique, and using the chloro-4-nitrophenols of the domestic 3-be easy to get as raw material, obtain 5-acetoxy-3-indole-carboxylic acid ethyl ester through replacement and reduction pass ring two-step reaction, wherein reduction is closed in the ring employing and is pressed hydrogenation means single stage method to complete, when simplifying the operation and reducing costs, the three wastes that also reduced whole technique produce, almost there is no the generation of solid slag, only have more tractable acid waste water on a small quantity to produce, the idea that meets Green Chemistry and Sustainable development.The method has advantages of that equipment is simple, reaction conditions is comparatively gentle, the also harmless environment of convenient operation, is convenient to suitability for industrialized production.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail.Should be appreciated that enforcement of the present invention is not limited to the following examples, any pro forma accommodation that the present invention is made and/or change all will fall into protection domain of the present invention.
In the present invention, if not refer in particular to, all part, per-cents are weight unit, and all equipment and raw material etc. all can be buied from market or the industry is commonly used.
Embodiment 1
A.2-chloro-4-acetoxyl group oil of mirbane preparation
Add the chloro-4-nitrophenols of 3-(173.5g in reaction flask, 1.0mol) and acetone (1735g), after stirring, continue to add salt of wormwood (151.8g, 1.1mol), be warming up to 40 ℃ after finishing, stir after 10 minutes, slowly drip wherein Acetyl Chloride 98Min. (86.3g, 1.1mol), in the dropping process, reaction mixture temperature is no more than 50 ℃, remove heating unit after dropwising, continue stirring reaction 6 hours, after reaction finishes, mixed solution is poured in frozen water, separate out solid, filter and collect, the chloro-4-acetoxyl group of the crude product 2-oil of mirbane obtained after drying, crude product obtains light yellow solid with 347g anhydrous methanol recrystallization, for the chloro-4-acetoxyl group of 2-oil of mirbane elaboration (207.9g), yield approximately 96.5%.
Fusing point: 67-68 ℃,
1h-NMR (CDCl
3): δ 2.29 (3H), 1.34-1.62 (4H), 7.45 (1H), 7.77 (1H), 8.19 (1H). MS (EI), m/z 217 (M+H).
B.2-(5-acetoxyl group-2-nitrophenyl) the preparation of diethyl malonate
Add diethyl malonate (192g in reaction flask, 1.2mol) and DMF (1724g), add the sodium hydride (36g that content is 80% after stirring, 1.2mol), continue at room temperature to stir 2 hours, then add the chloro-4-acetoxyl group of the 2-prepared in advance oil of mirbane (215.5g, 1.0mol) and mixing solutions DMF(431g), be warming up to 100 ℃ of stirring reactions 8 hours after finishing, after reaction finishes, mixed solution is poured into water, the solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) the diethyl malonate crude product, crude product obtains light yellow solid after 431g dehydrated alcohol recrystallization, for elaboration 2-(5-acetoxyl group-2-nitrophenyl) diethyl malonate (292.5g, ), yield approximately 86.3%.
1H-NMR(CDCl
3):δ?1.31(6H),2.24(3H),4.11-4.15?(4H),5.34(1H),?7.35(1H)?,?7.59(1H),8.11(1H).?MS(EI),m/z?340(M+H)。
C.5-the preparation of acetoxy-3-indole-carboxylic acid ethyl ester
Add 2-(5-acetoxyl group-2-nitrophenyl in middle pressure hydrogenation reactor) diethyl malonate (339g, 1.0mol) and anhydrous methanol (6750g), add the palladium-carbon catalyst (33.5g) that content is 10% after stirring, after stirring, closed reactor, be warming up to 55 ℃, then pass into hydrogen, making reactor pressure is 5MPa, keep under this pressure being warming up to 75 ℃, at this temperature, stirring reaction is 8 hours, after reaction finishes, the emptying reactor, making it pressure is the 0.1MPa left and right, open reactor, filtering recovering catalyst, filtrate decompression is concentrated obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester crude product except after desolventizing, crude product obtains the off-white color solid after dehydrated alcohol (678g) recrystallization, for elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (202.5g), yield approximately 82.0%.
1H-NMR(CDCl
3):δ?1.27(3H),2.25(3H),4.31-4.35(2H),7.34-7.43(2H),
8.22(1H),8.39(1H).?MS(EI),m/z?248(M+H)。
Embodiment 2
Other steps are identical with embodiment 1, and just the preparation method of the chloro-4-acetoxyl group of the 2-oil of mirbane of A step is as follows:
Add the chloro-4-nitrophenols of 3-(173.5g in reaction flask, 1.0mol) and acetone (350g), after stirring, continue to add salt of wormwood (138g, 1.0mol), be warming up to 40 ℃ after finishing, stir after 10 minutes, slowly drip wherein Acetyl Chloride 98Min. (78.5g, 1.0mol), in the dropping process, reaction mixture temperature is no more than 50 ℃, remove heating unit after dropwising, continue stirring reaction 4 hours, after reaction finishes, mixed solution is poured in frozen water, separate out solid, filter and collect, the chloro-4-acetoxyl group of the crude product 2-oil of mirbane obtained after drying, crude product obtains light yellow solid with 347g anhydrous methanol recrystallization, for the chloro-4-acetoxyl group of 2-oil of mirbane elaboration (188.3g), yield approximately 87.4%.
Embodiment 3
Other steps are identical with embodiment 1, and just the preparation method of the chloro-4-acetoxyl group of the 2-oil of mirbane of A step is as follows:
Add the chloro-4-nitrophenols of 3-(173.5g in reaction flask, 1.0mol) and acetone (1000g), after stirring, continue to add salt of wormwood (145g, about 1.05mol), be warming up to 40 ℃ after finishing, stir after 10 minutes, slowly drip wherein Acetyl Chloride 98Min. (82.5g, about 1.05mol), in the dropping process, reaction mixture temperature is no more than 50 ℃, remove heating unit after dropwising, continue stirring reaction 5 hours, after reaction finishes, mixed solution is poured in frozen water, separate out solid, filter and collect, the chloro-4-acetoxyl group of the crude product 2-oil of mirbane obtained after drying, crude product obtains light yellow solid with 347g anhydrous methanol recrystallization, for the chloro-4-acetoxyl group of 2-oil of mirbane elaboration (195.6g), yield approximately 90.8%.
Embodiment 4
Other steps are identical with embodiment 1, and just the preparation method of the chloro-4-acetoxyl group of the 2-oil of mirbane of A step is as follows:
Add the chloro-4-nitrophenols of 3-(173.5g in reaction flask, 1.0mol) and acetone (1700g), after stirring, continue to add sodium carbonate (116.6g, 1.1mol), be warming up to 40 ℃ after finishing, stir after 10 minutes, slowly drip wherein Acetyl Chloride 98Min. (86.3g, 1.1mol), in the dropping process, reaction mixture temperature is no more than 50 ℃, remove heating unit after dropwising, continue stirring reaction 6 hours, after reaction finishes, mixed solution is poured in frozen water, separate out solid, filter and collect, the chloro-4-acetoxyl group of the crude product 2-oil of mirbane obtained after drying, crude product obtains light yellow solid with 347g anhydrous methanol recrystallization, for the chloro-4-acetoxyl group of 2-oil of mirbane elaboration (203.4g), yield approximately 94.4%.
