TOLUENE-4-SULFONIC ACID OXETAN-3-YL ESTER

Scheme 613 Step 1 14 Step 2 15Step 1To a solution of 1.00 g (13.5 mmol) of compound 13 and 7.6 mL (54.0 mmol) of triethylamine in 27 mL of methylene chloride was added 5.15 g (27.0 mmol) of p- toluenesulfonyl chloride. The reaction mixture was stirred at room temperature overnight. After this time, the reaction was quenched with saturated 150 mL of aqueous sodium bicarbonate and extracted with three 50 mL portions of methylene chloride. The combined extracts were concentrated and the resulting residue was purified by column chromatography (silica, 0-25percent EtOAc/hexanes) to give 1.22 g (94percent) of 14 as white solid: NMR (CDCI3 500 MHz) δ 7.78 (d, J= 8.5 Hz, 2H), 7.36 (d, J= 9.0 Hz, 2H), 5.29 (m, 1H), 4.69 (m, 4H), 2.46 (s, 3H).At 0° C., aqueous NaOH solution (2 N, 15 mL) was added dropwise to a solution of oxetan-3-ol (1.48 g, 20 mmol) and p-toluene sulfonyl chloride (4.18 g, 22 mmol) in water (50 mL). After stirred for 3 hours, the mixture was treated with water (100 mL), extracted with dichloromethane (100 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=10:1) to give compound 39-c (3.9 g, yield: 85percent). LC-MS (ESI): m/z=229 [M+H];To a 50 mL two-neck flask were added oxetan-3-ol (1.00 g, 13.0 mmol) and anhydrous pyridine (25 mL), then paratoluensulfonyl chloride (3.10 g, 16.0 mmol) was added to the mixture under nitrogen protection. To a well-stirred 50° C. solution of Part D compound (7 g, 94 mmol) and p-TsCl (12.8 g, 67.1 mmol) in water (15 mL) was added dropwise a solution of NaOH (2.69 g, 67.1 mmol) in water (15 mL). The reaction was heated for 1 h at 50° C., then cooled to RT and toluene (10 mL) was added. The aqueous layer was extracted with toluene (5 mL.x.2). The combined organic extracts were washed with conc NHPreparation of toluene-4-sulfonic acid oxetan-3-yl ester; To a solution of oxetan-3-ol (1.0 g, 13.0 mmol) in anhydrous pyridine (25 ml_) at room temperature was added 4-toluene sulfonyl chloride (3.09 g, 16.2 mmol). After stirring the reaction mixture for 18 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography over silica gel eluting with a gradient of 0 to 30percent ethyl acetate in heptane to afford 1.9 g (62percent yield) of the desired product as a white solid.Step 1: To a stirred mixture of oxetan-3-ol (0.85 g, 11.5 mmol) in DCM (38 mL) were added TEA (3.3 mL, 23mmol) and 4-methylbenzene-1-sulfonyl chloride (2.7 g, 13.8 mmol). The reaction mixture was stirred at rt for 15 h. Themixture was partitioned between water and DCM. The organic layer was separated, dried over Na2SO4, filtered, andconcentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradientof 30percent DCM in petroleum ether to 100percent DCM to afford oxetan-3-yl 4-methylbenzenesulfonate (1.3 g, 50percent) as a whitesolid. 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 5.30 (m, 1H), 4.66 - 4.74 (m, 4H), 2.46 (s, 3H); LCMS (ESI) m/z 229 (M+H)+Using 3-bromo-4-fluorothiophenol (1 g, 5 mmol) in Example 33 as a raw material, under a nitrogen atmosphere, this was mixed with cyclobutyl bromide (810 mg, 6 mmol) and potassium carbonate (1.36 g, 10 mmol). ) Reaction at 60 degrees in 10 ml of dimethyl sulfoxide overnight. The system was diluted with water, extracted with ethyl acetate, the organic phase was washed with water, washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the compound (3-bromo-4 -Fluorophenyl) (cyclobutyl) sulfane (1.2 g, 92%).[1260]1H NMR (400MHz, d-CDCl 3): delta 7.47 (dd, J = 2.4, 6.4 Hz, 1H), 7.22-7.18 (m, 1H), 7.07 (t, J = 8.4 Hz, 1H), 3.35- 3.47 (m, 1H), 2.01-1.65 (m, 6H).; Taking 3-bromo-4-fluorothiophenol as a raw material, referring to the first step of Example 74, replacing cyclobutyl bromide with m-butyl-3-yl 4-methylbenzenesulfonate to obtain compound 3-( (3-Bromo-4-fluorophenyl)thio)oxabutyl ring (90%).[1358]1H NMR (400MHz, d-CDCl3): delta 7.47 (dd, J = 2.4, 6.4 Hz, 1H), 7.22 - 7.18 (m, 1H), 7.07 (t, J = 8.4 Hz, 1H), 5.07 (t , J = 7.6 Hz, 1H), 4.62 (t, J = 6.4 Hz, 2H), 4.44 - 4.37 (m, 1H).To a suspension of the product of Example 1H (0.100 g, 0.249 mmol) and cesium carbonate (0.324 g, 0.994 mmol) in dimethylformamide (1 mL) was added oxetan-3-yl-4- methylbenzenesulfonate (0.170 g, 0.746 mmol) and the resulting mixture was heated to 60 C. After 2 hours, the reaction mixture was cooled to ambient temperature, quenched with 1 M hydrochloric acid (2 mL) and diluted with ethyl acetate (2 mL). The aqueous layer was extracted with ethyl acetate (2 x 2 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (4 x 1 mL) followed by a 4:1 mixture of brine and 1 M hydrochloric acid, dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-l-fluoro-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}- 1 /', 2, 5-thiadiazolidinc- 1, 1, 3-trione , which was used without purification for the next reaction. MS (EST) m/z 457 [M-H]-.

Molecular Weight:228.27
XLogP3:1.3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:228.04563003
Monoisotopic Mass:228.04563003
Topological Polar Surface Area:61
Heavy Atom Count:15
Complexity:294
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes