CN116574039A - Polysubstituted aminobenzonitrile compound and preparation method thereof - Google Patents
Polysubstituted aminobenzonitrile compound and preparation method thereof Download PDFInfo
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- polysubstituted
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- -1 Polysubstituted aminobenzonitrile compound Chemical class 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 14
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 13
- 239000007787 solid Substances 0.000 claims abstract description 12
- 239000007858 starting material Substances 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 239000002274 desiccant Substances 0.000 claims abstract description 8
- 239000007800 oxidant agent Substances 0.000 claims abstract description 8
- 230000001590 oxidative effect Effects 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 238000004809 thin layer chromatography Methods 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 6
- 239000007789 gas Substances 0.000 claims abstract description 5
- 230000001681 protective effect Effects 0.000 claims abstract description 5
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical class NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- PCRAJOWHMTYSKR-UHFFFAOYSA-N iodobenzene;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.IC1=CC=CC=C1 PCRAJOWHMTYSKR-UHFFFAOYSA-N 0.000 claims description 2
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 claims description 2
- KZJPVUDYAMEDRM-UHFFFAOYSA-M silver;2,2,2-trifluoroacetate Chemical compound [Ag+].[O-]C(=O)C(F)(F)F KZJPVUDYAMEDRM-UHFFFAOYSA-M 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000008034 disappearance Effects 0.000 abstract description 2
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- LGFPDDKHVBSPBT-UHFFFAOYSA-N butyl(methylidyne)azanium Chemical group CCCC[N+]#C LGFPDDKHVBSPBT-UHFFFAOYSA-N 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- JYJVVHFRSFVEJM-UHFFFAOYSA-N iodosobenzene Chemical compound O=IC1=CC=CC=C1 JYJVVHFRSFVEJM-UHFFFAOYSA-N 0.000 description 3
- 150000001334 alicyclic compounds Chemical class 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000007867 post-reaction treatment Methods 0.000 description 2
- KAHOWFCMRDOJOA-UHFFFAOYSA-N 1,2-diethyl-3-iodobenzene Chemical compound C(C)C=1C(=C(C=CC1)I)CC KAHOWFCMRDOJOA-UHFFFAOYSA-N 0.000 description 1
- GPLXRIVINNIQFY-UHFFFAOYSA-N 4-methyl-n-(4-methylphenyl)benzenesulfonamide Chemical compound C1=CC(C)=CC=C1NS(=O)(=O)C1=CC=C(C)C=C1 GPLXRIVINNIQFY-UHFFFAOYSA-N 0.000 description 1
- BZNMIDYUSWEPOM-UHFFFAOYSA-N 5-amino-2-methoxybenzonitrile Chemical compound COC1=CC=C(N)C=C1C#N BZNMIDYUSWEPOM-UHFFFAOYSA-N 0.000 description 1
- YDZVQWCVKXYGIU-UHFFFAOYSA-N 5-amino-2-methylbenzonitrile Chemical compound CC1=CC=C(N)C=C1C#N YDZVQWCVKXYGIU-UHFFFAOYSA-N 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000801593 Pida Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- SLGBZMMZGDRARJ-UHFFFAOYSA-N Triphenylene Natural products C1=CC=C2C3=CC=CC=C3C3=CC=CC=C3C2=C1 SLGBZMMZGDRARJ-UHFFFAOYSA-N 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000008376 fluorenones Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- UNYHHKHLLANCKH-UHFFFAOYSA-N n-(2,4-dimethylphenyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=C(C)C=C1C UNYHHKHLLANCKH-UHFFFAOYSA-N 0.000 description 1
- JRAYUPSJGCRNDR-UHFFFAOYSA-N n-(3,4-dimethoxyphenyl)-4-methylbenzenesulfonamide Chemical compound C1=C(OC)C(OC)=CC=C1NS(=O)(=O)C1=CC=C(C)C=C1 JRAYUPSJGCRNDR-UHFFFAOYSA-N 0.000 description 1
- NQUKYTXPMUKVOZ-UHFFFAOYSA-N n-(3,4-dimethylphenyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=C(C)C(C)=C1 NQUKYTXPMUKVOZ-UHFFFAOYSA-N 0.000 description 1
