1-Hydroxybenzotriazole → Rac.-n-[2-chloro-4-[[[(1h-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester

HRID 1058412Notes

Reaction equation

HRID 1058412 reaction equation
F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:25][C:26]1[CH:34]=[C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[CH:41][CH:40]=2)=[O:36])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.[CH3:48][O:49][C:50](=[O:59])[CH:51]([P:53]([O:57][CH3:58])([O:55][CH3:56])=[O:54])[NH2:52].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:48][O:49][C:50](=[O:59])[CH:51]([P:53]([O:55][CH3:56])([O:57][CH3:58])=[O:54])[NH:52][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[CH:41][CH:40]=2)=[O:36])=[CH:34][C:26]=1[Cl:25]

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 11084793Methyl 2-amino-2-(dimethoxyphosphoryl)acetateHCID 186730192-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid

Product 1

HCID 23560740Rac.-n-[2-chloro-4-[[[(1h-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl esterYield 72%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.4 g, 6.4 mmol) was added to a solution of 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid (Example 117; 1.9 g, 5.8 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 2.10 g, 10.6 mmol) in N,N-dimethylformamide (20 mL). 1-hydroxybenzotriazole (861 mg, 6.4 mmol) was then added, followed by diisopropylethylamine (2 mL, 11.6 mmol). The solution was stirred overnight at room temperature and then it was concentrated under high vacuum to remove N,N-dimethylformamide. The residue was partitioned between water and ethyl acetate and the separated organic phase was washed in turn with cold 1N hydrochloric acid solution, cold saturated sodium bicarbonate solution and brine, then was dried (MgSO4), filtered and evaporated in vacuo. The crude product was chromatographed over silica gel (0-4% methanol/dichloromethane) to give rac.-N-[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (2.1 g, 72% yield) which was used in subsequent reactions without further purification.

Workup

  1. concentrationit was concentrated under high vacuum
  2. customto remove N,N-dimethylformamide
  3. customThe residue was partitioned between water and ethyl acetate
  4. washthe separated organic phase was washed in turn with cold 1N hydrochloric acid solution, cold saturated sodium bicarbonate solution and brine
  5. dry with materialwas dried (MgSO4)
  6. filtrationfiltered
  7. customevaporated in vacuo
  8. customThe crude product was chromatographed over silica gel (0-4% methanol/dichloromethane)

Sources & evidence

ORD record
ord-e68a5f6e859d4f20b699d18394921b61
Source dataset
uspto-grants-2003_02
Patent number
US06515124B2

Reaction notes

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