阅读说明：本技术 一种脱氧氟化试剂的制备方法 (Preparation method of deoxidation fluorination reagent ) 是由 周晓聪 胡金波 严普查 李原强 刘仁湘 何鑫奕 郑人杰 陈邦鑫 华允宇 于 2020-05-26 设计创作，主要内容包括：本发明属于有机合成领域,具体涉及一种脱氧氟化试剂的制备方法。本发明提供的N-甲苯磺酰基-4-氯苯磺酰亚胺氟的制备方法,以对氯苯磺酰氯为原料,经一锅法先制备得到N-甲苯磺酰基-4-氯苯磺酰亚胺氯,后与氟化钾等反应制备得到N-甲苯磺酰基-4-氯苯磺酰亚胺氟。本发明是一锅法合成,操作简便,收率高,是一种非常经济且适于工业化生产的制备方法。(The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a deoxygenation fluorination reagent. The invention provides a preparation method of N-tosyl-4-chlorobenzenesulfonyl imidofluoride, which comprises the steps of firstly preparing N-tosyl-4-chlorobenzenesulfonyl imidofluoride by using p-chlorobenzenesulfonyl chloride as a raw material through a one-pot method, and then reacting with potassium fluoride and the like to prepare the N-tosyl-4-chlorobenzenesulfonyl imidofluoride. The invention is a one-pot synthesis method, has simple and convenient operation and high yield, and is a preparation method which is very economical and suitable for industrial production.)

1. A preparation method of N-tosyl-4-chlorobenzenesulfonyl imide chloride is characterized in that p-chlorobenzenesulfonyl chloride is used as a raw material and is prepared by a one-pot reaction, other raw materials which are sequentially added in the one-pot reaction process are sodium salts, acid, sulfoxides and chloramines,

wherein Ts is p-toluenesulfonyl.

2. A preparation method of N-tosyl-4-chlorobenzenesulfonyl imide chloride is characterized in that p-chlorobenzenesulfonyl chloride is used as a raw material and is prepared by a one-pot reaction, wherein other raw materials which are sequentially added in the one-pot reaction process are sodium sulfite, sodium bicarbonate, hydrochloric acid, thionyl chloride and chloramine T,

3. the method for producing N-toluenesulfonyl-4-chlorobenzenesulfonylimide chloride according to claim 1 or 2, wherein the starting material is THF mixed solution of p-chlorobenzenesulfonyl chloride.

4. The method for producing N-toluenesulfonyl-4-chlorobenzenesulfonylimide chloride according to claim 1 or 2, comprising the step of adding hydrochloric acid to the aqueous phase after the reaction of the THF mixture of p-chlorobenzenesulfonyl chloride with sodium hydrogencarbonate and sodium sulfite is completed.

5. The method according to claim 1 or 2, wherein the step of reacting with chloramine T is carried out at a temperature of 30 to 60 ℃.

6. The method according to claim 5, wherein the reaction temperature is 30 to 35 ℃.

7. A process for producing N-toluenesulfonyl-4-chlorobenzenesulfonylimide fluoride which comprises fluorinating N-toluenesulfonyl-4-chlorobenzenesulfonylimide chloride produced by the process according to claim 1 or 2,

8. the method of claim 7, wherein the fluorinating agent is potassium fluoride, cesium fluoride, silver fluoride, or ammonium fluoride.

9. A process for producing N-toluenesulfonyl-4-chlorobenzenesulfonylimide fluoride which comprises reacting N-toluenesulfonyl-4-chlorobenzenesulfonylimide chloride produced in claim 1 or 2 with potassium fluoride and 18-crown-6.

10. The method of claim 7,8 or 9, wherein the post-treatment comprises rinsing with water to obtain the product N-tosyl-4-chlorobenzenesulfonylimidofluoride.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a deoxygenation fluorination reagent.

Background

Research of medicinal chemists finds that introduction of fluorine atoms or fluorine-containing groups into medicinal molecules can effectively change the pKa value, permeability, metabolic stability and lipid solubility of the medicinal molecules and influence in-vivo absorption, distribution, metabolism and interaction with biological targets of the medicinal molecules. Thanks to the development of many fluorination reagents and the discovery of fluorination reactions with good functional group compatibility, the research field of fluorine-containing drugs has been rapidly developed in recent decades. Many new drugs in clinical phase or those already on the market or those that have been on the market for many years also contain fluorine atoms. Such as: iflutinib, flumatinib, roflumilast, levofloxacin, fulvestrant and the like. In 2018, 18 fluorine-containing medicines in 38 small-molecule medicines approved by the FDA in the United states occupy Jiangshan in the middle half of the United states. Thus, chemists have developed an increasing number of fluorination processes to synthesize them. Among them, because of the abundance of natural and synthetic alcohols, deoxofluorination becomes a very attractive synthetic route.

The deoxidation and fluorination refers to that hydroxyl in an alcohol compound is substituted by fluorine atoms to prepare alkyl fluoride, the mechanism of the preparation is that the alcohol hydroxyl attacks a fluorination reagent to leave fluorine anions, meanwhile, O atoms are converted into a part of leaving groups, and then the fluorine anions attack C-O bonds through nucleophilic attack to realize the deoxidation and fluorination process.

The N-tosyl-4-chlorobenzenesulfonyl imido fluoride is a deoxidizing fluorinating reagent with good stability, strong reactivity and good application prospect. The use of this deoxofluorination reagent is disclosed in Journal literature European Journal 2019 (10.1002/chem.201901176). The reaction formula is as follows:

the journal literature and patent literature CN107245023A further disclose a preparation method of the deoxygenating and fluorinating reagent, which comprises reacting chlorobenzenesulfonyl chloride as a raw material with sodium sulfite, thionyl chloride and chloramine T to obtain N-toluenesulfonyl-4-chlorobenzenesulfonylimide chloride, and then reacting with potassium fluoride to obtain N-toluenesulfonyl-4-chlorobenzenesulfonylimide fluoride. The reaction formula is as follows:

in consideration of the wide application prospect of the N-tosyl-4-chlorobenzenesulfonylimide fluoride, the invention develops a preparation method of the deoxidation fluorination reagent.

Disclosure of Invention

The invention provides a preparation method of N-tosyl-4-chlorobenzenesulfonyl imidofluoride, which is synthesized by a one-pot method, has simple and convenient operation and high yield, and is a preparation method which is very economical and suitable for industrial production.

The invention provides a preparation method of a deoxidation fluorination reagent, namely N-tosyl-4-chlorobenzenesulfonyl imine fluoride. In order to realize the technical purpose of the invention, the technical scheme provided by the invention is as follows:

the invention firstly provides a preparation method of N-tosyl-4-chlorobenzenesulfonyl imide chloride. The p-chlorobenzene sulfonyl chloride is used as a raw material and is prepared by a one-pot reaction. The reaction formula is as follows:

wherein Ts is p-toluenesulfonyl.

In the one-pot reaction process, other raw materials required to be added are sodium salts, acids, sulfoxides, chloroamines and the like. The sodium salt can be sodium bicarbonate, sodium sulfite and the like; the acid may be hydrochloric acid; the sulfoxide can be thionyl chloride; the chloramines can be chloramine-T and the like. The reaction formula is as follows:

more preferably, the one-pot reaction process of the invention comprises the following steps:

the N-tosyl-4-chlorobenzenesulfonylimide chloride is prepared by salifying and acidifying p-chlorobenzenesulfonyl chloride, and reacting with thionyl chloride and chloramine T.

In the reaction step of the one-pot method of the present invention, the reaction temperature with chloramine T is 30 to 60 ℃, and preferably 30 to 35 ℃.

In another aspect, the invention provides a method for preparing N-tosyl-4-chlorobenzenesulfonylimidofluoride. The N-tosyl-4-chlorobenzenesulfonyl imide chloride prepared by the method is prepared by fluorination reaction. The reaction formula is as follows:

the fluorinating agent may be potassium fluoride, cesium fluoride, silver fluoride, ammonium fluoride, or the like.

The invention provides a preparation method of N-tosyl-4-chlorobenzenesulfonyl imidofluoride, which comprises the steps of firstly preparing N-tosyl-4-chlorobenzenesulfonyl imidofluoride by using p-chlorobenzenesulfonyl chloride as a raw material through a one-pot method, and then reacting with potassium fluoride and the like to prepare the N-tosyl-4-chlorobenzenesulfonyl imidofluoride.

The preparation method of the invention has the following advantages and effects: 1. the preparation method in the prior art has the problem of overlong reaction time during batch amplification reaction. Compared with the preparation method in the prior art, the preparation method has the advantages that the consumption of the dissolving reagent is greatly reduced, and the preparation method is more economical and suitable for industrial production. 3. Compared with the preparation method in the prior art, the preparation method provided by the invention has the advantages that the yield of the prepared product (the deoxidation fluorination reagent) is greatly improved, and the preparation method has a remarkable technical effect. 4. The method is an operation step of a one-pot method in the preparation of the amino-substituted sulfonyl chloride, namely the N-tosyl-4-chlorobenzenesulfonyl imide chloride, and is simple and convenient to operate. 5. In the preparation of the final product of the imido-sulfinyl fluoride, column chromatography purification is not needed in post-treatment, the product can be separated by adding water, and the yield is higher.

Detailed Description

In order to further understand the present invention, the following examples are provided to illustrate the preparation method of a deoxofluorination reagent of the present invention. It is to be understood that these examples are described merely to illustrate the features of the present invention in further detail, and not as limitations of the invention or of the scope of the claims appended hereto.

Example 1:

A2L four-necked round bottom flask was charged with 141.12g (2.0eq) of sodium bicarbonate, 105.87g (1.0eq) of sodium sulfite and 900mL of water, and 177.6g of p-chlorobenzenesulfonyl chloride in THF was added dropwise thereto, followed by reaction TLC to complete the reaction. Standing, adding 300mL of MTBE (methyl tert-butyl ether), extracting and separating liquid, taking a water phase, and dropwise adding 144mL of concentrated HCl into the water phase; 1.2L of DCM (dichloromethane) was added to the reaction solution, and after stirring, the organic phase was extracted, dried over anhydrous magnesium sulfate, filtered under suction and used directly in the next reaction.

Example 2:

placing the reaction solution in the previous step into a 3L four-mouth round-bottom flask, a constant pressure dropping funnel, and N₂Protection, tail gas absorption device and ice salt bath cooling. 134.9g (1.5eq) of thionyl chloride are added dropwise; after the reaction, the reaction mixture was concentrated by distillation under reduced pressure to obtain 461.4g of a yellow-green solution, which was used directly in the next reaction.

Example 3:

preparing a 2L four-mouth round-bottom flask, a thermometer and nitrogen protection; sequentially adding 224.1g (1.17eq) of chloramine T into a flask, adding 1120mL of toluene, adding a water bath to control the internal temperature to be 32-35 ℃, dropwise adding the toluene solution of the reaction solution prepared in the example 2, and maintaining the internal temperature to be 30-40 ℃ in the dropwise adding process after dropwise adding; TLC monitored the reaction complete and left to stand overnight at room temperature. Carrying out suction filtration and leaching with toluene twice; water diversion and water removal; the mixture was concentrated by distillation under reduced pressure and filtered by suction to obtain 220.84g of a white granular solid, which was N-toluenesulfonyl-4-chlorobenzenesulfonylimide chloride. The total yield of the one-pot reaction is calculated to be 72.3%.

Example 4:

preparing a 2L three-mouth round-bottom flask, a reflux pipe and a thermometer, and drying for later use; n is a radical of₂Under protection, 220.84g (0.606mol) of N-tosyl-4-chlorobenzenesulfonylimide chloride, 1500mL of acetonitrile, 70.5g (1.21mol) of KF and 3.21g (0.0121mol) of 18-crown-6 are sequentially added into a flask, stirred in an oil bath at a constant temperature of 45 ℃, and concentrated by reduced pressure distillation; addition of H₂O, stirring, filtering, leaching twice to obtain 289g of white crystalline solid, putting the white crystalline solid in a reduced-pressure oven overnight, weighing 206g, and obtaining the reaction yield of 97.9%.

Example 5:

the N-tosyl-4-chlorobenzenesulfonylimide chloride can be prepared by repeating the process in the patent CN 10724023, in particular the process in the embodiment I-2, and in particular the reaction of the N-tosyl-4-chlorobenzenesulfonylimide chloride on a small scale, and when the reaction is amplified in batches, the reaction time is long. The invention well solves the problem of long reaction time during batch amplification and has obvious technical effect.