5-AMINO-1,3,4-THIADIAZOLE-2-CARBOXYLIC ACID ETHYL ESTER

Light yellow solid

Step 1 ethyl 5-amino-l, 3, 4-thiadiazole-2-carboxylate To a solution of hydrazinecarbothioamide (10 g, 54.8 mmol) in POCIStep 1 ethyl 5-amino-l, 3, 4-thiadiazole-2-carboxylate To a solution of hydrazinecarbothioamide (10 g, 54.8 mmol) in POCIStep 1 ethyl 5-amino-l, 3, 4-thiadiazole-2-carboxylate To a solution of hydrazinecarbothioamide (10 g, 54.8 mmol) in POCI3 (25 mL) was added ethyl 2-chloro-2-oxacetate (6.1 mL, 54.8 mmol). The reaction was heated to 70°C and stirred for 5 h. POCI3 was completely removed from the reaction mixture under vacuum. The residue was diluted with ice cold water (150 mL) and basified to pH 8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (200 mL). The organic layer was separated and dried over a2S04, and the solvent was evaporated to obtain crude product. The crude product was purified by flash chromatography (silica gel 100-200?, 2percent methanol and dichloromethane) to afford ethyl 5-amino-l, 3, 4-thiadiazole-2-carboxylate as a yellow solid (3.1 g, 24percent yield). ' NMR (400 MHz, DMSO-d6): ' 7.94 (s, 2H), 4.29 (q, 2H), 1.27 (t, 3H); LC- MS m/z calcd for [M+H]+ 174.03, found 174.1.EXAMPLE 67-( { [5-( 1 -Ethyl- 1 -hvdroxypropyl)- 1.3.4-thiadiazol-2-yl]amino 1 methyl)-4-phenylquinoline-2-carbonitrile Step 1: Ethyl 5-amino-1.3.4-thiadiazole-2-carboxylateN-NQ S NH, EtOA mixture of ethyl chloro(oxo)acetate (0.5 g, 3.68 mmol) and hydrazinecarbothioamide (0.335 g, 3.68 mmol) was heated to 160° C for 5 h. The solvent was removed under reduce pressure and the crude purified on silica gel (eluting with 3percent methanol in DCM) to give the title product. 1H NMR (400 MHz, acetone-ds): delta 7.28 (bs, IH), 9.67 (bs, IH), 4.39 (q, 2H), 1.38 (t, 3H).General procedure: A 10-ml Schlenk tube equipped with a stir-bar was charged with compound 1 (0.2 mmol), compound 4 (0.3 mmol), Pd(OAc)2 (0.02 mmol), Xantphos (0.04 mmol), NaOtBu (0.3 mmol), anhydrous DMF (2 mL).The reaction tube was purged with argon. The Schlenk tube was placed in an oil-bath at 110 oC for 36 hours and then cooled to room temperature. The reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure and the crude residue purified by flash chromatography on silica gel (n-hexane:ethyl acetate = 1:1). The purified material was dried in vacuo to afford the corresponding product 5a-g.General procedure: A 10-ml Schlenk tube equipped with a stir-bar was charged with compound 1 (0.2 mmol), compound 4 (0.3 mmol), Pd(OAc)2 (0.02 mmol), Xantphos (0.04 mmol), NaOtBu (0.3 mmol), anhydrous DMF (2 mL).The reaction tube was purged with argon. The Schlenk tube was placed in an oil-bath at 110 oC for 36 hours and then cooled to room temperature. The reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure and the crude residue purified by flash chromatography on silica gel (n-hexane:ethyl acetate = 1:1). The purified material was dried in vacuo to afford the corresponding product 5a-g.To a solution of 5-amino-1 , 3, 4-thiadiazole-2-carboxylic acid ethyl ester (1.0 eq., 8.8 g, 50 mmol) in DMF (105 ml_), at 100°C, was added (slow dropwise) a solution of 3-bromo- 1 , 1-difluoro-propan-2-one (1.05 equiv., 9.0 g, 52 mmol) in DMF (5 ml_). The reaction mixture was heated at 100°C during 2 h. A saturated aqueous solution of NaHCC>3 was added and the organic layer was extracted with ethyl acetate (three times). The combined organic layers were washed with water (five times), dried over MgSCU, filtered and evaporated to dryness to give a brown solid (9.0 g). The crude was purified by flash chromatography Biotage Isolera Four (100 g KP-SNAP silica gel column in a gradient of 0percent to 10percent methanol in dichloromethane over 14 CV) and the pure fractions were evaporated under high vacuum to give ethyl 6-(difluoromethyl)imidazo[2, 1- b][1 , 3, 4]thiadiazole-2-carboxylate XIV (4.48 g, 18.1 mmol) as a beige solid. Yield: 36percent LC/MS: [M+H]+ = 248.2A suspension of 5-amino-[1 , 3, 4]thiadiazole-2-carboxylic acid ethyl ester (0.30 g, 1 .75 mmol), TFA (0.27 mL, 3.50 mmol), 4-chlorobenzaldehyde (0.27 g, 1 .93 mmol) and sodium triacetoxyborohydride (0.45 g, 2.10 mmol) in isopropanol (3.5 mL) was stirred at room temperature for 2 hours and then at 70°C for 1 6 hours. After this time the reaction mixture wasconcentrated under reduced pressure and purified by flash column chromatography, eluting with EtOAc/cyclohexane (0-50percent) to afford the title compound (44 mg). LCMS method: Method 3, RT: 4.81 mm, Ml: 298 [M+1] 1H NMR (500 MHz, CDCI3) O 7.32 (d, 2H), 7.29 (d, 2H), 4.53 (5, 2H), 4.41 (q, 2H), 1 .39 (t, 3H)0239-1 A solution of

Molecular Weight:173.20
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:3
Exact Mass:173.02589765
Monoisotopic Mass:173.02589765
Topological Polar Surface Area:106
Heavy Atom Count:11
Complexity:155
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes