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4-[(S)-Azido-((1S,2S,4S,5R)-5-ethyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl]-6-methoxy-quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A. To a 20 L jacket reactor, equipped with condenser, thermocouple and nitrogen sweep, was charged 1.2 kg of hydroquinine (3.676 mole, 1.0 eq), 1157.1 g of triphenyphosphine (4.41 1 mole, 1.2 eq.). The reaction was then charged with 7.2 L (6.0 vol) of methylene chloride. The reaction mixture was stirred at room temperature for approximately 10 minutes to afford a clear solution and then cooled to 0 ± 5 C. Ca. 888.0 g of diisopropyl azodicarboxylate (DIAD, 4.411 mole, 1.2 eq.) was added to the reaction mixture over 45 minutes while keeping the temperature to less than 5 C. After the temperature of the reaction mixture was stabilized at 0-5 C, a solution of 1215.9 g (4.411 mole, 1.2 eq.) of diphenylphosphoryl azide (DPPA) in 1.2 L (1 vol) of methylene chloride was added over an hour to the reaction mixture while keeping the temperature at 0 ± 5 C. The reaction mixture was warmed to 20 ± 5 C and stirred at this temperature for approximately 2 hours.
General procedure: To a well stirred mixture of quinine (6.48 g, 20 mmol), triphenylphosphine(6.56 g, 25 mmol) and hydrazoic acid (40 mL29.4 mmol) in 80 mL of absolute THF is slowly added DIAD (5.0 mL, 25 mmol) in 20 mL of THF at 0C. Then the mixture is stirred overnight at room temperature. Then triphenylphosphine (6.56g, 25 mmol) in 10 mL of THF is added in one portion. The mixture is heated at 50C until the gas evolution has ceased. The solution was cooled to room temperature, and water (10 mL) was added. After stirring for 24 h, the solvents were removed under vacuum and the residue is dissolved in CH2C12 and hydrochloric acid (1:1, 200 mL). The aqueous phase is washed with CH2C12 (5×100 mL). The resulting aqueous solution was adjusted to pH ~ 10-11 at 0 C with 2mol·L-1 NaOH solution and extracted with CH2Cl2 (5×30 mL). Concentration of the dried extracts afforded a residue, which was purified by column chromatography (dichloromethane: methanol: triethylamine = 30: 1:1 was used as eluent) to afford (8S,9S)-9-amino-(9-deoxy)-epiquinine 5 (4.58g. 71% yield).
With n-butyllithium; In tetrahydrofuran; hexane; water;
EXAMPLE 28 Preparation of Dihydroquinine and Dihydroquinidine To 20 ml. of anhydrous ether was added 1.98 ml. of a 1.62M solution of butyllithium in hexane. The resulting solution was cooled to -70 and with stirring under a nitrogen atmosphere a solution of 760 mg. of <strong>[42881-66-3]4-bromo-6-methoxyquinoline</strong> in 20 ml. of anhydrous tetrahydrofuran was added. After stirring the mixture containing 6-methoxy-4-quinolyllithium for 30 minutes at -70, a solution of 538 mg. of freshly distilled 5(R)-ethyl-4(S)-quinuclidine-2epsilon-carboxaldehyde in 10 ml. of anhydrous ether was added during 15 minutes. After completion of the addition, stirring was continued for two hours at -70. The reaction mixture then was hydrolyzed by the addition of water, allowed to warm up to room temperature and diluted with an equal volume of ether. The aqueous layer was separated and extracted three times with 15 ml. of ether each. The combined organic extract was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel plates (Merck F-254) with chloroform-triethylamine-methanol (85:10:5) as the solvent mixture. Elution of the lowest of the major bands with chloroform-methanol (1:1) gave 138 mg. of dihydroquinine, mp 169-170 after recrystallization from chloroform-ether, [alpha]25 D -144.5 (c 0.935, 95 percent ethanol).
1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-((R)-(2S,4S,8R)-8-ethylquinuclidin-2-yl)(tert-butyldiphenylsilyloxy)methyl)-(6-methoxyquinolin-5-yl)urea[ No CAS ]
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 0 - 20℃;
General procedure: To a stirred solution of N-heteroaromatic compounds in chloroform (0.5 M) was added meta-chloroperoxybenzoic acid (m-CPBA) (2.0 eq) in portions at 0 C. After the completion of this course, the reaction mixture was allowed up to room temperature and stirred overnight. An aqueous solution of saturated K2CO3 was added to the mixture to neutralize residual m-CPBA. The resulting mixture was extracted with CHCl3 and isopropanol (volume ratio = 9:1) three times (3 x 30 mL). The organic phase were combined and washed with saturated NaCl solution (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give crude products, which were purified by column chromatography. The new products were characterized by 1H NMR, 13C NMR and HRMS.