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With oxalyl dichloride; at 80℃; for 2h;Cooling with ice;
Production example 10370 mg of oxalyl chloride was added to a mixture of 400 mg of <strong>[5381-25-9]benzo[b]thiophene-3-carboxylic acid</strong> and 20 ml of methanol under ice cooling. This mixture was stirred for 2 hours at 80C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Tert-butyl methyl ether was added to the residues, and the residue was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure, thereby obtaining 380 mg of methyl benzo[b]thiophene-3-carboxylate (hereinafter, described as a "compound 12 of the present invention").1H-NMR (CDCl3) delta: 8.60 (m, 1H), 8.39 (s, 1H), 7.88 (m, 1H), 7.49 (m, 1H), 7.43 (m, 1H), 3.97 (s, 3H)
Preparation of methyl benzothiophene-3-carboxylate (D17) STR43
Preparation of methyl benzothiophene-3-carboxylate (D17) STR43 A stirred mixture of the acid (27.7 g, 0.156 mole, (D16)) and thionyl chloride (22.7 ml, 0.31 mole) in dry toluene (300 ml) was heated under reflux for 1 hour. The solution was then evaporated to dryness to leave a red oil. This was dissolved in dry ether (300 ml), the solution cooled in an ice bath, and treated with dry triethylamine (43 ml, 0.31 mole) followed by methanol (12.6 ml, 0.31 mole). The mixture was stirred at room temperature for 20 minutes, before acidifying with dilute hydrochloric acid. The organic layer was separated and the aqueous solution extracted with ether (1*150 ml). The organic solutions were combined and washed with 10% sodium carbonate solution, dilute hydrochloric acid and water; then dried (MgSO4) and evaporated to dryness to give the title compound as a red oil (90%). NMR: δ (CDCl3) 3.88 (s, 3H), 7.2-7.6 (m, 2H), 7.7-8.0 (m, 1H), 8.37 (s, 1H), 8.5-8.8 (m, 1H).
Benzthiophen-3-carbonbsaeure, CH2N2;
11
[ 22913-25-3 ]
[ 1079-66-9 ]
[ 730991-24-9 ]
Yield
Reaction Conditions
Operation in experiment
76%
With 2,2,6,6-tetramethylpiperidinyl-lithium In tetrahydrofuran
Multi-step reaction with 3 steps
1: 15.7 g / NaOEt / 1 h / Ambient temperature
2: Br2 / acetic acid / 2.5 h / Ambient temperature
3: AlCl3 / CS2 / 72 h / Ambient temperature
Multi-step reaction with 4 steps
1: 15.7 g / NaOEt / 1 h / Ambient temperature
2: Br2 / acetic acid / 2.5 h / Ambient temperature
3: AlCl3 / CS2 / 72 h / Ambient temperature
4: Na2CO3 / ethanol / 1.5 h / Ambient temperature
Multi-step reaction with 3 steps
1: 15.7 g / NaOEt / 1 h / Ambient temperature
2: Br2 / acetic acid / 2.5 h / Ambient temperature
3: AlCl3 / CS2 / 72 h / Ambient temperature
35 1'-[2-(Benzo[b]thiophen-3-ylmethyloxy)-1-ethyl]spiro[isobenzofuran-1(3H),4'-piperidine], fumarate, 35a.
EXAMPLE 35 1'-[2-(Benzo[b]thiophen-3-ylmethyloxy)-1-ethyl]spiro[isobenzofuran-1(3H),4'-piperidine], fumarate, 35a. An ether solution (50 ml) of methyl benzo[b]thiophene-3-carboxylate (15 g) was added dropwise to a suspension of lithium aluminium hydride (3.5 g) in ether (100 ml) followed by reflux for 2 h. Usual work-up gave benzo[b]thiophen-3-yl methanol (13.5 g) as an oil.
General procedure for the thermal DA reactions:
General procedure: All reactions were carried out in oven-dried glassware. An ampoule containing a solution of 1.0 mmol of the dienophile and the required amount of the diene in 0.5 mL of dry benzene was cooled in liquid nitrogen, sealed and heated in an oil bath. After completion of the reaction, it was cooled once more in liquid nitrogen and opened. The solvent was evaporated in vacuo to give the crude product, which was subjected to TLC and GC-MS spectrometry. For the case in which the reaction yield was moderate (i.e. DA reaction between 10 and 1), column chromatography and NMR analysis were also performed.
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