Potassium Carbonate → HCID 72192439, compound

HRID 531271Notes

Reaction equation

HRID 531271 reaction equation
O1CCOCC1.[F:7][C:8]([F:49])([F:48])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[C:33]([O:39][CH3:40])=[N:34][CH:35]=[C:36](Cl)[CH:37]=4)=[CH:30][N:29]=[C:28]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:27]=3)[C@H:20]2[CH3:47])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[CH:50]1([B-](F)(F)F)[CH2:52][CH2:51]1.[K+].C([O-])([O-])=O.[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[F:7][C:8]([F:49])([F:48])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[C:33]([O:39][CH3:40])=[N:34][CH:35]=[C:36]([CH:50]5[CH2:52][CH2:51]5)[CH:37]=4)=[CH:30][N:29]=[C:28]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:27]=3)[C@H:20]2[CH3:47])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 23697338Potassium cyclopropyltrifluoroborateHCID 72191835HCID 72191835, compound

Product 1

HCID 72192439HCID 72192439, compound

Reagents, catalysts & solvents 2

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 962WaterSolvent

Conditions

Temperature
130 °C

Procedure

Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11.20 mg, 0.016 mmol) was added to a degassed dioxane (700 μl)/Water (100 μl) solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(morpholin-4-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 11, 100 mg, 0.158 mmol), potassium cyclopropyltrifluoroborate (46.8 mg, 0.316 mmol) and K2CO3 (65.6 mg, 0.475 mmol). After further degassing with N2 and vacuum for 3 cycles, the reaction was capped and stirred for 30 minutes at 130° C. in a Biotage microwave reactor. LCMS showed >80% conversion to product. The reaction was diluted with 5 mL acetonitrile and filtered through a 1 g RP C18 silica cartridge, eluting with 15 mL acetonitrile until the filtrate was colorless. The filtrate was concentrated and the crude purified under the following conditions: X-Bridge 21.2×150 mm RP column, sample loaded in 7:3:1 CH3CN/water/DMSO (5 mL) with the column eluted using a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient at 15 mL/minute over 20 minutes to give the product as a white solid after lyophilization of the purified fractions. LCMS (M+H)+: 638.5. 1H NMR (500 MHz, CDCl3): δ 8.23 (br, 1H), 8.12 (br, 1H), 7.93 (br, 1H), 7.75 (br, 2H), 7.24 (br, 1H), 5.68 (m, 2H), 4.72 (d, J=17.6 Hz, 1H), 4.13 (d, J=17.6 Hz, 1H), 4.07 (m, 4H), 3.99 (s, 3H), 3.88 (m, 4H), 1.93 (m, 1H), 1.05 (m, 2H), 0.71 (m, 5H). SPA IC50: 530 nM

Workup

  1. customAfter further degassing with N2 and vacuum for 3 cycles
  2. customthe reaction was capped
  3. additionThe reaction was diluted with 5 mL acetonitrile
  4. filtrationfiltered through a 1 g RP
  5. washsilica cartridge, eluting with 15 mL acetonitrile until the filtrate
  6. concentrationThe filtrate was concentrated
  7. customthe crude purified under the following conditions
  8. washeluted
  9. customover 20 minutes

Sources & evidence

ORD record
ord-f3010e9ed70c4f37a9d23677b58a37ad
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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