Triphenylphosphine → (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

HRID 921096Notes

Reaction equation

HRID 921096 reaction equation
[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+]=[N-])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.O>CCOCC>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][NH2:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]

Participants

5

Reactant 3

HCID 11776TriphenylphosphineHCID 21881883Oxolane--water (1/1)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)acetate

Product 1

HCID 131734902(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 99%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.206 g, 0.412 mmol) and Ph3P (0.162 g, 0.618 mmol) in 9:1 THF/H2O) (15 mL) was refluxed for 2 h. Then, cooled, diluted with Et2O (50 mL) and extracted with 0.1M HCl (3×10 mL). The organic layer discarded and the combined aqueous. layers neutralized with sat Na2CO3 and extracted with CH2Cl2 (3×10 mL). The combined CH2Cl2 layers dried (MgSO4), filtered and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.193 g, 0.408 mmol, 99% yield) as pale yellow paste which was used in the next step without purification. To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.195 g, 0.412 mmol), 2-(allyl(4-fluoro-3-methylbenzyl)amino)-2-oxoacetic acid (0.207 g, 0.824 mmol) and DIEA (0.288 ml, 1.648 mmol) in DMF (5 mL) was added HATU (0.470 g, 1.236 mmol) at rt. After 17 h, the reaction mixture was taken up in Et2O (100 mL), washed with 1M HCl (5 mL), water (3×10 mL), brine (10 mL), dried (MgSO4), filtered, concentrated and purified by prep-HPLC to afford (S)-ethyl 2-(2-((2-(allyl(4-fluoro-3-methylbenzyl)amino)-2-oxoacetamido)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.1145 g, 0.162 mmol, 39.3% yield) as yellow paste. 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J=14.8 Hz, 1H), 7.03-7.16 (m, 2H), 6.91-6.99 (m, 1H), 6.42 (s, 1H), 5.69-6.07 (m, 3H), 5.43 (d, J=17.3 Hz, 1H), 5.11-5.26 (m, 3H), 5.00 (s, 1H), 4.68 (t, J=5.4 Hz, 2H), 4.54 (s, 1H), 4.38 (d, J=5.8 Hz, 1H), 4.12-4.27 (m, 3H), 3.95-4.05 (m, 3H), 3.92 (d, J=6.0 Hz, 1H), 2.59 (s, 3H), 2.26 (d, J=1.76 Hz, 3H), 1.81-2.03 (m, 3H), 1.72 (td, J=2.6, 7.0 Hz, 1H), 1.34 (s, 3H), 1.20-1.25 (m, 12H). LCMS (M+H)=707.7.

Workup

  1. temperaturewas refluxed for 2 h
  2. temperatureThen, cooled
  3. extractionextracted with 0.1M HCl (3×10 mL)
  4. extractionextracted with CH2Cl2 (3×10 mL)
  5. dry with materialThe combined CH2Cl2 layers dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-bdc5fe827ce74988b3fc75c086668b28
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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