Water → 6,6-Dimethyl-2-(6-{1-[2-(morpholin-4-yl)ethyl]-1h-pyrazol-4-yl}-2,3-dihydrobenzo[1,4]oxazin-4-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5h)-one

HRID 885959Notes

Reaction equation

HRID 885959 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[CH2:14]C(C)(C)N[C:17](=O)[C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:36]=2)O1.C([O-])([O-])=O.[K+].[K+].[OH2:52]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:5][C:6]1([CH3:23])[NH:7][C:14](=[O:52])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([C:32]5[CH:33]=[N:34][N:35]([CH2:37][CH2:38][N:39]6[CH2:40][CH2:41][O:42][CH2:43][CH2:44]6)[CH:36]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1

Participants

9

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 177499241-(2-Morpholinoethyl)-1H-pyrazole-4-boronic acid pinacol esterHCID 685972362-(6-Bromo-2,3-dihydrobenzo[1,4]oxazin-4-yl)-6,6-dimethyl-6,7-dihydro-[1,3]thiazolo[5,4-d]pyridin-4(5h)-one

Product 1

HCID 671876196,6-Dimethyl-2-(6-{1-[2-(morpholin-4-yl)ethyl]-1h-pyrazol-4-yl}-2,3-dihydrobenzo[1,4]oxazin-4-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-4(5h)-oneYield 41%

Reagents, catalysts & solvents 4

HCID 74236Tetrabutylammonium BromideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A stirred solution of Example 39 (0.1 g, 0.326 mmol), 4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}morpholine (0.051 g, 0.165 mmol), K2CO3 (0.054 g, 0.395 mmol), tetra-n-butylammonium bromide (0.122 g, 0.377 mmol), tetrakis(triphenylphosphine)palladium(0) (0.007 g, 0.006 mmol) and H2O (0.5 mL) in THF (1 mL) was heated at 125° C. in a sealed vessel for 2.5 days. After cooling to r.t. the reaction mixture was diluted with EtOAc and washed with water and brine. The organic fraction was dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-100% [9:1 EtOAc/MeOH]/heptane) followed by trituration with Et2O gave the title compound (0.026 g, 41%) as a white solid. δH (CDCl3) 8.00 (1H, d, J 2.1 Hz), 7.72 (1H, s), 7.68 (1H, s), 7.20 (1H, dd, J 8.5 and J 2.1 Hz), 6.97 (1H, d, J 8.5 Hz), 5.27 (1H, br. s), 4.39-4.26 (4H, m), 4.25-4.19 (2H, m), 3.78-3.69 (4H, m), 2.95-2.83 (4H, m), 2.61-2.49 (4H, m), 1.42 (6H, s). LCMS (ES+) 495.5 (M+H)+, RT 2.04 minutes (Method 1).

Workup

  1. washwashed with water and brine
  2. dry with materialThe organic fraction was dried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customPurification by column chromatography (SiO2, 0-100% [9:1 EtOAc/MeOH]/heptane)

Sources & evidence

ORD record
ord-f48a7cfd31564d4bb715fd711177075c
Source dataset
uspto-grants-2012_08
Patent number
US08242116B2

Reaction notes

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