Sodium Hydroxide → (2S)-2-(4,26-dimethyl-20,25-dioxa-1,5,7,8,11,12,13-heptazahexacyclo[24.2.2.16,9.111,14.115,19.02,7]tritriaconta-2,4,6(33),8,12,14(32),15(31),16,18-nonaen-3-yl)-2-[(2-methylpropan-2-yl)oxy]acetic acid

HRID 921084Notes

Reaction equation

HRID 921084 reaction equation
[CH2:1]([O:4][C:5]1([CH3:48])[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]=[C:28]([O:32][CH2:33]C=C)[CH:27]=5)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:38]([O:40]CC)=[O:39])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[OH-].[Na+]>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.CO.[Pd]>[C:44]([O:43][C@@H:37]([C:12]1[C:13]([CH3:36])=[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]([CH3:48])([O:4][CH2:1][CH2:2][CH2:3][CH2:33][O:32][C:28]2[CH:27]=[C:26]([C:24]4[N:23]=[N:22][N:21]([CH:25]=4)[CH2:20]3)[CH:31]=[CH:30][CH:29]=2)[CH2:6][CH2:7]1)[C:38]([OH:40])=[O:39])([CH3:45])([CH3:46])[CH3:47]

Participants

7

Reactant 2

HCID 14798Sodium HydroxideHCID 118318752(S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(3-(allyloxy)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 118318746(2S)-2-(4,26-dimethyl-20,25-dioxa-1,5,7,8,11,12,13-heptazahexacyclo[24.2.2.16,9.111,14.115,19.02,7]tritriaconta-2,4,6(33),8,12,14(32),15(31),16,18-nonaen-3-yl)-2-[(2-methylpropan-2-yl)oxy]acetic acidYield 37.7%

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 11763533(1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene)(dichloro)((2-((propan-2-yl)oxy)phenyl)methylidene)rutheniumCatalystHCID 111,2-DichloroethaneSolventHCID 887MethanolSolvent

Procedure

To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(3-(allyloxy)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.018 g, 0.027 mmol) in 1,2-dichloroethane (15 mL) was added at once Hoveyda-Grubbs catalyst 2nd generation (0.857 mg, 1.368 μmol) at 70° C. and refluxed for 2 h. Then, cooled, 10% Pd/C (2.91 mg, 2.74 μmol) was added and stirred under balloon H2 atmosphere for 5 h. Then, filtered, concentrated and the dark residue was refluxed with NaOH (0.137 ml, 0.137 mmol) in MeOH (2 mL) for 6 h. Then, cooled and purified by pre-HPLC to afford desired product (0.0064 g, 10.18 μmol, 37.2% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.16-7.20 (m, 1H), 6.90-6.95 (m, 1H), 6.61 (s, 1H), 5.73-5.87 (m, 3H), 4.24-4.37 (m, 2H), 4.16-4.23 (m, 1H), 3.73 (t, J=11.4 Hz, 1H), 3.49-3.59 (m, 3H), 3.03 (d, J=11.8 Hz, 1H), 2.59 (s, 3H), 1.88-2.04 (m, 4H), 1.74-1.82 (m, 2H), 1.52-1.72 (m, 2H), 1.26 (s, 3H), 1.25 (s, 9H). LCMS (M+H)=604.6.

Workup

  1. temperaturerefluxed for 2 h
  2. temperatureThen, cooled
  3. filtrationThen, filtered
  4. concentrationconcentrated
  5. temperatureThen, cooled
  6. custompurified by pre-HPLC

Sources & evidence

ORD record
ord-5d36fe436378434d9ef1b68b293dbba3
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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