* 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] Organic and Biomolecular Chemistry, 2016, vol. 14, # 38, p. 8966 - 8970
2
[ 37585-16-3 ]
[ 59236-37-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
With manganese(IV) oxide In dichloromethane at 20℃; for 23 h; Inert atmosphere
General procedure: To a solution of 1a (1.2 g, 7.61 mmol) in CH2Cl2 (20 mL) was added MnO2 (2.6 g, 30.1 mmol) and stirred at rt under an Ar atmosphere. After 23 h with stirring, the reaction mixture was filtrated and evaporated. The residue was crystallized from AcOEt to give 7a (1.0 g, 85percent) as a yellow needle crystal.
84%
With manganese(IV) oxide In dichloromethane at 20℃; for 48 h; Inert atmosphere
General procedure: Benzyl alcohol derivative 11 (1 eq.) was dissolved in CH2Cl2 (0.4 M). Manganese (IV) oxide (2.1 eq.)was added under argon and the solution was left to stir at room temperature for 48 h. The progress ofthe reaction was monitored by TLC analysis. After completion, manganese oxide was filtered off andthe resulting filtrate was concentrated under reduced pressure. The crude product was purified by silicacolumn chromatography employing mixtures of n-hexane and ethyl acetate as eluents to obtain thedesired product 10.
76.2%
With manganese(IV) oxide In dichloromethane at 20℃; for 40 h; Inert atmosphere
In a 2L 3-neck round bottom flask, the stirred solution of (2-amino-4-chlorophenyl)methanol 2 (32 g, 203.82 mmol) in DCM (765 mL), manganese(IV) oxide (150 g, 1.724 mol) was added at rt. The resulting reaction mixture was stirred at rt under argon atmosphere for 40 h. On completion of reaction the reaction mixture was filtered through CELITE™ pad and solid residue was washed thoroughly with DCM (1000 mL). The combined filtrate was concentrated under reduced pressure to give 2-amino-4-chlorobenzaldehyde as orange solid. Yield: 24g (76.2 percent).
74.1%
With manganese(IV) oxide In dichloromethane at 20℃; Inert atmosphere
A mixture of (2-amino-4- chlorophenyl)methanol (3.8 g, 24.2 mmol) and MnC (8.4 g, 96.8 mmol) in CH2CI2 (60 mL) was stirred at r.t. overnight under N2. The resulting mixture was filtered and concentrated under reduced pressure. The residue was re-crystallized from EtOAc/PE to give 2-amino-4-chlorobenzaldehyde (2.8 g, 74.1percent yield). LC-MS: m/z: 156 (M+H)+.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[2] ChemistryOpen, 2015, vol. 4, # 2, p. 107 - 110
[3] Angewandte Chemie - International Edition, 2017, vol. 56, # 35, p. 10573 - 10576[4] Angew. Chem., 2017, vol. 129, # 35, p. 10709 - 10712,4
[5] Synlett, 2017, vol. 28, # 14, p. 1724 - 1728
[6] Patent: WO2013/188724, 2013, A1, . Location in patent: Paragraph 00128
[7] Patent: WO2016/112088, 2016, A1, . Location in patent: Paragraph 0215
[8] Chemistry - A European Journal, 2012, vol. 18, # 18, p. 5530 - 5535
[9] Organic and Biomolecular Chemistry, 2016, vol. 14, # 38, p. 8966 - 8970
3
[ 22996-18-5 ]
[ 37585-16-3 ]
Yield
Reaction Conditions
Operation in experiment
97%
With iron; ammonium chloride In ethanol; water for 2 h; Reflux
General procedure: Iron powder (5.5 eq.) and NH4Cl (0.7 eq.) were suspended in EtOH : H2O 10 : 1 (0.05 M) and refluxedwith nitrophenyl derivative 12 (1 eq.) for 2 h. After completion (monitored by TLC analysis), thereaction mixture was filtrated on Celite® and rinsed with CH2Cl2. The solvent was evaporated underreduced pressure and CH2Cl2 was added. The mixture was washed with a saturated solution ofNaHCO3. The aqueous phase was extracted four times with CH2Cl2 and the combined organic phaseswere washed with brine, dried over magnesium sulfate and filtrated. Evaporation of the solvent underreduced pressure gave the desired product 11, which was used in the next step without furtherpurification.
77%
With hydrogen In ethanol at 20℃; for 1 h;
A suspension of (4-chloro-2-nitrophenyl)methanol (1 g, 5.33 mmol, ALDRICH) and platinum(IV) oxide (100 mg, 0.44 mmol) in ethanol (100 mL) was hydrogenated under 1300 mbar at room temperature for 1 hour. The resulting suspension was filtered, washed with ethanol and the filtrate concentrated to dryness to afford the crude (2-amino-4- chlorophenyl) methanol as a pale orange solid. The crude product was purified by flash <n="180"/>chromatography on silica gel eluting with 0 to 3percent methanol in dichloromethane. The solvent was evaporated to dryness to afford (2-amino-4-chlorophenyl)methanol (0.650 g, 77 percent) as a pale orange solid. NMR Spectrum (DMSOdψV. 4.34 (d, 2H), 5.06 (t, IH), 5.20 (s, 2H), 6.51 (dd, IH), 6.64 (d,IH), 7.05 (d, IH)
32.9 g
With hydrogen In ethanol for 2 h;
4-chloro-2-nitrophenyl)methanol (40.0 g, 0.21 mol) was dissolved in ethanol (700 mL) and hydrogenated under hydrogen gas (20 psi) in the presence of 5percent platinum on sulfided carbon (Pt-C/S, 5.00g). After 2 hours the catalyst was removed by filtration through Celite® and the solvent removed under reduced pressure. This provided the desired compound (2-amino-4-chlorophenyl)methanol (32.9 g) which was used without further purification. HPLC Rt =1.70 minutes. 1H NMR (CDCl3) δ 6.96 (d, 1H), 6.67 (m, 2H), 4.64 (s, 2H), 4.27 (bs, 2H), 1.56 (bs, 1H).
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 35, p. 10573 - 10576[2] Angew. Chem., 2017, vol. 129, # 35, p. 10709 - 10712,4
[3] Synlett, 2017, vol. 28, # 14, p. 1724 - 1728
[4] Patent: WO2008/104754, 2008, A1, . Location in patent: Page/Page column 178-179
[5] Journal of Medicinal Chemistry, 1993, vol. 36, # 22, p. 3397 - 3408
[6] Patent: WO2007/14054, 2007, A2, . Location in patent: Page/Page column 27
[7] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7252 - 7255,4
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7252 - 7255
4
[ 89-77-0 ]
[ 37585-16-3 ]
Yield
Reaction Conditions
Operation in experiment
88%
With borane-THF In tetrahydrofuran at 0 - 30℃; for 1.66667 h; Inert atmosphere
General procedure: To a solution of 6-chloroanthranilic acid (1.5 g, 8.74 mmol) in THF (5 mL) was added dropwise 1.08 M borane–tetrahydrofuran complex in THF (24.3 mL, 26.2 mmol) at 0 °C under an Ar atmosphere for 10 min. After 1.5 h with stirring at 30 °C, the solution was cooled at 0 °C, added aqueous THF (THF/H2O = 1:1, 60 mL) and potassium carbonate, and extracted with diethyl ether three times. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was crystallized from AcOEt to give 1a (1.2 g, 88percent) as a white needle crystal.
