1-(2,4-dihydroxy-5-isopropylphenylcarbonothioyl)-4-(1-Methyl-1H-indol-5-yl)seMicarbazide synthesis

Yield:1160618-89-2 59%

Reaction Conditions:

Stage #1: 2,4-dihydroxy-5-isopropylbenzenecarbodithioic acidwith sodium hydrogencarbonate;chloroacetic acid in N,N-dimethyl-formamide at 0 - 20; for 1.05 h;
Stage #2: N-(1-methyl-1H-indol-5-yl)hydrazinecarboxamide in N,N-dimethyl-formamide at 20 - 80; for 1.05 h;Product distribution / selectivity;

Steps:

2

STEP-2: To a stirred suspension of 5Og (220mmols) of 2 and 55.5g (660mmols) of NaHCO₃ in 65OmL of anhydrous DMF was added 21g (220mmols) of chloroacetic acid in 3 portions (for 3mins.) under ice-bath and stirred for Ih at room temperature under N₂ atmosphere. To the resultant mixture was added 45g (220mmols) of aminourea 3 in 3 portions (3mins) at room temperature and stirred at 80 ⁰C for Ih under N₂ atmosphere. Cooled the mixture and poured into 100OmL of ice water with stirring and acidified with 2N HCl till pH 3. The sticky precipitate thus obtained was processed under ultrasound for 25 min. and the precipitate thus obtained was filtered. The solid was dissolved in 1000ml EtOAc and washed with brine 3 times and dried over Na₂SO₄ and concentrated. The crude product was then recrystallized using hexane:ethylacetate mixture to obtain 42g of pale yellow solid. The mother liquor was concentrated and the remaining product was purified by column chromatography to give another 1Og of desired product 4 (yield 59%).

References:

WO2009/75890,2009,A2 Location in patent:Page/Page column 36-37