Preparation method of carbonyl fluoride and research on in-situ conversion of carbonyl fluoride into carbamyl fluoride

Abstract

The invention discloses a preparation method of carbonyl fluoride and a research result of in-situ conversion of carbonyl fluoride into carbamyl fluoride. The method comprises the following steps: in a nitrogen atmosphere, sequentially adding pyridine nitrogen oxide, secondary amine, a difluorocarbene precursor and an activating reagent thereof into a reaction solvent to obtain a mixture; wherein the difluorocarbene precursor and the activating reagent thereof are a combination of trifluoromethyltrimethylsilane (Ruppert-Prakash reagent) and sodium iodide or trimethylsilyl 2-(fluorosulfonyl) difluoroacetate (aged reagent) and sodium fluoride, stirring the mixture at 60 DEG C until the reaction is finished, and then adding a catalyst to obtain the difluorocarbene. And carrying out silica gel column chromatography separation on the crude product obtained by the reaction to obtain the carbamyl fluoride compound. The preparation method disclosed by the invention can be carried out under mild conditions and is simple and convenient to operate (high-toxicity carbonyl fluoride gas does not need to be directly used, and carbonyl fluoride is generated in situ in a reaction system by oxidizing difluorocarbene by pyridine nitrogen oxide), most of the adopted raw materials are simple, easy-to-obtain and commercialized reagents, the reaction cost is relatively low, and the method is suitable for industrial production. The method has the advantages of simple operation, good functional group compatibility and wide substrate application range (can be directly used for later derivatization research of some drug molecules), the obtained carbamyl fluoride compound contains fluorine and various functional groups such as amide, and it is predicted that the method has wide application prospects in the fields of drug research and development, life science and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and in particular relates to a method for in-situ generating carbonyl fluoride by oxidizing difluorocarbene and research on the subsequent conversion of the carbonyl fluoride into carbamoyl fluoride compounds. Background Art

[0002] Carbonyl fluoride is an irritating, colorless, toxic gas that can be used as a cleaning gas and etching gas for semiconductor manufacturing equipment. However, the preparation, storage and use of carbonyl fluoride are relatively troublesome to operate, thus greatly limiting its practical application in organic synthetic chemistry. In the past, the methods for generating carbonyl fluoride mainly include carbon monoxide electrofluorination, direct fluorination of carbon monoxide or carbon dioxide with fluorine gas, carbon monoxide and metal fluoride reaction, phosgene as raw material preparation of fluorophosgene method, and carbonyl fluoride synthesis method using fluorine-containing small molecules (fluoroform, chlorodifluoromethane or tetrafluoroethylene) as raw materials. There are very few studies on the generation of carbonyl fluoride using the method of oxidizing difluorocarbene. In addition, carbamoyl fluoride compounds, as a class of compounds containing fluorine atoms and amide functional groups at the same time, usually have unique physical and chemical properties and biological activity, and their related research has huge potential application value in the fields of new functional material development, drug research and development, and organic synthetic chemistry. Therefore, the preparation of carbamoyl fluoride compounds has received more and more widespread attention in recent years.

[0003] At present, the preparation of carbamoyl fluoride compounds mainly relies on halogen-fluorine exchange, reactions involving fluorophosgene or in-situ generated fluorophosgene, and other reactions without the participation of carbonyl fluoride, which will be explained below with examples. For example, reference 1 ( P.;Eisner, A.; L.;Weidlich, T.;Pejchal, V.; A. Tetrahedron Lett. 2008, 49, 6320) disclosed a method in which a carbamoyl chloride compound 1 and a fluorinating agent 2 are refluxed in toluene for 12 hours to obtain a corresponding carbamoyl fluoride compound at a conversion rate of 30% through chlorine-fluorine exchange. The specific reaction process is shown in the following formula:

[0004]

[0005] In the method disclosed in document 2 (Fawcett, FS; Tullock, CW; Coffman, DDJAm. Chem. Soc. 1962, 84, 4275), azadifluoroolefin can react with carbonyl fluoride in the presence of a catalytic amount of cesium fluoride at 150°C to produce N,N-ditrifluoromethylfluoroformamide. The specific reaction process is shown in the following formula:

[0006]

