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CN111635321A - Fluorinating agent and synthetic method thereof - Google Patents

Fluorinating agent and synthetic method thereof Download PDF

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CN111635321A
CN111635321A CN202010661022.8A CN202010661022A CN111635321A CN 111635321 A CN111635321 A CN 111635321A CN 202010661022 A CN202010661022 A CN 202010661022A CN 111635321 A CN111635321 A CN 111635321A
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fluoride
alpha
fluorinating agent
dichloro
solvent
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CN111635321B (en
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王友杰
刘聪
孙瑞楠
王志强
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Guobang Pharmaceutical Group Co Ltd
Shandong Guobang Pharmaceutical Co Ltd
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Guobang Pharmaceutical Group Co Ltd
Shandong Guobang Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/15—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
    • C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
    • C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
    • C07C22/08—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings containing fluorine
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom

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Abstract

The invention discloses a fluorinating agent and a preparation method thereof, and the fluorinating agent is prepared by reacting amide corresponding to the structural formula of a product with a halogenating agent to obtain corresponding alpha, alpha-dihaloamine and then reacting the alpha, alpha-dihaloamine with fluoride to obtain the corresponding fluorinating agent. The fluorinating agent has the advantages of stable storage, high yield of fluorinated hydroxyl, simple preparation method, easy obtainment of the adopted raw materials, high synthesis yield and high fluorination efficiency of the obtained product.

Description

Fluorinating agent and synthetic method thereof
Technical Field
The invention belongs to the technical field of organic chemical synthesis, also belongs to the technical field of synthesis of veterinary drugs and pharmaceutical raw materials, and relates to a fluorinating agent containing alpha, alpha-difluoroamine and a synthesis method thereof.
Background
Known fluorinating agents for fluorinating alcohols or carbonyl compounds are mainly sulfur tetrafluoride, diethylaminosulfur trifluoride (DAST) and bis (methoxyethyl) aminosulfur trifluoride (methoxy-DAST) (see U.S. Pat. No. 3,976,691, EP-A90448 and EP-A905109).
One disadvantage of the industrial use of sulfur tetrafluoride is its extremely high toxicity, so that corresponding safety measures have to be taken. Diethylaminosulfur trifluoride is explosive and must comply with strict legal regulations, and is a limiting chemical.
Another reagent for the fluorination of secondary alcohols and carboxylic acids is N, N-dimethyl-1, 1-difluorobenzylamine, which can be obtained by reacting N, N-dimethyl-benzamide with sulfur tetrafluoride at 150 ℃, but the range of use of the reagent is limited and only moderate yields can be provided.
Another known fluorinating agent for the fluorination of alcoholic hydroxyl groups is 2-chloro-1, 1, 2-trifluorodiethylamine, known as Yarovenko's reagent. However, the reagent is poorly stable and not suitable for storage and is difficult to prepare.
Another fluorinating agent, known as shichuan reagent, consists of a mixture of hexafluoropropyldialkylamine and pentafluorovinyl-dialkylamine. However, this reagent also has the disadvantages of poor stability, storage inconvenience, difficulty in preparation, and a large number of by-products.
Therefore, it is required to provide a fluorinating agent which has the properties of readily available reaction raw materials, storage stability, high yield of fluorinated hydroxyl groups and the like, and is used for industrial production of organic chemicals.
Disclosure of Invention
The first technical problem to be solved by the invention is as follows: provided is a fluorinating agent which is stable in storage, can fluorinate a hydroxyl group in a high yield, and can satisfy the demand in practical production.
The second technical problem to be solved by the invention is: a method for synthesizing a fluorinating agent is provided. The synthesis method is simple, the adopted raw materials are easy to obtain, the synthesis yield is high, and the fluorination efficiency of the obtained product is high.
The principle of the invention is as follows: the amide with a fluoride structural formula is used as an initial raw material, corresponding alpha, alpha-dichloroamine is obtained after halogenation, and the alpha, alpha-dichloroamine is replaced by hydrogen fluoride to obtain a target product alpha, alpha-difluoroamine.
