* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Acta Chimica Academiae Scientiarum Hungaricae, 1957, vol. 10, p. 227,229
[2] Chemical Communications, 2013, vol. 49, # 94, p. 11044 - 11046
2
[ 106-49-0 ]
[ 344-19-4 ]
Reference：
[1] Chemical Communications, 2013, vol. 49, # 94, p. 11044 - 11046
3
[ 2106-02-7 ]
[ 344-19-4 ]
Reference：
[1] Chemical Communications, 2013, vol. 49, # 94, p. 11044 - 11046
4
[ 392-16-5 ]
[ 344-19-4 ]
Reference：
[1] Acta Chimica Academiae Scientiarum Hungaricae, 1957, vol. 10, p. 227,229
(2,6-dichloro-4-fluorophenyl)hydrazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
Preparation 10 2,6 Dichloro-4-fluoro-phenylhydrazine hydrochlorideTo a 0 0C solution of 2,6 Dichloro-4-fluorophenylamine (3.0 g, 16.6 mmol) in 12 M HCl (30 mL) and TFA (20 mL) is added slowly and dropwise NaNO2 (20 mmol, 1.37 mL) in water (6 mL). The reaction is stirred at 0 0C for 1 h. A solution of SnCl2 (5.74 g, 25.6 mmol) in 12 M HCl (16 mL) is added over 15 minutes. The ice bath is removed and <n="24"/>the reaction is stirred for 18 h. The reaction is filtered and the solid is washed with isopropyl alcohol. The solid is dried to yield the title compound (3.0 g, 96 %). LC-ES/MS m/e 194.0 (M+ 1)
Step 1: (2,6-dichloro-4-fluorophenyl)hydrazine hydrochloride To a - 5 C solution (internal temperature, wet ice/acetone bath) of <strong>[344-19-4]2,6-dichloro-4-fluoroaniline</strong> (3.0 g, 17 mmol) in 37 % hydrochloric acid (30 mL) and trifluoroacetic acid (20 mL) was added dropwise an aqueous solution of sodium nitrite (1.4 g, 20 mmol, 6 mL water). The reaction was stirred for 90 minutes, then a solution of stannous chloride dihydrate (5.6 g, 25 mmol) in 37 % hydrochloric acid (16 mL) was added over 15 minutes, keeping the internal temperature ? 2 C. The mixture was stirred overnight at room temperature. The mixture was filtered and the collected solid was washed with isopropyl alcohol and dried under house vacuum to provide the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C6H6Cl2FN2: 195.0; found: 194.9.
PREPARATION CXXXVI; 2,6-dichloro-4-fluorobenzenesulphonyl chloride; A solution of 4.75 g (25 mM) of <strong>[344-19-4]2,6-dichloro-4-fluoroaniline</strong> in 50 ml of dichloromethane are added, at -15 C., to 4.75 ml of boron trifluoride etherate. 5 ml of tetrahydrofuran are added to dissolve the precipitate formed, then, slowly, 3.6 ml of t-butyl nitrite in solution in 25 ml of dichloromethane are added. The reaction mixture is agitated 10 minutes at -15 C. and then 20 minutes at +5 C. 200 ml of pentane are added, and agitation is maintained at 0 C. for 30 min and the precipitate is filtered off. After drying, 7.2 g of the diazonium salt are obtained. This salt is dissolved in 30 ml of acetonitrile and is added, at 10 C., to a mixture of a solution of sulphur dioxide in 90 ml of acetic acid to which 1.4 g of anhydrous copper (II) chloride and 23 ml of concentrated hydrochloric acid have been added. The reaction mixture is agitated 30 min at ambient temperature and then concentrated under reduced pressure. The residue from evaporation is taken up into 60 ml of dichloromethane and the insoluble salts are removed by filtration. The filtrate is concentrated under reduced pressure to give 4.71 g of the product sought after as orange crystals (yield=71%). M.Pt.=57 C.
With sodium hydroxide; sodium nitrite; In hydrogenchloride; water;
PREPARATION OF 2,6-DICHLORO-4-FLUOROPHENYLHYDRAZINE (INTERMEDIATE NO. 2) 9.0 g (0.05 mol) of <strong>[344-19-4]2,6-dichloro-4-fluoroaniline</strong> was added to 50 ml of concentrated hydrochloric acid, and a solution of 3.8 g (0.055 mol) of sodium nitrite in 25 ml of water was dropwise added thereto at a temperature of from 0 to 5 C. After completion of the dropwise addition, the mixture was stirred at the same temperature for further 1 hour. Insolubles were removed by filtration, and the filtrate was dropwise added at a temperature of from 0 to 10 C. to a solution of 33.8 g (0.15 mol) of stannous chloride dihydrate in 50 ml of concentrated hydrochloric acid. After completion of the dropwise addition, the mixture was stirred at the same temperature for further 2 hours. The precipitated hydrochloride was collected by filtration, and 50 ml of water was added thereto. The mixture was made alkaline with an addition of 20% sodium hydroxide, and the precipitated solid was extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue thereby obtained was washed with cold n-hexane to obtain 6.9 g (yield: 70.4%) of the desired compound as white feather-like crystals. Melting point: 117-119 C.