Embodiment 5
Other steps are identical with embodiment 1, and just the preparation method of the chloro-4-acetoxyl group of the 2-oil of mirbane of A step is as follows:
Add the chloro-4-nitrophenols of 3-(173.5g in reaction flask, 1.0mol) and acetone (750g), after stirring, continue to add sodium carbonate (110.0g, about 1.04mol), be warming up to 40 ℃ after finishing, stir after 10 minutes, slowly drip wherein Acetyl Chloride 98Min. (83.0g, about 1.06mol), in the dropping process, reaction mixture temperature is no more than 50 ℃, remove heating unit after dropwising, continue stirring reaction 5 hours, after reaction finishes, mixed solution is poured in frozen water, separate out solid, filter and collect, the chloro-4-acetoxyl group of the crude product 2-oil of mirbane obtained after drying, crude product obtains light yellow solid with 347g anhydrous methanol recrystallization, for the chloro-4-acetoxyl group of 2-oil of mirbane elaboration (191.1g), yield approximately 88.7%.
Embodiment 6
Other steps are identical with embodiment 1, just the 2-(5-acetoxyl group of B step-2-nitrophenyl) preparation method of diethyl malonate is as follows:
Add diethyl malonate (160g in reaction flask, 1.0mol) and DMF (862g), add the sodium hydride (30g that content is 80% after stirring, 1.0mol), continue at room temperature to stir 2 hours, then add the chloro-4-acetoxyl group of the 2-prepared in advance oil of mirbane (215.5g, 1.0mol) and mixing solutions DMF(431g), be warming up to 90 ℃ of stirring reactions 6 hours after finishing, after reaction finishes, mixed solution is poured into water, the solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) the diethyl malonate crude product, crude product obtains light yellow solid after 431g dehydrated alcohol recrystallization, for elaboration 2-(5-acetoxyl group-2-nitrophenyl) diethyl malonate (271.3g, ), yield approximately 80.0%.
Embodiment 7
Other steps are identical with embodiment 1, just the 2-(5-acetoxyl group of B step-2-nitrophenyl) preparation method of diethyl malonate is as follows:
Add diethyl malonate (176g in reaction flask, 1.1mol) and DMF (1200g), add the sodium hydride (33g that content is 80% after stirring, 1.1mol), continue at room temperature to stir 2 hours, then add the chloro-4-acetoxyl group of the 2-prepared in advance oil of mirbane (215.5g, 1.0mol) and mixing solutions DMF(431g), be warming up to 95 ℃ of stirring reactions 7 hours after finishing, after reaction finishes, mixed solution is poured into water, the solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) the diethyl malonate crude product, crude product obtains light yellow solid after 431g dehydrated alcohol recrystallization, for elaboration 2-(5-acetoxyl group-2-nitrophenyl) diethyl malonate (288.6g, ), yield approximately 85.1%.
Embodiment 8
Other steps are identical with embodiment 1, and just the preparation method of the 5-acetoxy-3 of C step-indole-carboxylic acid ethyl ester is as follows:
Add 2-(5-acetoxyl group-2-nitrophenyl in middle pressure hydrogenation reactor) diethyl malonate (339g, 1.0mol) and anhydrous methanol (3400g), add the palladium-carbon catalyst (17.0g) that content is 10% after stirring, after stirring, closed reactor, be warming up to 50 ℃, then pass into hydrogen, making reactor pressure is 3MPa, keep under this pressure being warming up to 70 ℃, at this temperature, stirring reaction is 6 hours, after reaction finishes, the emptying reactor, making it pressure is the 0.1MPa left and right, open reactor, filtering recovering catalyst, filtrate decompression is concentrated obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester crude product except after desolventizing, crude product obtains the off-white color solid after dehydrated alcohol (678g) recrystallization, for elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (178.4g), yield approximately 72.2%.
Embodiment 9
Other steps are identical with embodiment 1, and just the preparation method of the 5-acetoxy-3 of C step-indole-carboxylic acid ethyl ester is as follows:
Add 2-(5-acetoxyl group-2-nitrophenyl in middle pressure hydrogenation reactor) diethyl malonate (339g, 1.0mol) and anhydrous methanol (5300g), add the palladium-carbon catalyst (25.5g) that content is 10% after stirring, after stirring, closed reactor, be warming up to 53 ℃, then pass into hydrogen, making reactor pressure is 4MPa, keep under this pressure being warming up to 72 ℃, at this temperature, stirring reaction is 7 hours, after reaction finishes, the emptying reactor, making it pressure is the 0.1MPa left and right, open reactor, filtering recovering catalyst, filtrate decompression is concentrated obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester crude product except after desolventizing, crude product obtains the off-white color solid after dehydrated alcohol (678g) recrystallization, for elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (190.5g), yield approximately 77.1%.