- GFPBLDMXBCYORT-UHFFFAOYSA-N n-(4-methoxyphenyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1NS(=O)(=O)C1=CC=C(C)C=C1 GFPBLDMXBCYORT-UHFFFAOYSA-N 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a polysubstituted aminobenzonitrile compound and a preparation method thereof, wherein the compound has the structural formula:wherein, ts is p-toluenesulfonyl, R 1 Is methyl or methoxy, R 2 Is hydrogen, methyl, phenyl, methoxy or bipinnamate, R 3 Is hydrogen, methyl or phenyl. The method specifically comprises the following steps: stirring, mixing and reacting the polysubstituted arylamine compound, the first solvent, the oxidant and the drying agent; after the complete disappearance of the starting material was monitored by thin layer chromatography, the first solvent was spin-dried and the solid was transferred to a pressure-resistant tubeThe method comprises the steps of carrying out a first treatment on the surface of the Adding a second solvent, a catalyst and a cyanation reagent into a pressure-resistant pipe in a protective gas atmosphere, stirring, mixing and reacting; after the reaction is finished, cooling to room temperature, and purifying the crude product to obtain the compound. Compared with the prior art, the invention uses the cheap and easily-substituted aromatic amine compound as the raw material and tert-butyl isonitrile as the cyanation reagent, thereby realizing the simple and efficient synthesis of the polysubstituted aminobenzonitrile compound with regioselectivity.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a polysubstituted aminobenzonitrile compound and a preparation method thereof.
Background
The polysubstituted arylamine compounds are important synthetic fragments or synthetic precursor compounds, and in view of the fact that cyano groups have strong electron withdrawing performance, the space volume is small, the polysubstituted arylamine compounds can penetrate into interaction of target proteins and amino acid residues through hydrogen bonds, pi-pi bonds and other modes, and the polysubstituted aminobenzonitrile compounds have higher synthesis and application values, and can obviously enhance the biological activity of the compounds. The cyano can be efficiently converted into amido, methylamino, aldehyde carbonyl, imino and various nitrogen-containing heterocyclic ring fragments by a simple synthesis method, so that the polysubstituted aminobenzonitrile compound has great application value in the fields of organic synthesis, biological medicine and materials. For example: 5-amino-2-methylbenzonitrile is a key precursor in the synthesis of a highly efficient triphenylene conjugated dye for sensitizing solar cells (see: chow, t.j. Et. J. Mate. Chem.,2011,21,9523-9531); 5-amino-2-methoxybenzonitrile is a synthetic precursor to xanthine oxidase inhibitors with a micromolar level of efficiency (see: meng, f. —h.et al chem. Biol. Drug des.,2018,91,526-533); 4-amino- [1,1' -biphenyl ] -2-carbonitrile is useful for the synthesis of fluorenones, an important precursor in the fields of medicine and materials (see, document: hsieh J.- -C.et al. Org. Lett.,2013,15,2742-2745). However, in the prior art, there are few reports on the synthesis of polysubstituted aminobenzonitrile compounds, but more recently, the synthesis of polysubstituted aminobenzonitrile compounds from inexpensive and easily available polysubstituted aromatic amine compounds as raw materials has been reported.
The traditional polysubstituted aminobenzonitrile compounds are generally synthesized through the processes of the prior nitration reaction, the cyanation reaction, the reduction of nitro into amino and the like of polysubstituted halogenated aromatic hydrocarbon (see literature: khalafi-Nezhad, A.et.Inorg.Chim.acta, 2019,494,256-265). Most of the relevant synthetic literature inevitably uses metal cyanides with relatively high toxicity, such as zinc cyanide and the like (see literature: kung, P.P.et. Bioorg. Med. Chem. Lett.,2008,18,6273-6278). Meanwhile, the conventional method inevitably uses a large amount of nitric acid in synthesis, so that the problems of more reaction steps, difficult post-reaction treatment, higher cost, poorer functional group tolerance, serious environmental pollution caused by residual metal cyanide and the like exist.
