CN104058985B - The acetyl grouptransfer of the chloro-1H-indazole of a kind of 1-ethanoyl-4-is to the method for primary aromatic amine - Google Patents
The acetyl grouptransfer of the chloro-1H-indazole of a kind of 1-ethanoyl-4-is to the method for primary aromatic amine Download PDFInfo
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- CN104058985B CN104058985B CN201410235121.4A CN201410235121A CN104058985B CN 104058985 B CN104058985 B CN 104058985B CN 201410235121 A CN201410235121 A CN 201410235121A CN 104058985 B CN104058985 B CN 104058985B
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- indazole
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Abstract
The invention belongs to technical field of organic synthesis; be specifically related to a kind of by the acetyl grouptransfer of chloro-for 1-ethanoyl-4-1H-indazole to the method for primary aromatic amine; comprise 1:1 in molar ratio and get the chloro-1H-indazole of 1-ethanoyl-4-and primary aromatic amine; fully dissolve in organic solvent; stirring and refluxing is reacted, and uses thin-layer chromatography identification reaction process, steams organic solvent after reaction terminates; by gained solid by pillar layer separation, obtain the chloro-1H-indazole of 4-and N-acetylize substituted aromatic amines compounds.Method provided by the invention can be used for the deacetylation of 1-ethanoyl-1H-indazole analog derivative, and does not need to use inorganic strong alkali, compared with prior art has clear superiority; Also can be used for the acetylize protection of aromatic primary amine compounds.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of by the acetyl grouptransfer of chloro-for 1-ethanoyl-4-1H-indazole to the method for primary aromatic amine.
Background technology
Indazole (also known as benzo [c] pyrazoles, 1,2-benzodiazepine azoles) analog derivative is that a class has extensive bioactive nitrogen-containing heterocycle compound, attracts people and carries out synthesis optimizing and modified with functional group to it.In recent years, various have bioactive replacement 1H-indazole derivatives and in succession synthesize report, the multiple kinase inhibitor of the up-to-date research and development of Ge great drugmaker of the world is just containing indazole ring, as the pazopanib of GlaxoSmithKline PLC company and the Axitinib of Pfizer go on the market at present, its structure contains 3-substituted indazole structure, the Linifalib (ABT-869) of Abbott and the Pictillsib (GDC-0941) of Genentech company enters clinical investigation phase, and the two all belongs to 4-and replaces-1H-indazole analog derivative.
Have numerous paper about the structure of indazole and the conversion reaction of functional group and monograph has done abundant summary and systematically discussed, but wherein relevant to the acyl group shift reaction of indazole compounds discussion is also very limited.In general; rearrangement reaction in the acyl moieties of indazole compounds usually occurs between N1 and N2; although this is applicable to some acylations indazole derivatives; but similar reaction can be there is in not all N1 and N2 acylations indazole derivatives; as being adopt different methods to synthesize respectively for N1-acylations indazole and N2-acylations indazole derivatives, instead of obtained by the mutual conversion reaction between them.Ethanoyl rearrangement reaction between indazole compounds and other compound molecules then often occurs between its 2-position atom N and skeleton atom N of other nitrogen heterocyclic ring compounds; as reacted when N2-acetylize indazole compounds and pyrazole compound; N2-ethanoyl deacylation or intermolecular acyl migration can be experienced; final generation 1H-indazole and 1-ethanoyl-1H-pyrazoles, but similar reaction can not be there is with pyrazole compound in N1-acetylize indazole compounds.
The deacetylation of existing 1-ethanoyl-1H-indazole analog derivative needs mineral alkali catalysis, usually as lithium hydroxide, sodium hydroxide etc.For the traditional method of aromatic primary amine compounds acetylize protection, usually need Acetyl Chloride 98Min., the severe condition such as diacetyl oxide or acetic acid, for preventing aniline oxidized also need under severe conditions from adding some special reductive agents, as zinc powder etc., reaction conditions is harsher.
Summary of the invention
The object of the invention is to, for prior art Problems existing, provide one directly to transform, and do not need the method for acetyl grouptransfer to primary aromatic amine of the chloro-1H-indazole of 1-ethanoyl-4-using catalyzer.
For achieving the above object, the present invention is by the following technical solutions: 1:1 gets the chloro-1H-indazole of 1-ethanoyl-4-and primary aromatic amine in molar ratio, fully dissolve in organic solvent, stirring and refluxing is reacted, and use thin-layer chromatography identification reaction process, steam organic solvent after reaction terminates, by gained solid by pillar layer separation, obtain the chloro-1H-indazole of 4-and N-acetylize substituted aromatic amines compounds; Its reaction formula is as follows:
Further, in the structural formula of described primary aromatic amine R be H, to methyl, to fluorine, to chlorine or trifluoromethyl.
Further, described organic solvent is toluene or dimethyl formamide.
Further, moving phase is adopted to be ethyl acetate during described pillar layer separation: sherwood oil=1:1 ~ 3.
Further, during described thin-layer chromatography identification reaction process, developping agent used is: ethyl acetate: sherwood oil=1:1 ~ 3.
Further, described reflux time is 13.5 ~ 16h.
Compared with prior art; the present invention is by being dissolved in back flow reaction in organic solvent by chloro-for 1-ethanoyl-4-1H-indazole and primary aromatic amine; obtain the chloro-1H-indazole of 4-and N-acetylize substituted aromatic amines compounds; the method can be used for the deacetylation of 1-ethanoyl-1H-indazole analog derivative; and do not need to use inorganic strong alkali, compared with prior art there is clear superiority.The present invention also can be used for the acetylize protection of aromatic primary amine compounds, and because present method carries out back flow reaction in organic solvent, compared with traditional method, reaction conditions is gentle, has clear superiority than traditional method.
Embodiment
The acetyl grouptransfer of the chloro-1H-indazole of a kind of 1-ethanoyl-4-provided by the invention is to the method for primary aromatic amine; comprise 1:1 in molar ratio and get the chloro-1H-indazole of 1-ethanoyl-4-and primary aromatic amine; fully dissolve in organic solvent toluene or dimethyl formamide; back flow reaction 13.5 ~ 16h under magnetic agitation; and using thin-layer chromatography identification reaction process, developping agent used is: ethyl acetate: sherwood oil=1:1 ~ 3.Steam organic solvent after reaction terminates, by gained solid by pillar layer separation, moving phase is ethyl acetate: sherwood oil=1:1 ~ 3; Obtain the chloro-1H-indazole of 4-and N-acetylize substituted aromatic amines compounds; Its reaction formula is as follows:
In the structural formula of wherein primary aromatic amine R be H, to methyl, to fluorine, to chlorine or trifluoromethyl.
Embodiment 1
1:1 gets the chloro-1H-indazole (1) of 1-ethanoyl-4-of 1.03mmol respectively in molar ratio, open-chain crown ether (2a) adds in single port flask, get toluene or dimethyl formamide 10.0mL does organic solvent, raw material is dissolved completely, back flow reaction under magnetic agitation, by the process of thin-layer chromatography identification reaction, developping agent used is: ethyl acetate: sherwood oil=1:1 ~ 3, reaction times is 13.5 hours, organic solvent is removed under reduced pressure after reaction terminates, obtain white solid, for the mixture of the chloro-1H-indazole of product 3:4-and compound 4a:N-acetylmethyl aniline, pass through pillar layer separation, moving phase is ethyl acetate: sherwood oil=1:2, obtain product yellow solid 3:0.10g respectively, productive rate: 63.8%, with white crystal 4a:0.10g, productive rate: 65.4%, compound 3, fusing point is: m.p.155-157 DEG C, and nuclear magnetic data is
1hNMR (CDCl
3, 400MHz) and δ: 10.4 (s, w, 1H, 1-NH), 8.10 (s, 1H, Pyrazole-2CH), 7.40 (d, 1H, Phenyl-7-C-H), 7.25 (dd, 1H, Phenyl-6-CH), 7.10 (d, 1H, Phenyl-5-C-H),
13cNMR (CDCl
3, 400MHz): δ 140.99 (7a-C), 133.53 (3-C), 127.54 (6-C), 126.65 (4-C), 122.69 (3a-C), 120.71 (5-C), 108.38 (7-C), MS (EI) m/z153 (M
+ 1).Compound 4b, m.p.148-151 DEG C,
1hNMR (CDCl
3, 400MHz) and δ: 7.57 (s, br, 1H, NH), 7.38-7.36 (d, 2H, Phenyl-2,6-CH), 7.10-7.08 (d, 2H, Phenyl-3,5-CH), 2.04 (s, 3H, Phenyl-CH
3), 1.98 (s, 3H, CO-CH
3), MS (EI): M
+ 1150.
Embodiment 2
1:1 gets the chloro-1H-indazole (1) of 1-ethanoyl-4-of 1.03mmol and aniline (2b) adds in single port flask respectively in molar ratio, get toluene or dimethyl formamide 10.0mL does organic solvent, raw material is dissolved completely, back flow reaction under magnetic agitation, by the process of thin-layer chromatography identification reaction, developping agent used is: ethyl acetate: sherwood oil=1:1 ~ 3, reaction times is 13.5 hours, organic solvent is removed under reduced pressure after reaction terminates, obtain gray solid mixture, for the mixture of the chloro-1H-indazole of product 3:4-and product 4:N-ethanoyl aniline, this mixture can through pillar layer separation, moving phase is ethyl acetate: sherwood oil=1:2, obtain yellow solid 3, MS (EI): M
+ 1153, and white crystal 4b, MS (EI): M
+ 1136, calculate productive rate and be respectively: 48.0% and 47.0%.M.p.114-115 DEG C of (document: 114-115 DEG C, Buchi, G.; J.Am.Chem.Soc., 1956,78,689-690).
Embodiment 3
1:1 gets the chloro-1H-indazole (1) of 1-ethanoyl-4-of 1.03mmol and p-Chlorobenzoic acid amide (2c) adds in single port flask respectively in molar ratio; get 10.0mL toluene and do organic solvent; raw material is dissolved completely; back flow reaction under magnetic agitation; by the process of thin-layer chromatography identification reaction; developping agent used is: ethyl acetate: sherwood oil=1:2; reaction times is 16 hours; toluene is removed under reduced pressure after reaction terminates; the solid obtained passes through pillar layer separation; moving phase is ethyl acetate: sherwood oil=1:2, obtains product 3, MS (EI): M respectively
+ 1153, compound 4c, MS (EI): M
+ 1170, calculate productive rate and be respectively: 56.0% and 33.0%.Product 3 is the chloro-1H-indazole of 4-, and compound 4c is N-ethanoyl p-Chlorobenzoic acid amide.
Embodiment 4
1:1 gets the chloro-1H-indazole (1) of 1-ethanoyl-4-of 1.03mmol and para-fluoroaniline (2d) adds in single port flask respectively in molar ratio, get 10.0mL toluene and do organic solvent, raw material is dissolved completely, back flow reaction under magnetic agitation, by the process of thin-layer chromatography identification reaction, developping agent used is: ethyl acetate: sherwood oil=1:1 ~ 3; Reaction times is 14 hours, after reaction terminates, remove toluene under reduced pressure, and the solid obtained is by pillar layer separation, and moving phase is ethyl acetate: sherwood oil=1:2, obtains product 3, MS (EI): M respectively
+ 1153, compound 4d, MS (EI): M
+ 1154, calculate productive rate and be respectively: 46.0% and 44.0%.Product 3 is the chloro-1H-indazole of 4-, and compound 4d is N-ethanoyl para-fluoroaniline.
Embodiment 5
1:1 gets the chloro-1H-indazole (1) of 1-ethanoyl-4-of 1.03mmol and 5-trifluoromethylaniline (2e) adds in single port flask respectively in molar ratio, get toluene or dimethyl formamide 10.0mL does organic solvent, raw material is dissolved completely, back flow reaction under magnetic agitation, by the process of thin-layer chromatography identification reaction, developping agent used is: ethyl acetate: sherwood oil=1:1 ~ 3, reaction times is 15 hours, solvent is removed under reduced pressure after reaction terminates, obtain the mixture of the chloro-1H-indazole (3) of 4-and N-ethanoyl 5-trifluoromethylaniline (4e), this mixture can through pillar layer separation, moving phase is ethyl acetate: sherwood oil=1:2.
Method provided by the invention also can be used for various substituted indazole compounds 1-acetylize deprotection, and any skilled addressee by expanding to other similar structures to step disclosed in this invention, can should belong to the scope of protection of the invention.
Claims (7)
1. the acetyl grouptransfer of the chloro-1H-indazole of 1-ethanoyl-4-is to the method for primary aromatic amine, it is characterized in that: 1:1 gets the chloro-1H-indazole of 1-ethanoyl-4-and primary aromatic amine in molar ratio, fully dissolve in organic solvent, stirring and refluxing is reacted, and use thin-layer chromatography identification reaction process, steam organic solvent after reaction terminates, by gained solid by pillar layer separation, obtain the chloro-1H-indazole of 4-and N-acetylize substituted aromatic amines compounds; Its reaction formula is as follows:
。
2. the acetyl grouptransfer of the chloro-1H-indazole of a kind of 1-ethanoyl-4-according to claim 1 is to the method for primary aromatic amine, it is characterized in that: in the structural formula of described primary aromatic amine R be H, to methyl, to fluorine, to chlorine or trifluoromethyl.
3. the acetyl grouptransfer of the chloro-1H-indazole of a kind of 1-ethanoyl-4-according to claim 1 is to the method for primary aromatic amine, it is characterized in that: when described organic solvent gets 10mL, gets 1-ethanoyl-4-chloro-1H-indazole 1.03mmol.
4. the acetyl grouptransfer of the chloro-1H-indazole of a kind of 1-ethanoyl-4-according to claim 3 is to the method for primary aromatic amine, it is characterized in that: described organic solvent is toluene or dimethyl formamide.
5. the acetyl grouptransfer of the chloro-1H-indazole of a kind of 1-ethanoyl-4-according to claim 1 is to the method for primary aromatic amine, it is characterized in that: adopt moving phase to be ethyl acetate during described pillar layer separation: sherwood oil=1:1 ~ 3.
6. the acetyl grouptransfer of the chloro-1H-indazole of a kind of 1-ethanoyl-4-according to claim 1 is to the method for primary aromatic amine, it is characterized in that: during described thin-layer chromatography identification reaction process, developping agent used is: ethyl acetate: sherwood oil=1:1 ~ 3.
7. the acetyl grouptransfer of the chloro-1H-indazole of a kind of 1-ethanoyl-4-according to claim 1 is to the method for primary aromatic amine, it is characterized in that: described reflux time is 13.5 ~ 16h.
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| GB761776A (en) * | 1953-10-30 | 1956-11-21 | Ici Ltd | Metallisable azo dyestuffs |
| JP4812619B2 (en) * | 2004-03-24 | 2011-11-09 | 公益財団法人新産業創造研究機構 | Acetylation of aniline derivatives by microorganisms and microorganism-derived enzymes. |
| JP2008044880A (en) * | 2006-08-15 | 2008-02-28 | Bayer Cropscience Ag | Insecticidal isooxazolines |
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