CN109553528A - A kind of synthetic method of 2- methyl -4- acetylbenzoic acid methyl esters - Google Patents
A kind of synthetic method of 2- methyl -4- acetylbenzoic acid methyl esters Download PDFInfo
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- CN109553528A CN109553528A CN201811570802.0A CN201811570802A CN109553528A CN 109553528 A CN109553528 A CN 109553528A CN 201811570802 A CN201811570802 A CN 201811570802A CN 109553528 A CN109553528 A CN 109553528A
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- C07—ORGANIC CHEMISTRY
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C07—ORGANIC CHEMISTRY
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- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
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- C07—ORGANIC CHEMISTRY
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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Abstract
The present invention provides a kind of synthetic methods of 2- methyl -4- acetylbenzoic acid methyl esters, comprising the following steps: acylating reagent progress acylation reaction S1, is added in the solution dissolved with 2- toluene fluoride, obtains the fluoro- 3- methyl acetophenone of 4-；S2, cyanating reagent progress cyanogenation will be added after the fluoro- 3- methyl acetophenone dissolution of 4-, and will obtain 3- methyl -4- cyano-acetophenone；S3, reaction is hydrolyzed in addition acid in 3- methyl -4- cyano-acetophenone, obtains 2- methyl -4- acetylbenzoic acid；S4, methanol progress esterification is added in 2- methyl -4- acetylbenzoic acid, obtains 2- methyl -4- acetylbenzoic acid methyl esters.Method of the invention is easy to operate, and reaction yield is higher, and drug and instrument used are easily purchased, and cost is relatively low, has feasibility in specific practice principle.
Description
Technical field
The present invention relates to organic synthesis fields, and in particular to a kind of synthesis side of 2- methyl -4- acetylbenzoic acid methyl esters
Method.
Background technique
2- methyl -4- acetylbenzoic acid methyl esters is the important intermediate for synthesizing many insecticides.It synthesizes among this at present
The route of body can substantially be divided into two classes: one kind be by 3- methyl -4- bromoacetophenone and carbon monoxide under catalyzing by metal palladium
Target product is generated, but Metal Palladium belongs to rare metal, it is expensive, and carbon monoxide is toxic, is unfavorable for being mass produced.
Second class synthetic route obtains product with 3- methyl -4- bromoacetophenone and cyaniding nak response, but potassium cyanide is hypertoxic, to personnel,
Environmental requirement is very strict, is not suitable for large-scale production.
So finding suitable reaction route, established for extensive synthesis 2- methyl -4- acetylbenzoic acid methyl esters later
Basis.
Summary of the invention
The purpose of the invention is to provide a kind of synthetic methods of 2- methyl -4- acetylbenzoic acid methyl esters, including with
Lower step:
S1, acylation reaction: acylating reagent is added in the solution dissolved with 2- toluene fluoride, is acylated at a temperature of -10-100 DEG C
Reaction, obtains the fluoro- 3- methyl acetophenone of reaction intermediate 4-；
S2, cyanogenation: cyanating reagent will be added after the fluoro- 3- methyl acetophenone dissolution of 4-, cyanogen is carried out at a temperature of 100-200 DEG C
Change reaction, obtains reaction intermediate 3- methyl -4- cyano-acetophenone；
S3, hydrolysis: being added acid in 3- methyl -4- cyano-acetophenone, is then hydrolyzed at a temperature of 20-120 DEG C anti-
It answers, obtains reaction intermediate 2- methyl -4- acetylbenzoic acid；
S4, esterification: being added methanol in 2- methyl -4- acetylbenzoic acid, and carries out being esterified anti-at a temperature of 20-80 DEG C
It answers, 2- methyl -4- acetylbenzoic acid methyl esters can be obtained.
The amount of acylating reagent needed for acylation reaction is 1-5 equivalent in S1, preferential to select 1.2 equivalents.Reaction temperature is 0 DEG C,
Reaction time is 3 hours, and used solvent is methylene chloride, in carbon tetrachloride, chloroform, carbon disulfide, 1,2- dichloroethanes
Any one, preferentially select methylene chloride.The molar ratio of 2- toluene fluoride and acylating reagent is 1:1.1-1.5 in acylation reaction,
Preferential selection 1:1.2.
Cyanogenation required temperature is 140 DEG C in S2, and solvent for use is n,N-Dimethylformamide, N- substituted pyrrolidin
Ketone, N- methylimidazole, N- ethyl imidazol(e), N- butyl imidazole, any one in N- butyl imidazole, preferentially select N, N- dimethyl
Formamide.Cyanating reagent used is potassium ferrocyanide, cuprous cyanide, any one in zinc cyanide, preferentially selects ferrocyanide
Potassium.
Acid used in hydrolysis is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, any one in trifluoroacetic acid in S3,
Preferential selection sulfuric acid.Reaction temperature is 80 DEG C.
Addition acid catalyst is needed in S4 in esterification, acid catalyst is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, trifluoro second
Any one in acid, preferentially selects sulfuric acid.Reaction temperature is 70 DEG C.
The present invention is to synthesize 2- methyl-by acylation, cyanalation, hydrolysis, esterification using 2- toluene fluoride as starting material
4- acetylbenzoic acid methyl esters.Operation of the present invention is simple, and reaction yield is higher, and drug and instrument used are easily purchased, and cost is relatively low,
There is feasibility in specific practice principle.
Detailed description of the invention
Fig. 1 is that the hydrogen of 2- methyl -4- acetylbenzoic acid methyl esters is composed.
Specific embodiment
The preferred embodiment of invention will be described in detail below.Example be in order to preferably to summary of the invention into
Row, is not that summary of the invention is only limitted to example.Nonessential modifications and adaptations according to summary of the invention to embodiment, still fall within
Invention scope.
<embodiment 1>
The preparation of the fluoro- 3- methyl acetophenone of 4-
11 grams of 2- toluene fluoride (0.1mol), 33.4 grams of (0.25mol) alchlors, dichloromethane are added in the three-necked bottle of 250ml
Alkane 100ml, temperature are controlled at -5 DEG C, and 8.6 grams of dropwise addition careful (0.11mol) chloroacetic chlorides are warming up to often after being added dropwise to complete
Temperature is reacted 2 hours, TLC detection, after complete reaction, the ice water of 50mL, the dilute hydrochloric acid of 25mL is added at 0 DEG C, liquid separation is washed
It washs, dry, revolving obtains 13.5 grams of colourless liquid, yield 88%.
The preparation of 3- methyl -4- cyano-acetophenone
The 4- fluorine 3- methyl acetophenone of 7.6 grams (0.05mol), the Asia of 21.2 grams (0.05mol) are added in the small flask of 250ml
The potassium ferricyanide, 10% four butyl bromation amine, the n,N-Dimethylformamide of 100ml are warming up to 140 DEG C, react 16 hours, TLC
Detection, after raw material has reacted, is cooled to 80 DEG C, and the ethyl acetate of 100ml is added, and flows back 1 hour, stops heating, filters, respectively
It is dry with the water washing of 100ml, obtain the solid of 6.2 grams of yellow, yield 78%.
The preparation of 2- methyl -4- acetylbenzoic acid
By 1mmol(1.59 grams) 3- methyl -4- cyano-acetophenone is added in the flask of 100mL, it is added the sulfuric acid of 10ml80%, 100
DEG C reaction 12 hours, TLC detection, after reflection, 10% sodium carbonate melt is added, be adjusted to pH value be 2, extracted with ethyl acetate
It takes 3 times, merges organic phase, it is dry, it is evaporated, obtains 1.42 grams of buff white solid, yield 80%.
The preparation of 2- methyl -4- acetylbenzoic acid methyl esters
By 0.5mmol(0.18 grams) 2- methyl -4- acetylbenzoic acid be added 100mL flask in, be added 10ml anhydrous methanol,
Add a few drop concentrated sulfuric acids, 70 DEG C are reacted 12 hours, and after completion of the reaction, 10% sodium carbonate melt is added, being adjusted to pH value is in TLC detection
7, methanol is steamed, is extracted with ethyl acetate 3 times, organic phase is merged, it is dry, it is evaporated, obtains 0.19 gram of buff white solid, yield
99%。
<embodiment 2>
The preparation of the fluoro- 3- methyl acetophenone of 4-:
11 grams of 2- toluene fluoride (0.1mol), 33.4 grams of (0.25mol) alchlors, three chloromethanes are added in the three-necked bottle of 250ml
Alkane 100ml, temperature are controlled at -5 DEG C, and 8.6 grams of dropwise addition careful (0.11mol) chloroacetic chlorides are warming up to often after being added dropwise to complete
Temperature is reacted 2 hours, TLC detection, after complete reaction, the ice water of 50mL, the dilute hydrochloric acid of 25mL is added at 0 DEG C, liquid separation is washed
It washs, dry, revolving obtains 14 grams of colourless liquid, yield 91%.
