Perchloric Acid → (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

HRID 1400771Notes

Reaction equation

HRID 1400771 reaction equation
[CH2:1]([O:4][C:5]1([CH3:28])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([Br:20])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:21])[C:12]=2[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CB1N2CCC[C@@H:33]2[C:32]([C:44]2C=CC=CC=2)([C:38]2C=CC=CC=2)O1.CC#N.C(=O)=O.[B]1OC2C(=CC=CC=2)O1.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C(OC(C)=O)(C)(C)C>[CH2:1]([O:4][C:5]1([CH3:28])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([Br:20])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:21])[C:12]=2[C@H:22]([O:27][C:32]([CH3:44])([CH3:38])[CH3:33])[C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]

Participants

10

Reactant 6

HCID 24247Perchloric AcidHCID 516892Sodium BicarbonateHCID 6327445Benzcatechinborane2×HCID 9838490(R)-2-Methyl-CBS-oxazaborolidine2×HCID 86587134Acetonitrile dry iceHCID 86710823Methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate

Product 1

HCID 86710824(S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 34%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolvent5×HCID 6344DichloromethaneSolventHCID 10908tert-Butyl acetateSolvent

Procedure

A solution of methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (9.20 g, 20.3 mmol, 1 equiv) and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (12.2 mL of a 1 M solution in toluene, 12.2 mmol, 0.6 equiv) in toluene (200 mL) was cooled to −25° C. (MeCN/CO2). Catecholborane (6.8 mL of a 50% solution in toluene, 28.4 mmol, 1.4 equiv) was then added and temperature was held between −15° C. and −25° C. for 18 h. At this point, more and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (4 mL of a 1 M solution in toluene, 4 mmol, 0.2 equiv) and catecholborane (3 mL of a 50% solution in toluene, 12.5 mmol, 0.6 equiv) were added. The reaction was then stirred a further 4 h. The reaction was then quenched with 10% aqueous K2CO3 (100 mL) and EtOAc (100 mL) and removed from cooling bath. After stirring 45 min, the mixture was added to water and extracted with ether (×4). The combined ether extracts were dried (MgSO4) and concentrated in vacuo to provide the crude product as a yellow foam. This was taken up in DCM (50 mL) and tBuOAc (150 mL). To this solution was added 70% perchloric acid (3.7 mL, 60.9 mmol, 3 equiv) to give a cloudy orange solution. After stirring 3 h, the reaction was added cautiously to saturated aqueous sodium bicarbonate and extracted with DCM (X3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to provide the crude product. The crude product was purified via silica gel flash chromatography (0-100% EtOAc/hex) to provide (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (3.56 g, 34%) 1H NMR (500 MHz, CDCl3) δ 6.54 (s, 1H), 6.09-5.97 (m, 1H), 5.83 (br. s., 1H), 5.48 (d, J=17.8 Hz, 1H), 5.24 (d, J=9.8 Hz, 1H), 4.50-3.00 (very broad m, 4H), 4.05-3.98 (m, 2H), 3.76 (s, 3H), 2.59 (s, 3H), 2.04-1.90 (m, 2H), 1.36 (s, 3H), 1.24 (s, 9H). LCMS (M+1)=509.09.

Workup

  1. customThe reaction was then quenched with 10% aqueous K2CO3 (100 mL) and EtOAc (100 mL)
  2. customremoved
  3. temperaturefrom cooling bath
  4. stirringAfter stirring 45 min
  5. additionthe mixture was added to water
  6. extractionextracted with ether (×4)
  7. dry with materialThe combined ether extracts were dried (MgSO4)
  8. concentrationconcentrated in vacuo
  9. customto provide the crude product as a yellow foam
  10. customto give a cloudy orange solution
  11. stirringAfter stirring 3 h
  12. extractionextracted with DCM (X3)
  13. dry with materialThe combined DCM extracts were dried (Na2SO4)
  14. concentrationconcentrated in vacuo
  15. customto provide the crude product
  16. customThe crude product was purified via silica gel flash chromatography (0-100% EtOAc/hex)

Sources & evidence

ORD record
ord-1b9d963f1e03497db127d125c0a82a93
Source dataset
uspto-grants-2014_12
Patent number
US08906929B2

Reaction notes

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