(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-((allyloxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate → ethyl (2S)-2-(4,28-dimethyl-22,27-dioxa-1,5,7,8,11,12,13-heptazahexacyclo[26.2.2.16,9.111,14.02,7.015,20]tetratriaconta-2,4,6(34),8,12,14(33),15,17,19,24-decaen-3-yl)-2-[(2-methylpropan-2-yl)oxy]acetate

HRID 921081Notes

Reaction equation

HRID 921081 reaction equation
[CH2:1]([O:4][C:5]1([CH3:49])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[CH2:32][O:33][CH2:34][CH:35]=C)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:37])[C:12]=2[C@H:38]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:7][CH2:6]1)[CH:2]=C>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:45]([O:44][C@@H:38]([C:12]1[C:13]([CH3:37])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:49])([O:4][CH2:1][CH:2]=[CH:35][CH2:34][O:33][CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:24]2[N:23]=[N:22][N:21]([CH:25]=2)[CH2:20]3)[CH2:6][CH2:7]1)[C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH3:46])([CH3:47])[CH3:48]

Participants

4

Reactant 1

HCID 118318742(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-((allyloxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 131734901ethyl (2S)-2-(4,28-dimethyl-22,27-dioxa-1,5,7,8,11,12,13-heptazahexacyclo[26.2.2.16,9.111,14.02,7.015,20]tetratriaconta-2,4,6(34),8,12,14(33),15,17,19,24-decaen-3-yl)-2-[(2-methylpropan-2-yl)oxy]acetateYield 16.89%

Reagents, catalysts & solvents 2

HCID 11763533(1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene)(dichloro)((2-((propan-2-yl)oxy)phenyl)methylidene)rutheniumCatalystHCID 111,2-DichloroethaneSolvent

Procedure

To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(2-((allyloxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.055 g, 0.082 mmol) in 1,2-dichloroethane (20 mL) was added at once Hoveyda-Grubbs catalyst 2nd generation (2.56 mg, 4.09 μmol) at 70° C. and refluxed for 5 h. Then, cooled, concentrated and purified by prep-HPLC to afford a mixture of products and one major isomer. Trans-isomer (0.0089 g, 0.014 mmol, 16.89% yield), off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.37 (s, 1H), 7.94 (dd, J=1.1, 7.7 Hz, 1H), 7.39-7.46 (m, 2H), 7.32-7.36 (m, 1H), 6.73 (s, 1H), 6.00-6.13 (m, 2H), 5.98 (s, 1H), 5.89 (d, JAB=14.3 Hz, 1H), 5.65 (d, JAB=14.3 Hz, 1H), 4.58 (dt, J=2.3, 12.4 Hz, 1H), 4.49 (d, JAB=10.5 Hz, 1H), 4.40 (d, JAB=10.5 Hz, 1H), 4.08-4.22 (m, 4H), 3.95-4.05 (m, 2H), 3.75-3.82 (m, 1H), 3.03 (td, J=2.0, 11.5 Hz, 1H), 2.73-2.79 (m, 1H), 2.61 (s, 3H), 2.00 (dd, J=2.4, 13.6 Hz, 1H), 1.90 (dd, J=2.1, 13.7 Hz, 1H), 1.67-1.74 (m, 2H), 1.31 (s, 3H), 1.24 (s, 9H), 1.18 (t, J=7.1 Hz, 3H). LCMS (M+H)=644.6. This is contaminated with minor isomer.

Workup

  1. temperaturerefluxed for 5 h
  2. temperatureThen, cooled
  3. concentrationconcentrated
  4. custompurified by prep-HPLC
  5. customto afford
  6. additiona mixture of products and one major isomer

Sources & evidence

ORD record
ord-21cde064754241d88ac0cd8512d7b1e2
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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