CN119431186A - Preparation method of N-alkylamino substituted benzonitrile compound - Google Patents
Preparation method of N-alkylamino substituted benzonitrile compound Download PDFInfo
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- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 title claims abstract description 17
- -1 benzonitrile compound Chemical class 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 239000012025 fluorinating agent Substances 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 16
- 150000008359 benzonitriles Chemical class 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 239000011698 potassium fluoride Substances 0.000 claims description 8
- 235000003270 potassium fluoride Nutrition 0.000 claims description 8
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 claims description 4
- 229910001634 calcium fluoride Inorganic materials 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000011775 sodium fluoride Substances 0.000 claims description 4
- 235000013024 sodium fluoride Nutrition 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 229910052784 alkaline earth metal Chemical class 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 150000004673 fluoride salts Chemical group 0.000 claims description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 3
- BRKFQVAOMSWFDU-UHFFFAOYSA-M tetraphenylphosphanium;bromide Chemical compound [Br-].C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BRKFQVAOMSWFDU-UHFFFAOYSA-M 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 150000003983 crown ethers Chemical class 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 claims description 2
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 150000004714 phosphonium salts Chemical group 0.000 claims description 2
- 229920000570 polyether Polymers 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 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 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 239000005703 Trimethylamine hydrochloride Substances 0.000 claims 1
- 125000005207 tetraalkylammonium group Chemical class 0.000 claims 1
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 10
- 239000003513 alkali Substances 0.000 abstract description 7
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- NHWQMJMIYICNBP-UHFFFAOYSA-N 2-chlorobenzonitrile Chemical group ClC1=CC=CC=C1C#N NHWQMJMIYICNBP-UHFFFAOYSA-N 0.000 description 4
- GDHXJNRAJRCGMX-UHFFFAOYSA-N 2-fluorobenzonitrile Chemical group FC1=CC=CC=C1C#N GDHXJNRAJRCGMX-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KMLGFOAKCYHXCQ-UHFFFAOYSA-N 4-(diethylamino)benzonitrile Chemical compound CCN(CC)C1=CC=C(C#N)C=C1 KMLGFOAKCYHXCQ-UHFFFAOYSA-N 0.000 description 2
- UUAVWKKVLMXOFV-UHFFFAOYSA-N 4-[ethyl(methyl)amino]benzonitrile Chemical compound CCN(C)C1=CC=C(C#N)C=C1 UUAVWKKVLMXOFV-UHFFFAOYSA-N 0.000 description 2
- ZNMSYUCZLWETII-UHFFFAOYSA-N 4-pyrrolidin-1-ylbenzonitrile Chemical compound C1=CC(C#N)=CC=C1N1CCCC1 ZNMSYUCZLWETII-UHFFFAOYSA-N 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004334 fluoridation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- GVWISOJSERXQBM-UHFFFAOYSA-N n-methylpropan-1-amine Chemical compound CCCNC GVWISOJSERXQBM-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- MPNXSZJPSVBLHP-UHFFFAOYSA-N 2-chloro-n-phenylpyridine-3-carboxamide Chemical compound ClC1=NC=CC=C1C(=O)NC1=CC=CC=C1 MPNXSZJPSVBLHP-UHFFFAOYSA-N 0.000 description 1
- GJNGXPDXRVXSEH-UHFFFAOYSA-N 4-chlorobenzonitrile Chemical compound ClC1=CC=C(C#N)C=C1 GJNGXPDXRVXSEH-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229910001515 alkali metal fluoride Inorganic materials 0.000 description 1
- 229910001618 alkaline earth metal fluoride Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011161 development Methods 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
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000002474 experimental method Methods 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
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of an N-alkylamino substituted benzonitrile compound, which comprises the step of reacting a compound shown in a formula (II) with a compound shown in a formula (III) in an organic solvent under the action of alkali, a fluorinating agent and a catalyst to obtain the compound shown in the formula (I). The preparation method provided by the invention directly obtains the target compound by adopting one-step reaction, and has the advantages of low raw material cost, high yield, convenience in operation and the like.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of an N-alkylamino substituted benzonitrile compound.
Background
N-alkylamino substituted benzonitrile compounds are important organic synthesis intermediates and are widely applied to the fields of pesticides, medicines, dyes, materials and the like. The existing preparation method mainly comprises the following steps:
the first method takes amino-substituted benzonitrile and different alkylating reagents as raw materials, and the target product is obtained through two-step substitution reaction in the presence of alkali:
In the second method, fluorobenzonitrile and alkyl substituted primary amine are used as raw materials, an intermediate is obtained through substitution reaction in the presence of alkali, and then the intermediate is reacted with an alkylating reagent to obtain a target product:
In the third method, chlorobenzonitrile and alkyl substituted secondary amine are used as raw materials, and a target product is directly obtained under the catalysis of a metal catalyst:
Analysis of the three preparation methods shows that the first method has the problems of high raw material cost, low reaction selectivity, low yield of less than 50 percent, low yield, difficult purification and the like, the second method also has the problems of high raw material cost, the third method needs to use an expensive metal catalyst, and the reaction condition is harsh, and usually needs to be carried out under the conditions of high temperature, no water and the like. Therefore, development of a new process route suitable for industrial production is required.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of N-alkylamino substituted benzonitrile compounds, which directly obtains target compounds by adopting one-step reaction and has the advantages of low raw material cost, high yield, convenient operation and the like.
The preparation method of the N-alkylamino substituted benzonitrile compound comprises the following steps of:
reacting a compound shown in a formula (II) with a compound shown in a formula (III) in an organic solvent under the action of fluoride to obtain a compound shown in a formula (I):
in the compounds shown in the structural formula, each substituent is as follows:
R 1、R2 is each independently selected from hydrogen, C 1-C6 alkyl, halogenated C 1-C6 alkyl, C 3-C6 cycloalkyl, halogenated C 3-C6 cycloalkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, or The structure is in a ring-closure form;
x is selected from chlorine, bromine or iodine;
R 3 is selected from hydrogen, C 1-C6 alkyl, halogenated C 1-C6 alkyl, C 3-C6 cycloalkyl, halogenated C 3-C6 cycloalkyl, C 1-C6 alkoxy, halogenated C 1-C6 alkoxy, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkylcarbonyl, C 1-C6 alkoxycarbonyl, C 1-C6 alkanoyloxy, cyano, hydroxy, amino or nitro;
n is an integer of 0 to 3.
Wherein the organic solvent is at least one selected from tetrahydrofuran, 1, 4-dioxane, acetonitrile, propionitrile, acetone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.
Preferably, the organic solvent is at least one selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone.
Wherein the fluoride is selected from inorganic fluorinating agents selected from alkali metal and alkaline earth metal fluoride salts or organic fluorinating agents selected from tetraalkylammonium fluoride salts.
Preferably, the inorganic fluorinating agent is at least one selected from sodium fluoride, potassium fluoride, cesium fluoride and calcium fluoride, and the organic base is at least one selected from triethylamine, diisopropylethylamine, pyridine and N, N-dimethylaminopyridine.
The reaction system further comprises a base and a catalyst, wherein the base is selected from inorganic base or organic base, the inorganic base is selected from carbonate, bicarbonate or hydroxide of alkali metal and alkaline earth metal, the organic base is selected from one of sodium alkoxide of C 1-C4, potassium alkoxide of C 1-C4, triethylamine, diisopropylethylamine, pyridine, N-dimethylaminopyridine and picoline, and the catalyst is selected from crown ether, polyether, tertiary amine, quaternary ammonium salt or quaternary phosphonium salt.
Preferably, the inorganic fluorinating agent is at least one selected from sodium fluoride, potassium fluoride, cesium fluoride and calcium fluoride, the organic fluorinating agent is at least one selected from tetramethyl ammonium fluoride and tetrabutyl ammonium fluoride, and the catalyst is at least one selected from trimethyl ammonium chloride, tetrabutyl ammonium bromide, tetraphenyl phosphonium bromide and methyltriphenyl phosphonium bromide.
Wherein the saidThe structure is selected from any one of the following:
Wherein R 4 is selected from hydrogen, C 1-C6 alkyl, halogenated C 1-C6 alkyl, C 3-C6 cycloalkyl and halogenated C 3-C6 cycloalkyl, and m is an integer of 0 to 3.
Under the condition of using alkali and a catalyst, the mol ratio of the compound shown in the formula (II), the compound shown in the formula (III), the alkali, the fluoride and the catalyst is (1-10): 1 (0-5): 0-1, the reaction temperature is 0-250 ℃, and the reaction time is 1-24 hours.
Preferably, when the base and the catalyst are used, the molar ratio of the compound shown in the formula (II), the compound shown in the formula (III), the base, the fluoride and the catalyst is (2-5): 1 (0-2): 0-1): 0-0.2, the reaction temperature is 60-180 ℃, and the reaction time is 4-12 hours.
Preferably, in the preparation process of the invention:
Preferably, R 1、R2 is independently selected from C 1-C3 alkyl, C 3-C6 cycloalkyl, or The structure is in a ring-closing form:
Preferably, R 4 is independently selected from hydrogen, C 1-C3 alkyl;
Preferably, m is an integer of 0 to 2.
Preferably, the substituents X are independently selected from chloro.
Preferably, R 3 is independently selected from hydrogen, C 1-C3 alkyl, C 1-C3 alkoxy, C 1-C3 alkylcarbonyl, C 1-C3 alkoxycarbonyl, C 1-C3 alkanoyloxy.
Preferably, n is an integer of 0 to 2.
