Tetrahydrofuran → HCID 67959520, compound

HRID 1427779Notes

Reaction equation

HRID 1427779 reaction equation
C([O-])(=O)C.[NH4+].ClC(Cl)(Cl)C[O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:50])[C@@H:19]([NH:35][C:36](=[O:49])[C@@H:37]([NH:41][C:42](OC(C)(C)C)=[O:43])[CH:38]([CH3:40])[CH3:39])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:22]=2)[NH:13]1)=[O:11].O1[CH2:57][CH2:56][CH2:55][CH2:54]1>O.[Zn]>[C:31]([Si:28]([CH3:29])([CH3:30])[O:27][C:23]1[CH:22]=[C:21]([CH2:20][C@H:19]([NH:35][C:36](=[O:49])[C@@H:37]([NH:41][C:42](=[O:43])[CH2:57][CH2:56][CH:55]=[CH2:54])[CH:38]([CH3:40])[CH3:39])[C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]([OH:9])=[O:11])[NH:13]2)=[O:50])[CH:26]=[CH:25][CH:24]=1)([CH3:33])([CH3:34])[CH3:32]

Participants

6

Reactant 3

HCID 8028TetrahydrofuranHCID 517165Ammonium AcetateHCID 71225144HCID 71225144, compound

Product 1

HCID 67959520HCID 67959520, compoundYield 97%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 962WaterSolvent

Procedure

Ammonium acetate (548 mg, 7.11 mmol) was added to a mixture of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (750 mg, 1.016 mmol) and zinc dust (664 mg, 10.16 mmol) in tetrahydrofuran (20 mL) and water (7 mL) and the reaction mixture was stirred for 3 days at room temperature. The mixture was filtered through celite and the residue was washed with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and water, dried over anhydrous sodium sulfate and the solvent evaporated to afford (S)-1-[(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-((S)-3-methyl-2-pent-4-enoylamino-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (599 mg, 97%) as a colourless foam which was used crude in the next step. N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (265 mg, 1.38 mmol) and 4-dimethylaminopyridine (60 mg, 0.494 mmol) was added to a solution of (S)-1-[(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-((S)-3-methyl-2-pent-4-enoylamino-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (599 mg, 0.987 mmol) and (4-vinyl-pyridin-2-yl)-methanol (1.34 mmol) in dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 18 hours. The solution was washed with aqueous citric acid and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:4 to afford the title compound (386 mg, 54%) as a colourless foam. 1H NMR (300 MHz, CDCl3) δ0.20 (s, 6H), 0.88 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H), 0.97 (s, 9H), 1.46 (s, 9H), 1.5-2.2 (m, 7H), 2.6-3.1 (m, 3H), 3.55-3.65 (m, 1H), 3.92-3.98 (m, 1H), 4.25-4.35 (m, 1H), 5.07 (d, J=8.7 Hz, 1H), 5.27-5.31 (m, 2H), 5.57 (d, J=10.9 Hz, 1H), 5.72-5.80 (m, 1H), 6.03 (d, J=17.6 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 6.67-6.82 (m, 4H), 7.05-7.10 (m, 1H), 7.37 (s, 1H), 8.56 (d, J=5.1 Hz, 1H). LCMS (m/z) 724 [M+H], Tr=5.75 min.

Workup

  1. filtrationThe mixture was filtered through celite
  2. washthe residue was washed with ethyl acetate
  3. washThe organic layer was washed with an aqueous citric acid solution and water
  4. dry with materialdried over anhydrous sodium sulfate
  5. customthe solvent evaporated

Sources & evidence

ORD record
ord-c5dda96a5c6e4344a1eea27e101bf477
Source dataset
uspto-grants-2015_01
Patent number
US08933015B2

Reaction notes

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