The process route is as follows:
Figure BDA0002578529630000021
in order to solve the technical problems, the technical scheme of the invention is as follows:
a fluorinating agent having the formula:
Figure BDA0002578529630000022
wherein R is1Is C4-C15Aralkyl or C1-C12Alkyl radical, R2Is C4-C15Aralkyl or C1-C12An alkyl group.
Preferably, said C1-C12Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 1-ethylpropyl, cyclohexyl, cyclopentyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, adamantyl, isomenthyl, n-nonyl, n-decyl and n-dodecylA group;
C4-C15aralkyl includes pyridyl, pyrrolidinyl, morpholinyl and the like.
Further, said R1Is C1-C8Alkyl radical, R2Is C1-C8An alkyl group; more preferably R1Is methyl, ethyl or isopropyl, R2Is methyl, ethyl or isopropyl.
A method for synthesizing a fluorinating agent, comprising the following steps:
a. under the protection of protective gas, amide corresponding to the structural formula of the product reacts with a halogenating agent in a solvent at the temperature of-20-150 ℃ and the reaction pressure of 0.8-20 mpa to obtain alpha, alpha-dihaloamine;
b. under the protection of a protective gas body, the product obtained in the step a and fluoride are reacted under the action of an organic solvent and the reaction pressure of 0.8-30 mpa to obtain the product.
Preferably, the molar ratio of the halogenating agent to the amide in the step a is 0.9: 1-10: 1.
Further, the molar ratio of the halogenating agent to the amide in the step a is 1: 1-2: 1; more preferably 1.02: 1 to 1.5: 1.
Preferably, the halogenating agent in step a is phosphorus pentachloride, phosphorus pentabromide, thionyl chloride, thionyl bromide, phosgene or oxalyl chloride.
Further, in the step a, the halogenating agent is phosphorus pentachloride, thionyl chloride, phosgene or oxalyl chloride.
Preferably, the solvent in step a is gasoline, benzene, toluene, xylene, chlorobenzene, isomeric dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, dioxane, tetrahydrofuran, chloroform or ether; the ether is diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether or ethylene glycol diethyl ether.
Further, the solvent in step a is dichloromethane or chloroform.
The water content of the solvent in step a is 0.2% or less, more preferably 0.05% or less, because the product obtained in step a is very susceptible to hydrolysis.
Preferably, after the reaction in the step a is finished, low-boiling components are removed by distillation, and the product is obtained by drying under high vacuum.
Preferably, the product obtained in step a is 1, 1-dichloromethyl-N, N-dimethylamine, 1-dichloromethyl-N, N-diethylamine, 1-dichloromethyl-N, N-diisopropylamine, 1-dichloro-N, N-2-trimethyl-1-propylamine, 1-dichloro-N, N-2, 2-tetramethyl-1-propylamine, N-diethyl-alpha, alpha-dichloro-2, 2-dimethyl-1-propylamine, N- (1, 1-dichloromethyl) morpholine, N-diethyl-alpha, alpha-dichloro-3-pyridylmethylamine, N-diethyl-alpha, alpha-dichloro-2-pyridylmethylamine or 2, 2-dichloro-1, 3, 3-trimethylpyrrolidine.
Preferably, the fluoride in step b is an ionic fluoride, and the ionic fluoride is one or a mixture of two of quaternary ammonium fluoride and alkali metal fluoride.
Further, in the step b, the ionic fluoride is sodium fluoride, potassium fluoride, cesium fluoride or hydrogen fluoride. More preferably hydrogen fluoride.
Preferably, the molar ratio of the fluoride in the step b to the product obtained in the step a is 0.7-5. Preferably 0.9 to 2, and more preferably 1.1 to 1.7.
Preferably, the organic solvent in step b is a nitrile or an amide, wherein the nitrile includes acetonitrile, propionitrile, benzonitrile and butyronitrile; amides include N, N-dimethylformamide, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, and dimethylimidazolidinone.
Preferably, the reaction temperature in step b is determined according to the boiling point of the selected organic solvent, wherein the boiling point of the organic solvent is selected to be at most 180 ℃, and more preferably at most 110 ℃; the preferred reaction pressure is 1 to 2 mpa.
Preferably, the protective gas in step a and step b is inert gas, nitrogen, carbon dioxide, etc.
Due to the adoption of the technical scheme, the invention has the beneficial effects that:
the synthetic method is simple, the prepared fluorinating agent can be stably stored, and hydroxyl and carbonyl compounds can be converted into corresponding fluorine compounds with high yield;
the raw material of the invention is a bulk reagent, which is easy to obtain, and the fluorination efficiency is high, and the target product can be obtained with high yield.
In a word, the invention provides the fluorinating agent and the synthesis method thereof, and the synthesis method has the advantages of simple process, environmental friendliness, cheap and easily-obtained raw materials, high product yield, strong market competitiveness, stable storage of the synthesized fluorinating agent and good fluorination effect.
Detailed Description
The invention is further illustrated by the following examples.
Example oneAdopting products prepared in step a from different raw materials
1, 1-dichloromethyl-N, N-dimethylamine
A three-necked flask equipped with a precision glass stirrer was initially charged with 14.62g (200mmol) of N, N-dimethylformamide and 130ml of dichloromethane under protective gas at 20 ℃. 26.59g (210mmol) of oxalyl chloride are added dropwise to the reaction mixture, after the addition is complete, the mixture is stirred until no gas evolution takes place and the excess oxalyl chloride and the solvent are evaporated in vacuo. Finally, the vessel was heated in a boiling water bath until the water pump reached full vacuum (10mm Hg, about 2 hours) to obtain a light yellow solid, i.e., 1-dichloromethyl-N, N-dimethylamine, yield: 25.09g (196mmol) 98.00%
1, 1-Dichloromethyl-N, N-diethylamine
A three-necked flask equipped with a precision glass stirrer was initially charged with 10.12g (100mmol) of N, N-diethylformamide and 130ml of dichloromethane under protective gas at 20 ℃. 14.28g (110mmol) of thionyl chloride are added dropwise to the reaction mixture, after the addition is complete, the mixture is stirred until no gas evolution takes place, and the excess thionyl chloride and the solvent are evaporated in vacuo. Finally, the vessel was heated in a boiling water bath until the water pump reached full vacuum (10mm Hg, about 2 hours) to obtain a brown colloid, i.e., 1-dichloromethyl-N, N-diethylamine yield: 15.61g (100mmol) 100%
(iii) 1, 1-Dichloromethyl-N, N-diisopropylamine
12.92g (100mmol) of N, N-diethylformamide and 130ml of methyl tert-butyl ether are initially charged under protective gas at 20 ℃ in a three-necked flask equipped with a precision glass stirrer. 13.96g (110mmol) of oxalyl chloride are added dropwise to the reaction mixture, after the addition is complete, the mixture is stirred until no gas evolution takes place, and the excess oxalyl chloride and the solvent are evaporated in vacuo. Finally, the vessel was heated in a boiling water bath until the water pump reached full vacuum (10mm Hg, about 2 hours) to obtain a dark brown liquid, i.e., 1-dichloromethyl-N, N-diethylamine yield: 12.27g (95mmol) 95.00%
Preparation of 1, 1-dichloro-N, N-2, 2-tetramethyl-1-propylamine
27.8g (210mmol) of N, N-dimethylpivaloamide and 250ml of methyl tert-butyl ether are initially charged in a three-necked flask equipped with a precision glass stirrer under protective gas at 20 ℃. 27.7g (220mmol) of oxalyl chloride were added dropwise to the reaction mixture and a colorless solid precipitated out during the addition. After the addition was complete, the mixture was stirred until no gas evolved (about 2 hours) and the mixture was heated to 40 ℃ for 0.5 hours. After distillation of the low-boiling components under high vacuum, colorless 1, 1-dichloro-N, N-2, 2-tetramethyl-1-propylamine was obtained in yield: 38.0g (202mmol) 96.00%.
Preparation of N, N-diethyl-alpha, alpha-dichloro-3-pyridylmethylamine
18.5g (104mmol) of N, N-diethylnicotinamide and 150ml of methyl tert-butyl ether are initially charged under protective gas at 20 ℃ in a three-necked flask equipped with a precision glass stirrer. 13.5g (106mmol) of oxalyl chloride were added dropwise to the reaction mixture and a colorless solid precipitated out during the addition. After the addition was complete, the mixture was stirred to 20 ℃ for 1 hour and heated to reflux for an additional 4 hours. After cooling to 20 ℃, the solvent was removed under vacuum and the remaining residue was washed with a small amount of cold diethyl ether. After drying under high vacuum, N-diethyl- α, α -dichloro-3 pyridylmethylamine was obtained as a pale yellow solid in yield: 22.9g (98.8 mmol; 95.00%).
Example twoFluoro products prepared from the above different chloro products
Preparation of 1, 1-difluoromethyl-N, N-dimethylamine
A high-pressure vessel was initially charged with 10g (64mmol) of 1, 1-dichloromethyl-N, N-dimethylamine under protective gas, cooled to 0 ℃ and then 5.6ml (320mmol) of HF were added and the mixture was stirred at 0 ℃ for 3 hours with stirring. After completion of the reaction, excess HF and HCl which had formed were removed under high vacuum and the product was distilled off in absolute water as a pale yellow liquid in a yield of 75%.
Preparation of 1, 1-difluoromethyl-N, N-diethylamine
A high-pressure vessel was initially charged with 10g (64mmol) of 1, 1-dichloromethyl-N, N-dimethylamine under protective gas, cooled to 0 ℃ and then 5.6ml (320mmol) of HF were added and the mixture was stirred at 0 ℃ for 5 hours with stirring. After completion of the reaction, excess HF and HCl which had formed were removed under high vacuum and the product was distilled off in absolute water as a pale yellow liquid in a yield of 75%.
Preparation of 1, 1-difluoromethyl-N, N-diisopropylamine
A polyethylene flask was charged with 10.4g (68.9mmol) of 1, 1-dichloromethyl-N, N-diisopropylamine under a protective gas atmosphere, cooled to 0 ℃ and 6.03g (344.5mmol) of HF added and the mixture stirred at 0 ℃ for 8 h. After completion of the reaction, excess HF and HCl which had formed were removed under high vacuum and 8.02g (53mmol) of the product was distilled off under absolute water as a pale yellow liquid in 77% yield.
Preparation of 1, 1-difluoro-N, N-2, 2-tetramethyl-1-propylamine
A polyethylene flask was charged with 12.99g (68.90mmol) of 1, 1-dichloromethyl-N, N-diisopropylamine under a protective gas atmosphere, cooled to 0 ℃ and 6.03g (344.5mmol) of HF added and the mixture stirred at 0 ℃ for 8 h. After completion of the reaction, excess HF and HCl formed were removed under high vacuum and 8.24g (53.05mmol) of the product was distilled off under absolute water as a pale yellow liquid in 77% yield
Preparation of N, N-diethyl-alpha, alpha-dichloro-3-pyridylmethylamine
17.8g (424mmol) of sodium fluoride are added under protective gas to a suspension of 19.5g (107mmol) of 1, 1-dichloro-N, N-2, 2-tetramethyl-1-propylamine, 75ml of dimethylimidazolidinone are added and stirring is carried out at 20 ℃ for 25 h. The inorganic salts are filtered off under a protective gas atmosphere and washed twice with 20ml of dimethylimidazolidinone each time. The crude product was distilled and condensed from the reaction solution under high vacuum to a low temperature receiver to give 1, 1-difluoro-N, N-2, 2-tetramethyl-1-propylamine as a pale yellow liquid. Yield: 13.6g (90 mmol; 84%).
EXAMPLE IIIPractical application of fluorinating agent 1, 1-difluoromethyl-N, N-dimethylamine of the invention
A solution of 5.99g (63mmol) of 1, 1-difluoromethyl-N, N-dimethylamine is initially introduced under protective gas. 7.32g (60mmol) of a-phenylethyl alcohol was added to 30ml of chloroform, and then the mixture was added dropwise to a system of 1, 1-difluoromethyl-N, N-dimethylamine, and the mixture was heated to 60 ℃ and stirred for 6.0 hours. After the reaction has ended, the mixture is cooled to 20 ℃ and 100ml of ice-water are added, each time with 50ml of CHCl3The aqueous phase was extracted twice. The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated. The residue was subsequently distilled to yield 6.30g (50.80 mmol; 85%) of 1-fluoroethylbenzene.
TABLE 1 reaction of different alcohols or aldehydes with 1, 1-difluoromethyl-N, N-dimethylamine
Figure BDA0002578529630000071
Example fourPractical application of fluorinating agent 1, 1-difluoromethyl-N, N-diethylamine
Firstly, a solution of 7.76g (63mmol) of 1, 1-difluoromethyl-N, N-dimethylamine is added under protective gas, 7.32g (60mmol) of α -phenethyl alcohol is added into 30ml of chloroform, then the mixed solution is dripped into a system of 1, 1-difluoromethyl-N, N-dimethylamine, the mixture is heated to 80 ℃ and stirred for 7.0h, after the reaction is finished, the mixture is cooled to 20 ℃, 100ml of ice water is added, 50ml of CHCl is used for each time3The aqueous phase was extracted twice. Combined organic phasesThrough anhydrous Na2SO4Dried, filtered and concentrated. The residue was subsequently distilled to yield 6.30g (50.80 mmol; 88%) of 1-fluoroethylbenzene.
TABLE 2 reaction of different alcohols or aldehydes with the product 1, 1-difluoromethyl-N, N-diethylamine
Figure BDA0002578529630000081
EXAMPLE fivePractical application of fluorinating agent 1, 1-difluoromethyl-N, N-diisopropylamine
9.51g (63mmol) of a solution of 1, 1-difluoromethyl-N, N-diisopropylamine are initially introduced under a protective gas atmosphere 7.32g (60mmol) of α -phenylethyl alcohol are added to 30ml of chloroform, the mixture is then added dropwise to a system of 1, 1-difluoromethyl-N, N-diisopropylamine and the mixture is heated to 80 ℃ and stirred for 10.0h, after the reaction has ended, the mixture is cooled to 20 ℃ and 100ml of ice water are added, each time with 50ml of CHCl3The aqueous phase was extracted twice. The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated. The residue was subsequently distilled to yield 6.45g (52 mmol; 87%) of 1-fluoroethylbenzene.
TABLE 3 results of the reaction of different alcohols or aldehydes with 1, 1-difluoromethyl-N, N-diisopropylamine
Figure BDA0002578529630000082
Figure BDA0002578529630000091
EXAMPLE sixPractical application of fluorinating agent N, N-diethyl- α -dichloro-3-pyridylmethylamine
Firstly, 12.60g (63mmol) of N, N-diethyl- α -dichloro-3-pyridylmethylamine solution is added under a protective gas atmosphere, 7.32g (60mmol) of α -phenethyl alcohol is added to 30ml of chloroform, then the mixture is added dropwise to a system of N, N-diethyl- α -dichloro-3-pyridylmethylamine, and the mixture is heated to 80 ℃ and stirred for 6.0hAfter this time, the mixture was cooled to 20 ℃ and 100ml of ice-water were added, each time with 50ml of CHCl3The aqueous phase was extracted twice. The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated. The residue was subsequently distilled to yield 6.45g (52 mmol; 92%) of 1-fluoroethylbenzene.
TABLE 4 results of reaction of various alcohols or aldehydes with 1, 1-difluoromethyl-N, N-diisopropylamine
Figure BDA0002578529630000092
To summarize:
through the embodiments, the fluorinating agent has wide raw material sources, the preparation method is simple and easy to operate, the obtained fluorinating agent has better fluorination effect on different alcohols and aldehydes, the fluorination efficiency is basically more than 80 percent, the yield is relatively higher, and the corresponding amide of the fluorinating agent is obtained after the subsequent fluorination, can be recycled, reduces the generation of hazardous wastes in the industrial production, and meets the requirement of green production.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.

Claims (10)

1. A fluorinating agent, characterized by the following structural formula:
Figure FDA0002578529620000011
wherein R is1Is C4-C15Aralkyl or C1-C12Alkyl radical, R2Is C4-C15Aralkyl or C1-C12An alkyl group.
2. Fluorination as claimed in claim 1An agent characterized by: said C is1-C12Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 1-ethylpropyl, cyclohexyl, cyclopentyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, adamantyl, isomeryl menthyl, n-nonyl, n-decyl and n-dodecyl; said C is4-C15Aralkyl includes pyridyl, pyrrolidinyl, morpholinyl.
3. A fluorinating agent according to claim 2, wherein: the R is1Is C1-C8Alkyl radical, R2Is C1-C8An alkyl group.
4. A fluorinating agent according to claim 3, wherein: the R is1Is methyl, ethyl or isopropyl, R2Is methyl, ethyl or isopropyl.
5. A process for the synthesis of a fluorinating agent according to claim 1, wherein: the method comprises the following steps:
a. under the protection of protective gas, amide corresponding to the structural formula of the product reacts with a halogenating agent in a solvent at the temperature of-20-150 ℃ and the reaction pressure of 0.8-20 mpa to obtain alpha, alpha-dihaloamine;
b. and c, under the protection of protective gas, reacting the product obtained in the step a with fluoride under the action of an organic solvent and the reaction pressure of 0.8-30 mpa to obtain the product.
6. A process for the synthesis of a fluorinating agent according to claim 5, wherein: the molar ratio of the halogenating agent to the amide in the step a is 0.9: 1-10: 1; the halogenating agent is phosphorus pentachloride, phosphorus pentabromide, thionyl chloride, thionyl bromide, phosgene or oxalyl chloride; the solvent is gasoline, benzene, toluene, xylene, chlorobenzene, isomeric dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, dioxane, tetrahydrofuran, chloroform or ether; wherein the ether is diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether or ethylene glycol diethyl ether; the water content of the solvent is 0.2% or less.
7. A process for the synthesis of a fluorinating agent according to claim 6, wherein: the molar ratio of the halogenating agent to the amide in the step a is 1: 1-2: 1; the halogenating agent is phosphorus pentachloride, thionyl chloride, phosgene or oxalyl chloride; the solvent is dichloromethane or chloroform; the water content of the solvent is 0.05% or less.
8. A process for the synthesis of a fluorinating agent according to claim 5, wherein: the product obtained in the step a is 1, 1-dichloromethyl-N, N-dimethylamine, 1-dichloromethyl-N, N-diethylamine, 1-dichloromethyl-N, N-diisopropylamine, 1-dichloro-N, N-2-trimethyl-1-propylamine, 1-dichloro-N, N-2, 2-tetramethyl-1-propylamine, N-diethyl-alpha, alpha-dichloro-2, 2-dimethyl-1-propylamine, N- (1, 1-dichloromethyl) morpholine, N-diethyl-alpha, alpha-dichloro-3-pyridylmethylamine, N-diethyl-alpha, alpha-dichloro-2-pyridylmethylamine or 2, 2-dichloro-1, 3, 3-trimethylpyrrolidine.
9. A process for the synthesis of a fluorinating agent according to claim 5, wherein: the fluoride in the step b is ionic fluoride which is one or a mixture of two of quaternary ammonium fluoride and alkali metal fluoride; the molar ratio of the fluoride to the product obtained in the step a is 0.7-5; the organic solvent is nitrile or amide; the reaction temperature is determined according to the boiling point of the selected organic solvent; the reaction pressure is 1-2 mpa.
10. A process for the synthesis of a fluorinating agent according to claim 9, wherein: in the step b, the ionic fluoride is sodium fluoride, potassium fluoride, cesium fluoride or hydrogen fluoride; the molar ratio of the fluoride to the product obtained in the step a is 0.9-2; nitriles include acetonitrile, propionitrile, benzonitrile and butyronitrile; amides include N, N-dimethylformamide, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, and dimethylimidazolidinone.
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