2-Chloro-5-thiazolecarboxylic acid

Step 1 : A resealable reaction vial was charged with 5-chloropyrazine-2- carboxylic acid (200 mg, 1.26 mmol) and thionyl chloride (2.29 mL, 31.5 mmol). The resulting mixture was stirred at 80C for 3 hours. After cooling to RT, the volatiles were removed under reduced pressure and the residue taken up in 10 mL of toluene, which was also removed under reduced pressure (3x) to remove any trace thionyl chloride. The resulting solid was suspended in DCM (2 mL), cooled to 0-5C and treated with triethylamine (701 pL, 5.04 mmol) (become a light brown solution) and a solution of 1, 2, 3, 4- tetrahydro-l, 5-naphthyridine (169 mg, 1.26 mmol) in DCM (1 mL). The reaction mixture was allowed to come to RT slowly and stirred overnight at RT. To the mixture was added 2 mL of sat'd NaHC03 and the aqueous layer extracted with DCM (2 x 5 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to give (2-chlorothiazol-5-yl)(3, 4- dihydro- 1 , 5-naphthyridin- 1 (2//)-yl)methanone as a brown oil. This material was used as is in subsequent reactions.To a stirred solution of thiazole compound X (20.0 g, 1 19 mmol) in aq. H2SO4 (70%) (453.5 g) was added aq. HNO3 (65 %, 73.2 g) dropwise at 1 10 C. After stirring 12 hours at 1 10C the starting material was consumed. The reaction mixture was poured into water and extracted with ethyl acetate, dried over anhydrous Na2S04 and concentrated to give 14.8 g of crude product. The crude compound was dissolved in DCM-methanol, adsorbed on silica-gel and then purified using combiflash chromatography (10% methanol / 90% dichloromethane). 14.2 g (86.8 mmol) of product XIV were obtained (yield 72.9%).-NMR (400 MHz, DMSO), delta (ppm): 8.22 (s, 1 H), 13.9 (broad s, 1 H).3C-NMR (100 MHz, DMSO), delta (ppm): 133.00, 146.32, 155.13, 160.87.LC-MS: iR 1.05 min; m/z = 164/166 [M+H]+. Method CTo a stirred solution of thiazole compound XVII (1 g, 6.78 mmole) in aq. H2SO4 (70%) (26 g) was added aq. HNO3 (65 %, 4 g) dropwise at 1 10 C. After stirring 1 hour at 1 10C the starting material was consumed. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 20 ml). The combined organic phases were dried over anhydrous Na2S04, and concentrated. The was purified by combiflash chromatography (70% ethyl acetate; 30%hexane) to give 870 mg (5.32 mmol) of the product XIV (yield 78%).-NMR (400 MHz, DMSO), delta (ppm): 8.23 (s, 1 H), 13.9 (broad s, 1 H).To a stirred solution of thiazole compound XVI (1 g, 6.68 mmole) in aq. H2SO4 (70%) (26 g) was added aq. HNO3 (65 %, 4 g) dropwise at 1 10 C. After stirring 1 hour at 1 10C the starting material was consumed. The reaction mixture was poured into the crust ice and extracted with ethyl acetate (3 x 20 ml). The combined organic phases were dried over anhydrous Na2S04, and concentrated. The was purified by column chromatography (70% ethyl acetate; 30%hexane) 810 mg (4.95 mmol) of the product XIV was obtained as a white solid (yield 74%).-NMR (400 MHz, DMSO), delta (ppm): 8.24 (s, 1 H), 13.8 (broad s, 1 H).To a solution of A mixture of 2-Ch[oro-1, 3-thiazo[e-4-carboxy[ic acid [CAS RN: 5198-87-8] (430 mg, 2.55 mmo[, 1.0 eq) in 17 mL ethyl. acetate was treated with T3P solution [50 % in ethyl acetate] (3.80 mL, 6.37 mmol, 2.5 eq) and with acetohydrazide [CASRN: 1068-57-1] (189 mg, 2.55 mmol, 1.0 eq). The resulting solution was stirred at 80 C overnight. The reaction mixture was hydrolysed with ice-water and extracted with ethyl acetate (3x). The combined organic phases were washedwith brine. The phases were separated by the use of a Whatman filter. The volatile components of the resulting organic phase were removed in vacuo and the crude material contained 350 mg (50% yield of theory) of the title compound in 80% purity (UPLC area-%), which were used without further purification.UPLC-MS (Method 2): R = 0.90 mm; MS (EI0): m/z = 202 [M+H].1H-NMR (400 MHz, DMSO-d6): oe [ppm] = 2.41 (5, 3H), 8.71 (5, 1H).2-Chloro-1, 3-thiazole-5-carboxylic acid [CAS RN: 101012-12-8] (500 mg, 2.96mmol, 1.0 eq) in 20 mL ethyl acetate was treated with T3P solution [50 % in ethyl acetate] (4.41 mL, 7.41 mmol, 2.5 eq) and with acetohydrazide [CAS-RN:1068-57-1] (219 mg, 2.96 mmol, 1.0 eq). The resulting solution was stirred for6.5 h at 80 C. The reaction mixture was hydrolysed and extracted with ethyl acetate (3x). The combined organic phases were washed with brine. After phase separation via a Whatman-filter the volatile components were removed. The material observed this way (230 mg, 26% yield of theory, -70 % purity based on UPLC area-%) was used in the following step without further purification.UPLC-MS (Method 1): R = 0.80 mm; MS (EI0): m/z = 202 [M+H].2-Ch[oro-1, 3-thiazo[e-5-carboxy[ic acid [CAS RN: 101012-12-8] (500 mg, 2.96mmo[, 1.0 eq) in 20 mL ethyl. acetate was treated with T3P solution [50 % in ethyl acetate] (4.41 mL, 7.41 mmol, 2.5 eq) and with N-hydroxyethanimidamide [CAS-RN: 22059-22-9] (219 mg, 2.96 mmol, 1.0 eq). The resulting solution was stirred for 2 h at 80 C. The reaction mixture was hydrolysed and extracted with ethyl acetate (3x). The combined organic phases were washed with brine. Afterphase separation via a Whatman-filter the volatile components were removed. The material observed this way 310 mg (52% yield of theory) were used in the following step without further purification.UPLC-MS (Method 1): R = 1 .01 mm; MS (EI0): m/z = 202 [M+H]. 1H-NMR (400 MHz, DMSO-d6): oe [ppm] = 2.40 (5, 3H), 8.59 (5, 1H).

Molecular Weight:163.58
XLogP3:1.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:162.9494772
Monoisotopic Mass:162.9494772
Topological Polar Surface Area:78.4
Heavy Atom Count:9
Complexity:132
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes