Triethylamine → (3R)-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-N-{2-oxo-2-[(3R)-3-(2H-tetrazol-5-yl)pyrrolidin-1-yl]ethyl}-3-[4-(trifluoromethoxy)benzyl]-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamide

HRID 1040545Notes

Reaction equation

HRID 1040545 reaction equation
C(O[C:6](=[O:41])[CH2:7][NH:8][C:9]([C:11]1[N:15]2[C@:16]([CH3:40])([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[C:17](=[O:27])[N:18]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:14]2=[N:13][CH:12]=1)=[O:10])(C)(C)C.Cl.O1CCOCC1.[NH:49]1[CH2:53][CH2:52][C@@H:51]([C:54]2[N:55]=[N:56][NH:57][N:58]=2)[CH2:50]1.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([N:18]2[C:17](=[O:27])[C@@:16]([CH3:40])([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:33][CH:34]=3)[N:15]3[C:11]([C:9]([NH:8][CH2:7][C:6](=[O:41])[N:49]4[CH2:53][CH2:52][C@@H:51]([C:54]5[N:55]=[N:56][NH:57][N:58]=5)[CH2:50]4)=[O:10])=[CH:12][N:13]=[C:14]23)[CH:24]=[C:23]([Cl:25])[CH:22]=1

Participants

8

Reactant 6

HCID 8471TriethylamineHCID 181649HOAtHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 204431481,4-Dioxane hydrochlorideHCID 21025944(R)-5-(Pyrrolidin-3-yl)-2H-tetrazoleHCID 58431140{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-acetic acid tert-butyl ester

Product 1

HCID 58431106(3R)-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-N-{2-oxo-2-[(3R)-3-(2H-tetrazol-5-yl)pyrrolidin-1-yl]ethyl}-3-[4-(trifluoromethoxy)benzyl]-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamideYield 66.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

{[(R)-7-(3,5-Dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-acetic acid tert-butyl ester (0.061 g, 0.1 mmol) was dissolved in CH2Cl2 (0.5 mL) and 4N HCl/dioxane (1 mL) added. The solution was agitated on an orbital shaker for 14 h and then concentrated in vacuo. The resulting residue was dissolved in DMA (2 mL), and (R)-5-pyrrolidin-3-yl-2H-tetrazole (0.21 g, 0.15 mmol), HOAt (0.041 g, 0.3 mmol), triethylamine (0.09 mL, 0.6 mmol) and HATU (0.057 g, 0.15 mmol) were added. The reaction mixture was agitated for 14 h and then concentrated in vacuo. The residue was dissolved in DMSO (1 mL) and water (0.1 mL) and purified via reverse phase HPLC purification to afford 0.045 g of (3R)-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-N-{2-oxo-2-[(3R)-3-(2H-tetrazol-5-yl)pyrrolidin-1-yl]ethyl}-3-[4-(trifluoromethoxy)benzyl]-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamide as a white solid, m/z 680.1 [M+1]+

Workup

  1. concentrationconcentrated in vacuo
  2. dissolutionThe resulting residue was dissolved in DMA (2 mL)
  3. stirringThe reaction mixture was agitated for 14 h
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue was dissolved in DMSO (1 mL)
  6. customwater (0.1 mL) and purified via reverse phase HPLC purification

Sources & evidence

ORD record
ord-f7f4cbd8cfab4cc5b46a8b6ae0bb2c01
Source dataset
uspto-grants-2013_10
Patent number
US08552205B2

Reaction notes

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