CN116535327B - A method for improving the stability of aromatic difluoromethyl compounds during preparation and use - Google Patents
A method for improving the stability of aromatic difluoromethyl compounds during preparation and use Download PDFInfo
- Publication number
- CN116535327B CN116535327B CN202310197096.4A CN202310197096A CN116535327B CN 116535327 B CN116535327 B CN 116535327B CN 202310197096 A CN202310197096 A CN 202310197096A CN 116535327 B CN116535327 B CN 116535327B
- Authority
- CN
- China
- Prior art keywords
- aromatic
- difluoromethyl
- compound
- difluoromethyl compound
- fluoride salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- -1 aromatic difluoromethyl compound Chemical class 0.000 claims abstract description 58
- 150000004673 fluoride salts Chemical class 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 229910001506 inorganic fluoride Inorganic materials 0.000 claims abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 111
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 46
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 24
- FRVATKJLVXRQHU-UHFFFAOYSA-N 4-(difluoromethyl)aniline Chemical compound NC1=CC=C(C(F)F)C=C1 FRVATKJLVXRQHU-UHFFFAOYSA-N 0.000 claims description 13
- 239000011698 potassium fluoride Substances 0.000 claims description 12
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 10
- ZVGDKOQPJCOCLI-UHFFFAOYSA-N 3-chloropyridine-4-carbaldehyde Chemical compound ClC1=CN=CC=C1C=O ZVGDKOQPJCOCLI-UHFFFAOYSA-N 0.000 claims description 9
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 235000003270 potassium fluoride Nutrition 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- GUNJVIDCYZYFGV-UHFFFAOYSA-K antimony trifluoride Chemical compound F[Sb](F)F GUNJVIDCYZYFGV-UHFFFAOYSA-K 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 11
- 125000006575 electron-withdrawing group Chemical group 0.000 abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 8
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000004076 pyridyl group Chemical group 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000012043 crude product Substances 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000005457 ice water Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 238000002390 rotary evaporation Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- CQNIYQCVDLBGPY-UHFFFAOYSA-N 2-chloro-4-(difluoromethyl)pyridine Chemical compound FC(F)C1=CC=NC(Cl)=C1 CQNIYQCVDLBGPY-UHFFFAOYSA-N 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- RMHPWPAKPAVHTB-UHFFFAOYSA-N 1-(difluoromethyl)-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(C(F)F)C=C1 RMHPWPAKPAVHTB-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VATYWCRQDJIRAI-UHFFFAOYSA-N p-aminobenzaldehyde Chemical compound NC1=CC=C(C=O)C=C1 VATYWCRQDJIRAI-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- VSPBWOAEHQDXRD-UHFFFAOYSA-N 1h-indole-6-carbaldehyde Chemical compound O=CC1=CC=C2C=CNC2=C1 VSPBWOAEHQDXRD-UHFFFAOYSA-N 0.000 description 1
- UMZKSQJPDSRGJG-UHFFFAOYSA-N 4-(difluoromethyl)benzaldehyde Chemical compound FC(F)C1=CC=C(C=O)C=C1 UMZKSQJPDSRGJG-UHFFFAOYSA-N 0.000 description 1
- SSZMGMWFFIVDPL-UHFFFAOYSA-N 6-(difluoromethyl)-1h-indole Chemical compound FC(F)C1=CC=C2C=CNC2=C1 SSZMGMWFFIVDPL-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 150000002221 fluorine Chemical class 0.000 description 1
- ZSNUOIONTCOONQ-UHFFFAOYSA-M hexadecyl(trimethyl)azanium;fluoride Chemical compound [F-].CCCCCCCCCCCCCCCC[N+](C)(C)C ZSNUOIONTCOONQ-UHFFFAOYSA-M 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000004812 organic fluorine compounds Chemical class 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/16—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for improving the stability of an aromatic difluoromethyl compound in preparation and use, which comprises the steps of adding inorganic fluoride salt into a reaction system in the process of using the aromatic difluoromethyl compound with an electron donating group connected with a benzene ring, so that the stability of the aromatic difluoromethyl compound in a reaction state can be effectively improved, and further, the yield of a target product is improved, and in addition, when the aromatic difluoromethyl compound with an electron withdrawing group or a pyridyl group connected with the benzene ring is prepared, adding the organic fluoride salt into the reaction system, so that the yield of the aromatic difluoromethyl compound of the target product can be effectively improved. The method is simple and easy to operate, the required fluoride salt is low in cost, easy to obtain and easy to separate, the stability of the aromatic difluoromethyl compound in a preparation or reaction state can be effectively improved, the yield of a target product is improved, the functional group tolerance of the aromatic difluoromethyl compound is improved, and the method has important scientific significance and use value in the aspect of organic synthesis.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for improving the stability of an aromatic difluoromethyl compound during preparation and use.
Background
The introduction of fluorine atoms can change the properties of lipophilicity, hydrogen bonding, bioavailability and the like of the compound, and the introduction of fluorine atoms into a drug structure is a common means of drug design, wherein about 20% -25% of drug molecules contain fluorine atoms, and common fluorine-containing functional groups comprise fluorine atoms F, trifluoromethyl CF 3, difluoromethyl CF 2, trifluoromethoxy OCF 3 and the like. Fluorine-containing drug molecules are an important direction in the development of new drugs in the future.
Difluoromethyl groups can be divided into two main groups, namely direct connection with aromatic groups and direct connection with aliphatic groups, wherein the application of the difluoromethyl groups directly connected with aromatic groups is more extensive, and the aromatic difluoromethyl compounds are usually obtained by reacting aromatic aldehyde, diethylaminosulfur trifluoride (DAST) and other fluorinating agents in Dichloromethane (DCM), and the reaction general formula is as follows:
The difluoromethyl stability in the product will vary greatly due to the nature of the substituent R on the aromatic compound. When the substituent R is an Electron Donating Group (EDG), the stability of the product is poor, for example, 4-difluoromethylaniline is hydrolyzed to 4-aminobenzaldehyde when dissolved in methylene chloride containing a trace amount of water, and the reaction formula is as follows:
also for example, an aqueous solution of the difluoromethyl derivative 6-difluoromethyl indole at Ph >13 will hydrolyze very rapidly to 6-formylindole (Tetrahedron Letters,30,1989,6117-6120).
When the substituent R is an Electron Withdrawing Group (EWG), although the stability of difluoromethyl in the product molecule to water is greatly improved, the stability of the product molecule to other nucleophiles is reduced to a certain extent, for example, when 4-pyridylaldehyde or 4-nitrobenzaldehyde is subjected to difluoromethylation by DAST, a byproduct of diethylamine substituted fluorine is easily obtained. This not only reduces the reaction yield, but also introduces by-products that are difficult to separate, which greatly limits difluoromethylation of this type of substrate.
In summary, for aromatic difluoromethyl compounds, whether the substituent is EDG or EWG, the stability of the compound has many uncertain factors, and the aromatic ring in the drug molecule often has various substituents, which clearly limits the introduction of difluoromethyl and the subsequent reaction of the compound to a great extent. Difluoromethyl is used as an important functional group in drug molecules, and the problem of improving the stability of difluoromethyl without changing the molecular structure of a compound is long-felt by chemists.
Disclosure of Invention
The invention aims to provide a method for improving the stability of an aromatic difluoromethyl compound in preparation and use, which effectively improves the yield of a target product taking the aromatic difluoromethyl compound as a reactant or a product by adding fluoride salt in the process of preparing or using the aromatic difluoromethyl compound.
In order to solve the technical problems, the invention provides the following technical scheme:
The invention provides a method for improving the stability of an aromatic difluoromethyl compound in preparation and use, wherein fluoride salt is added into a reaction system in the preparation or use process of the aromatic difluoromethyl compound, and the aromatic difluoromethyl compound has the following structural general formula:
Wherein Ar is R 1 is an electron donating group or an electron withdrawing group, and R 2 is H or halogen.
