(S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2,4-difluoro-6-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid → (2S)-2-(tert-butoxy)-2-[(20S)-14,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17,22-octaen-3-yl]acetic acid

HRID 921127Notes

Reaction equation

HRID 921127 reaction equation
[CH2:1]([O:4][C:5]1([CH3:47])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[C:28]([O:29][C@H:30]([CH2:32][CH:33]=C)[CH3:31])=[CH:27][C:26]([F:35])=[CH:25][C:24]=4[F:36])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:37])[C:12]=2[C@H:38]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:39]([OH:41])=[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.[Cu]I>[C:43]([O:42][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]([CH3:47])([O:4][CH2:1][CH:2]=[CH:33][CH2:32][C@H:30]([CH3:31])[O:29][C:28]2[C:23]([CH2:22][O:21][CH2:20]3)=[C:24]([F:36])[CH:25]=[C:26]([F:35])[CH:27]=2)[CH2:6][CH2:7]1)[C:39]([OH:41])=[O:40])([CH3:45])([CH3:44])[CH3:46]

Participants

5

Reactant 1

HCID 118307077(S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2,4-difluoro-6-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid

Product 1

HCID 123222684(2S)-2-(tert-butoxy)-2-[(20S)-14,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17,22-octaen-3-yl]acetic acidYield 8.3%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 11763533(1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene)(dichloro)((2-((propan-2-yl)oxy)phenyl)methylidene)rutheniumCatalystHCID 111,2-DichloroethaneSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2,4-difluoro-6-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (0.030 g, 0.046 mmol) in DCE (4 mL) were added Hoveyda-Grubbs catalyst 2nd generation (7.16 mg, 0.011 mmol) and copper(I) iodide (8.70 mg, 0.046 mmol) and the mixture was stirred at 90° C. After 1.5 h, the mixture was cooled to rt and filtered and concentrated. The crude material was purified via preparative HPLC to afford (2S)-2-(tert-butoxy)-2-[(20S)-14,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17,22-octaen-3-yl]acetic acid (2.4 mg, 5.67% yield). 1H NMR (500 MHz, DMSO-d6) δ: 6.91 (d, J=11.7 Hz, 1H), 6.77 (t, J=9.5 Hz, 1H), 6.51 (s, 1H), 6.09-5.95 (m, 1H), 5.87 (d, J=8.1 Hz, 1H), 5.81-5.62 (m, 1H), 4.81-4.61 (m, 4H), 4.57-4.39 (m, 2H), 3.96-3.70 (m, 3H), 2.61-2.39 (m, 7H), 1.96-1.79 (m, 2H), 1.75-1.61 (m, 1H), 1.61-1.46 (m, 1H), 1.29 (s, 1H), 1.24-1.19 (m, 3H), 1.18-1.12 (m, 9H). LCMS (M+H) calcd for C33H43F2N4O6: 629.31. found: 629.3.

Workup

  1. temperaturethe mixture was cooled to rt
  2. filtrationfiltered
  3. concentrationconcentrated
  4. customThe crude material was purified via preparative HPLC

Sources & evidence

ORD record
ord-68a3f0f76f014f46a1de34ec8a99911b
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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