Embodiment 10
Other steps are identical with embodiment 1, and just the preparation method of the 5-acetoxy-3 of C step-indole-carboxylic acid ethyl ester is as follows:
Add 2-(5-acetoxyl group-2-nitrophenyl in middle pressure hydrogenation reactor) diethyl malonate (339g, 1.0mol) and dehydrated alcohol (6500g), add the palladium-carbon catalyst (33.8g) that content is 10% after stirring, after stirring, closed reactor, be warming up to 55 ℃, then pass into hydrogen, making reactor pressure is 4.5MPa, keep under this pressure being warming up to 75 ℃, at this temperature, stirring reaction is 8 hours, after reaction finishes, the emptying reactor, making it pressure is the 0.1MPa left and right, open reactor, filtering recovering catalyst, filtrate decompression is concentrated obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester crude product except after desolventizing, crude product obtains the off-white color solid after dehydrated alcohol (678g) recrystallization, for elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (198.3g), yield approximately 80.3%.
Embodiment 11
Other steps are identical with embodiment 1, and just the preparation method of the 5-acetoxy-3 of C step-indole-carboxylic acid ethyl ester is as follows:
Add 2-(5-acetoxyl group-2-nitrophenyl in middle pressure hydrogenation reactor) diethyl malonate (339g, 1.0mol) and dehydrated alcohol (3400g), add the palladium-carbon catalyst (17.5g) that content is 10% after stirring, after stirring, closed reactor, be warming up to 50 ℃, then pass into hydrogen, making reactor pressure is 3MPa, keep under this pressure being warming up to 70 ℃, at this temperature, stirring reaction is 6 hours, after reaction finishes, the emptying reactor, making it pressure is the 0.1MPa left and right, open reactor, filtering recovering catalyst, filtrate decompression is concentrated obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester crude product except after desolventizing, crude product obtains the off-white color solid after dehydrated alcohol (678g) recrystallization, for elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (172.7g), yield approximately 69.9%.
Embodiment 12
Other steps are identical with embodiment 1, and just the preparation method of the 5-acetoxy-3 of C step-indole-carboxylic acid ethyl ester is as follows:
Add 2-(5-acetoxyl group-2-nitrophenyl in middle pressure hydrogenation reactor) diethyl malonate (339g, 1.0mol) and dehydrated alcohol (5000g), add the palladium-carbon catalyst (28.0g) that content is 10% after stirring, after stirring, closed reactor, be warming up to 52 ℃, then pass into hydrogen, making reactor pressure is 4MPa, keep under this pressure being warming up to 72 ℃, at this temperature, stirring reaction is 7 hours, after reaction finishes, the emptying reactor, making it pressure is the 0.1MPa left and right, open reactor, filtering recovering catalyst, filtrate decompression is concentrated obtains 5-acetoxy-3-indole-carboxylic acid ethyl ester crude product except after desolventizing, crude product obtains the off-white color solid after dehydrated alcohol (678g) recrystallization, for elaboration 5-acetoxy-3-indole-carboxylic acid ethyl ester (187.2g), yield approximately 75.8%.
Above-described embodiment is a kind of preferably scheme of the present invention, not the present invention is done to any pro forma restriction, also has other variant and remodeling under the prerequisite that does not exceed the technical scheme that claim puts down in writing.
