Pyridine → ethyl 2-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-(dimethylamino)prop-1-ynyl)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate

HRID 472010Notes

Reaction equation

HRID 472010 reaction equation
[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][N:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]=2[CH:20]=1)#[N:2].[CH:21]12[N:27]([C:28]3[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([C:35]#[C:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH:29]=3)[CH:24]([CH2:25][CH2:26]1)[CH2:23][CH2:22]2.N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1.C(OCC)(=O)C>[CH:21]12[N:27]([C:28]3[CH:34]=[CH:33][C:31]([NH:32][C:12]([CH:10]4[O:11][C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=5[N:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]4)=[O:14])=[C:30]([C:35]#[C:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH:29]=3)[CH:24]([CH2:25][CH2:26]1)[CH2:23][CH2:22]2

Participants

7

Reactant 4

HCID 1049PyridineHCID 111923Propylphosphonic anhydrideHCID 575168474-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-(3-(dimethylamino)prop-1-ynyl)anilineHCID 593949876-Cyano-4-ethoxycarbonyl-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid

Product 1

HCID 67458399ethyl 2-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-(dimethylamino)prop-1-ynyl)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylateYield 61%

Reagents, catalysts & solvents 2

HCID 73012-MethyltetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 6-cyano-4-ethoxycarbonyl-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid (30 mg, 0.11 mmol) and 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)aniline (29 mg, 0.11 mmol) in 2-methyltetrahydrofuran (300 μL) was added pyridine (35 μL, 0.43 mmol) followed by T3P (173 μl, of 50% w/w, 0.27 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with ethyl acetate (10 mL) and washed with aqueous 10% NaHCO3 (2×5 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0-20% ethyl acetate/hexanes) provided ethyl 2-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-(dimethylamino)prop-1-ynyl)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (35 mg, 61% yield). LC/MS m/z 528.5 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.16 (s, 1H), 7.56 (dd, J=2.0, 8.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.96-6.92 (m, 2H), 5.17 (t, J=4.5 Hz, 1H), 4.23 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 4.10 (d, J=4.4 Hz, 2H), 3.44 (d, J=2.2 Hz, 2H), 2.23 (s, 6H), 1.62 (d, J=7.0 Hz, 4H), 1.38 (d, J=6.8 Hz, 4H), 1.24 (t, J=7.1 Hz, 3H).

Workup

  1. washwashed with aqueous 10% NaHCO3 (2×5 mL) and brine (10 mL)
  2. dry with materialThe organic phase was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customPurification by silica gel chromatography (0-20% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-0e633d9837e54721b824690d2834864b
Source dataset
uspto-grants-2014_01
Patent number
US08633189B2

Reaction notes

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