1-Hydroxybenzotriazole → 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl 3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester

HRID 1726783Notes

Reaction equation

HRID 1726783 reaction equation
C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:25])[C@H:14]([CH2:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[NH2:15].[Cl:26][C:27]1[CH:35]=[C:34]([C:36]([NH:38][CH2:39][C:40]2[CH:48]=[CH:47][CH:46]=[C:45]3[C:41]=2[CH:42]=[N:43][N:44]3[CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:37])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]([NH:38][CH2:39][C:40]2[CH:48]=[CH:47][CH:46]=[C:45]3[C:41]=2[CH:42]=[N:43][N:44]3[CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:37])[CH:33]=[CH:32][C:28]=1[C:29]([NH:15][C@H:14]([C:13]([O:12][CH3:11])=[O:25])[CH2:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])=[O:30]

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 226615142-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acidHCID 688207093-(thiophene-2-carbonyl)amino-L-alanine methyl ester hydrochloride

Product 1

HCID 1317230362-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl 3-(thiophene-2-carbonyl)amino-L-alanine, methyl esterYield 102.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Diisopropylethylamine (0.147 mL, 0.84 mmol) was added to a solution of 3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester hydrochloride (Example 301; 58 mg, 0.22 mmol), 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid (Example 39; 70 mg, 0.169 mmol), HBTU (78 mg, 0.21 mmol), and HOBT (27 mg, 0.20 mmol) in DMF (2 mL). The solution was allowed to stir at room temperature overnight, and it was then concentrated to remove most of the DMF. Ethyl acetate was added, and the solution was washed with saturated aqueous sodium hydrogen carbonate (twice), dilute acid, and brine, dried (MgSO4), filtered, evaporated and chromatographed (2% methanol/dichloromethane) to give N-[2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (108 mg, 102%) as a tan solid.

Workup

  1. concentrationit was then concentrated
  2. customto remove most of the DMF
  3. additionEthyl acetate was added
  4. washthe solution was washed with saturated aqueous sodium hydrogen carbonate (twice),
  5. additiondilute acid, and brine
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customchromatographed (2% methanol/dichloromethane)

Sources & evidence

ORD record
ord-2a64f51972e945fd823f3a1753873137
Source dataset
uspto-grants-2009_02
Patent number
US07491741B2

Reaction notes

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