5-Bromo-thiophene-2-carboxylic acid methyl ester

Weigh 950 mg (4.62 mmol) of 5-bromo-2-carboxythiophene in 10 mL of MeOH, slowly add 2 mL of SOCl2, After completion of the reaction, the mixture was cooled to room temperature, evaporated under reduced pressure, And with a certain amount of toluene dissolved dry, Repeated 3 times to getIntermediates5-bromothiophene-2-carboxylate1.0 g, yield 100percent.A solution of 5-bromothiophene-2-carboxylic acid (4.995 g, 24.1 mmol) in 30 mL CH3OH/8 mL acetyl chloride was heated at 65 °C. After 22 h, the reaction was allowed to cool to room temperature and then was evaporated. The residue was partitioned between 100 mL saturated NaHC05-(2-Amino-phenyl)-thiophene-2-carboxylic acid methyl ester (47)SStep 1: LE23 Dissolve 5-Bromo-thiophene-2-carboxylic acid (45) (1.5Og, 7.24mmol) in methanol (1OmL) and add cone, sulfuric acid (0.39mL, 7.24mmol). Stir the reaction mixture for 2Oh at 75°C. Cool mixture to it, remove solvent under reduced pressure and resolve the residue in EtOAc. Wash this organic layer 3 times with 5percent aqu. NaStep 1: LE23 Dissolve 5-Bromo-thiophene-2-carboxylic acid (45) (1.50 g, 7.24 mmol) in methanol (10 mL) and add conc. sulfuric acid (0.39 mL, 7.24 mmol). Stir the reaction mixture for 20 h at 75° C. Cool mixture to rt, remove solvent under reduced pressure and resolve the residue in EtOAc. Wash this organic layer 3 times with 5percent aqu. Na5-Bromo-thiophene-2-carboxylic acid (10 g, 48 mmol) was taken up in CH30H and HCl was bubbled through the solution for 10 min at room temperature. The reaction was then stirred for 16 h at room temperature. The CH30H/HCl was removed under reduced pressure and the residue was taken up in EtOAc and the organic layer was washed with NaHCO3. The organic layer was washed with water, with brine then dried over anhydrous MgS04. The solution was removed under reduced pressure providing 8.7 g of 5-bromo-thiophene-2-carboxylic acid methyl ester as a white solid, pure enough to use in next step. Yield 87percent. Pd (PPh3) 4 (132 mg, 10percent) was added to a degassed solution of 5-bromo-thiophene-2- carboxylic acid methyl ester (220 mg, 1 mmol) and pyridine-4-ylboronic acid (246 mg, 2 mmol) in 3 mL of DMF. Sodium carbonate (530mg, 5 mmol) and a few drops of water were added. The reaction vessel was microwave heated at 140°C for 20 min. The Pd catalyst was separated from the reaction mixture by filtration. The mixture was diluted with EtOAc and water. The combined organic extracts were washed with a NaHCO3 saturated solution, brine, dried with MgS04, filtered and concentrated. The residue was purified to yield 130 mg of 5-pyridin-4-yl-thiophene-2-carboxylic acid methyl ester. Yield 30percent. 5-Pyridin-4-yl-thiophene-2-carboxylic acid methyl ester was dissolved in 6 mL THF, 2 mL MeOH and added 1N LiOH and stirred overnight. The solvent was removed. 1N HCl was added and a yellow precipitate formed. LC/MS showed only product. The suspension was diluted with water and the precipitate collected by filtration to yield 130 mg of the title compound as a light yellow solid. Yield 68percent.Preparation of /V-{(1 S)-2-amino-1-[(3, 4-difluorophenyl)methyl1ethyl}-5-(1 /-/-pyrazol-4-yl)-2- thiophenecarboxamide; a) methyl 5-bromo-2-thiophenecarboxylate; To a solution of δ-bromo^-thiophenecarboxylic acid (2.07 g, 10.00 mmol) inMethanol (50 ml.) was added sulfuric acid (2.66 ml_, 50.0 mmol) dropwise. The mixture was heated at 60 Preparation 3; Methyl 5-allylthiophene-2-carboxylate Step 1. Preparation of the methyl ester Acetyl chloride (6.9 mL, 96.6 mmol) was added to a solution of 5-bromo-2-thiophenecarboxylic acid (4.0 g, 19.3 mmol) in methanol (30 mL) at rt. After 17 h at rt, the reaction was heated at reflux for 1.5 h to drive it to completion. The reaction was then cooled to rt and concentrated in vacuo to remove methanol. Saturated aqueous NH5-(3-{(1 R, 2S, 3R, 5R)-5-Chloro-3-hydroxy-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-propyl)-thiophene-2-carboxylic acid methyl ester. Acetyl chloride (6.87 mL, 96.6 mmol) was added to a solution of 5-Bromo-thiophene-2-carboxylic acid (4.0 g, 19.3 mmol) in methanol (30 mL). The reaction was allowed to stir overnight and then was heated to reflux for 1.5 h. The reaction was allowed to cool to room temperature and then was evaporated. The residue was treated with 120 mL saturated sodium bicarbonate solution and the resulting mixture was extracted with dichloromethane (3.x.100 mL). The combined dichloromethane solution was dried (NaAcetyl chloride (6.9 mL, 96.6 mmol) was added to a solution of 5-bromo-2-thiophenecarboxylic acid (4.0 g, 19.3 mmol) in methanol (30 mL) at rt. After 17 h at rt, the reaction was heated at reflux for 1.5 h to drive it to completion. The reaction was then cooled to rt and concentrated in vacuo to remove methanol. Saturated aqueous NH5-(3-{(1R, 2S, 3R, 5R)-5-ChIoro-3-hydroxy-2-[4-(1-hydroxy-hexyl)-phenyl]-cycIopentyl}-propyl)-thiophene-2- ) carboxylic acid methyl ester.; The title compound was prepared using an analogous procedure to that described for EPO General procedure: 5-Halide thiophene-2-carboxylate (1equiv) was solved in 3ml absolute methanol, and concentrated sulfuric acid (2.2equiv) was added. The reaction mixture was heated under reflux conditions overnight. After cooling to room temperature, the solvent was evaporated. Purified water was added, and the reaction mixture was neutralized with saturated NaHCOGeneral procedure: NBS (63 mg, 0.35 mmol) was added to a solution of 1 (100 mg, 0.70 mmol) in 10 mL of THF – CH3OH (1:1, v/v) at 0 C and the mixture was stirred at roomtemperature. After 2 h, NBS (50.4 mg, 0.28 mmol) was added again to the mixture at 0 C, and it was stirred at room temperature for 2 h. The solvent wasremoved in vacuo, and water (15 mL) was added to the residue. The aqueouslayer was extracted three times with EtOAc (30 mL). The organic layers weregathered together, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. Et2O (10 mL) was added to the dry residue todiscard succinimide. The filtrate was concentrated in vacuo, and heptane(10 mL) was added to the dry residue to afford 4 as an orange powder (68.6 mg, 44percent yield).[0498] Preparation of methyl 5-bromothiophene-2-carboxylate [0499] To an iced-cooled solution consisting of 5-bromo-2-thiophene carboxylic acid (Oakwood Products, 5.1 g, 25 mmol) in ethyl acetate (200 mL) and methanol (20 mL) was added TMS diazomethane (2M in diethyl ether, 20 ml, 40 mmol) over 20 minutes. Gas evolution was observed and the reaction mixture was stirred for one hour. The mixture was then allowed to warm to room temperature overnight. The volatile material was removed and the residue was purified by silica gel chromatography. Elution with ethyl acetate- heptane (1 :50 v/v) afforded the title intermediate (5.4 g, 98percent) as a white solid; TLC R/0.60 (solvent system 90: 10 v/v heptanes: ethyl acetate); 'H-NMR (CDC1jO4llj Step 1: Preparation of methyl 5-bromo-2-thiophene carboxylateCOMeBPj0412j To an ice-cooled mixture consisting of 5-bromo-2-thiophene carboxylic acid (5.25 g, 25.4 mmol) in ethyl acetate (200 mL) and methanol (20 mL) was added trimethylsilyldiazomethane (2M in diethyl ether, 20 mL, 40 mmol) over 20 minutes. The reaction mixture was stirred for 24 hours. The solvent was removed and the residue was purified by silica gel chromatography eluting with ethyl acetate-heptanes (1:50 v/v) to afford the title intermediate (5.5 g, 98percent) as a white solid; TLC R1 0.60 (solvent system 1:9 v/v ethyl acetate-heptanes); ‘H-NMR (CDC13) ö 7.5 (d, 1H), 7.1 (d, 1H), 4.9 (s, 3H).Preparation of methyl 5-bromothiophene-2-carboxylate [0607] To an iced-cooled solution consisting of 5-bromo-2-thiophene carboxylic acid (Oakwood Products, 5.1 g, 25 mmol) in ethyl acetate (200 mL) and methanol (20 mL) was added TMS diazomethane (2M in diethyl ether, 20 ml, 40 mmol) over 20 minutes. Gas evolution was observed and the reaction mixture was stirred for one hour. The mixture was then allowed to warm to room temperature overnight. The volatile material was removed and the residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (1 :50 v/v) afforded the title intermediate (5.4 g, 98percent) as a white solid; TLC PyO.60 (solvent system 90: 10 v/v heptanes: ethyl acetate); ^-NMR (CDC1Step 1 Preparation 3; Methyl 5-allylthiophene-2-carboxylateStep 1. Preparation of the Methyl EsterAcetyl chloride (6.9 mL, 96.6 mmol) was added to a solution of 5-bromo-2-thiophenecarboxylic acid (4.0 g, 19.3 mmol) in methanol (30 mL) at rt. After 17 h at rt, the reaction was heated at reflux for 1.5 h to drive it to completion. The reaction was then cooled to rt and concentrated in vacuo to remove methanol. Saturated aqueous NH

Molecular Weight:221.07
XLogP3:2.8
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:219.91936
Monoisotopic Mass:219.91936
Topological Polar Surface Area:54.5
Heavy Atom Count:10
Complexity:140
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes