CN107382742A - A kind of new synthetic method of fluorine 4 (trifluoromethyl) anilinechloride of 5 chlorine of fragrance intermediate containing trifluoromethyl 2 - Google Patents
A kind of new synthetic method of fluorine 4 (trifluoromethyl) anilinechloride of 5 chlorine of fragrance intermediate containing trifluoromethyl 2 Download PDFInfo
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- CN107382742A CN107382742A CN201710634979.1A CN201710634979A CN107382742A CN 107382742 A CN107382742 A CN 107382742A CN 201710634979 A CN201710634979 A CN 201710634979A CN 107382742 A CN107382742 A CN 107382742A
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- trifluoromethyl
- synthetic method
- fragrant
- acetyl group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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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
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
Abstract
The invention discloses a kind of new synthetic method of fluorine 4 (trifluoromethyl) anilinechloride of 5 chlorine of fragrant intermediate containing trifluoromethyl 2.Comprise the following steps：1) iodide reaction occurs for the fluoroaniline of 5 chlorine 2 and elemental iodine etc. in ethanol solution；2) using dichloromethane as solvent, obtained fragrant iodo thing is subjected to acetylization reaction；3) under the conditions of 80 DEG C, trifluoromethylation reaction occurs for fragrant iodo thing and fluorosulfonyl methyl difluoroacetate of acetyl group protection etc.；4) finally, carry out deacetylation with 6mol/L hydrochloric acid in ethanol and obtain target product.The present invention has highway route design novelty, good product purity, simple and safe operation；And steady progress, process are easily controlled in a solvent for reaction, crude product impurity is few, is easy to purify, and improves the quality and yield of product.Route total recovery 66%, product purity have higher research and development application value up to 98.5%.
Description
Technical field
The present invention relates to a kind of new synthetic method, is specifically a kind of synthesis chloro- 2- of 5- fluoro- 4- (trifluoromethyl) aniline salt
The midbody compound and its synthetic method of hydrochlorate.
Background technology
Fluorochemical have higher membrane permeability, antimetabolic stability and with the affinity of adipose membrane, heat endurance and
The features such as chemical stability, it is widely used in agricultural chemicals.The high selectivity of fluoro-containing pesticide, high adaptive, high added value, it is low into
Sheet, low toxicity, low-residual, it is environmentally friendly the advantages that, meet the trend of contemporary Agrochemicals.Nearly ten years, it is newly developed in the world
Chemical pesticide in, fluoro-containing pesticide accounting 40% or so, but China production 200 Multiple Pesticides kinds in, upper large-scale production
Fluoro-containing pesticide only accounts for 8% or so, and yields poorly, single varieties, is had a long way to go with the development level of the advanced agricultural chemicals in the world.Fluorine chemistry
Product are the focuses of people's exploitation, and fluoro-containing pesticide is also the focus of people's exploitation.
The chloro- 2- of 5- fluoro- 4- (trifluoromethyl) aniline is a kind of organic centre of fluorine-containing aromatic class with higher application value
Body is production and formulates the key intermediate of some agricultural chemicals.Up to now, only has a patent in Reaxys databases
（EP246061A2,1987）The synthesis of this compound was reported, but this step yield of the method introducing trifluoromethyl is relatively low, is only
20%。
The content of the invention
The purpose of the present invention is in prior art basis, there is provided a kind of new fluoro- 4- of the chloro- 2- of synthesis 5- (trifluoromethyl)
The midbody compound and its synthetic method of anilinechloride, the synthesis are that a kind of method is simple, yield is high, cost is low and product
The synthetic method of the high organic synthesis intermediate of purity, has widened the application of prior art.
In order to solve the above technical problems, the invention provides following technical scheme：
The midbody compound of one kind synthesis chloro- 2- of 5- fluoro- 4- (trifluoromethyl) anilinechloride, has following chemical constitution
Formula：
The present invention is using the chloro- 2- fluoroanilines of 5- as initiation material, through iodo, acetylation protection, trifluoromethylation and deacetylated etc. 4
Step reaction, the chloro- 2- of 5- fluoro- 4- (trifluoromethyl) anilinechloride midbody compound has been obtained with higher yields.Through overtesting
Condition is constantly groped, and this step yield of trifluoromethylation can be up to 78%.
The present invention has positive effect, in terms of being mainly reflected in following four.
1st, it is cheap and easy to get using raw material.
2nd, reaction condition is gentle, simple to operation.
3rd, this method has wide applicability.
4th, the product yield high that method of the invention obtains, purity are high.
Brief description of the drawings
Fig. 1 is the synthetic route chart of the chloro- 2- of 5- fluoro- 4- (trifluoromethyl) anilinechloride
Fig. 2 is the fluoro- 4- Iodoanilines NOE nuclear magnetic spectrograms of the chloro- 2- of 5-.
Fig. 3 isN- (the chloro- 2- of 5- fluoro- 4- (trifluoromethyl) benzene) acetamide1H NMR nuclear magnetic spectrograms.
Embodiment
The present invention is further illustrated with embodiment below, but the present invention is not intended to be limited thereto.
Embodiment 1
In 2 L three-necked flasks, by 68.58 g（270 mmol）Elemental iodine and 83.7 g（270 mmol）Silver sulfate is dissolved in
In 1.5 L ethanol solutions, the stirring of this reaction solution is cooled to 0-5 DEG C.39.15 g（270 mmol）The chloro- 2- fluoroanilines of 5- are fast
Speed is added in this reaction solution, and reaction temperature is maintained at 0 ~ 5 DEG C in adition process, is then slowly increased to room temperature, reacts 1 hr.
TLC（Petrol ether/ethyl acetate=1/8）Track raw material to disappear, add water（250 mL）It is quenched, ethyl acetate extraction（3×250
mL）.The hypo solution of organic phase saturation（35.6%）Washing（3×300 mL）, anhydrous sodium sulfate drying.Remove molten
Agent, crude product（About 80 g）Purified through column chromatography（Gradient elution program：Petroleum ether, petrol ether/ethyl acetate=3/10）, will
Eluant, eluent is placed under normal temperature environment, and evaporation and concentration obtains the g of compound as white solid A 71.7（Yield 98%）.Due in iodo
During iodine position may the ortho position of amino and contraposition react, so obtained product by NOE (400 MHz,
DMSO-d6 correct structure) is verified as, NOE nuclear magnetic spectrograms are shown in Fig. 2.
Embodiment 2
In 2 L three-necked flask, by 54.2 g（200 mmol）Compound A and 55.3 mL（400 mmol）Triethylamine dissolves
In the dichloromethane solution that 1.5 L are dried, the stirring of this reaction solution is cooled to 0-5 DEG C.Sequentially add 17.1 mL（240 mmol）
Chloroacetic chloride is slowly added dropwise in so far reaction solution, and reaction temperature is maintained at 0 ~ 5 DEG C in adition process, is then slowly increased to room temperature,
React 1 hr.TLC（Petrol ether/ethyl acetate=1/10）Track raw material to disappear, add water（250 mL）It is quenched, dichloromethane extraction
（3×200 mL）.Organic phase is washed with saturated nacl aqueous solution（3×200 mL）, anhydrous sodium sulfate drying, evaporation and concentration obtains
The g of compound B white solids 60.0（Yield 96%）.
In 1 L three-necked flask, by 31.3 g（100 mmol）Compound B, the g of HMPA 89.5（500
mmol）With the g of cuprous iodide 29.2（150 mmol）It is dissolved in the dimethyl formamide solution of 0.6 L dryings, in room temperature and nitrogen
Under gas shielded effect, the mL of fluorosulfonyl methyl difluoroacetate 63.6（500 mmol）Slowly it is added dropwise in reaction solution.It is added dropwise
Afterwards, reacting liquid temperature rises to 80 DEG C, reacts 24 hr.TLC（Petrol ether/ethyl acetate=1/10）Track raw material to disappear, question response
Temperature adds the mL of ethyl acetate 300 after being down to room temperature, is filtered, is washed with water by diatomite（3×300 mL）.Organic phase is used
Saturated nacl aqueous solution washs（3×200 mL）, anhydrous sodium sulfate drying, crude product purifies through column chromatography（Gradient elution program：
Petroleum ether, petrol ether/ethyl acetate=1/8）, eluant, eluent is placed under normal temperature environment, evaporation and concentration obtains faint yellow solid
The g of compound C 20（Yield 78%）.1H NMR(400 MHz, DMSO-d6) δ: 2.15 (3 H, s), 7.83 (1 H, d,
J =11.1), 8.45 ~ 8.47 (1 H, m), 10.25(1 H, s).Nuclear magnetic spectrogram is shown in Fig. 3.
Embodiment 3
In 500 mL three-necked flasks, by compound C12.75 g（50 mmol）It is dissolved in 200 mL ethanol solutions, room
The lower mL of hydrochloric acid 100 for adding 6 mol/L of temperature（600 mmol）, reaction solution is heated to reflux 3 hr, is then slowly increased to room temperature.
TLC（Petrol ether/ethyl acetate=1/7）Track raw material to disappear, this reaction solution is concentrated by evaporation at low temperature to obtain brown solid
The g of compound D 11.2（Yield 90%）.1H NMR(400 MHz, DMSO-d6) δ: 6.92 ~7.06 (4 H, m), 7.42 ~
7.50 (1 H, m)。
Claims (4)
1. the midbody compound of one kind synthesis chloro- 2- of 5- fluoro- 4- (trifluoromethyl) anilinechloride, has following chemical constitution
Formula：
The synthetic method of the midbody compound, comprises the following steps：
(i) iodide reaction occurs for the chloro- 2- fluoroanilines of 5- and elemental iodine, obtains corresponding fragrant iodo thing；
(ii) in the presence of triethylamine, fragrant iodo thing and excess acetyl chloride, the fragrant iodo thing of acetyl group protection is obtained；
(iii) fragrant iodo thing, HMPA, cuprous iodide and the fluorosulfonyl difluoroacetic acid first of acetyl group protection
Trifluoromethylation reaction occurs in dimethyl formamide solution for ester, obtains the trifluoromethylation product of acetyl group protection；
(iv) under hydrochloric acid effect deacetylation occurs for the trifluoromethylation product of acetyl group protection, that is, obtains described
Midbody compound.
2. synthetic method according to claim 1, it is characterised in that in step (i), the diiodo reagent be elemental iodine andN-
N-iodosuccinimide（NIS）.
3. synthetic method according to claim 1, it is characterised in that in step (iii), the trifluoromethyl reagent is fluorine sulphur
Acyl group methyl difluoroacetate and fluorosulfonyl ethyl difluoro, additive are HMPA and cuprous iodide.
4. synthetic method according to claim 1, it is characterised in that in step (iv), the deacetylation reagent be hydrochloric acid and
Sulfuric acid.
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|---|---|---|---|
| CN201710634979.1A CN107382742A (en) | 2017-07-30 | 2017-07-30 | A kind of new synthetic method of fluorine 4 (trifluoromethyl) anilinechloride of 5 chlorine of fragrance intermediate containing trifluoromethyl 2 |
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| CN201710634979.1A CN107382742A (en) | 2017-07-30 | 2017-07-30 | A kind of new synthetic method of fluorine 4 (trifluoromethyl) anilinechloride of 5 chlorine of fragrance intermediate containing trifluoromethyl 2 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112174832A (en) * | 2020-10-29 | 2021-01-05 | 阿里生物新材料（常州）有限公司 | Method for synthesizing 5-chloro-2-methyl-4- (trifluoromethyl) aniline in one step |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0246061A2 (en) * | 1986-05-13 | 1987-11-19 | Sumitomo Chemical Company, Limited | A benzoylurea derivative and its production and use |
| CN106488910A (en) * | 2013-10-10 | 2017-03-08 | 亚瑞克西斯制药公司 | Inhibitors of kras g12c |
-
2017
- 2017-07-30 CN CN201710634979.1A patent/CN107382742A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0246061A2 (en) * | 1986-05-13 | 1987-11-19 | Sumitomo Chemical Company, Limited | A benzoylurea derivative and its production and use |
| CN106488910A (en) * | 2013-10-10 | 2017-03-08 | 亚瑞克西斯制药公司 | Inhibitors of kras g12c |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112174832A (en) * | 2020-10-29 | 2021-01-05 | 阿里生物新材料（常州）有限公司 | Method for synthesizing 5-chloro-2-methyl-4- (trifluoromethyl) aniline in one step |
| CN112174832B (en) * | 2020-10-29 | 2022-05-13 | 阿里生物新材料（常州）有限公司 | Method for synthesizing 5-chloro-2-methyl-4- (trifluoromethyl) aniline in one step |
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Application publication date: 20171124 |