Trifluoroacetic acid → N-(2-(2-(2-(4-(1-((E)-3-(6-Bromopyridin-2-yl)-2-cyanoacrylamido)butyl)phenoxy)ethoxy)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide

HRID 2406598Notes

Reaction equation

HRID 2406598 reaction equation
[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:47]#[N:48])/[C:10]([NH:12][CH:13]([C:17]2[CH:46]=[CH:45][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:30]([C:38](OC(C)(C)C)=[O:39])C(OC(C)(C)C)=O)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1C(=O)N(OC([CH2:66][CH2:67][CH2:68][CH2:69][C@@H:70]2[S:74][CH2:73][C@@H:72]3[NH:75][C:76]([NH:78][C@H:71]23)=[O:77])=O)C(=O)C1.CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:47]#[N:48])/[C:10]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][NH:30][C:38](=[O:39])[CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]3[C@@H:71]4[C@@H:72]([NH:75][C:76](=[O:77])[NH:78]4)[CH2:73][S:74]3)=[CH:45][CH:46]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 6710714Biotin N-hydroxysuccinimide esterHCID 88569330(E)-(2-(2-(2-(4-(1-(3-(6-Bromopyridin-2-yl)-2-cyanoacrylamido)butyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester

Product 1

HCID 87168264N-(2-(2-(2-(4-(1-((E)-3-(6-Bromopyridin-2-yl)-2-cyanoacrylamido)butyl)phenoxy)ethoxy)ethoxy)ethyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamideYield 51.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of (E)-(2-(2-(2-(4-(1-(3-(6-bromopyridin-2-yl)-2-cyanoacrylamido)butyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (47; 105 mg, 0.14 mmol) and trifluoroacetic acid (0.3 mL) was stirred in dichloromethane (3 mL) for 1.5 hours. The solution was concentrated and the residue was dissolved in N,N-dimethylformamide. To this solution at ice bath temperature was added D-biotin N-hydroxysuccinimide ester (49 mg, 0.14 mmol) and DIPEA (75 μL, 0.43 mmol). The resulting mixture was stirred at this temperature for 2 hours and then partitioned between dichloromethane and water. The organic phase was washed with water (2×) and sat. brine, dried over sodium sulfate, and concentrated to afford an oil. Purification by flash silica gel column chromatography, eluting with 7:93 methanol/dichloromethane, provided 48 (55 mg, 51%) as a pale yellow oil: (MS (ES+) m/z 757.2 (M+H)+.

Workup

  1. concentrationThe solution was concentrated
  2. dissolutionthe residue was dissolved in N,N-dimethylformamide
  3. custompartitioned between dichloromethane and water
  4. washThe organic phase was washed with water (2×) and sat. brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated
  7. customto afford an oil
  8. customPurification by flash silica gel column chromatography
  9. washeluting with 7:93 methanol/dichloromethane

Sources & evidence

ORD record
ord-273e9ab7e60649ca9346139ca20daeaf
Source dataset
uspto-grants-2014_08
Patent number
US08809377B2

Reaction notes

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