5-AMINO-2-METHYL-THIAZOLE-4-CARBOXYLIC ACID ETHYL ESTER

Add acetoamidocyanoacetate [(1000G, ] 5. 88 mol) to a 22L 3-necked RB flask equipped with reflux condenser, thermometer, mechanical stirrer then add toluene [(12L).] Add to this suspension at RT Lawesson's reagent [(1187G, ] 2. 93mol). Stir the resulting yellow slurry at [70°C] for 16 h, cool to RT. Pour the top yellow solution away from the gummy material on the bottom of the flask into a separation funnel. Add IN [HC1] solution (2. 5L) and TBEA (2. [5L)] and stir the mixture. [AFTERL 5] min. , combine the bi-phase solution was into the toluene, solution in the funnel. Gummy material maybe left in the flask. Repeat the above procedure again. Separate the aqueous and wash the combine organic solution with IN [HC1] (2 x 2. [5L).] Separate the organic layer and combine the aqueous and basify with 2N KOH solution. Add ethyl acetate (3 x 4L) and extract the product. Combine the organic layer, dry over anhydrous sodium sulfate, and evaporate to give 552 g as a pale yellow solid. Dissolve the remaining gummy in methanol [(1L)] and evaporate to dryness. Add MTBE (2. 5L) and IN [HC1] (4L) and stir the mixture. After 15 min., separate the organic layer and basify the aqueous with 2N KOH solution Extract the product with ethyl acetate (2 x 2L). Combine the organic layers and dry over anhydrous sodium sulfate and evaporate to give 165 g as a pale yellow solid. (Total: 717 g, 65percent). Mass spectrum (m/e): 187 (M+1) [;APOS;HNMR (300MHZ, DMSO-D6, PPM)] : 8 [1.] [21] (t, 3H), 2.38 (s, 3H), 4.21 (q, 2H), 7.21 (bs, [2H). L3CNMR] (75MHz, DMSO, ppm): [8] 15.1, 19.2, 59.8, 119.3, 145.6, 161.7, 164.1. Formula: [C7H1ON202S.To a solution of acetylamino-cyano-acetic acid ethyl ester (27.2 g, 0.160 mol) in anhydrous toluene (300 mL) was added Lawesson's reagent (32.0 g, 0.079 mol) and the resulting mixture heated at reflux for 18 h. The resulting yellow suspension was partitioned between an aqueous solution of HCl (1 M) and tert-butyl methyl ether. The layers were separated and the organic layer extracted with an aqueous solution of HCl (1 M). The combined aqueous layers was basified to pH 10 with an aqueous solution of NaOH (2 M), then extracted with EtOAc. The organic layer was isolated, dried (NaEXAMPLE 101; 2-Methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (3-chloro-phenyl)-amide; The title compound was prepared as illustrated in schemes 2 and 3. A) A suspension of 2-acetylamino-cyanoacetic acid ethyl ester (1.70 g, 10.00 mmol) and 2, 4-bis(4-methoxyphenyl)-1, 3, 2, 4-dithiadiphosphetane 2, 4-disulfide (Lawesson's reagent) (2.02 g, 5.00 mmol) in toluene (25.00 ml) was heated under argon to 110° C. and stirred for 22 h. The solvent was then evaporated, and the residue purified by flash chromatography (heptane/ethyl acetate 1:1) to yield 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.94 g, 50.5percent) as a yellow solidExample 252; 2-Methvl-5-ureido-thiazole-4-carboxylic acid azepan-3-ylamide; ethyl 5-amino-2-methyl-1, 3-thiazole-4-carboxylate. ; To a stirred solution of ethyl N-acetyl-3- nitriloalaninate (1.0 eq) in dry toluene (40 mL) was added Lawesson's reagent (0.5 eq) and the resulting mixture was heated to reflux for 24 h. The mixture was diluted with EtOAc and the organic extracts were washed with H20, brine and dried (MgS04). Evaporation of the solvents gave a brown oil. Purification by Gilson (5percent-95percent MeCN-H2O) afforded the title compound as yellow solid (50percent). LC/MS (ES, M+H=187).Ethyl 2-amino-2-cyanoacetate, p-toluenesulfonate salt (1 g, 3.34 mmol) was free- based by dissolving it in lOmL saturated aqueous sodium bicarbonate, then extracting with dichloromethane (3 x 10 ml). The combined dichloromethane layers were dried overs sodium sulfate, filtered and concentrated to 25mL volume. To this solution was added N, N-dimethylaminopyridine (0.04 1 g, 0.334 mmol), followed by acetic anhydride(0.347 mL, 3.67 mmol). After the stirring lh at room temperature, the reaction mixture was quenched with 5 ml of sat. aq. sodium bicarbonate, and 5 ml of water. The reaction mixture was extracted with DCM (3 x 25 ml). The combined DCM layers were dried over sodium sulfate, filtered and concentrated to afford the crude product, ethyl 2-acetamido- 2-cyanoacetate (0.51 g, 3.00 mmol, 90 percent yield) as a yellow solid. A portion of thismaterial (334mg, 1.963 mmol) was then dissolved in toluene (7mL). To this solution was added Lawesson’s reagent (397mg, 0.981 mmol) and the resulting mixture was stirred at 80°C overnight. After cooling to room temperature, the reaction mixture was evaporated onto Celite. The material was purified first by 24g silica gel column, eluting with 0-100percent EtOAc in hexanes, and then by a second 24g silica gel column purification, eluting with 0-10percent MeOH in DCM. Concentration of the pure fractions afforded ethyl 5-amino-2- methylthiazole-4-carboxylate (84a) (35 mg, 0.188 mmol, 10 percent yield) as a colorless oil.LC retention time 0.54 mm [Al. MS (E+) m/z: 187 (MHj.’H NMR (400MHz, CHLOROFORM-d) 6.03 - 5.76 (m, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.60 - 2.51 (m, 3H), 1.45 - 1.37 (m, 3H).

Molecular Weight:186.23
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:186.04629874
Monoisotopic Mass:186.04629874
Topological Polar Surface Area:93.4
Heavy Atom Count:12
Complexity:177
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes