5-Bromo-2-chlorobenzaldehyde

Appearance :white crystal powde

60 g PCC and 60 g silica gel powder were added to a round bottom flask; after mixing, 500 mL dichloromethane was added; cooled to 0° C., and 45 g of compound 1-1 in dichloromethane (300 mL) was added dropwise with stirring; maintaining 0° C.The reaction was monitored by TLC; after the reaction was completed, the reaction solution was spin-dried; 38 g of Compound 1-2 was isolated by column separation, and the yield in two steps was 90percent.Step 1: Pyridinium dichromate (3.82 g, 10.2 mmol) was added to a solution of 5-bromo-2- chlorobenzylalcohol (1.5g, 6.8 mmol) in CH2CI2 (30 mL). The reaction was stirred for 5 hours and then celite was added. The mixture was stirred for 20 mins and then filtered through a pad of celite washing with ether. The filtrate was concentrated to a brown oil. The residue was purified by flash silica gel chromatography (0percent to 10percent EtOAc in hexanes) to give the title compound as a clear oil (1.28g, 86percent).'H NMR (400 MHz, CDCI3) : 5 7.35 (d, J=8.6 Hz, 1 H), 7.65 (dd, J=8.3, 2.5 Hz, 1 H), 8.04 (d, J=2.5 Hz, 1 H), 10.41 (s, 1 H).Pyridinium dichromate (3.82 g, 10.2 mmol) was added to a solution of 5-bromo-2-chlorobenzylalcohol (1.5 g, 6.8 mmol) in CH140kg of 2-chlorobenzaldehyde was dissolved in 400kg of methylene chloride and stirred in an ice bath for 30min. Then 180kg of NBS was added in batches to keep the temperature of the reaction system below 5°C. After the addition was completed, the reaction was performed for 10h.After the reaction was completed, the mixture was filtered, and the filtrate was washed with 300 kg of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was washed with water until neutral to recover methylene chloride.The residual solid was recrystallized from petroleum ether:ethyl acetate (1:1) to give 212 kg of a white solid with a yield of 98percent.Take 140 kg of 2-chlorobenzaldehyde and dissolve it in 400 kg of dichloromethane.Stir for 30 min in an ice bath, then add 180 kg of NBS in batches.Keep the temperature of the reaction system below 5 ° C. After the addition, the reaction is carried out for 10 h. After the reaction is completed, Filtration, the filtrate was washed with 300 kg of saturated sodium bicarbonate solution, The organic layer is then washed with water until neutral, and dichloromethane is recovered.The residual solid was recrystallized from petroleum ether: ethyl acetate (1:1) to yield a white solid (yield: 98percent).5-Bromo-2-chlorobenzaldehyde (74c). A solution of pyrrolidine (4.00 g, 56.0 mmol) in MTBE (12 mL) was added dropwise over 20 min to a solution of Red-Al.(R). (3.4 M solution in toluene, 16 ml, 54.4 mmol) in MTBE (33 mL) maintained at -20 °C. The mixture was stirred for 1 h at 25 °C. A solution of potassium tert-butoxide (0.60 g, 5.36 mmol) in THF (3 mL) was added. The resulting solution was added dropwise to a solution of 2-chloro-5-bromobenzoic acid methyl ester (72, 6.80 g, 27.3 mmol) in MTBE (15 mL) at 10 °C. After 15 min the mixture was quenched with 2 N HCl (300 mL). Repeated recystallizations (hexanes) of the recovered material gave a crude solid (3.22 g, 54percent, mp 43-46 °C), which was used without further purification in the next step.; The synthesis of benzaldehyde chlorooxime synthons 52 is depicted in Scheme 4, below. Of the eight aldehydes 44e-f and 74a-f, only 44e and 74d were commercially available. The preparation of aldehyde 44f began with the known three-step transformation of 4-methyl-3-nitrobenzonitrile 63 to methoxy compound 64. See Reiner, J. E., et al., Bioorg. Med. Chem. Lett., 12, 1203-1208 (2002). α-Bromination of 64 using one equivalent of N-bromosuccinimide gave little selectivity between the mono- and dibromo adducts, but the analogous reaction using 2.5 equivalents gave dibromide 65 almost exclusively. Silver nitrate oxidation of dibromide 65 gave aldehyde 44f. See Hill. R. A., et al., J. Chem. Soc., Perkin Trans., 1, 2209-2215 (1987). The reaction of the o-nitrotoluene 63 with N, N-dimethylformamide dimethyl acetal in DMF gave the enamine 66, which underwent oxidative cleavage using sodium periodate in THF, see Riesgo, E. C., et al., J. Org. Chem., 61, 3017-3022 (1996), to give aldehyde 74a via a more facile preparation than previously reported. See Dann, O., et al., Liebigs Ann. Chem., 3, 409-425 (1984). Aldehyde 74b also has been prepared previously. See Schultz, E. M., et al., J. Med. Chem., 19(6), 783-787 (1976). A more expedient preparation of 74b began with chlorotoluene 67 undergoing α-bromination to 68, see Gilbert, A. M., et al., J. Med. Chem., 43, 1203-1214 (2000), by a modification of the original procedure. See Liu, P., et al., Synthesis, 14, 2078-2080 (2001). The reaction of 68 with 2-nitropropane and sodium ethoxide in ethanol gave 74b. See Mallory, F. M., et al., Tetrahedron, 57, 3715-3724 (2001). Commercially available aldehyde 69 and aldehyde 71, see Hino, K., et al., Chem. Pharm. Bull., 36(6), 3462-3467 (1988), which had been prepared via a Sandmeyer reaction from commercially available 70, were converted to methyl esters 72 and 73, respectively. The esters were converted to aldehydes 74c and 74e, respectively, using Red-Al.(R).(sodium bis(2-methoxyethoxy)aluminium hydride) (Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, United States of America), pyrrolidine, and potassium tert-butoxide in methyl tert-butyl ether. See Abe, T., et al., Tetrahedron, 57, 2701-2710 (2001). Cyanoaldehyde 74f was prepared by debromocyanation of 44d. See Laali, K. K., et al., J. Org. Chem., 58, 1385-1392 (1993). Aldehydes 44e-44f and 74a-74f were converted to oxime derivatives 75a-h (of which 75a, e were known previously), see Quan, M. L., et al., J. Med. Chem., 42(15), 2752-2759 (1999), using hydroxylamine hydrochloride in either water/ethanol or pyridine/ethanol. The oximes were treated with N-chlorosuccinimide in DMF to give chlorooximes 52a-h, following the procedure reported for 52e. See Liu. K.-C., et al., J. Org. Chem., 45, 3916-3918 (1980). The chlorooximes 52 were reacted with acetylenes 51 without further purification.; Reagents and conditions: (a) HPreparation Example 5 Synthesis of 2-(5-bromo-2-chlorobenzyl)-1-benzothiophene; Oxalyl chloride (3.78 mL, 0.0441 mmol) and N, N-dimethylformamide (0.06 mL) were added to a chloroform (20 mL) solution of 5-bromo-2-chlorobenzoic acid (10.0 g, 0.0425 mol). After the reaction mixture was stirred at room temperature for one day, the reaction mixture was evaporated under reduced pressure. The obtained yellow oily substance was dissolved in chloroform (20 mL). This solution was added dropwise to a mixture of N, O-dimethoxyhydroxylamine hydrochloride (4.56 g, 0.0468 mol), triethylamine (12.3 mL, 0.0882 mol) and chloroform (50 mL) for 15 minutes, while maintaining the reaction temperature at 5°C to 10°C. After stirred for 15 minutes, the reaction mixture was warmed to room temperature. After water (20 mL) was added to the reaction mixture, the organic layer was separated and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (11.8 g, 99.7percent) as a colorless crystal. This was used in the next reaction without purification. LiAlHAmide compound of Formula III (wherein X=bromo; 88 gms) and toluene (440ml) were added in to a round bottom flask at 25-35°C and allowed to cool to -65°C to -70°C. Diisobutyl aluminium hydride (lLt, 25percentsolution in toluene) was added to the reaction mass and stirred for 30 min at same temperature. The reaction mass was quenched with aqueous sodium potassium tartrate solution and heated the reaction mass to 25-35°C. The layers were separated and the aqueous layer was extracted with toluene then the organic layers were combined and washed with aqueous sodium chloride and dried over sodium sulphate. The organic layer was concentrated under reduced pressure at 45 °C and the obtained residue was diluted in heptane (200ml) and allowed to cool to 5-10°C. The reaction mass was stirred for l-2hrs at 5-10°C, filtered, washed with chilled heptane and dried at 30-35 °C to get the title compound. Yield: 65gms.Step 2: Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (3-methoxypropyl)triphenylphosphonium bromide (49.3 g, 118.5 mmol) in THF (200 mL). Then, NaHMDS (118.4 mL, 118.5 mmol, 1 M in THF) was added at 0 C. and stirred for 30 mins. Then

Molecular Weight:219.46
XLogP3:2.7
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:217.91341
Monoisotopic Mass:217.91341
Topological Polar Surface Area:17.1
Heavy Atom Count:10
Complexity:129
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes