* 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] Patent: CN105237317, 2016, A, . Location in patent: Paragraph 0081; 0082
2
[ 13324-11-3 ]
[ 52301-88-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: at -78℃; for 4 h; Inert atmosphere Stage #2: With water In hexane; dichloromethane at 20℃; for 0.333333 h; Inert atmosphere
In a 250 mL round bottom flask, methyl 2-chloro-4-nitrobenzoate (5 g, 23 mmol) was dissolved in anhydrous dichloromethane (100 mL). The solution was cooled to -78°C under nitrogen. Bis(2-methylpropyl)alumane (35 mL, 35mmol, 1 M in hexane) was added dropwise. The mixture was stirred at -78°C for 4 hours and quenched by addition of water (5 mL). The resulting mixture was warmed up to room temperature in 20 minutes. Na2SO4 (15 g) was added. After 10 minutes, the mixture was filtered. The filtrate was evaporated to provide (2-chloro-4-nitrophenyl)methanol (95percent yield).
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1 h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 20℃; for 16 h;
λ/,iV'-Carbonyldiimidazole (19.91 g, 122 mmol) is added batchwise to 2-chloro-4- nitrobenzoic acid (25 g, 90 percent purity, 111 mmol) in anhydrous THF (420 mL) at RT and stirred for 1 h. At 15 - 20 0C, NaBH (13.09 g, 346 mmol) in water (85 mL) is added dropwise thereto and the mixture is stirred for 16 h at RT. The reaction mixture is adjusted to pH 1 with 6 N HCl and exhaustively extracted with EtOAc. The combined organic <n="26"/>phases are washed with 15 percent potassium carbonate solution (2 x 150 mL) and saturated saline solution (150 mL), dried, filtered and evaporated down. Yield: 20.60 g (98 percent
97%
Stage #1: With borane In tetrahydrofuran at 20℃; for 16 h; Stage #2: With water; potassium carbonate In tetrahydrofuran
Starting with acid 52: a solution of 2-chloro-4-nitrobenzoic acid (15.95 g, 79 mmol, 1.0 equiv.) in THF (200 mL) was cooled to 0 0C. BH3 (118.7 mL, 118.7 mmol, 1 M solution in THF, 1.5 equiv.) was added dropwise. Reaction mixture was allowed to warm to room temperature and stirred for 16 h. A sat'd solution OfK2CO3 in water was added dropwise untill gas evolution stopped. After precipitation of a white solid, the r.m. was filtered and washed with EtOAc. Filtrate and washings were combined and concentrated in vacuo. The product was redissolved in EtOAc, washed with IN HCl (2x), sat'd NaHCO3 and brine and dried on Na2SO4. After filtration and concentration in vacuo, compound 53 was obtained as a yellowish solid in 97percent yield (14.45 g)-
Reference：
[1] Patent: CN105237317, 2016, A, . Location in patent: Paragraph 0081; 0082
5
[ 7073-36-1 ]
[ 52301-88-9 ]
Yield
Reaction Conditions
Operation in experiment
54%
With sodium tetrahydroborate In methanol; 1,2-dimethoxyethane
Starting with acid chloride 51: 2-chloro-4-nitrobenzoylchloride 51 (6.22 g, 28.3 mmol, 1.0 equiv.) can be reduced by using NaBH4 (1.1 g, 28.3 mmol, 1.0 equiv.) in a DME (30 mL) / MeOH (15 mL) mixture. After workup, product 53 was obtained in 54percent yield (2.89 g).
Reference：
[1] Patent: WO2008/51826, 2008, A2, . Location in patent: Page/Page column 56-58
[2] Chemical and Pharmaceutical Bulletin, 2004, vol. 52, # 7, p. 818 - 829
Compound 54; A solution of oxalyl chloride (8.6 ml, 100 mmol, 1.3 equiv.) in DCM (250 ml) was cooled to -70 0C. A solution of DMSO (8.9 ml, 125 mmol, 1.6 equiv.) in DCM (50 ml) was added slowly, maintaining temperature below -70 0C. The mixture was stirred for 15 minutes. Compound 52 (14.45 g, 77 mmol, 1.0 equiv.) was dissolved in DCM (150 ml) and the solution was added dropwise to the mixture. After addition, the mixture was stirred at -70 0C for 45 minutes. Et3N (54 mL, 385 mmol, 5.0 equiv.) was added to the mixture, then the mixture was allowed to warm to the room temperature and stirred overnight. The mixture was diluted with DCM (500 mL) and washed with sat'd NH4Cl (2x), water and brine. After drying on Na2SO4, filtration and concentration in vacuo, compound 54 was obtained as a solid in a quantitative yield (14.29 g).
With sodium tetrahydroborate; In methanol; 1,2-dimethoxyethane;Product distribution / selectivity;
Starting with acid chloride 51: 2-chloro-4-nitrobenzoylchloride 51 (6.22 g, 28.3 mmol, 1.0 equiv.) can be reduced by using NaBH4 (1.1 g, 28.3 mmol, 1.0 equiv.) in a DME (30 mL) / MeOH (15 mL) mixture. After workup, product 53 was obtained in 54% yield (2.89 g).
In the same manner as in Preparation Example 14-1, the objective compound (3.56 g) was obtained as brown crystals from <strong>[52301-88-9]2-chloro-4-nitrobenzyl alcohol</strong> (2.5 g) and methanesulfonyl chloride (1.68 g). 1H-NMR(DMSO-d6): 3.12(3H, s), 5.40(2H, s), 7.73(1H, d, J=8 Hz), 8.18(1H, dd, J=2, 8 Hz), 8.79(1H, d, J=2 Hz).
lambda/,iV'-Carbonyldiimidazole (19.91 g, 122 mmol) is added batchwise to 2-chloro-4- nitrobenzoic acid (25 g, 90 % purity, 111 mmol) in anhydrous THF (420 mL) at RT and stirred for 1 h. At 15 - 20 0C, NaBH (13.09 g, 346 mmol) in water (85 mL) is added dropwise thereto and the mixture is stirred for 16 h at RT. The reaction mixture is adjusted to pH 1 with 6 N HCl and exhaustively extracted with EtOAc. The combined organic <n="26"/>phases are washed with 15 % potassium carbonate solution (2 x 150 mL) and saturated saline solution (150 mL), dried, filtered and evaporated down. Yield: 20.60 g (98 %
97%
Starting with acid 52: a solution of 2-chloro-4-nitrobenzoic acid (15.95 g, 79 mmol, 1.0 equiv.) in THF (200 mL) was cooled to 0 0C. BH3 (118.7 mL, 118.7 mmol, 1 M solution in THF, 1.5 equiv.) was added dropwise. Reaction mixture was allowed to warm to room temperature and stirred for 16 h. A sat'd solution OfK2CO3 in water was added dropwise untill gas evolution stopped. After precipitation of a white solid, the r.m. was filtered and washed with EtOAc. Filtrate and washings were combined and concentrated in vacuo. The product was redissolved in EtOAc, washed with IN HCl (2x), sat'd NaHCO3 and brine and dried on Na2SO4. After filtration and concentration in vacuo, compound 53 was obtained as a yellowish solid in 97% yield (14.45 g)-
Method S - (2-chloro-4-nitrophenyl)methanolH2/Nl Amine (Method K) (Method J) iV,iV'-carbonyldiimidazole (19.91 g, 122 mmol) is added batchwise at RT to 2-chloro-4- nitrobenzoic acid (25 g, 90% purity, 111 mmol) in anhydrous THF (420 mL) and the mixture is stirred for I h. At 15 - 200C sodium borohydride (13.09 g, 346 mmol) in water (85 mL) is added dropwise and the mixture is stirred for 16 h at RT. The reaction mixture is adjusted to pH 1 with 6 N HCl and extracted exhaustively with EtOAc. The combined organic phases are washed with 15 % potassium carbonate solution (2 x 150 mL) and saturated saline solution (150 mL), dried on sodium sulphate, filtered and evaporated down. Yield: 20.6 g