Claims (5)
1. the preparation method of 5-acetoxy-3-indole-carboxylic acid ethyl ester, is characterized in that the method comprises the steps:
A.2-the preparation of chloro-4-acetoxyl group oil of mirbane:
Weight ratio according to 1:2-10 in reactor adds the chloro-4-nitrophenols of 3-and acetone, add again sodium carbonate or salt of wormwood, being warming up to 40 ℃ stirs 10 minutes, then drip Acetyl Chloride 98Min. at this temperature, the 0.45-0.50 that the add-on of Acetyl Chloride 98Min. is the chloro-4-nitrophenols of 3-weight doubly, drip the process control mixture temperature and be no more than 50 ℃, remove heating unit after dropwising, continue stirring reaction 4-6 hour, after reaction finishes, reaction mixture is poured in frozen water, filter and collect the solid of separating out, obtain crude product after drying, the crude product recrystallizing methanol, the 1-2 that the consumption of methyl alcohol is the chloro-4-nitrophenols of 3-weight doubly, obtain the chloro-4-acetoxyl group of 2-oil of mirbane,
B.2-(5-acetoxyl group-2-nitrophenyl) the preparation of diethyl malonate:
2-chloro-4-acetoxyl group oil of mirbane and diethyl malonate are dissolved in respectively to organic solvent, the 0.74-0.90 that the consumption of diethyl malonate is the chloro-4-acetoxyl group of 2-oil of mirbane weight doubly, adding content in the mixture of diethyl malonate and organic solvent is 80%(weight) sodium hydride, the 0.13-0.17 that the add-on of sodium hydride is the chloro-4-acetoxyl group of 2-oil of mirbane weight doubly, finish rear stirring at room 2 hours, and then add the mixed solution of the 2-before prepared chloro-4-acetoxyl group oil of mirbane and organic solvent, the mixture obtained under agitation is warming up to 90-100 ℃ of reaction 6-8 hour, after reaction finishes, mixed solution is poured into water, the solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) the diethyl malonate crude product, dry by ethyl alcohol recrystallization, obtain elaboration 2-(5-acetoxyl group-2-nitrophenyl) diethyl malonate,
C.5-the preparation of acetoxy-3-indole-carboxylic acid ethyl ester:
Add 2-(5-acetoxyl group-2-nitrophenyl to the weight ratio according to 1:10-20 in middle pressure hydrogenation reactor) diethyl malonate and organic solvent, adding content is 10%(weight again) palladium-carbon catalyst, after stirring, closed reactor, be warming up to 50-55 ℃, then pass into hydrogen, making reactor pressure is 3-5MPa, keep being warming up to 70-75 ℃ under this pressure, stirring reaction 6-8 hour at this temperature, after reaction finishes, the emptying reactor, making it pressure is 0.1MPa, open reactor, filtering recovering catalyst, filtrate decompression is concentrated obtains the product crude product except after desolventizing, it is 5-acetoxy-3-indole-carboxylic acid ethyl ester.
2. the preparation method of a kind of 5-acetoxy-3 according to claim 1-indole-carboxylic acid ethyl ester, it is characterized in that: the organic solvent in step B is DMF, the organic solvent in step C is dehydrated alcohol or anhydrous methanol.
3. the preparation method of a kind of 5-acetoxy-3 according to claim 1-indole-carboxylic acid ethyl ester, it is characterized in that: in steps A, doubly, the 0.79-0.88 that the add-on of salt of wormwood is the chloro-4-nitrophenols of 3-weight doubly for the 0.61-0.68 that the add-on of described sodium carbonate is the chloro-4-nitrophenols of 3-weight.
4. according to the preparation method of the described a kind of 5-acetoxy-3 of claim 2 or 3-indole-carboxylic acid ethyl ester, it is characterized in that: in steps A, doubly, the 0.79-0.88 that the add-on of salt of wormwood is the chloro-4-nitrophenols of 3-weight doubly for the 0.61-0.68 that the add-on of described sodium carbonate is the chloro-4-nitrophenols of 3-weight.
