CN108276254A - A method of the synthesis chloro- 4- trifloro methyl phenols of 2- - Google Patents
A method of the synthesis chloro- 4- trifloro methyl phenols of 2- Download PDFInfo
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- CN108276254A CN108276254A CN201810253791.7A CN201810253791A CN108276254A CN 108276254 A CN108276254 A CN 108276254A CN 201810253791 A CN201810253791 A CN 201810253791A CN 108276254 A CN108276254 A CN 108276254A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/60—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by oxidation reactions introducing directly hydroxy groups on a =CH-group belonging to a six-membered aromatic ring with the aid of other oxidants than molecular oxygen or their mixtures with molecular oxygen
Abstract
The invention discloses a kind of methods of synthesis 2 chlorine, 4 trifloro methyl phenol, include the following steps：（1）Oxidation reaction：In the reaction vessel, 4 are added（Trifluoromethyl）Benzaldehyde, organic solvent, oxidant, 0 DEG C or more is obtained by the reaction 4（Trifluoromethyl）Phenol；（2）Halogenation：Under inert gas conditions, in another reaction vessel, halide reagent, organic solvent is added, catalyst and step are sequentially added under low temperature（1）4 obtained（Trifluoromethyl）Phenol is stirred to react to obtain 2 chlorine, 4 trifloro methyl phenol at room temperature.The preparation method, raw material is more easy to get, by-product is less, pollution less, the reaction time it is shorter, substantially increase yield, and with easy to operate, product is easily isolated with reaction system, it is convenient to post-process, obtained product has the features such as higher purity, and reliable foundation is provided for industrialized production.
Description
Technical field
The present invention relates to herbicide preparing technical field, the method for specifically a kind of synthesis chloro- 4- trifloro methyl phenols of 2-.
Background technology
Acifluorfen, fomesafen, lactofen, fluoroglycofen-ethyl belong to diphenyl ether herbicide, main to use
Broad leaved weed is removed in seedling rear defence, the low feature of active height, broad weed-killing spectrum, toxicity is applied to cereal crop, in China north
It is square that oneself is widely used.And the chloro- 4- trifloro methyl phenols of 2- be synthesize diphenyl ether herbicide important intermediate, pesticide,
It also has a wide range of applications in medicine synthesis.Up to the present, it is developed the synthesis chloro- 4- trifluoromethylbenzenes phenolate of 2-
The various methods of object are closed, there are mainly three types of prior synthesizing methods：First method is passed through using p-trifluoromethyl-phenol as raw material
Then chlorosulfuric acid chlorination reaction obtains the chloro- 4- trifloro methyl phenols of intermediate 2-；Second method is with p-trifluoromethylaniline
For starting material, after chlorosulfuric acid chlorination, diazotising, hydrolysis obtain the chloro- 4- trifloro methyl phenols of intermediate 2-；The third side
Method is with 3,4-, bis- chloro- benzotrifluorides for raw material, alkalizes in aprotic polar solvent, is acidified and obtains the chloro- 4- of intermediate 2- tri-
Methyl fluoride phenol.And the life of raw material p-trifluoromethyl-phenol and p-trifluoromethylaniline due to being used in preceding two synthetic routes
It is higher to produce cost, therefore first two synthesis route should not be used.The raw materials used bis- chloro- fluoroforms of 3,4- of Article 3 process route
Benzene is easy to get, feasible process, but its reaction time is longer, and yield is relatively low.
Invention content
To solve the above problems, the present invention provide it is a kind of synthesis the chloro- 4- trifloro methyl phenols of 2- method, have raw material compared with
To be easy to get, by-product is less, pollution less, the features such as reaction time is shorter, yield is higher.
The technical solution adopted by the present invention is：A method of the synthesis chloro- 4- trifloro methyl phenols of 2-, including following step
Suddenly：（1）Oxidation reaction：, in the reaction vessel, 4- is added（Trifluoromethyl）Benzaldehyde, organic solvent, oxidant, 0 DEG C or more
4- is obtained by the reaction（Trifluoromethyl）Phenol；（2）Halogenation：Under inert gas conditions, in another reaction vessel, halogenation is added
Reagent, organic solvent sequentially add catalyst and step under low temperature（1）Obtained 4-（Trifluoromethyl）Phenol stirs at room temperature
The chloro- 4- trifloro methyl phenols of 2- are obtained by the reaction.
Step（1）In, the oxidant is metachloroperbenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peroxide benzene first
One kind in acid etc..The amount of oxidant will produce larger impact for the result of reaction, and the dosage of oxidant is less than the 0.1 of raw material
When times measuring, reaction conversion ratio is relatively low, and when the dosage of oxidant is higher than 10 times of raw material amounts, increase the dosage of oxidant for anti-
The raising of product yield has no positive effect.Therefore oxidant and 4-（Trifluoromethyl）The molar ratio of benzaldehyde is（0.1 ~ 10）：
1。
Step（1）And step（2）In, the organic solvent is one in dichloromethane, chloroform, 1,2- dichloroethanes etc.
Kind.
Step（1）In, when reaction temperature is less than 0 DEG C, reaction cannot occur, secondary when reaction temperature is higher than 40 DEG C
React more, so when reaction temperature is 0 ~ 40 DEG C, the effect of reaction is preferable.
Step（2）In, the halide reagent is one kind in halogen, the hypohalogenous acids tert-butyl ester, N- N-halosuccinimides.Instead
The amount of halide reagent in answering will produce larger impact for the result of reaction, and the dosage of halide reagent is less than 4-（Trifluoromethyl）
When 0.1 times of amount of phenol, reaction conversion ratio is relatively low, and the dosage of halide reagent is higher than 4-（Trifluoromethyl）10 times of amounts of phenol
When, the dosage for increasing halide reagent has no positive effect for the raising of reaction yield.Therefore halide reagent and 4-（Fluoroform
Base）The molar ratio of phenol is（0.1 ~ 10）：1.
Step（2）In, the catalyst is one kind in zirconium chloride, copper chloride, stannous chloride, when catalyst amount is low
In 4-（Trifluoromethyl）When 0.1 mol% of phenol, more difficult generation is reacted, and when the dosage of catalyst is higher than 4-（Trifluoromethyl）
When 30 mol% of phenol usage, the dosage for increasing catalyst is not obvious the promotion of reaction yield, and considering can rise
Under the premise of being reacted to catalysis, catalyst and 4-（Trifluoromethyl）The molar ratio of phenol is（0.001 ~0.3）：1.
If organic solvent can not dissolve completely less than 10 times of amounts of material quality, raw material, reaction conversion ratio is low, if quantity of solvent
It is measured higher than 100 times, reaction system concentration is too low, and feed stock conversion is relatively low, therefore the mass ratio of organic solvent and raw material is（10~
100）:1.
The beneficial effects of the invention are as follows：Raw material is more easy to get, by-product is less, pollution less, the reaction time it is shorter, carry significantly
High yield, and with easy to operate, product is easily isolated with reaction system, it is convenient to post-process, and obtained product has higher
Purity the features such as, provide reliable foundation for industrialized production.
Specific implementation mode
In order to deepen the understanding of the present invention, below in conjunction with embodiment, the invention will be further described, the embodiment
It is only used for explaining the present invention, be not intended to limit the scope of the present invention.
Embodiment 1
4- is added in round-bottomed flask（Trifluoromethyl）Benzaldehyde（6.75 mmol, 1.0 equiv）, CH2Cl2（20 mL）, so
After mCPBA is added（6.78 mmol, 1.0 equiv）, 2 h are stirred at room temperature, add 15 ml to be saturated to system after reaction
NaHSO3Aqueous solution is transferred in separatory funnel and is extracted, and collects and merge organic phase, and anhydrous sodium sulfate dry filter is added to obtain
To 4-（Trifluoromethyl）Phenol solution, monitoring yield are 85%.Under inert gas conditions, NCS is added in round-bottomed flask
（5.74mmol）And CH2Cl2（20.0 mL）, -78 DEG C are cooled to, ZrCl is added4（0.115 mmol）, 4- is then added（Trifluoro
Methyl）Phenol solution, reaction is stirred at room temperature 6 hours, after reaction with saturation NaHCO3Aqueous solution is extracted, and is collected
And merge organic phase, obtain the chloro- 4- trifloro methyl phenols of 2-, yield 88% after removing solvent.
Embodiment 2
4- is added in round-bottomed flask（Trifluoromethyl）Benzaldehyde（6.75 mmol, 1.0 equiv）, CH2Cl2（20 mL）, so
After mCPBA is added（0.68 mmol, 0.1 equiv）, 2 h are stirred at room temperature, add 15 ml to be saturated to system after reaction
NaHSO3Aqueous solution is transferred in separatory funnel and is extracted, and collects and merge organic phase, and anhydrous sodium sulfate dry filter is added to obtain
To 4-（Trifluoromethyl）Phenol solution, monitoring yield are 44%.Under inert gas conditions, NCS is added in round-bottomed flask（2.97
mmol）And CH2Cl2（20.0 mL）, -78 DEG C are cooled to, ZrCl is added4（0.06 mmol）, 4- is then added（Trifluoromethyl）
Phenol solution, reaction is stirred at room temperature 6 hours, after reaction with saturation NaHCO3Aqueous solution is extracted, and is collected and is closed
And organic phase, obtain the chloro- 4- trifloro methyl phenols of 2-, yield 88% after removing solvent.
Embodiment 3
4- is added in round-bottomed flask（Trifluoromethyl）Benzaldehyde（6.75 mmol, 1.0 equiv）, CH2Cl2（40 mL）, so
After mCPBA is added（67.8 mmol, 10 equiv）, 2 h are stirred at room temperature, add 30 ml to be saturated to system after reaction
NaHSO3Aqueous solution is transferred in separatory funnel and is extracted, and collects and merge organic phase, and anhydrous sodium sulfate dry filter is added to obtain
To 4-（Trifluoromethyl）Phenol solution, monitoring yield are 86%.Under inert gas conditions, NCS is added in round-bottomed flask（2.9
Mmol,）And CH2Cl2（20.0 mL）, -78 DEG C are cooled to, ZrCl is added4（0.116 mmol）, 4- is then added（Fluoroform
Base）Phenol solution, reaction is stirred at room temperature 6 hours, after reaction with saturation NaHCO3Aqueous solution is extracted, and is collected simultaneously
Merge organic phase, the chloro- 4- trifloro methyl phenols of 2-, yield 70% are obtained after removing solvent.
Embodiment 4
4- is added in round-bottomed flask（Trifluoromethyl）Benzaldehyde（6.75 mmol, 1.0 equiv）, CH2Cl2（20 mL）, so
After mCPBA is added（6.78 mmol, 1.0 equiv）, 2 h are stirred at room temperature, add 15 ml to be saturated to system after reaction
NaHSO3Aqueous solution is transferred in separatory funnel and is extracted, and collects and merge organic phase, and anhydrous sodium sulfate dry filter is added to obtain
To 4-（Trifluoromethyl）Phenol solution, monitoring yield are 85%.Under inert gas conditions, NCS is added in round-bottomed flask（5.74
mmol）And CH2Cl2（20.0 mL）, -78 DEG C are cooled to, ZrCl is added4（0.023 mmol）, 4- is then added（Trifluoromethyl）
Phenol solution, reaction is stirred at room temperature 6 hours, after reaction with saturation NaHCO3Aqueous solution is extracted, and is collected and is closed
And organic phase, obtain the chloro- 4- trifloro methyl phenols of 2-, yield 35% after removing solvent.
