p-Toluenesulfonic acid → (2S)-2-(tert-Butoxy)-2-{4,25-dimethyl-10-oxo-19-oxa-1,7,11,30-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetic acid

HRID 1481974Notes

Reaction equation

HRID 1481974 reaction equation
[CH2:1]([O:4][C:5]1[CH:45]=[CH:44][CH:43]=[CH:42][C:6]=1[CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C@H:20]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:21]([O:23]C)=[O:22])=[C:15]([N:30]3[CH2:35][CH2:34][C:33]([CH2:37][CH2:38]C=C)([CH3:36])[CH2:32][CH2:31]3)[N:14]2[CH:41]=1)=[O:10])[CH:2]=[CH2:3].CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+].C([O-])(O)=O.[Na+].O[Li].O>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.O>[C:26]([O:25][C@@H:20]([C:16]1[C:17]([CH3:19])=[CH:18][C:13]2=[N:12][C:11]3=[CH:41][N:14]2[C:15]=1[N:30]1[CH2:35][CH2:34][C:33]([CH3:36])([CH2:37][CH2:38][CH2:3][CH2:2][CH2:1][O:4][C:5]2[CH:45]=[CH:44][CH:43]=[CH:42][C:6]=2[CH2:7][NH:8][C:9]3=[O:10])[CH2:32][CH2:31]1)[C:21]([OH:23])=[O:22])([CH3:29])([CH3:27])[CH3:28]

Participants

9

Reactant 5

HCID 6101p-Toluenesulfonic acidHCID 168937Lithium hydroxide, monohydrateHCID 516892Sodium BicarbonateHCID 4311764Sodium borohydrideHCID 118308904(S)-methyl 2-(2-((2-(allyloxy)benzyl)carbamoyl)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 118316260(2S)-2-(tert-Butoxy)-2-{4,25-dimethyl-10-oxo-19-oxa-1,7,11,30-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetic acidYield 33.3%

Reagents, catalysts & solvents 3

HCID 11763533(1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene)(dichloro)((2-((propan-2-yl)oxy)phenyl)methylidene)rutheniumCatalystHCID 111,2-DichloroethaneSolventHCID 962WaterSolvent

Procedure

A solution of (S)-methyl 2-(2-((2-(allyloxy)benzyl)carbamoyl)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.023 g, 0.037 mmol, 1 equiv) and TsOH (7 mg, 0.037 mmol, 1 equiv) in DCE (19 mL) was heated to 80° C. The Hoveyda Grubbs 2nd generation catalyst (5 mg, 0.007 mmol, 0.2 equiv) was added. The pale green brown solution was stirred for 2 h. Upon cooling to ambient temperature, the reaction was washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. The dark residue was then taken up in MeOH (2 mL) and NaBH4 (2 mg, 0.052 mmol, 1.4 equiv) was added. After stirring 1 h, the reaction was added to saturated aqueous NaHCO3 and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was taken up in 9:1 MeOH:water (2 mL) and LiOH.H2O (78 mg, 1.684 mmol, 50 equiv) was added. The reaction was heated to 60° C. for 6 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (7.1 mg, 31%). 1H NMR (500 MHz, DMSO-d6) δ 8.71-8.61 (m, 1H), 8.08 (s, 1H), 7.36 (d, J=7.0 Hz, 1H), 7.27-7.18 (m, 2H), 7.07 (d, J=8.2 Hz, 1H), 6.85 (t, J=7.3 Hz, 1H), 5.90 (s, 1H), 4.44-4.28 (m, 2H), 4.14 (td, J=10.6, 6.0 Hz, 2H), 3.68 (br. s., 2H), 3.06 (d, J=7.9 Hz, 1H), 2.57 (br. s., 1H), 2.37 (s, 3H), 2.09-1.93 (m, 3H), 1.68-1.25 (m, 9H), 1.17 (s, 9H), 0.98 (s, 3H); LCMS (ESI, M+1): 577.5.

Workup

  1. washthe reaction was washed with saturated aqueous NaHCO3
  2. dry with materialdried (Na2SO4)
  3. concentrationconcentrated in vacuo
  4. stirringAfter stirring 1 h
  5. extractionextracted with DCM (×3)
  6. dry with materialThe combined DCM extracts were dried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. temperatureThe reaction was heated to 60° C. for 6 h
  9. temperatureUpon cooling to ambient temperature
  10. filtrationthe reaction was filtered
  11. custompurified via preparative LC/MS with the following conditions
  12. waitGradient: 30-70% B over 20 minutes
  13. customa 5-minute hold

Sources & evidence

ORD record
ord-d1c52197f9434492ab27d9a9dfb70645
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

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