[0007] In the method disclosed in Document 3 (Song, H.-X.; Hah, Z.-Z.; Zhang, C.-P. Chem. Eur. J. 2019, 25, 10907), a secondary amine and trifluoromethyl trifluoromethanesulfonate can react rapidly in an acetonitrile solution at room temperature to generate carbamoyl fluoride compounds. The trifluoromethoxy anion formed by the reaction of the secondary amine with trifluoromethyl trifluoromethanesulfonate can generate carbonyl fluoride in situ by fluorine elimination. The specific reaction process is shown in the following formula:

[0008]

[0009] In the method disclosed in document 4 (Baars, H.; Engel, J.; Mertens, L.; Meister, D.; Bolm, C. Adv. Synth. Catal. 2016, 358, 2293), hydroxylamine and sodium bromodifluoroacetate are heated to 95° C. in a DMF solution to prepare carbamoyl fluoride compounds. It should be pointed out that the author speculates that the reaction undergoes a rearrangement process and does not involve the formation of carbonyl fluoride. The specific reaction process is shown in the following formula:

[0010]

[0011] In the method disclosed in document 5 (Onida, K.; Tlili, A. Angew. Chem. Int. Ed. 2019, 58, 12545), in a carbon dioxide atmosphere, secondary amines, diethylaminosulfur trifluoride (DAST) and 4-dimethylaminopyridine dissolved in acetonitrile interact to generate carbamoyl fluoride compounds, wherein the carbonyl group in the formyl fluoride functional group comes from carbon dioxide, and the fluorine comes from DAST. The specific reaction process is shown in the following formula:

[0012]

[0013] In the method disclosed in Document 6 (Song, JW; Lim, HN Org. Lett. 2021, 23, 5394), under mild reaction conditions, oxime derived from methyl amide ketone and diethylamino sulfur trifluoride (DAST) undergo selective fluorination Beckmann rearrangement to generate carbamoyl fluoride compounds. The specific reaction process is shown in the following formula:

[0014]

[0015] In the method disclosed in document 7 (Taponard, A.; Jarrosson, T.; Khrouz, L.; Médebielle, M.; Broggi, J.; Tlili, A. Angew. Chem. Int. Ed. 2022, 61, e202204623), the Tlili research group developed a new fluorination reagent and used it to replace diethylaminosulfur trifluoride (DAST), realizing the conversion of secondary amines, 4-dimethylaminopyridine and carbon dioxide as raw materials to prepare carbamoyl fluoride compounds. The specific reaction process is shown in the following formula:

[0016]

[0017] However, these strategies all have some shortcomings, such as the relatively difficult synthesis of starting materials, complex operations, limited substrate applicability, and the use of explosive reagents (DAST). Therefore, it is still of great significance to develop simple, convenient and practical new strategies for the preparation of carbamoyl fluoride compounds. Such research is expected to play a significant role in organic synthesis and drug development. Summary of the invention

[0018] The primary purpose of the present invention is to provide a novel in-situ preparation method of carbonyl fluoride and its application research case in the synthesis process of carbamoyl fluoride compounds, aiming to solve the problems existing in the existing synthesis methods of carbamoyl fluoride compounds, such as the difficulty in synthesizing starting materials, complex operations, limited application range of substrates, and the use of explosive reagents.

[0019] Another object of the present invention is to provide other related applications of the above-mentioned carbamoyl fluoride compounds and the carbonyl fluoride formed in situ by the difluorocarbene oxidation strategy.

[0020] The present invention is achieved by providing a carbamoyl fluoride compound, the chemical structure of which is shown in the following formula (I):

[0021]

[0022] In formula (I), R 1 benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-trifluoromethylbenzyl, α-naphthylmethyl, diphenylmethylene, pyridine-3-methylene, pyridine-4-methylene, 2-ethoxyethyl, methylenecarboxylic acid ethyl ester, allyl, cyclic hydrocarbon group, substituted cyclic hydrocarbon group, indanyl, desloratadine, paroxetine, amoxapin and other drug molecule fragments and other alkyl or functionalized alkyl groups;

[0023] R 2It is methyl, ethyl, benzyl, isopropyl, trimethylsilylmethylene, allyl, 2-ethoxyethyl, methylenecarboxylic acid ethyl ester, cyclic hydrocarbon group, substituted cyclic hydrocarbon group, indanyl group, desloratadine, paroxetine, amoxapin and other drug molecular fragments and other alkyl or functionalized alkyl groups;

[0024] The present invention further discloses a method for preparing the above-mentioned carbamoyl fluoride compound, which comprises the following steps:

[0025] (1) Under a nitrogen atmosphere, an oxidant, a secondary amine, a difluorocarbene precursor and an activator are sequentially added to a reaction solvent in a molar ratio of (1.0-5.0):1.0:(1.0-5.0):(1.0-5.0) to obtain a mixture; wherein the oxidant is pyridine-N-oxide or other suitable oxidants, the difluorocarbene precursor is trifluoromethyltrimethylsilane, trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (Chen's reagent) or other suitable difluorocarbene precursors, and the activator is sodium iodide, sodium fluoride or other activating agents.

[0026] (2) The mixture of step (1) is stirred at a suitable temperature until the reaction is complete, and the crude reaction product is separated by short silica gel column chromatography to obtain the desired carbamoyl fluoride compound.

[0027] Preferably, in step (1), the secondary amine is R 1 and / or R 2 Amine compounds substituted with a group; wherein R 1 benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-trifluoromethylbenzyl, α-naphthylmethyl, diphenylmethylene, pyridine-3-methylene, pyridine-4-methylene, 2-ethoxyethyl, methylenecarboxylic acid ethyl ester, allyl, cyclic hydrocarbon group, substituted cyclic hydrocarbon group, indanyl, desloratadine, paroxetine, amoxapin and other drug molecule fragments and other alkyl or functionalized alkyl groups;

[0028] R 2 It is methyl, ethyl, benzyl, isopropyl, trimethylsilylmethylene, allyl, 2-ethoxyethyl, methylenecarboxylic acid ethyl ester, cyclic hydrocarbon group, substituted cyclic hydrocarbon group, dihydroindanyl, desloratadine, paroxetine, amoxapin and other drug molecule fragments and other alkyl or functionalized alkyl groups.

[0029] Preferably, in step (1), the reaction solvent is acetonitrile; in step (2), the mixture is stirred at 60 degrees Celsius for 12 hours or 1 hour.

[0030] The present invention further discloses a method for producing carbonyl fluoride by in-situ oxidation of difluorocarbene produced by a difluorocarbene precursor and an activator with a suitable oxidant and subsequent conversion applications thereof, such as the synthesis of carbamoyl fluoride compounds.

[0031] The present invention overcomes the shortcomings of the prior art and provides a method for preparing carbonyl fluoride and a strategy for in-situ generation of carbamoyl fluoride with a secondary amine. Under a nitrogen atmosphere, an oxidant, a secondary amine, a difluorocarbene precursor and an activator are sequentially added to a reaction solvent in a molar ratio of (1.0-5.0):1.0:(1.0-5.0):(1.0-5.0) to obtain a mixture; wherein the oxidant is pyridine-N-oxide or other suitable oxidants, the difluorocarbene precursor is trifluoromethyltrimethylsilane, trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (Chen's reagent) or other suitable difluorocarbene precursors, and the activator is sodium iodide, sodium fluoride or other activating agents; the above mixture is stirred at a suitable temperature to react until completion, and the reaction product is separated by short silica gel column chromatography to obtain the expected carbamoyl fluoride compound.

[0032] In the preparation method of the present invention, when the oxidant is pyridine-N-oxide, the difluorocarbene precursor is trifluoromethyltrimethylsilane, and the activator is sodium iodide, the preparation reaction equation of the carbamoyl fluoride compound is as follows:

[0033]

[0034] In the preparation method of the present invention, when the oxidant is pyridine-N-oxide, the difluorocarbene precursor is trimethylsilyl 2-(fluorosulfonyl) difluoroacetate (Chen's reagent), and the activator is sodium fluoride, the preparation reaction equation of the carbamoyl fluoride compound is as follows:

[0035]

[0036] Therefore, in the present invention, a commercial difluorocarbene precursor is formed into difluorocarbene under the action of an activator, and the difluorocarbene can be in situ oxidized by easily prepared pyridine-N-oxide to produce carbonyl fluoride, and the important carbamoyl fluoride compounds can be prepared by a one-pot reaction of carbonyl fluoride with a widely available secondary amine.

[0037] Fluorine atoms or fluorine-containing groups and amide bonds are functional structural fragments of many important biologically active molecules. The carbamoyl fluoride compounds prepared in the present invention are expected to have great development potential in the research and development of small molecule drugs. In addition, such compounds can also be converted into more fluorine-containing or non-fluorinated compounds with the help of mature organic synthetic chemistry, and these compounds can also play a very important role in synthetic chemistry or medicinal chemistry.

[0038] Compared with the shortcomings and deficiencies of the prior art, the present invention has the following advantages:

[0039] (1) The preparation method of the present invention can be carried out under mild conditions, and carbonyl fluoride gas can be generated in situ by oxidizing difluorocarbene. The operation is simple, the raw materials used are simple and easy to obtain, the cost is low, the compatibility of the reaction functional groups is good, and the substrate application range is also wide. It should be particularly pointed out that the preparation method of the present invention can be used for direct derivatization functionalization research of some drug small molecules;

[0040] (2) The method for preparing carbamoyl fluoride provided by the present invention can be used for the functionalization research of drug molecules in the later stage, and has broad application prospects in drug development and organic synthesis. In addition, the pyridine byproducts produced by the reaction can be recycled and reused, thereby improving the overall atomic economy of the reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 is the hydrogen spectrum of compound 5 in the embodiment of the present invention;

[0042] Figure 2 is the fluorine spectrum of compound 5 in the embodiment of the present invention;

[0043] Figure 3 is the carbon spectrum of compound 5 in the embodiment of the present invention;

[0044] Figure 4 is the hydrogen spectrum of compound 21 in the example of the present invention;

[0045] Figure 5 is the fluorine spectrum of compound 21 in the examples of the present invention;

[0046] Figure 6 It is the carbon spectrum of compound 21 in the example of the present invention. DETAILED DESCRIPTION

[0047] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0048] Example 1

[0049] (1) Under a nitrogen atmosphere, an oxidizing agent, pyridine-N-oxide 1, a secondary amine, N-methylbenzylamine, a difluorocarbene precursor (trifluoromethyltrimethylsilane), and an activator (sodium iodide) were sequentially added to a reaction solvent, acetonitrile, in a molar ratio of 1.0:1.0:3.0:1.0 to obtain a mixture.

[0050] (2) The mixture of step (1) is stirred at 60° C. for 12 h, and then the crude product is separated by short silica gel column chromatography to obtain the desired carbamoyl fluoride compound 5.

[0051] Its structural formula is as follows:

[0052]

[0053] The H-NMR, F-NMR and C-NMR spectra of compound 5 are shown in Figure 1 , Figure 2 and Figure 3 shown.

[0054] Embodiments 2 to 35

[0055] Examples 2 to 35 are substantially the same as Example 1, except that the substituent R in the secondary amine 1 and R 2 The specific structures of secondary amines are shown in the table below:

[0056] Table 1 Examples 2 to 35

[0057]

[0058]

[0059]

[0060] Embodiment 36

[0061] (1) Under a nitrogen atmosphere, an oxidizing agent, pyridine-N-oxide 1, a secondary amine, diethyl iminodiacetate, a difluorocarbene precursor (trimethylsilyl 2-(fluorosulfonyl) difluoroacetate (Chen's reagent)) and an activating agent (sodium fluoride) were added sequentially to a reaction solvent, acetonitrile, in a molar ratio of 1.0:1.0:2.0:1.0, to obtain a mixture.

[0062] (2) The mixture of step (1) was stirred at 60° C. for 1 h, and then the crude product was separated by short silica gel column chromatography to obtain the expected carbamoyl fluoride compound 21. Its structural formula is shown below:

[0063]

[0064] The H NMR, F NMR and C NMR spectra of compound 21 are shown in Figure 4 , Figure 5 and Figure 6 shown.

[0065] Embodiments 37 to 45

[0066] Examples 37 to 45 are substantially the same as Example 36, except that the substituent R in the secondary amine 1 and R 2 The specific structures of secondary amines are shown in the table below:

[0067] Table 2 Examples 37 to 45

[0068]

[0069] Embodiment 46

[0070] This example is basically the same as Example 6, except that the scale of the reaction is enlarged from 0.2 mmol to 7.02 mmol, and the corresponding reaction time is shortened from the original 12 h to 0.5 h. It should be noted that the byproduct 4 can be recycled with a yield of 84% (compound 4 can be oxidized by m-chloroperbenzoic acid to generate nitrogen oxide 1, which is then used in the synthesis of carbamoyl fluoride compounds developed by us).

[0071] The reaction equation involved in the embodiment of the present invention is as follows:

[0072]

[0073] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A class of carbamoyl fluoride compounds can be prepared by reacting in situ formed carbonyl fluoride (difluorocarbene generated by a difluorocarbene precursor and an activator is in situ oxidized by a suitable oxidant to generate carbonyl fluoride) with a secondary amine, characterized in that: The chemical structure of this type of compound is shown in the following formula (I): In formula (I), R 1 benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-trifluoromethylbenzyl, α-naphthylmethyl, diphenylmethylene, pyridine-3-methylene, pyridine-4-methylene, 2-ethoxyethyl, methylenecarboxylic acid ethyl ester, allyl, cyclic hydrocarbon group, substituted cyclic hydrocarbon group, indanyl, desloratadine, paroxetine, amoxapin and other drug molecule fragments and other alkyl or functionalized alkyl groups; R 2 It is methyl, ethyl, benzyl, isopropyl, trimethylsilylmethylene, allyl, 2-ethoxyethyl, methylenecarboxylic acid ethyl ester, cyclic hydrocarbon group, substituted cyclic hydrocarbon group, dihydroindanyl, desloratadine, paroxetine, amoxapin and other drug molecule fragments and other alkyl or functionalized alkyl groups.

2. The method for preparing the carbamoyl fluoride compound according to claim 1, characterized in that: The method comprises the following steps: (1) Under a nitrogen atmosphere, an oxidant, a secondary amine, a difluorocarbene precursor and an activator are sequentially added to a reaction solvent in a molar ratio of (1.0-5.0):1.0:(1.0-5.0):(1.0-5.0) to obtain a mixture; wherein the oxidant is pyridine-N-oxide or other suitable oxidants, the difluorocarbene precursor is trifluoromethyltrimethylsilane, trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (Chen's reagent) or other suitable difluorocarbene precursors, and the activator is sodium iodide, sodium fluoride or other activating agents. (2) The mixture of step (1) is stirred at a suitable temperature until the reaction is complete, and the crude reaction product is separated by short silica gel column chromatography to obtain the desired carbamoyl fluoride compound.

3. The method for preparing carbamoyl fluoride compounds according to claim 2, wherein In step (1), the secondary amine is R 1 and / or R 2 A secondary amine substituted with a group; wherein R 1 benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-trifluoromethylbenzyl, α-naphthylmethyl, diphenylmethylene, pyridine-3-methylene, pyridine-4-methylene, 2-ethoxyethyl, methylenecarboxylic acid ethyl ester, allyl, cyclic hydrocarbon group, substituted cyclic hydrocarbon group, indanyl, desloratadine, paroxetine, amoxapin and other drug molecule fragments and other alkyl or functionalized alkyl groups; R 2 It is methyl, ethyl, benzyl, isopropyl, trimethylsilylmethylene, allyl, 2-ethoxyethyl, methylenecarboxylic acid ethyl ester, cyclic hydrocarbon group, substituted cyclic hydrocarbon group, dihydroindanyl, desloratadine, paroxetine, amoxapin and other drug molecule fragments and other alkyl or functionalized alkyl groups.

4. The method for preparing carbamoyl fluoride compounds according to claim 2, wherein In step (1), the reaction solvent is acetonitrile; in step (2), the mixture is stirred at 60 degrees Celsius for 12 hours or 1 hour.

5. The method of claim 1 for producing carbonyl fluoride by in-situ oxidation of difluorocarbene produced by using a difluorocarbene precursor and an activator with a suitable oxidant and its subsequent conversion application, such as synthesizing carbamoyl fluoride compounds.

Images