Amine synthesis (via azido group, Staudinger reaction):


To a stirred solution of Azido compound (2.5 g, 8.99 mmol) in anhydrous THF (20 ml) was added triphenylphosphine (3.5 g, 13.5 mmol) in portions over 30 min at 0°C. After the addition, the reaction mixture was stirred at room temperature overnight. 200 ml of concentrated ammonia was added. Then the reaction mixture was heated to reflux. Upon completion, the reaction mixture was cooled to room temperature, concentrated in vacuo, adjusted to pH=1 -2 with 2 N HCI and washed with EtOAc (50 ml in 6 portions). The aqueous phase was made alkaline to pH = 12-13 and extracted with CH2CI2 (50 ml x 2). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (CH2CI2:MeOH = 100:1) which gave the title amine compound as a yellow oil (1.2 g, 35%).


Patent reference: WO2010016005 (Pfizer)

Staudinger reaction

Amine synthesis (via nitro reduction):


To a solution of 1-(2-chloro-5-nitropyridin-4-yl)ethanone (1.0 equiv.) in acetic acid (0.3 M) was added iron (6.0 equiv.). The solution was vigorously stirred for 4 hours, at which time it was filtered through a celite pad (9cm x 3 inches) eluting with MeOH and then ethyl acetate. The volatiles were removed in vacuo, and the crude material was partitioned between ethyl acetate and Na2CO3(sat), The organic layer was washed further with Na2CO3(sat) (3x), with NaCl(sat), dried over MgSO4, filtered and concentrated yielding 1-(5-amino-2-chloropyridin-4-yl)ethanone (87%).


Patent reference: WO2010026121 (Novartis)

Amine synthesis (via nitro reduction):


To a solution of 3-nitro-4-(piperidin-l-yl)pyridine (1.0 equiv.) in ethanol, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 15 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding 4-(piperidin-l-yl)pyridin-3-amine (93%) as an oil.


Patent reference: WO2010026122 (Novartis)

Amine synthesis (via nitro reduction):


To dimethyl 3-nitro-2,5-thiophenedicarboxylate (25 g, 102 mmol) was added 500mL of AcOHZn dust (40g, 612mmol) was then added portionwise (the reaction generated heat). The mixture was stirred at RT for 1 h. After TLC (25% EtOAc in hexanes) showed the starting material was consumed completely, the mixture was filtered and washed with AcOH. The filtrate was combined and concentrated. The crude product was obtained as yellow solid (17.3g, 79%).


Patent reference: WO2010022308 (GSK)

Amine synthesis (via nitro reduction): 


(8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-nitro-phenyl)-amine (4.2 g) and SnCl(5eq.) were mixed together in ethanol (50 mL). The reaction mixture was stirred at 80°C for 4 hours. The resulting solution was filtered and the mother liquor was basified with NaOH IN and extracted with EtOAc. The organic layer was dried and evaporated to afford 800 mg of a first batch. The filtrated green solid was taken up in NaOH IN and extracted with EtOAc. The organic layer was dried over MgSOand evaporated to afford 2.8 g of the reduced compound with a total yield of 65%. The compound was used in the next step without further purification.


Patent reference: WO2010010184 (Galapagos)

Amine synthesis (via nitro reduction):


To a solution of the above described (R)-indan-l-yl-(6-nitro-4H-benzo[d][l,3]oxazin-2-yl)-amine (3.44 g, 11.1 mmol; ηPLC 1.954 min) in tetrahydrofuran (85 mL) at 23°C were added three Pasteur pipettes of Raney-Nickel (ready to use 10% suspension in water) and the mixture was vigourously stirred under an atmospheric pressure of hydrogen for 23 h. The catalyst was filtered off, washed with tetrahydrofuran, the solvent was removed in vacuum to give the title compound as a light yellow foam (3.19 g, 98%). 


Patent reference: WO2010026110 (Roche)














Amine synthesis (Gabriel reaction): 


Hydrazine hydrate (0.947ml, 19.5mnnol) was added to a suspension of biphenyl-2-yl-carbamic acid 1-(2- {4-[2-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-ethyl]-phenyl}-ethyl)-piperidin-4-yl ester (5.6g, 9.76mnnol) in ethanol (120ml) and the mixture heated to 90 C for 3 hours. The mixture was cooled to room temperature, the solid was collected by filtration and the filtrate concentrated in vacuo. The resulting residue was triturated with dichloromethane (50ml) and the insoluble material discarded. The solvent was removed in vacuo to give the title compound as a white solid, 3.34 g, 77%.


Patent reference: WO201007561 (Pfizer)

Gabriel synthesis

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