Propylamine → 1-[4-amino-7-(1,3-dioxolan-2-ylmethoxy)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol

HRID 2203621Notes

Reaction equation

[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19].[CH3:22][O:23][CH2:24][CH2:25][C:26](Cl)=O.C(OC1C=[CH:42][C:40]([NH2:41])=[CH:39]C=1)C1C=CC=CC=1.C(N)CC.C([O:50][CH2:51][C:52](Cl)=[O:53])C.C(OC1C=CC2[C:67]3[N:75](CC(C)(O)C)C(CCOC)=[N:73][C:68]=3[CH:69]=NC=2C=1)C1C=CC=CC=1.NC1C2N=C(CCOC)N(CC(O)(C)C)C=2C2C=CC(O)=CC=2N=1.BrCC1OCCO1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:13]2[C:39]3[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:26]([CH2:25][CH2:24][O:23][CH3:22])=[N:41][C:40]=3[CH:42]=[N:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH2:75][C:67]1[C:68]2[N:73]=[C:26]([CH2:25][CH2:24][O:23][CH3:22])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:69]=2[C:13]2[CH:14]=[CH:15][C:9]([O:8][CH2:1][CH:2]3[O:50][CH2:51][CH2:52][O:53]3)=[CH:10][C:11]=2[N:12]=1

Participants

Conditions

Temperature: 70 °C

Procedure

[7-Benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol was prepared according to a modification of the methods described in Parts A-H of Example 2, with 3-benzyloxyaniline, 1-amino-2-methylpropan-2-ol, and 3-methoxypropanoyl chloride used in lieu of 4-benzyloxyaniline, propylamine, and ethoxyacetyl chloride, respectively. The general methods described in Parts H through J of Example 1 were used to convert [7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol to 4-amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol. A mixture of 4-amino-1-(2-hydroxy-2-methylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol (375 mg, 1.13 mmol), 2-bromomethyl-1,3-dioxolane (208 mg, 1.24 mmol) and potassium carbonate (312 mg, 2.26 mmol) in DMF (15 mL) was heated at 70° C. overnight. The temperature was increased to 130° C. and additional 2-bromomethyl-1,3-dioxolane and potassium carbonate were added over 3 days. The reaction mixture was allowed to cool to room temperature, then was filtered to remove the solids. The filtrate was concentrated under reduced pressure and the residue was slurried in dichloromethane. Again, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. Purification by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-35% methanol/dichloromethane (20:80) in dichloromethane) followed by recrystallization from acetonitrile provide 20 mg of 1-[4-amino-7-(1,3-dioxolan-2-ylmethoxy)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as off white crystals, mp 131.0-136.0° C.

Workup

temperatureThe temperature was increased to 130° C.
temperatureto cool to room temperature
filtrationwas filtered
customto remove the solids
concentrationThe filtrate was concentrated under reduced pressure
customAgain, the solids were removed by filtration
concentrationthe filtrate was concentrated under reduced pressure
customPurification by chromatography
washon a HORIZON HPFC system (silica gel, gradient elution with 0-35% methanol/dichloromethane (20:80) in dichloromethane)
customfollowed by recrystallization from acetonitrile

Sources & evidence

ORD record: ord-3f0a258a5a7642c883bac48bdccdf262
Source dataset: uspto-grants-2016_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09365567B2

Reaction notes

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