Triethylamine → (R)-1-[8-((R)-1-phenyl-propylcarbamoyI)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester

HRID 926396Notes

Reaction equation

HRID 926396 reaction equation
[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22](O)=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:48][O:49][C:50]([C@H:52]1[CH2:56][CH2:55][CH2:54][NH:53]1)=[O:51].C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH3:48][O:49][C:50]([C@H:52]1[CH2:56][CH2:55][CH2:54][N:53]1[C:22]([C:15]1[N:16]2[C:17]([CH2:18][O:19][CH2:20][CH2:21]2)=[C:13]([C:11](=[O:12])[NH:10][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH3:9])[CH:14]=1)=[O:23])=[O:51]

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 44629857Methyl D-prolinate hydrochlorideHCID 89726203HCID 89726203, compound

Product 1

HCID 89726390(R)-1-[8-((R)-1-phenyl-propylcarbamoyI)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid methyl esterYield 21%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of 8-((R)-1-phenyl-propylcarbamoyI)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11a) (200 mg, 0.61 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (91 mg, 0.670 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (128 mg, 0.670 mmol). The mixture was stirred for 45 min at 25° C., then (R)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (111 mg, 0.670 mmol) and triethylamine (123 mg, 1.218 mmol) were added and the mixture was stirred at 25° C. overnight. Excess dichloromethane was added and the mixture was washed consecutively with water, aqueous sodium hydrogencarbonate and brine. The organic layer was evaporated to dryness. The crude product was purified by flash chromatography (silica gel, elution with heptane/ethyl acetate) to give 55 mg (21%) of (R)-1-[8-((R)-1-phenyl-propylcarbamoyI)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester). LC/MS (method 4): Rt=1.21 min; m/z=440.29 (M+H+).

Workup

  1. stirringthe mixture was stirred at 25° C. overnight
  2. washthe mixture was washed consecutively with water, aqueous sodium hydrogencarbonate and brine
  3. customThe organic layer was evaporated to dryness
  4. customThe crude product was purified by flash chromatography (silica gel, elution with heptane/ethyl acetate)

Sources & evidence

ORD record
ord-1e207a771c8a48c1b6524f1f03b54527
Source dataset
uspto-grants-2016_03
Patent number
US09284333B2

Reaction notes

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