1-Hydroxybenzotriazole → N-((1R)-1-(N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-carbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester

HRID 366194

Reaction equation

HRID 366194 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=C[C:17]=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C@@H:43]([NH:48][CH3:49])[C:44]([NH:46][CH3:47])=[O:45].C(N(C(C)C)CC)(C)C.C(OC(CNC([CH2:72][C:73]1[CH:82]=[CH:81][C:80]2[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=2)[CH:74]=1)C(O)=O)=O)(C)(C)C.ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@@H:9]([C:10](=[O:12])[N:48]([C@@H:43]([C:44](=[O:45])[NH:46][CH3:47])[CH2:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[F:35])[CH3:49])[CH2:72][C:73]1[CH:82]=[CH:81][C:80]2[C:75](=[CH:76][CH:77]=[CH:78][CH:79]=2)[CH:74]=1)[CH3:17])([CH3:2])([CH3:3])[CH3:4]

Participants

9

Reactant 7

HCID 757711-HydroxybenzotriazoleHCID 78288N-(tert-butoxycarbonyl)glycineHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 223270012-(Tert-butoxycarbonylmethylamino)-3-(2-naphthyl)propionic acidHCID 54111884(2R)-3-(2-Fluorophenyl)-N-methyl-2-(methylamino)propionamide

Product 1

HCID 53671638N-((1R)-1-(N-((1R)-2-(2-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-carbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylesterYield 69%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

Tert-Butoxycarbonylaminoacetic acid (0.18 g; 2.39 mmol) was dissolved in methylene chloride (20 mL). 1-Hydroxybenzotriazole (0.32 g; 2.39 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.55 g; 2.87 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-3-(2-Fluorophenyl)-N-methyl-2-(methylamino)propionamide (1.0 g; 4.78 mmol) and diisopropylethylamine (0.9 mL; 5.26 mmol) was added and the reaction mixture was stirred for 12 hours at room temperature. A mixture of 2-(tert-butoxycarbonylmethylamino)-3-(2-naphthyl)propionic acid (0.78 g; 2.39 mmol), 1-hydroxy-7-azabenzotriazole (0.33 g; 2.39 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.55 g; 2.87 mmol) were dissolved in methylene chloride (20 mL) and added to the reaction mixture. The reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (50 mL) was added and the reaction mixture was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 30 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 30 mL) and water (30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2.5×30 cm) using ethyl acetate/heptane (2:1) as eluent to afford 0.86 g of N-((1R)-1-(N-((1R)-2-(2-fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methyl-carbamic acid tert-butylester.

Workup

  1. stirringthe reaction mixture was stirred for 12 hours at room temperature
  2. additionadded to the reaction mixture
  3. stirringThe reaction mixture was stirred for 12 hours at room temperature
  4. washthe reaction mixture was washed with water (30 mL)
  5. dry with materialan aqueous solution of sodium hydrogen sulfate (10%; 30 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 30 mL) and water (30 mL) and dried (magnesium sulfate)
  6. customThe solvent was removed in vacuo
  7. customthe residue was chromatographed on silica (2.5×30 cm)

Sources & evidence

ORD record
ord-b7f07d609a0d482bab4ae05f7823e7e8
Source dataset
uspto-grants-2000_10
Patent number
US06127391

Linked notes

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