Further, the electron donating group comprises amino, alkoxy and alkenyl, but is not limited to the groups, and strong electron donating substituents with lone pair electrons or pi electrons such as amino, alkoxy and alkenyl can be conjugated with large pi bonds on the benzene ring, so that the electron cloud density of the benzene ring is increased, and the electron donating effect on the benzene ring is generated.
Further, the electron withdrawing group comprises a nitro group, a cyano group and a halogen, but is not limited to the above groups, wherein the nitro group, the cyano group and the halogen have electron withdrawing capability in an induced manner, the nitro group also has conjugated electron withdrawing capability, and when the benzene ring is connected with the substituent, the electron cloud density on the benzene ring can be reduced.
Further, the fluoride salt is an inorganic fluoride salt and/or an organic fluoride salt.
Further, the inorganic fluoride salt includes at least one of potassium fluoride, cesium fluoride, antimony fluoride, but is not limited to the above-listed inorganic fluoride salts, and inorganic fluoride salts which can serve the same or similar functions are suitable.
Further, the organic fluoride salts include tetrabutylammonium fluoride and cetyltrimethylammonium fluoride, but are not limited to the above-listed organic fluoride salts, and organic fluoride salts which can perform the same or similar functions are suitable.
Further, in the process of using the aromatic difluoromethyl compound, inorganic fluoride salt is added into a reaction system, wherein R 1 in the aromatic difluoromethyl compound is an electron donating group.
When aryl in the aromatic difluoromethyl compound is phenyl substituted by an electron donating group, the aromatic difluoromethyl compound has poor stability, is easy to generate hydrolysis reaction in an aqueous environment, and the corresponding difluoromethyl is hydrolyzed into an aldehyde group, according to the invention, the inorganic fluoride salt is introduced to enable the solution to be filled with fluoride ions, and the nucleophilic attack of water molecules on difluoromethyl can be effectively inhibited by high-concentration fluoride ions, so that the stability of the aromatic difluoromethyl compound is improved, and the yield of a target product is further improved.
Further, the molar ratio of the aromatic difluoromethyl compound to the inorganic fluoride is 1:10 to 20, for example, 1:10, 1:12, 1:14, 1:15, 1:17, 1:18, 1:20, etc., but is not limited to the above-listed ratios.
In some preferred embodiments, when the aromatic difluoromethyl compound is 4-difluoromethylaniline, 4-difluoromethylaniline is reacted with 4-methylbenzenesulfonyl chloride in the presence of an acid-binding agent, an inorganic fluoride salt and a solvent to produce the product N- (4' -difluoromethylphenyl) -4-methylbenzenesulfonamide.
Further, in the process of preparing the aromatic difluoromethyl compound, adding organic fluoride salt into a reaction system, wherein Ar in the aromatic difluoromethyl compound isR 1 is an electron withdrawing group, and R 2 is H or halogen.
When the aromatic difluoromethyl compound with aryl substituted by electron withdrawing group or pyridyl is prepared, organic fluoride salt is added into a solvent (especially aprotic solvent), so that high concentration of fluoride ions is maintained in a reaction system, and the yield of the aromatic difluoromethyl compound is effectively improved.
Further, the molar ratio of the aromatic dimethyl compound to the organofluoride is 1:1-5, for example, 1:1, 1:2, 1:3, 1:4, 1:5, etc., and is not limited to the above-listed ratio.
Further, the aromatic difluoromethyl compound is prepared by reacting Ar-CHO with diethylaminosulfur trifluoride in the presence of organic fluoride salt and solvent, wherein Ar in Ar-CHO isR 1 is an electron withdrawing group, and R 2 is H or halogen.
Further, ar-CHO, organic fluoride salt and solvent are added into a reaction device, diethylaminosulfur trifluoride is added dropwise under ice water bath, stirring is carried out for 2-4 hours at 20-30 ℃ after the dropwise addition, a sodium bicarbonate solution is used for quenching reaction, organic phases are combined after multiple times of extraction and dried by anhydrous sodium sulfate, the solvent is removed through rotary evaporation, a crude product is obtained, and the crude product is purified by column chromatography to obtain the aromatic difluoromethyl compound.
In some preferred embodiments, the Ar-CHO is 3-chloro-4-pyridinecarboxaldehyde or 4-nitrobenzaldehyde.
Further, the solvent is one or more of dichloromethane, N-dimethylformamide, acetonitrile and water.
Compared with the prior art, the invention has the beneficial effects that:
1. According to the invention, the fluoride salt is introduced in the process of preparing or using the aromatic difluoromethyl compound, so that the stability of the aromatic difluoromethyl compound in a preparation or reaction state is effectively improved, and the yield of a corresponding target product is obviously improved. For example, in the presence of 4-difluoromethylaniline and 4-methylbenzenesulfonyl chloride, the target product N- (4' -difluoromethylphenyl) -4-methylbenzenesulfonamide is hardly obtained, but in the presence of potassium fluoride, the yield of the target product is as high as 67%, 3-chloro-4-pyridinecarboxaldehyde and diethylamino trifluoride are directly reacted, the yield of the product 2-chloro-4-difluoromethylpyridine is only 48%, the yield is increased to 81% in the presence of tetrabutylammonium fluoride, the yield of 4-nitrobenzaldehyde and diethylamino sulfur trifluoride are directly reacted to 79%, and in the presence of tetrabutylammonium fluoride, the yield is as high as 95%.
2. The method improves the stability of the aromatic difluoromethyl compound in the preparation and use processes, not only effectively improves the yield of target products, but also increases the functional group tolerance of the aromatic difluoromethyl compound when participating in the reaction, and is beneficial to promoting the novel application of the aromatic difluoromethyl compound in the aspect of chemical synthesis.
3. The fluoride salt for improving the stability of the aromatic difluoromethyl compound in the preparation and use processes is low in cost, easy to obtain and separate, does not influence the purity of the product, and is suitable for industrial production.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items. The term "comprising" or "comprises" as used herein means that it may include or comprise other components in addition to the components described. The term "comprising" or "comprising" as used herein may also be replaced by "being" or "consisting of" closed.
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the invention and practice it.
Example 1
This example relates to the preparation of N- (4' -difluoromethylphenyl) -4-methylbenzenesulfonamide by reacting 4-difluoromethylaniline with 4-methylbenzenesulfonyl chloride in the presence of the solvents Dichloromethane (DCM), KF and triethylamine, wherein the reaction equation is as follows:
The specific operation is as follows:
In a 50mL round bottom flask equipped with a magnetic stirrer, 4-difluoromethylaniline (143.1 mg,1 mmol), 4-methylbenzenesulfonyl chloride (228.8 mg,1.2 mmol), KF (580 mg,10 mmol) and DCM (10 mL) were added, the round bottom flask was placed under an ice-water bath, triethylamine (Et 3 N,121.4mg,1.2 mmol) was further added, stirring was performed at room temperature for 4h, then water (10 mL) was added, the liquid was separated, the aqueous phase was extracted with DCM (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give the crude product. Purification of the crude product by column chromatography (N-hexane: ethyl acetate=10:1) afforded the product N- (4' -difluoromethylphenyl) -4-methylbenzenesulfonamide (200 mg,0.67mmol, yield ：67％).1H NMR(400MHz,CDCl3):δ(ppm)＝10.11(br,1H),7.76(d,2H),7.45(d,2H),7.34(d,2H),7.15(d,2H),6.45(t,3H),2.40(s,3H).
Example 2
This example relates to the preparation of 2-chloro-4-difluoromethylpyridine by reacting 3-chloro-4-pyridinecarbaldehyde with diethylaminosulfur trifluoride (DAST) in the presence of Dichloromethane (DCM) and tetrabutylammonium fluoride as solvents, the reaction equation being as follows:
The specific operation is as follows:
In a 250mL round bottom flask equipped with a magnetic stirrer, 3-chloro-4-pyridinecarboxaldehyde (14.2 g,100 mmol), tetrabutylammonium fluoride (26.1 g,100 mol) and DCM (100 mL) were added, the round bottom flask was placed under an ice-water bath, DAST (24.2 g,150 mmol) was then added dropwise, the mixture was stirred at room temperature for 2h, the reaction was quenched with sodium bicarbonate solution, extracted with DCM (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give the crude product. Purification of the crude product by column chromatography (n-hexane: ethyl acetate=100:1) gave the product 2-chloro-4-difluoromethylpyridine (13.2 g,81mmol, yield: 81%). 1H NMR(400MHz,CDCl3 ) δ (ppm) =8.51 (d, 1H), 7.45 (s, 1H), 7.34 (d, 1H), 6.61 (t, 1H).
Example 3
This example relates to the preparation of 4-difluoromethyl nitrobenzene by reacting 4-nitrobenzaldehyde with diethylaminosulfur trifluoride (DAST) in the presence of the solvents Dichloromethane (DCM) and tetrabutylammonium fluoride, with the following reaction equation:
The specific operation is as follows:
In a 250mL round bottom flask equipped with a magnetic stirrer, 4-nitrobenzaldehyde (15.1 g,100 mmol), tetrabutylammonium fluoride (26.1 g,100 mol) and DCM (100 mL) were added, the round bottom flask was placed under an ice-water bath, DAST (24.2 g,150 mmol) was then added dropwise, stirring was completed at room temperature for 2h, the reaction was quenched with sodium bicarbonate solution, extracted with DCM (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give the crude product. Purification of the crude product by column chromatography (n-hexane: ethyl acetate=50:1) gave the product 4-difluoromethyl nitrobenzene (16.5 g,95mmol, yield: 95%). 1H NMR(400MHz,CDCl3 ) δ (ppm) =8.33 (d, 2H), 7.72 (d, 2H), 6.75 (t, 1H).
Comparative example 1
This comparative example relates to the preparation of N- (4' -difluoromethylphenyl) -4-methylbenzenesulfonamide using 4-difluoromethylaniline and 4-methylbenzenesulfonyl chloride as reactants and reacting in the presence of the solvents Dichloromethane (DCM) and triethylamine, differing from example 1 only in that KF was not added.
The specific operation is as follows:
in a 50mL round bottom flask equipped with a magnetic stirrer, 4-difluoromethylaniline (143.1 mg,1 mmol), 4-methylbenzenesulfonyl chloride (228.8 mg,1.2 mmol) and DCM (10 mL) were added, the round bottom flask was placed under an ice-water bath, then Et 3 N (121.4 mg,1.2 mmol) was added, stirred at room temperature for 4h, water (10 mL) was added, the solution was separated, the aqueous phase was extracted with DCM (10 mL. Times.3), the organic phases were combined, TLC showed only a very small number of product spots in the organic phase, while a large amount of hydrolytic impurity (4-difluoromethyl benzaldehyde) was formed, the product lost purification meaning, and the reaction failed substantially.
Comparative example 2
This comparative example relates to the preparation of N- (4' -difluoromethylphenyl) -4-methylbenzenesulfonamide using 4-difluoromethylaniline and 4-methylbenzenesulfonyl chloride as reactants in the presence of the solvents Dichloromethane (DCM), tetrabutylammonium fluoride and triethylamine, differing from example 1 only in that tetrabutylammonium fluoride was used instead of KF.
The specific operation is as follows:
In a50 mL round bottom flask equipped with a magnetic stirrer, 4-difluoromethylaniline (143.1 mg,1 mmol), 4-methylbenzenesulfonyl chloride (228.8 mg,1.2 mmol), tetrabutylammonium fluoride (2.61 g,10 mmol) and DCM (10 mL) were added, the round bottom flask was placed under an ice-water bath, then Et 3 N (121.4 mg,1.2 mmol) was added, stirring was performed at room temperature for 4h, water (10 mL) was added, the liquid was separated, the aqueous phase was extracted with DCM (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give the crude product. Purification of the crude product by column chromatography (N-hexane: ethyl acetate=10:1) gave the product N- (4' -difluoromethylphenyl) -4-methylbenzenesulfonamide (38.6 mg,0.13mmol, yield: 13%).