With titanium tetrachloride; triethylamine; In dichloromethane; at 0 - 20℃; for 5h;
Method 2:Example 43 :2-(2,6-Dichloro-4-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)- amineStep 1 : [l-(4-Azido-5-fluoropyridin-3-yl)-meth-(£)-ylidene]-(2,6-dichloro-4-fluorophenyl)-amineTo a cooled (0 C) solution of 4-azido-5-fluoro-pyridine-3-carbaldehyde (2.44 g, 14.7 mmol), 2,6-dichloro-4- fluorophenylamine (2.65 g, 14.7 mmol) and triethylamine (6.1 mL, 44 mmol) in DCM (50 mL) was added titanium tetrachloride (1M in DCM, 8.8 mL, 8.8 mmol) dropwise. The reaction mixture was stirred at 0 C for 1 hour, warmed to room temperature, and stirred for a further 4 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in toluene and filtered through Celite. The filtrate was concentrated under to dryness under reduced pressure to afford the title compound that was used without further purification.
With titanium tetrachloride; triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h;Inert atmosphere;
Method 2: Example 27: [2-(2,6-Dichloro-4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)amine Step 1 : l-(4-Azidopyridin-3-yl)meth-(E)-ylidene]-(2,6-dichloro-4-fluorophenyl)amine Titanium tetrachloride (1M, 4.0 mL, 4.15 mmol) was added to a cooled (0 C) mixture of 4-azidopyridine-3- carbaldehyde (1.0 g, 6.75 mmol), <strong>[344-19-4]2,6-dichloro-4-fluorophenylamine</strong> (1.22 g, 6.75 mmol) and triethylamine (2.8 mL, 20.3 mmol) in DCM (24 mL), under nitrogen. The reaction was stirred for 30 minutes at 0 C, warmed to room temperature, stirred for an additional 2 h, and concentrated under reduced pressure. The residue was dissolved in toluene and filtered though a pad of Celite. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid (2.09 g, quant.). This crude material was employed in the next step without further purification or analysis.
Aniline 1 (12 g, 67 mmol) was taken up in concentrated HCI (13 mL) and water (51 mL) at 0 C. After stirring for 15 min, a solution of NaN02 (4.85 g, 70.3 mmol) in water (10 mL) was added drop-wise at 0C and the mixture was stirred for 45 min. A solution of MeSNa (35 g, 100 mmol) and Na2C03 (10.6 g, 100 mmol) in water (100 mL) was then added to the above solution drop- wise at 50 C. After addition, the mixture was stirred for 1 hour, then extracted with EtOAc and the combined organic layers were dried (MgSC ), filtered and the filtrate concentrated in vacuo to give the crude product. Flash chromatography using neat 60-90 petrol ether afforded thi- oether 2 (4.7 g, 34%). H NMR (CDCI3, 400MHz): delta 7.17 (d, 2H), 2.41 (s, 3H).
34%
<strong>[344-19-4]2,6-dichloro-4-fluoro-aniline</strong> (12 g, 67 mmol) was taken up in concentrated H0I (13 mL)and water (Si mL) at 0 00 After stirring for iS mm, a solution of NaNO2 (4.85 g, 70.3 mmol) in 147water (10 mL) was added drop-wise at 0 00 and the mixture was stirred for 45 mm. A solution of MeSNa (35 g, 100 mmol) and Na2CO3 (10.6 g, 100 mmol) in water (100 mL) was then added to the above solution drop-wise at 50 00. After addition, the mixture was stirred for 1 hour, then extracted with Et0Ac and the combined organic layers were dried (MgS04), filtered and thefiltrate concentrated in vacuo to give the crude product. Flash chromatography using neat 60-90 petrol ether afforded 1 ,3-d ichloro-5-fluoro-2-methylsulfanyl-benzene (4.7 g, 34%).1H NMR (ODd3, 400MHz): 57.17 (d, 2H), 2.41 (s, 3H).
Procedure adapted from Guan, Z. et ah , Organometallics, 2011, (30), 2432-2452. To a solution of <strong>[344-19-4]2,6-dichloro-4-fluorobenzenamine</strong> (1.8 g, 10 mmol) in dichloromethane (36 mL) was added 3-chloroperoxybenzoic acid (6.88 g, 40 mmol). The mixture was heated to reflux and stirred for 5 h. The reaction mixture was cooled to 0 C in an ice bath and then filtered. The filtrate was then washed with 1 N potassium hydroxide (2 x 50 mL), the organic layer was concentrated in vacuum to afford a brown solid, which was dissolved in 18 mL of glacial acetic acid. To this solution was added a 30% H202 solution (9 mL) and concentrated nitric acid (1.8 mL). The mixture was heated to reflux and stirred for 3 h, then poured into 50 mL of ice water and left to stand overnight at 4 C. The suspension was filtered and the solid washed with water, dissolved in ethyl acetate (50 mL) and dried (Na2S04) and concentrated. The crude was purified by silica gel column chromatography to afford the title compound as a white solid (, 517 mg, 26%): mp 78-80 C; ]H NMR (400 MHz, CDC13) delta 7.24 (dd, J = 7.7, 1.0 Hz, 2H); EIMS m/z 209.
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