2-AMINO-5-FLUOROBENZOTHIAZOLE

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Compound 20 (270 mg, 1.59 mmol) was dissolved in CH2Cl2 (3 ml) at 0 ° C and bromine(279 mg, 1.74 mmol) in CH2Cl2 (1 mL) was slowly added at 10 °C or lower for 30 minutes, and the mixture was refluxed for 3 hours. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was distilled under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane: 1: 1), dried over anhydrous magnesium sulfate, & Lt; / RTI & gt; As a result, compound No. 21 (183 mg, yield 68percent) was obtained.To a stirred solution of methanesulfonic acid (45.4 mL) in acetic acid (13.3 mL) was added 1-(3-fluorophenyl)thiourea (Example 182A, 7.0 g, 41.2 mmol) portionwise in keeping the temperature below 30 °C. The resulting mixture was then cooled to 5-10 °C and a freshly prepared solution of N-bromosuccinimide (7.0 g, 39.14 mmol) in methanesulfonic acid (15 mL, 231 mmol) was added at 5-10 °C over 20 min. The reaction was stirred at this temperature for 30 min., then warmed to 50 °C and stirred for another 60 min. and finally cooled to RT. The mixture was added to 21percent aq. NaOH (84 g in 400 mL water) prechilled at 5 °C and the temperature was kept below 30 °C during the addition. The solid was isolated by filtration and washed with water until the pH of the washings was in the range of 6 to 8 (~1L). The title material (3.3 g, 19.6 mmol) was obtained as an off-white solid. LCMS: Anal. Calcd. for CA solution of bromine (29.08 g, 182 mmol) in CHGeneral procedure: Carboxylic acid 3 (0.2 mmol, 1 equiv.) and HATU (0.2 mmol, 1 equiv.) were dissolved in 1 mL DCE in a one dram vial charged with a stir bar. DIPEA (0.1 mL, 0.6 mmol, 3 equiv.) was added and the resulting solution was stirred at RT for 10 minutes. Amine 2 (0.2 mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 C and stirred overnight. Upon completion the reaction mixture was condensed and loaded onto a 60g C-18 cartridge and purified over a gradient of 5-95% ACN/H2O. The fractions containing product were identified by LC-MS and condensed under vacuum to give the final product 4. The final product was characterized by NMR.General procedure: The substituted aniline (1eq.) and ammonium thiocyanate (2eq.) in 150mL glacial acetic acid were cooled in an ice bath and stirred mechanically. To the sulution, bromine (2eq.) in 25ml glacial acetic acid was added dropwise at such arate to keep the temperature below 10oC throughout the addition. Stirring was continued for additional 30 min after the bromine addition. The precipitate was collected and recrystallization from ethanol to give 2-aminobenzthiazoles. Then, the substituted 2-aminobenzthiazoles (1eq) in ethylene glycol were added hydrazine hydrate (2eq.) and hydrazine dihydrochloride (2eq). The mixture was heated at 140 oC for 2h. After cooling, the precipitate was filtered to give used directly for next step without further purification. Then, the hydrazino compound was added to thionyl chloride (1eq.) for 2h at 50 oC. After evaporated under reduced pressure, the residue was taken up in ethyl acetate and washed with 1 M NaHCO3 and brine each for twice. The organic layer was dried and evaporated to give the crude final product. The crude product was purified by silica gel column chromatography using PE-EA as an eluent.General procedure: To a solution of the commercially available aniline (1.0 eq) in acetic acid (0.5 M), was added ammonium thiocyanate (5.0 eq) at rt. After 90 min, the thick suspension was cooled to 0C, and bromine (1.1 eq) in acetic acid (1.0 M) was added. After 1 h, the reaction was allowed to warm to rt. After a subsequent 1 h, the mixture wasconcentrated to remove acetic acid. A small amount of water was added, then the mixture was adjusted to pH 12 with concentrated ammonium hydroxide. The resulting mixture was extracted with EtOAc (x3) and the combined organics were washed withNaHC03(Sat), brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography and/or recrystallization from EtOAc/Hex to yield the appropriate 2-aminobenzothiazole.

Molecular Weight:168.19
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Exact Mass:168.01574750
Monoisotopic Mass:168.01574750
Topological Polar Surface Area:67.2
Heavy Atom Count:11
Complexity:155
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes