CN108863820B - Synthesis method of substituted o-phenylenediamine - Google Patents
Synthesis method of substituted o-phenylenediamine Download PDFInfo
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- CN108863820B CN108863820B CN201810853500.8A CN201810853500A CN108863820B CN 108863820 B CN108863820 B CN 108863820B CN 201810853500 A CN201810853500 A CN 201810853500A CN 108863820 B CN108863820 B CN 108863820B
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- phenylenediamine
- dimethylformamidine
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- 150000004987 o-phenylenediamines Chemical class 0.000 title claims abstract description 17
- 238000001308 synthesis method Methods 0.000 title claims description 6
- -1 N' - (2-fluorophenyl) -N, N-dimethyl formamidine derivative Chemical class 0.000 claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 11
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims abstract description 6
- 150000003973 alkyl amines Chemical class 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 7
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical class NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 abstract description 4
- 239000000460 chlorine Substances 0.000 abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 abstract description 4
- 239000011737 fluorine Substances 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000007858 starting material Substances 0.000 description 10
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000002390 rotary evaporation Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000012265 solid product 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 7
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 6
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical compound NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 description 4
- WRXNJTBODVGDRY-UHFFFAOYSA-N 2-pyrrolidin-1-ylethanamine Chemical compound NCCN1CCCC1 WRXNJTBODVGDRY-UHFFFAOYSA-N 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 238000004176 ammonification Methods 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229910052979 sodium sulfide Inorganic materials 0.000 description 3
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- FTSMQTKWARNKTQ-UHFFFAOYSA-N 2-(2-amino-3-nitroanilino)ethanol Chemical compound NC1=C(NCCO)C=CC=C1[N+]([O-])=O FTSMQTKWARNKTQ-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- YAQFGXYPGJATMT-UHFFFAOYSA-N 2-bromo-6-fluoro-4-nitroaniline Chemical compound NC1=C(F)C=C([N+]([O-])=O)C=C1Br YAQFGXYPGJATMT-UHFFFAOYSA-N 0.000 description 1
- LETNCFZQCNCACQ-UHFFFAOYSA-N 2-fluoro-4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1F LETNCFZQCNCACQ-UHFFFAOYSA-N 0.000 description 1
- BHWHYGWMNMCXBA-UHFFFAOYSA-N 2-fluoro-6-nitroaniline Chemical compound NC1=C(F)C=CC=C1[N+]([O-])=O BHWHYGWMNMCXBA-UHFFFAOYSA-N 0.000 description 1
- DATUDYKWTCYSMM-UHFFFAOYSA-N 8-bromo-3-methyl-1,7-dipropylpurine-2,6-dione Chemical compound CN1C(=O)N(CCC)C(=O)C2=C1N=C(Br)N2CCC DATUDYKWTCYSMM-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000005485 electric heating Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Abstract
The invention discloses a method for synthesizing substituted o-phenylenediamine, which comprises the steps of heating an N' - (2-fluorophenyl) -N, N-dimethyl formamidine derivative and an alkylamine derivative to 180-220 ℃ for reaction to obtain the substituted o-phenylenediamine; the reaction process is as follows:
wherein R is1Is chlorine, bromine, nitro, methoxycarbonyl, cyano or acetyl, R2Is hydrogen, fluorine, bromine, R3Is 2-hydroxyethyl, 2-methoxyethyl, (tetrahydrofuran-2-yl) methyl, 2- (pyrrolidin-1-yl) ethyl.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a synthesis method of substituted o-phenylenediamine.
Background
The o-phenylenediamine is an important chemical intermediate, is mainly used for synthesizing pesticides, dyes, auxiliaries, photosensitive materials and the like, and has wide application and wide market prospect. Because the substituted o-phenylenediamine can be used for synthesizing antipsychotic drugs and the like, the pharmaceutical industry is the field of o-phenylenediamine with the most development potential. The substituted o-phenylenediamine is obtained by substitution reaction of o-phenylenediamine. At present, only 3 synthesis routes with industrialization or industrialization prospect are available, namely an o-nitrochlorobenzene ammoniation sodium sulfide reduction method, an o-dichlorobenzene ammoniation method and an o-nitrochlorobenzene ammoniation catalytic hydrogenation reduction method.
The o-nitrochlorobenzene ammonification sodium sulfide reduction method takes o-nitrochlorobenzene as a starting material to react with strong ammonia water at 180-190 ℃ for about 8 hours to obtain o-nitroaniline. Then the obtained o-nitroaniline is subjected to reduction reaction by using a sodium sulfide solution at a proper temperature, and the o-phenylenediamine product is obtained through separation and refining operations.
The ammonification method of o-dichlorobenzene takes copper as a catalyst, and carries out ammonolysis reaction on o-dichlorobenzene and strong ammonia water in a high-pressure kettle at a higher temperature to obtain o-phenylenediamine.
The o-nitrochlorobenzene ammonification catalytic hydrogenation reduction method takes o-nitrochlorobenzene as a starting material to react with strong ammonia water at 180-190 ℃ for about 8 hours to obtain o-nitroaniline. Then putting the catalyst and the obtained o-nitroaniline into a high-pressure reaction kettle, introducing hydrogen, and carrying out catalytic hydrogenation reaction at a certain temperature and pressure to obtain the o-phenylenediamine product.
However, no matter what kind of o-phenylenediamine is synthesized, the synthesis of o-phenylenediamine cannot be avoided when substituted o-phenylenediamine is prepared, and the synthesis steps are complicated.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a method for synthesizing substituted o-phenylenediamine, which is simple in preparation method.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for synthesizing substituted o-phenylenediamine comprises the steps of heating an N' - (2-fluorophenyl) -N, N-dimethyl formamidine derivative and an alkylamine derivative to 150-220 ℃ for reaction to obtain the substituted o-phenylenediamine;
the reaction process is as follows:
wherein R is1Is chlorine, bromine, nitro, methoxycarbonyl, cyano or acetyl, R2Is hydrogen, fluorine, bromine, R3Is 2-hydroxyethyl, 2-methoxyethyl, (tetrahydrofuran-2-yl) methyl, 2- (pyrrolidin-1-yl) ethyl.
The invention has the advantages that:
the invention provides a novel synthesis method of substituted o-phenylenediamine, which has simple steps and high yield.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. 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 application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As described in the background art, the existing synthesis of substituted o-phenylenediamine requires substitution reaction of o-phenylenediamine, and the synthesis process is complex.
The typical embodiment of the application provides a method for synthesizing substituted o-phenylenediamine, which comprises the steps of heating an N' - (2-fluorophenyl) -N, N-dimethyl formamidine derivative and an alkylamine derivative to 150-220 ℃ for reaction to obtain the substituted o-phenylenediamine;
the reaction process is as follows:
wherein R is1Is chlorine, bromine, nitro, methoxycarbonyl, cyano or acetyl, R2Is hydrogen, fluorine, bromine, R3Is 2-hydroxyethyl, 2-methoxyethyl, (tetrahydrofuran-2-yl) methyl, 2- (pyrrolidin-1-yl) ethyl.
Preferably, R1Is nitro, R2Is hydrogen or bromine.
Further preferred, the N' - (2-fluorophenyl) -N, N-dimethylformamidine derivative is selected from the group consisting of:
preferably, R3Is 2-hydroxyethyl or 2- (pyrrolidin-1-yl) ethyl.
Preferably, the solvent used is dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF) or hexamethylphosphoric triamide (HMPA).
The heating method is oil bath heating or microwave heating, preferably oil bath heating, steam heating, electric heating or microwave heating.
Preferably, the molar ratio of the N' - (2-fluorophenyl) -N, N-dimethyl formamidine derivative to the alkylamine derivative is 1: 1-20.
Preferably, the synthesis method of the N' - (2-fluorophenyl) -N, N-dimethyl formamidine derivative comprises the following steps: carrying out aldehyde-amine condensation reaction on the 2-fluoroaniline derivative and N, N-dimethylformamide to obtain an N' - (2-fluorophenyl) -N, N-dimethylformamidine derivative;
the reaction process is as follows:
wherein R is1Is chlorine, bromine, nitro, methoxycarbonyl, cyano or acetyl, R2Is hydrogen, fluorine, bromine, R3Is 2-hydroxyethyl, 2-methoxyethyl, (tetrahydrofuran-2-yl) methyl, 2- (pyrrolidin-1-yl) ethyl.
Further preferably, the catalyst used is benzene sulfonyl chloride.
Further preferably, the molar ratio of the 2-fluoroaniline derivative to the benzenesulfonyl chloride is 1: 1.5-2.5.
In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.
Synthesis of raw materials:
(E) -N' - (2-fluoro-6-nitrophenyl) -N, N-dimethylformamidine
To a 250mL round bottom flask equipped with a magnetic stir bar was added DMF (60mL), benzenesulfonyl chloride (27.2g, 154 mmol). The solution was stirred for 20 minutes and the color of the solution turned light yellow. 2-fluoro-6-nitroaniline (12g, 77mmol) was added and the mixture was stirred at room temperature for 30 minutes. A large amount of solid product was formed, and the solid was filtered, washed with ether and dried under vacuum. The resulting solid was then transferred to another 250mL round bottom flask and neutralized by the addition of NaOH (4M) solution (50mL) and ethyl acetate (150 mL). The solution was transferred to a funnel and separated and the inorganic layer was extracted with 2X 100mL of ethyl acetate. After combining the organic layers, they were washed with brine and dried over anhydrous sodium sulfate for 3 hours to give (E) -N' - (2-fluoro-6-nitrophenyl) -N, N-dimethylformamidine as a yellow solid after rotary evaporation in 15.5g, 95% yield.1H NMR(500MHz,DMSO-d6)δppm 2.97(s,3H),3.08(s,3H),7.35(m,1H),7.79(d,J＝8.77,3.40Hz,1H),7.90(dd,J＝7.63,2.75Hz,1H),7.98(s,1H)；13C NMR(126MHz,DMSO-d6)δppm 33.92,39.04,39.20,39.37,39.53,39.70,39.87,39.96,40.04,116.10,116.14,116.20,116.39,117.21,117.28,141.19,141.28,144.20,155.73,158.20,160.22；HRMS calcd.for C9H10FN3O2:211.0757,found 211.0750.
(E) -N' - (2-fluoro-4-nitrophenyl) -N, N-dimethylformamidine
To a 250mL round bottom flask equipped with a magnetic stir bar was added DMF (60mL), benzenesulfonyl chloride (27.2g, 154 mmol). The solution was stirred for 20 minutes and the color of the solution turned light yellow. 2-fluoro-4-nitroaniline (12g, 77mmol) was added and the mixture was stirred at room temperature for 30 minutes. A large amount of solid product was formed, and the solid was filtered, washed with ether and dried under vacuum. The resulting solid was then transferred to another 250mL round bottom flask and neutralized by the addition of NaOH (4M) solution (50mL) and ethyl acetate (150 mL). The solution was transferred to a funnel, separated and the inorganic layer extracted with 2X 100mL of ethyl acetate. After combining the organic layers, it was washed with brine and dried over anhydrous sodium sulfateAfter 3 hours rotary evaporation, a yellow solid, (E) -N' - (2-fluoro-4-nitrophenyl) -N, N-dimethylformamidine was obtained, 13.2g, yield 81%.1H NMR(500MHz,DMSO-d6)δppm 2.95(s,3H),3.07(s,3H),8.10(m,1H),7.97(m,1H),7.90(m,1H),7.98(s,1H)；13C NMR(126MHz,DMSO-d6)δppm 33.91,39.02,39.21,39.40,39.52,39.71,39.88,39.97,40.03,116.09,116.12,116.21,116.40,117.22,117.29,141.20,141.30,144.26,155.74,158.22,160.21；HRMS calcd.for C9H10FN3O2:211.0757,found 211.0748.
(E) -N' - (2-bromo-6-fluoro-4-nitrophenyl) -N, N-dimethylformamidine
To a 250mL round bottom flask equipped with a magnetic stir bar was added DMF (80mL), benzenesulfonyl chloride (27.2g, 154 mmol). The solution was stirred for 30 minutes and the color of the solution turned pale yellow. 2-bromo-6-fluoro-4-nitroaniline (18g, 77mmol) was added and the mixture was stirred at room temperature for 50 minutes. A large amount of solid product was formed, and the solid was filtered, washed with ether and dried under vacuum. The resulting solid was then transferred to another 250mL round bottom flask and neutralized by the addition of NaOH (4M) solution (60mL) and ethyl acetate (160 mL). The solution was transferred to a funnel, separated and the inorganic layer extracted with 3X 100mL of ethyl acetate. After combining the organic layers, they were washed with brine and dried over anhydrous sodium sulfate for 6 hours to give (E) -N' - (2-bromo-6-fluoro-4-nitrophenyl) -N, N-dimethylformamidine as a yellow solid after rotary evaporation, 19.1g, 86% yield.1H NMR(500MHz,DMSO-d6)δppm 2.99(s,3H),3.05(s,3H),8.20(m,1H),7.99(m,1H),7.94(m,1H),7.88(s,1H)；13C NMR(126MHz,DMSO-d6)δppm 33.90,39.01,39.28,39.42,39.51,39.72,39.87,39.93,40.05,116.03,116.22,116.19,116.36,117.18,117.22,141.21,141.32,144.25,155.72,158.21,160.25；HRMS calcd.for C9H9BrFN3O2:288.9862,found 288.9871.
Example 1
To a 20mL Biotage reaction tube were added (E) -N' - (2-fluoro-6-nitrophenyl) -N, N-dimethylformamidine (2mmol,422mg), DMSO (12mL), 2-aminoethanol (10mmol,610mg) and a magnetic stirrer, and the reaction tube was capped and placed in an oil bath with magnetic stirring to heat to 180 ℃ for 1 hour. TLC analysis indicated that the starting material (E) -N' - (2-fluoro-6-nitrophenyl) -N, N-dimethylformamidine disappeared and a new spot appeared. LC-MS analysis confirms the generation of the target product. After the reaction solution cooled to room temperature, it was poured into a 250mL round bottom flask containing water (50mL) and stirred for 10 minutes. The mixture was then transferred to a separatory funnel and extracted with ethyl acetate (4X 50 mL). After the organic phases were combined, they were washed with water (60mL) and dried over anhydrous sodium sulfate for 6 hours. And obtaining viscous light yellow liquid after rotary evaporation. Silica gel column chromatography (mobile phase: ethyl acetate: n-hexane ═ 1: 5) was performed to obtain 305mg of 2- (2-amino-3-nitrophenylamino) ethanol, a solid product, in a yield of 77%.1H NMR(500MHz,DMSO-d6)δppm 2.23(br,1H),3.21(m,2H),4.12(br,1H),4.6(br,2H),7.60(s,1H),6.65(m,1H),6.51(m,1H)；HRMS calcd.for C8H11N3O3:197.0800,found 197.0809.
Example 2
A50 mL single neck round bottom flask was charged with (E) -N' - (2-fluoro-6-nitrophenyl) -N, N-dimethylformamidine (6mmol,1.266g), DMSO (25mL), 2-aminoethanol (30mmol,1.83g), and a magnetic stirrer, and the reaction flask was placed in an oil bath with magnetic stirring and heated to reflux (189 deg.C) for 2 hours. TLC analysis indicated that the starting material (E) -N' - (2-fluoro-6-nitrophenyl) -N, N-dimethylformamidine disappeared and a new spot appeared. LC-MS analysis confirms the generation of the target product. After the reaction solution cooled to room temperature, it was poured into a 500mL round bottom flask containing water (150mL) and stirred for 10 minutes. The mixture was then transferred to a separatory funnel and extracted with ethyl acetate (3X 160 mL). After the organic phases were combined, they were washed with water (200mL) and dried over anhydrous sodium sulfate overnight. And obtaining viscous light yellow liquid after rotary evaporation. Silica gel column chromatography (mobile phase: ethyl acetate: n-hexane ═ 1: 5) gave 1.01g of 2- (2-amino-3-nitrophenylamino) ethanol as a solid product, in 85% yield.
Example 3
To a 20mL Biotage reaction tube were added (E) -N' - (2-fluoro-4-nitrophenyl) -N, N-dimethylformamidine (2mmol,0.422g), DMSO (12mL), 2- (pyrrolidin-1-yl) ethylamine (10mmol,1.14g) and a magnetic stirrer, and the reaction tube was capped and placed in a magnetic stirred oil bath and heated to 180 ℃ for 1 hour. TLC analysis showed the starting material (E) -N' - (2-fluoro-4-nitrophenyl) -N, N-dimethylformamidine was still present and after a further 30 minutes, TLC analysis showed the disappearance of the starting material. LC-MS analysis confirms the generation of the target product. After the reaction solution cooled to room temperature, it was poured into a 250mL round bottom flask containing water (50mL) and stirred for 10 minutes. The mixture was then transferred to a separatory funnel and extracted with ethyl acetate (3X 50 mL). After the organic phases were combined, they were washed with water (50mL) and dried over anhydrous sodium sulfate for 6 hours. And obtaining viscous light yellow liquid after rotary evaporation. Silica gel column chromatography (mobile phase: ethyl acetate: N-hexane: 1: 5) to obtain solid product 5-nitro-N1- (2- (pyrrolidin-1-yl) ethyl) benzene-1, 2-diamine 0.398g, yield 80%.1H NMR(500MHz,DMSO-d6)δppm 1.66(m,4H),2.28(t,4H),2.61(t,2H),3.19(m,2H),4.11(br,1H),4.58(br,2H),7.34(m,1H),7.19(s,1H),6.49(m,1H)；HRMS calcd.for C12H18N4O2:250.1430,found 250.1442.
Example 4
To a 20mL Biotage reaction tube was added (E) -N' - (2-fluoro-4-nitrophenyl) -N, N-dimethylformamidine (2 mmo)l,0.422g), DMSO (12mL), 2- (pyrrolidin-1-yl) ethylamine (10mmol,1.14g) and a magnetic stirrer, the reaction tube was capped and placed in a microwave oven (Biotage). The reaction was heated at 220 ℃ for 20 minutes and TLC analysis showed the disappearance of the starting material (E) -N' - (2-fluoro-4-nitrophenyl) -N, N-dimethylformamidine. LC-MS analysis confirms the generation of the target product. After the reaction solution cooled to room temperature, it was poured into a 250mL round bottom flask containing water (50mL) and stirred for 10 minutes. The mixture was then transferred to a separatory funnel and extracted with ethyl acetate (3X 50 mL). After the organic phases were combined, they were washed with water (50mL) and dried over anhydrous sodium sulfate for 6 hours. And obtaining viscous light yellow liquid after rotary evaporation. Silica gel column chromatography (mobile phase: ethyl acetate: N-hexane: 1: 5) to obtain solid product 5-nitro-N1- (2- (pyrrolidin-1-yl) ethyl) benzene-1, 2-diamine 0.371g, yield 74%.
Example 5
To a 20mL Biotage reaction tube were added (E) -N' - (2-bromo-6-fluoro-4-nitrophenyl) -N, N-dimethylformamidine (2mmol,0.580g), DMSO (12mL), 2- (pyrrolidin-1-yl) ethylamine (10mmol,1.14g) and a magnetic stirrer, and the reaction tube was capped and placed in an oil bath with magnetic stirring to heat to 180 ℃ for 1 hour. TLC analysis showed the starting material (E) -N' - (2-fluoro-4-nitrophenyl) -N, N-dimethylformamidine remained present and continued for an additional 1 hour, TLC analysis showed disappearance of starting material. LC-MS analysis confirms the generation of the target product. After the reaction solution cooled to room temperature, it was poured into a 250mL round bottom flask containing water (50mL) and stirred for 10 minutes. The mixture was then transferred to a separatory funnel and extracted with ethyl acetate (3X 50 mL). After the organic phases were combined, they were washed with water (50mL) and dried over anhydrous sodium sulfate overnight. And obtaining viscous light yellow liquid after rotary evaporation. Silica gel column chromatography (mobile phase: ethyl acetate: N-hexane ═ 1: 6) to obtain solid product 3-bromo-5-nitro-N1- (2- (pyrrolidin-1-yl) ethyl) benzene-1, 2-diamine 0.290g, yield 44%.1H NMR(500MHz,DMSO-d6)δppm 1.65(m,4H),2.27(t,4H),2.60(t,2H),3.20(m,2H),4.10(br,1H),4.60(br,2H),7.41(s,1H),7.23(s,1H),6.49(m,1H)；HRMS calcd.for C12H17BrN4O2:328.0535,found 328.0527.
