1,8-Diazabicyclo(5.4.0)undec-7-ene → (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

HRID 921075Notes

Reaction equation

HRID 921075 reaction equation
[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]O)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].P([N:51]=[N+:52]=[N-:53])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOCC>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:51]=[N+:52]=[N-:53])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]

Participants

6

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 123414Diphenylphosphoryl azideHCID 118318735(S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 118318736(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 68.4%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent

Procedure

To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.70 g, 1.475 mmol) and diphenyl phosphorazidate (0.381 ml, 1.770 mmol) in toluene (10 mL) was added DBU (0.222 ml, 1.475 mmol) at 0° C. After 2 h, cold bath was removed, stirred for 22 h at rt. LCMS at 8 and 22 h is same and incomplete. So, added THF (10 mL) to the turbid reaction mixture and heated at 55° C. for 5 h. Then diluted with Et2O (100 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4), filtered, concentrated and purified by flash chromatography using 15 and 20% EtOAc/Hex to provide (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.5038 g, 1.008 mmol, 68.4% yield) as colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.51 (s, 1H), 6.00-6.09 (m, 1H), 5.92 (br. s., 1H), 5.46 (d, J=16.6 Hz, 1H), 5.23 (dd, J=1.4, 10.4 Hz, 1H), 4.46-4.53 (m, 2H), 4.15-4.29 (m, 2H), 4.00-4.04 (m, 2H), 2.63 (s, 3H), 1.90-2.04 (m, 3H), 1.67-1.76 (m, 1H), 1.36 (s, 3H), 1.23-1.27 (m, 12H). 4H of piperidine are missing. LCMS (M+H)=500.5.

Workup

  1. customcold bath was removed
  2. customat 8 and 22 h
  3. additionSo, added THF (10 mL)
  4. customto the turbid reaction mixture
  5. temperatureheated at 55° C. for 5 h
  6. washwashed with water (2×10 mL), brine (10 mL)
  7. dry with materialdried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. custompurified by flash chromatography

Sources & evidence

ORD record
ord-a65218437f1043c49d333029e4e49360
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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