Water → (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3'-hydroxy-[1,1'-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

HRID 1400695Notes

Reaction equation

HRID 1400695 reaction equation
[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].CC1(C)C(C)(C)OB([C:50]2[CH:51]=[C:52]([OH:56])[CH:53]=[CH:54][CH:55]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:50]6[CH:55]=[CH:54][CH:53]=[C:52]([OH:56])[CH:51]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]

Participants

6

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 27346233-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenolHCID 86710751(2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 86710748(2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3'-hydroxy-[1,1'-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 73.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (120 mg, 0.188 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61.9 mg, 0.281 mmol) and 2M Na2CO3 (0.188 mL, 0.375 mmol) in DMF (2 mL) was degassed for 15 min by bubbling N2 through the reaction mixture. Then, tetrakis(triphenylphosphine)pallafium(0) (15.17 mg, 0.013 mmol) was added and the degassing was continue for another 5 min. The mixture was then heated at 90° C. for 16 h. After cooling to room temperature, water was added and the mixture was extracted with ether (2×50 mL), washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by biotage (10-40% EtOAc/hexane) to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.138 mmol, 73.5% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.02 (t, J=1.6 Hz, 1H), 7.82 (dt, J=7.6, 1.4 Hz, 1H), 7.54-7.51 (m, 1H), 7.47-7.43 (m, 1H), 7.33-7.29 (m, 1H), 7.19-7.13 (m, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.02-7.00 (m, 1H), 6.98 (s, 2H), 6.93 (s, 1H), 6.81 (ddd, J=8.0, 2.5, 0.9 Hz, 1H), 6.42 (dd, J=8.1, 2.3 Hz, 2H), 6.39-6.35 (m, 1H), 6.10-5.98 (m, 1H), 5.40-5.30 (m, 2H), 5.07 (s, 1H), 4.29-4.18 (m, 2H), 3.67 (s, 3H), 3.18 (t, J=4.4 Hz, 2H), 2.87 (s, 3H), 1.18 (s, 9H). LCMS (M+H)=653.4.

Workup

  1. customwas degassed for 15 min
  2. customby bubbling N2 through the reaction mixture
  3. temperatureAfter cooling to room temperature
  4. extractionthe mixture was extracted with ether (2×50 mL)
  5. washwashed with brine (25 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was then purified by biotage (10-40% EtOAc/hexane)

Sources & evidence

ORD record
ord-74a6244e073a43d5bda773a5759bc5c8
Source dataset
uspto-grants-2014_12
Patent number
US08906929B2

Reaction notes

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