((2R,3R,4R,5R)-3-(benzoyloxy)-5-bromo-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate synthesis

10synthesis methods

Product Name:((2R,3R,4R,5R)-3-(benzoyloxy)-5-bromo-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate
CAS Number:1199809-24-9
Molecular formula:C20H18BrFO5
Molecular Weight:437.26

1199809-22-7 Synthesis

((2R,3R,4R)-3-(Benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)methyl benzoate

1199809-22-7
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D-erythro-Pentofuranosyl bromide, 2-deoxy-2-fluoro-2-methyl-, 3,5-dibenzoate, (2R)-

1233335-84-6
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((2R,3R,4R,5R)-3-(benzoyloxy)-5-bromo-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate

1199809-24-9
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Yield:1199809-24-9 89%

Reaction Conditions:

with carbon tetrabromide;triphenylphosphine in dichloromethane at -22 - -17; for 0.833333 h;Inert atmosphere;

Steps:

Anhydrous dichloromethane (5.6 L) was charged into a reactor and cooled to -22°C or below. Triphenylphosphine (205.4 g, 0.783 mol) was added to the cold solvent and the suspension was stirred to form a solution. The lactol (2, 209.4 g, 0.559 mol) in solid form was added to the cold solution and stirred for 15 mins. Carbon tetrabromide (278.2 g, 0.839 mol) was added portion-wise while maintaining the temperature of the solution between -22⁰C to -20 °C under a flow of nitrogen gas (approx. 30 min). After finishing the addition OfCBr₄, the temperature was slowly raised to -17°C over 20 mins. The reaction was judged to be >95% complete by TLC (R_fS 0.61 (a), 0.72 (β), 0.36 lactol; 20% EtOAc in hexanes). The reaction solution was immediately transferred to a vessel containing 230 g of flash chromatography grade silica gel (40-63 microns). The stirred mixture was immediately passed through a pad of silica gel (680 g) in a 2.5 L sintered glassBuchner funnel. The filtrate was concentrated under reduced pressure to about 800 mL and the ratio of a/β isomers of the crude product was 10:1 as determined by ¹H- NMR. (CDCl₃) δ = 6.35, (s, a Cl-H), 6.43, (d, β Cl-H). The residue was purified by plug column chromatography using 2.1 kg of silica gel in a 6 L sintered glass Buchner funnel and eluted (via suction) with a stepwise gradient elution of 1%, 5%, 8% 12% EtOAc in hexane (ca 4 L each) to remove non-polar impurities followed by 12%, 25% EtOAc in hexane (6 L total) to elute the product. The product containing fractions were combined into two fractions, concentrated under reduced pressure, dried under vacuum (0.1 mmHg, ambient temp., 20 h) to colorless oils. Main fraction (197 g, 89% alβ = 20: 1). The alpha isomer crystallized from a small portion of the oil upon standing at O⁰C for several weeks to give large, thin plates, mp 59-61⁰C. The pure beta isomer crystallized from a mixture of alpha and beta product oil from an earlier less selective run to give needles, mp 77-79⁰C.¹H-NMR 03-bromide) (CDCl₃): δ = 8.08 (m, 2 H, atom.), 8.04 (m, 2 H, arom.), 7.62 (m, 1 H, arom.), 7.54-7.45 (m, 3 H, arom.), 7.35 (m, 2 H, arom.), 6.43 (d, 1 H, Cl-H), 6.04 (dd, 1 H, C3-H), 4.78-4.73 (m, 2 H, C4-H and C5-Ha), 4.63- 4.58 (m, 1 H, C5-Hb), 1.76 (d, 3 H, CH₃). α-bromide, a/β = 20:1) (CDCl₃): δ 8.13 (m, 2 H, arom.), 8.02 (m, 2 H, arom.), 7.63-7.56 (m, 2 H, arom.), 7.50-7.42 (m, 4 H, arom.), 6.34 (s, 1 H, Cl-H), 5.29 (dd, 1 H, C3-H), 4.88 (m, 1 H, C4-H), 4.78 (dd, 1 H, C5-Ha), 4.63 (dd, 1 H, C5-Hb), 1.72 (d, 3 H, CH₃).