Cycloalkyl-fused tetrahydroquinolines as crth2 receptor modulators
a technology of cycloalkylfused tetrahydroquinolines and receptors, which is applied in the field of cycloalkylfused tetrahydroquinolines, can solve the problems of limiting the dose that can be administered, affecting the safety of patients, and posing a number of systemic side effects
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example 1
Preparation of Racemic Benzyl cis,cis-9-(cyclopropylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate (1E)
Step 1: Benzyl 2-allyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
[0443]
[0444]A solution of allylmagnesium bromide (1.00 M in tetrahydrofuran, 101 mL, 101 mmol, 2.00 equiv) was added to a solution of 4-methoxy quinoline (8.00 g, 50.3 mmol, 1 equiv) in tetrahydrofuran (335 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, then benzyl chloroformate (14.35 mL, 101.0 mmol, 2.00 equiv) was added via syringe over 5 min. The reaction mixture was stirred for an additional 15 minutes at −78° C., then the cooling bath was removed and the reaction mixture was allowed to warm to 23° C. After 1 h, added methanol (40 mL). After stirring for 5 min, aqueous hydrochloric acid solution (2 N, 20 mL) was added and the mixture was stirred for 10 min. The mixture was then concentrated by rotary evaporation to remove most of the tetrahydrofuran and methanol, and...
example 2
Preparation of Racemic Benzyl cis,cis-9-amino-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate (2)
[0453]
[0454]Sodium cyanoborohydride (78 mg, 1.2 mmol, 2.0 equiv) was added to a mixture of benzyl cis-9-oxo-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate (200 mg, 0.622 mmol, 1 equiv) and ammonium acetate (480 mg, 6.22 mmol, 10 equiv) in methanol (6.2 mL). The reaction vessel was sealed and heated to 70° C. After stirring at 70° C. for 90 min, the reaction mixture was cooled to 23° C. and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (50% ethyl acetate-hexanes, grading to ethyl acetate, then flushing with 10% methanol-dichloromethane) to afford 2.
example 3
Preparation of Racemic Benzyl cis,cis-9-(acetylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate (3)
[0455]
[0456]Acetic anhydride (0.250 mL, 2.65 mmol, 5.00 equiv) was added to a solution of benzyl cis,cis-9-amino-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate 2 (171 mg, 0.530 mmol, 1 equiv) and N,N-diisopropylethylamine (0.278 mL, 1.59 mmol, 3.00 equiv) in dioxane (5.3 mL) at 23° C. The reaction mixture was stirred for 10 min, and then was partitioned between ethyl acetate and aqueous hydrochloric acid solution (1 N). The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 3. [M+H]+: 365.2.
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