Triethylamine → N-[(1R)-1-[3-chloro-4-(trifluoromethyl)phenyl]propyl]-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide

HRID 926389Notes

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]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[Cl:44][C:45]1[CH:46]=[C:47]([C@H:55]([NH2:58])[CH2:56][CH3:57])[CH:48]=[CH:49][C:50]=1[C:51]([F:54])([F:53])[F:52].C(N(CC)CC)C>CN(C)C=O>[Cl:44][C:45]1[CH:46]=[C:47]([C@H:55]([NH:58][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:20])[CH2:56][CH3:57])[CH:48]=[CH:49][C:50]=1[C:51]([F:53])([F:54])[F:52]

Participants

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) (75 mg, 0.270 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol). The mixture was stirred for 2 h at 50° C., then (R)-1-(3-chloro-4-trifluoromethyl-phenyl)-propylamine hydrochloride (81 mg, 0.3 mmol) and triethylamine (82 mg, 0.81 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 98 mg (73%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(3-chloro-4-trifluoromethyl-phenyl)-propyl]-amide as white solid. LC/MS (method 3): Rt=2.03 min; m/z=498.22 (M+H+). 1H-NMR: δ (ppm)=8.20 (1H, d), 7.83 (1H, d), 7.67 (1H, s), 7.50 (1H, d), 7.25 (1H, s), 4.96 (1H, d), 4.83-4.91 (m, 2H), 4.18-4.30 (2H, m), 3.92-4.01 (2H, m), 3.79-3.85 (1H, m), 3.69 (2H, bs), 2.07 (1H, m), 1.96 (1H, m), 1.76-1.85 (3H, m), 1.54-1.60 (1H, m), 1.19 (3H, d), 0.90 (3H, t).

Workup

stirringthe mixture was stirred at 25° C. overnight
filtrationThe mixture was filtered through a small filter cartridge
customthe solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record: ord-e33c3d9868ec4f709391bc4a02e04985
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09284333B2

Reaction notes

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