Methyl 4-amino-2-chlorobenzoate

off white powder

7V-(3-Chloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[l, 2-fl]pyridine-2-yl)-l, 3, 4- thiadiazol-2-yl) Phynyl)methanesulfonamide; Methyl-4-amino-2-chlorobenzoate (100).; To a stirred solution of methyl-2-chloro-4- nitro benzoate 99 (0.50 g, 2.3 mmol) in EtOH was added stannous chloride (2.62 g, 11.6 mmol) at 0 A solution of methyl 2-chloro-4-nitrobenzoate (46, 0.116 mol) in methanol and 30percent w/w of Raney 2800 nickel slurry in water (activecatalyst-Aldrich), was stirred under hydrogen in a hydrogenation apparatus atroom temperature for 4 hours. The catalyst was removed by filtration on celiteand solvent removed in vacuum. Recrystallized from methanol gave 90percent yield of a white solid, mp 108.5-109.5 C. Step 2: To a stirred solution of methyl 2-chloro-4-nitrobenzoate (468 mg, 2.17 mmol) in ethanol was added Sn(ll) chloride and heated to reflux for 1 .5 h. TLC showed complete consumption of starting material. The reaction mixture was cooled to room temperature. The solvent was removed in vacuo and extracted with EtOAc. The organic layer was washed with water and brine. The extract was dried over MgSO4 and concentrated under reduced pressure to give desired product methyl 4-amino-2-chlorobenzoate (407 mg).To a solution of 4-amino-2-chlorobenzoic acid (2 g, 1 1.66 mmol) in MeOH (55.5 mL) was added thionyl chloride (3.40 mL, 46.6 mmol) dropwise at 0°C. The resulting solution was stirred at rt. After 32h the solvent was removed. The crude product was taken up in EtOAc and washed with sat. aqueous NaHC0To a 200 mL MeOH solution of 4-amino-2-chlorobenzoic acid (12 g, 67.84 mmol) was added 2 equivalents of SOCl2 (11 mL, 135.7 mmol) at 0° C. The ice-water bath was removed after the addition and the reaction mixture was heated to reflux until the starting material had disappeared, as indicated by LC-MS. After the reaction was cooled back to RT, solvent and excess of SOCl2 were removed under reduced pressure. The residue was suspended in 10percent aqueous Na2CO3 solution. The precipitate that formed was filtered and washed with water until the washes became neutral. The filter cake was then re-dissolved in 200 mL of ethyl acetate, and the ethyl acetate layer was washed with water, brine, and dried over anhydrous Na2SO4. After concentrated under reduced pressure and vacuum drying, 12.27 g of product was obtained (97.4percent). M+H+(186).Example E To methanol at 0 °C was added dropwise acetyl chloride (314.7 mmol, 22.4 mL). After the addition of acetyl chloride, the reaction mixture was stirred at rt for30 mm, then 4-amino-2-chlorobenzoic acid 1(116.6 mmol, 20.0 g) was added in one portion. The reaction mixture was heated at reflux for 18 hours, cooled to 0 °C, and concentrated under vacuum. The residue was suspended in 250 mL of ethyl acetate, cooled to 0 °C, and saturated aqueous NaHCO3 was added (pH was 8). The mixture was partitioned and extracted with ethyl acetate (200 mL). Combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum to afford 20.9 g of title compound as a yellow solid which was used as such in next step without purification. 