Diethylamine → (S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-Acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoylamino}-3-methyl-butyrylamino)-3-(3-methyl-oxetan-3-ylmethoxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloroethyl ester

HRID 2285417Notes

Reaction equation

HRID 2285417 reaction equation
[Cl:1][C:2]([Cl:50])([Cl:49])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:48])[C@@H:14]([NH:23][C:24](=[O:47])[C@@H:25]([NH:29][C:30](OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[O:31])[CH:26]([CH3:28])[CH3:27])[CH2:15][O:16][CH2:17][C:18]2([CH3:22])[CH2:21][O:20][CH2:19]2)[NH:8]1)=[O:6].[CH2:51]([NH:53][CH2:54][CH3:55])[CH3:52].C(O[C@@H](C1C=CC2[C:64](=[CH:65][C:66](/[CH:72]=[CH:73]/[C:74](C)([CH3:78])[C:75](O)=O)=[CH:67]C=2)N=1)C)(=O)C.[CH:80](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:122]([O:125][CH2:126][CH3:127])(=[O:124])[CH3:123]>C(#N)C>[Cl:49][C:2]([Cl:1])([Cl:50])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:48])[C@@H:14]([NH:23][C:24](=[O:47])[C@@H:25]([NH:29][C:30](=[O:31])[C:74]([CH3:78])([CH3:75])/[CH:73]=[CH:72]/[C:66]2[CH:67]=[C:54]3[C:55]([CH:80]=[CH:52][C:51]([C@H:126]([O:125][C:122](=[O:124])[CH3:123])[CH3:127])=[N:53]3)=[CH:64][CH:65]=2)[CH:26]([CH3:27])[CH3:28])[CH2:15][O:16][CH2:17][C:18]2([CH3:22])[CH2:19][O:20][CH2:21]2)[NH:8]1)=[O:6]

Participants

8

Reactant 6

HCID 8021DiethylamineHCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 866211442-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate MethanaminiumHCID 86709704(E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoic acidHCID 86709712(S)-1-[(S)-2-[(S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-methyl-butyrylamino]-3-(3-methyl-oxetan-3-ylmethoxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

Product 1

HCID 89945276(S)-1-[(S)-2-((S)-2-{(E)-4-[2-((R)-1-Acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoylamino}-3-methyl-butyrylamino)-3-(3-methyl-oxetan-3-ylmethoxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloroethyl esterYield 53%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To (S)-1-[(S)-2-[(S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-butyrylamino]-3-(3-methyl-oxetan-3-ylmethoxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.1 g, 1.46 mmol) in anhydrous acetonitrile (20 mL) at room temperature and under an atmosphere of nitrogen was added diethylamine (3.0 mL, 29.2 mmol). The reaction mixture was stirred for 2 h before concentrating in vacuo and co-evaporating from dichloromethane. This residue was dissolved in anhydrous acetonitrile (10 mL) and at 0° C. and under an atmosphere of nitrogen was added (E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoic acid (478 mg, 1.46 mmol), N,N-diisopropylethylamine (1.3 mL, 7.30 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (778 mg, 2.05 mmol). The solution was warmed to room temperature and stirred for 16 h. The reaction was diluted with ethyl acetate and quenched with 1 M hydrochloric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×). The organic layer was then dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 then 0:1 to give the title compound (650 mg, 53%) as a viscous clear oil. 1H NMR (300 MHz, CDCl3) δ 0.89 (d, J=6.5 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 1.22 (s, 3H), 1.49 (s, 3H), 1.63 (s, 3H), 1.69 (d, J=6.7 Hz, 3H), 1.63-1.95 (m, 4H), 2.08-2.14 (m, 1H), 2.18 (s, 3H), 3.26-3.45 (m, 3H), 3.48-3.60 (m, 1H), 3.71-3.87 (m, 2H), 3.89-4.03 (m, 1H), 4.23 (d, J=9.2 Hz, 1H), 4.27-4.41 (m, 3H), 4.47 (d, J=5.6 Hz, 1H), 4.51 (d, J=5.6 Hz, 1H), 4.67 (d, J=11.8 Hz, 1H), 4.92 (d, J=11.8 Hz, 1H), 5.69-5.80 (m, 1H), 6.06 (q, J=6.5 Hz, 1H), 6.39 (d, J=8.3 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.64, 6.78 (ABq, J=16.3 Hz, 2H), 7.44 (d, J=8.5 Hz, 1H), 7.63-7.71 (m, 1H), 7.77 (d, J=8.5 Hz, 1H), 8.05 (s, 1H), 8.13 (d, J=8.5 Hz, 1H). LCMS (m/z) 842.4 [M+H], Tr=3.02 min.

Workup

  1. concentrationbefore concentrating in vacuo and co-evaporating from dichloromethane
  2. dissolutionThis residue was dissolved in anhydrous acetonitrile (10 mL) and at 0° C. and under an atmosphere of nitrogen
  3. stirringstirred for 16 h
  4. customquenched with 1 M hydrochloric acid
  5. customThe organic layer was separated
  6. washwashed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×)
  7. customThe organic layer was then dried through a hydrophobic frit
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-be920d8532f24159b4d618eacf9cf987
Source dataset
uspto-grants-2015_09
Patent number
US09145441B2

Reaction notes

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