3-Methyl-5-(tributylstannyl)isoxazole → 2-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-9-(3-methylisoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

HRID 926313Notes

Reaction equation

HRID 926313 reaction equation
[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:24]([CH3:25])=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:26])[CH2:11][N:10]=3)=[C:19](I)[CH:18]=[CH:17][CH:16]=5)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:27][C:28]1[CH:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[O:30][N:29]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:24]([CH3:25])=[C:14]4[C:15]5[C:20]([CH2:21][CH2:22][N:13]4[C:12](=[O:26])[CH2:11][N:10]=3)=[C:19]([C:31]3[O:30][N:29]=[C:28]([CH3:27])[CH:32]=3)[CH:18]=[CH:17][CH:16]=5)[CH:8]=2)[CH2:3][CH2:2]1

Participants

5

Reactant 2

HCID 27632553-Methyl-5-(tributylstannyl)isoxazoleHCID 867113832-(4-cyclopropyl-1H-imidazol-1-yl)-9-iodo-1-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Product 1

HCID 733359232-(4-cyclopropyl-1H-imidazol-1-yl)-1-methyl-9-(3-methylisoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-oneYield 56.9%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

Example 107. A mixture of 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-iodo-1-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (8 mg, 17 μmol), 3-methyl-5-(tributylstannyl)isoxazole (10 mg, 26 μmol) and Pd(PPh3)4 (1.0 mg, 0.9 μmol) in dioxane (0.2 mL) is heated to 140° C. for 1.5 h under N2 in a microwave reactor. The mixture was then concentrated in vacuo the residue obtained was purified by SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton; eluent: 8% MeOH/CO2 for 1 min, then from 8% MeOH/CO2 to 13% MeOH/CO2 in 6 min; then from 13% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) to afford the title compound (4 mg) as a beige solid. UPLC-MS: MS 414.2 (M+H+); UPLC rt 0.88 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.74-0.88 (m, 4 H); 1.74-1.91 (m, 1 H); 2.18 (s, 3 H); 2.42 (s, 3 H); 2.81 (td, J=14.68, 5.27 Hz, 1 H); 3.17 (td, J=13.49, 3.64 Hz, 1 H); 3.45 (m., 1 H); 3.91-4.02 (m, 2 H); 4.70 (d, J=10.79 Hz, 1 H); 6.32 (s, 1 H); 6.95 (s, 1 H); 7.45 (t, J=7.65 Hz, 1 H); 7.56 (d, J=7.78 Hz, 1 H); 7.66-7.76 (m, 2 H).

Workup

  1. concentrationThe mixture was then concentrated in vacuo the residue
  2. customobtained
  3. customwas purified by SFC (column
  4. waitfrom 8% MeOH/CO2 to 13% MeOH/CO2 in 6 min
  5. waitthen from 13% MeOH/CO2 to 50% MeOH/CO2 in 1 min

Sources & evidence

ORD record
ord-9a10fff92b594a5dbbdddeee93c92237
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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