Methanol → (4R,5R)-4-(2-fluoro-5-((5-fluoropyridin-3-yl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one

HRID 2362450노트

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HRID 2362450 반응식
Br[C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[O:12][C:11](=[O:21])[NH:10]2)[C:5]([F:8])=[N:6][CH:7]=1.[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(N(CC)CC)C.C(=O)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:5]([NH:6][CH2:7][CH3:2])[CH3:4].[F:8][C:5]1[C:4]([C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[O:12][C:11](=[O:21])[NH:10]2)=[CH:3][C:2]([C:23]#[C:22][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)=[CH:7][N:6]=1

참가 물질

10

반응물 4

HCID 887MethanolHCID 11776TriphenylphosphineHCID 569723593-Ethynyl-5-fluoropyridineHCID 69083956(4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one

생성물 2

HCID 8021Diethylamine수율 0.1%HCID 69082769(4R,5R)-4-(2-fluoro-5-((5-fluoropyridin-3-yl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one수율 147.6%

시약·촉매·용매 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)촉매HCID 178418476HCID 178418476, 화합물촉매HCID 280Carbon Dioxide용매HCID 8471Triethylamine용매

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온도
90 °C

실험 절차

To a 15 ml sealable vial was added a mixture of (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (30 mg, 0.084 mmol) and its regioisomer in triethylamine (2 mL). To this suspension was added 3-ethynyl-5-fluoropyridine (12.28 mg, 0.101 mmol), triphenylphosphine (6.65 mg, 0.025 mmol) and copper(I) iodide (0.322 mg, 1.690 μmol). The solution was degassed with nitrogen for 20 min, then bis(triphenylphosphine)palladium(II) chloride (1.186 mg, 1.690 μmol) was quickly added and the vial was sealed, heated to 90° C., and allowed to stir overnight. The next day the suspension had turned homogeneous and the reaction was cooled to room temperature and the solvent was evaporated in vacuo. The crude residue was purified by silica gel chromotagraphy 1% MeOH/99% CH2Cl2 affording a single peak. This single peak was a 60:40 mixture of regioisomers and was subsequently purified by chiral supercritical fluid chromatography Chiralpak AD-H column, 4.6×250 mm, 5 um particle size mobile phase: 35% MeOH in CO2 (w/0.1% diethylamine) column temp: 35 C flow rate: 2 mL/min., affording (4R,5R)-4-(2-fluoro-5-((5-fluoropyridin-3-yl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (25 mg, 0.062 mmol, 73.4% yield). 1H-NMR (CDCl3, 400 MHz) δ 8.63 (s, 1H), 8.51 (d, J=4.0, 1H), 8.45 (s, 1H), 8.14 (dd, J=8.0, 4.0, 1H), 7.69-7.64 (m, 1H), 7.60-7.54 (m, 1H), 7.50-7.43 (m, 1H), 7.21-7.13 (m, 2H), 6.05 (brs, 1H), 5.39 (d, J=4.0, 1H), 5.04 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.01 min. Mass=396.20 (MH)+.

후처리

  1. additionTo a 15 ml sealable vial was added
  2. customThe solution was degassed with nitrogen for 20 min
  3. customthe vial was sealed
  4. temperaturethe reaction was cooled to room temperature
  5. customthe solvent was evaporated in vacuo
  6. customThe crude residue was purified by silica gel chromotagraphy 1% MeOH/99% CH2Cl2 affording a single peak
  7. additiona 60:40 mixture of regioisomers
  8. customwas subsequently purified by chiral supercritical fluid chromatography Chiralpak AD-H column, 4.6×250 mm, 5 um particle size mobile phase

출처 및 근거

ORD 기록
ord-83825df92c7141959fef6d845d33fc6f
출처 데이터셋
uspto-grants-2014_04
특허 번호
US08691821B2

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