CN106565522A - Method for preparing alkyloxy aromatic compound from fluoroaromatic compound - Google Patents
Method for preparing alkyloxy aromatic compound from fluoroaromatic compound Download PDFInfo
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- CN106565522A CN106565522A CN201610861044.2A CN201610861044A CN106565522A CN 106565522 A CN106565522 A CN 106565522A CN 201610861044 A CN201610861044 A CN 201610861044A CN 106565522 A CN106565522 A CN 106565522A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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Abstract
The invention discloses a method for preparing an alkyloxy aromatic compound from a fluoroaromatic compound. The alkyloxy aromatic compound is highly-efficiently prepared through a reaction of the fluoroaromatic compound, a strong alkali, dimethyl sulfoxide and alcohol under certain conditions. The method has the advantages of no metal catalyst, mild and controllable reaction, simple process, good universality, and suitableness for large-scale industrial production.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to one kind prepares alkoxyl aromatics by fluoro aromatic
The method of thing.
Background technology
Alkoxy-aromatic cpds are widely used in field of medicaments, and the compound as shown in formula I is new drug
Idalopirdine, can improve the cognitive function of the moderate Alzheimer's disease patient for receiving Donepezil treatment；Formula (II) institute
Show that compound is then weight pound target anticancer new drug AZD9291, be efficient selective EGFR mutant inhibitor, exon 19 is lacked
The IC50 of mistake type EGFR, L858R/T790M EGFR is respectively 12.92nM and 11.44nM, for pulmonary carcinoma has notable therapeutic effect.
Therefore the chemical synthesis process of novel alkoxy-aromatic cpds is developed, has wide market application foreground, together
When can provide more multi-path selecting solution for many medicine synthesising process.Taken using alcohols in the chemical synthesis process of such compound
It is relatively conventional for the approach of halogenated aromatic compound, but need metallic catalyst to participate in catalysis mostly, reaction condition has high demands, after
Process loaded down with trivial details；Or needing halogenated aromatic compound per se with strong electron-withdrawing group group, reaction universality is relatively low.
The content of the invention
It is an object of the invention to provide one kind does not use metallic catalyst, reaction is gentle controllable, and technical process is easy, generally
Adaptability is good, and is adapted to the method for preparing alkoxy-aromatic cpds by fluoro aromatic of large-scale industrial production.
To solve above-mentioned technical problem, the present invention is adopted the following technical scheme that：
A kind of method for preparing alkoxy-aromatic cpds by fluoro aromatic, it is comprised the following steps：
1) with dimethyl sulfoxide as reaction dissolvent, by fluoro aromatic, highly basic, alcohol by 1: (1-10): rubbing (1-10)
You are reacted at ratio, and reaction temperature is 0-100 DEG C, and the response time is 12-48 hours；
2) by reactant liquor organic solvent diluting, and saturated common salt water washing is used, by organic faciess desiccant dryness, rotation
It is dry, then go up silica gel or neutral alumina chromatographic column is separated, eluting is carried out by mobile phase of non-polar organic solvent, collect
Eluent is simultaneously concentrated, is dried, and obtains alkoxy-aromatic cpds sterling,
The fluoro aromatic is monosubstituted on aromatic rings or polysubstituted fluorobenzene, fluoronaphthalene, fluorine anthracene, fluorine phenanthrene or polyfluoro
One kind in benzene, many fluoronaphthalenes, polyfluoro anthracene, polyfluoro phenanthrene.
Preferably, the highly basic is the one kind in potassium hydroxide, sodium hydroxide, Lithium hydrate.
Preferably, the alcohol is methanol, ethanol, normal propyl alcohol, isopropanol, pure benzyl, the tert-butyl alcohol, isobutanol, n-butyl alcohol, second two
Alcohol, glycerol, n-amyl alcohol, isoamyl alcohol, 1,3-PD, BDO, the one kind in 2- phenylethanols, Hexalin.
Preferably, the organic solvent is selected from ethyl acetate, dichloromethane, chloroform, isopropyl acetate, normal hexane, hexamethylene
Alkane, the one kind in petroleum ether；
Preferably, the desiccant is in anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, Anhydrous potassium carbonate
Kind.
Preferably, the non-polar organic solvent is in petroleum ether, normal hexane, hexamethylene, ethyl acetate, dichloromethane
One or more of any mixing.
Preferably, the fluoro aromatic, highly basic, the mol ratio of alcohol are 1: 2: 2.