85.4%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2 h; Inert atmosphere
To a mixture of L1AIH4 (4.4 g, 116.6 mmol) in dry THF (116 mL) at 0°C under N2 was added dropwise a solution of 2-amino-4-chlorobenzoic acid (10 g, 58.3 mmol) in dry THF (80 mL). The mixture was stirred at r.t. for 2 hr, then quenched, in sequence, by addition of H2O (4 mL), aq. NaOH (15 wt, 8 mL), and H2O (12 mL). The resulting mixture was filtered, and the filtrate was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was re -crystallized from EtOAc/PE to give (2-amino-4-chlorophenyl)methanol (7.8 g, 85.4percent yield). LC-MS: m/z 158(M+H)+.
81.6%
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 8 h; Inert atmosphere
In a 500 niL round bottom flask, the stirred solution of 2-amino-4-chlorobenzoic acid (42.8 g, 250.29 mmol, Aldrich) was dissolved anhydrous THF (200 mL) and the solution was cooled in an ice-bath. Lithium aluminum hydride (11.76 g, 312.86 mmol) was added portionwise to the above solution at the ice-bath temperature under nitrogen atmosphere. The resulting mixture was stirred at rt for 8 h. On completion of reaction the reaction mixture was cooled to ice-bath temperature and quenched by sequential addition of cold water (12 mL), 15percent NaOH (12 mL) and water (36 mL). The resulting slurry was stirred at rt for 30 min and filtered through a CELITE™ pad. The solid residue was washed with ethyl acetate (1000 mL) and combined filtrate was concentrated under reduced pressure to give (2-amino 4-chlorophenyl)methanol as an off white solid. Yield: 32g (81.6 percent). LCMS (ESI, m/z): 181 (M+23)+.
Reference：
[1] ACS Catalysis, 2013, vol. 3, # 4, p. 622 - 624
[2] Chemical Communications, 2017, vol. 53, # 1, p. 216 - 219
[3] Organic Letters, 2017, vol. 19, # 12, p. 3219 - 3222
[4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[5] Patent: WO2016/112088, 2016, A1, . Location in patent: Paragraph 0214
[6] Patent: WO2013/188724, 2013, A1, . Location in patent: Paragraph 00128
[7] Synlett, 1997, vol. 1997, # 6, p. 704 - 706
[8] Chemistry - A European Journal, 2012, vol. 18, # 18, p. 5530 - 5535
[9] Tetrahedron, 2014, vol. 70, # 34, p. 5114 - 5121
[10] Tetrahedron, 2014, vol. 70, # 34, p. 5114 - 5121
[11] Synthesis (Germany), 2014, vol. 46, # 24, p. 3365 - 3373
[12] Angewandte Chemie, International Edition, 2014, vol. 53, # 36, p. 9603 - 9607,5[13] Angewandte Chemie, 2014, vol. 126, # 36, p. 9757 - 9761,5
[14] Organic Letters, 2015, vol. 17, # 19, p. 4750 - 4753
[15] Organic Letters, 2018,
[16] Patent: JP2015/212297, 2015, A, . Location in patent: Paragraph 0150; 0151
[17] Organic and Biomolecular Chemistry, 2016, vol. 14, # 38, p. 8966 - 8970
[18] Tetrahedron Letters, 2017, vol. 58, # 45, p. 4264 - 4268
5
[ 5900-58-3 ]
[ 37585-16-3 ]
Yield
Reaction Conditions
Operation in experiment
69%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2.16667 h; Stage #2: With water; sodium sulfate In tetrahydrofuran at 0℃;
(2-Amino-4-chlorophenyl)methanol. Methyl 2-amino-4-chlorobenzoate (1.5 g, 8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH (429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0° C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0° C. with saturated Na2SO4 (50 mL), extracted with Et2O (2.x.70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69percent yield); 1H NMR (400 MHz, MeOD) δ ppm 4.50 (s, 2H), 6.58 (dd, J=8.06, 2.01 Hz, 1H), 6.70 (d, J=2.01 Hz, 1H), 7.01 (d, J=8.06 Hz, 1H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO 157.03.
69%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2.16667 h; Stage #2: With water In tetrahydrofuran
(2-Amino-4-chlorophenyl)methanol; Methyl 2-amino-4-chlorobenzoate (1.5 g,8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH(429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0° C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0° C. with saturated Na2SO4 (50 mL), extracted with Et2O (2.x.70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69percent yield); 1H NMR (400 MHz, MeOD) δ ppm 4.50 (s, 2 H), 6.58 (dd, J=8.06, 2.01 Hz, 1 H), 6.70 (d, J=2.01 Hz, 1 H), 7.01 (d, J=8.06 Hz, 1 H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO2 157.03.
With iron; ammonium chloride; In ethanol; water; for 2h;Reflux;
General procedure: Iron powder (5.5 eq.) and NH4Cl (0.7 eq.) were suspended in EtOH : H2O 10 : 1 (0.05 M) and refluxedwith nitrophenyl derivative 12 (1 eq.) for 2 h. After completion (monitored by TLC analysis), thereaction mixture was filtrated on Celite and rinsed with CH2Cl2. The solvent was evaporated underreduced pressure and CH2Cl2 was added. The mixture was washed with a saturated solution ofNaHCO3. The aqueous phase was extracted four times with CH2Cl2 and the combined organic phaseswere washed with brine, dried over magnesium sulfate and filtrated. Evaporation of the solvent underreduced pressure gave the desired product 11, which was used in the next step without furtherpurification.
77%
With hydrogen;platinum(IV) oxide; In ethanol; at 20℃; under 975.0980000000001 Torr; for 1h;
A suspension of (4-chloro-2-nitrophenyl)methanol (1 g, 5.33 mmol, ALDRICH) and platinum(IV) oxide (100 mg, 0.44 mmol) in ethanol (100 mL) was hydrogenated under 1300 mbar at room temperature for 1 hour. The resulting suspension was filtered, washed with ethanol and the filtrate concentrated to dryness to afford the crude (2-amino-4- chlorophenyl) methanol as a pale orange solid. The crude product was purified by flash <n="180"/>chromatography on silica gel eluting with 0 to 3% methanol in dichloromethane. The solvent was evaporated to dryness to afford (2-amino-4-chlorophenyl)methanol (0.650 g, 77 %) as a pale orange solid. NMR Spectrum (DMSOdthetaV. 4.34 (d, 2H), 5.06 (t, IH), 5.20 (s, 2H), 6.51 (dd, IH), 6.64 (d,IH), 7.05 (d, IH)
With hydrogen;5% platinum on sulfided carbon; In ethanol; for 2h;
(4-chloro-2-nitrophenyl)methanol (40.0 g, 0.21 mol) was dissolved in ethanol (700 ml_) and hydrogenated under hydrogen gas (20 psi) in the presence of 5% platinum on sulfided carbon (Pt-C/S) (5.0Og). After 2 hours the catalyst was removed by filtration through Celiteand the solvent removed under reduced pressure. This provided the desired compound (2-amino-4-chlorophenyl)methanol (32.9 g) which was used without further purification. HPLC Rt =1.70 minutes. 1H NMR (CDCI3) delta 6.96 (d, 1 H), 6.67 (m, 2H), 4.64 (s, 2H), 4.27 (bs, 2H)1 1.56 (bs, 1 H).
32.9 g
With hydrogen; In ethanol; under 1034.32 Torr; for 2h;
4-chloro-2-nitrophenyl)methanol (40.0 g, 0.21 mol) was dissolved in ethanol (700 mL) and hydrogenated under hydrogen gas (20 psi) in the presence of 5% platinum on sulfided carbon (Pt-C/S, 5.00g). After 2 hours the catalyst was removed by filtration through Celite and the solvent removed under reduced pressure. This provided the desired compound (2-amino-4-chlorophenyl)methanol (32.9 g) which was used without further purification. HPLC Rt =1.70 minutes. 1H NMR (CDCl3) delta 6.96 (d, 1H), 6.67 (m, 2H), 4.64 (s, 2H), 4.27 (bs, 2H), 1.56 (bs, 1H).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0℃; for 0.5h;
N-(5-Chloro-2-(hydroxymethyl)phenyl)pivalamide. Trimethylacetyl chloride (0.72 mL, 5.82 mmol) was fast dropwise added to <strong>[37585-16-3](2-amino-4-chlorophenyl)methanol</strong> (874 mg, 5.55 mmol) in CH2Cl2 (20 mL) and THF (6 mL) at 0 C., and followed by the addition of DIEA (2.41 mL, 13.9 mmol). The resulting mixture was stirred for 30 min. Then the mixture was partitioned between saturated NaHCO3 (50 mL) and CH2Cl2 (100 mL). After separation, the organic phase was washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected crude product (1.34, 100% yield), which was pure enough to be used in next step. Mass spec. 242.08 (MH+), Calc. for C12H16ClNO2 241.09.
100%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0℃; for 0.5h;
N-(5-Chloro-2-(hydroxymethyl)phenyl)pivalamide; Trimethylacetyl chloride (0.72 mL, 5.82 mmol) was fast dropwise added to <strong>[37585-16-3](2-amino-4-chlorophenyl)methanol</strong> (874 mg, 5.55 mmol) in CH2Cl2 (20 mL) and THF(6mL) at 0 C., and followed by the addition of DIEA (2.41 mL, 13.9 mmol). The resulting mixture was stirred for 30 min. Then the mixture was partitioned between saturated NaHCO3 (50 mL) and CH2Cl2 (100 mL). After separation, the organic phase was washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected crude product (1.34, 100% yield), which was pure enough to be used in next step. Mass spec. 242.08 (MH+), Calc. for C12H16ClNO2 241.09.
(2-Amino-4-chlorophenyl)methanol. Methyl 2-amino-4-chlorobenzoate (1.5 g, 8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH (429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0 C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0 C. with saturated Na2SO4 (50 mL), extracted with Et2O (2×70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69% yield); 1H NMR (400 MHz, MeOD) delta ppm 4.50 (s, 2H), 6.58 (dd, J=8.06, 2.01 Hz, 1H), 6.70 (d, J=2.01 Hz, 1H), 7.01 (d, J=8.06 Hz, 1H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO 157.03.
69%
(2-Amino-4-chlorophenyl)methanol; Methyl 2-amino-4-chlorobenzoate (1.5 g,8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH(429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0 C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0 C. with saturated Na2SO4 (50 mL), extracted with Et2O (2×70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69% yield); 1H NMR (400 MHz, MeOD) delta ppm 4.50 (s, 2 H), 6.58 (dd, J=8.06, 2.01 Hz, 1 H), 6.70 (d, J=2.01 Hz, 1 H), 7.01 (d, J=8.06 Hz, 1 H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO2 157.03.
With sodium hydroxide; triethylamine; In methanol; dichloromethane; water;
B. N-(Benzylcarbonyl)-5-chloro-2-hydroxymethylaniline To a suspension of 5-chloro-2-hydroxymethyl aniline (8.00 g) in dichloromethane (400 ml) under nitrogen at room temperature, was added triethylamine (15.6 ml). The reaction mixture was cooled to 0 C. then phenyl acetyl chloride (14.80 ml) was added dropwise over 10 mins, and the reaction mixture was allowed to warm to room temperature and stir for 2 h. The mixture was washed with 1N HCl (2*250 ml) and brine (1*250 ml). The aqueous layers were re-extracted using CH2 Cl2 (1*250 ml) and the combined organic layers were dried (MgSO4), filtered and the solvent was removed under vacuum to leave an orange solid. The solid was suspended in MeOH (400 ml), sodium hydroxide (2.20 g) was added in water (100 ml) and the reaction mixture was allowed to stir under gentle heating (50 C.) for 45 mins. The methanol was removed in vacuo, then the aqueous residue was extracted with dichloromethane (1*200 ml) and the organic layer was washed with brine (1*150 ml) and saturated sodium hydrogen carbonate solution (1*150 ml). The organic layer was dried (MgSO4), filtered and the solvent was removed under vacuum to leave a solid. Trituration with diethyl ether gave the required compound (10.00 g).