5. the preparation method of a kind of 5-acetoxy-3 according to claim 1-indole-carboxylic acid ethyl ester, is characterized in that the method specifically comprises the steps:
A.2-the preparation of chloro-4-acetoxyl group oil of mirbane:
Weight ratio according to 1:2-10 in reactor adds the chloro-4-nitrophenols of 3-and acetone, add again sodium carbonate or salt of wormwood, doubly, the 0.79-0.88 that the add-on of salt of wormwood is the chloro-4-nitrophenols of 3-weight doubly for the 0.61-0.68 that the add-on of sodium carbonate is the chloro-4-nitrophenols of 3-weight; Being warming up to 40 ℃ stirs 10 minutes, then drip Acetyl Chloride 98Min. at this temperature, the 0.45-0.50 that the add-on of Acetyl Chloride 98Min. is the chloro-4-nitrophenols of 3-weight doubly, drip the process control mixture temperature and be no more than 50 ℃, remove heating unit after dropwising, continue stirring reaction 4-6 hour, after reaction finishes, reaction mixture is poured in frozen water, filter and collect the solid of separating out, obtain crude product after drying, the crude product recrystallizing methanol, the 1-2 that the consumption of methyl alcohol is the chloro-4-nitrophenols of 3-weight doubly, obtains the chloro-4-acetoxyl group of 2-oil of mirbane;
B.2-(5-acetoxyl group-2-nitrophenyl) the preparation of diethyl malonate:
Weight ratio according to 1:2 in reactor adds 2-chloro-4-acetoxyl group oil of mirbane and DMF (DMF), and stirring at room is evenly rear stand-by, add diethyl malonate and DMF in another reactor, the 0.74-0.90 that the add-on of diethyl malonate is the chloro-4-acetoxyl group of 2-oil of mirbane weight doubly, the 4-8 that the add-on of DMF is the chloro-4-acetoxyl group of 2-oil of mirbane weight doubly, after finishing, stir, add again the sodium hydride that content is 80%, the 0.13-0.17 that the add-on of sodium hydride is the chloro-4-acetoxyl group of 2-oil of mirbane weight doubly, finish rear stirring at room 2 hours, and then add the solution of the 2-before prepared chloro-4-acetoxyl group oil of mirbane and DMF, then mixture under agitation is warming up to 90-100 ℃ of reaction 6-8 hour, after reaction finishes, mixed solution is poured into water, the solid of separating out is 2-(5-acetoxyl group-2-nitrophenyl) the diethyl malonate crude product, dry by ethyl alcohol recrystallization, the 1-2 that the consumption of ethanol is the chloro-4-acetoxyl group of 2-oil of mirbane weight doubly, obtain elaboration 2-(5-acetoxyl group-2-nitrophenyl) diethyl malonate,
C.5-the preparation of acetoxy-3-indole-carboxylic acid ethyl ester:
Add 2-(5-acetoxyl group-2-nitrophenyl to the weight ratio according to 1:10-20 in middle pressure hydrogenation reactor) diethyl malonate and dehydrated alcohol or anhydrous methanol, add again the palladium-carbon catalyst that content is 10%, the add-on of palladium-carbon catalyst is 2-(5-acetoxyl group-2-nitrophenyl) 0.05-0.1 of diethyl malonate (IV) weight is doubly, after stirring, closed reactor, be warming up to 50-55 ℃, then pass into hydrogen, making reactor pressure is 3-5MPa, keep being warming up to 70-75 ℃ under this pressure, stirring reaction 6-8 hour at this temperature, after reaction finishes, the emptying reactor, making it pressure is 0.1MPa, open reactor, filtering recovering catalyst, filtrate decompression is concentrated obtains the product crude product except after desolventizing, through ethyl alcohol recrystallization, the ethanol consumption is 2-(5-acetoxyl group-2-nitrophenyl) 2 times of diethyl malonate weight, obtain elaboration, it is 5-acetoxy-3-indole-carboxylic acid ethyl ester.
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