Triethylamine → (S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

HRID 921074Notes

Reaction equation

[CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20](O)=[O:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:23])[C:12]=2[C@H:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CCN(CC)CC.ClC(OC(C)C)=O.C1(C)C=CC=CC=1.[BH4-].[Na+]>C1COCC1.O>[CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][OH:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:23])[C:12]=2[C@H:24]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]

Participants

Conditions

Temperature: 0 °C

Procedure

To a stirred solution of (S)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (2.443 g, 5 mmol) and Et3N (0.836 ml, 6.00 mmol) in THF (100 mL) was added 1M isopropyl chloroformate/toluene (6.00 ml, 6.00 mmol) at 0° C. After 1 h, a solution of NaBH4 (0.567 g, 15.00 mmol) in cold water (20 mL) was added at once and stirred for at 0° C. LCMS after 1 h showed formation of desired product and presence of unreacted mixed unhydride intermediate. So, added additional NaBH4 (0.284 g, 7.5 mmol) and continued stirring for 3 h while allowing reaction mixture to slowly warm to 10° C. LCMS at this point showed still remaining about 10% unreacted material. So, added additional NaBH4 (0.189 g) and stirred for 1 h at 10° C. Then the reaction was quenched with AcOH (1 mL), diluted with Et2O (200 mL), washed with water (2×50 mL) and brine (25 mL). The organic layer dried (MgSO4), filtered and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (2.7 g, 5.12 mmol, 102% yield, 90% purity) as pale yellow paste which was used in next step without purification. LCMS (M+H)=475.2.

Workup

waitLCMS after 1 h showed

Sources & evidence

ORD record: ord-2b865ad8664d4a9292c8a9d733840d12
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09273067B2

Reaction notes

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