* 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 hydrogenchloride; tin(IV) chloride In ethyl acetate at 20℃; for 16 h;
Reference Example 2 Preparation of Methyl 2-amino-5-chlorobenzoate A mixture of methyl 5-chloro-2-nitrobenzoate (534 gm) as obtained in reference example 1 and concentrated hydrochloric acid (2250 ml) was added to ethyl acetate (1120 ml). To the reaction mixture was added a solution of tin chloride (1680 gm) in ethyl acetate (2250 ml). The reaction mass was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with aqueous sodium hydroxide solution (2650 ml). The separated aqueous layer was extracted with ethyl acetate and then concentrated to obtain a residual solid of methyl 2-amino-5-chlorobenzoate (345 gm).
Reference：
[1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754
[2] Patent: WO2012/46244, 2012, A1, . Location in patent: Page/Page column 6
[3] Patent: US2013/190490, 2013, A1, . Location in patent: Paragraph 0048; 0049
2
[ 51282-49-6 ]
[ 6628-86-0 ]
Yield
Reaction Conditions
Operation in experiment
97%
With diisobutylaluminium hydride In dichloromethane at -78℃; for 0.75 h;
Example 114; This example concerns the synthesis of Aldehyde 11: To a stirred solution of 80 (8.20 g, 38.0 mmol) and dry CH2Cl2 (205 mL) was added DIBAL-H (48.0 mL, 48.0 mmol, 1.0 M in CH2Cl2) at -780C. After 45 min, MeOH (20 mL) was added and the solution was allowed to warm to rt. Next, aq. sodium tartrate (200 mL, 10percent w/v) was added and the suspension was left to stir vigorously until a bilayer was distinct. The solution was diluted with CH2Cl2 (100 mL) and washed with H2O (2 x 100 mL), sat. aq. NaCl (2 x 100 mL). The dried (Na2SO4) extract was purified via flash chromatography over silica gel, eluting with 20-50percent EtOAc/Hexanes to give the known aldehyde 13 (6.80 g, 36.7 mmol, 97percent). 1H NMR (400 MHz, CDCl3) δ 10.46 (s, IH), 8.15 (d, J= 8.7 Hz, IH), 7.94 (d, J= 2.3 Hz, IH), 7.74 (dd, J= 2.4, 8.7 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 187.0, 147.5, 141.0, 133.5, 132.7, 129.4, 126.2.
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 26, p. 9857 - 9865
[2] Patent: WO2008/156656, 2008, A2, . Location in patent: Page/Page column 44; 180
3
[ 2516-95-2 ]
[ 74-88-4 ]
[ 51282-49-6 ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 40℃; for 1 h;
Example 113; This example concerns the synthesis of Methyl ester 80: To a stirred solution of 9 (9.393 g, 46.60 mmol) in dry DMF (155 mL) at 00C was added K2CO3 <n="181"/>(13.23 g, 95.72 mmol) and MeI (19.38 g, 8.5 mL, 136.5 mmol) and warmed to 400C. After 1 h, the solution was cooled to rt and diluted with EtOAc (1 15 mL). The solution was washed with H2O (3 x 100 mL), and sat. aq. NaCl (3 x 100 mL). The dried (Na2SO4) extract was concentrated in vacuo and purified via flash chromatography over silica gel, eluting with 40-60percent EtOAc/Hexanes, to give the known methyl ester 80 (9.244 g, 42.87 mmol, 92percent) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J =8.7 Hz, IH), 7.73 (d, J= 2.3 Hz, IH), 7.63 (dd, J = 8.7, 2.3 Hz, IH), 3.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.7, 146.1, 139.7, 131.6, 129.8, 129.4, 125.5, 53.6.
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 26, p. 9857 - 9865
[2] Patent: WO2008/156656, 2008, A2, . Location in patent: Page/Page column 44; 179-180
4
[ 2516-95-2 ]
[ 77-78-1 ]
[ 51282-49-6 ]
Yield
Reaction Conditions
Operation in experiment
78%
With sodium carbonate In acetone for 3 h; Heating
Example14:1 (Procedure R)2-(4-Chloro-phenylamino)-5-r4-(4-chlorophenylamino)phenylsulfanvnbenzoic acidStep 1 : Methyl 5-chloro-2-nitrobenzoateDimethyl sulfate (15 ml_, 150 mmol) was added dropwise to a mixture of 5-chloro-2-nitro benzoic acid (20 g, 100 mmol), Na2CO3 (15.9 g, 150 mmol) in acetone.The mixture was heated at rx for 3 h, cooled, filtered and concentrated. Extractive workup (EtOAc, water, brine), drying (Na2SO4) gave a solution from which the sub-title compound was obtained as a solid after addition of a small amount of petroleum ether and standing in the cold. Yield: 16.9 g (78percent).
534 g
With potassium carbonate In [(2)H6]acetone for 0.5 h; Reflux
Reference Example 1 Preparation of Methyl 5-chloro-2-nitrobenzoate Potassium carbonate (515 gm) was added to a solution of 5-chloro-2-nitro benzoic acid (500 gm) in acetone (2750 ml) at room temperature. Dimethyl sulphate (306.5 gm) was added to the reaction mixture slowly and heated to reflux for 30 minutes. The reaction mass was filtered and then concentrated to obtain a residual mass. The residual mass was poured to the ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual solid of methyl 5-chloro-2-nitrobenzoate (534 gm).
5-Chloro-2-nitro-benzoic acid (compound A') (5.0 g) was dissolved in methanol (150 ml). Thionyl chloride (9.5 ml) was added to the solution at 0°C, and the mixture was heated under reflux with stirring for 15 hr. After the completion of the reaction, distilled water was added thereto at 0°C, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with distilled water and saturated brine, was dried over sodium sulfate, and was then concentrated to give 5-chloro-2-nitro-benzoic acid methyl ester as a useful intermediate (12.9 g, yield 92percent).
Reference：
[1] Patent: EP1614676, 2006, A1, . Location in patent: Page/Page column 161
[2] Asian Journal of Chemistry, 2011, vol. 23, # 5, p. 2007 - 2010
[3] Synthetic Communications, 2008, vol. 38, # 23, p. 4107 - 4115
[4] Patent: US2010/280268, 2010, A1, . Location in patent: Page/Page column 10
[5] Asian Journal of Chemistry, 2011, vol. 23, # 12, p. 5471 - 5476
[6] Asian Journal of Chemistry, 2012, vol. 24, # 6, p. 2573 - 2578
6
[ 2516-95-2 ]
[ 51282-49-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1900, vol. 19, p. 55
[2] Patent: US4259510, 1981, A,
7
[ 2516-95-2 ]
[ 121-44-8 ]
[ 79-22-1 ]
[ 51282-49-6 ]
Reference：
[1] Patent: US5202322, 1993, A,
[2] Patent: US5256667, 1993, A,
8
[ 74-88-4 ]
[ 51282-49-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2, 2002, # 8, p. 1449 - 1454
[2] Journal of the Chemical Society, Perkin Transactions 2, 2002, # 8, p. 1449 - 1454
9
[ 67-56-1 ]
[ 41994-44-9 ]
[ 51282-49-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1900, vol. 19, p. 55
10
[ 2905-65-9 ]
[ 7697-37-2 ]
[ 51282-49-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1900, vol. 19, p. 55
11
[ 51282-49-6 ]
[ 150683-30-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754
12
[ 51282-49-6 ]
[ 160129-45-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754
13
[ 51282-49-6 ]
[ 137973-76-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754
With diisobutylaluminium hydride; In dichloromethane; at -78℃; for 0.75h;
Example 114; This example concerns the synthesis of Aldehyde 11: To a stirred solution of 80 (8.20 g, 38.0 mmol) and dry CH2Cl2 (205 mL) was added DIBAL-H (48.0 mL, 48.0 mmol, 1.0 M in CH2Cl2) at -780C. After 45 min, MeOH (20 mL) was added and the solution was allowed to warm to rt. Next, aq. sodium tartrate (200 mL, 10percent w/v) was added and the suspension was left to stir vigorously until a bilayer was distinct. The solution was diluted with CH2Cl2 (100 mL) and washed with H2O (2 x 100 mL), sat. aq. NaCl (2 x 100 mL). The dried (Na2SO4) extract was purified via flash chromatography over silica gel, eluting with 20-50percent EtOAc/Hexanes to give the known aldehyde 13 (6.80 g, 36.7 mmol, 97percent). 1H NMR (400 MHz, CDCl3) delta 10.46 (s, IH), 8.15 (d, J= 8.7 Hz, IH), 7.94 (d, J= 2.3 Hz, IH), 7.74 (dd, J= 2.4, 8.7 Hz, IH); 13C NMR (100 MHz, CDCl3) delta 187.0, 147.5, 141.0, 133.5, 132.7, 129.4, 126.2.
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 40℃; for 1h;
Example 113; This example concerns the synthesis of Methyl ester 80: To a stirred solution of 9 (9.393 g, 46.60 mmol) in dry DMF (155 mL) at 00C was added K2CO3 <n="181"/>(13.23 g, 95.72 mmol) and MeI (19.38 g, 8.5 mL, 136.5 mmol) and warmed to 400C. After 1 h, the solution was cooled to rt and diluted with EtOAc (1 15 mL). The solution was washed with H2O (3 x 100 mL), and sat. aq. NaCl (3 x 100 mL). The dried (Na2SO4) extract was concentrated in vacuo and purified via flash chromatography over silica gel, eluting with 40-60percent EtOAc/Hexanes, to give the known methyl ester 80 (9.244 g, 42.87 mmol, 92percent) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.95 (d, J =8.7 Hz, IH), 7.73 (d, J= 2.3 Hz, IH), 7.63 (dd, J = 8.7, 2.3 Hz, IH), 3.98 (s, 3H); 13C NMR (100 MHz, CDCl3) delta 164.7, 146.1, 139.7, 131.6, 129.8, 129.4, 125.5, 53.6.
EXAMPLE 1A Methyl 5-Chloro-2-nitrobenzoate 5-Chloro-2-nitrobenzoic acid (20.1 g,; 0.10 mol), is dissolved in anhydrous methanol (100 ml) and anhydrous hydrogen chloride gas is bubbled into the reaction mixture for 4 hours at room temperature. The reaction mixture is then poured into water and the aqueous mixture triturated with hexane, the hexane layer decanted, dried (anhd. MgSO4) and the solvent removed under vacuum to afford 11.7 g of methyl 5-chloro-2-nitrobenzoate, mp 50°-51° C.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 90℃; for 16h;
To a stirred solution of 5-chloro-2- nitrobenzoic acid methyl ester [(LG,] 4.6 mmol) in dimethylformamide (15ml), was added potassium carbonate (0.96g), and 2-chlorophenol (0.66g). The reaction mixture was stirred at [90C] for 16 hours. After this time the reaction mixture was poured into ethyl acetate [(50ML)] and washed with water (50ml), brine (50ml), dried [(MGS04),] and evaporated. The residue was purified by flash chromatography (1: 9 ethyl acetate: pet ether) to give the sub-titled compound as a yellow oil (1.22g, 85percent yield). 1H NMR [(400] MHz, [CDC13)] [8] 8. [05 (1H,] m), 7.6-7. 0 (6H, m), 3.95 (3H, s) ppm.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 160℃; for 2h;
[0142] Methyl 5-chloro-2-nitrobenzoate (73 g, 0.34 mol), 2,4-difluorophenol (51.1 g, 0.39 mol) and potassium carbonate (73 g, 0.53 mol) in NMP (200 mL) were stirred at 160 C. for 2 h. The reaction mixture was cooled to room temperature poured into water (250 mL) and extracted into EtOAc (2*100 mL). The organic layer was washed several times with water, dried over sodium sulfate, concentrated in vacuo, and the residue was purified by flash chromatography eluting with hexane: EtOAc (95:5) to yield 66.8 g of 5-(2,4-difluoro-phenoxy)-2-nitro-benzoic acid methyl ester (1A).
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 75℃; for 15h;
5-Chloro-2-nitro-benzoic acid methyl ester (2.2 g) produced by the above reaction was dissolved in N,N-dimethylformamide (20 ml). Piperidine (compound D) (1.5 g) and potassium carbonate (1.5 g) were added to the solution at room temperature, and the mixture was stirred at 75°C for 15 hr, After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with distilled water and saturated brine, was dried over sodium sulfate, and was then concentrated to give 2-nitro-5-piperidin-1-yl-benzoic acid methyl ester as a useful intermediate (1.86 g, crude yield 69percent).
With thionyl chloride; at 80℃; for 4h;Cooling with ice; Reflux;
To a stirred solution of 5-chloro-2-nitrobenzoic acid 3 (4.02 g, 20 mmol) in 125 ml of methanol, under ice-cooling, was added thionyl chloride (10 ml, 150 mmol) dropwise over 10 minutes. Then the solution was heated to 80, and kept refluxing for about 4 h. Methanol is distilled out and 50 ml of water is added. The separated ester was extracted with EtOAc and washed with 50 ml of saturated sodium bicarbonate solution. Drying (Na2SO4) and evaporation of the EtOAc gave the white solid (4.0 g, 93percent). HPLC purity 98.2percent; 1H NMR (300 MHz, DMSO-d6) delta 8.14 (dd, J = 8.6, 1.8 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.94 ? 7.88 (m, 1H), 3.87 (d, J = 1.5 Hz, 3H); ESI-MS m/z: 216.2 [M+H]+.
92%
With thionyl chloride; at 0℃; for 15h;Heating / reflux;
5-Chloro-2-nitro-benzoic acid (compound A') (5.0 g) was dissolved in methanol (150 ml). Thionyl chloride (9.5 ml) was added to the solution at 0C, and the mixture was heated under reflux with stirring for 15 hr. After the completion of the reaction, distilled water was added thereto at 0C, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with distilled water and saturated brine, was dried over sodium sulfate, and was then concentrated to give 5-chloro-2-nitro-benzoic acid methyl ester as a useful intermediate (12.9 g, yield 92%).
With thionyl chloride; for 40h;Reflux;Product distribution / selectivity;
5-Chloro-2-nitro-benzoic acid (50 g, 247.5 mmol) was dissolved in methanol (700 ml), and thionylchloride was added slowly (12.65 ml, 173.3 mmol). The solution was refluxed for 40 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed with a sodium bicarbonate-solution, dried over sodium sulfate and evaporated under reduced pressure. The crude product was used in the next step without further purification (42.94 g, 80.46%).MS: [M+H]+=216
Step B Preparation of methyl 5-(morpholin-4-yl)-2-nitrobenzoate A solution of 2.0 g (9.28 mmol) product from Step A and 1.6 mL (18.6 mmol) morpholine in 20 mL DMF was heated to 90° C. for 6 hours. After the mixture had cooled to room temperature, the DMF was stripped off in vacuo. The crude material was then redissolved in methanol and stirred with 20 g Amberlyst-A26.(R). for about 20 minutes. The mixture was then stripped of solvent and used without further purification in the next step. Rf 0.20 in 40percent EtOAc/hexane, visualized by UV and visible light.
