CN117362186A - Aromatic compound nitration method, nitrobenzene compound and nitroaniline compound preparation method - Google Patents
Aromatic compound nitration method, nitrobenzene compound and nitroaniline compound preparation method Download PDFInfo
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- CN117362186A CN117362186A CN202311295504.6A CN202311295504A CN117362186A CN 117362186 A CN117362186 A CN 117362186A CN 202311295504 A CN202311295504 A CN 202311295504A CN 117362186 A CN117362186 A CN 117362186A
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- nitric acid
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- 238000000034 method Methods 0.000 title claims abstract description 166
- 150000001491 aromatic compounds Chemical class 0.000 title claims abstract description 52
- -1 nitrobenzene compound Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000006396 nitration reaction Methods 0.000 title claims description 10
- 239000002904 solvent Substances 0.000 claims abstract description 58
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- 229940125904 compound 1 Drugs 0.000 claims abstract description 52
- 230000001546 nitrifying effect Effects 0.000 claims abstract description 44
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 37
- 229940126214 compound 3 Drugs 0.000 claims abstract description 29
- 229940125782 compound 2 Drugs 0.000 claims abstract description 26
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 25
- 238000002156 mixing Methods 0.000 claims abstract description 20
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 14
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 238000002844 melting Methods 0.000 claims abstract description 7
- 230000008018 melting Effects 0.000 claims abstract description 7
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- 150000002367 halogens Chemical class 0.000 claims description 29
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical class [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 14
- 125000001188 haloalkyl group Chemical group 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000002252 acyl group Chemical group 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 22
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 16
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 16
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 16
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 16
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 15
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 12
- 238000012216 screening Methods 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 11
- 239000011737 fluorine Substances 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 229910017604 nitric acid Inorganic materials 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- FYSIGSQCZXQTIH-UHFFFAOYSA-N 4-fluoro-2-methoxy-5-nitroaniline Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1N FYSIGSQCZXQTIH-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 108010075324 emt protein-tyrosine kinase Proteins 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000005181 nitrobenzenes Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 101001050476 Homo sapiens Tyrosine-protein kinase ITK/TSK Proteins 0.000 description 1
- 102100023345 Tyrosine-protein kinase ITK/TSK Human genes 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZDGGJQMSELMHLK-UHFFFAOYSA-N m-Trifluoromethylhippuric acid Chemical compound OC(=O)CNC(=O)C1=CC=CC(C(F)(F)F)=C1 ZDGGJQMSELMHLK-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
Abstract
The invention relates to the field of organic synthesis, in particular to a method for nitrifying an aromatic compound, a nitrobenzene compound and a method for preparing the nitroaniline compound. In the method for nitrifying the aromatic compound, the reaction formula is as follows:wherein R is 1 Selected from-OR 3 、‑OH、‑NHCOR 3 、R 3 Any one of R 2 Either or both R selected from C1-C4 haloalkyl, -H, C1-C4 alkyl 2 Anhydride bound to five-or six-membered atomsA ring, X is selected from halogen, R 3 An alkyl group selected from C1-C6, the preparation method comprising: mixing the compound 1, the compound 2 and the first solvent, adding fuming nitric acid, and performing post-treatment to obtain a compound 3; or mixing the compound 1 and the compound 2 with the melting point less than or equal to 20 ℃, adding fuming nitric acid, and performing post-treatment to obtain the compound 3. In the method for nitrifying the aromatic compound, the acid anhydride is used as a reaction reagent, the acyl is introduced to protect the amino, and then the nitrifying is performed, so that the reaction process is mild, the target product can be prepared by a one-pot method, and the reaction yield is improved.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a method for nitrifying an aromatic compound, a nitrobenzene compound and a method for preparing the nitroaniline compound.
Background
Chinese patent CN 115087655a discloses a benzimidazole derivative, which is useful as an inhibitor of interleukin-2 inducible T cell kinase (ITK) for the treatment of diseases mediated by ITK, in particular skin diseases such as dermatitis (e.g. atopic dermatitis), 4-fluoro-2-methoxy-5-nitroaniline being an important intermediate for the synthesis of the above compounds.
In the prior art, there are various methods for introducing nitro groups into aromatic compounds, but the reaction process of the methods is severe, and the methods have a certain danger in industrial production.
For example, chinese patent CN 110078732a discloses a method for preparing 4-fluoro-2-methoxy-5-nitroaniline by using concentrated sulfuric acid as solvent and potassium nitrate as nitrifying agent, said method is a conventional method for introducing nitro group, and its reaction yield is 83.7%.
For another example, patent WO 2018207120A1 discloses a method for preparing 4-fluoro-2-methoxy-5-nitroaniline by protecting amino group with acetyl group, then nitrifying and deprotecting, wherein concentrated sulfuric acid is used as solvent, nitro group is introduced by reacting with fuming nitric acid, the total yield of two steps of acetyl group protection and nitro group introduction is 65.1%, and the yield is lower.
In summary, the existing methods for preparing 4-fluoro-2-methoxy-5-nitroaniline all use strong acid as solvent, which has high requirements on reaction equipment and pollution, and a large amount of alkali is needed for neutralization in the post-treatment.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a method for nitrifying an aromatic compound under mild reaction conditions in a relatively high yield, and to provide a nitrobenzene compound and a method for producing nitroaniline compounds using the same.
In a first aspect, the invention provides a process for the nitration of an aromatic compound having the formula:
wherein R is 1 Selected from-OR 3 、-OH、-NHCOR 3 、R 3 Any one of the above-mentioned materials,
R 2 either or both R selected from C1-C4 haloalkyl, -H, C1-C4 alkyl 2 Bonded to form a five-membered or six-membered anhydride ring,
the haloalkyl is a halogen substituted for one or more hydrogens on the alkyl,
x is selected from halogen, and the halogen is selected from halogen,
R 3 selected from the group consisting of C1-C6 alkyl,
the preparation method comprises the following steps:
mixing the compound 1, the compound 2 and the first solvent, adding fuming nitric acid, post-treating to obtain a compound 3,
the first solvent is an aprotic acid solvent.
In a second aspect, the invention provides another process for the nitration of aromatic compounds having the formula:
wherein R is 1 Selected from-OR 3 、-OH、-NHCOR 3 、R 3 Any one of the above-mentioned materials,
R 2 either or both R selected from C1-C4 haloalkyl, -H, C1-C4 alkyl 2 Bonded to form a five-membered or six-membered anhydride ring,
the haloalkyl is a halogen substituted for one or more hydrogens on the alkyl,
x is selected from halogen, and the halogen is selected from halogen,
R 3 selected from the group consisting of C1-C6 alkyl,
the preparation method comprises the following steps:
mixing the compound 1 with the compound 2 with the melting point less than or equal to 20 ℃, adding fuming nitric acid, and performing post-treatment to obtain the compound 3.
The third aspect of the invention provides a nitrobenzene compound with the following structural formula:
in formula 3a, X is selected from halogen.
In a fourth aspect, the present invention provides a method for preparing nitroaniline compounds, the reaction formula is as follows:
wherein R is 1 Selected from-OR 3 、-OH、-NHCOR 3 、R 3 Any one of the above-mentioned materials,
R 2 either or both R selected from C1-C4 haloalkyl, -H, C1-C4 alkyl 2 Bonded to form a five-membered or six-membered anhydride ring,
the haloalkyl is a halogen substituted for one or more hydrogens on the alkyl,
x is selected from halogen, and the halogen is selected from halogen,
R 3 selected from the group consisting of C1-C6 alkyl,
comprises any one of the following two preparation methods:
the method comprises the following steps: step A1: mixing the compound 1, the compound 2 and the first solvent, adding fuming nitric acid, post-treating to obtain a compound 3,
and (B) step (B): mixing the compound 3, alkali or hydrochloric acid and a second solvent, reacting completely to obtain a compound 4,
the second method is as follows: step A2: mixing the compound 1 and the compound 2 with the melting point less than or equal to 20 ℃, adding fuming nitric acid, post-treating to obtain a compound 3,
and (B) step (B): and mixing the compound 3, alkali or hydrochloric acid and a second solvent, and obtaining the compound 4 after the reaction is completed.
Compared with the prior art, the invention has the following beneficial effects:
according to the method for nitrifying the aromatic compound, the acid anhydride is used as a reaction reagent, the acyl is introduced to protect the amino, and then the nitrifying is carried out, so that the reaction process is mild, the target product can be prepared by a one-pot method, and the reaction yield is improved. The highest reaction yield can reach 92.2 percent.
According to the method for preparing nitroaniline compound, the target product can be obtained in high yield because of selecting alkali or hydrochloric acid. The highest reaction yield can reach 91.9 percent.
Drawings
FIG. 1 is a schematic illustration of the product of example 1 of the present invention 1 HNMR diagram.
Detailed Description
Embodiments of a specifically disclosed method for nitrifying an aromatic compound, a nitrobenzene compound, and a method for producing an nitroaniline compound are described in detail below.
Definition of terms
The following words, phrases and symbols used in the present specification have the meanings as described below in general unless otherwise indicated.
Generally, the nomenclature used herein (e.g., IUPAC nomenclature) and the laboratory procedures described below (including those used in cell culture, organic chemistry, analytical chemistry, pharmacology, and the like) are those well known and commonly employed in the art. Unless defined otherwise, all scientific and technical terms used herein in connection with the disclosure described herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, in the claims and/or the specification, the terms "a" or "an" when used in conjunction with the term "comprising" or noun may have the meaning of "one" but are also consistent with the meaning of "one or more", "at least one", and "one or more". Similarly, the term "another" or "other" may mean at least a second or more.
It will be understood that whenever aspects are described herein by the terms "comprising" or "including," other similar aspects are provided as described by "consisting of …" and/or "consisting essentially of ….
The term "alkyl" used herein, alone or in combination, may be straight or branched, and the number of carbon atoms may be, for example, C1 to C6, C1 to C5, C1 to C4, C1 to C3, or C1 to C2, etc. By way of example, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and the like.
In the term "haloalkyl" used herein, alone or in combination, haloalkyl is a halogen substituted for one or more hydrogens on the alkyl, and the number of carbon atoms may be, for example, C1-C4, C1-C3, or C1-C2, etc. By way of example, haloalkyl includes, but is not limited to, -CF 3 、-CHF 2 、-CH 2 F、-CH 2 CF 3 Etc.
In this context, bonding to form a ring means that an anhydride ring, in particular a five-or six-membered anhydride ring, is formed.
The term "halogen" as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.
Method for nitrifying aromatic compound
In a first aspect, the invention provides a process for the nitration of aromatic compounds having the characteristics of the formula:
wherein R is 1 Selected from-OR 3 、-OH、-NHCOR 3 、R 3 Any one of R 2 Either or both R selected from C1-C4 haloalkyl, -H, C1-C4 alkyl 2 Bonded to a five-or six-membered anhydride ring, said haloalkyl groups being substituted with halogen in one or more hydrogens on the alkyl group, X being selected from halogen, R 3 Selected from the group consisting of C1-C6 alkyl,
the preparation method comprises the following steps:
and mixing the compound 1, the compound 2 and a first solvent, adding fuming nitric acid, and performing post-treatment to obtain a compound 3, wherein the first solvent is an aprotic acid solvent.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: r is R 1 Selected from-OR 3 Wherein R is 3 Selected from C1-C6 alkyl groups. Alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Further alternatively, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: r is R 1 Selected from-OH.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: r is R 1 Selected from the group consisting of NHCOR 3 Wherein R is 3 Selected from C1-C6 alkyl groups. Alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Further alternatively, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein R is 1 Selected from R 3 Wherein R is 3 Selected from C1-C6 alkyl groups. Alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Further alternatively, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein, preferably, R 1 Selected from-OCH 3 。
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein R is 2 Selected from C1-C4 haloalkyl, optionally R 2 Selected from-CF 3 、-CHF 2 、-CH 2 F、-CH 2 CF 3 Etc., preferably R 2 Selected from-CF 3 。
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein R is 2 Selected from-H.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein R is 2 Selected from C1-C4 alkyl groups. Alternatively, R 2 Selected from C1-C3 alkyl groups. Further alternatively, R 2 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein two R 2 And is bonded to form a five-membered or six-membered anhydride ring. For example
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein the compound 1 isAlternatively, R 3 Selected from C1-C6 alkyl groups. Further alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Preferably, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl. Alternatively, X is selected from fluorine, chlorine, bromine or iodine. Preferably, X is fluorine.
Preferably, when R 3 When methyl and X are fluorine, the compound 1 is
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein the first solvent is selected from any one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, N-dimethylformamide, dimethyl sulfoxide and methyl tertiary butyl ether.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein the molar ratio of the compound 1 to the compound 2 is 1: (1.0-2.0). Alternatively, the molar ratio of compound 1 to compound 2 may be, for example, 1: (1.0-1.2), 1: (1.2-2), 1: (1.0-1.5) or 1: (1.5-2), etc.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein the molar ratio of the compound 1 to the fuming nitric acid is 1: (1.0-2.0). Alternatively, the molar ratio of the compound 1 to the fuming nitric acid may be, for example, 1: (1.0-1.2), 1: (1.2-2), 1: (1.0-1.5) or 1: (1.5-2), etc.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein the mass volume ratio of the compound 1 to the first solvent is 1g: (3.0-5.0) mL. Optionally, the mass to volume ratio of the compound 1 to the first solvent is 1g: (3.0-4.0) mL or 1g: (4.0-5.0) mL, etc.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein the reaction temperature is 0-20 ℃. Alternatively, the reaction temperature may be, for example, 0℃to 5℃5℃to 20℃5℃to 10℃10℃to 15℃or 15℃to 20 ℃.
Method for nitrifying aromatic compound
In a second aspect the invention provides a further process for the nitration of aromatic compounds having the characteristics of the formula:
wherein R is 1 Selected from-OR 3 、-OH、-NHCOR 3 、R 3 Any one of R 2 Either or both R selected from C1-C4 haloalkyl, -H, C1-C4 alkyl 2 Bonded to a five-or six-membered anhydride ring, said haloalkyl groups being substituted with halogen in one or more hydrogens on the alkyl group, X being selected from halogen, R 3 Selected from the group consisting of C1-C6 alkyl,
the preparation method comprises the following steps:
mixing the compound 1 with the compound 2 with the melting point less than or equal to 20 ℃, adding fuming nitric acid, and performing post-treatment to obtain the compound 3.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: r is R 1 Selected from-OR 3 Wherein R is 3 Selected from C1-C6 alkyl groups. Alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Further alternatively, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
The method for nitrifying an aromatic compound according to the present invention may have such a feature that：R 1 Selected from-OH.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: r is R 1 Selected from the group consisting of NHCOR 3 Wherein R is 3 Selected from C1-C6 alkyl groups. Alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Further alternatively, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein R is 1 Selected from R 3 Wherein R is 3 Selected from C1-C6 alkyl groups. Alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Further alternatively, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein, preferably, R 1 Selected from-OCH 3 。
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein R is 2 Selected from C1-C4 haloalkyl, optionally R 2 Selected from-CF 3 、-CHF 2 、-CH 2 F、-CH 2 CF 3 Etc., preferably R 2 Selected from-CF 3 。
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein R is 2 Selected from-H.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein R is 2 Selected from C1-C4 alkyl groups. Alternatively, R 2 Selected from C1-C3 alkyl groups. Further alternatively, R 2 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
The method for nitrifying an aromatic compound according to the present invention may further comprise the steps ofIs characterized by: wherein two R 2 And is bonded to form a five-membered or six-membered anhydride ring. For example
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein the compound 1 isAlternatively, R 3 Selected from C1-C6 alkyl groups. Further alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Preferably, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl. Alternatively, X is selected from fluorine, chlorine, bromine or iodine. Preferably, X is fluorine.
Preferably, when R 3 When methyl and X are fluorine, the compound 1 is
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein the molar ratio of the compound 1 to the fuming nitric acid is 1: (1.0-2.0). Alternatively, the molar ratio of the compound 1 to the fuming nitric acid may be, for example, 1: (1.0-1.2), 1: (1.2-2), 1: (1.0-1.5) or 1: (1.5-2), etc.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein the mass volume ratio of the compound 1 to the compound 2 is 1g: (8.0-10.0) mL. Alternatively, the mass to volume ratio of the compound 1 to the compound 2 may be, for example, 1g: (8.0-9.0) mL or 1g: (9.0-10.0) mL, etc.
In the method for nitrifying an aromatic compound provided by the present invention, the method may further have the following features: wherein the reaction temperature is 0-20 ℃. Alternatively, the reaction temperature may be, for example, 0℃to 5℃5℃to 20℃5℃to 10℃10℃to 15℃or 15℃to 20 ℃.
Nitrobenzene compounds
The third aspect of the invention provides a nitrobenzene compound, which has the characteristics as follows:
in formula 3a, X is selected from halogen. Wherein halogen may for example refer to fluorine, chlorine, bromine or iodine.
The nitrobenzene compounds provided by the invention can also have the following characteristics: preferably, formula 3a is
Process for preparing nitroanilines
The invention provides a method for preparing nitroaniline compounds, which has the characteristics that the reaction formula is as follows:
wherein R is 1 Selected from-OR 3 、-OH、-NHCOR 3 、R 3 Any one of the above-mentioned materials,
R 2 either or both R selected from C1-C4 haloalkyl, -H, C1-C4 alkyl 2 Bonded to a five-or six-membered anhydride ring, said haloalkyl groups being substituted with halogen in one or more hydrogens on the alkyl group, X being selected from halogen, R 3 Selected from the group consisting of C1-C6 alkyl,
comprises any one of the following two preparation methods:
the method comprises the following steps: step A1: mixing the compound 1, the compound 2 and the first solvent, adding fuming nitric acid, post-treating to obtain a compound 3,
and (B) step (B): mixing the compound 3, alkali or hydrochloric acid and a second solvent, reacting completely to obtain a compound 4,
the second method is as follows: step A2: mixing the compound 1 and the compound 2 with the melting point less than or equal to 20 ℃, adding fuming nitric acid, post-treating to obtain a compound 3,
and (B) step (B): and mixing the compound 3, alkali or hydrochloric acid and a second solvent, and obtaining the compound 4 after the reaction is completed.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein R is 1 Selected from-OR 3 Wherein R is 3 Selected from C1-C6 alkyl groups. Alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Further alternatively, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: r is R 1 Selected from-OH.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: r is R 1 Selected from the group consisting of NHCOR 3 Wherein R is 3 Selected from C1-C6 alkyl groups. Alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Further alternatively, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein R is 1 Selected from R 3 Wherein R is 3 Selected from C1-C6 alkyl groups. Alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Further alternatively, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein, preferably, R 1 Selected from-OCH 3 。
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein R is 2 Selected from C1-C4 haloalkyl, optionally R 2 Selected from-CF 3 、-CHF 2 、-CH 2 F、-CH 2 CF 3 Etc., preferably R 2 Selected from-CF 3 。
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein R is 2 Selected from-H.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein R is 2 Selected from C1-C4 alkyl groups. Alternatively, R 2 Selected from C1-C3 alkyl groups. Further alternatively, R 2 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein two R 2 And is bonded to form a five-membered or six-membered anhydride ring. For example
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein the compound 1 isAlternatively, R 3 Selected from C1-C6 alkyl groups. Further alternatively, R 3 Selected from the group consisting of C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl. Preferably, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl. Alternatively, X is selected from fluorine, chlorine, bromine or iodine. Preferably, X is fluorine.
Preferably, when R 3 When methyl and X are fluorine, the compound 1 is
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: in the step A1, the first solvent is an aprotic acid solvent, and optionally, the first solvent is selected from any one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, N-dimethylformamide, dimethyl sulfoxide and methyl tert-butyl ether.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein in step A1, the molar ratio of the compound 1 to the compound 2 is 1: (1.0-2.0). Alternatively, the molar ratio of compound 1 to compound 2 may be, for example, 1: (1.0-1.2), 1: (1.2-2), 1: (1.0-1.5) or 1: (1.5-2), etc.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein in the step A1, the molar ratio of the compound 1 to the fuming nitric acid is 1: (1.0-2.0). Alternatively, the molar ratio of the compound 1 to the fuming nitric acid may be, for example, 1: (1.0-1.2), 1: (1.2-2), 1: (1.0-1.5) or 1: (1.5-2), etc.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: in the step A1, the mass volume ratio of the compound 1 to the first solvent is 1g: (3.0-5.0) mL. Optionally, the mass to volume ratio of the compound 1 to the first solvent is 1g: (3.0-4.0) mL or 1g: (4.0-5.0) mL, etc.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein, in the step A1, the reaction temperature is 0-20 ℃. Alternatively, the reaction temperature may be, for example, 0℃to 5℃5℃to 20℃5℃to 10℃10℃to 15℃or 15℃to 20 ℃.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein in the step A2, the molar ratio of the compound 1 to the fuming nitric acid is 1: (1.0-2.0). Alternatively, the molar ratio of the compound 1 to the fuming nitric acid may be, for example, 1: (1.0-1.2), 1: (1.2-2), 1: (1.0-1.5) or 1: (1.5-2), etc.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein in the step A2, the mass-volume ratio of the compound 1 to the compound 2 is 1g: (8.0-10.0) mL. Alternatively, the mass to volume ratio of the compound 1 to the compound 2 may be, for example, 1g: (8.0-9.0) mL or 1g: (9.0-10.0) mL, etc.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein, in the step A2, the reaction temperature is 0-20 ℃. Alternatively, the reaction temperature may be, for example, 0℃to 5℃5℃to 20℃5℃to 10℃10℃to 15℃or 15℃to 20 ℃.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: in the step B, the second solvent is any one of methanol and ethanol.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: in the step B, the alkali is any one of potassium carbonate and sodium carbonate.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein in the step B, the mass volume ratio of the compound 3 to the alkali is 1g: (4-6) mL. Alternatively, the mass to volume ratio of the compound 3 to the base may be 1g: (4-5) mL or 1g: (5-6) mL, etc.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: in step B, the mass-to-volume ratio of the compound 3 to the hydrochloric acid may be, for example, 1g: (4-6) mL. Alternatively, the mass to volume ratio of the compound 3 to the hydrochloric acid may be, for example, 1g: (4-5) mL or 1g: (5-6) mL.
In the method for preparing nitroaniline compounds provided by the invention, the method can also have the following characteristics: wherein in the step B, the mass-volume ratio of the compound 3 to the second solvent is 1g: (4-6) mL. Alternatively, the mass to volume ratio of the compound 3 to the second solvent may be, for example, 1g: (4-5) mL or 1g: (5-6) mL.
In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention is specifically described below with reference to the embodiments and the drawings.
In the examples described below, each of the reaction materials was a commercially available product unless otherwise specified.
The purity of each product of each example of the present invention exceeded 98% unless specifically stated.
Example 1 ]
Preparation of Compound 3a
This example provides a process for the preparation of compound 3a, having the following formula:
the method comprises the following steps:
under the protection of nitrogen, 40g of compound 1a (0.28 mol,1.0 eq), 71.42g of compound 2a (0.34 mol,1.2 eq) and 160mL of methylene chloride are added into a reaction vessel, stirred for 4 hours at 5 ℃, 21.42g of fuming nitric acid (0.34 mol,1.2 eq) is added dropwise, stirred for 16 hours at 5 ℃, 20% by mass of sodium bicarbonate solution is added, the pH is adjusted to 7, filtration is carried out, a filter cake is taken, the filtrate is separated, an organic phase is taken, the organic phase and the filter cake are combined, the solvent is distilled off under reduced pressure, n-heptane is added for washing, and the yield is 92.2%.
Of products 1 The HNMR spectra are shown in FIG. 1.
Example 2 ]
Preparation of Compound 3b
This example provides a method for preparing compound 3b, which has the following reaction formula:
the method comprises the following steps:
under the protection of nitrogen, 40g of compound 1a (0.28 mol,1.0 eq) and 320mL of acetic anhydride are added into a reaction vessel, stirred for 4 hours at 5 ℃, 21.42g of fuming nitric acid (0.34 mol,1.2 eq) is added dropwise, stirred for 16 hours at 5 ℃, 800mL of water is added, stirred, filtered, and the filter cake is dried to constant weight at 50 ℃ by blowing air, and the yield is 76.6%.
Example 3 ]
Screening of first solvent in method one
In this example, the first solvent was selected in method one on the basis of example 1, and the other steps were the same as those described in example 1 except for the parameters listed in the following table. Wherein, number 3 corresponds to example 1.
The screening results are shown in Table 1.
TABLE 1 screening of first solvents
| Sequence number | First solvent | Product yield (%) |
| 1 | 98wt% sulfuric acid | 45.7 |
| 2 | Acetic acid a | N.R |
| 3 | Dichloromethane (dichloromethane) | 92.2 |
a is the reaction temperature of 25 ℃.
As can be seen from the above table, when the first solvent is acetic acid, a large amount of raw materials remain, no product is produced, when the first solvent is sulfuric acid, the yield of the product is only 45.7%, the reaction effect is poor, and when the first solvent is dichloromethane, the yield of the product is high.
Example 4 ]
Screening of nitric acid concentration
In this example, nitric acid concentration was selected based on example 1, and the procedure was the same as that described in example 1 except for the parameters listed in the following table. Wherein, the number 1 corresponds to the embodiment 1.
The screening results are shown in Table 2.
TABLE 2 screening of nitric acid concentrations
| Sequence number | Concentration of nitric acid (%) | Product yield (%) |
| 1 | 98 | 92.2 |
| 2 | 68 | N.R |
| 3 | 68 b | 43.2 |
b is the reaction temperature of 40 DEG C
As is clear from the above table, when the concentration of the nitric acid is 68%, no product is produced at 5 ℃ and the reaction can be carried out at 40 ℃, but the reaction yield is only 43.2%; when the concentration of the nitric acid is 98%, the yield of the product is higher, so fuming nitric acid is selected as a reaction reagent.
Example 5 ]
Screening of solvent and its dosage in method II
In this example, the solvent and the amount thereof used in method two were selected based on example 2, and the procedure was the same as that described in example 2, except for the parameters listed in the following table. Wherein, number 1 corresponds to example 2.
The screening results are shown in Table 3.
TABLE 3 screening of solvents and amounts thereof in method two
| Sequence number | Solvent and dosage thereof in method II | Product yield (%) |
| 1 | Acetic anhydride (320 mL) | 76.6 |
| 2 | Dichloromethane (160 mL) and acetic anhydride (80 mL) | 49.7 |
| 3 | Dichloromethane (160 mL) and 98wt% sulfuric acid (80 mL) | 27.9 |
As is clear from the above table, when the solvent was methylene chloride and acetic anhydride, the yield of the product was low, 49.7%, and when the solvent was methylene chloride and sulfuric acid, the yield of the product was only 27.9%, and therefore acetic anhydride was the most preferable solvent.
Example 6 ]
Preparation of Compound 4a
This example provides a process for the preparation of compound 4a, having the following formula:
the method comprises the following steps:
40g of Compound 3a (0.14 mol,1.0 eq), 200mL of a 20% strength by mass aqueous potassium carbonate solution and 200mL of methanol were added to a reaction vessel, reacted at 25℃for 20 hours, water was added, stirred, filtered, and the cake was dried to give a yield of 91.9%.
Example 7 ]
Acid and alkali screening
In this example, acid and alkali were screened on the basis of example 6, and the procedure was the same as that described in example 6, except for the parameters listed in the following table. Wherein number 1 corresponds to example 6.
The screening results are shown in Table 4.
TABLE 4 screening of acid and base
| Sequence number | Acid and base | Product yield (%) |
| 1 | 20% aqueous potassium carbonate solution | 91.9 |
| 2 | 20% aqueous sodium carbonate solution | 86.3 |
| 3 | Hydrochloric acid | 84.2 |
As shown in the table above, when the alkali is 20% of potassium carbonate or sodium carbonate aqueous solution, the reaction can obtain better effect, and the yields of the products are 91.9% and 86.3% respectively; in the case of hydrochloric acid, a good reaction yield can also be obtained.
Comparative example 1 ]
Preparation of Compound 3b
This example provides a method for preparing compound 3b, which has the following reaction formula:
the method comprises the following steps:
40g of Compound 1a (0.28 mol,1.0 eq), 34.71g of Compound 2b (0.34 mol,1.2 eq) and 160mL of dichloromethane are added to a reaction vessel, stirred at 5℃for 4h, 21.42g of fuming nitric acid (0.34 mol,1.2 eq) is added dropwise, stirred at 5℃for 16h, 20% by mass sodium bicarbonate solution is added, the pH is adjusted to 7, filtration is carried out, a filter cake is taken, the filtrate is separated, an organic phase is taken, the organic phase and the filter cake are combined, the solvent is distilled off under reduced pressure, washing with n-heptane is added, and the yield is 49.7%.
In the method for preparing the compounds 3a and 3b, the reaction is carried out by taking equivalent acetic anhydride and fuming nitric acid as reaction reagents and taking methylene dichloride as a solvent, and the yield of the product is only 49.7 percent. Thus, a high yield of 90% or more can be obtained by using trifluoroacetic anhydride as a reactant.
Effects and effects of the examples
According to the method for nitrifying an aromatic compound according to the above example, since methylene chloride is selected as a solvent in the first method (for example, example 1), a higher reaction yield can be obtained than acetic acid and sulfuric acid.
Because fuming nitric acid is selected as the reactant, the target product can be obtained in a high yield.
Since acetic anhydride is selected as the solvent in the second method, a higher reaction yield can be obtained.
According to the method for producing nitroaniline according to the above embodiment, since 20% aqueous potassium carbonate or sodium carbonate solution is selected as the base or hydrochloric acid is selected as the acid, the target product can be obtained in a high yield.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
The applicant states that the present invention is described by way of the above examples as a method for nitrating an aromatic compound and a method for producing a nitroaniline compound, but the present invention is not limited to the above examples, i.e. it is not meant that the present invention must be practiced in dependence upon the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention. However, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (10)
1. A process for the nitration of aromatic compounds, characterized by the following reaction scheme:
wherein R is 1 Selected from-OR 3 、-OH、-NHCOR 3 、R 3 Any one of the above-mentioned materials,
R 2 either or both R selected from C1-C4 haloalkyl, -H, C1-C4 alkyl 2 Bonded to form a five-membered or six-membered anhydride ring,
the haloalkyl is a halogen substituted for one or more hydrogens on the alkyl,
x is selected from halogen, and the halogen is selected from halogen,
R 3 selected from the group consisting of C1-C6 alkyl,
the preparation method comprises the following steps:
mixing the compound 1, the compound 2 and the first solvent, adding fuming nitric acid, post-treating to obtain a compound 3,
the first solvent is an aprotic acid solvent.
2. The method for nitrifying an aromatic compound according to claim 1, characterized in that:
the compound 1 isWherein R is 3 X is as defined in claim 1.
3. The method for nitrifying an aromatic compound according to claim 1, characterized in that:
the first solvent is selected from any one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, N-dimethylformamide, dimethyl sulfoxide and methyl tertiary butyl ether;
and/or the molar ratio of the compound 1 to the compound 2 is 1: (1.0-2.0);
and/or the molar ratio of the compound 1 to the fuming nitric acid is 1: (1.0-2.0);
and/or the mass to volume ratio of the compound 1 to the first solvent is 1g: (3.0-5.0) mL;
and/or, the reaction temperature is 0 ℃ to 20 ℃.
4. A process for the nitration of aromatic compounds, characterized by the following reaction scheme:
wherein R is 1 Selected from-OR 3 、-OH、-NHCOR 3 、R 3 Any one of the above-mentioned materials,
R 2 either or both R selected from C1-C4 haloalkyl, -H, C1-C4 alkyl 2 Bonded to form a five-membered or six-membered anhydride ring,
the haloalkyl is a halogen substituted for one or more hydrogens on the alkyl,
x is selected from halogen, and the halogen is selected from halogen,
R 3 selected from the group consisting of C1-C6 alkyl,
the preparation method comprises the following steps:
mixing the compound 1 with the compound 2 with the melting point less than or equal to 20 ℃, adding fuming nitric acid, and performing post-treatment to obtain the compound 3.
5. The process for the nitration of aromatic compounds according to claim 4, characterized in that:
the compound 1 isWherein R is 3 X is as defined in claim 4.
6. The process for the nitration of aromatic compounds according to claim 4, characterized in that:
the mass volume ratio of the compound 1 to the compound 2 is 1g: (8.0-10.0) mL;
and/or the molar ratio of the compound 1 to the fuming nitric acid is 1: (1.0-2.0);
and/or the reaction temperature is 0 ℃ to 20 ℃.
7. A nitrobenzene compound is characterized by having the following structural formula:
in formula 3a, X is selected from halogen.
8. The nitrobenzene compound according to claim 7, wherein:
3a is
9. A method for preparing nitroaniline compounds, which is characterized by the following reaction formula:
wherein R is 1 Selected from-OR 3 、-OH、-NHCOR 3 、R 3 Any one of the above-mentioned materials,
R 2 either or both R selected from C1-C4 haloalkyl, -H, C1-C4 alkyl 2 Bonded to form five or more membersAn acid anhydride ring of six-membered atoms,
the haloalkyl is a halogen substituted for one or more hydrogens on the alkyl,
x is selected from halogen, and the halogen is selected from halogen,
R 3 selected from the group consisting of C1-C6 alkyl,
comprises any one of the following two preparation methods:
the method comprises the following steps: step A1: mixing the compound 1, the compound 2 and the first solvent, adding fuming nitric acid, post-treating to obtain a compound 3,
and (B) step (B): mixing the compound 3, alkali or hydrochloric acid and a second solvent, reacting completely to obtain a compound 4,
the second method is as follows: step A2: mixing the compound 1 and the compound 2 with the melting point less than or equal to 20 ℃, adding fuming nitric acid, post-treating to obtain a compound 3,
and (B) step (B): and mixing the compound 3, alkali or hydrochloric acid and a second solvent, and obtaining the compound 4 after the reaction is completed.
10. The method for preparing nitroaniline compound according to claim 9, wherein:
in the step A1, the first solvent is selected from any one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, N-dimethylformamide, dimethyl sulfoxide and methyl tertiary butyl ether;
and/or, in step A1, the molar ratio of the compound 1 to the compound 2 is 1: (1.0-2.0);
and/or, in step A1, the molar ratio of the compound 1 to the fuming nitric acid is 1: (1.0-2.0);
and/or, in step A1, the mass-to-volume ratio of the compound 1 to the first solvent is 1g: (3.0-5.0) mL;
and/or, in the step A1, the reaction temperature is 0-20 ℃;
and/or, in step A2, the mass-to-volume ratio of the compound 1 to the compound 2 is 1g: (8.0-10.0) mL;
and/or, in step A2, the molar ratio of the compound 1 to the fuming nitric acid is 1: (1.0-2.0);
and/or, in the step A2, the reaction temperature is 0-20 ℃;
and/or in the step B, the second solvent is any one of methanol or ethanol;
and/or in the step B, the alkali is any one of potassium carbonate or sodium carbonate;
and/or in step B, the mass to volume ratio of the compound 3 to the base is 1g: (4-6) mL;
and/or, in the step B, the mass-volume ratio of the compound 3 to the hydrochloric acid is 1g: (4-6) mL;
and/or in step B, the mass to volume ratio of the compound 3 to the second solvent is 1g: (4-6) mL.
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