Diisopropylethylamine → (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

HRID 921097Notes

Reaction equation

HRID 921097 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][NH2:21])[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].[CH2:35]([N:38]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([F:51])=[C:47]([CH3:52])[CH:46]=1)[C:39](=[O:43])[C:40](O)=[O:41])[CH:36]=[CH2:37].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOCC>[CH2:35]([N:38]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([F:51])=[C:47]([CH3:52])[CH:46]=1)[C:39](=[O:43])[C:40]([NH:21][CH2:20][C:18]1[CH:19]=[C:15]2[N:14]=[C:13]([CH3:22])[C:12]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([N:8]3[CH2:9][CH2:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH3:34])[CH2:6][CH2:7]3)[N:16]2[N:17]=1)=[O:41])[CH:36]=[CH2:37]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 1183071432-(Allyl(4-fluoro-3-methylbenzyl)amino)-2-oxoacetic acidHCID 131734902(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 118318768(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)acetateYield 39.3%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

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. customwas used in the next step without purification
  2. washwashed with 1M HCl (5 mL), water (3×10 mL), brine (10 mL)
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. custompurified by prep-HPLC

Sources & evidence

ORD record
ord-cb80331ce4e04d4f8ecb3d364daa41bb
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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