Step A Preparation of methyl 5-chloro-2-nitrobenzoate To a solution of 10 g (49.6 mmol) of 5-chloro-2-nitrobenzoic acid and 9 mL (64.5 mmol) Et3 N in 300 ml CH2 Cl2 at 0° C. was added 4.6 mL (59.5 mmol) methyl chloroformate. The cold bath was removed and after 10 minutes, 0.200 mL methanol was added. Bubbles of CO2 could be seen rising from the solution. After 2 hours, the mixture was diluted with Et2 O, was washed with 5percent HCl, was washed with saturated NaHCO3 solution, was washed with brine, was dried over MgSO4 and decolorized with charcoal, then was stripped of solvent in vacuo to give the product. Rf 0.35 in 15percent EtOAc/hexane, visualized by UV; 1 H-NMR (400 MHz, CDCl3): delta 7.92 (d, J=8.6 Hz, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.59 (dd, J1 =2.2 Hz, J2 =8.8 Hz, 1H), 3.94 (s, 3H).
In methanol; dichloromethane;
Step A Preparation of methyl 5-chloro-2-nitrobenzoate To a solution of 10 g (49.6 mmol) of 5-chloro-2-nitrobenzoic acid and 9 mL (64.5 mmol) Et3 N in 300 ml CH2 Cl2 at 0° C. was added 4.6 mL (59.5 mmol) methyl chloroformate. The cold bath was removed and after 10 minutes, 0.200 mL methanol was added. Bubbles Of CO2 could be seen rising from the solution. After 2 hours, the mixture was diluted with Et2 O, was washed with 5percent HC1, was washed with saturated NaHCO3 solution, was washed with brine, was dried over MgSO4 and decolorized with charcoal, then was stripped of solvent in vacuo to give the product. Rf 0.35 in 15percent EtOAc/hexane, visualized by UV; 1 H--NMR (400 MHz, CDCl3): delta7.92 (d, J=8.6 Hz, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.59 (dd, J1 =2.2 Hz, J2 =8.8 Hz, 1H), 3.94 (s, 3H).
EXAMPLE 1 Methyl 2-nitro-5-(2',4',6'-trichlorophenoxy)benzoate A stirred solution of <strong>[51282-49-6]methyl 5-chloro-2-nitro-benzoate</strong> (17.0 g, 0.079 mole) and the potassium salt of 2,4,6-trichlorophenol (18.6 g., 0.079 mole) in dimethyl sulfoxide (100 ml.) was heated at 90 C. for 17 hours. The cooled reaction mixture was diluted with water (500 ml.) and then extracted with ether (3*100 ml.). The combined ether fractions were washed with 10% sodium hydroxide solution (2*30 ml.) and then with a saturated aqueous sodium chloride solution. The ether solution was dried (Na2 SO4) and the solvent evaporated to give a dark oil. Two crystallizations (petroleum ether) gave 1.91 g. of a pale yellow solid, m.p. 101-103 C.
In dimethyl sulfoxide;
EXAMPLE 1 Methyl 2-nitro-5-(2',4',6'-trichlorophenoxy)benzoate. A stirred solution of <strong>[51282-49-6]methyl 5-chloro-2-nitrobenzoate</strong> (17.0 g., 0.079 mole) and the potassium salt of 2,4,6-trichlorophenol (18.6 g., 0.079 mole) in dimethyl sulfoxide (100 ml.) was heated at 90 for 17 hours. The cooled reaction mixture was diluted with water (500 ml.) and then extracted with ether (3*100 ml.). The combined ether fractions were washed with 10% sodium hydroxide solution (2*30 ml.) and then with a saturated aqueous sodium chloride solution. The ether solution was dried (Na2 SO4) and the solvent evaporated to give a dark oil. Two crystallizations (petroleum ether) gave 1.91 g. of a pale yellow solid, m.p. 101-103.
In dimethyl sulfoxide;
EXAMPLE 1 Methyl 2-nitro-5-(2',4',6'-trichlorophenoxy)benzoate A stirred solution of <strong>[51282-49-6]methyl 5-chloro-2-nitro-benzoate</strong> (17.0 g., 0.079 mole) and the potassium salt of 2,4,6-trichlorophenol (18.6 g., 0.079 mole) in dimethyl sulfoxide (100 ml.) was heated at 90 for 17 hours. The cooled reaction mixture was diluted with water (500 ml.) and then extracted with ether (3*100 ml.). The combined ether fractions were washed with 10% sodium hydroxide solution (2*30 ml.) and then with a saturated aqueous sodium chloride solution. The ether solution was dried (Na2 SO4) and the solvent evaporated to give a dark oil. Two crystallizations (petroleum ether) gave 1.91 g. of a pale yellow solid, m.p. 101-103.
In dimethyl sulfoxide;
EXAMPLE 1 Methyl 2-nitro-5-(2',4',6'-trichlorophenoxy)benzoate A stirred solution of <strong>[51282-49-6]methyl 5-chloro-2-nitro-benzoate</strong> (17.0 g., 0.079 mole) and the potassium salt of 2,4,6-trichlorophenol (18.6 g., 0.079 mole) in dimethyl sulfoxide (100 ml.) was heated at 90 C. for 17 hours. The cooled reaction mixture was diluted with water (500 ml.) and then extracted with ether (3*100 ml.). The combined ether fractions were washed with 10% sodium hydroxide solution (2*30 ml.) and then with a saturated aqueous sodium chloride solution. The ether solution was dried (Na2 SO4) and the solvent evaporated to give a dark oil. Two crystallizations (petroleum ether) gave 1.91 g. of a pale yellow solid. M.P. 101-103 C. IR (Nujol): C=O 1723, C--O 1240, and 1260 cm.-1 NMR (CDCl3): methyl 3.91 p.p.m. (3H), quartet 6.96 p.p.m. (1H, J=2.5 and 8 c.p.s.), doublet 7.05 p.p.m. (1H, J=2.5 c.p.s.), broad singlet 7.05 p.p.m. (2H), and doublet 8.01 p.p.m. (1H, J=8 c.p.s.).
In dimethyl sulfoxide;
EXAMPLE 1 Methyl 2-nitro-5-(2',4',6'-trichlorophenoxy)benzoate A stirred solution of <strong>[51282-49-6]methyl 5-chloro-2-nitrobenzoate</strong> (17.0 g., 0.079 mole) and the potassium salt of 2,4,6-trichlorophenol (18.6 g., 0.079 mole) in dimethyl sulfoxide (100 ml.) was heated at 90 for 17 hours. The cooled reaction mixture was diluted with water (500 ml.) and then extracted with ether (3 * 100 ml.). The combined ether fractions were washed with 10% sodium hydroxide solution (2 * 30 ml.) and then with a saturated aqueous sodium chloride solution. The ether solution was dried (Na2 SO4) and the solvent evaporated to give a dark oil. Two crystallizations (petroleum ether) gave 1.91 g. of a pale yellow solid, m.p. 101-103. Example 1 I.r. (numol): c=o 1723, c=o 1240, and 1260 cm-1; Nmr (cdcl3): methyl 3.91 ppm (3H), quartet; 6.96 ppm (1H, J = 2.5 and 8 c.p.s.), doublet; 7.05 ppm (1H, J = 2.5 c.p.s.), broad singlet; 7.05 ppm (2H), and doublet 8.01 ppm (1H, J = 8 c.p.s.).
In dimethyl sulfoxide;
EXAMPLE 1 Methyl 2-nitro-5-(2',4',6'-trichlorophenoxy)benzoate A stirred solution of <strong>[51282-49-6]methyl 5-chloro-2-nitro-benzoate</strong> (17.0 g., 0.79 mole) and the potassium salt of 2,4,6,-trichlorophenol (18.6 g., 0.79 mole) in dimethyl sulfoxide (100 ml.) was heated at 90 C for 17 hours. The cooled reaction mixture was diluted with water (500 ml.) and then extracted with ether (3 * 100 ml.). The combined ether fractions were washed with 10% sodium hydroxide solution (2 * 30 ml.) and then with a saturated aqueous sodium chloride solution. The ether solution was dried (Na2 SO4) and the solvent evaporated to give a dark oil. Two crystallizations (petroleum ether) gave 1.91 g. of a pale yellow solid, m.p. 101-103 C.