Patent CN110526832a discloses a method for preparing a polysubstituted alicyclic compound, after an aryl hypervalent iodine compound is activated by an activating reagent, a rearrangement reaction is carried out with an alpha-tin or silicon substituted nitrile compound at-100 to-70 ℃ to obtain an electrophilic dearomatization intermediate, and the intermediate reacts with a nucleophilic reagent to obtain the polysubstituted alicyclic compound. However, although cyano groups are introduced, this patent uses a highly toxic organotin compound as a cyanation reagent, and uses ultralow temperature conditions, and the safety and environmental friendliness of the reaction are poor, and the reaction conditions are high.
Disclosure of Invention
The invention aims to overcome at least one defect in the prior art and provide a polysubstituted aminobenzonitrile compound and a preparation method thereof.
The aim of the invention can be achieved by the following technical scheme:
the invention provides a polysubstituted aminobenzonitrile compound, which has the structural formula:
wherein, ts is p-toluenesulfonyl, R 1 Is methyl or methoxy, R 2 Is hydrogen, methyl, phenyl, methoxy or bipinnamate, R 3 Is hydrogen, methyl or phenyl.
The invention provides a preparation method of a polysubstituted aminobenzonitrile compound, which comprises the following steps:
(1) Stirring, mixing and reacting the polysubstituted arylamine compound, the first solvent, the oxidant and the drying agent;
(2) After monitoring by Thin Layer Chromatography (TLC) that the starting material was completely disappeared, spin-drying the first solvent and transferring the solid into a thick-walled pressure-resistant tube;
(3) Adding a second solvent, a catalyst and a cyanation reagent into a thick-wall pressure-resistant pipe in a protective gas atmosphere, stirring, mixing and reacting;
(4) And cooling to room temperature after the reaction is finished, and directly purifying the crude product without post-treatment to obtain the corresponding polysubstituted aminobenzonitrile compound.
The method is characterized in that a simple and easily available tertiary butyl isonitrile is used as a cyanation reagent, and a high-valence iodine reagent is used as an oxidant to perform dearomatization-aromatization reaction on a low-cost polysubstituted arylamine compound, so that the corresponding polysubstituted aminobenzonitrile compound is synthesized in a regioselective manner on the premise of keeping the integral benzene ring structure and substituents on the benzene ring.
Further, the structural formula of the polysubstituted arylamine compound in the step (1) is as follows:
wherein, ts is p-toluenesulfonyl, R 1 Is methyl or methoxy, R 2 Is hydrogen, methyl, phenyl, methoxy or bipinnamate, R 3 Hydrogen, methyl or phenyl;
the first solvent adopts methanol or ethanol, the oxidant adopts a hypervalent iodine reagent, the hypervalent iodine reagent adopts iodinylidene benzene, iodobenzene diethyl ester or trifluoroacetate iodobenzene, and the drying agent adopts anhydrous sodium sulfate or anhydrous magnesium sulfate;
in the step (3), the protective gas adopts nitrogen or argon, the second solvent adopts acetonitrile, benzonitrile, chlorobenzene or dimethyl sulfoxide, the catalyst adopts silver trifluoromethane sulfonate, silver tetrafluoroborate or silver trifluoroacetate, and the cyanation reagent adopts tert-butyl isonitrile.
Further, in the step (1), the molar ratio of the polysubstituted arylamine compound to the oxidant to the drying agent is (0.3-0.4), the molar ratio of the polysubstituted arylamine compound to the drying agent is (0.36-0.40), the molar ratio of the polysubstituted arylamine compound to the first solvent is (0.5-2.0), and the molar ratio of the polysubstituted arylamine compound to the first solvent is (0.3-0.4 mmol), and the molar ratio of the polysubstituted arylamine compound to the first solvent is (2.0-3.0 mL).
Further, in the step (1), the stirring speed is 400-500rpm, the reaction temperature is 20-25 ℃ and the time is 15-30min.
As a preferred embodiment, the first solvent is removed in step (2) under vacuum at a certain temperature.
As a preferable technical scheme, the temperature is 30-35 ℃, and the vacuum degree is 100-200kPa.
Further, in the step (3), the molar ratio of the polysubstituted arylamine compound to the catalyst to the cyanation reagent is (0.3-0.4) (0.03-0.06) (1.5-1.6), and the dosage ratio of the polysubstituted arylamine compound to the second solvent is (0.3-0.4 mmol) (0.75-1.0 mL).
Further, in the step (3), the stirring speed is 400-500rpm, the reaction temperature is 85-120 ℃ and the time is 18-24h.
As a preferable technical scheme, the thick-wall pressure-resistant pipe in the step (3) is placed in an oil bath for heating.
Further, the purification in the step (4) adopts silica gel column chromatography or recrystallization.
Further, the silica gel column chromatography developing agent adopts petroleum ether and ethyl acetate with the volume ratio of (5-15): 1 or a mixed solvent of normal hexane and ethyl acetate.
Further, the recrystallization step specifically comprises: and (5) heating the mixed solvent of n-hexane and ethyl acetate or petroleum ether and ethyl acetate with the volume ratio of (50-60) to 60-70 ℃ until the crude product is completely dissolved, standing, cooling and crystallizing.
Compared with the prior art, the invention has the following advantages:
(1) The invention takes the cheap and easily available polysubstituted aromatic amine compound as the raw material, takes the liquid tertiary butyl isonitrile with low toxicity and easy operation as the cyanation reagent, and realizes the efficient synthesis of the polysubstituted aminobenzonitrile compound with regioselectivity;
(2) The method is simple to operate, and column chromatography or recrystallization purification can be performed without post-treatment after the experiment is finished;
(3) The polysubstituted aminobenzonitrile compound synthesized by the method has better development potential and application prospect in the fields of organic synthesis, biological medicine and materials.
Detailed Description
The present invention will be described in detail with reference to specific examples. The present embodiment is implemented on the premise of the technical scheme of the present invention, and a detailed implementation manner and a specific operation process are given, but the protection scope of the present invention is not limited to the following examples.
The equipment used in the following examples is representative of conventional equipment in the art unless otherwise specified; unless otherwise indicated, all reagents used are commercially available or prepared by methods conventional in the art, and all of the following examples, not specifically described, are accomplished by means of conventional experimentation in the art.
A polysubstituted aminobenzonitrile compound has the structural formula:
wherein, ts is p-toluenesulfonyl, R 1 Is methyl or methoxy, R 2 Is hydrogen, methyl, phenyl, methoxy or bipinnamate, R 3 Is hydrogen, methyl or phenyl.
A preparation method of a polysubstituted aminobenzonitrile compound comprises the following steps:
(1) Polysubstituted arylamine compounds, hypervalent iodine reagents and anhydrous sodium sulfate (Na 2 SO 4 ) A10 mL reaction flask was charged with a molar ratio of 0.3mmol to 0.36mmol to 5.0mmol and 2mL of methanol (MeOH) solvent, and the hypervalent iodinated reagent was prepared using iodosobenzene (PhIO) or diethyl iodobenzene (PIDA), followed by stirring at 25℃and 500rpmReacting for 15-30min;
(2) After monitoring by Thin Layer Chromatography (TLC) that the starting material was completely disappeared, the methanol was spin-dried and the solid was transferred to a 15mL thick-walled pressure-resistant tube, and methanol was removed in vacuo at 30℃at 200 kPa;
(3) 0.75mL of acetonitrile (MeCN) was added to a thick-walled pressure-resistant tube, and silver trifluoromethane sulfonate (AgOTf) and t-butylisonitrile were added t BuNC) in a molar ratio of 0.03mmol to 1.5mmol in nitrogen (N) 2 ) Respectively adding the materials into thick-wall pressure-resistant pipes under protection, placing the thick-wall pressure-resistant pipes into an oil bath at 85-120 ℃ and stirring at 500rpm for reaction for 18h;
(4) After the reaction is finished, cooling to room temperature, and directly carrying out silica gel column chromatography or recrystallization purification without post-treatment.
The reaction mechanism adopted in this example is:
wherein, ts is p-toluenesulfonyl, R 1 Is methyl or methoxy, R 2 Is hydrogen, methyl, phenyl, methoxy or bipinnamate, R 3 Is hydrogen, methyl or phenyl.
Example 1:
a preparation method of an N- (3-cyano-4-methylphenyl) -4-methylbenzenesulfonamide compound comprises the following specific steps:
(1) 4-methyl-N-p-tolylbenzenesulfonamide (78.4 mg,0.3 mmol), methanol solvent (2 mL), iodosobenzene (79.2 mg,0.36 mmol) and anhydrous sodium sulfate (213.1 mg,1.5 mmol) were sequentially added to a 10mL reaction flask, and reacted at 25℃and 500rpm with stirring for 15min;
(2) The disappearance of the reaction material was monitored by TLC, the methanol solvent was dried by spin-drying and the solid was transferred to a 15mL thick-walled pressure-resistant tube, and methanol was removed under vacuum at 30℃at 200 kPa;
(3) Acetonitrile (0.75 mL), silver trifluoromethane sulfonate (7.7 mg,0.03 mmol) and t-butyl isonitrile (124.7 mg,1.5 mmol) were sequentially added to a thick-walled pressure-resistant tube under nitrogen protection, and the mixture was stirred at 120℃in an oil bath at 500rpm for 18 hours;
(4) After the reaction, cooling to room temperature, directly purifying the crude product through silica gel column chromatography without post-treatment, wherein the developing solvent adopts a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 10:1 to obtain colorless solid (68.7 mg, the yield is 80%), namely the N- (3-cyano-4-methylphenyl) -4-methylbenzenesulfonamide compound with the structural formula:
the melting point is 145-146 ℃.
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):3229,2232,1595,1653,1495,1470,1519,1360,1295,1211,1118,1079,1020,912,755,697,591,489；
1 H NMR(400MHz,CDCl 3 ):δ7.67(dd,J＝8.2,4.5Hz,2H),7.45(brs,1H),7.31-7.26(m,2H),7.23(t,J＝1.9Hz,2H),7.18(d,J＝8.4Hz,1H),2.45(s,3H),2.39(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ144.62,138.93,135.54,135.06,131.44,130.05,127.31,126.04,124.72,117.46,113.57,21.69,19.95；
HRMS(ESI)m/z:calcd for C 15 H 15 N 2 O 2 S[M+H] + 286.0776,found 286.0773.
example 2:
a process for preparing an N- (3-cyano-4-methoxyphenyl) -4-methylbenzenesulfonamide compound substantially the same as in example 1, except that N- (4-methoxyphenyl) -4-methylbenzenesulfonamide (83.2 mg,0.3 mmol) is used as the starting material to give a white solid (72.0 mg, yield: 79%) which is an N- (3-cyano-4-methoxyphenyl) -4-methylbenzenesulfonamide compound having the structural formula:
the melting point is 116-118 ℃.
The basic parameters of this compound are as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.81-7.40(m,2H),7.33(dd,J＝9.0,2.7Hz,1H),7.26-7.21(m,2H),7.19(d,J＝2.7Hz,1H),7.12(s,1H),6.85(d,J＝9.1Hz,1H),3.87(s,3H),2.38(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ159.45,144.51,135.46,130.10,130.00,129.55,128.28,127.34,115.74,112.27,102.18,56.42,21.70.
example 3:
a process for preparing an N- (3-cyano-4, 5-dimethylphenyl) -4-methylbenzenesulfonamide compound substantially the same as in example 1, except that N- (3, 4-dimethylphenyl) -4-methylbenzenesulfonamide (82.6 mg,0.3 mmol) was used as the starting material to give a colorless solid (64.0 mg, yield: 72%), namely an N- (3-cyano-4, 5-dimethylphenyl) -4-methylbenzenesulfonamide compound having the structural formula:
the melting point is 155-156 ℃.
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):3214,2230,1610,1489,1393,1325,1162,1145,1091,1033,917,879,812,730,660,562,544；
1 H NMR(400MHz,CDCl 3 ):δ7.69(d,J＝8.3Hz,2H),7.56(brs,1H),7.25(d,J＝8.3Hz,2H),7.15(dd,J＝16.4,2.1Hz,2H),2.38(s,3H),2.35(s,3H),2.21(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ144.50,139.60,137.38,135.67,134.92,130.01,127.31,127.16,122.04,118.12,113.62,21.67,20.30,17.47；
HRMS(ESI)m/z:calcd for C 16 H 17 O 2 N 2 S[M+H] + 301.1006,found 301.1005.
example 4:
a process for preparing an N- (3-cyano-4, 5-dimethoxyphenyl) -4-methylbenzenesulfonamide compound substantially the same as in example 1 except that N- (3, 4-dimethoxyphenyl) -4-methylbenzenesulfonamide (92.2 mg,0.3 mmol) is used as a starting material to give a white solid (73.0 mg, 73% yield) which is an N- (3-cyano-4, 5-dimethoxyphenyl) -4-methylbenzenesulfonamide compound having the structural formula:
the melting point is 130-131 ℃.
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):3243,2917,2233,1592,1490,1462,1428,1394,1325,1279,1162,1087,1012,929,571；
1 H NMR(400MHz,CDCl 3 ):δ7.66(d,J＝8.2Hz,2H),7.41(s,1H),7.26(d,J＝8.4Hz,2H),6.99(d,J＝2.5Hz,1H),6.71(s,1H),3.93(s,3H),3.80(s,3H),2.39(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ153.24,149.48,144.73,135.39,133.14,130.08,127.34,116.40,115.71,111.59,107.03,61.90,56.30,21.71；
HRMS(ESI)m/z:calcd for C 16 H 17 N 2 O 4 S[M+H] + 350.1169,found 350.1167.
example 5:
a process for preparing an N- (5-cyano-2, 4-dimethylphenyl) -4-methylbenzenesulfonamide compound substantially the same as in example 1, except that N- (2, 4-dimethylphenyl) -4-methylbenzenesulfonamide (82.6 mg,0.3 mmol) was used as the starting material to give a colorless solid (48.0 mg, yield 55%), namely an N- (5-cyano-2, 4-dimethylphenyl) -4-methylbenzenesulfonamide compound having the structural formula:
the melting point is 200-201 ℃.
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):3288,2223,1504,1456,1402,1337,1295,1199,1166,1089,901,888,813,603,548,530；
1 H NMR(400MHz,CDCl 3 ):δ7.63(d,J＝8.3Hz,2H),7.47(s,1H),7.27(s,1H),7.25(s,1H),7.05(s,1H),6.59(s,1H),2.44(s,3H),2.41(s,3H),2.07(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ144.51,139.75,137.50,136.28,133.03,132.90,130.00,127.95,127.24,117.62,111.17,21.69,19.95,18.13；
HRMS(ESI)m/z:calcd for C 16 H 17 N 2 O 2 S[M+H] + 301.1005,found 301.1005.
example 6:
a process for the preparation of an N- (4-cyano-5-methyl- [1,1' -biphenyl ] -2-yl) -4-methylbenzenesulfonamide compound substantially the same as in example 1, except that the starting material was 4-methyl-N- (5-methyl-1, 1' -biphenyl) -2-methylbenzenesulfonamide (101.3 mg,0.3 mmol) to give a colorless solid (89.4 mg, 82% yield), i.e., an N- (4-cyano-5-methyl- [1,1' -biphenyl ] -2-yl) -4-methylbenzenesulfonamide compound having the structural formula:
the melting point is 142-144 ℃.
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):3292,2227,1597,1474,1384,1332,1260,1184,1165,1091,1032,955,871,824,765,667,546；
1 H NMR(400MHz,CDCl 3 ):δ7.89(d,J＝8.5Hz,1H),7.45-7.35(m,5H),7.31(d,J＝8.5Hz,1H),7.23(d,J＝8.0Hz,2H),6.74(d,J＝7.9Hz,2H),6.31(s,1H),2.52(s,3H),2.44(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ144.53,139.19,137.26,135.71,133.33,132.89,130.44,129.89,129.68,129.59,129.04,127.27,125.79,116.49,114.28,21.72,20.54；
HRMS(ESI)m/z:calcd for C 21 H 19 N 2 O 2 S[M+H] + 363.1162,found 363.1158.
example 7:
a process for the preparation of an N- (5-cyano-6-methyl-1, 1' -biphenyl) -3-yl) -4-methylbenzenesulfonamide compound substantially the same as in example 1, except that the starting material was 4-methyl-N- (6-methyl-1, 1' -biphenyl) -3-methylbenzenesulfonamide (101.3 mg,0.3 mmol) to give a yellow liquid (92.4 mg, yield 90%), i.e., an N- (5-cyano-6-methyl-1, 1' -biphenyl) -3-yl) -4-methylbenzenesulfonamide compound having the structural formula:
the basic parameters of this compound are as follows:
IR(KBr,cm -1 ):3243,3061,2230,1699,1598,1464,1437,1368,1326,1185,1161,1090,975,704,665,558；
1 H NMR(400MHz,CDCl 3 ):δ7.72(d,J＝8.4Hz,2H),7.50(s,1H)7.45-7.32(m,4H),7.28(d,J＝8.0Hz,2H),7.18-7.11(m,3H),2.41(s,3H),2.34(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ144.65,144.55,139.25,136.37,135.60,134.99,130.08,129.15,128.91,128.59,128.24,128.10,127.40,126.99,123.47,117.90,114.56,21.71,18.48；
HRMS(ESI)m/z:calcd for C 21 H 19 N 2 O 2 S[M+H] + 363.1162,found 363.1158.
example 8:
a process for producing N- (3-cyano-4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylbenzenesulfonamide compound, which was substantially the same as in example 1, except that 4-methyl-N- (4-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzenesulfonamide (116.2 mg,0.3 mmol), iodobenzene diethyl ester (116.0 mg,0.36 mmol) was used as the starting material, step (1) was reacted for 30 minutes, step (3) oil bath at 85 ℃, step (4) directly adding the crude product into a mixed solvent with the volume ratio of N-hexane and ethyl acetate of 50:1, heating to 65 ℃, standing, cooling and crystallizing to obtain a white solid (80.0 mg, yield 60%), namely an N- (3-cyano-4-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4-methylbenzenesulfonamide compound with the structural formula:
the melting point is 218-220 ℃.
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):3227,3063,2980,2929,2229,1592,1451,1347,1224,1157,1091,1032,987,902,848,813,676,551；
1 H NMR(400MHz,C 2 D 6 SO):δ10.42(s,1H),7.60(d,J＝8.3Hz,2H),7.55(d,J＝2.6Hz,1H),7.44(d,J＝2.5Hz,1H),7.32(d,J＝8.0Hz,2H),2.49(s,3H),2.30(s,3H),1.24(s,12H)；
13 C NMR(101MHz,C 2 D 6 SO):δ144.22,143.38,136.63,136.13,131.91,130.39,127.31,125.67,118.26,113.74,84.69,25.10,21.49,19.72；
HRMS(ESI)m/z:calcd for C 21 H 26 BN 2 O 4 S[M+H] + 413.1701,found 413.1699.
in the embodiment, the corresponding polysubstituted aminobenzonitrile compound is synthesized by taking the simple and easily available polysubstituted arylamine compound as a raw material and taking the low-toxicity and easily operated tertiary butyl isonitrile as a cyanation reagent. The method has the advantages of simple reaction operation, no need of post-reaction treatment, low-cost and easily-obtained raw materials and the like, and has great development potential and application prospect in the fields of organic synthesis, biological medicine and materials.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (10)
1. The polysubstituted aminobenzonitrile compound is characterized in that the structural formula of the compound is as follows:
wherein, ts is p-toluenesulfonyl, R 1 Is methyl or methoxy, R 2 Is hydrogen, methyl, phenyl, methoxy or bipinnamate, R 3 Is hydrogen, methyl or phenyl.
2. A process for the preparation of the polysubstituted aminobenzonitrile as claimed in claim 1, characterized in that it comprises the following steps:
(1) Stirring, mixing and reacting the polysubstituted arylamine compound, the first solvent, the oxidant and the drying agent;
(2) After monitoring by thin layer chromatography that the starting material is completely disappeared, spin-drying the first solvent and transferring the solid into a pressure-resistant tube;
(3) Adding a second solvent, a catalyst and a cyanation reagent into a pressure-resistant pipe in a protective gas atmosphere, stirring, mixing and reacting;
(4) And cooling to room temperature after the reaction is finished, and purifying the crude product to obtain the polysubstituted aminobenzonitrile compound.
3. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 2, wherein the polysubstituted arylamine compound in the step (1) has the structural formula:
wherein, ts is p-toluenesulfonyl, R 1 Is methyl or methoxy, R 2 Is hydrogen, methyl, phenyl, methoxy or bipinnamate, R 3 Hydrogen, methyl or phenyl;
the first solvent adopts methanol or ethanol, the oxidant adopts a hypervalent iodine reagent, the hypervalent iodine reagent adopts iodinylidene benzene, iodobenzene diethyl ester or trifluoroacetate iodobenzene, and the drying agent adopts anhydrous sodium sulfate or anhydrous magnesium sulfate;
in the step (3), the protective gas adopts nitrogen or argon, the second solvent adopts acetonitrile, benzonitrile, chlorobenzene or dimethyl sulfoxide, the catalyst adopts silver trifluoromethane sulfonate, silver tetrafluoroborate or silver trifluoroacetate, and the cyanation reagent adopts tert-butyl isonitrile.
4. The method for preparing the polysubstituted aminobenzonitrile compound according to claim 2, wherein in the step (1), the molar ratio of the polysubstituted aromatic amine compound, the oxidant and the drying agent is (0.3-0.4): (0.36-0.40): (1.5-2.0), and the dosage ratio of the polysubstituted aromatic amine compound and the first solvent is (0.3-0.4 mmol): (2.0-3.0 mL).
5. The method for producing a polysubstituted aminobenzonitrile compound according to claim 2, wherein the stirring speed in the step (1) is 400-500rpm, the reaction temperature is 20-25 ℃ and the time is 15-30min.
6. The method for preparing the polysubstituted aminobenzonitrile compound according to claim 2, wherein in the step (3), the molar ratio of the polysubstituted aromatic amine compound to the catalyst to the cyanation reagent is (0.3-0.4): (0.03-0.06): (1.5-1.6), and the dosage ratio of the polysubstituted aromatic amine compound to the second solvent is (0.3-0.4 mmol): (0.75-1.0 mL).
7. The method for producing a polysubstituted aminobenzonitrile compound according to claim 2, wherein the stirring speed in the step (3) is 400-500rpm, the reaction temperature is 85-120 ℃ and the time is 18-24 hours.
8. The method for producing a polysubstituted aminobenzonitrile according to claim 2, wherein the purification in step (4) is performed by silica gel column chromatography or recrystallization.
9. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 8, wherein the silica gel column chromatography developing agent adopts petroleum ether and ethyl acetate with the volume ratio of (5-15): 1 or a mixed solvent of n-hexane and ethyl acetate.
10. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 8, wherein the recrystallization step specifically comprises: and (5) heating the mixed solvent of n-hexane and ethyl acetate or petroleum ether and ethyl acetate with the volume ratio of (50-60) to 60-70 ℃ until the crude product is completely dissolved, standing, cooling and crystallizing.
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