* 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.
With sodium dithionite In ethanol; water at 65℃; for 4 h;
To a suspension of 2, 4-dichloro-6-nitrophenol (60.0 g, 288 mmol) in ethanol (250 mL) and water (250 mL) was added portionwise sodium hydrosulfite (251 g, 1.44 mmol). The mixture was stirred at 65°C for 4 h. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate solution (500 mL) , extracted with ethyl acetate (200 mL X 4 ) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel EPO <DP n="81"/>eluting with a 0-50percent ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound (30.6 g, 172 mmol, 60percent) as a colorless powder. 1H NMR (CDCl3) δ 3.92 (s, 2H), 5.36 (s, IH), 6.59 (d, J = 2.1 Hz, IH), 6.71 (d, J = 2.1 Hz, IH). MS Calcd.: 177; MS Found: 178 (M+H) .
Reference:
[1] Liebigs Annalen der Chemie, 1994, # 3, p. 269 - 276
[2] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 14, p. 1923 - 1928
[3] Patent: WO2008/51533, 2008, A2, . Location in patent: Page/Page column 79-80
[4] Patent: US2002/156081, 2002, A1,
[5] Patent: US6921763, 2005, B2,
[6] Biochemical Journal, 1957, vol. 67, p. 607,608
[7] Justus Liebigs Annalen der Chemie, 1870, vol. Suppl.7, p. 185
[8] Chimica Therapeutica, 1970, vol. 5, p. 337 - 342
[9] Journal of Organic Chemistry, 1983, vol. 48, p. 3849
[10] Journal of Medicinal Chemistry, 1998, vol. 41, # 16, p. 3015 - 3021
[11] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3515 - 3523
[12] Patent: US5215925, 1993, A,
[13] Patent: US4239699, 1980, A,
[14] Patent: US2005/124667, 2005, A1, . Location in patent: Page/Page column 12
2
[ 609-89-2 ]
[ 7772-99-8 ]
[ 527-62-8 ]
Reference:
[1] Patent: US5886044, 1999, A,
[2] Patent: US5780483, 1998, A,
[3] Patent: US6262113, 2001, B1,
3
[ 609-89-2 ]
[ 527-62-8 ]
Reference:
[1] Patent: US4723010, 1988, A,
4
[ 139137-46-5 ]
[ 527-62-8 ]
Reference:
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 758,762, 765
5
[ 120-83-2 ]
[ 527-62-8 ]
Reference:
[1] Justus Liebigs Annalen der Chemie, 1870, vol. Suppl.7, p. 185
6
[ 108-95-2 ]
[ 527-62-8 ]
Reference:
[1] Justus Liebigs Annalen der Chemie, 1870, vol. Suppl.7, p. 185
With sodium dithionite; In ethanol; water; at 65℃; for 4h;
To a suspension of 2, 4-dichloro-6-nitrophenol (60.0 g, 288 mmol) in ethanol (250 mL) and water (250 mL) was added portionwise sodium hydrosulfite (251 g, 1.44 mmol). The mixture was stirred at 65C for 4 h. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate solution (500 mL) , extracted with ethyl acetate (200 mL X 4 ) and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel EPO <DP n="81"/>eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound (30.6 g, 172 mmol, 60%) as a colorless powder. 1H NMR (CDCl3) delta 3.92 (s, 2H), 5.36 (s, IH), 6.59 (d, J = 2.1 Hz, IH), 6.71 (d, J = 2.1 Hz, IH). MS Calcd.: 177; MS Found: 178 (M+H) .
10%
In aqueous ammonium acetate; 2-amino-6-chlorophenol; acetonitrile;
a 2-Amino-4,6-dichlorophenol 2-Amino-4,6-dichlorophenol was prepared from 2,4-dichloro-6-nitrophenol (0.625 g, 2.40 mmol) in a manner similar to that described for 2-amino-6-chlorophenol. The compound was formed as a black solid (0.044g, 10%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 A, 5 mum, 250*4.6 mm column) tr=9.033 min., 74%; m/z 177 (MH+).
10%
In aqueous ammonium acetate; 2-amino-6-chlorophenol; acetonitrile;
a) 2-amino-4,6-dichlorophenol 2-amino-4,6-dichlorophenol was prepared from 2,4-dichloro-6-nitrophenol (0.625 g, 2.40 mmol) in a manner similar to that described for 2-amino-6-chlorophenol. The compound was formed as a black solid (0.044 g, 10%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 A, 5 mum, 250*4.6 mm column) tr=9.033 min., 74%; m/z 177 (MH+).
With hydrogenchloride; sodium hydroxide; In methanol; water;
Synthesis of 2-amino-4,6-dichlorophenol The starting material, 2,4-dichloro-6-nitrophenol (260 g, 1 mole, 20% in water), was mixed with methanol (2 liters) and platinum oxide catalyst, and the resulting slurry was reacted with hydrogen at 4.2 kg/cm2 (60 psi) and room temperature. The resulting solution was filtered to remove the catalyst and concentrated hydrochloric acid (150 ml) was added to the filtrate. The methanol was then removed by evaporation and the residual solid was redissolved in hot water (2 liters) with a little concentrated HCl added. The solution was filtered to remove dark, insoluble material and cooled to 30 C. Dilute NaOH solution was added until the pH was about 6, and the mixture was chilled in an ice bath. The resulting white solid was filtered off and dried at room temperature under nitrogen. The compound yield was about 142 g (80% of theoretical) and it had a m.p. of 93-95 C.
palladium; In acetic acid;
A. Preparation of 2,4-Dichloro-6-aminophenol A mixture of 10 g (0.048 moles) of 2,4-dichloro-6-nitrophenol and 0.2 g of 5% palladium on carbon slurried in 250 ml of glacial acetic acid was placed in a hydrogenation bottle. The bottle was stoppered under an atmosphere of 40 psi hydrogen and shaken at room temperature. The hydrogen was replenished during reaction. After four and one-half hours the hydrogen uptake was complete. The mixture then was filtered through a sintered glass funnel and the filtrate was stripped of solvent under reduced pressure. The yield of product was quantitative.
With hydrogen;nickel; In methanol; under 760.051 Torr; for 4h;
60 g of 4,6 dichloro-2 nitrophenol were dissolved in 600 ml methanol and 5 g. Raney nickel were added. This solution was hydrogenated under atmospheric pressure for 4 hours and filtrated. After evaporation of methanol, the residue was crystallized in isopropyl ether to give 40.5 g of IA as a grey solid (mp=33 C.).
25 g of 1A was dissolved in 250 ml THF and the solution was cooled at 5 C. 2-chloroethylchloroformate (16 ml) were added dropwise under cooling and then the reaction mixture was allowed to return to RT and stirred for 8 h. The solution mixture was the concentrated to half-volume and isopropyl ether was added. The precipitate was filtrated out and washed with isopropyl ether to give 24 g of a white-off solid. (mp: 190 C.). 1H NMR (DMSO-d6): 10.9 (1H,s)), 7.82 (1H, d, J=2 Hz), 7.38 (1H, d, J=2 Hz), 4.30 (2H, d, J=9 Hz, 1.35 (3H, t, J=9 Hz).
N,N'-Bis-(3,5-dichloro-2-hydroxy-phenyl)-oxalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; at 20℃; for 1h;
To 1 g of a solution of 1A in 20 ml THF was added 0.25 ml of oxalyldichloride. The mixture was stirred at RT for 1 h, filtrated and the precipitate was washed with acetone to give 330 mg of Example 1 as a white product, melting at 325 C. Microanalysis: theory (%): C, 41.0; H, 1.97; N, 6.83. obtained (%): C, 41.04; H, 2.00; N, 6.63.