EXAMPLE 20 7-Chloro-3-(4-hydroxyphenyl)-2(1H)-quinolone 2-Amino-4-chlorobenzyl alcohol (4 g, 25.3 mol) and 4-methoxyphenyl acetic acid (14.0 g, 76.4 mmol) were reacted in a similar manner to that described in Example 19 to give 7-chloro-3-(4-methoxyphenyl)-2(1H)-quinolone; mp 256-257 C. (ethyl acetate).
A. 5-Chloro-2-hydroxymethyl aniline To a solution of 4-chloro-2-nitro benzyl alcohol (25.00 g) in methanol (1 ltr) under nitrogen at room temperature, was added platinum on sulfided carbon (2.5 g, 10% by wt). The reaction mixture was shaken under 50 psi of hydrogen until the theoretical uptake of hydrogen had occurred. Filtration, then removal of the solvent in vacuo afforded the desired compound as a solid (21.00 g). delta (360 MHz, DMSO-d6) 4.35 (2H, d, J=4.95 Hz, CH2 OH), 5.17 (1H, t, J=4.95 Hz, CH2 OH), 6.77 (1H, dd, J=7.98 Hz, J=2.18 Hz, 4-H), 7.06 (1H, d, J=2.18 Hz, 6-H), 7.18 (1H, d, J=7.98 Hz, 3-H), 8.08 (1H, bs, NH2), 8.47 (1H, bs, NH).
A suspension of <strong>[37585-16-3](2-amino-4-chlorophenyl)methanol</strong> (5.9 g) in ethyl acetate (100 ml_) was heated until the former dissolved. Acetic anhydride (8 ml_) was added and the mixture removed from the heat. The precipitate was filtered to give a white solid and the filtrate was concentrated and slurried with hexane and filtered to give further white solid. The two batches were combined to give 5.3 g of the alcohol intermediate. The first phase of the experiment was repeated on 3x the scale described above. 21 g of the combined products was dissolved in DCM (65OmL) and added to a solution of thionyl chloride (23 ml_) in DCM (225 ml_) at room temperature under argon. The mixture was stirred for 30 minutes and concentrated to give a yellow/red solid. The solid was dissolved in DCM (500 ml_), washed with saturated sodium bicarbonate (200 ml_) and dried over magnesium sulfate. Removal of the solvent gave the 22 g of the title compound as a yellow/brown solid. 1H NMR (CDCI3) delta 8.01 (d, 1 H), 7.52 (br. s, 1 H), 7.23 (d, 1 H), 7.12 (dd, 1 H), 4.58 (s, 2H), 2.25 (s, 3H).
In ethyl acetate;
A suspension of <strong>[37585-16-3](2-amino-4-chlorophenyl)methanol</strong> (5.9 g) in ethyl acetate (100 mL) was heated until the former dissolved. Acetic anhydride (8 mL) was added and the mixture removed from the heat. The precipitate was filtered to give a white solid and the filtrate was concentrated and slurried with hexane and filtered to give further white solid. The two batches were combined to give 5.3 g of the alcohol intermediate. The first phase of the experiment was repeated on 3x the scale described above. 21 g of the combined products was dissolved in DCM (650mL) and added to a solution of thionyl chloride (23 mL) in DCM (225 mL) at room temperature under argon. The mixture was stirred for 30 minutes and concentrated to give a yellow/red solid. The solid was dissolved in DCM (500 mL), washed with saturated sodium bicarbonate (200 mL) and dried over magnesium sulfate. Removal of the solvent gave the 22 g of the title compound as a yellow/brown solid.