The invention has the beneficial effects as follows：The present invention need not use metallic catalyst, and just height can be synthesized by single step reaction
The alkoxy-aromatic cpds of purity, and reaction condition is gently controllable, and technical process is easy, product yield high.Energy of the present invention
For the synthesis of various alkoxy-aromatic cpds, therefore with universal adaptability, meet the requirement of large-scale industrial production.
Specific embodiment
By the following examples the present invention is described in detail.
Embodiment 1
Successively by adjacent fluorobenzamide (27.8g, 0.2mol), high-purity KOH (22.4g, 0.4mol), methanol (12.8g,
0.4mol), DMSO (200mL) is added to reactor, stirring reaction 16 hours at 20 DEG C.Reaction terminates to be added in backward system
800mL diluted ethyl acetates, and using 200mL saturated common salts water washing 5 times.Separate organic faciess, with anhydrous sodium sulfate drying after,
Filter, be evaporated, afterwards separated its loading to silica gel chromatographic column, with petroleum ether:Ethyl acetate=4:1 (volume ratio)
Mixed solvent as eluent, until there is product after, the solution containing product will be collected and is evaporated, subsequently use
Vacuum pump is drained, and obtains O-methoxy Benzoylamide sterling, yield 80%.
Embodiment 2
Successively by adjacent fluorobenzamide (27.8g, 0.2mol), high-purity KOH (22.4g, 0.4mol), isopropanol (24g,
0.4mol), DMSO (200mL) is added to reactor, stirring reaction 16 hours at 20 DEG C.Reaction terminates to be added in backward system
500mL chloroforms dilute, and using 100mL saturated common salts water washing 3 times.Organic faciess are separated, after anhydrous sodium sulfate drying, mistake
Filter, be evaporated, afterwards separated its loading to silica gel chromatographic column, with petroleum ether:Ethyl acetate=10:1 (volume ratio)
Mixed solvent as eluent, until there is product after, the solution containing product will be collected and is evaporated, subsequently use
Vacuum pump is drained, and obtains adjacent isopropoxy Benzoylamide sterling, yield 74%.
Embodiment 3
Successively by adjacent fluorobenzamide (27.8g, 0.2mol), high-purity KOH (22.4g, 0.4mol), benzylalcohol (43.2g,
0.4mol), DMSO (200mL) is added to reactor, stirring reaction 16 hours at 20 DEG C.Reaction terminates to be added in backward system
1000mL diluted ethyl acetates, and using 150mL saturated common salts water washing 4 times.Organic faciess are separated, anhydrous sodium sulfate drying is used
Afterwards, filter, be evaporated, afterwards separated its loading to silica gel chromatographic column.With petroleum ether:Ethyl acetate=3:1 (volume
Than) mixed solvent as eluent, until there is product after, by collect the solution containing product be evaporated, with
Drained with vacuum pump afterwards, obtain adjacent benzyloxy yl-benzamide sterling, yield 30%.
Embodiment 4
Successively by adjacent fluorobenzamide (27.8g, 0.2mol), high-purity KOH (22.4g, 0.4mol), Hexalin (40g,
0.4mol), DMSO (200mL) is added to reactor, stirring reaction 16 hours at 20 DEG C.Reaction terminates to be added in backward system
600mL dchloromethanes, and using 200mL saturated common salts water washing 3 times.Organic faciess are separated, after being dried with anhydrous magnesium sulfate,
Filter, be evaporated, afterwards separated its loading to chromatography on neutral alumina post, using normal hexane as eluent,
After until product occur, the solution containing product will be collected and be evaporated, subsequently drained with vacuum pump, obtain adjacent cyclohexyloxy benzene
Methanamide sterling, yield 62%.
Embodiment 5
Successively by fluorobenzene (19.2g, 0.2mol), high-purity KOH (22.4g, 0.4mol), methanol (12.8g, 0.4mol),
DMSO (200mL) is added to reactor, stirring reaction 24 hours at 100 DEG C.Reaction terminates to add 1200mL in backward system
Diluted ethyl acetate, and using 250mL saturated common salts water washing 4 times.Organic faciess are separated, after being dried with anhydrous calcium chloride, filter,
Revolving is evaporated, and is afterwards separated its loading to chromatography on neutral alumina post, using petroleum ether as eluent, until going out
After existing product, the solution containing product will be collected and be evaporated, obtain methoxybenzene sterling, yield 53%.
Embodiment 6
Successively by 1- fluorine anthracenes (39.2g, 0.2mol), high-purity KOH (22.4g, 0.4mol), methanol (12.8g, 0.4mol),
DMSO (200mL) is added to reactor, stirring reaction 24 hours at 100 DEG C.Reaction terminates to add 800mL second in backward system
Acetoacetic ester dilutes, and using 300mL saturated common salts water washing 5 times.Organic faciess are separated, after anhydrous sodium sulfate drying, filtered, revolved
Steaming is evaporated, and is afterwards separated its loading to chromatography on neutral alumina post, using hexamethylene as eluent, until occurring
After product, the solution containing product will be collected and be evaporated, obtain 1- methoxyl group anthracene sterlings, yield 64%.
Embodiment 7
Successively by the fluoro- N-methyl-benzamides (46g, 0.2mol) of the bromo- 2- of 4-, high-purity KOH (22.4g, 0.4mol), methanol
(12.8g, 0.4mol), DMSO (200mL) are added to reactor, stirring reaction 48 hours at 0 DEG C.Reaction terminates backward system
Middle addition 1000mL dchloromethanes, and using 200mL saturated common salts water washing 3 times.Organic faciess are separated, anhydrous sodium sulfate is used
After drying, filter, be evaporated, afterwards separated its loading to chromatography on neutral alumina post, with petroleum ether:Ethyl acetate
=4:The mixed solvent of 1 (volume ratio) as eluent, until there is product after, by collect containing product solution rotation
Steaming is evaporated, and is subsequently drained with vacuum pump, obtains the bromo- 2- methoxy-. N-methyls Benzoylamide sterlings of 4-, yield 86%.
Embodiment 8
Successively by fluorobromobenzene (34.8g, 0.2mol), high-purity N aOH (16g, 0.4mol), methanol (12.8g, 0.4mol),
DMSO (200mL) is added to reactor, stirring reaction 24 hours at 100 DEG C.Reaction terminates to add 1500mL in backward system
Normal hexane dilutes, and using 250mL saturated common salts water washing 4 times.Organic faciess are separated, after being dried with Anhydrous potassium carbonate, filtered, revolved
Steaming is evaporated, and is afterwards separated its loading to silica gel chromatographic column, using dichloromethane as eluent, until there is product
After, the solution containing product will be collected and be evaporated, obtain to methoxybromobenzene sterling, yield 51%.
Embodiment 9
Successively by 3,4,5- trifluorobromobenzenes (41.8g, 0.2mol), high-purity LiOH (9.6g, 0.4mol), methanol (8g,
0.25mol), DMSO (200mL) is added to reactor, stirring reaction 24 hours at 100 DEG C.Reaction terminates to add in backward system
Enter the dilution of 800mL hexamethylene, and using 300mL saturated common salts water washing 5 times.Separate organic faciess, with anhydrous sodium sulfate drying after,
Filter, be evaporated, afterwards separated its loading to silica gel chromatographic column, with normal hexane:Ethyl acetate=9:1 (volume ratio)
Mixed solvent as eluent, until there is product after, by collect the solution containing product be evaporated, obtain 2,6-
Two fluoro- 4 bromo- methoxybenzene sterlings, yield 81%.
Embodiment 10
Successively by 3,4- difluoro nitrobenzenes (31.8g, 0.2mol), high-purity N aOH (16g, 0.4mol), methanol (8g,
0.25mol), DMSO (200mL) is added to reactor, stirring reaction 12 hours at 20 DEG C.Reaction terminates to add in backward system
Enter 800mL diluted ethyl acetates, and using 200mL saturated common salts water washing 5 times.Organic faciess are separated, anhydrous sodium sulfate drying is used
Afterwards, filter, be evaporated, afterwards separated its loading to silica gel chromatographic column, with petroleum ether:Ethyl acetate=4:1 (volume
Than) mixed solvent as eluent, until there is product after, by collect the solution containing product be evaporated, with
Drained with vacuum pump afterwards, obtain the fluoro- 4- methoxy nitrobenzenes sterlings of 3-, yield 57%.
Claims (7)
1. a kind of method that alkoxy-aromatic cpds are prepared by fluoro aromatic, it is characterised in that comprise the following steps：
1) with dimethyl sulfoxide as reaction dissolvent, fluoro aromatic, highly basic, alcohol are pressed into 1: (1-10): mol ratio (1-10)
Reacted, reaction temperature is 0-100 DEG C, the response time is 12-48 hours；
2) by reactant liquor organic solvent diluting, and saturated common salt water washing is used, by organic faciess desiccant dryness, is spin-dried for, so
Silica gel is gone up afterwards or neutral alumina chromatographic column is separated, by mobile phase of non-polar organic solvent eluting is carried out, collect eluting
Liquid is simultaneously concentrated, is dried, and obtains alkoxy-aromatic cpds sterling,
The fluoro aromatic be luxuriant and rich with fragrance monosubstituted on aromatic rings or polysubstituted fluorobenzene, fluoronaphthalene, fluorine anthracene, fluorine or many fluorobenzene,
One kind in many fluoronaphthalenes, polyfluoro anthracene, polyfluoro phenanthrene.
2. the method for as claimed in claim 1 alkoxy-aromatic cpds being prepared by fluoro aromatic, it is characterised in that：Institute
Highly basic is stated for the one kind in potassium hydroxide, sodium hydroxide, Lithium hydrate.
3. the method for as claimed in claim 1 alkoxy-aromatic cpds being prepared by fluoro aromatic, it is characterised in that：Institute
State alcohol for methanol, ethanol, normal propyl alcohol, isopropanol, benzylalcohol, the tert-butyl alcohol, isobutanol, n-butyl alcohol, ethylene glycol, glycerol, n-amyl alcohol,
Isoamyl alcohol, 1,3-PD, BDO, the one kind in 2- phenylethanols, Hexalin.
4. the method for as claimed in claim 1 alkoxy-aromatic cpds being prepared by fluoro aromatic, it is characterised in that：Institute
Organic solvent is stated selected from ethyl acetate, dichloromethane, chloroform, isopropyl acetate, normal hexane, hexamethylene, the one kind in petroleum ether.
5. the method for as claimed in claim 1 alkoxy-aromatic cpds being prepared by fluoro aromatic, it is characterised in that：Institute
Desiccant is stated for the one kind in anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, Anhydrous potassium carbonate.
6. the method for as claimed in claim 1 alkoxy-aromatic cpds being prepared by fluoro aromatic, it is characterised in that：Institute
Non-polar organic solvent is stated for any of one or more in petroleum ether, normal hexane, hexamethylene, ethyl acetate, dichloromethane
Mixing.
7. the method for as claimed in claim 1 alkoxy-aromatic cpds being prepared by fluoro aromatic, it is characterised in that：Institute
It is 1: 2: 2 to state fluoro aromatic, highly basic, the mol ratio of alcohol.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610861044.2A CN106565522A (en) | 2016-09-29 | 2016-09-29 | Method for preparing alkyloxy aromatic compound from fluoroaromatic compound |
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| CN201610861044.2A CN106565522A (en) | 2016-09-29 | 2016-09-29 | Method for preparing alkyloxy aromatic compound from fluoroaromatic compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109251711A (en) * | 2018-08-06 | 2019-01-22 | 宁波联城住工科技有限公司 | The preparation method of silane modified polyether seal glue |
| US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
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| CN105473544A (en) * | 2013-06-06 | 2016-04-06 | 安瑟生物科技私人有限公司 | Compounds of '3-(5-sustituted oxy-2,4-dinitro-phenyl)-2-oxo-propionic acid ester', process and applications thereof |
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2016
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105473544A (en) * | 2013-06-06 | 2016-04-06 | 安瑟生物科技私人有限公司 | Compounds of '3-(5-sustituted oxy-2,4-dinitro-phenyl)-2-oxo-propionic acid ester', process and applications thereof |
Non-Patent Citations (3)
| Title |
|---|
| HYO-SOON PARK等: "Palladium-Catalyzed Carbonylative Esterification of Primary Alcohols with Aryl Chlorides through Dehydroxymethylative C−C Bond Cleavage", 《ACS CATALYSIS》 * |
| ROSSI, ROBERTO A.等: "Aromatic substitution by the SRN1 reaction", 《ORGANIC REACTIONS》 * |
| WEN-BIN WU等: "Electrochemical hydrodefluorination of fluoroaromatic compounds", 《TETRAHEDRON LETTERS》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
| US11098030B2 (en) | 2016-05-26 | 2021-08-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
| US12049460B2 (en) | 2016-05-26 | 2024-07-30 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
| CN109251711A (en) * | 2018-08-06 | 2019-01-22 | 宁波联城住工科技有限公司 | The preparation method of silane modified polyether seal glue |
| CN109251711B (en) * | 2018-08-06 | 2021-07-30 | 广东联城住工装备信息科技有限公司 | Preparation method of silane modified polyether sealant |
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