1-Hydroxybenzotriazole → (s)-n-((2s,3r)-4-((1s,3r)-3-(Allyloxy)-6-methoxy-2,3-dihydro-1h-inden-1-yl-amino)-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-yl)-2-(n-methylpentyl-sulfon-amido)pent-4-enamide

HRID 501758Notes

Reaction equation

HRID 501758 reaction equation
[CH3:1][N:2]([C@@H:11]([CH2:15][CH:16]=[CH2:17])[C:12]([OH:14])=O)[S:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])=[O:4].CCN=C=NCCC[N+](C)(C)C.[I-].ON1C2C=CC=CC=2N=N1.[CH2:41]([O:44][C@H:45]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[C@@H:47]([NH:56][CH2:57][C@@H:58]([OH:70])[C@@H:59]([NH2:69])[CH2:60][C:61]2[CH:66]=[C:65]([Cl:67])[CH:64]=[C:63]([Cl:68])[CH:62]=2)[CH2:46]1)[CH:42]=[CH2:43]>C(N(CC)CC)C.CN(C)C=O>[CH2:41]([O:44][C@H:45]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[C@@H:47]([NH:56][CH2:57][C@@H:58]([OH:70])[C@@H:59]([NH:69][C:12](=[O:14])[C@@H:11]([N:2]([CH3:1])[S:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:4])=[O:5])[CH2:15][CH:16]=[CH2:17])[CH2:60][C:61]2[CH:62]=[C:63]([Cl:68])[CH:64]=[C:65]([Cl:67])[CH:66]=2)[CH2:46]1)[CH:42]=[CH2:43]

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 1222421-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide methiodideHCID 59423741(s)-2-(n-Methylpentylsulfonamido)pent-4-enoic acidHCID 59423767(2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-dichloro-phenyl)butan-2-ol

Product 1

HCID 68464736(s)-n-((2s,3r)-4-((1s,3r)-3-(Allyloxy)-6-methoxy-2,3-dihydro-1h-inden-1-yl-amino)-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-yl)-2-(n-methylpentyl-sulfon-amido)pent-4-enamideYield 44%

Reagents, catalysts & solvents 2

HCID 8471TriethylamineCatalystHCID 6228DimethylformamideSolvent

Procedure

Step DL (1): A mixture of 28.7 mg (S)-2-(N-methylpentylsulfonamido)pent-4-enoic acid (0.11 mmol, from Preparation J), 24.8 mg 1-[3-(dimethyamino)propyl]-3-ethyl carbodiimide methiodide (0.083 mmol), 18 mg 1-hydroxybenzotriazole, 3 drops triethylamine and 1 mL dimethyl-formamide was stirred for 15 minutes at rt. The mixture was then added to 21 mg (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-dichloro-phenyl)butan-2-ol (0.046 mmoles, from Preparation BG) and the reaction mixture was allowed to stand at rt overnight. The reaction mixture was subjected to preparative HPLC, with the peak at 9.8 min collected to yield 14.1 mg (S)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl-amino)-1-(3,5-dichlorophenyl)-3-hydroxybutan-2-yl)-2-(N-methylpentyl-sulfon-amido)pent-4-enamide as a clear oil. LC-MS Rt 2.18 min (method A), (M+H)+=696.0, 698.0; HRMS (M+H)+=696.2653; 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J=8.2, 1H) 7.19 (s, 1H) 7.14 (s, 2H) 6.94 (d, J=2.1, 1H) 6.84 (d of d, J=8.2, 2.4, 1H) 6.68 (d, J=9.1, 1H) 5.95 (m, 1H) 5.69 (m, 1H) 5.31 (d, J=17, 1H) 5.2-5.08 (m, 3H) 4.77 (t, J=5.5, 1H) 4.17 (d of d, J=9.5, 5.7, 1H) 4.10 (m, 1H) 3.80 (s, 3H) 3.51 (m, 1H) 3.12 (d of d, J=14.3, 3.7, 1H) 2.90 (m, 4H) 2.67 (m, 4H) 2.54 (s, 3H) 2.31 (m, 2H) 1.93 (d, J=13.4 of t, J=4.6, 1H) 1.75 (m, 2H) 1.33 (m, 4H) 0.90 (t, J=7, 3H).

Workup

  1. waitto stand at rt overnight
  2. waitThe reaction mixture was subjected to preparative HPLC, with the peak at 9.8 min
  3. customcollected

Sources & evidence

ORD record
ord-ab49b931bfa5443eae070fb25b38b661
Source dataset
uspto-grants-2010_08
Patent number
US07772221B2

Reaction notes

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