3-(BROMOMETHYL)TETRAHYDROFURAN

To a stirring solution of (3-oxolanyl) methyl methanesulfonate (42.16 g, 239.5 mmol) in dry acetone (600 mL) was added lithium bromide (101.7 g, 1198 mmol). The reaction mixture was heated to reflux for 3 h, then it was cooled and the solvent removed by rotary evaporation. The residue was dissolved in water (200 mL) and extracted with dichloromethane (2 x 100 mL). The combined extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to afford a light brown liquid. It was distilled at 70° C and 1mm of pressure to give 33.00 g (86.77 percent) of 3- (bromomethyl)oxolane as a colorless liquid. To a stirring solution of (3-oxolanyl)methyl methanesulfonate (42.16 g, 239.5 mmol) in dry acetone (600 mL) was added lithium bromide (101.7 g, 1198 mmol). The reaction mixture was heated to reflux for 3 h, then it was cooled and the solvent removed by rotary evaporation. The residue was dissolved in water (200 mL) and extracted with dichloromethane (2 x 100 mL). The combined extracts were dried (NaStep 2: To solution of (tetrahydrofuran-3-yl)methyl methanesulfonate (5.6 g) in acetone (80 mL) is added lithium bromide (13.6 g). The mixture is heated to reflux for 4 hours. Then the solvent is evaporated in vacuo and the residue is partitioned between dichloromethane and water. The organic phase is separated and dried (MgSOTo solution of (tetrahydrofuran-3-yl)methyl methanesulfonate (5.6 g) in acetone (80 ml_) is added lithium bromide (13.6 g). The mixture is heated to reflux for 4 hours. Then the solvent is evaporated in vacuo and the residue is partitioned between dichloromethane and water. The organic phase is separated and dried (MgSOA solution of General procedure: A mixture of 3-bromo-1, 1, 1-trifluoropropan-2-ol (14.46 mg, 0.075 mmol), 5-(4- amino-5-(trifluoromethyl)pyrrolo[2, 1-f][1, 2, 4]triazin-7-yl)-N-((3R, 4S)-4- fluoropyrrolidin-3-yl)-2-methoxynicotinamide, TFA (15 mg, 0.027 mmol), and K2CO3 (22.48 mg, 0.163 mmol) in DMF (60 muL) was brought to 60 C and stirred ON. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by prep HPLC (C18, (0802) Acetonitrile/Water/Ammonium acetate) gave 5-(4-amino-5-(trifluoromethyl)pyrrolo[2, 1- f][1, 2, 4]triazin-7-yl)-N-(4-fluoro-1-(3, 3, 3-trifluoro-2-hydroxypropyl)pyrrolidin-3-yl)-2- methoxynicotinamide (isolate 01, first eluting peak, racemic). (0803) MS ESI m/z 552.3 (M+H) (0804) 1H NMR (500MHz, CD3OD) delta 8.97 (q, J=2.4 Hz, 2H), 8.08 (s, 1H), 7.41 (s, 1H), 5.40 - 5.12 (m, 1H), 4.77 - 4.64 (m, 1H), 4.19 - 4.17 (m, 3H), 4.17 - 4.10 (m, 1H), 3.29 - 2.98 (m, 3H), 2.94 - 2.86 (m, 1H), 2.85 - 2.74 (m, 2H). (0805) Racemic material (at alcohol center) was separated by Chiral SFC (Chiralpak AS 5 mum, 30 x 250 mm, 10% MeOH (0.1% DEA) in CO2, 150 bar, 35 oC) to give the homochiral title compound: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2, 1-f][1, 2, 4]triazin-7- yl)-N-((3R, 4S)-4-fluoro-1-(3, 3, 3-trifluoro-2-hydroxypropyl)pyrrolidin-3-yl)-2- methoxynicotinamide (first eluting peak (24.10 min), absolute stereochemistry at alcohol center undefined). (0806) 44-1: MS ESI m/z 552.2 (M+H) (0807) 1H NMR (500MHz, CDCl3) delta 9.02 (d, J=2.4 Hz, 1H), 8.99 (d, J=2.6 Hz, 1H), 8.55 - 8.44 (m, 1H), 8.13 (s, 1H), 7.28 (s, 2H), 5.87 (br s, 2H), 5.35 - 5.08 (m, 1H), 4.88 - 4.74 (m, 1H), 4.20 (s, 3H), 4.04 (ddd, J=9.8, 6.5, 3.6 Hz, 1H), 3.41 - 3.21 (m, 2H), 3.10 - 2.72 (m, 4H). (0808) 44-2: And its enantiomer (second eluting peak (25.51 min), absolute (0809) stereochemistry at alcohol center undefined): (0810) MS ESI m/z 552.3 (M+H) (0811) 1H NMR (500MHz, CDCl3) delta 9.02 (d, J=2.4 Hz, 1H), 9.00 - 8.97 (m, 1H), 8.55 - 8.44 (m, 1H), 8.12 (s, 1H), 7.28 (s, 1H), 5.97 (br s, 2H), 5.33 - 5.07 (m, 1H), 4.91 - 4.67 (m, 1H), 4.25 - 4.16 (m, 3H), 4.12 - 4.00 (m, 1H), 3.45 - 3.28 (m, 2H), 3.19 - 3.06 (m, 1H), 3.01 - 2.86 (m, 2H), 2.82 - 2.73 (m, 1H).Compound 58c (200 mg, 0.88 mmol), 3-(Bromomethyl)tetrahydrofuran (175 mg, 1.06 mmol)Potassium tert-butoxide (197 mg, 1.76 mmol) was dispersed in ethanol (5 mL).Reacted under reflux for 10 minutes, Cooled to room temperature, quenched with water, extracted three times with ethyl acetate, the combined organic phases, the organic phase washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentratedThe crude product was purified by column chromatography ( petroleum ether: ethyl acetate = 2:1)The title compound 58d (100 mg, 0.32 mmol) was obtained as a colourless oil.The yield was 36%.To a solution of (E)-1-((E)-4-((E)-5-carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5- carbonyl)imino)-3-methyl-2, 3-dihydro-1H-benzo[d]imidazol-1-yl)-2, 3-dimethylbut-2-en-1- yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-7-hydroxy-3-methyl-2, 3-dihydro-1H- benzo[d]imidazole-5-carboxamide (49 mg, 0.063 mmol) in DMF (1 mL) was added 3- (bromomethyl)tetrahydrofuran (20.95 mg, 0.127 mmol) followed by potassium carbonate (11.40 mg, 0.083 mmol). The reaction mixture was stirred at 90 °C for 24 h. The mixture was directly purified by preparative HPLC (Phenomenex Eclipse, 5 um packing, 50x30 mm column, 25-55percent gradient of MeCN/water with 0.1percent TFA modifier). The corresponding fractions were pooled and concentrated in vacuo. The residue was partitioned between EtOAc and an aqueous solution of sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to provide (E)-1-((E)-4-((E)-5- carbamoyl-2-((1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino)-3-methyl-2, 3-dihydro-1H- benzo[d]imidazol-1-yl)-2, 3-dimethylbut-2-en-1-yl)-2-((1-ethyl-3-methyl-1H-pyrazole-5- carbonyl)imino)-3-methyl-7-((tetrahydrofuran-3-yl)methoxy)-2, 3-dihydro-1H- benzo[d]imidazole-5-carboxamide (22.5 mg, 0.027 mmol, 42.6percent yield) as a white solid.1H NMR (400 MHz, DMSO-d6) delta ppm 8.11 - 8.15 (m, 1 H), 8.05 - 8.11 (m, 1 H), 7.99 - 8.05 (m, 1 H), 7.79 (s, 2 H), 7.50 (br. s., 3 H), 7.18 - 7.28 (m, 1 H), 6.46 (s, 1 H), 6.37 (s, 1 H), 5.06 (br. s., 2 H), 4.86 (br. s., 2 H), 4.42 - 4.56 (m, 4 H), 3.97 - 4.12 (m, 2 H), 3.65 - 3.73 (m, 1 H), 3.59 (s, 3 H), 3.57 (s, 3 H), 3.45 - 3.53 (m, 2 H), 2.11 (s, 3 H), 2.08 (s, 3 H), 1.62 (br. s., 4 H), 1.48 (br. S., 4 H), 1.15' 1.36 (m, 8 H). LCMS (m/z): 833.5 [M + H]+.

Molecular Weight:165.03
XLogP3:1.2
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:163.98368
Monoisotopic Mass:163.98368
Topological Polar Surface Area:9.2
Heavy Atom Count:7
Complexity:56
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes