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Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)propan-2-yl)-1H-indole-3-carboxylate hydrochloride

IP.com Disclosure Number: IPCOM000250124D
Publication Date: 2017-Jun-02
Document File: 2 page(s) / 208K

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Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)propan-2-yl)-

1H-indole-3-carboxylate hydrochloride

A mixture of tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate

tert-butylmethylether solvate (23.8 g), 4-(piperidin-4-yl)morpholine (7.61 g), THF (100 ml),

NaHMDS 40% in THF (97 ml) and Allyl[1,3-bis(2,6-diisopropylphenyl)imidazol-2-

ylidene]chloropalladium (II) (2.67 g) was heated at 30ºC for 1 h. The mixture was partitioned

between THF and 20% aqueous solution of ammonium chloride (100 ml) and the organic layer

was washed with brine (86 ml). N-acetyl cysteine (0.63 g) and water (1.4 ml) were added to the

organic layer and then heated up to 40ºC for 1 h. The insoluble matters were filtered and the

filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetone

(114 ml) and a solution of pyridinium chloride (5.3 g) in acetone (9 ml) and ethanol (9 ml) was

added. The suspension was cooled down to 10ºC and the solid filtered and dried. The title

compound was obtained as an acetone solvate (22 g of a white solid; Yield 91%, Acetone 5.2%

w/w by 1H-NMR, HPLC purity 95% area).

1H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 11.02 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.94 (d, J

= 1.4 Hz, 1H), 7.46 (dd, J = 8.3, 1.5 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.87 (dd, J = 8.0, 1.9 Hz,

1H), 6.79 (d, J = 1.9 Hz, 1H), 3.95 (d, J = 12.2 Hz, 2H), 3.84 (t, J = 12.0 Hz , 2H), 3.41 (d, J =

12.3 Hz, 2H), 3....