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
25.3 g of 1A was dissolved in 250 ml dichloromethane and 40 ml triethylamine were added. The mixture was cooled by an ice-water bath and then 12.7 ml of oxalyldichloride were added. Temperature was left to return to RT and the mixture was stirred 3 h. at RT. 100 ml water were added and the obtained precipitate was filtrated out and washed by dichloromethane to yield 17 g of raw product which were recristallized in 500 ml acetonitrile to give 9.5 g of 22A as an off-white product (mp: 303 C.) 1H NMR (DMSO-d6): 12 (s,1H)), 7.33 (1H, d, J=2 Hz), 7.05 (1H, t, J=2 Hz)
N-(3,5-Dichloro-2-hydroxy-phenyl)-N'-(2,3,5-trichloro-6-hydroxy-phenyl)-oxalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In xylene; for 10h;Heating / reflux;
310 mg of the product of 27A and 200 mg of 2A were dissolved in xylene and refluxed for 10 hours. The mixture was left to return to RT, filtrated, and the collected crystals were washed with dichloromethane to yield crystals melting at 280 C. Microanalysis: theory (%): C, 37.8; H, 1.59; N, 6.30. obtained (%): C, 38.8; H, 1.59; N, 6.21.
2-[(3,5-Dichloro-2-hydroxy-phenylaminooxalyl)-amino]-4-methyl-thiophene-3-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; at 20℃; for 5h;
To a solution of 1 g of ethyl-2-amino-4-methyl thiophen3-carboxylic acid in dichloromethane was added dropwise 5 ml of oxalyl chloride. The reaction was stirred one night at RT, then the dichloromethane was evaporated, the residue taken in THF and one equivalent of a solution of the product of Preparation 1 was added. After stirring for five hours at RT, THF was evaporated and the residue crystallized in acetone to give 800 mg of a off-white product melting at 242 C. Microanalysis: theory (%): C, 46.0; H, 3.38; N, 6.71. obtained (%): C, 45.6, H, 3.34; N, 6.53.
N-(3,5-Dichloro-2-hydroxy-phenyl)-N'-(3,5-dichloro-pyridin-2-yl)-oxalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane; at 20℃; for 5h;
To a solution of 1 g of 2-amino-3,5 dichloropyridine in dichloromethane was added dropwise 5 ml of oxalyl chloride. The reaction was stirred one night at RT, then the dichloromethane was evaporated, the residue taken in THF and one equivalent of a solution of the product of Preparation 1 was added. After stirring for five hours at RT, THF was evaporated and the residue crystallized in acetone to give 800 mg of a off-white product melting at 245 C. Microanalysis: theory (%): C, 39.5; H, 1.18; N, 10.6. obtained (%): C, 39.7; H, 1.34; N, 10.65.
b) Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dichloro-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.245 mmol) and <strong>[527-62-8]2-amino-4,6-dichlorophenol</strong> (0.044 g, 0.245 mmol) in a manner similar to that used in the synthesis of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl} phenyl)-4-methyl-1,3-benzoxazol-2-amine (PH4042235). The compound was formed as an off-white solid (0.008 g, 6%): RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 A, 5 mum, 250*4.6 mm column) tr=8.93 min., 95%; m/z 594 (My).
6%
b) Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dichloro-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.245 mmol) and <strong>[527-62-8]2-amino-4,6-dichlorophenol</strong> (0.044 g, 0.245 mmol) in a manner similar to that used in the synthesis of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine (PH4042235). The compound was formed as an off-white solid (0.008 g, 6%): RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 A, 5 mum, 250*4.6 mm column) tr=8.93 min., 95%; m/z 594 (MH+).
a) Preparation of 2-amino-4,6-dichlorophenol A mixture of 4,6-dichloro-2-nitrophenol(1 g, 4.8 mmol) and tin (II) chloride (3.2 g, 14.4 mmol) in ethanol(50 mL) was heated at 80 C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2 Cl2) gave the desired product(685 mg, 80%). 1 H NMR (CD3 OD): delta 6.75 (s, 1H), 6.61 (s, 1H).
80%
In ethanol;
a)Preparation of 2-amino-4,6-dichlorophenol A mixture of 4,6-dichloro-2-nitrophenol(1 g, 4.8 mmol) and tin (II) chloride (3.2 g, 14.4 mmol) in ethanol(50 mL) was heated at 80 C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2 Cl2) gave the desired product(685 mg, 80%). 1 H NMR (CD3 OD): d 6.75 (s,1H), 6.61 (s, 1H).
80%
In ethanol;
a) Preparation of 2-amino-4,6-dichlorophenol A mixture of 4,6-dichloro-2-nitrophenol (1 g, 4.8 mmol) and tin (II) chloride (3.2 g, 14.4 mmol) in ethanol (50 mL) was heated at 80 C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (685 mg, 80 %). 1H NMR (CD3OD): d 6.75 (s, 1H), 6.61 (s, 1H).
f) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and <strong>[527-62-8]2-amino-4,6-dichlorophenol</strong> there is obtained 6,8-dichloro-3(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one or m.p. 237-239 (from ethanol/ether) and
EXAMPLE 6 2-Chloromethyl-5,7-dichlorobenzoxazole To a solution of 2,4-dichloro-6-nitrophenol (10.0 g) in water (450 ml) containing sodium bicarbonate (4.8 g) was added sodium dithionate in a quantity sufficient to turn the original dark solution colorless. The hot reaction mixture was filtered and the filtrate was cooled to room temperature and the crystallized product, 2-amino-4,6-dichlorophenol was collected (1.6 g).
With sodium hydroxide; thionyl chloride; In N,N-dimethyl-aniline; acetone;
(Compound-2) STR11 Acetylsalicylic acid (1.73 g.) was admixed with thionyl chloride (10 ml.) and stirred overnight at 35 C. After the reaction was completed, the excess thionyl chloride was removed by evaporation under reduced pressure. The residue, crude acetylsalicyloyl chloride, was admixed with acetone (20 ml.) to make a uniform solution. Then 6-amino-2,4-dichlorophenol (1.7 g.) and N,N-dimethylaniline (2.5 ml.) were dissolved in acetone (30 ml.) which was cooled at 0 to 5 C. Into this solution the acetone solution of acetylsalicyloyl chloride was added by drops. The solution was warmed up to room temperature and condensed by evaporation under reduced pressure. The residual oily condensate thus obtained was admixed with 2N sodium hydroxide solution (30 ml.) and stirred at room temperature. After the deacetylation reaction was completed, acidification of the solution with hydrochloric acid gave a precipitate which was subjected to decolorization with active charcoal and then recrystallized from aqueous acetone to give colorless, needle-like crystals (1.4 g.) of 3',5'-dichloro-2,2'-dihydroxybenzanilide. Yield: 49%. The melting point of the product is 222-223 C.
Example 13 : (3,5-Dichloro-2-hydroxy-phenyl)-carbamic acid phenyl ester According to method F 2-amino-4,6-dichloro-phenol (25 mg, 1 eq) and phenylchloroformate (23 muL, 1 eq) gave 10.9 mg (26 %) of the title compound as a white solid. NMR-1H (DMSO-d6) delta = 7.43 (m, 2 H), 7.25 (m, 2H), 7.5 (s, 2H) NMR-13C (DMSO-d6) delta = 109.1, 118.8, 121.4, 128.2, 129.4, 132.6, 153.2, 157.3
10.9 mg (26%)
Example 13 : (3,5-Dichloro-2-hydroxy-phenyl)-carbamic acid phenyl ester According to method F 2-amino-4,6-dichloro-phenol (25 mg, 1 eq) and phenylchloroformate (23 muL, 1 eq) gave 10.9 mg (26 %) of the title compound as a white solid. NMR-1H (DMSO-d6) delta = 7.43 (m, 2 H), 7.25 (m, 2H), 7.5 (s, 2H) NMR-13C (DMSO-d6) delta= 109.1, 118.8, 121.4, 128.2, 129.4, 132.6, 153.2, 157.3
To a suspension of 2-amino-4, 6-dichlorophenol (25.0 g, 140 mmol) in acetonitrile (300 mL) were added formaldehyde (36-38% solution in water; 110 mL) , sodium cyanoborohydride (26.1 g, 415 mmol) and acetic acid (6.0 mL) . The mixture was stirred at 00C for 2 h. The mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (400 mL) , concentrated in vacuo, and extracted with ethyl acetate (300 mL X 3) . The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from diisopropyl ether- n-hexane to give the title compound (18.5 g, 89.7 mmol, 64%) as colorless crystals.1H NMR (CDCl3) delta 2.67 (s, 6H), 6.60 (brs, IH), 6.98 (d, J = 2.7 Hz, IH), 7.09 (d, J = 2.7 Hz, IH). MS Calcd. : 205; MS Found: 206 (M+H) .
55.16%
With sodium cyanoborohydride; acetic acid; In water; acetonitrile; at 20℃; for 12h;Cooling with ice;
A solution of 0.4 g of <strong>[527-62-8]2-amino-4,6-dichlorophenol</strong> was dissolved in 20 ml of acetonitrile, ice bath stirring, 10 ml of a formaldehyde aqueous solution and 0.7 g of NaBH3CN were added, acetic acid 2ml, the reaction was allowed to proceed at room temperature for 12 hours. Acetonitrile was distilled off under reduced pressure, and the mixture was dispersed with ethyl acetate and washed with a saturated aqueous solution of sodium hydrogencarbonate, the organic layer was dried, column chromatography, petroleum ether: ethyl acetate = 25: 1 to 20: 1, to obtain the product 2-dimethylamino-4,6-dichlorophenol 257mg, yield 55.16%.
With pyridine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
A solution of 3-(4-trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride (3) (512 mg, 1.17 mmol) in dry dichloromethane (15 ml) was added dropwise to a mixture of <strong>[527-62-8]2-amino-4,6-dichlorophenol</strong> (276 mg, 1.55 mmol) in dry dichloromethane (5 ml) and dry pyridine (0.1 ml) at 0 C under nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was washed with 1 M hydrochloric acid (2 ml), water (2 × 15 ml) and brine 10 (ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by silica gel column chromatography using 1% methanol in methylene chloride as eluent to afford the compound (4) as a brown solid (655 mg, 96%). 1H NMR (CDCl3, 400 MHz): 7.82-7.78 (1H, m), 7.59-7.55 (1H, d, J = 5.6), 7.43 (2H, m), 7.06 (1H, m), 6.94-6.90 (1H, d, J=), 5.32 (1H, s), 4.04-4.02 (4H, m), 3.94 (s, 3H), 3.11 (4H, m). HRMS calculated (FAB+): C19H18Cl5N3O5S, 574.9410, Observed, 574.9400
5-((3,5-dichloro-2-hydroxyphenyl)amino)methyl-2-cyanopyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With sodium cyanoborohydride; acetic acid; In methanol; at 60℃;
Compound 21C (1 g, 7.57 mmol),2-Amino-4,6-dichlorophenol and acetic acid (10 drops) were dissolved in 30 mL of methanol.Sodium cyanoborohydride (2.38 g, 37.8 mmol) was added at room temperature with stirring.The reaction solution was stirred at 60 C overnight, and after cooling to room temperature, 100 mL of water was added.The precipitate is precipitated and filtered to obtain the target crude product.The crude product was isolated by reverse phase column chromatography to afford pale yellow compound 21 (1.2 g, 53% yield)