A solution of <strong>[37585-16-3](2-amino-4-chlorophenyl)methanol</strong> (5.00 g, 31.85 mmol) and pyridine (3.1 mL) in anhydrous chloroform (150 mL) was treated dropwise with a solution of 4- chlorobenzenesulfonyl chloride (7.26g ,34.58 mmol) in chloroform (30 mL) over 20 minutes at room temperature. The reaction mixture was stirred for 5 hours and evaporated to dryness. The resulting residue was taken up in ethyl acetate (200 mL) and aqueous ammonium chloride (100 mL). After stirring for 30 minutes the organic phase was separated and further washed with dilute ammonium chloride (2 x 50 mL), dried EPO <DP n="29"/>over sodium sulfate, filtered and evaporated to give an oil. This was triturated in hot hexane (10OmL) and then stirred at ambient temperature for 2 hours. The solid was collected and washed with hexane to give the title compound (10.0 g). HPLC Rt = 3.04 minutes. 1H NMR (CDCI3) delta 7.75 (d, 2H), 7.53 (s, 1H), 7.45 (d, 2H), 7.09 (dd, 1 H), 7.01 (d, 1 H), 4.40 (s, 2H).
With N-ethyl-N,N-diisopropylamine; In pentanol, 2-; at 100℃; for 84h;
<strong>[37585-16-3](2-amino-4-chlorophenyl)methanol</strong> (100 mg, 0.63 mmol), 2,4-dichloropyrimidine (99 mg, 0.67 mmol) and N-ethyl-N-isopropylpropan-2-amine (DIPEA) (0.221 mL, 1.27 mmol) in 2-pentanol (2 mL) were stirred at 100 0C for 3.5 days. The reaction mixture was concentrated to dryness and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to afford the crude product as an orange oil. The crude product was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford (4-chloro-2-(2-chloropyrimidin-4-ylamino)phenyl)methanol (38.0 mg, 22 %) as a colorless oil which crystallised on standing. Mass Spectrum: M+H+ 270.NMR Spectrum (DMSOdfl: 4.46 (s, 2H), 5.36 (bs, IH), 6.67 (d, IH), 7.32 (dd, IH), 7.51 (d, IH), 7.55 (d, IH), 8.15 (d, IH), 9.47 (bs, IH)
With manganese(IV) oxide; In dichloromethane; at 20℃; for 23h;Inert atmosphere;
General procedure: To a solution of 1a (1.2 g, 7.61 mmol) in CH2Cl2 (20 mL) was added MnO2 (2.6 g, 30.1 mmol) and stirred at rt under an Ar atmosphere. After 23 h with stirring, the reaction mixture was filtrated and evaporated. The residue was crystallized from AcOEt to give 7a (1.0 g, 85%) as a yellow needle crystal.
84%
With manganese(IV) oxide; In dichloromethane; at 20℃; for 48h;Inert atmosphere;
General procedure: Benzyl alcohol derivative 11 (1 eq.) was dissolved in CH2Cl2 (0.4 M). Manganese (IV) oxide (2.1 eq.)was added under argon and the solution was left to stir at room temperature for 48 h. The progress ofthe reaction was monitored by TLC analysis. After completion, manganese oxide was filtered off andthe resulting filtrate was concentrated under reduced pressure. The crude product was purified by silicacolumn chromatography employing mixtures of n-hexane and ethyl acetate as eluents to obtain thedesired product 10.
76.2%
With manganese(IV) oxide; In dichloromethane; at 20℃; for 40h;Inert atmosphere;
In a 2L 3-neck round bottom flask, the stirred solution of <strong>[37585-16-3](2-amino-4-chlorophenyl)methanol</strong> 2 (32 g, 203.82 mmol) in DCM (765 mL), manganese(IV) oxide (150 g, 1.724 mol) was added at rt. The resulting reaction mixture was stirred at rt under argon atmosphere for 40 h. On completion of reaction the reaction mixture was filtered through CELITE pad and solid residue was washed thoroughly with DCM (1000 mL). The combined filtrate was concentrated under reduced pressure to give 2-amino-4-chlorobenzaldehyde as orange solid. Yield: 24g (76.2 %).