Claims (6)
1. a kind of method of the synthesis chloro- 4- trifloro methyl phenols of 2-, which is characterized in that include the following steps：（1）Oxidation reaction：,
In the reaction vessel, 4- is added（Trifluoromethyl）Benzaldehyde, organic solvent, oxidant, 0 DEG C or more is obtained by the reaction 4-（Fluoroform
Base）Phenol；（2）Halogenation：Under inert gas conditions, in another reaction vessel, halide reagent, organic solvent is added, it is low
Catalyst and step are sequentially added under temperature（1）Obtained 4-（Trifluoromethyl）Phenol is stirred to react to obtain at room temperature the chloro- 4- of 2- tri-
Methyl fluoride phenol.
2. a kind of method of synthesis chloro- 4- trifloro methyl phenols of 2- according to claim 1, which is characterized in that step（1）
In, the oxidant is one kind in metachloroperbenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, benzoyl hydroperoxide, oxidation
Agent and 4-（Trifluoromethyl）The molar ratio of benzaldehyde is（0.1 ~ 10）：1.
3. a kind of method of synthesis chloro- 4- trifloro methyl phenols of 2- according to claim 1, which is characterized in that step（1）
In, the organic solvent is one kind in dichloromethane, chloroform, 1,2- dichloroethanes.
4. a kind of method of synthesis chloro- 4- trifloro methyl phenols of 2- according to claim 1, which is characterized in that step（1）
In, reaction temperature is 0 ~ 40 DEG C.
5. a kind of method of synthesis chloro- 4- trifloro methyl phenols of 2- according to claim 1, which is characterized in that step（2）
In, the halide reagent is one kind in halogen, the hypohalogenous acids tert-butyl ester, N- N-halosuccinimides, halide reagent and 4-（Trifluoro
Methyl）The molar ratio of phenol is（0.1 ~ 10）：1.
6. a kind of method of synthesis chloro- 4- trifloro methyl phenols of 2- according to claim 1, which is characterized in that step（2）
In, the catalyst is one kind in zirconium chloride, copper chloride, stannous chloride, catalyst and 4-（Trifluoromethyl）Phenol rubs
You are at ratio（0.001 ~0.3）：1.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017127371A1 (en) * | 2016-01-21 | 2017-07-27 | Sunnylife Pharma Inc. | Bruton's tyrosine kinase inhibitors |
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2018
- 2018-03-26 CN CN201810253791.7A patent/CN108276254A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017127371A1 (en) * | 2016-01-21 | 2017-07-27 | Sunnylife Pharma Inc. | Bruton's tyrosine kinase inhibitors |
Non-Patent Citations (6)
| Title |
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| EMERSON TEIXEIRA DA SILVA等: "Improved Solvent-Free Dakin Oxidation Protocol", 《SYNTHETIC COMMUNICATIONS》 * |
| HIROO KOYAMA等: "(2R)-2-Methylchromane-2-carboxylic acids: Discovery of selective PPARα agonists as hypolipidemic agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| JOSÉ BARLUENGA等: "Modular Synthesis of Indoles from Imines and o-Dihaloarenes or o-Chlorosulfonates by a Pd-Catalyzed Cascade Process", 《J.AM.CHEM.SOC》 * |
| MARKUS NEUMEYER等: "Controlling the Substitution Pattern of Hexasubstituted Naphthalenes by Aryne/Siloxyfuran Diels–Alder Additions: Regio- and Stereocontrolled Synthesis of Arizonin C1 Analogs", 《EUR.J.ORG.CHEM.》 * |
| QIANG-SHUAIGU等: "Enantioselective Synthesis of (+)-Mitomycin K by a Palladium-Catalyzed Oxidative Tandem Cyclization", 《ANGEW.CHEM.INT.ED.》 * |
| RUHUAI MEI等: "Concise Synthesis of Lamellarin Alkaloids by C–H/N–H Activation: Evaluation of Metal Catalysts in Oxidative Alkyne Annulation", 《SYNLETT》 * |
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