A-Methyl 5-(4-trifluoromethylphenoxy)-2-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium carbonate; In methanol hydrochloride; dimethyl sulfoxide;
Step A--Methyl 5-(4-trifluoromethylphenoxy)-2-nitrobenzoate p-Hydroxybenzotrifluoride (0.22 g, 1.36 mmol), powdered potassium carbonate (0.185 g, 1.34 mmol), and <strong>[51282-49-6]methyl 5-chloro-2-nitrobenzoate</strong> (0.288 g, 1.34 mmol) were heated at 70° C. under a nitrogen atmosphere in 3 ml of dimethyl sulfoxide. After 50 minutes, an aliquot was quenched in methanolic HCl. (By gas chromatography, the reaction is 45percent complete.) After 18 hours (overnight), the reaction mixture was cooled to room temperature, diluted with water, and extracted with ether. The organic extracts are shaken with brine, dried (MgSO4) and concentrated to afford methyl 5-(4-trifluoromethylphenoxy)-2-nitrobenzoate in 85percent yield.
With triethylamine; In N,N-dimethyl acetamide; at 100℃; for 0.0833333h;Microwave irradiation;
Example 87 2-Amino-5-[[l-[(3,4-dichlorobenzyl]-4-piperidyl]carbamoylmethylsulfanyl]benzoic acida) 5-Carboxymethylsulfanyl-2-nitro-benzoic acid methyl ester Methyl 5-chloro-2-nitrobenzoate (0.074 g) was charged to a microwave tube.Mercaptoacetic acid (0.1325 g, 0.1 ml), N,N-dimethylacetamide (1 ml) and triethylamine (150 mul) were added, the tube was capped and heated to 100 °C in a micromave for 5 min. The reaction mixture was diluted with water and the resulting solution was extracted thrice with ethyl acetate. The organic phases were washed with brine, dried, filtered and evaporated to give the subtitle compound. LCMS RT 0.62 ES- 270 (M-H) (Standard)
With potassium carbonate; In dimethyl sulfoxide; at 80℃;
A mixture of <strong>[51282-49-6]methyl 5-chloro-2-nitrobenzoate</strong> 1a (2.27 g, 10.5 mmol), K2CO3 (2.19 g, 15.8 mmol) and 2-bromophenol 1b (1.83 mL, 15.8 mmol) in dry DMSO (30 mL) is heated to 800C. After stirring overnight at 8O0C, the mixture is diluted in EtOAc and washed with water and brine. The organic phase is dried with MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (EtOAc/Hex) affords diarylether 1c.
With potassium carbonate; In dimethyl sulfoxide; at 20 - 80℃; for 22h;
Exam ple 1A: Com pound 10Psi4Step. Add anhydrous potassium carbonate (483 g, 349 mmol) to a mixture of chloro-nitro arene (1a1, 498 g, 231 mmol) and 2-bromoptiersoi (1a2 34 ml, 293 mmoi) in DMSO (30 ml) and heat for about 6 h at 80°C Bnng the rnmture to RT and leave at RT For about a further 16 h Dilute the mtxtore with water (150 ml) and extract with t- BME .pound.3 x 100 mL) Combine the organic portions, and wash successively with 1 N NaOH (aqueous, 2 x 50 mL), water {50 mL), and bnne (50 mL) Subsequent drymg with anhydrous MgSO4, filtering, and evaporation of the volatiles provides 1a3
With potassium carbonate; In dimethyl sulfoxide; at 20 - 95℃;
A mixture of <strong>[51282-49-6]methyl 5-chloro-2-nitrobenzoate</strong> 1a (Example 1) (750 mg, 3.5 mmol), K2CO3 (720 mg, 5.2 mmol) and phenol 2b (1.0 g, 3.5 mmol) in dry DMSO (8 mL) is heated to 950C. The mixture is allowed to stir 7.5 hours at 950C, then at room temperature overnight, then is added to saturated aqueous NH4CI. The mixture is extracted three times with EtOAc and the combined organic extracts are washed with water and brine. The organic phase is dried with MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (8percent EtOAc/Hex) affords diarylether 2c.
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 1h;
A mixture of methyl 5-chloro-2-nitrobepizoate 1a (Example 1) (1.08 g, 5.0 mmol),K2CO3 (0.90 g, 6.5 mmol) and 2-trifluoromethylthiophenol 3a (1.07 g, 6.0 mmol) in dry <n="64"/>DMSO (10 ml.) is stirred at ambient temperature for 1 hour. The mixture is diluted with EtOAc and washed with 1N HCI, water, 1N NaOH and brine. The organic phase is dried with MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (EtOAc/Hex) affords diarylthioether 3b.
Methyl 5-chloro-2-nitrobenzoate acid (1 g, 4.50 mmol) and JV-methylpiperazine (3 niL, 27 mmol) are stirred in the microwave for 30 min at 150 0C. The reaction mixture is stirred in water (50 mL), the pH is adjusted to 5 with NH4Cl, and the mixture is washed with EtOAc. The aqueous phase is freeze-dried, the residue is stirred with THF (200 mL) and filtered. The filtrate is evaporated down and the residue is digested with MeCN. Yield: 434 mg (36 percent)
With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 6h;
EXAMPLE 1APREPARATION OF COMPOUND 1001Step 1aTo a mixture of phenol (5 O g, 53 mmol) and methyl-5-chloro-2-niotatrobenzoate 1a1 (7 6 g, 35 mmol) in DMSO (20 mL) is added anhydrous K2CO3 (7 3 g, 53 mmol) The mixture is heated to 9O0C and stirred 6 hours The mixture is diluted in water then extracted with EtOAc (x 2) The combined organic extracts are washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure
With 18-crown-6 ether; potassium carbonate; In DMF (N,N-dimethylformamide); at 20℃; for 24h;
Step 2: Methyl 2-nitro-5-(4-nitrophenylthio)benzoate A mixture of <strong>[51282-49-6]methyl 5-chloro-2-nitrobenzoate</strong> (5.0 g, 23.2 mmol), 4-nitrothiophenol (3.96 g, 25.5 mmol), K2CO3 (9.60 g, 69.6 mmol) 18-crown-6 (55 mg, 0.21 mmol) and DMF (40 ml_) was stirred at rt for 24 h. Dilution with water (400 ml.) and extractive workup (EtOAc1 water, brine), drying (Na2SO4), concentration and chromatography gave sub-title compound. Yield: 5.17 g (67percent).
With sodium carbonate; In N,N-dimethyl-formamide; at 120℃; for 16h;Product distribution / selectivity;
5-Chloro-2-nitro-benzoic acid methyl ester (2593.7 mg, 12.031 mmol), 6-hydroxy-quinoline (1782 mg, 12.031 mmol) and sodium carbonate were dissolved in DMF (100 ml). The solution was heated at 120° C. for 16 hours. The solution was filtered and evaporated under reduced pressure. The residue was purified by column chromato-graphy (SiO2) on elution with dichloromethane: methanol 100:0 to 99:1 (2467.7 mg, 57percent).MS: [M+30]+=324
With caesium carbonate; In dimethyl sulfoxide; at 70℃; for 2h;
To a solution of 12a1 (300 mg, 1.83 mmol) in DMSO (5 mL) at RT is added Cs2C03 (894 mg, 2.76 mmol) and the <strong>[51282-49-6]methyl-5-chloro-2-nitrobenzoate</strong> (397 mg, 1.84 mmol). The reaction mixture is stirred 2 h at 70 °C. The resulting mixture is diluted with EtOAc and washed with water and brine. The organic phase is dried over MgS04, filtered and concentrated under vacuum followed by combiflash purification (20-50percent EtOAc/Hex) to afford 12b1.
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