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

HRID 921093Notes

Reaction equation

HRID 921093 reaction equation
[CH2:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH:2]=[CH2:3].C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[CH2:22]([O:25][C:26]1([CH3:55])[CH2:31][CH2:30][N:29]([C:32]2[N:37]3[N:38]=[C:39]([CH2:41][NH2:42])[CH:40]=[C:36]3[N:35]=[C:34]([CH3:43])[C:33]=2[C@H:44]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:28][CH2:27]1)[CH:23]=[CH2:24].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:42][CH2:41][C:39]1[CH:40]=[C:36]2[N:35]=[C:34]([CH3:43])[C:33]([C@H:44]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:32]([N:29]3[CH2:30][CH2:31][C:26]([O:25][CH2:22][CH:23]=[CH2:24])([CH3:55])[CH2:27][CH2:28]3)[N:37]2[N:38]=1)=[O:8])[CH:2]=[CH2:3]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 27529912-Allylbenzoic AcidHCID 21906498HCID 21906498, compoundHCID 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 118318759(S)-ethyl 2-(2-((2-allylbenzamido)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 47.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

A solution 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 (0.10 g, 0.200 mmol) and Ph3P (0.063 g, 0.240 mmol) in 9:1 THF/H2O (5 mL) stirred at rt for 1 h and at 45° C. for 4 h. Then, diluted with Et2O (25 mL) and extracted with 0.5M HCl (2×5 mL). The combine aqueous layers neutralized with sat Na2CO3 and extracted with CH2Cl2 (2×20 mL). The combine 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 as viscous pale yellow oil which was used in the subsequent step without purification. To a stirred solution of 2-allylbenzoic acid (0.065 g, 0.400 mmol) in CH2Cl2 (5 mL) containing cat. DMF was added 2M oxalyl chloride/DCM (0.400 ml, 0.801 mmol) at rt. After 1 h, concentrated and the resulting residue was re-dissolved in CH2Cl2 (3 mL) and added to a 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 and DIEA (0.105 ml, 0.600 mmol) in CH2Cl2 (2 mL) at rt. After 2 h the reaction was quenched with a drop of MeOH, concentrated and purified prep-HPLC to afford (S)-ethyl 2-(2-((2-allylbenzamido)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.059 g, 0.096 mmol, 47.7% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.50 (dd, J=1.2, 7.7 Hz, 1H), 7.37-7.41 (m, 1H), 7.24-7.30 (m, 3H), 6.46-6.53 (m, 1H), 6.49 (s, 1H), 5.98-6.06 (m, 1H), 5.83-5.98 (m, 2H), 5.39 (dd, J=1.6, 17.2 Hz, 1H), 5.14 (d, J=9.8 Hz, 1H), 5.06 (qd, J=1.5, 10.1 Hz, 1H), 5.01 (qd, J=1.7, 17.2 Hz, 1H), 4.84 (d, J=5.4 Hz, 2H), 4.15-4.28 (m, 2H), 3.97 (d, J=4.6 Hz, 2H), 3.64 (d, J=6.3 Hz, 2H), 2.61 (s, 3H), 1.98 (d, J=13.2 Hz, 1H), 1.84-1.94 (m, 2H), 1.70 (d, J=9.3 Hz, 1H), 1.31 (s, 3H), 1.21-1.26 (m, 12H). LCMS (M+H)=618.5.

Workup

  1. customwas used in the subsequent step without purification
  2. concentrationconcentrated
  3. dissolutionthe resulting residue was re-dissolved in CH2Cl2 (3 mL)
  4. customAfter 2 h the reaction was quenched with a drop of MeOH
  5. concentrationconcentrated
  6. custompurified prep-HPLC

Sources & evidence

ORD record
ord-37d00b10e04a496597add37f27335d4c
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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