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 2h;Heating / reflux;
(2-Chloro-4-nitrophenyl)methanol (19 g, 101 mmol) is stirred in a mixture of anhydrous DCM (400 mL), thionyl chloride (15 mL) and DMF (1 mL) for 2 h at boiling temperature. The reaction mixture is evaporated down, the residue is taken up in EtOAc (250 mL), washed with water (5 x 150 mL) and saturated saline solution (150 mL), dried, filtered and evaporated down. Yield: 20.40 g (98%)
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; for 2h;Heating / reflux;
Method T - 2-chloro-l-chloromethyl-4-nitrobenzene<strong>[52301-88-9](2-chloro-4-nitrophenyl)methanol</strong> (19 g, 101 mmol) is stirred in a mixture of anhydrous dichloromethane (400 mL), thionyl chloride (15 mL) and DMF (1 mL) for 2 h at boiling temperature. The reaction mixture is evaporated down, the residue is taken up in EtOAc (250 mL), washed with water (5 x 150 mL) and saturated saline solution (150 mL), dried on sodium sulphate, filtered and evaporated down. Yield: 20.4 g
In a 250 mL round bottom flask, methyl 2-chloro-4-nitrobenzoate (5 g, 23 mmol) was dissolved in anhydrous dichloromethane (100 mL). The solution was cooled to -78C under nitrogen. Bis(2-methylpropyl)alumane (35 mL, 35mmol, 1 M in hexane) was added dropwise. The mixture was stirred at -78C for 4 hours and quenched by addition of water (5 mL). The resulting mixture was warmed up to room temperature in 20 minutes. Na2SO4 (15 g) was added. After 10 minutes, the mixture was filtered. The filtrate was evaporated to provide (2-chloro-4-nitrophenyl)methanol (95% yield).
<strong>[52301-88-9](2-chloro-4-nitrophenyl)methanol</strong> (707 mg, 3.73 mmol) was dissolved in dichloromethane (15 mL) at 00C under nitrogen. Tribromophosphane (0.7 mL, 7.46 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by addition of 10% NaHCO3 solution (2 mL). After 10 minutes, Na2SO4 (15 g) was added. The solvent was filtered and evaporated to provide l-(bromomethyl)-2-chloro-4-nitrobenzene, which was used without further purification.
Adding a time fresh material in the oxidation reactor is 2-chloro-4-nitro toluene and catalyst is dissolved in the acetic acid Co(Ac)2·4H2O, having the general formula (IV) of a metal phthalocyanine structure (R1=CH3CH2, R2=H, M=Mn), having the general formula (I) structural metal porphyrin (R1=R2=H, R3=CH3, M=Cu) mixture, the total concentration is 225 ppm, acetic acid and 2-chloro-4-nitrotoluene mass ratio of 0. 04. When the device was operated in steady state, the flow rate of the fresh material in the oxidation reactor was 4. 3mL / h. The average residence time of the oxidation reactor in liquid phase was 4.0 hours, the mass fraction of oxygen was 6% oxygen-enriched air was continuously fed into the oxidation reactor to maintain the reaction temperature of 130 C and the reaction pressure of 0.7 MPa. The volume ratio of the water fed into the hydrolysis reactor to the oxidation reaction liquid entering the hydrolysis reactor was 0. 57: 1 and oxygen-enriched air with 60% oxygen content was continuously fed to maintain the reaction temperature in the hydrolysis reactor 83 C and the reaction pressure was 0.5 MPa. The residence time of the liquid phase in the hydrolysis reactor was 3.6 h. The liquid phase at the outlet of the hydrolysis reactor was continuously fed into a liquid-liquid delaminator at a temperature of 51 C and a pressure of 0.4 MPa. The conversion of 2-chloro-4-nitrotoluene in the system was 97.2%, and 2-chloro-4-nitrobenzyl alcohol, 2-chloro-4-nitrobenzaldehyde and 2-chloro-4-nitrobenzoic acid were 65.6%, 24.2% and 10.2%, respectively. Other by-products were not detected.
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