Example 6
To a 20mL Biotage reaction tube were added (E) -N' - (2-bromo-6-fluoro-4-nitrophenyl) -N, N-dimethylformamidine (2mmol,0.580g), DMSO (12mL), 2- (pyrrolidin-1-yl) ethylamine (10mmol,1.14g) and a magnetic stirrer, and the reaction tube was capped and placed in a microwave reaction oven (Biotage). The reaction was heated at 220 ℃ for 20 minutes and TLC analysis indicated the disappearance of the starting material (E) -N' - (2-bromo-6-fluoro-4-nitrophenyl) -N, N-dimethylformamidine. LC-MS analysis confirms the generation of the target product. After the reaction solution cooled to room temperature, it was poured into a 250mL round bottom flask containing water (50mL) and stirred for 10 minutes. The mixture was then transferred to a separatory funnel and extracted with ethyl acetate (3X 50 mL). After the organic phases were combined, they were washed with water (50mL) and dried over anhydrous sodium sulfate for 6 hours. And obtaining viscous light yellow liquid after rotary evaporation. Silica gel column chromatography (mobile phase: ethyl acetate: N-hexane ═ 1: 6) gave solid product 3-bromo-5-nitro-N' - (2- (pyrrolidin-1-yl) ethyl) benzene-1, 2-diamine 0.255g, 39% yield.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (8)
1. A method for synthesizing substituted o-phenylenediamine is characterized in that an N' - (2-fluorophenyl) -N, N-dimethyl formamidine derivative and an alkylamine derivative are heated to 180-220 ℃ for reaction to obtain the substituted o-phenylenediamine;
the reaction process is as follows:
wherein R is1Is nitro, R2Is hydrogen or bromine, R3Is 2-hydroxyethyl, 2-methoxyethyl, (tetrahydrofuran-2-yl) methyl, 2- (pyrrolidin-1-yl) ethyl;
the solvent adopted is dimethyl sulfoxide DMSO, N-dimethylformamide DMF or hexamethylphosphoric triamide HMPA.
2. The method of claim 1, wherein the N' - (2-fluorophenyl) -N, N-dimethylformamidine derivative is selected from the group consisting of:
3. the synthetic method according to claim 1, wherein R is3Is 2-hydroxyethyl or 2- (pyrrolidin-1-yl) ethyl.
4. The method according to claim 1, wherein the heating method is oil bath heating or microwave heating.
5. The method according to claim 1, wherein the molar ratio of the N' - (2-fluorophenyl) -N, N-dimethylformamidine derivative to the alkylamine derivative is 1:1 to 20.
6. The method as claimed in claim 1, wherein the N' - (2-fluorophenyl) -N, N-dimethylformamidine derivative is synthesized by the following steps: carrying out aldehyde-amine condensation reaction on the 2-fluoroaniline derivative and N, N-dimethylformamide to obtain an N' - (2-fluorophenyl) -N, N-dimethylformamidine derivative;
the reaction process is as follows:
wherein the content of the first and second substances,R1is nitro, R2Is hydrogen or bromine, R3Is 2-hydroxyethyl, 2-methoxyethyl, (tetrahydrofuran-2-yl) methyl, 2- (pyrrolidin-1-yl) ethyl.
7. The process according to claim 6, wherein the 2-fluoroaniline derivative is subjected to an aldehyde-amine condensation reaction with N, N-dimethylformamide in the presence of a catalyst which is benzenesulfonyl chloride.
8. The synthesis method according to claim 6, wherein the molar ratio of the 2-fluoroaniline derivative to the benzenesulfonyl chloride is 1: 1.5-2.5.
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Denomination of invention: A synthetic method for replacing o-phenylenediamine Granted publication date: 20210706 Pledgee: Zaozhuang Rural Commercial Bank Co.,Ltd. Xuecheng sub branch Pledgor: Shandong Kairui Chemical Co.,Ltd. Registration number: Y2024980008855 |