CN106431871A - Preparation method for 2'-bromo-o-fluoroacetophenone - Google Patents
Preparation method for 2'-bromo-o-fluoroacetophenone Download PDFInfo
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- CN106431871A CN106431871A CN201610674425.XA CN201610674425A CN106431871A CN 106431871 A CN106431871 A CN 106431871A CN 201610674425 A CN201610674425 A CN 201610674425A CN 106431871 A CN106431871 A CN 106431871A
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- preparation
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- bromo
- fluoro acetophenone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Abstract
The invention discloses a preparation method for 2'-bromo-o-fluoroacetophenone. The preparation method comprises the following steps: (1) adding raw materials, i.e., o-fluoroacetophenone and methyl tert-butyl ether into a reaction vessel, and carrying out cooling treatment; (2) adding a catalyst into the reaction vessel in the step (1); (3) adding a solvent into the reaction vessel in the step (1) in batches, and meanwhile, adopting TLC to track a solution reaction until the reaction ends; and (4) carrying out recrystallization treatment on the solution obtained through reactions from the step (1) to the step (3), thereby obtaining a product. The preparation method disclosed by the invention achieves the effects of high yield, moderate reaction, safety in operation and no pollution.
Description
Technical field
The present invention relates to a kind of preparation method of 2 '-bromo o-fluoro acetophenone, particularly under NBS, Aluminium Trichloride as Catalyst
Under substitution reaction synthesis a kind of 2 '-bromo o-fluoro acetophenone method.
Background technology
2 '-bromo o-fluoro acetophenone is the key intermediate of military field new drug Wo Nuolazan.Wo Nuolazan (Vonopra zan
Fumarate) be by the competitive acid blocker of potassium ion of Japanese Wu Tian company exploitation, on December 26th, 2014 in Japan
City, trade name Takecab, for treating erosive esophagitis, gastric ulcer, duodenal ulcer, helicobacter pylori eradication.Fertile
It is the new drug for treating gastrointestinal disease that Nola praises, and administration is few, and good drug efficacy, is that other similar medicines are incomparable so far.Market
Prospect will be very good.The synthesis of the intermediate at present has other patent reports, but the heat release that operates is obvious, to periphery
Environment has obvious pollution.Original technology scheme：
It is more than the method for designing of prior art, bromine is dangerous extremely strong material, and the eyes to people, respiratory tract have pole
Strong corrosivity, before in addition bromine is added dropwise to reactant liquor, first will be mixed with ethyl acetate, bromine is diluted, but both
In mixing, substantial amounts of heat can be released, temperature rises rapid, ethyl acetate boiling, produces a large amount of redness gas (Br of HBr2
Gas).There is red cigarette in a large number in the emptying mouth of pipe, the pollution to periphery is very big, and Br2Can react with ethyl acetate so that Br2Have
Effect amount is reduced, and the bromine amount for therefore participating in above reaction also reduces, and therefore declines target product yield.
Content of the invention
The present invention provides a kind of preparation method of 2 '-bromo o-fluoro acetophenone, to solve existing bromo o-fluoro acetophenone
Amount of heat being discharged during preparation method, produce toxic gas, pollutes the shortcoming of environment.
Detailed technology scheme of the present invention is：
A kind of preparation method of 2 '-bromo o-fluoro acetophenone, the preparation method is comprised the following steps：
The first step, raw material o-fluoro acetophenone and methyl tertiary butyl ether(MTBE) are added in reaction vessel, carry out cooling process；
Second step, adds catalyst in the reaction vessel of the first step；
3rd step, is dividedly in some parts solvent in the reaction vessel of the first step, while solution reaction is tracked using TLC, until
Reaction terminates；
4th step, the crude product for being obtained to step 3 reaction by step one carries out recrystallization process, obtains product.
Further, the catalyst is AlCl3.
Further, the bromating agent is NBS.
Further, the cooling processing method is：Cool-down method is stirred by ice bath cooling means or brine system.
Further, the re-crystallization step is：The solution for obtaining after step 3 reaction in claim 1 is terminated,
By decompression concentrated solution to 50%, a large amount of water being added in substrate, washing by-product, separate oil reservoir, oil reservoir is with anhydrous
Na2SO4 is dried, filters, filtrate decompression rectification, collects the fraction of 82～84 DEG C (5mmHg), obtains product.
The Advantageous Effects brought by the present invention are：The present invention replaces bromine using bromating agent NBS, adds AlCl3Urge
Change, high income has been reached, reaction relaxes, safe operation, free of contamination effect；O-fluoro acetophenone is mixed with methyl tertiary butyl ether(MTBE)
Afterwards, under cooling, catalyst is added, is dividedly in some parts NBS, TLC and tracks to raw material reaction and terminate.Stopped reaction, is processed, and is taken thick
Product, obtain fine work, yield 50% with recrystallizing methanol；In this method, solvent is particularly significant to the single bromination of control.In addition, adding
AlCl3Catalyst accelerates reaction, and reacts complete, significant to industrialized production.
Specific embodiment
In order that the objects, technical solutions and advantages of the present invention become more apparent, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that specific embodiment described herein is not used to only in order to explain the present invention
Limit the present invention.
The course of reaction of the present invention is：
Embodiment 1
50g (0.42mol) o-fluoro acetophenone and 50ml methyl tertiary butyl ether(MTBE) are added in 500ml there-necked flask, using ice
Bath cooling means, is simultaneously introduced 0.5g AlCl3, NBS 75g (0.42mol) is dividedly in some parts under stirring, is finished, is removed ice bath, from
Room temperature is so warming up to.
After reaction 2h, solution reaction is tracked using TLC, until reaction terminates, no raw material point is terminal, molten by obtained
Liquid concentrating under reduced pressure solvent adds a large amount of water to 50% in substrate, washs by-product, separates oil reservoir (lower floor), anhydrous Na2SO4
Dry, filter, filtrate decompression rectification, 82～84 DEG C of (5mmHg) fractions are collected, product 72-81g is obtained, calculated yield is 75-
78%.
Embodiment 2
O-fluoro acetophenone 250kg, 500 liters of methyl tertiary butyl ether(MTBE) is added in 1000 liters of reactors.Brine system is opened, is stirred
Mix and 0 DEG C is cooled to, 2.5kg aluminum chloride is added, after about 15min, be dividedly in some parts NBS 375kg (adding by 25kg every time), control
Temperature is less than 5 DEG C.Finish, warm naturally to room temperature.
After reaction 4h, point plate monitoring no raw material point, the solution decompression concentrated solvent for obtaining to 50% is added in substrate
A large amount of water, wash by-product, separate oil reservoir (lower floor), anhydrous Na2SO4 dries, and filters, filtrate decompression rectification, collects 82～84
DEG C (5mmHg) fraction, calculated yield is to be higher by 5% 80%, than lab scale, amplifies and has reached expection.
The preparation method of invention 2 '-bromo o-fluoro acetophenone has reached high income, and reaction relaxes, and safe operation is no dirty
The effect of dye, possesses very big prospects for commercial application.
Presently preferred embodiments of the present invention is the foregoing is only, not in order to limit the present invention, all essences in the present invention
Any modification, equivalent and improvement that is made within god and principle etc., should be included within the scope of the present invention.
The present invention does not address part and is applied to prior art.
Claims (5)
1. a kind of preparation method of 2 '-bromo o-fluoro acetophenone, it is characterised in that the preparation method is comprised the following steps：
The first step, raw material o-fluoro acetophenone and methyl tertiary butyl ether(MTBE) are added in reaction vessel, carry out cooling process；
Second step, adds catalyst in the reaction vessel of the first step；
3rd step, is dividedly in some parts solvent in the reaction vessel of the first step, while solution reaction is tracked using TLC, until reaction
Terminate；
4th step, the solution for being obtained to step 3 reaction by step one carries out recrystallization process, obtains product.
2. the preparation method of 2 '-bromo o-fluoro acetophenone according to claim 1, it is characterised in that：The catalyst is
AlCl3.
3. the preparation method of 2 '-bromo o-fluoro acetophenone according to claim 1, it is characterised in that：The solvent is
nbs.
4. the preparation method of 2 '-bromo o-fluoro acetophenone according to claim 1, it is characterised in that the cooling is processed
Method is：Cool-down method is stirred by ice bath cooling means or brine system.
5. the preparation method of 2 '-bromo o-fluoro acetophenone according to claim 1, it is characterised in that the recrystallization step
Suddenly it is：The solution for obtaining after step 3 reaction in claim 1 is terminated, by decompression concentrated solution to 50%, in substrate
A large amount of water are added, by-product is washed, separates oil reservoir, oil reservoir anhydrous Na2SO4 is dried, filters, filtrate decompression rectification, receives
The fraction of collection 82～84 DEG C (5mmHg), obtains product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610674425.XA CN106431871A (en) | 2016-08-17 | 2016-08-17 | Preparation method for 2'-bromo-o-fluoroacetophenone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610674425.XA CN106431871A (en) | 2016-08-17 | 2016-08-17 | Preparation method for 2'-bromo-o-fluoroacetophenone |
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| CN106431871A true CN106431871A (en) | 2017-02-22 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919323A (en) * | 1974-08-08 | 1975-11-11 | Sandoz Ag | Acyl substituted dibenzylethers |
| CN1939887A (en) * | 2005-07-28 | 2007-04-04 | 索尔蒂格有限责任公司 | Process for preparation of optionally substituted trifluoromethyl phenacyl bromide |
| CN101300229A (en) * | 2005-08-30 | 2008-11-05 | 武田药品工业株式会社 | 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors |
| WO2010129665A2 (en) * | 2009-05-05 | 2010-11-11 | Cambria Pharmaceuticals, Inc. | Pyrimidine-2,4,6-triones for use in the treatment of amyotrophic lateral sclerosis |
-
2016
- 2016-08-17 CN CN201610674425.XA patent/CN106431871A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919323A (en) * | 1974-08-08 | 1975-11-11 | Sandoz Ag | Acyl substituted dibenzylethers |
| CN1939887A (en) * | 2005-07-28 | 2007-04-04 | 索尔蒂格有限责任公司 | Process for preparation of optionally substituted trifluoromethyl phenacyl bromide |
| CN101300229A (en) * | 2005-08-30 | 2008-11-05 | 武田药品工业株式会社 | 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors |
| WO2010129665A2 (en) * | 2009-05-05 | 2010-11-11 | Cambria Pharmaceuticals, Inc. | Pyrimidine-2,4,6-triones for use in the treatment of amyotrophic lateral sclerosis |
Non-Patent Citations (2)
| Title |
|---|
| RODOLFO GONZÁLEZ-CHÁVEZ等: "De Novo Design of Non-coordinating Indolones as Potential Inhibitors for Lanosterol 14-α-Demethylase(CYP51)", 《CHEM. PHARM. BULL.》 * |
| 苏冰等: "对甲氧基-α-溴代苯乙酮的合成", 《中国医药工业杂志》 * |
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Application publication date: 20170222 |