Benzothiophenecarboxamide derivatives and PGD2 antagonist comprising them
A technology of phenylsulfonyloxy and compound, which is applied in the field of benzothiophene amide derivatives and its intermediates, and can solve the problems such as the great influence on prostaglandin synthesis
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Embodiment 3
[0069] Preparation of (1R, 2S, 3S, 5S)-2-(2-amino-6,6-dimethylbis Cyclo[3.1.1]hept-3-yl)ethanol (IVA-b-1) and (IR, 2R, 3S, 5S) -2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol (IVA- c-1)
[0070] According to the literature method, compound (6) (Chem.Pharm.Bull.Vol.37, No. 6 1524-1533 (1989)) can be reduced with sodium, and compound (IVA-a-1) can be removed by filtration as benzoate. The mother liquor (79 g) was suspended in 150 ml of ethyl acetate, 260 ml of 1N HCl was added and stirred. The aqueous phase separated from the two phases was basified with 65 ml of 4N NaOH solution and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily residue (6.7 g out of 30 g) was dissolved in 40 ml of 90% methanol and washed with 500 ml of ion exchange resin-Amberlite CG-50 (NH 4 + ) type I absorption and was eluted with a gradient of 2.2 liters of water an...
Embodiment 1
[0074] Preparation of (5Z)-7-{(1R,2R,3S,5S)-2-(5-Hydroxybenzo[b] Thiophen-3-ylcarbonylamino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl}-5- Sodium Heptenate (IVA-a-6) (step 1)
[0075] To a solution of 1.450 mg (5.2 mmol) of compound (IIA-a-1) (see Japanese Patent Publication (Kokoku) No. 23170 / 1994) in 25 ml of tetrahydrofuran, 2.6 ml (18.7 mmol) of triethylamine and 1.454 mg (1.1 mmol) of ) 5-acetoxybenzo[b]thiophene-3-carbonyl chloride (5) (prepared by Reference Example 2) was stirred for 1.5 hours, and the mixture was diluted with water and extracted with toluene. The organic phase was washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (eluent toluene:ethyl acetate=9:1) to obtain 2.481 mg of compound IA-a-10). Yield 96.1%. [α] D 23 =+48.0° (c=1.01%, CH 3 OH) elemental analysis (C 28 h 35 NO 5 S·0.1H 2 O) Theoretical (%): C, 67.34; H, 7.10; N,...
Embodiment 2
[0077] To a solution of 2.03 mg (0.46 mmol) of the compound (IA-a-5) obtained above in 3 ml of methanol was added 0.42 ml (0.42 mmol) of 1N NaOH, and the mixture was concentrated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate and diluted with n-hexane. The insoluble matter was dissolved in methanol and concentrated under reduced pressure to obtain 210 mg of the target compound (IA-a-6), with a yield of 98.5%. [α] D 25 =+38.9° (c=1.00%, CH 3 OH) elemental analysis (C 25 h 30 NO 4 SNa·0.5H 2 O) Theoretical value (%): C, 63.54; H, 6.61; N, 2.96; S, 6.78; Na, 4.86 Measured value (%): C, 63.40; H, 6.69; , 4.68 Example 2 Preparation of (5Z)-7-[(1R,2S,3R,5S)-2-(5-Hydroxybenzo[b] Thiophen-3-yl-carbonylamino)-6.6-dimethyl-bicyclo[3.1.1]hept-3-yl]- 5-Heptenoic acid (IA-b-1) (step 1)
[0078] To 916mg (3mmol) (1R, 2S, 3S, 5S)-2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol benzoate in 3ml of water 3.1 ml of 1N HCl was added ...
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