Coupling Reagents in Amide Synthesis

EDCI coupling

EDCI,HCl (1.27g, 6.61 mmol) andN, N- diisopropylethylamine (2.40 ml, 13.8 mmol) were added to a solution ofbiphenyl-2-yl-carbamic acid 1-{2- [4-(2-amino-ethyl)-phenyl}-ethyl}-piperidin-4-yl ester (2.445g, 5.51 mmol), 2-fluoro-4- hydroxybenzoic acid (860mg, 5.51 mmol) and HOBt (1.01 g, 6.61 mmol) in dimethylformamide(50ml) and stirred for 24 hours at room temperature under nitrogen. The solvent was removed in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia, 97:3:0.3 to 95:5:0.5 (by volume), to furnish the title compound as a white foam, 95% yield, 3.08 g.


Patent reference: WO201007561 (Pfizer)

HATU coupling

A 50 mL vial was charged with a magnetic spin bar, (Z)-5-((2-(piperazin-l- yl)pyridin-3-yl)methylene)thiazolidine-2,4-dione hydrochloride (0.125 g, 0.38 mmol), 3-(tert-butoxycarbonylamino)propanoic acid (0.109 g, 0.57 mmol), DMF (1.912 ml), anddiisopropylethylamine (0.334 ml, 1.91 mmol). With stirring, HATU (0.291 g, 0.76 mmol) was added and the reaction was warmed to 50°C for 3 h. The reaction was then diluted with water and extracted with ethyl acetate (3X50 mL). The combined organic extract was dried with MgSO4, filtered through a bed of Celite, and cone, in vacuo to yield the product which was purified via silica gel chromatography (80 g) using ethyl acetate/hexanes (1:1) as eluent to provide the title compound as an off white solid. (0.080 g, 45.3 %).


Patent reference: WO2010001169 (Astrazeneca)


HBTU coupling

To a suspension of 3-fluoro-4-[(1 ,3-thiazol-2-ylamino)sulfonyl]benzoic acid

(2.88g, 9.54mmol) and 1-[3-chloro-4- (trifluoromethoxy)phenyl] methanamine (3.0g, 11.4mmol) and Et3N (4.81 ml, 34.5mmol) in DMSO (30mL) was added HBTU (4.34g, 34.5mmol) and the mixture stirred at room temperature for 18 hours. The reaction was then diluted with EtOAc (100ml) before washing with water (100mL) and brine (3 x 100mL). The EtOAc layer was dried (Na2SO4), filtered and concentrated in vacuo leaving a brown solid (6.38g). The crude product was triturated with MTBE, dried in vacuo and stirred in EtOAc for 20 minutes and the resulting off- white solid filtered off and dried in vacuo overnight to provide the title compound (3.97g, 7.8mmol).


Patent reference: WO2010035166 (Pfizer)

TBTU coupling

(4-Methyl-piperazin-l-yl)-acetic acid (167 mg, 1.1 mmol), N-N-diisopropyl ethyl amine (398 mg, 3.1 mmol) and TBTU (452 mg, 1.4 mmol) were dissolved in dichloromethane 25 mL) and dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 30 minutes. N-(2-Cycloheptyl-4H-benzo[d][l,3]oxazine-2,6-diamine (228 mg, 0.88 mmol) was added and stirring was continued overnight. The reaction mixture was diluted with water and thrice extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The crude product was purified by column chromatography (silica gel, dichloromethane/methanol/ammonia 100:0:0 -> 110:10:1). The title compound (144 mg, 41%) was obtained as an off-white foam.


Patent reference: WO2010026110 (Roche)


T3P coupling

T3P (1.6M in THF, 51.3 mL) was added dropwise to a stirred suspension of tert-butyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (18.1 g), 2-ethylthiazole-4-carboxylic acid (12 g) and triethylamine (52 mL) in DMF (120 mL) under nitrogen and the mixture stirred at ambient temperature for 20 hours. It was diluted with water and extracted into ethyl acetate (x 3). The combined extracts were washed successively with 10% brine, 30% brine and saturated brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash silica chromatography, eluting with ethyl acetate. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a yellow oil. Yield : 73%, 24.0  g.

Patent reference: WO2011012896 (Astrazeneca)