Dimethylformamide → HCID 73335341, compound

HRID 926283Notes

Reaction equation

HRID 926283 reaction equation
Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[C:7]12.[CH3:23][N:24](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[O:17]=[C:16]1[N:6]2[CH2:5][CH2:4][C:3]3[C:2]([C:23]#[N:24])=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]2=[CH:12][C:13]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[N:14][CH2:15]1

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 73335237HCID 73335237, compound

Product 1

HCID 73335341HCID 73335341, compound

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
170 °C

Procedure

A microwave flask was charged with 9-bromo-2-(thiophen-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 29) (145 mg, 0.39 mmol), Zn(CN)2 (191 mg, 1.63 mmol) and Pd(PPh3)4 (47 mg, 0.041 mmol) in DMF (4 mL) was heated to 170° C. for 18 h. The reaction was allowed to cool to RT, taken up in AcOEt and washed with H2O. The org. layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, hexane to hexan/AcOEt 1:1) and prep. HPLC (column: RP-C18 sunfire, 5 μm, 100×300 mm; solvent A: H2O+0.1% TFA; solvent B CH3CN; gradient (% B): 10-30% in 16 min; 50 mL/min). The product obtained was passed onto a SPE cartridge to release the free base, and the residue obtained was triturated in heptane/AcOEt to give the title compound (8 mg) as a yellow solid. UPLC-MS: MS 320.2 (M+H+); UPLC rt 0.87 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 3.07 (t, J=5.55 Hz, 2 H); 3.87 (br. s., 2 H); 4.29 (br. s., 2 H); 7.11 (t, J=4.14 Hz, 1 H); 7.51 (s, 1 H); 7.56 (t, J=7.87 Hz, 1 H); 7.66 (d, J=4.24 Hz, 2 H); 7.93 (d, J=7.47 Hz, 1 H); 8.42 (d, J=8.07 Hz, 1 H).

Workup

  1. temperatureto cool to RT
  2. washwashed with H2O
  3. dry with materiallayer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by flash chromatography (SiO2, hexane to hexan/AcOEt 1:1)
  7. customThe product obtained
  8. customthe residue obtained
  9. customwas triturated in heptane/AcOEt

Sources & evidence

ORD record
ord-9d5f95fdc82f4f7b91ddf0d4288fe266
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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