Ethyl 2-methylthiazole-5-carboxylate

2- [2-(5-Methyl-3-phenyl-isoxazol-4-yl)-ethyl] -thiazole-5-carboxylic acid isopropyl- amidea) 2-Methyl-thiazole-5-carboxylic acid ethyl esterTo a stirred solution of ethyl 2-chloro-2-formyl acetate (5.0 g, 33 mmol) in benzene (50 mL) at reflux under argon was added thioamide (2.5 g, 33 mmol). After 4 h the reaction mixture was cooled, diluted with water (50 mL) and neutralized to pH 7 with a saturated solution of sodium hydro gencarbonate. The reaction mixture was extracted with ethyl acetate then the combined extracts were washed with water and brine, then dried, filtered and concentrated in vacuo. Purification by chromatography (silica, 0 to 50percent ethyl acetate in heptane) gave the title compound (2.68 g, 47percent) as a yellow liquid. MS: m/e = 172.0 [M+H]To a stirred solution of ethyl 2-chloro-3-oxopropanoate 61 (26 g, 173.33 mmol) in ethanol (200 mL) under argon atmosphere were added ethanethioamide 62 (10 g, 133.33 mmol), dry magnesium sulfate (10 g) at RT and heated to reflux for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with EtOAc (500 mL). The combined organic extracts were washed with saturated sodium bicarbonatesolution (2 x 200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through flash column chromatography using6percent EtOAc/ hexanes to afford compound 63 (8 g, 35percent) as brown syrup. TLC: 25percent EtOAc/hexanes (Rf: 0.7); ‘H-NMR (DMSO-d6, 500 MHz): ö 8.24 (s, 1H), 4.27 (q, J = 7.2 Hz, 2H), 2.70 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).To a stirring solution of compound 96 (110 g, 733.33 mmol) in ethanol (1.2 L) under Ar atmosphere were added ethanethioamide (54.99 g, 733.33 mmol) and anhydrous magnesium sulfate (55 mg, 454.66 mmol) at room temperature, followed by heating to 80 To a stirred suspension of lithium aluminium hydride (3.1 g, 93.56 mmol) in dry THF (10 mL) under inert atmosphere was added compound 63 (8 g, 46.78 mmol) in dry THF (50 mL) dropwise for 15 mm at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with15percent aqueous sodium hydroxide solution (10 mL), filtered through celite and washed withEtOAc (3 x 100 mL). The filtrate was dried over sodium sulfate, filtered and concentrated invacuo to afford compound 64 (5 g, 83percent) as an off-white solid. TLC: 50percent EtOAc/ hexanes (Rf:0.3). LC-MS: 97.32percent; 130.22 (M+1) (column; X-select CSH C18, (50 x 3.0 mm, 2.5 jim); RT0.65 mm. 2.5 mM Aq. NH4OAc: ACN: 0.8 mL/min).B. 5-(Hydroxymethyl)-2-methylthiazole Using the procedure of Example 1P, but replacing ethyl thiazole-5-carboxylate with crude Step 1: Intermediate 15-a To a solution of To a solution of intermediate 7-c (22.2 g, 130.0 mmol) in THF (430 ml) cooled to 0°C was added a 1.0 M solution LiAIH4 in THF (91.0 ml, 91.0 mmol). The solution was slowly warmed to room temperature and stirred for 2 hours. Water (3.5 ml) was slowly added, followed by 3.5 ml 15percent NaOH (3.5 ml) and water (10.5 ml) and the mixture was stirred for 1 hour. The reaction was filtered through celite and the filtrate collected. Volatiles were removed in vacuo to provide intermediate 7-d as a yellow oil.Step 3: Intermediate 5-d; To a solution of intermediate 5-c (22.2 g, 130.0 mmol) in THF (430 ml) cooled to 0°C was added a 1.0 M solution LiAIH4 in THF (91.0 ml, 91.0 mmol) and the solution was slowly warmed to room temperature and stirred for 2 hours. Water (3.5 ml) was slowly added, followed by 3.5 ml lSpercent NaOH (3.5 ml) and water (10.5 ml) and the mixture was stirred for 1 hour. The reaction was filtered over celite and volatiles were removed under reduced pressure to provide intermediate 5-d as yellow oil.To a stirred solution of Step 4: Intermediate 29-d [0172] To a solution of intermediate 29-c (22.2 g, 130.0 mmol) in THF (430 ml) cooled to 0° C. was added a 1.0 M solution of LiAlH4 in THF (91.0 ml, 91.0 mmol) and the solution was slowly warmed to room temperature and stirred for 2 hours. Water (3.5 ml) was slowly added, followed by 3.5 ml 15percent NaOH (3.5 ml) and water (10.5 ml) and the mixture was stirred for 1 hour. The reaction was filtered over celite and volatiles were removed in vacuo to provide intermediate 29-d as yellow oil.Step 1: Synthesis of 2-methyl-5-hydroxymethylthiazole: At room temperature, lithium aluminum hydride (8.88g, 234mmol) was dispersed in anhydrous tetrahydrofuran (THF, 100mL). The resulting mixture was cooled to 0-5°C in an ice-water bath. To the cooled mixture was dropwise added a solution of

Molecular Weight:171.22
XLogP3:1.9
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:171.03539970
Monoisotopic Mass:171.03539970
Topological Polar Surface Area:67.4
Heavy Atom Count:11
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes