CN102557909A - Preparation method for 5-fluorin-2-hydroxyacetophenone - Google Patents
Preparation method for 5-fluorin-2-hydroxyacetophenone Download PDFInfo
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- CN102557909A CN102557909A CN 201010618179 CN201010618179A CN102557909A CN 102557909 A CN102557909 A CN 102557909A CN 201010618179 CN201010618179 CN 201010618179 CN 201010618179 A CN201010618179 A CN 201010618179A CN 102557909 A CN102557909 A CN 102557909A
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- CN
- China
- Prior art keywords
- preparation
- fluorin
- hydroxyacetophenone
- ethanoyl
- amino
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- KOFFXZYMDLWRHX-UHFFFAOYSA-N 1-(5-fluoro-2-hydroxyphenyl)ethanone Chemical compound CC(=O)C1=CC(F)=CC=C1O KOFFXZYMDLWRHX-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 6
- SXLHPBDGZHWKSX-UHFFFAOYSA-N 1-(5-amino-2-hydroxyphenyl)ethanone Chemical compound CC(=O)C1=CC(N)=CC=C1O SXLHPBDGZHWKSX-UHFFFAOYSA-N 0.000 claims description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 4
- 235000019439 ethyl acetate Nutrition 0.000 claims description 4
- DIQSYMRVTOVKQT-UHFFFAOYSA-N n-(3-acetyl-4-hydroxyphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(O)C(C(C)=O)=C1 DIQSYMRVTOVKQT-UHFFFAOYSA-N 0.000 claims description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 230000021736 acetylation Effects 0.000 claims description 2
- 238000006640 acetylation reaction Methods 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract description 2
- 239000011737 fluorine Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract 2
- 238000005618 Fries rearrangement reaction Methods 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- 238000006193 diazotization reaction Methods 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000011780 sodium chloride Substances 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000001149 thermolysis Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method for 5-fluorin-2-hydroxyacetophenone. The preparation method comprises the following steps of: performing double esterification on amino groups and phenolic hydroxy in one step by taking amino-phenol as a raw material; performing Fries rearrangement under the condition of aluminum chloride/sodium chloride; heating a hydrolyzate after performing fluorine diazotization to obtain finished 5-fluorin-2-hydroxyacetophenone. The preparation method has the advantages of low prices of raw materials, relatively mild reaction conditions, total yield of up to 54.5 percent and industrial production application value.
Description
Technical field
The present invention relates to the fluorine chemical field, be specifically related to the compound method of 5-fluoro-2-hydroxy acetophenone.
Background technology
5-fluoro-2-hydroxy acetophenone another name 2-ethanoyl-4-fluorophenol is a kind of important medicine intermediate, can be used as multiple beta-blockers synthetic intermediate, has vast market prospect.The general preparation method of report is that the employing p-fluorophenol is a raw material at present, through acylated hydroxy, and then adopts Fries to reset synthetic.Adopt such method synthesis material expensive, particularly the fluorine atom on the aromatic ring is a strong electron-withdrawing group, possibly and reset yield to acidylate and produce considerable influence.
Summary of the invention
The object of the present invention is to provide from the method for the synthetic 5-fluoro-2-hydroxy acetophenone of the initial catalysis of the reagent that is easy to obtain.Have now found that a kind of preparation method of 5-fluoro-2-hydroxy acetophenone, it comprises following step:
A. prepare 4-acetaminophenol acetic ester with the amino-phenol acetylize;
B. carry out Fries with 4-acetaminophenol acetic ester and reset preparation 2-ethanoyl-4-acetaminophenol;
C. prepare 2-ethanoyl-4-amino-phenol with 2-ethanoyl-4-acetaminophenol;
D. prepare 5-fluoro-2-hydroxy acetophenone with 2-ethanoyl-4-amino-phenol.
Wherein, select for use diacetyl oxide as acetylation reagent among the step a.
Wherein, select for use sodium-chlor as solubility promoter among the step b.
Wherein, select for use acidic conditions to be hydrolyzed among the step c.
Preferably, in the organic solvent that is selected from halogenated or not halogenated aliphatic series, alicyclic, aromatic hydrocarbon, carry out said reaction, the preferred hexane of said organic solvent, hexanaphthene, methylcyclohexane, toluene, mono chloro benzene, glycerine.
According to batch mode, optional solvent, reactant and catalyzer are infeeded in the reactor drum.Be heated to the temperature that preceding text limit.Apply desirable pressure and maintenance.When reaction finishes, according to the solid/liquid separation technique of routine, preferably via filtration, separating catalyst.Reclaim the product that is obtained by routine, preferably perhaps pass through liquid/liquid extraction through distillation.
Embodiment
Provide below and be used to illustrate and nonrestrictive exemplary of the present invention.