The invention uses cheap and easily available chlorobenzonitrile to replace fluorobenzonitrile as a raw material, adopts one-step reaction to directly synthesize the target compound, and solves the problems that the chlorobenzonitrile has low reaction activity and can not directly generate amination reaction with alkylamine. The conventional method is to prepare the fluorobenzonitrile with higher reaction activity by firstly using the chlorobenzonitrile, and then react the fluorobenzonitrile with alkylamine to prepare the N-alkylamino substituted benzonitrile. The method has the defects that two steps of reaction are required to be carried out for two post-treatments, the operation is complex, the three wastes are generated, the first step of reaction requires to add excessive fluoridation reagent (usually 1-2 equivalents of potassium fluoride), and the second step of reaction requires to add alkali and solvent again. The invention only needs to throw in a small amount of fluoridation reagent (about 0.4 equivalent of potassium fluoride and the potassium fluoride can be recycled in the reaction process), and the alkali and the solvent only need to throw in one time, thus having the advantages of low raw material cost, high yield, convenient operation and the like.
Compared with the prior art, the invention has the following advantages:
The invention provides a brand new preparation method of N-alkylamino substituted benzonitrile compounds, which directly obtains target compounds by adopting one-step reaction and has the advantages of low raw material cost, high yield, convenient operation and the like.
Detailed Description
The invention will be further illustrated with reference to the following specific examples, without limiting the invention to these specific embodiments. It will be appreciated by those skilled in the art that the invention encompasses all alternatives, modifications and equivalents as may be included within the scope of the claims.
The experimental methods described in the examples are conventional methods unless otherwise specified, and the materials, reagents, etc. used in the examples are commercially available.
Example 1
Synthesis of 4- (N-ethyl-N-methylamino) benzonitrile (CAS: 154667-33-1)
4-Chlorobenzonitrile (5 g,36.3 mmol), N-methylethylamine (8.59 g,145.4 mmol), spray dried potassium fluoride (0.85 g,14.5 mmol), tetraphenylphosphonium bromide (0.76 g,1.82 mmol), anhydrous potassium carbonate (5.01 g,36.3 mmol) and 40ml of N, N-dimethylacetamide were added to a reaction vessel, the reaction vessel was closed, and heated to 150℃for 14 hours. Cooling after the reaction, vacuum filtering, adding deionized water 100ml into the filtrate, extracting with ethyl acetate (100 ml x 2), washing the organic phase with saturated saline water (50 ml), drying with anhydrous magnesium sulfate, filtering, concentrating the filtrate, vacuum distilling, collecting 120-130 ℃ per 0.7mbar fraction to obtain 4- (N-ethyl-N-methylamino) benzonitrile pure product 5.5g, yield 95％.1HNMR(CDCl3,400MHz)δ:7.44(d,J＝9.2Hz,2H,Ph-H),6.62(d,J＝9.2Hz,2H,Ph-H),3.44(q,J＝7.2Hz,2H,-CH2),2.98(s,3H,-CH3),1.15(t,J＝7.2Hz,3H,-CH3).
Example 2
Synthesis of 4- (N-N-propyl-N-methylamino) benzonitrile (CAS: 1094931-44-8)
N-methyl-N-propylamine (7.96 g,108.9 mmol) was used in place of N-methylethylamine in example 1, the remainder was the same as in example 1, and the final yield was 92％.1H NMR(CDCl3,400MHz)δ:7.44(d,J＝9.2Hz,2H,Ph-H),6.61(d,J＝8.8Hz,2H,Ph-H),3.33(t,J＝7.6Hz,2H,-CH2),3.00(s,3H,-CH3),1.66-1.57(m,2H,-CH2),0.94(t,J＝7.6Hz,3H,-CH3).
Example 3
Synthesis of 4- (N, N-diethylamino) benzonitrile (CAS: 2873-90-7)
N-methylethylamine in example 1 was replaced with diethylamine (7.96 g,108.9 mmol), and the remaining operations were the same as in example 1, with a final yield of 93％.1HNMR(CDCl3,400MHz)δ:7.42(d,J＝9.2Hz,2H,Ph-H),6.59(d,J＝8.8Hz,2H,Ph-H),3.38(q,J＝7.2Hz,4H,-CH2),1.17(t,J＝7.2Hz,6H,-CH3).
Example 4
Synthesis of 4- (tetrahydropyrrole-1-yl) benzonitrile (CAS: 10282-30-1)
The procedure of example 1 was repeated except that tetrahydropyrrole (7.74 g,108.9 mmol) was used instead of N-methylethylamine in example 1 to give a final yield 92％.1H NMR(CDCl3,400MHz)δ:7.38(d,J＝8.8Hz,2H,Ph-H),6.45(d,J＝8.8Hz,2H,Ph-H),3.27(t,J＝6.4Hz,4H,-CH2),2.02-1.99(m,4H,-CH2).
Examples 5 to 15
Referring to the method of example 1, N-alkylamino substituted benzonitriles as shown in examples 5 to 15 in Table 1 below can be prepared. The substituent R 1-R3 in Table 1 is a substituent of the compound represented by the formula (I),
TABLE 1
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