74.1%
With manganese(IV) oxide; In dichloromethane; at 20℃;Inert atmosphere;
A mixture of (2-amino-4- chlorophenyl)methanol (3.8 g, 24.2 mmol) and MnC (8.4 g, 96.8 mmol) in CH2CI2 (60 mL) was stirred at r.t. overnight under N2. The resulting mixture was filtered and concentrated under reduced pressure. The residue was re-crystallized from EtOAc/PE to give 2-amino-4-chlorobenzaldehyde (2.8 g, 74.1% yield). LC-MS: m/z: 156 (M+H)+.
General procedure: A solution of 4-toluene sulfonyl chloride (4.58 g, 1.2 equiv) or methanesulfonyl chloride (1.9 mL, 1.2 equiv) and pyridine (2 mL, 1.3 equiv) in 20 mL CH2Cl2 was added slowly to the solution of compound 11 (0.02 mol) in 40 mL CH2Cl2. The mixture was stirred overnight at room temperature. Then 30 mL diluted HCl solution was added to the reaction mixture, the organic layer was separated using separating funnel. Subequently, the aqueous phase was extracted with 15 mL CH2Cl2 three times, the combined organic layers were washed separately with saturated NaHCO3 (30 mL) and saturated NaCl (30 mL) three times. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography using petroleum ether/EtOAc = 1/1 to give the product 12.
With pyridine; In dichloromethane; at 20℃;
General procedure: The corresponding (2-aminophenyl)methanol (10 mmol) was dissolved in dichloromethane (1.2 M, 8.5 mL) and pyridine (0.809 mL, 10 mmol, 1 eq.) and the corresponding benzenesulfonyl chloride (12 mmol, 1.2 eq.)were added. The reaction was stirred at room temperature until all the starting (2-aminophenyl)methanol was consumed as judged by TLC (typically 8-20 hours). The reaction was concentrated under reduced pressure and triturated with n-hexane to give N-(2-(hydroxymethyl)phenyl)benzenesulfonamides sufficiently pure.
With pyridine; In chloroform; at 20℃; for 2h;
General procedure: The product S1 was dissolved in CHCl3. Then pyridine (1.2 equiv) and 4-toluenesulfonyl chloride (1.2 equiv) were added to the solution. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride, and the mixture was extracted with ethyl acetate and dried over Na2SO4. After removal off the solvent, the crude product S2 was used directly without further purification.
With phosphoric acid; In isopropyl alcohol; at 20℃;
4-chloro-2- (3-fluoro-benzyloxy)-7-methoxy-quinazoline (3.18, 10 mmol) and 4-chloro-2-amino-benzyl alcohol (1.57 g, 10 mmol) were dissolved in isopropanol (30 ml) to form a solution, and phosphoric acid (0.20 ml) was added dropwise to the solution. The reaction was carried out according to General Method I for preparing the intermediate III to obtain a white solid intermediate M-35 (3.83 g, 80.63%).
General procedure: A 100-mL, three-necked flask equipped with a condenser was charged with Ph3P (2.20 g, 8.4 mmol), Et3N (0.85 g, 8.4 mmol),CBr4 (2.79 g, 8.4 mmol), and fluorine-containing carboxylic acid(2.8 mmol) in toluene (25.0 mL) at 0 C under a nitrogen atmosphereand the solution was then stirred for 10 min. 2-Aminobenzyl alcohol 1 (2.8 mmol) was added to the reaction mixture. Once theaddition was complete, the reaction mixture was heated to reflux for1-3 h. After cooling, the solvent was removed by rotary evaporator,the residue was then carefully washed three times with hexane-EtOAc (4:1), and the precipitate was removed by filtration. The filtratewas combined and concentrated by rotary evaporator. The residue was then purified by column chromatography (hexane-EtOAc,4:1) to give the product.
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