In an embodiment, transformation efficiency is corresponding to the ratio of the substrate mole number that transforms with the substrate mole number that infeeds, and given yield is corresponding to the ratio of the product mole number that forms with the substrate mole number that infeeds.
Embodiment 1
With PARA AMINOPHENOL 32.7g and diacetyl oxide 76.5g, drop in the 250mL benzene, stirring heating is in 80 ℃ of back flow reaction 3h.Reaction finishes, and vacuum distillation recovered solvent is to doing, and cooling adds 300L water, separates out solid, suction filtration dry off-white color solid 55.0g, yield 93.0%, need not purifying and directly is used for next step reaction by m.p.151 ℃.
Embodiment 2
With the product of embodiment 1 preparation (38.6g, 0.2mol), aluminum trichloride (anhydrous) (80g, and sodium-chlor (40g throws in the reaction flask, is stirred and heated to 120 ℃, and reaction mixture is scattered paste shape, and is attended by a large amount of sour gas and emits; Insulation reaction 3h when no longer including gas and emit, is chilled to 60 ℃ with reaction mixture, in this mixture, slowly adds 160mL water, vigorous stirring, freezing, suction filtration, dry faint yellow solid 36.3g, yield 94.0%, m.p.162 ℃.
Embodiment 3
With last embodiment gained (38.6g, 0.2mol), (400mL 6mol/L) adds in the 500mL round-bottomed flask hydrochloric acid, keeps reflux state 6h.Reflux and finish, pH value to 6～7 are regulated in cooling, separate out solid, and drying is weighed, and obtains solid 18.9g, yield 75.6%, m.p.167 ℃.
Embodiment 4
With the product of last embodiment gained (30.2g, 0.2mol) add excessive hydrogen fluoride (11.4g, 0.6mol) in, temperature is reduced to-5 ℃, progressively add solid sodium nitrite (17.3g, 0.2mol), temperature of reaction after adding, keeps reaction 5h at 0～5 ℃; Be warming up to 40 ℃ then gradually, carry out thermolysis; After decomposing fully, regulate pH value to 6～7, steam distillation and obtain white crystal product 25.1g, yield 82%.
Claims (4)
1. the preparation method of a 5-fluoro-2-hydroxy acetophenone, it comprises following step:
A. prepare 4-acetaminophenol acetic ester with the amino-phenol acetylize;
B. carry out Fries with 4-acetaminophenol acetic ester and reset preparation 2-ethanoyl-4-acetaminophenol;
C. prepare 2-ethanoyl-4-amino-phenol with 2-ethanoyl-4-acetaminophenol;
D. prepare 5-fluoro-2-hydroxy acetophenone with 2-ethanoyl-4-amino-phenol.
2. the method for claim 1 is characterized in that, selects for use diacetyl oxide as acetylation reagent among the step a.
3. the method for claim 1 is characterized in that, selects for use sodium-chlor as solubility promoter among the step b.
4. the method for claim 1 is characterized in that, selects for use acidic conditions to be hydrolyzed among the step c.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010618179 CN102557909A (en) | 2010-12-30 | 2010-12-30 | Preparation method for 5-fluorin-2-hydroxyacetophenone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010618179 CN102557909A (en) | 2010-12-30 | 2010-12-30 | Preparation method for 5-fluorin-2-hydroxyacetophenone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102557909A true CN102557909A (en) | 2012-07-11 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010618179 Pending CN102557909A (en) | 2010-12-30 | 2010-12-30 | Preparation method for 5-fluorin-2-hydroxyacetophenone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102557909A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699578A (en) * | 2015-11-13 | 2017-05-24 | 江苏先声药业有限公司 | Synthesis method of important pharmaceutical and chemical intermediate 4-amino-3-chlorophenol |
| CN113045398A (en) * | 2021-03-24 | 2021-06-29 | 河南科锐化工有限公司 | Preparation process of 5-fluoro-2-hydroxyacetophenone |
| CN113636990A (en) * | 2021-06-22 | 2021-11-12 | 山东盛安贝新能源有限公司 | Method for preparing diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone |
-
2010
- 2010-12-30 CN CN 201010618179 patent/CN102557909A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699578A (en) * | 2015-11-13 | 2017-05-24 | 江苏先声药业有限公司 | Synthesis method of important pharmaceutical and chemical intermediate 4-amino-3-chlorophenol |
| CN113045398A (en) * | 2021-03-24 | 2021-06-29 | 河南科锐化工有限公司 | Preparation process of 5-fluoro-2-hydroxyacetophenone |
| CN113636990A (en) * | 2021-06-22 | 2021-11-12 | 山东盛安贝新能源有限公司 | Method for preparing diacalol intermediate 5-acetamido-2- (2, 3-epoxypropoxy) acetophenone |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120711 |