运用有机磷类缩合剂制备酰胺

To a solution of theacid 33 in dry CH2Cl2(5 ml / mmol) was added diisopropyl ethylamine (DIEA, 1 equiv) under nitrogen,and the mixture was stirred for 10 min. Then,BOP-Cl (1 equiv), amine 32 (1.1 equiv) and again DIPEA (2 equiv) wereadded. After it was stirred overnight,most of the DCM was removed under reduced pressure and ethyl acetate (100 ml)was added. The solution was washed threetimes with 5% NaHCO3 solution and once consecutively with water, 2M HCl solution, water and saturatedbrine (50 ml each). The organic layerwas dried over Na2SO4, and the solvent was evaporated to give the desired amide34.

T3P was dosed to a mixture of acid, amine, and pyridine in 2:1 v/v MeCN/EtOAc. This solvent ratio, upon quenching with 0.5 M aqueous HCl, provided the direct-drop crystallization of free base amide 112 (34.1 kg, 88% yield) with high purity (>99% achiral, 0.5% ent-112) and purging of pyridine, excess aminonicotinate 111, andT3P byproducts to the mother liquor。

【 Org. Process Res. Dev. 2012, 16, 1635】

2mmol of a carboxylic acid 37, 2 mmolof an amine 38, 2 mmol oftriethylamine, and 2 mmol of carbon tetrabromide are dissolved in 5 mL of drymethylene chloride. Solid triphenylphosphine (2 mmol, 554 mg) is then added portionwise over 5 min to the solutionstirred at room temperature. After afurther period of 10 min., the solvent is evaporated, and a 1:1 mixture ofhexane and ethyl acetate is added. Thesolid triphenyl phosphine oxide is filtered off, the solvents are evaporatedand the crude material can be purified by conventional methods.

【 Synth.Commun ., 1990, 1105】

A mixture of benzoic acid (122 mg, 1mmol) andhexachloroacetone (132 mg, 0.5 mmol) in methylene chloride (2 mL) was stirredunder argon and cooled down to -78 ℃. Triphenylphosphine (262 mg, 1 mmol) inmethylene chloride (1 mL) was added dropwise and the mixture was stirred for 20min. The acyl chloride solution was thentreated with a solution of benzylamine (107 mg, 1 mmol) in methylene chloride(1 mL) dropwise, followed by triethylamine (101 mg, 1mmol) in methylenechloride (1 mL) the reaction mixture wasthen allowed to reach room temperature after which the solvent was evaporated under highvacuum. The dry residue was suspended in20% ethyl acetate in hexane (4 mL) and silica gel added in order to obtain pasta. This pasta was added onto the top of a silicagel column and the elution performed with the same solvent. The pure fractions provided the titlecompound as a white solid (187 mg, 95%): m. p. 102 ℃.

【 Tetrahedron lett. 1997, 6489】

To a stirred solution of triphenylphosphine (2.55 mmol, 0.67 g) and hexanoic acid (2.5 mmol, 0.29 g) in anhydrous dichloromethane (5ml) at 0 ℃was added N -bromosuccinimide (NBS,2.8 mmol, 0.50 g) in one portion. The reaction mixture containing 0.25 mmol of 40was thereafter set aside at roomtemperature while a new solution was being prepared: 3-Aminophenol (2.5 mmol, 0.28 g) and pyridine (3.20 mmol, 0.26 g) was dissolved in THF (5 ml). The mixture was cooled to about -25 ℃(ethanol/granular CO2), and vigorously stirred while the ready-made solution of 40was added dropwise. The cooling bath was removed after a few minand the temperature allowed to rise towards room temperature. Most of the solvents were removed under reducedpressure and the product purified by flash chromatography on Merck No. 9385 silica gel60, using ether as eluent. Removal ofthe solvent gave N -(3-hydroxyphenyl)-hexanamide 41(0.52 g, 98 %) as a colourless solid, m.p. 139-140 ℃. 1 H NMR (200 MHz, acetone-d6): δ0.90 (m, 3H, CH3), 1.35 (m, 4H, CH2), 1.65(m, 2H, CH2), 2.35 (t, 2H, CH2), 6.52 (m, IH, H ~o,~), 7.0 (m, 2H, H~om.), 7.42(s, 1H, H~o), 8.4 (s, 1H, OH), 9.05 (s, 1H, NH); MS (70 eV): m/z(%) 207 (17, M + ),151 (6.5), 109 (100).

【 Tetrahedron lett. 1997, 5359】

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