Acetate → 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4lambda5[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

HRID 562433Notes

Reaction equation

HRID 562433 reaction equation
[CH3:1][P:2]1(=[O:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[N:37]([CH3:58])[C:38]3[C:47]4[C:46](=[O:48])[NH:45][C:44]([CH:49](OC(=O)C)[CH:50]=[CH2:51])=[C:43]([CH3:56])[C:42]=4[CH:41]=[CH:40][C:39]=3[N:57]=2)=[C:31]([CH3:59])[CH:30]=1.C([O-])(=O)C>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[N:37]([CH3:58])[C:38]3[C:47]4[C:46](=[O:48])[NH:45][C:44]([CH:49]=[CH:50][CH2:51][N:5]5[CH2:6][CH2:7][P:2]([CH3:1])(=[O:8])[CH2:3][CH2:4]5)=[C:43]([CH3:56])[C:42]=4[CH:41]=[CH:40][C:39]=3[N:57]=2)=[C:31]([CH3:59])[CH:30]=1

Participants

6

Reactant 4

HCID 175AcetateHCID 11776TriphenylphosphineHCID 552988994-Methyl-1,4lambda5-azaphosphinan-4-one2×HCID 66832334acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester

Product 1

HCID 668329372-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4lambda5[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-oneYield 42%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a glass scintillation vial was added 4-methyl-[1,4]azaphosphinane 4-oxide (100 mg, 0.75 mmol). To a separate glass vial was added tris(dibenzylacetone)dipalladium (28 mg, 0.031 mmol), triphenylphosphine (30 mg, 0.12 mmol), and THF (2.5 mL). The resulting solution was stirred for 20 minutes, then acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (0.270 g, 0.621 mmol) was added as a solution in THF (7.0 mL), followed by TEA (0.90 mL, 12.2 mmol). Of the resulting solution, 2.4 mL (0.15 mmol total allylic acetate) was transferred to the vial containing 4-methyl-[1,4]azaphosphinane 4-oxide. The solution was stirred at room temperature for 20 h. The solvent was removed in vacuo and the resulting solid redissolved in MeCN (2 mL) and DMSO (2 mL). The solution was filtered, then purified directly by preparative reverse-phase HPLC (0% to 100% MeCN:H2O+0.1% formic acid) to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ5[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (32 mg, 42%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.33 (br s, 1H), 10.68 (br s, 1H), 7.79 (d, 1H, J=8.6 Hz), 7.72 (d, 1H, J=8.6 Hz), 7.56 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.9 Hz, J2=9.8 Hz), 7.25 (td, 1H, J1=3.1 Hz, J2=8.6 Hz), 7.19-7.15 (m, 2H), 6.54-6.48 (m, 1H), 4.18 (s, 3H), 4.10-4.00 (br s, 2H), 3.80-3.30 (br m, 4H), 3.16 (s, 3H), 2.36 (s, 3H), 3.31 (s, 3H), 2.30-2.10 (br m, 4H), 1.7-1.6 (br m, 3H); ESMS (m/z): found, 508.

Workup

  1. stirringThe solution was stirred at room temperature for 20 h
  2. customThe solvent was removed in vacuo
  3. dissolutionthe resulting solid redissolved in MeCN (2 mL)
  4. filtrationThe solution was filtered
  5. custompurified directly by preparative reverse-phase HPLC (0% to 100% MeCN:H2O+0.1% formic acid)

Sources & evidence

ORD record
ord-2b7992ddbc3f45bface88f964a803f24
Source dataset
uspto-grants-2011_11
Patent number
US08067395B2

Reaction notes

Loading…