Comparative example 3
This comparative example relates to the preparation of 2-chloro-4-difluoromethylpyridine from 3-chloro-4-pyridinecarbaldehyde and diethylaminosulfur trifluoride (DAST) in the presence of Dichloromethane (DCM), which is a solvent, differing from example 2 only in that tetrabutylammonium fluoride is not added.
The specific operation is as follows:
in a 250mL round bottom flask equipped with a magnetic stirrer, 3-chloro-4-pyridinecarboxaldehyde (14.2 g,100 mmol) and DCM (100 mL) were added, the round bottom flask was placed under an ice-water bath, DAST (24.2 g,150 mmol) was then added dropwise, stirring was completed at room temperature for 2h, the reaction was quenched with sodium bicarbonate solution, DCM extracted (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give the crude product. Purification of the crude product by column chromatography (n-hexane: ethyl acetate=100:1) afforded the product 2-chloro-4-difluoromethylpyridine (7.8 g,48mmol, yield: 48%).
Comparative example 4
This comparative example relates to the preparation of 2-chloro-4-difluoromethylpyridine, using 3-chloro-4-pyridinecarbaldehyde and diethylaminosulfur trifluoride (DAST) as reactants, in the presence of solvents Dichloromethane (DCM), KF, differing from example 2 only in the substitution of KF for tetrabutylammonium fluoride.
In a 250mL round bottom flask equipped with a magnetic stirrer, 3-chloro-4-pyridinecarboxaldehyde (14.2 g,100 mmol), KF (5.8 g,100 mol) and DCM (100 mL) were added, the round bottom flask was placed under an ice-water bath, DAST (24.2 g,150 mmol) was then added dropwise, the mixture was stirred at room temperature for 2h after the addition was completed, the reaction was quenched with sodium bicarbonate solution, the DCM was extracted (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give the crude product. Purification of the crude product by column chromatography (n-hexane: ethyl acetate=100:1) gave the product 2-chloro-4-difluoromethylpyridine (9.3 g,57mmol, yield: 57%).
Comparative example 5
This comparative example relates to the preparation of 4-difluoromethyl nitrobenzene by reacting 4-nitrobenzaldehyde with diethylaminosulfur trifluoride (DAST) in the presence of the solvent Dichloromethane (DCM) with the exception that tetrabutylammonium fluoride was not added to example 3.
In a 250mL round bottom flask equipped with a magnetic stirrer, 4-nitrobenzaldehyde (15.1 g,100 mmol), tetrabutylammonium fluoride (26.1 g,100 mol) and DCM (100 mL) were added, the round bottom flask was placed under an ice-water bath, DAST (24.2 g,150 mmol) was then added dropwise, stirring was completed at room temperature for 2h, the reaction was quenched with sodium bicarbonate solution, extracted with DCM (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give the crude product. Purification of the crude product by column chromatography (n-hexane: ethyl acetate=50:1) gave the product 4-difluoromethyl nitrobenzene (13.7 g,79mmol, yield: 79%).
The products prepared in the above examples and comparative examples and the yields are shown in the following table:
TABLE 1
As can be seen from table 1, examples 1 to 3 effectively improve the yields of the corresponding target products by introducing fluoride salts during the preparation (examples 2, 3) or use (example 1) of the aromatic difluoromethyl compounds. The effect of introducing KF is better than that of tetrabutylammonium fluoride in the process of preparing N- (4' -difluoromethyl phenyl) -4-methylbenzenesulfonamide by utilizing the reaction of 4-difluoromethylaniline and 4-methylbenzenesulfonyl chloride, the yield of a reaction product is greatly improved after fluoride salt is introduced in the process of preparing a corresponding aromatic difluoromethyl compound by utilizing the reaction of 3-chloro-4-pyridylaldehyde and diethylaminosulfur trifluoride, the improvement effect of tetrabutylammonium fluoride is obviously better than that of KF, and meanwhile, the tetrabutylammonium fluoride also shows good yield improvement effect in the process of preparing 4-difluoromethyl nitrobenzene.
