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 1863905Notes

Reaction equation

HRID 1863905 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 preperative 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=8.6Hz), 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 r, 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 preperative reverse-phase HPLC (0% to 100% MeCN:H2O+0.1% formic acid)

Sources & evidence

ORD record
ord-14d84beae7974b4a97ee98198b4950a2
Source dataset
uspto-grants-2009_12
Patent number
US07625880B2

Reaction notes

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