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

HRID 1400699Notes

Reaction equation

HRID 1400699 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:55]=[CH:54][CH:53]=[CH:52][C:51]=2[OH:56])O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[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]=[CH:52][C:51]=6[OH:56])[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

7

Reactant 3

HCID 11430Potassium CarbonateHCID 27346222-(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 86710750(2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(2'-hydroxy-[1,1'-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a 2-5 ml microwave tube was added (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 (0.240 g, 0.375 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.124 g, 0.563 mmol), and 2M aqueous K2CO3 (0.375 ml, 0.750 mmol) in 1,4-dioxane (3.0 ml) and water (0.75 ml). The reaction was sparged with nitrogen for 10 minutes, treated with Pd(Ph3P)4 (0.043 g, 0.038 mmol), then sparged for 15 min. The reaction tube was sealed and heated (90° C., heating block) for 90 min. The reaction was cooled, diluted with water (5 mL) and extracted with Et2O. The ether layer was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was adsorbed onto silica gel, then purified by biotage column chromatography (5%-55% EtOAc in hexanes). The product fractions were pooled and concentrated under reduced pressure to afford (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (500 MHz, CDCl3) δ 7.94 (t, J=1.5 Hz, 1H), 7.86 (dt, J=7.7, 1.4 Hz, 1H), 7.47-7.52 (m, 1H), 7.39-7.45 (m, 1H), 7.25 (s, 1H), 6.95-7.02 (m, 5H), 6.88-6.92 (m, 1H), 5.96-6.10 (m, 1H), 5.51 (br. s., 1H), 5.29-5.37 (m, 1H), 5.24 (dd, J=10.3, 1.5 Hz, 1H), 5.04-5.09 (m, 1H), 4.24 (t, J=4.4 Hz, 2H), 3.67-3.76 (m, 1H), 3.65 (s, 2H), 3.58 (dd, J=15.2, 6.1 Hz, 1H), 3.16-3.23 (m, 2H), 2.84 (s, 3H), 1.95 (s, 1H), 1.17 (s, 9H). LCMS (M+H)=653.4.

Workup

  1. customThe reaction was sparged with nitrogen for 10 minutes
  2. customsparged for 15 min
  3. customThe reaction tube was sealed
  4. temperatureheated
  5. temperatureThe reaction was cooled
  6. additiondiluted with water (5 mL)
  7. extractionextracted with Et2O
  8. washThe ether layer was washed with brine
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. custompurified by biotage column chromatography (5%-55% EtOAc in hexanes)
  13. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-4675e1b2c6a24b93b0d5d76030535a4e
Source dataset
uspto-grants-2014_12
Patent number
US08906929B2

Reaction notes

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