Tetrahydrofuran → (4S,5R)-5-(3,5-Difluorophenyl)-3-{[2-(3-fluoroazetidin-1-yl)-5-(5-isopropyl-2-methoxypyridin-3-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

HRID 531273Notes

Reaction equation

HRID 531273 reaction equation
C1COCC1.Br[C:7]1[C:8]([CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)[O:21][C:20]2=[O:33])=[N:9][C:10]([N:13]2[CH2:16][CH:15]([F:17])[CH2:14]2)=[N:11][CH:12]=1.[CH:34]([C:37]1[CH:38]=[C:39](B(O)O)[C:40]([O:43][CH3:44])=[N:41][CH:42]=1)([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O>[F:32][C:27]1[CH:26]=[C:25]([C@H:22]2[O:21][C:20](=[O:33])[N:19]([CH2:18][C:8]3[C:7]([C:39]4[C:40]([O:43][CH3:44])=[N:41][CH:42]=[C:37]([CH:34]([CH3:36])[CH3:35])[CH:38]=4)=[CH:12][N:11]=[C:10]([N:13]4[CH2:16][CH:15]([F:17])[CH2:14]4)[N:9]=3)[C@H:23]2[CH3:24])[CH:30]=[C:29]([F:31])[CH:28]=1

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 90009148(4S,5R)-3-{[5-bromo-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one2×HCID 900091535-Isopropyl-2-methoxypyridin-3-ylboronic acid

Product 1

HCID 72192440(4S,5R)-5-(3,5-Difluorophenyl)-3-{[2-(3-fluoroazetidin-1-yl)-5-(5-isopropyl-2-methoxypyridin-3-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Reagents, catalysts & solvents 2

HCID 178454861HCID 178454861, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

1,1′-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (25.07 mg, 0.038 mmol) was added to a degassed THF (15 mL)/Water (3 mL) solution of (4S,5R)-3-{[5-bromo-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 15, 200 mg, 0.385 mmol), 5-isopropyl-2-methoxypyridin-3-ylboronic acid (128 mg, 0.462 mmol) and K2CO3 (159 mg, 1.154 mmol). After further de-gassing with N2 and vacuum, the reaction was heated for 1 h at 50° C. LCMS showed complete conversion to product. The reaction was diluted with 50 mL ethyl acetate and poured into 100 mL sat′d NH4Cl soln. The ethyl acetate layer was washed with brine (100 mL) filtered through a 20 g plug of sodium sulfate, eluting with 50 mL ethyl acetate. The filtrate was concentrated prior to purification with an X-Bridge 21.2×150 mm RP column. The sample was loaded in 7:3:1 CH3CN/water/DMSO (5 mL), after which a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient at 15 mL/minutes over 20 minutes was run. The product of interest eluted in 80% portion of above gradient. Pure fractions (rich cut; impure discarded) were concentrated and lyophilized to give product as a white solid. LCMS (M+H)+: 528.5. 1H NMR (500 MHz, CDCl3): δ 8.15 (s, 1H), 8.10 (d, J=2.1 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 6.84 (m, 3H), 5.52 (m, 1.5H), 5.42 (m, 0.5H), 4.64 (d, J=17.3 Hz, 1H), 4.51 (m, 2H), 4.33 (m, 2H), 4.02 (d, J=17.4 Hz, 1H), 3.94 (s, 3H), 2.96 (m, 1H), 1.30 (d, J=6.9 Hz, 6H), 0.77 (d, J=6.6 Hz, 3H). RTA IC50: 16 nM.

Workup

  1. customAfter further de-gassing with N2 and vacuum
  2. additionThe reaction was diluted with 50 mL ethyl acetate
  3. additionpoured into 100 mL
  4. washThe ethyl acetate layer was washed with brine (100 mL)
  5. filtrationfiltered through a 20 g plug of sodium sulfate
  6. washeluting with 50 mL ethyl acetate
  7. concentrationThe filtrate was concentrated
  8. customto purification with an X-Bridge 21.2×150 mm RP column
  9. washThe product of interest eluted in 80% portion of above gradient
  10. concentrationPure fractions (rich cut; impure discarded) were concentrated
  11. customto give product as a white solid

Sources & evidence

ORD record
ord-783ea51cfd134d90bf43bda4de3104df
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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