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

HRID 1400694Notes

Reaction equation

HRID 1400694 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].[CH2:42]([C:46]1[CH:47]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:49]=[CH:50][CH:51]=1)[CH2:43][CH:44]=[CH2:45].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:49]=[CH:48][CH:47]=[C:46]([CH2:42][CH2:43][CH:44]=[CH2:45])[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 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)acetateHCID 899709762-(3-(But-3-en-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Product 1

HCID 89971474(2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3'-(but-3-en-1-yl)-[1,1'-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 61.7%

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 (75 mg, 0.117 mmol), 2-(3-(but-3-en-1-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45.4 mg, 0.176 mmol) and 2N Na2CO3 (0.117 mL, 0.234 mmol) in DMF (1 mL) was degassed for 15 min. tetrakis(triphenylphosphine)pallafium(0) (9.48 mg, 8.20 μmol) was then 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 (2×25 mL), washed with brine (15 mL), dried (Na2SO4), filtered and concentrated. Crude was then purified by biotage (0-15% 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′-(but-3-en-1-yl)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.072 mmol, 61.7% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 8.05 (t, J=1.6 Hz, 1H), 7.85-7.82 (m, 1H), 7.57-7.54 (m, 1H), 7.45 (dd, J=4.6, 2.5 Hz, 3H), 7.41-7.35 (m, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.00 (d, J=5.0 Hz, 2H), 6.95-6.93 (m, 1H), 6.11-6.00 (m, 1H), 5.91 (ddt, J=17.0, 10.3, 6.6 Hz, 1H), 5.35 (dd, J=17.2, 1.6 Hz, 1H), 5.26 (dd, J=10.2, 1.6 Hz, 1H), 5.12-5.07 (m, 2H), 5.04-5.00 (m, 1H), 4.27 (t, J=4.4 Hz, 2H), 3.79-3.72 (m, 1H), 3.67 (s, 3H), 3.63 (dd, J=15.1, 6.1 Hz, 1H), 3.28-3.17 (m, 2H), 2.86 (s, 3H), 2.83-2.78 (m, 2H), 2.49-2.41 (m, 2H), 1.20 (s, 9H). LCMS (M+H)=691.5.

Workup

  1. additionwas then added
  2. temperatureAfter cooling to room temperature
  3. extractionthe mixture was extracted with ether (2×25 mL)
  4. washwashed with brine (15 mL)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customCrude was then purified by biotage (0-15% EtOAc/hexane)

Sources & evidence

ORD record
ord-feff8e9453a244428a6bd81397debdc3
Source dataset
uspto-grants-2014_12
Patent number
US08906929B2

Reaction notes

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