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 2285417ノート

反応式

HRID 2285417 の反応式
[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]

参加物

8

反応物 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

生成物 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 ester収率 53%

試薬・触媒・溶媒 1

HCID 6342Acetonitrile溶媒

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-be920d8532f24159b4d618eacf9cf987
出典データセット
uspto-grants-2015_09
特許番号
US09145441B2

反応ノート

読み込み中…