4-Pentenoic acid → HCID 67960544, compound

HRID 1895782Notes

Reaction equation

[Cl:1][C:2]([Cl:40])([Cl:39])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:38])[C@@H:14]([NH:30][C:31](=[O:37])[C@@H:32]([NH2:36])[CH:33]([CH3:35])[CH3:34])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:17]=2)[NH:8]1)=[O:6].[C:41](O)(=[O:46])[CH2:42][CH2:43][CH:44]=[CH2:45].C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>C(#N)C>[Cl:40][C:2]([Cl:1])([Cl:39])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:38])[C@@H:14]([NH:30][C:31](=[O:37])[C@@H:32]([NH:36][C:41](=[O:46])[CH2:42][CH2:43][CH:44]=[CH2:45])[CH:33]([CH3:35])[CH3:34])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24])[CH:17]=2)[NH:8]1)=[O:6]

Participants

Conditions

Temperature: 0 °C

Procedure

A solution 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 (2.21 g, 3 mmol) in dichloromethane (30 mL) was stirred at 0° C. under nitrogen. Trimethylsilyl trifluoromethanesulfonate (1.00 g, 0.82 mL, 4.5 mmol) was added and the reaction mixture was stirred at 0° C. for 40 minutes. N,N-Diisopropylethylamine (1.55 g, 2.1 mL, 12 mmol) was added and the solvent was evaporated to afford (S)-1-{(S)-2-((S)-2-amino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (3 mmol), which was used crude in the next step. A mixture of crude (S)-1-{(S)-2-((S)-2-amino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (3 mmol) in acetonitrile (30 mL) was stirred at 0° C. under nitrogen. 4-Pentenoic acid (330 mg, 3.3 mmol) and N,N-diisopropylethylamine (1.55 g, 2.1 mL, 12 mmol) was added followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.6 g, 4.2 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic extract was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 3:1 to 1:3 to afford the title compound (1.46 g, 68%) as a gum. 1H NMR (300 MHz, CDCl3) δ0.20 (s, 6H), 0.92 (d, J=6.2 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 0.99 (s, 9H), 1.50-2.50 (m, 10H), 2.80-3.02 (m, 3H), 3.50 (d, J=10.7 Hz, 1H), 4.20-4.26 (m, 1H), 4.31 (dd, J=8.5, 6.0 Hz, 1H), 4.62 (d, J=12.0 Hz, 1H), 4.92 (d, J=12.0 Hz, 1H), 5.03 (dd, J=10.2, 1.5 Hz, 1H), 5.10 (dd, J=17.2, 1.5 Hz, 1H), 5.70-5.90 (m, 2H), 6.10 (d, J=8.5 Hz, 1H), 6.43 (d, J=8.3 Hz, 1H), 6.68-6.74 (m, 2H), 6.82 (d, J=7.6 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H). LCMS (m/z) 719/721 [M+H], Tr=3.89 min.

Workup

stirringthe reaction mixture was stirred at room temperature for 3 hours
customThe solvent was evaporated
customthe residue was partitioned between ethyl acetate and water
extractionThe organic extract
customwas separated
washwashed with brine
dry with materialdried over anhydrous sodium sulfate
customevaporated
customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record: ord-b97b00ef421d4afd96e7354d48c28b95
Source dataset: uspto-grants-2013_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08513184B2

Reaction notes

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