The preparation of 3- methyl -4- cyano-acetophenone:
The 4- fluorine 3- methyl acetophenone of 7.6 grams (0.05mol), the Asia of 21.2 grams (0.05mol) are added in the small flask of 250ml
The potassium ferricyanide, 10% four butyl bromation amine, the N- methylimidazole of 100ml are warming up to 160 DEG C, react 14 hours, TLC detection,
After raw material has reacted, 80 DEG C are cooled to, the ethyl acetate of 100ml is added, is flowed back 1 hour, heating is stopped, filtering is used respectively
The water washing of 100ml, it is dry, obtain 7 grams of yellow solids, yield 88%.
The preparation of 2- methyl -4- acetylbenzoic acid
By 1mmol(1.59 grams) 3- methyl -4- cyano-acetophenone be added 100mL flask in, be added 10ml concentrated hydrochloric acid, 100 DEG C
Reaction 12 hours, TLC detection, after completion of the reaction, is added 10% sodium carbonate melt, and being adjusted to pH value is 2, is extracted with ethyl acetate 3
It is secondary, merge organic phase, it is dry, it is evaporated, obtains 1.42 grams of buff white solid, yield 80%.
The preparation of 2- methyl -4- acetylbenzoic acid methyl esters
By 0.5mmol(0.18 grams) 2- methyl -4- acetylbenzoic acid be added 100mL flask in, be added 10ml anhydrous methanol,
Add a few drop concentrated sulfuric acids, 80 DEG C are reacted 12 hours, and after completion of the reaction, 10% sodium carbonate melt is added, being adjusted to pH value is in TLC detection
7, methanol is steamed, is extracted with ethyl acetate 3 times, organic phase is merged, it is dry, it is evaporated, obtains 0.19 gram of buff white solid, yield
99%。
<embodiment 3>
The preparation of the fluoro- 3- methyl acetophenone of 4-
11 grams of 2- toluene fluoride (0.1mol), 16.2 grams of (0.1mol) ferric trichlorides, carbon tetrachloride are added in the three-necked bottle of 250ml
100ml, temperature are controlled at -5 DEG C, and 8.6 grams of dropwise addition careful (0.11mol) chloroacetic chlorides are warming up to 80 DEG C after being added dropwise to complete,
Reaction 8 hours, TLC detection, to which the ice water of 50mL, the dilute hydrochloric acid of 25mL after reaction, are added at 0 DEG C, liquid separation is washed, and is done
Dry, revolving obtains 7.8 grams of colourless liquid, yield 50.7%.
The preparation of 3- methyl -4- cyano-acetophenone
The 4- fluorine 3- methyl acetophenone of 7.6 grams (0.05mol), the Asia of 21.2 grams (0.05mol) are added in the small flask of 250ml
The potassium ferricyanide, 10% four butyl bromation amine, the N- butyl imidazole of 100ml are warming up to 140 DEG C, react 14 hours, TLC detection,
After raw material has reacted, 80 DEG C are cooled to, the ethyl acetate of 100ml is added, is flowed back 1 hour, heating is stopped, filtering is used respectively
The water washing of 100ml, it is dry, obtain 7.5 grams of yellow solids, yield 94%.
The preparation of 2- methyl -4- acetylbenzoic acid
By 1mmol(1.59 grams) 3- methyl -4- cyano-acetophenone be added 100mL flask in, be added 10ml trifluoroacetic acid, 60 DEG C
Reaction 12 hours, TLC detection, after completion of the reaction, is added 10% sodium carbonate melt, and being adjusted to pH value is 2, is extracted with ethyl acetate 3
It is secondary, merge organic phase, it is dry, it is evaporated, obtains 1.50 grams of buff white solid, yield 84%.
The preparation of 2- methyl -4- acetylbenzoic acid methyl esters
By 0.5mmol(0.18 grams) 2- methyl -4- acetylbenzoic acid be added 100mL flask in, be added 10ml anhydrous methanol,
Acetic acid is added, 100 DEG C are reacted 24 hours, and after completion of the reaction, 10% sodium carbonate melt is added in TLC detection, and being adjusted to pH value is 7,
Methanol is steamed, is extracted with ethyl acetate 3 times, organic phase is merged, it is dry, it is evaporated, column chromatographs to obtain buff white solid 0.11g, produces
Rate 68%.
Claims (5)
1. a kind of synthetic method of 2- methyl -4- acetylbenzoic acid methyl esters, it is characterised in that the following steps are included:
S1, acylation reaction: acylating reagent is added in the solution dissolved with 2- toluene fluoride, is acylated at a temperature of -10-100 DEG C
Reaction, obtains the fluoro- 3- methyl acetophenone of reaction intermediate 4-；
S2, cyanogenation: cyanating reagent will be added after the fluoro- 3- methyl acetophenone dissolution of 4-, cyanogen is carried out at a temperature of 100-200 DEG C
Change reaction, obtains reaction intermediate 3- methyl -4- cyano-acetophenone；
S3, hydrolysis: being added acid in 3- methyl -4- cyano-acetophenone, is then hydrolyzed at a temperature of 20-120 DEG C anti-
It answers, obtains reaction intermediate 2- methyl -4- acetylbenzoic acid；
S4, esterification: being added methanol in 2- methyl -4- acetylbenzoic acid, and carries out being esterified anti-at a temperature of 20-80 DEG C
It answers, 2- methyl -4- acetylbenzoic acid methyl esters can be obtained.
2. a kind of synthetic method of 2- methyl -4- acetylbenzoic acid methyl esters according to claim 1, it is characterised in that S1
The amount of acylating reagent needed for middle acylation reaction is 1-5 equivalent, and reaction temperature is 0 DEG C, and the reaction time is 3 hours, used molten
Agent is methylene chloride, carbon tetrachloride, chloroform, carbon disulfide, any one in 1,2- dichloroethanes, 2- fluorine first in acylation reaction
The molar ratio of benzene and acylating reagent is 1:1.1-1.5.
3. a kind of synthetic method of 2- methyl -4- acetylbenzoic acid methyl esters according to claim 1, it is characterised in that S2
Middle cyanogenation required temperature is 140 DEG C, and solvent for use is n,N-Dimethylformamide, N- substituted pyrrolidone, N- methyl miaow
Azoles, N- ethyl imidazol(e), N- butyl imidazole, any one in N- butyl imidazole, cyanating reagent used is potassium ferrocyanide, cyaniding
Cuprous, any one in zinc cyanide.
4. a kind of synthetic method of 2- methyl -4- acetylbenzoic acid methyl esters according to claim 1, it is characterised in that S3
Acid used in middle hydrolysis is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, any one in trifluoroacetic acid, and reaction temperature is
80℃。
5. a kind of synthetic method of 2- methyl -4- acetylbenzoic acid methyl esters according to claim 1, it is characterised in that S4
Need addition acid catalyst in middle esterification, acid catalyst is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, any in trifluoroacetic acid
One kind, reaction temperature are 70 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111018740A (en) * | 2019-12-20 | 2020-04-17 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester |
| CN115477577A (en) * | 2022-10-25 | 2022-12-16 | 台州臻挚生物科技有限公司 | Novel method for preparing 2-methyl-4-acetylbenzoic acid and derivatives thereof |
| CN116478057A (en) * | 2022-01-17 | 2023-07-25 | 洛阳惠中兽药有限公司 | Preparation method of fluororalrana intermediate |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018740A (en) * | 2019-12-20 | 2020-04-17 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester |
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| CN116478057A (en) * | 2022-01-17 | 2023-07-25 | 洛阳惠中兽药有限公司 | Preparation method of fluororalrana intermediate |
| CN115477577A (en) * | 2022-10-25 | 2022-12-16 | 台州臻挚生物科技有限公司 | Novel method for preparing 2-methyl-4-acetylbenzoic acid and derivatives thereof |
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Application publication date: 20190402 |