1-Hydroxybenzotriazole → 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(4-trifluoromethyl-phenyl)-propyl]-amide

HRID 926392Notes

Reaction equation

HRID 926392 reaction equation
[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18](O)=[O:19])[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:43][C:44]([F:56])([F:55])[C:45]1[CH:50]=[CH:49][C:48]([C@H:51]([NH2:54])[CH2:52][CH3:53])=[CH:47][CH:46]=1>CN(C)C=O>[F:43][C:44]([F:55])([F:56])[C:45]1[CH:46]=[CH:47][C:48]([C@H:51]([NH:54][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:19])[CH2:52][CH3:53])=[CH:49][CH:50]=1

Participants

6

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 51440026(R)-1-(4-(Trifluoromethyl)phenyl)propan-1-amineHCID 897267566-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid

Product 1

HCID 716961946-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(4-trifluoromethyl-phenyl)-propyl]-amideYield 65%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (150 mg, 0.593 mmol) in dimethylformamide (4 ml) was added 1-hydroxybenzotriazole (80 mg, 0.593 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.593 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(4-trifluoromethyl-phenyl)-propylamine (120 mg, 0.593 mmol) was added and the mixture was stirred at 25° C. overnight. The mixture was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 163 mg (65%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(4-trifluoromethyl-phenyl)-propyl]-amide as white solid. LC/MS (method 4): Rt=1.29 min; m/z=464.22 (M+H+). 1H-NMR: δ (ppm)=8.18 (1H, d), 7.69 (2H, d), 7.55 (2H, d), 7.26 (1H, s), 4.96 (1H, d), 4.83-4.92 (2H, m), 4.20-4.30 (2H, m), 3.92-3.99 (2H, m), 3.80-3.85 (1H, m), 3.69, (2H, bs), 2.06 (1H, m), 1.96 (1H, m), 1.76-1.85 (3H, m), 1.54-1.59 (1H, m), 1.19 (3H, d), 0.90 (3H, t).

Workup

  1. stirringthe mixture was stirred at 25° C. overnight
  2. customThe mixture was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-3cf8466728f54cd4840c18261f070075
Source dataset
uspto-grants-2016_03
Patent number
US09284333B2

Reaction notes

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