3,6-Dioxabicyclo[3.1.0]hexane

clear yellow liquid

Step 1 : To the solution of 24a (5.04g, 0.072mol) in 15OmL of DCM was added 85percent mCPBA(18.86g, 0.093mol) at OExample 24 Preparation of 5-[5-Fluoro-2-oxo-1, 2-dihydro-indol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (4-hydroxy-tetrahydro-furan-3-yl)-amide Preparation of 4-Amino-tetrahydro-furan-3-ol Step 1: To the solution of 24a (5.04 g, 0.072 mol) in 150 mL of DCM was added 85percent mCPHA(18.86 g, 0.093mol) at 0° C. using ice-water bath. The mixture was stirred over weekend at r.t. and the precipitate was filtered off. The filtrated was washed successfully with saturated aqueous NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to give a mixture of white solid and yellow oil (5.24 g, 84.6percent).2, 4-Dihydrofuran (7) (5.3 mL, 71.3 mmol) was added to a 500 mL round bottom flask containing CHTo a solution of 2, 5-dihydrofuran SM 1 (5.0 g, 71 mmol) in DCM (100 mL) was added mCPBA (18.9 g, 109 mmol) at 0 °C, then the reaction mixture was stirred at reflux for 15 h. Quenched with water and extracted with EtOAc, dried and evaporated to give compound 1 (3.5 g, 57percent).The reaction was performed under a nitrogen atmosphere. Freshly activated magnesium turnings (3.0 g) were suspended in 250 ml dry tetrahydrofuran. Iodine (20 mg) was added and the reaction mixture was heated to reflux. 4-Bromo-2-ethoxy-1-methoxybenzene (compound I, 28.0 g) was dissolved in 60 ml dry tetrahydrofuran. About 20 ml of this solution were added within 15 mm under reflux. After start of the Grignard reaction (about 45 mm reflux) the remaining solution was added within 45 mm. The reac30 tion mixture was refluxed until nearly no magnesium was left over. The reaction was performed under a nitrogen atmosphere. The in step 2 prepared Grignard solution was cooled to RT, Cul (1.0 g) was added and the reaction mixture was stirred for 15 mm and subse35 quently cooled with an ice bath. A solution of In a vial charged with a stirring bar, 1-19 (300 mg, 1.209 mmol) was mixed with potassium carbonate (251 mg, 1.814 mmol) in 3, 6-dioxabicyclo[3. 1.0]hexane (2 mL, 1.209 mmol)/DMF (1 mL). The mixture was stirred at 100 °C for 1 hours. The reaction was diluted by adding 30 mL of EtOAc and 20 mL of water. After separation, aqueous layer was extracted with EtOAc (20 mL x3). Organic phases were combined and washed with brine, and concentrated. The crude product was purified by silica gel chromatography (24 g column , 0-100percent EtOAc/hexane gradient). Collecting the desired fractions and removing solvent gave trans-4-((2-bromo-5-iluorobenzo[d]thiazol-6-yl)oxy)tetrahydrofuran-3-ol (207 mg, 0.619 mmol, 51.2 percent yield) as a white solid. 19F NMR (376MHz, DMSO-d6) delta -133.27 (s, 1 F); 1H NMR (400MHz, DMSO-d6) 6 7.97 (d, i 5 Hz, 1 H), 7, 97 (d, ./ 8.0 Hz, 1 H), 5.53 id. ./ 4.0 Hz, 1H). 4.77 (d, ./ 4.0 Hz, 1 H), 4.30 (br s, 1 H), 4.07 (d, J = 4.2 Hz, 1 H), 3, 95 (d, ./ 4.6 Hz, 1 H), 3.62 (dd, J=9.5, 2, 0 Hz, 1 H); LC-MS: method H, RT 0 80 mm, MS (ESI) m/z: 334, 0 and 335.9 {M+H)+.To a solution of Step I: Synthesis oflnt-lb A solution of To a solution of 3, 6-dioxabicyclo[3.1 .0]hexane (11 .62mmol) in EtCH (39 mL), cooled to 0 °C, was addeddropwise hydrazine hydrate (55-60percent in water, 29.04 mmol). The reaction was stirred at RT for 10 mm and thenheated at 60 °C for 16 h. The reaction was concentrated under reduced pressure to give crude the titled compound (11.61 mmol). 1H NMR (400 MHz, DMSO-d6, ): 4.06-4.02 (m, 1H), 3.80-3.71 (m, 2H), 3.52-3.43 (m, 2H), 3.07-3.02 (m, 1H).(3S, 4R)-4-(dimethylamino)-tetrahydrofuran-3-ol At 50° C., Example 234. Synthesis of 3-fluoro-2-(4-(l-((3R, 4R)-4- hydroxytetrahydrofuran-3-yl)-lH-pyrazol-3-yl)-5-oxo-6, 7-dihydro-5H-pyrrolo[3, 4- b]pyridin-2-yl)benzonitrile, 1-234 Synthesis of compound 234.2. To a solution of 234.1 (5.0g, 25.77mmol, 1.0 eq) in THF (15mL) was added LDA (2M in THF ) (14mL, 28.33mmol, 1.1 eq) at -78°C. Reaction mixture was stirred at -40 °C for lh. To this added solution of To a suspension of CuT (265 mg, 1.39 mmol) in THF (10 mL), cooled in ice-water bath, was added phenylmagnesium bromide (7.7 mL, 3 N in EtOEt, 23.2 mmol) drop-wise. The mixture was stirred at that temperature for 10 mm, and At room temperature, the reaction vessel in an organic solvent DMSO was added the above formula (II) compound, the compound of formula (III), elemental Se, CuCl and K3PO4.Wherein the molar ratio of the compound of formula (II) and the formula (III) is 1: 1.2, the compound with elemental Se molar ratio of formula (II) is 1: 2.8, the molar amount of CuCl is of formula (II) compound molar amount 25 percent, with a compound of formula (II) K3PO4The molar ratio of 1: 0.9, and then purged with nitrogen, and replaced twice, in a nitrogen atmosphere such that the reaction environment; was warmed to 130 , and incubated for 29 hours the reaction.After post-treatment to give the product of formula (the I), in a yield of 84.9percent, purity 98.3percent (HPLC).

Used in pharmaceutical intermediates.

Molecular Weight:86.09
XLogP3:-0.4
Hydrogen Bond Acceptor Count:2
Exact Mass:86.036779430
Monoisotopic Mass:86.036779430
Topological Polar Surface Area:21.8
Heavy Atom Count:6
Complexity:63.9
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes