CN102321046B - Method for preparing 2-(N-alkyl)aminothiazole and 2-(N-alkyl) aminooxazole derivative by N-alkylation reaction - Google Patents
Method for preparing 2-(N-alkyl)aminothiazole and 2-(N-alkyl) aminooxazole derivative by N-alkylation reaction Download PDFInfo
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Abstract
The invention provides a new method for preparing 2-(N-alkyl)aminothiazole and a 2-(N-alkyl) aminooxazole derivative. The method comprises the following steps: adding 2-aminothiazole or a 2-aminooxazole derivative, a catalyst, alkali, alcohol and an organic solvent (or organic solvent-free) in a reactor under the condition of nitrogen protection or air to react for hours at the temperature of 100-150 DEG C; evaporating to remove surplus solvents or reactants; and carrying out column separation so as to obtain a target compound. The preparation method provided by the invention has the following four obvious advantages that 1) nearly-nontoxic alcohol is used as an alkylation reagent; 2) in the process of reaction, water is just generated as a byproduct, thus no environmental hazards are generated; 3) the reaction has high atom economy; and 4) the reaction system is not merely limited to benzyl alcohol, and has high reaction activity on fatty alcohol, secondary alcohol and the like, moreover, the reaction system is not merely limited to 2-aminobenzothiazole derivatives, and has high reaction activity on non-benzo 2-aminothiazole and 2-aminooxazole, thus the range of substrates is greatly expanded in the reaction. The new method in the invention has wide development prospect.
Description
Technical field
The invention belongs to technical field of organic chemistry, be specifically related to the amino preparation method who dislikes derivative of a kind of 2-(N-alkyl) aminothiazole and 2-(N-alkyl).
Background technology
2-(N-alkyl) aminothiazole and the amino oxazole derivatives of 2-(N-alkyl) are important bioactive compoundss, this compounds shows wide pharmacology and physiologically active, for example use them as galactopyranose mutase inhibitor, two orexin receptor antibody and hepatitis C virus NS 3 proteinase inhibitor (E. C. Dykhuizen, J. F. May, A. Tongpenyai, L. Kiessling
j. Am. Chem. Soc. 2008,
130, 6706-6707, C. D. Cox, M. J. Breslin, D. B. Whitman, J. D. Schreier, G. B. McGaughey, M. J. Bogusky, A. J. Roecker, S. P. Mercer, R. A. Bednar, W. Lemaire, J. G. Bruno, D. R. Reiss, C. M. Harrell, K. L. Murphy, S. L. Garson, S. M. Doran, T. Prueksaritanont, W. B. Anderson, C. Tang, S. Roller, T. D. Cabalu, D. Cui, G. D. Hartman, S. D. Young, K. S. Koblan, C. J. Winrow, J. Renger, P. J. Coleman,
j. Med. Chem. 2010,
53, 5320-5332, T. Zhang, Z. Yan, A. Sromek, B. I. Knapp, T. Scrimale, J. M. Bidlack, J. L. Neumeyer,
j. Med. Chem. 2011,
54, 1903-1913.)
This compounds be also many bioactive moleculess important structure unit (S. Huang et. al,
bioorg. Med. Chem. Lett., 2008,
18, 2324; Z. Y. Sun et al,
bioorg. Med. Chem. Lett., 2009,
19, 6801.) and important organic synthesis intermediate (J. Patman et al,
bioorg. Med. Chem. Lett., 2007,
17, 2540; C. Liu et al,
bioorg. Med. Chem. Lett., 2008,
18, 1874), this compounds also for example as histaminase H3 inhibitor and neuropeptide inhibitor (I. D. Linney et al,
j. Med. Chem., 2000,
43, 2362; U. Z. Y. Sun et al.,
bioorg. Med. Chem. Lett., 2009,
19, 6801).
Just due to 2-(N-alkyl) aminothiazole and the amino oxazole of 2-(N-alkyl) extremely important, so develop simple and efficient synthetic method, prepare this compounds and paid attention to always.At present, the adjacent halogen phenylurea of transition metal-catalyzed ring structure or the adjacent halobenzene amine of concentrate/coupling/ring structure of polycomponent, sulfurous gas and amino alkane are used, it is by product that but this method reaction generates haloid acid, not only cause serious environmental hazard, and the atomic efficiency of reaction is also low, and can only synthesize 2-(N-alkyl) aminothiazole and the amino oxazole derivatives of 2-(N-alkyl) of benzo.（L. L. Joyce, G. Evindar, R. A. Batey,
Chem. Commun.
2004, 446-447; P. Saha, T. Ramana, N. Purkait, M. A. Ali, R. Paul, T. Punniyamurthy,
J. Org. Chem. 2009,
74, 8719-8725; Q. Ding, X. He, J. Wu,
J. Comb. Chem. 2009,
11, 587-591; K. Inamoto, C. Hasegawa, K. Hiroya, T. Doi,
Org. Lett. 2008,
10, 5147-5150; L. L. Joyce, R. A. Batey,
Org. Lett. 2009,
11, 2792-2795; D. Ma, X. Lu, L, Shi, H. Zhang, Y. Jiang, X. Liu, Angew.
Chem.Int. Ed. 2011,
50, 1118-1121.）
Transition metal-catalyzed direct oxidisability coupling azoles and amine, chloramines and methane amide are the preparation methods of another kind of preparation 2-(N-alkyl) aminothiazole and the amino oxazole of 2-(N-alkyl), but this method need to be used the catalyzer of high capacity amount, more than the oxygenant of metering or other additive, low functional group is compatible.（D. Monguchi, T. Fujiwara, H. Furukawa, A. Mori,
Org. Lett. 2009,
11, 1607-1610; J. Y. Kim, S. H. Cho, J. Joseph, S. Chang,
Angew. Chem. Int. Ed. 2010,
49, 9899-9903; T. Kawano, K. Hirano, T. Satoh, M. Miura,
J. Am. Chem. Soc. 2010,
132, 6900-6901; S. H. Cho, J. Y. Kim, S. Y. Lee, S. Chang,
Angew. Chem. 2009,
121, 9291-9294;
Angew. Chem. Int. Ed. 2009,
48, 9127-9130.）
Recently, we have reported use copper/alkali systems catalysis 2-aminobenzothiazole and benzylalcohol and react and generate 2-(N-benzylamino) benzothiazole derivant (F. Li, H. Shan, Q. Kang, L. Chen.
chem. Commun. 2011.
47, 5058-5060).In original system, only have benzyl primary alconol just can react, can not there is any reaction in non-benzylalcohol (particularly fatty alcohol, secondary alcohol).In addition, the type of amino azoles is also confined to 2-aminobenzothiazole.Therefore, former reaction has significant limitation.
Summary of the invention
The invention provides the novel method of a kind of 2-of preparation (N-alkyl) aminothiazole and the amino oxazole derivatives of 2-(N-alkyl) (formula 1)
By thiazolamine and the amino oxazole derivatives (formula 2) of 2-
With reacting of compound alcohol (formula 3)
R wherein
1, R
2define as described herein.Reaction is to occur under transition metal iridium or rhodium complex and alkali existence.Its reaction expression is
Wherein, R
1represent optional one or more substituting group, substituting group can be identical or different, is selected from hydrogen, C
1-C
10alkyl, C
1-C
10alkoxyl group, C
1-C
10single or two replacement alkane nitrogen bases, halogen, aryl, trifluoromethyl, trifluoromethoxy, fluoroform sulfydryl, cyano group, nitro, carboxylic acid ester groups.
R
2be selected from phenyl, alkyl phenyl, C
1-C
10alkoxyl phenyl, C
1-C
10single or two replacement alkane nitrogen base phenyl, list or phenyl polyhalide base, trifluoromethyl, Trifluoromethoxyphen-l, fluoroform sulfydryl phenyl, nitrophenyl, pyridyl, furyl, thienyl, naphthyl, C
1-C
10alkyl, C
1-C
10alkoxyl group, C
1-C
10single or two replacement alkane nitrogen bases.
The technical solution that realizes the object of the invention is: under nitrogen protection or air, in reaction vessel, add the amino oxazole derivatives of thiazolamine or 2-, transition-metal catalyst, alkali, alcohol and organic solvent (or not solubilizing agent).Reaction mixture is at 100-150
ounder C after stoichiometric number hour, cool to room temperature.Rotary evaporation is removed unnecessary solvent or reactant, then separated by post, obtains target compound.
Compared with the existing technology, the present invention is from commercialization or easy synthetic thiazolamine and the amino oxazole derivatives of 2-, by with alcohol generation alkylated reaction, the 2-obtaining (N-alkyl) aminothiazole and the amino oxazole derivatives of 2-(N-alkyl), reaction shows four significant advantages: 1) use and be bordering on nontoxic alcohol for alkylating reagent; 2) only to generate water be by product in reaction, without environmental hazard; 3) reaction of atomic economy is high; 4) with respect to original copper/alkali systems, this reaction system is not confined to benzylalcohol, and for fatty alcohol, secondary alcohol etc. all show high reactive behavior.In addition, reaction system is not confined to 2-amino-benzothiazole derivatives, and the thiazolamine of non-benzo and the amino oxazole of 2-are also shown to very high reactive behavior, and therefore, substrate scope has been expanded in this reaction greatly, has vast potential for future development.
Embodiment
Show that example illustrates some embodiment of the present invention, and should not be construed as and limit the scope of the invention.To content disclosed by the invention, can on method and reaction conditions, carry out many improvement simultaneously from material, change and change.All these improve, within variation and change all fall into the spirit and scope of the present invention definitely.
embodiment 1: the preparation of N-butyl benzothiazole-2-amine
N-butylbenzo[d]thiazol-2-amine
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 95%
mp 69.6-70.6
oC;
1H NMR (500 MHz, CDCl
3) δ 7.58 (d,
J = 7.9 Hz, 1H, ArH), 7.52 (d,
J = 8.1 Hz, 1H, ArH), 7.29 (t,
J = 7.6 Hz, 1H, ArH), 7.07 (t,
J = 7.6 Hz, 1H, ArH), 5.49 (br s, 1H, NH), 3.42 (t,
J = 7.1 Hz, 2H, CH
2N), 1.68 (quint,
J = 7.3 Hz, 2H, CH
2), 1.45 (sext,
J = 7.4 Hz, 2H, CH
2), 0.97 (t,
J = 7.4 Hz, 3H, CH
3);
13C NMR (125MHz, CDCl
3) δ 168.0, 152.4, 130.2, 125.9, 121.2, 120.7, 118.5, 45.4, 31.6, 20.0, 13.7。
embodiment 2: the preparation of N-hexyl benzothiazole-2-amine
N-hexylbenzo[d]thiazol-2-amine
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and n-hexyl alcohol (510 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 93%
mp 58.5-59.4
oC;
1H NMR (500 MHz, CDCl
3) δ 7.58 (d,
J = 7.9 Hz, 1H, ArH), 7.53 (d,
J = 8.1 Hz, 1H, ArH), 7.29 (t,
J = 7.7 Hz, 1H, ArH), 5.39 (br s, 1H, NH), 3.41 (t,
J = 7.1Hz, 2H, CH
2N), 1.68 (quint,
J = 7.3 Hz, 2H, CH
2), 1.41 (quint,,
J = 7.2 Hz, 2H, CH
2), 1.34-1.30 (m, 4H, 2xCH
2), 0.90 (t,
J = 7.1Hz, 3H, CH
3);
13C NMR (125MHz, CDCl
3) δ 168.0, 152.5, 130.2, 125.8, 121.2, 120.7, 118.5, 45.7, 31.4, 29.5, 26.5, 22.5, 13.9。
embodiment 3: the preparation of N-octyl group benzothiazole-2-amine
N-octylbenzo[d]thiazol-2-amine
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and n-Octanol (650 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 86%
mp 43.0-44.3
oC;
1H NMR (500 MHz, CDCl
3) δ 7.58 (d,
J = 7.7 Hz, 1H, ArH), 7.50 (d,
J = 8.1 Hz, 1H, ArH) 7.28 (t,
J = 7.8 Hz, 1H, ArH),7.06 (t,
J = 7.6 Hz, 1H, ArH), 6.3 (br s, 1H, NH), 3.4 (t,
J = 7.1 Hz, 2H, CH
2N), 1.67 (quint,
J = 7.3 Hz, 2H, CH
2), 1.38 (quint, J = 7.3 Hz, 2H, CH
2), 1.33-1.23 (m, 8H, 4xCH
2), 0.87 (t,
J = 7.0 Hz, 3H, CH
3)。
embodiment 4: the preparation of N-ethyl benzothiazole-2-amine
N-ethylbenzo[d]thiazol-2-amine
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (40 mg, 1 mmol, 100 mol%) and ethanol (230 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 92%
1H NMR (500 MHz, CDCl
3) δ 7.59 (d,
J = 7.9 Hz, 1H, ArH), 7.53 (d,
J = 8.1Hz, 1H, ArH), 7.29 (t,
J = 7.7 Hz, 1H), 7.08 (t,
J = 7.6 Hz, 1H), 5.56 (br s, 1H, NH), 3.47 (q,
J = 7.2 Hz, 2H, CH
2N), 1.33 (t,
J = 7.3 Hz, 3H, CH
3)。
embodiment 5: the preparation of N-isopentyl benzo thiazole-2-amine
N-isopentylbenzo[d]thiazol-2-amine
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and primary isoamyl alcohol (440 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 97%
mp 76.8-77.7
oC;
1H NMR (500 MHz, CDCl
3) δ 7.58 (d,
J = 8.0 Hz, 1H, ArH), 7.53 (d,
J = 8.0 Hz, 1H, ArH), 7.29 (t,
J = 7.7 Hz, 1H, ArH), 7.07 (t,
J = 7.6 Hz, 1H, ArH), 5.45 (brs, 1H, NH), 3.43 (t,
J = 7.4 Hz, 2H, CH
2N), 1.72 (m, 1H, CH), 1.05 (quart,
J = 7.2 Hz, 2H, CH
2), 0.96 (d,
J = 6.6 Hz, 6H, 2xCH
3)。
embodiment 6: the preparation of N-iso-octyl benzothiazole-2-amine
N-(2-ethylhexyl)benzo[d]thiazol-2-amine
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and isooctyl alcohol (650 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 87%
mp 80.2-81.2
oC;
1H NMR (500 MHz, CDCl
3) δ 7.58 (d,
J = 7.8 Hz, 1H, ArH), 7.51 (d,
J = 8.2 Hz, 1H, ArH), 7.29 (t,
J = 7.3 Hz, 1H, ArH), 7.07 (t,
J = 7.1 Hz, 1H, ArH) 5.50 (brs, 1H, NH), 3.32 (d,
J = 6.2 Hz, 2H, CH
2N), 1.61 (sept,
J = 6.1 Hz, 1H, CH
3), 1.41 (quint,
J = 7.2 Hz, 2H, CH
2), 1.37-1.26 (m, 6H, 3xCH
2), 0.94-0.88 (m, 6H, 2xCH
3)。
embodiment 7: the preparation of N-(2-methoxy ethyl) benzothiazole-2-amine
N-(2-methoxyethyl)benzo[d]thiazol-2-amine
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (40 mg, 1 mmol, 100 mol%) and ethylene glycol monomethyl ether (380 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 86%
Oil;
1H NMR (500 MHz, CDCl
3) δ 7.56-7.54 (m, 2H, ArH), 7.28 (t,
J = 8.1 Hz, 1H, ArH), 7.07 (t,
J = 7.6 Hz, 1H), 6.13 (br s, 1H, NH), 3.65-3.60 (m, 4H, CH
2N, CH
2O), 3.37 (J = 3.8 Hz, 3H)。
embodiment 8: the preparation of N-(2-methoxy ethyl) benzothiazole-2-amine
N-(2-(phenylthio)ethyl)benzo[d]thiazol-2-amine (8c)
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (40 mg, 1 mmol, 100 mol%) and ethylene glycol monomethyl ether (380 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 91%
mp 147.5-148.7
oC;
1H NMR (500 MHz, CDCl
3) δ 7.57 (d,
J = 7.7 Hz, 1H, ArH), 7.54 (d,
J = 8.1 Hz, 1H, ArH), 7.42 (d, J = 7.6 Hz, 2H, ArH), 7.32-7.28 (m, 3H, ArH), 7.23 (t,
J = 7.4 Hz, 1H, ArH), 7.09 (t,
J = 7.6 Hz, 1H, ArH), 5.61 (br s, 1H, NH), 3.67 (t,
J = 6.4 Hz, 2H, CH
2N), 3.24 (t,
J = 6.4 Hz, 2H, CH
2S)。
embodiment 9: the preparation of N-styroyl benzothiazole-2-amine
N-phenethylbenzo[d]thiazol-2-amine
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and 2 phenylethyl alcohol (680 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 94%
mp 143.6-144.4
oC;
1H NMR (500 MHz, CDCl
3) δ 7.59 (d,
J = 7.9 Hz, 1H, ArH), 7.53 (d,
J = 8.1 Hz, 1H, ArH), 7.34-7.28 (m, 3H, ArH), 7.27-7.23 (m, 4H, ArH), 7.09 (t,
J = 7.6 Hz, 1H, ArH), 5.42 (br s, 1H, NH), 3.70 (t,
J = 6.9 Hz, 2H, CH
2N), 3.01 (t,
J = 6.9 Hz, 2H, CH
2Ph)。
embodiment 10: the preparation of N-(3-hydrocinnamyl) benzothiazole-2-amine
N-(3-phenylpropyl)benzo[d]thiazol-2-amine
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and 3-phenylpropyl alcohol (680 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 96%
mp 101.2-102.0
oC;
1H NMR (500 MHz, CDCl
3) δ 7.58 (d,
J = 7.9 Hz, 1H, ArH), 7.53 (d,
J = 8.0 Hz, 1H, ArH), 7.31-7.28 (m, 3H, ArH), 7.23-7.19 (m, 3H, ArH), 7.09 (t,
J = 7.6 Hz, 1H), 5.54 (br s, 1H, NH), 3.45 (t,
J = 7.0 Hz, 2H, CH
2N), 2.75 (t,
J = 7.6 Hz, 2H, CH
2Ph), 2.04 (quint,
J = 7.3 Hz, 2H, CH
2)。
embodiment 11: the preparation of N-benzyl benzothiazole-2-amine
N-benzylbenzo[d]thiazol-2-amine (1c)
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and phenylcarbinol (540 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 97%
mp 164.4-165.2
oC (lit.
2 mp 164-168
oC);
1H NMR (500 MHz, DMSO-d
6) δ 8.51 (t,
J = 5.5 Hz, 1H, NH), 7.67 (d,
J = 7.8 Hz, 1H, ArH), 7.39-7.33 (m, 5H, ArH), 7.26 (t,
J = 7.1Hz, 1H, ArH), 7.22 (t,
J = 7.7 Hz, 1H, ArH), 7.02 (t,
J = 7.5 Hz, 1H, ArH), 4.60 (s, 2H, CH
2N)。
embodiment 12: the preparation of N-(4-methoxybenzyl) benzothiazole-2-amine
N-(4-methoxybenzyl)benzo[d]thiazol-2-amine
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and p-methoxybenzyl alcohol (691 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 94%
mp 173.5-174.0
oC;
1H NMR (500 MHz, CDCl
3) δ 7.58 (d,
J = 7.8 Hz, 1H, ArH), 7.52 (d,
J = 8.1 Hz, 1H, ArH), 7.33-7.28 (m, 3H, ArH ), 7.09 (t,
J = 7.6 Hz, 1H, ArH), 6.90-6.88 (m, 2H, ArH), 5.86 (br s, 1H, NH), 4.57 (s, 2H, CH
2N), 3.81 (s, 3H, OCH
3)。
embodiment 13: the preparation of N-(2-chlorobenzyl) benzothiazole-2-amine
N-(2-chlorobenzyl)benzo[d]thiazol-2-amine (5c)
2
Under nitrogen protection, by 2-aminobenzothiazole (150 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and adjacent chlorobenzene methanol (713 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 93%
mp 188.2-188.8
oC (lit.
2 mp 175-180
oC);
1H NMR (500 MHz, DMSO-d
6) δ 8.53 (t,
J = 5.7 Hz, 1H, NH), 7.67 (d,
J = 7.6 Hz, 1H, ArH), 7.42-7.37 (m, 5H, ArH), 7.22 (t,
J = 7.6 Hz, 1H, ArH), 7.03 (t,
J = 7.6 Hz, 1H, ArH), 4.59 (d,
J = 3.8 Hz, 2H, CH
2N)。
embodiment 14: the preparation of N-butyl-6-methylbenzothiazole-2-amine
N-butyl-6-methylbenzo[d]thiazol-2-amine
Under nitrogen protection, by 6-methyl 2-aminobenzothiazole (164 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 94%
mp 90.7-91.7
oC;
1H NMR (500 MHz, CDCl
3) δ 7.41 (d,
J = 8.2 Hz, 1H, ArH), 7.38 (s, 1H, ArH), 7.09 (d,
J = 8.2 Hz, 2H, ArH), 5.56 (br s, 1H, NH), 3.39 (t,
J = 7.0 Hz, 2H, CH
2N), 2.39 (s, 3H, CH
3Ar), 1.66 (quint,
J = 7.3 Hz, 2H), 1.43 (sext,
J = 7.5 Hz, 2H), 0.96 (t,
J = 7.4 Hz, 3H, CH
3)。
embodiment 15: the preparation of N-butyl-6-phenoxy group benzothiazole-2-amine
N-butyl-6-phenoxybenzo[d]thiazol-2-amine
Under nitrogen protection, by 6-phenoxy group-2-aminobenzothiazole (242 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 97%
mp 116.0-116.7
oC;
1H NMR (500 MHz, CDCl
3) δ 7.48 (d,
J = 8.8 Hz, 1H, ArH), 7.31 (t,
J = 8.0 Hz, 2H, ArH), 7.25 (s, 1H, ArH), 7.06 (t,
J = 7.4 Hz, 1H, ArH), 7.00 (dd,
J = 8.3 Hz and 2.5 Hz, 1H, ArH), 6.98 (d,
J = 7.9 Hz, 1H, ArH), 5.23 (brs, 1H, NH), 3.41 (t,
J = 7.1 Hz, 2H, CH
2N), 1.67 (quint,
J = 7.4 Hz, 2H, CH
2), 1.45 (sext,
J = 7.4 Hz, 2H), 0.97 (t,
J = 7.4 Hz, 3H, CH
3)。
embodiment 16: N-butyl-4, the preparation of 6-dimethyl-benzothiazole-2-amine
N-butyl-4,6-dimethylbenzo[d]thiazol-2-amine
Under nitrogen protection, by 4,6-dimethyl-2-aminobenzothiazole (178 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 88%
mp 46.0-47.2
oC;
1H NMR (500 MHz, CDCl
3) δ 7.24 (s, 1H, ArH), 6.93 (s, 1H, ArH), 5.29 (br s, 1H, NH) 3.34 (quart,
J = 5.8 Hz, 2H, CH
2N), 2.51 (s, 3H, CH
3Ar), 2.35 (s, 3H, CH
3Ar), 1.65 (quint,
J = 5.8 Hz, 2H, CH
2), 1.44 (sext,
J = 7.4 Hz, 2H, CH
2), 0.96 (t,
J = 7.4 Hz, 3H, CH
3)。
embodiment 17: the preparation of N-butyl-6-fluoro benzothiazole-2-amine
N-butyl-6-fluorobenzo[d]thiazol-2-amine
Under nitrogen protection, by the fluoro-2-aminobenzothiazole of 6-(168 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 90%
mp 95.8-96.6
oC;
1H NMR (500 MHz, CDCl
3) δ 7.43 (dd,
J = 8.7 Hz and 4.8 Hz, 1H), 7.29 (dd,
J = 8.2 Hz and 2.5 Hz, 1H, ArH), 7.00 (td,
J = 8.9 Hz and 2.6 Hz, 1H, ArH), 5.40 (br s, 1H, NH), 3.40 (t,
J = 7.1 Hz, 2H, CH2N), 1.67 (quint,
J = 7.3 Hz, 2H, CH
2), 1.44 (sext,
J = 7.5 Hz, 2H, CH
2), 0.96 (t,
J = 7.4 Hz, 3H, CH
3)。
embodiment 18: the preparation of N-butyl-6-chloro benzothiazole-2-amine
N-butyl-6-chlorobenzo[d]thiazol-2-amine
8
Under nitrogen protection, by the chloro-2-aminobenzothiazole of 6-(185 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 92%
mp 109.5-110.6
oC;
1H NMR (500 MHz, CDCl
3) δ 7.54 (d,
J = 2.1 Hz, 1H, ArH), 7.41 (d,
J = 8.7 Hz, 1H, ArH), 7.24 (dd,
J = 8.7 Hz and 2.4 Hz, 1H, ArH), 5.44 (br s, 1H, NH), 3.41 (t,
J = 7.1 Hz, 2H, ArH), 1.67 (quint,
J = 7.3 Hz, 2H, CH
2), 1.44 (sext,
J = 7.5 Hz, 2H, CH
2), 0.97 (t,
J = 7.3 Hz, 3H, CH
3)。
embodiment 19: the preparation of N-butyl-6-trifluoromethoxy benzo thiazole-2-amine
N-butyl-6-(trifluoromethoxy)benzo[d]thiazol-2-amine
Under nitrogen protection, by 6-trifluoromethoxy-2-aminobenzothiazole (234 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (40 mg, 1 mmol, 100 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 90%
mp 76.4-77.4
oC;
1H NMR (500 MHz, CDCl
3) δ 7.48-7.45 (m, 3H, ArH), 7.15 (d,
J = 8.7 Hz, 1H, ArH), 5.47 (br s, 1H, NH), 3.42 (t,
J = 7.0 Hz, 2H, CH
2N), 1.68 (quint,
J = 7.3 Hz, 2H, CH
2), 1.45 (sext,
J = 7.5 Hz, 2H, CH
2), 0.97 (t,
J = 7.4 Hz, 3H, CH
3)。
embodiment 20: the preparation of the chloro-4-methylbenzothiazole-2-of N-butyl-6-amine
N-butyl-6-chloro-4-methylbenzo[d]thiazol-2-amine
Under nitrogen protection, by the chloro-4-methyl-2-amino of 6-benzothiazole (199 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 85%
mp 70.1-71.4
oC;
1H NMR (500 MHz, CDCl
3) δ 7.40 (s, 1H, ArH), 7.08 (s, 1H, ArH), 5.32 (br s, 1H, NH), 3.36 (quart,
J = 6.1 Hz, CH
2NH), 2.51 (s, 3H,CH
3Ar), 1.66 (quint,
J = 7.3 Hz, 2H, CH
2), 1.44 (sext,
J = 7.4 Hz, 2H, CH
2), 0.97 (t,
J = 7.4 Hz, 3H, CH
3)。
embodiment 21: N-butyl-4, how also 5-dihydro the preparation of thiazole-2-amine
N-butyl-4,5-dihydronaphtho[1,2-d]thiazol-2-amine
Under nitrogen protection, by 4,5-dihydro-naphtho [1,2-d] thiazole-2-amine (202 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (40 mg, 1 mmol, 100 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 81%
mp 89.8-90.6
oC;
1H NMR (500 MHz, CDCl
3) δ 7.70 (d,
J = 7.6 Hz, 1H, ArH), 7.23 (t,
J = 7.3 Hz, 1H, ArH), 7.17-7.11 (m, 3H, ArH), 5.1 (br s, 1H, NH), 3.27 (q,
J = 6.5 Hz, 2H, CH
2N), 3.02 (t,
J = 7.8 Hz, 2H, CH
2), 2.85 (t,
J = 7.8 Hz, 2H, CH
2), 1.65 (quint,
J = 7.3 Hz, 2H, CH2), 1.43 (sext,
J = 7.5 Hz, 2H, CH
2), 0.96 (t,
J = 7.3 Hz, 3H, CH
3)。
embodiment 22: the preparation of N-butyl-5-methyl 4-phenyl thiazole-2-amine
N-butyl-5-methyl-4-phenylthiazol-2-amine
Under nitrogen protection, by 5-methyl 4-phenyl-thiazolamine (190 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 96%
mp 55.4-56.8
oC; 1H NMR (500 MHz, CDCl
3) δ 7.57 (d,
J = 7.8 Hz, 2H, ArH), 7.38 (t,
J = 7.7 Hz, 2H, ArH), 7.28 (t,
J = 7.4 Hz, 1H, ArH), 5.26 (br s, 1H, NH), 3.20 (quart,
J = 6.0 Hz, 2H, CH
2), 3.40 (s, 3H, CH
3), 1.59 (quint,
J = 7.3 Hz, 2H, CH
2), 1.39 (quint,
J = 7.4 Hz, 2H, CH
2), 0.94 (t,
J = 7.4 Hz, 3H, CH
3)。
embodiment 23: N-butyl-4, the preparation of 5-phenylbenzene thiazole-2-amine
N-butyl-4,5-diphenylthiazol-2-amine
Under nitrogen protection, by 4,5-phenylbenzene-thiazolamine (252 mg, 1 mmol), [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (40 mg, 1 mmol, 100 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 88%
mp 116.2-117.0;
1H NMR (500 MHz, CDCl
3) δ 7.47 (dd,
J = 7.9 Hz and 2.2 Hz, 2H, ArH), 7.27-7.17 (m, 8H, ArH), 6.15 (br s 1H, NH), 3.14 (quart,
J = 6.2 Hz, 2H, CH
2N), 1.51 (quint，
J = 7.4 Hz, 2H, CH
2) 1.33 (sext,
J = 7.4 Hz, 2H, CH
2), 0.90 (t,
J = 7.3 Hz, 3H, CH
3)。
embodiment 24: the preparation of N-butyl-5-chlorobenzene diozaiole-2-amine
N-butyl-5-chlorobenzo[d]oxazol-2-amine
Under nitrogen protection, by the amino benzoxazoles (169 mg, 1 mmol) of the chloro-2-of 5-, [Cp*IrCl
2]
2(1.6 mg, 0.002 mmol, 0.2 mol%), sodium hydroxide (8.0 mg, 0.2 mmol, 20 mol%) and propyl carbinol (371 mg, 5 mmol) are added in 20 ml Schlenk reaction flasks successively.Reaction mixture is 150
ounder C, react after 12 hours cool to room temperature.Rotary evaporation is except desolventizing, then by column chromatography (developping agent: ethyl acetate/petroleum ether) obtain pure target compound, productive rate: 92%
mp 116.2-117.0;
1H NMR (500 MHz, CDCl
3) δ 7.47 (dd,
J = 7.9 Hz and 2.2 Hz, 2H, ArH), 7.27-7.17 (m, 8H, ArH), 6.15 (br s 1H, NH), 3.14 (quart,
J = 6.2 Hz, 2H, CH
2N), 1.51 (quint，
J = 7.4 Hz, 2H, CH
2) 1.33 (sext,
J = 7.4 Hz, 2H, CH
2), 0.90 (t,
J = 7.3 Hz, 3H, CH
3)。
embodiment 25: except using [IrCl (cod)]
2(1.3 mg, 0.002 mmol, 0.2 mol%) replaces [Cp*IrCl
2]
2,, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 90%.
embodiment 26: except using [Cp*RhCl
2]
2(1.2 mg, 0.002 mmol, 0.2 mol%) replaces [Cp*IrCl
2]
2,, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 55%.
embodiment 27:except replacing sodium hydroxide with salt of wormwood (27.6 mg, 0.2 mmol, 20 mol%), reaction raw materials, product and other conditions are with embodiment 1, productive rate: 35%.
embodiment 28:except replacing sodium hydroxide with cesium carbonate (65.2 mg, 0.2 mmol, 20 mol%), reaction raw materials, product and other conditions are with embodiment 1, productive rate: 90%.
embodiment 29:except replacing sodium hydroxide with potassium hydroxide (11.2 mg, 0.2 mmol, 20 mol%), reaction raw materials, product and other conditions are with embodiment 1, productive rate: 92%.
embodiment 30:except replacing sodium hydroxide with sodium tert-butoxide (19.2 mg, 0.2 mmol, 20 mol%), reaction raw materials, product and other conditions are with embodiment 1, productive rate: 93%.
embodiment 31:except replacing sodium hydroxide with potassium tert.-butoxide (22.4 mg, 0.2 mmol, 20 mol%), reaction raw materials, product and other conditions are with embodiment 1, productive rate: 91%.
embodiment 32:except [Cp*IrCl
2]
2consumption be 0.8 mg, 0.001 mmol, 0.1 mol%, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 84%.
embodiment 33:except [Cp*IrCl
2]
2consumption be 0.4 mg, 0.0005 mmol, 0.05 mol%, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 68%.
embodiment 34:except the consumption of NaOH is 4 mg, 0. 1 mmol, 10 mol%, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 91%.
embodiment 35:except the consumption of NaOH is 40 mg, 1 mmol, 100 mol%, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 96%.
embodiment 36:except the consumption of propyl carbinol is 296 mg, 4 mmol, 400 mol%, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 91%.
embodiment 37:except the consumption of propyl carbinol is 222 mg, 3 mmol, 300 mol%, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 83%.
embodiment 38:except reaction solvent is dioxane (1 ml), reaction raw materials, product and other conditions are with embodiment 1, productive rate: 75%.
embodiment 39:except reaction solvent is p-Xylol (1 ml), reaction raw materials, product and other conditions are with embodiment 1, productive rate: 80%.
embodiment 40:except temperature of reaction is 130
oc, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 86%.
embodiment 41:except temperature of reaction is 100
oc, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 73%.
embodiment 42:except the reaction times is 8 hours, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 77%.
embodiment 43:except the reaction times is 4 hours, reaction raw materials, product and other conditions are with embodiment 1, productive rate: 45%.
Claims (5)
1. N-alkylated reaction is prepared a method for 2-(N-alkyl) aminothiazole and the amino oxazole derivatives of 2-(N-alkyl), it is characterized in that reaction product 1
By thiazolamine and the amino oxazole derivatives 2 of 2-
Compound 3 with alcohol
Under the complex compound catalyst of transition metal iridium and the existence of alkali, react and obtain,
Wherein, R
1optional one or more substituting group, is selected from hydrogen, C
1-C
10alkyl, C
1-C
10alkoxyl group, C
1-C
10single or two replacement alkylaminos, halogen, aryl, trifluoromethyl, trifluoromethoxy, fluoroform sulfydryl, cyano group, nitro, carboxylic acid ester groups;
R
2be selected from phenyl, alkyl phenyl, C
1-C
10alkoxyl phenyl, C
1-C
10single or two replacement alkylamino phenyl, list or phenyl polyhalide base, trifluoromethyl, Trifluoromethoxyphen-l, fluoroform sulfydryl phenyl, nitrophenyl, pyridyl, furyl, thienyl, naphthyl, C
1-C
10alkyl, C
1-C
10alkoxyl group, C
1-C
10single or two replacement alkylaminos;
Wherein, the complex compound of described iridium is [Cp*IrCl
2]
2or [IrCl (cod)]
2; Described alkali is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, sodium tert-butoxide or potassium tert.-butoxide.
2. the preparation method of 2-according to claim 1 (N-alkyl) aminothiazole and the amino oxazole derivatives of 2-(N-alkyl), is characterized in that described reaction carries out under solvent-free state or organic solvent; Described catalyst levels is (0.0005 ~ 0.002) with respect to the mol ratio of thiazolamine derivative: 1, described alkali is (0.1 ~ 1) with respect to the mol ratio of 2-amino-benzothiazole derivatives: 1, and described alcohol is (3 ~ 5) with respect to the mol ratio of 2-amino-benzothiazole derivatives: 1.
3. the preparation method of 2-according to claim 2 (N-alkyl) aminothiazole and the amino oxazole derivatives of 2-(N-alkyl), is characterized in that organic solvent is p-Xylol or dioxane.
4. the preparation method of 2-according to claim 1 (N-alkyl) aminothiazole and the amino oxazole derivatives of 2-(N-alkyl), is characterized in that described temperature of reaction is 100 ~ 150 ℃.
5. the preparation method of 2-according to claim 1 (N-alkyl) aminothiazole and the amino oxazole derivatives of 2-(N-alkyl), is characterized in that the described reaction times is 4 ~ 12 hours.
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| Title |
|---|
| Cp*Ir-catalyzed N-alkylation of amines with alcohols. A versatile and atom economical method for the synthesis of amines;Ken-ichi Fujita et al;《Tetrahedron》;20071221;第64卷;第1943-1954页 * |
| Feng Li et al.Regioselective N-alkylation of 2-aminobenzothiazoles with benzylic alcohols.《Chem.Comm.》.2011,第47卷第5058-5060页. |
| Ken-ichi Fujita et al.Cp*Ir-catalyzed N-alkylation of amines with alcohols. A versatile and atom economical method for the synthesis of amines.《Tetrahedron》.2007,第64卷第1943-1954页. |
| Regioselective N-alkylation of 2-aminobenzothiazoles with benzylic alcohols;Feng Li et al;《Chem.Comm.》;20110325;第47卷;第5058-5060页 * |
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