A-METHYL-6-QUINOLINEMETHANOL synthesis

Yield:880782-86-5 97%

Reaction Conditions:

Stage #1: quinoline-5-carbaldehyde;methyl magnesium iodide in tetrahydrofuran;diethyl ether at 0; for 2 h;
Stage #2: with water in tetrahydrofuran;diethyl ether;

Steps:

E.E

A solution of quinoline-5-carbaldehyde (available from Lancaster or Rare Chemicals GmbH) (4.65 g, 29.5 mmol) in THF (250 mL) was treated with MeMgI (11.8 mL, 35.4 mmol of a 3M solution in ether) in a dropwise fashion at 0° C. After 2 h the mixture was quenched with water, diluted with ethyl acetate, filtered through celite and separated into two layers. The aqueous layer was extracted with ethyl acetate/hexane. The organic fractions were pooled, dried over MgSO₄, filtered, and evaporated to dryness. The alcohol, 1-quinolin-5-yl-ethanol was used without further purification, 5.0 g (97%). The alcohol, 1-quinolin-5-yl-ethanol (5.0 g, 28.9 mmol) in chloroform was treated with a dropwise addition of thionyl chloride (5.26 mL, 72.1 mmol) at rt. After 1 h the mixture was cooled to 0° C. and carefully quenched with a sat. solution of NaHCO₃ followed by 2M NaOH until the pH was >8. The aqueous layer was extracted with chloroform and the organic fractions were combined, dried over MgSO₄, filtered, and freed of solvent. The residue was purified by chromatography on SiO₂ eluting with 30% ethyl acetate:hexane. The product, 5-(1-chloro-ethyl)-quinoline (Intermediate E1) was obtained as a clear oil, 4.22 g (76%). A solution of N-(diphenylmethylene)aminoacetonitrile (5.84 g, 26.0 mmol, commercially available from Aldrich) in THF (20 mL) and hexamethylphosphoramide (HMPA) (5.43 mL, 31 mmol) at -78° C. was reacted with lithium diisopropylamide (LDA) (15.4 mL of a 2M soln in heptane/THF/ethylbenzene) (commercially available from Aldrich). After 1 h, 5-(1-chloro-ethyl)-quinoline (Intermediate E1) (4.15 g, 21.7 mmol) in THF (15 mL) was introduced by dropwise addition. The mixture was kept at -78° C. for 5 m before removal of the cold bath. After 5 m, the mixture was quenched with cold water and extracted with ethyl acetate (3×). The organic solution was dried over MgSO₄, filtered and concentrated to give 2-(benzhydrylidene-amino)-3-quinolin-5-yl-butyronitrile that was used in the next step without further purification. 2-(Benzhydrylidene-amino)-3-quinolin-5-yl-butyronitrile (8.36 g, 22.3 mmol) in dioxane (90 mL) was hydrolyzed with 1M HCl (90 mL) and the solution was stirred at rt for 16 h. The dioxane was removed under vacuum and the mixture was made basic with 2 M NaOH. The aqueous solution was extracted with chloroform:isopropanol (3:1). The organic extracts were pooled, dried over MgSO₄, filtered and evaporated to leave an oil. The oily residue was purified by chromatography on SiO₂, eluting with ethyl acetate and 5% methanol:ethyl acetate to give 2-amino-3-quinolin-5-yl-butyronitrile (Intermediate-E2) as a yellow solid 3.61 g (77%). In a Parr bottle, a mixture of 2-amino-3-quinolin-5-yl-butyronitrile (Intermediate-E2) (5.38 g, 25.4 mmol) in MeOH (100 mL) and ethylene diamine (3.2 mL, 47.8 mmol) was reacted with Raney 2800 nickel (18.9 g) and bubbled with ammonia gas for 10 m. The Parr bottle was pressurized with hydrogen at 50 psi and shaken on a Parr apparatus for 2.5 h at rt. The mixture was filtered through celite, washed with MeOH (3×) and evaporated to leave a residue. This material was placed onto a column and eluted with a gradient of 1% to 5% sat. NH₃-MeOH:CH₂Cl₂ to give 3-quinolin-5-yl-butane-1,2-diamine (Intermediate E3) 3.9 g (71%). 3-Quinolin-5-yl-butane-1,2-diamine (Intermediate E3) (1.8 g, 8.35 mmol) in CH₂Cl₂ (20 mL) was treated with a solution of 1,1'-thiocarbonyldiimidazole (1.52 g, 8.54 mmol) in CH₂Cl₂ (40 L1) at 0° C. for 1 h. The mixture was diluted with chloroform (40 mL) and water (60 mL). The aqueous layer was extracted with chloroform (3×30 mL) and CH₂Cl₂ (6×30 mL). The organic solution was dried over MgSO₄, filtered and evaporated to give a residue. The material was purified by chromatography on SiO₂ with 3% NH₃-MeOH:CH₂Cl₂ to give 4-(1-quinolin-5-yl-ethyl)-imidazolidine-2-thione (Intermediate E4) 2 g (93%). A mixture of 4-(1-quinolin-5-yl-ethyl)-imidazolidine-2-thione (Intermediate E4) (4.0 g, 15.5 mmol) in ethanol (120 mL) was treated with p-methoxybenzylchloride (4.22 mL, 27 mmol). The solution was heated in an oil bath (bath temp. 100° C.) for 1 h. The solvent was removed under vacuum and replaced with 10% NaOH (160 mL). The aqueous mixture was extracted with CH₂Cl₂ (2×100 mL) and chloroform (2×100 mL). The organic solution was dried over MgSO₄, filtered, evaporated and purified by chromatography on SiO₂ eluting with 2 to 4% NH₃-MeOH:CH₂Cl₂. The product was 5-{1-[2-(4-methoxy-benzylsulfanyl)-4,5-dihydro-3H-imidazol-4-yl]-ethyl}-quinoline (Intermediate E5) 4.16 g (71%). A Swern-type reagent was formed in standard fashion: oxalyl chloride (9.15 mL as a 2M soln. in CH₂Cl₂) in CH₂Cl₂ (23 mL) was cooled to -78° C. and treated with a solution of DMSO (2.85 mL, 36.8 mmol) in CH₂Cl₂ (23 mL) for 30 m. To this solution was added 5-{-[2-(4-methoxy-benzylsulfanyl)-4,5-dihydro-3H-imidazol-4-yl]-ethyl}-quinoline (Intermediate E5) (4.7 g, 12.4 mmol) in CH₂Cl₂ (30 mL) and stirring continued for 45 m at -78° C. Triethylamine (9 mL) was added at -78° C. and warmed to rt for 40 m. The reaction mixture was diluted with brine and CH₂Cl₂. The aqueous layer was extracted with ethyl acetate. The organic solution was dried over MgSO₄, filtered and evaporated to dryness. Chromatography on SiO₂ with 80 to 100% ethyl acetate:hexanes yielded 5-{1-[2-(4-methoxy-benzylsulfanyl)-3H-imidazol-4-yl]-ethyl}-quinoline (Intermediate E6) 3.45 g (74%). 5-{1-[2-(4-Methoxy-benzylsulfanyl)-3H-imidazol-4-yl]-ethyl}-quinoline (Intermediate E6) (3 g, 8.0 mmol) and trifluoroacetic acid (100 mL) in a resealable tube was heated to 115° C. for 1 h 20 m. The mixture was cooled to rt and TFA removed under vacuum. The residual acid was quenched with NH₃-MeOH. The residue was evaporated and resolvated with 3:1 chloroform:isopropanol (500 mL). The organic solution was washed with water (3×40 mL) and brine (1×30 mL). The solution was dried over MgSO₄, filtered, and evaporated to leave a solid. This material was purified on a short column of silica gel by gradient elution with 3 to 9% NH₃-MeOH:CH₂Cl₂ to give 4-(1-quinolin-5-yl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound 7) 1.44 g (71%). ¹H NMR (300 MHz, methanol-d⁴): δ 8.85 (dd, J=4.2, 1.5 Hz, 1H), 8.67 (d, J=8.4 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H), 7.73 (dd, J=8.4, 7.2 Hz, 1H), 7.58 (dd, J=8.7, 4.5 Hz, 1H), 7.42 (d, J=6.6 Hz, 1H), 6.62 (s, 1H), 4.80-4.85 (m, 1H), 1.67 (d, J=7.2 Hz, 3H).

References:

US2006/69144,2006,A1 Location in patent:Page/Page column 23-25