1H NMR (400 MHz, CDCI3): 67.78 (d, J= 8.6 Hz, 1H), 6.70 (d, J= 2.3 Hz, 1H), 6.52 (dd, J= 8.6, 2.3 Hz, 1H), 4.09 (bs, 1H), 3.86 (s, 3H). LCMS (M+1) 186.1, 188.1.4-Amino-2-chloro-benzoic acid (2.50 g) and lithium hydroxide monohydrate (611 mg) were suspended in tetrahydrofuran (20 ml), and the suspension was stirred at room temperature for 20 min. Thereafter, dimethylsulfuric acid (1.38 ml) was added to the reaction mixture, and the mixture was stirred under reflux for 2 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and was extracted with diethyl ether. The diethyl ether layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure to give methyl 4-amino-2-chloro-benzoate (1.68 g, yield 62percent). Methyl 4-amino-2-chloro-benzoate (1.68 g) and 5-methoxymethylene-2, 2-dimethyl-[1, 3]dioxan-4, 6-dione (1.53 g) were dissolved in 2-propanol (25 ml), and the mixture was stirred at 100°C for 15.5 hr. The solvent was removed by distillation under the reduced pressure, and the residue was washed with diethyl ether to give methyl 2-chloro-4-[(2, 2-dimethyl-4, 6-dioxo-[1, 3]dioxan-5-ylidenemeth yl)-amino]-benzoate (1.92 g, yield 63percent).Acetyl chloride (2.5 ml) was added drop-wise to a solution of 2-chloro-4-cyano-benzoic acid (2.22 g, 12.94 mmol) in methanol (75 ml) while stirring. The mixture was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was taken up in ethyl acetate, washed with saturated NaHCO3 and brine and concentrated in vacuo to give a beige solid identified as 4-amino-2-chloro-benzoic acid methyl ester (2.32 g, 97percent).(a) Methyl 4-amino-2-chlorobenzoate. A solution of methyl 2-chloro-4-nitrobcnzoate (4.5 g, 20.9 mmol) and tin (II) chloride dihydrate (18.84 g, 83.5 mmol) in 100 mL EtOAc was heated cautiously to 70C for 30 minutes. After cooling, the reaction mixture was diluted with EtOAc and washed with H2O (2x), then with saturated NaCI solution, dried over MgSO4 and concentrated under reduced pressure. In this manner, the title compound was isolated as an off-while solid (99%). 1H NMR (CDCl3) delta: 3.86 (s, 3H), 4.10 (br s, 2H), 6.53 (d, 1H, J = 8.5Hz with fine splitting), 6.70 (s, 1H, with fine splitting), 7.78 (d, 1H, J = 8.5Hz). Anal. (C8H8NO2Cl) C, H, N, Cl.EXAMPLE 4 2-{6-Chloro-5-[5-(4-fluoro-benzyl)3a, 6a, dimethyl-hexahydro-pyrrolo[3, 4-c]pyrrole-2-carbonyl]-1-methyl-1H-indol-3-yl}-N, N-dimethyl-2-oxo-acetamide To a suspension of p-toluenesulfonamide (27.5 g, 1660 mMol) and anhydrous K2CO3 (45 g) in anhydrous acetonitrile (250 ml) was added 3-chloro-2-(chloromethyl)-1-propene (20 g, 160 mMol) in acetonitrile (25 mL) dropwise. The reaction mixture was refluxed for 4 h, and then concentrated. The residue was extracted with hot ethyl acetate (3*). The combined extracts were concentrated and the crude solid was re-crystallized from ethyl acetate to give 21 g (60%) of the title compound 1 as a colorless crystalline.General procedure: Example thirteen to twenty investigated the reactivity of the sulfur-doped palladium catalyst on the carbon material of different halo nitrobenzene hydrogenation of halogenated aniline.In 500ml stainless steel autoclave was added 100g halonitrobenzene, 200ml methanol, 1g Example embodiments a sulfur-doped carbon material prepared palladium catalyst, reactor shut down, the air replaced with nitrogen three times in the reactor, then hydrogen three substitution; the temperature was raised to 80 , a hydrogen pressure of 0.8MPa, began stirring, stirring rate 900r / min, the reaction for 2.5 h; reaction was stopped until the temperature decreased to room temperature, the reaction solution was taken out, the catalyst was removed by filtration, the filtrate by gas spectrum analysis.The results shown in Table 2.Table 2 Sulfur-doped catalytic hydrogenation catalyst palladium carbon material properties different halo nitrobenzene.

Used as pharmaceutical intermediate

Molecular Weight:185.61
XLogP3:2.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:185.0243562
Monoisotopic Mass:185.0243562
Topological Polar Surface Area:52.3
Heavy Atom Count:12
Complexity:174
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes