Water → [4-Chloro-2-methoxy-3-[(4-pyrazol-1-ylphenyl)methyl]quinolin-6-yl]-(2,3-dimethylimidazol-4-yl)-(3-methyltriazol-4-yl)methanol

HRID 926585Notes

Reaction equation

C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[N:12]1([C:17]2[CH:45]=[CH:44][C:20]([CH2:21][C:22]3[C:23]([O:42][CH3:43])=[N:24][C:25]4[C:30]([C:31]=3[Cl:32])=[CH:29][C:28]([C:33]([C:35]3[N:39]([CH3:40])[C:38]([CH3:41])=[N:37][CH:36]=3)=[O:34])=[CH:27][CH:26]=4)=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[N:13]1.O>O1CCCC1>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([CH2:21][C:22]3[C:23]([O:42][CH3:43])=[N:24][C:25]4[C:30]([C:31]=3[Cl:32])=[CH:29][C:28]([C:33]([C:35]3[N:39]([CH3:40])[C:38]([CH3:41])=[N:37][CH:36]=3)([C:11]3[N:7]([CH3:6])[N:8]=[N:9][CH:10]=3)[OH:34])=[CH:27][CH:26]=4)=[CH:44][CH:45]=2)[CH:16]=[CH:15][CH:14]=[N:13]1

Participants

Conditions

Temperature: 23 °C

Procedure

A solution of n-butyllithium in hexanes (2.5 M, 0.32 mL, 0.81 mmol) was added dropwise to a stirring solution of 1-methyl-1H-1,2,3-triazole (70.4 mg, 0.848 mmol, prepared according to PCT Int. Appl., 2008098104) in tetrahydrofuran (1 mL) at −50° C. After 20 minutes, a solution (gently warmed with a heat gun to dissolve the ketone starting material) of (3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (200 mg, 0.42 mmol, Intermediate 21: step b) in tetrahydrofuran (1 mL) was added dropwise. After 5 minutes, the flask was allowed to warm to 23° C. After 20 minutes, water (1 mL) was added. The biphasic mixture was partitioned between saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried with sodium sulfate. The dried solution was filtered. Silica gel (2 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound which was further purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (s, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 7.60-7.53 (m, 2H), 7.41-7.33 (m, 3H), 7.11 (d, J=1.4 Hz, 1H), 6.46-6.39 (m, 1H), 6.08-6.02 (m, 1H), 4.27 (s, 2H), 4.08 (s, 3H), 3.89 (s, 3H), 3.35 (s, 3H), 2.20 (s, 3H); MS (ESI): mass calcd. for C29H27ClN8O2, 554.2. m/z found, 555.2 [M+H]+.

Workup

temperaturea solution (gently warmed with a heat gun
additionwas added dropwise
waitAfter 5 minutes
waitAfter 20 minutes
customThe biphasic mixture was partitioned between saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL)
customThe layers were separated
dry with materialthe organic layer was dried with sodium sulfate
filtrationThe dried solution was filtered
additionSilica gel (2 g) was added to the filtrate
concentrationthe mixture was concentrated by rotary evaporation
customto afford a free-flowing powder
customThe powder was loaded onto a silica gel column for flash column chromatography purification
washElution with dichloromethane initially

Sources & evidence

ORD record: ord-7db4cb22d74f4a30ab15bb7cf8537897
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09284308B2

Reaction notes

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