Ethyl-2-fluoro-5-iodobenzoate

N, N-Dibutyl-4-chloro- 1 -(2-((5)-3-(hydroxymethyl)- 1 , 2, 3 , 4-tetrahydroisoquinoline-2- carbonyl)-4-(naphthalen-2-ylsulfonylcarbamoyl)phenyl)-5-methyl-lH-pyrazole-3- carboxamideIntermediate 91 A: Ethyl 2-fluo -5-iodobenzoate[00316] To a solution of 2-fluoro-5-iodobenzoic acid (Oakwood, 0.99 g, 3.72 mmol) in EtOH (7.4 mL) was added HAdd NaH (3.71 g, 92.8 mmol, 60.0% purity, 1.3e q) to dry THF (131.0 mL).Compound 2 (21.0 g, 71.4 mmol, 1 eq) and 1-vinylpyrrolidin-2-one (8.49 g, 76.4 mm ol, 8.17 mL, 1.07 eq).The mixture was stirred at 80 C for 3 hours.It was then cooled to room temperature.Then 10% HCl solution (30 mL) was slowly added and stirred at 100 C for 10 hours.The progress of the reaction was detected by TLC (P etroleum ether/Ethyl acetate = 4/1, Rf = 0.68).When the reaction is over, In the condition of an ice bath, Gradually add 1M NaOH solution, The pH of the reaction solution was adjusted to 8.0.Further extraction with DCM (50.0 mL x 2), And by column chromatography (SiO2, Petroleum ether/Ethyl acetate=8/1to 5/1), Obtained white compound 3 (1.60 g, 5.53 mmol, 7.75% yield).Figure 4 shows the results of TLC chromatography for this reaction.The NMR data for Compound 3 is:Under nitrogen atmosphere, starting Ester Intermediate 5e (5.0 g, 15.3 mmol) was dissolved in THF (40 mL), the reaction mixture was cooled to -50C and stirred for 10 minutes. Isopropyl-magnesium-chloride (1 1 mL of a 2M solution in THF) was added dropwise and the reaction mixture was stirred at -50C for 2h. The reaction mixture was cooled to -78C and a solution of cyclobutanone (2.15 g, 30.6 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -78C for 1 h, then warmed to room temperature and stirred for 18h. The solvent was removed under vacuum, dichloromethane was added and the reaction mixture was washed with a saturated solution of NaHCO3, The organic phase was concentrated under vacuum and the crude product obtained was purified by flash chromatography (eluent from 90:10 to 80:20 Cy/EtOAc) to obtain the desired product (3.0 g). GC-MS (Method 10): Rt = 10.91 min MS : m/z = 210 (M-28)+10586] Under nitrogen atmosphere, starting Ester Intermediate Se (5.0 g, 15.3 mmol) was dissolved inTHF (40 mE), the reaction mixture was cooled to -50 C. and stirred for 10 minutes. Isopropyl-magnesium-chioride (11 mE of a 2M solution in THF) was added dropwise and the reaction mixture was stirred at -50 C. for 2 h. The reaction mixture was cooled to -78 C. and a solution of cyclobutanone (2.15 g, 30.6 mmol) in THF (10 mE) was added dropwise. The reaction mixture was stirred at -78 C. for 1 h, then warmed to room temperature and stirred for 18 h. The solvent was removed under vacuum, dichloromethane was added and the reaction mixture was washed with a saturated solution of NaHCO3, The organic phase was concentrated under vacuum and the crude product obtained was purified by flash chromatography (eluent from 90:10 to 80:20 Cy/EtOAc) to obtainthe desired product (3.0 g).10587] GC-MS (Method 10): R=10.91 mm10588] MS: mlz=210 (M-28)General procedure: Intermediate 3: .0 To a mixture of commercially available 2-chloro-5-hydroxybenzoic acid (4 g, 23.18mmol) in dry EtOH ( 90 mL), concentrated sulphuric acid (1 mL, 17.62mmol) was added. The mixture was stirred under reflux overnight, then solvent evaporated under reduced pressure and the residue dissolved with DCM. A saturated solution of NaHCO3 was added, phases were separated, organics dried over sodium sulphate , filtered and evaporated to obtain 5 g of the corresponding 2-chloro-5-hydroxy- benzoic acid ethyl ester. HPLC-MS (Method 2): Rt = 1 .0 min MS: m/z = 201 .6 (M+H)+General procedure: To a mixture of commercially available 2-chloro-5- hydroxybenzoic acid (4 g, 23.18 mmol) in dry EtOR (90 mE), concentrated sulphuric acid (1 mE, 17.62 mmol) was added. The mixture was stirred under reflux overnight, then solvent evaporated under reduced pressure and the residue dissolved with DCM. A saturated solution of NaHCO3 was added, phases were separated, organics dried over sodium sulphate, filtered and evaporated to obtain 5 g of the corresponding 2-chioro-5-hydroxybenzoic acid ethyl ester.10567] HPEC-MS (Method 2): R=1 .0 mm10568] MS: mlz=201.6 (M+H7

Molecular Weight:294.06
XLogP3:2.9
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:293.95531
Monoisotopic Mass:293.95531
Topological Polar Surface Area:26.3
Heavy Atom Count:13
Complexity:187
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes