Hydrochloric Acid → HCID 178485521, compound

HRID 1014523Notes

Reaction equation

Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[C:32]([N:35]1[C:44]2[C:39](=[CH:40][C:41]([O:46][CH3:47])=[C:42]([NH2:45])[CH:43]=2)[CH2:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33].Cl.[C:49](=O)(O)[O-].[Na+].CN.[OH-].[K+]>FC(F)(F)CO.O>[C:32]([N:35]1[C:44]2[C:39](=[CH:40][C:41]([O:46][CH3:47])=[C:42]([NH:45][C:2]3[NH:7][C:6]4=[N:8][CH:9]=[CH:10][C:5]4=[C:4]([NH:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=4[C:24]([NH:26][CH3:49])=[O:25])[N:3]=3)[CH:43]=2)[CH2:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]

Participants

Conditions

Temperature: 90 °C

Procedure

A mixture of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (0.2 g, 0.44 mmol), 1-acetyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (0.10 g mg, 0.43 mmol) was taken in 2,2,2-trifluoroethanol (10 mL) and hydrochloric acid (1.0 mL, 4.0 mmol, 4M in 1,4-dioxane) was added. The mixture was heated at 90° C. in a sealed tube for 24 h. The reaction was cooled; excess saturated aqueous sodium bicarbonate was added, and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, diluted with tetrahydrofuran (10 mL) and treated with excess methyl amine (5.0 mL, 10 mmol, 2M in THF). The reaction was stirred for 16 h, diluted with water, and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, concentrated, and purified by flash silica gel column chromatography (0 to 20% methanol/dichloromethane spiked with aqueous ammonia). “Pure” fractions were isolated, concentrated, dissolved in 1,4-dioxane (7.0 mL), treated with 85% potassium hydroxide (750 mg, 11.4 mmol), water (1.0 mL), and stirred for 24 h at 80° C. The reaction was cooled; the organic layer was separated, dried over sodium sulfate, and purified by flash silica gel column chromatography. Further purification via reverse phase HPLC (5 to 90% acetonitrile/water, 0.05% trifluoroacetic acid) provided 2-[(2-{[1-acetyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.03 g, 0.06 mmol, 14% over 3 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.92 (m, 2 H), 2.16 (s, 3 H), 2.64-2.72 (m, 2 H), 2.78 (d, J=4.2 Hz, 3 H), 3.68 (t, J=6.2 Hz, 2 H), 3.87 (s, 3 H), 6.32 (bs, 1 H), 6.84 (m, 1 H), 6.94-7.03 (m, 2 H), 7.40-7.47 (m, 1 H), 7.50 (s, 1 H), 8.17-8.26 (m, 1 H), 8.46 (s, 1H), 8.52-8.59 (m, 1 H), 10.07 (s, 1 H), 11.42 (bs, 1 H); ESIMS (M+H)+=504.

Workup

temperatureThe reaction was cooled
extractionextracted with dichloromethane
customThe organic layer was separated
dry with materialdried over magnesium sulfate
filtrationfiltered
concentrationconcentrated
additiondiluted with tetrahydrofuran (10 mL)
extractionextracted with ethyl acetate
customThe organic layer was separated
dry with materialdried over sodium sulfate
concentrationconcentrated
custompurified by flash silica gel column chromatography (0 to 20% methanol/dichloromethane spiked with aqueous ammonia)
custom“Pure” fractions were isolated
concentrationconcentrated
dissolutiondissolved in 1,4-dioxane (7.0 mL)
stirringstirred for 24 h at 80° C
temperatureThe reaction was cooled
customthe organic layer was separated
dry with materialdried over sodium sulfate
custompurified by flash silica gel column chromatography
customFurther purification via reverse phase HPLC (5 to 90% acetonitrile/water, 0.05% trifluoroacetic acid)

Sources & evidence

ORD record: ord-e04bdb0659944d3cbce9d931d15a6f1e
Source dataset: uspto-grants-2011_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07981903B2

Reaction notes

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