The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310197096.4A CN116535327B (en) | 2023-03-03 | 2023-03-03 | A method for improving the stability of aromatic difluoromethyl compounds during preparation and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310197096.4A CN116535327B (en) | 2023-03-03 | 2023-03-03 | A method for improving the stability of aromatic difluoromethyl compounds during preparation and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116535327A CN116535327A (en) | 2023-08-04 |
| CN116535327B true CN116535327B (en) | 2025-03-14 |
Family
ID=87454888
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310197096.4A Active CN116535327B (en) | 2023-03-03 | 2023-03-03 | A method for improving the stability of aromatic difluoromethyl compounds during preparation and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116535327B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2888845B1 (en) * | 2005-07-19 | 2007-10-12 | Rhodia Chimie Sa | PROCESS FOR THE PREPARATION OF MONO- OR DIFLUORO HYDROCARBON COMPOUNDS |
| CN102153430B (en) * | 2011-02-01 | 2014-12-31 | 江苏威耳化工有限公司 | Preparation method for fluoride aromatic organic compound |
| US20210155561A1 (en) * | 2019-11-26 | 2021-05-27 | South Dakota Board Of Regents | Method and reagent for deoxyfluorination |
-
2023
- 2023-03-03 CN CN202310197096.4A patent/CN116535327B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN116535327A (en) | 2023-08-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1845084B1 (en) | Process for producing (z)-1-phenyl-1-(n,n-diethylaminocarbonyl)idomethylcyclopropane | |
| CN109053505B (en) | Synthesis method of important intermediate of feloxicib | |
| CN107540598B (en) | Method for preparing N-difluoromethylthio phthalimide compound | |
| EP2401253B1 (en) | A process for the preparation of etoricoxib | |
| CN116535327B (en) | A method for improving the stability of aromatic difluoromethyl compounds during preparation and use | |
| CN112876404B (en) | Synthesis method of phthalimide trifluoro-methionation reagent | |
| CN110790689B (en) | Synthetic method of 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound | |
| JP2005536558A (en) | Process for the production of nitrooxy derivatives of naproxen | |
| EP3307717B1 (en) | A novel process for preparing enzalutamide | |
| CN112194548A (en) | α-Amino-γ-butyrolactone compound and preparation method thereof | |
| CN110724040B (en) | Synthetic method of iodo trifluoromethoxy compound | |
| CN105189447B (en) | The method for manufacturing nitrobenzene compound | |
| CN103694162B (en) | (1S, 2R)-1-phenyl 2-(phthalimide) methyl-N, the preparation method of N-diethyl-ring propyl formamide | |
| CN106748884B (en) | Preparation method of bicalutamide intermediate | |
| EP1468983B1 (en) | Process for producing 2,5-bis(trifluoromethyl)nitrobenzene | |
| CN112279849A (en) | N-difluoromethyl azaindole compound and synthesis method thereof | |
| CN110746336B (en) | Green preparation method of N-methyl-2-cyano-3-arylpyrrole compound | |
| CN113387946B (en) | A kind of ultrasound-assisted multi-component synthesis method of 2-phenyl-3-arylaminomethylimidazopyridine derivatives | |
| JP7628505B2 (en) | Method for producing 4-(aminomethyl)cyclohexanecarboxylic acid | |
| US20070265458A1 (en) | Process for the Preparation of Glycidyl Derivatives | |
| CN107857729B (en) | A kind of synthetic method of the pyrazole compound of 4- iodate-N- arylation | |
| JP3959994B2 (en) | Method for producing 4-phthalonitrile derivative | |
| CN118993984A (en) | Synthesis method of N-amido carbazole compound | |
| CN108164431B (en) | 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid and preparation method thereof | |
| WO2007132990A1 (en) | Process for the preparation of chiral glycidylphthalimide in highly optical purity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |