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Preparation method of 4, 5-dihydro-6H-cyclopenta[b]thiophene-6-ketone
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A technology of cyclopentane and thiophene, which is applied in the field of compound preparation, can solve the problems of difficulty in post-processing, complex products, and low yield, and achieve the effects of reducing post-processing, simple synthesis process, and low production cost
Inactive Publication Date: 2014-07-16
YANCHENG INST OF TECH
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Yamabe et al. (Journal of Americal Chemical. Society. 2005, 127: 3248-3249) used trimethylsilylpropynylalcohol derivatives as starting materials for cyclization under the catalysis of transition metalruthenium complexes, and then removed trimethyl Silicon-based to obtain the target product, the yield is 32%, the yield is not high, and the raw materials are relatively expensive
[0005] Baraznenok et al. (Synthesis. 1997, 465-468.) reported the use of dimethylacrylamide / trifluoromethanesulfonic anhydride complex to synthesize the target product in one pot, with a yield of 45%. The product of this reaction is relatively complex, so There is a certain degree of difficulty in the post-processing of the product
[0006] Another example is literature (Journal of the Chemical Society, Chemical Communications. 1994, 2249–2250; Journal of Organic Chemistry. 1967, 32 (4): 1226-1229) reported that the cheap 3-thiophene carboxaldehyde was used as the raw material to obtain the target product through 4 steps of reaction, and the yield of the last step was very low at 28%.
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Embodiment 1
[0049] Example 1: Synthesis of 3-(3-thienyl)acrylic acid (Compound 2).
[0050] Add 45g of 3-thiophenecarbaldehyde (0.4mol), 50g of malonic acid (0.48) and 48ml of pyridine into the reaction flask, heat to 90°C, and track with TLC (PE / EA=3 / 1). Cool down after the reaction, pour the reaction solution into ice water, add 2N hydrochloric acid to adjust Ph=2-3, add 10ml of petroleumether, stir for 15-30 minutes, filter and rinse with water to obtain a white solid 3-(3-thienyl) Acrylic acid was directly used in the next reaction. 1H NMR (300 MHz, DMSO) δ 7.91 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 4.6, 2.8 Hz, 1H), 7.52 (dd, J = 6.3, 5.7 Hz, 2H), 6.34 (d, J = 15.9 Hz, 1H), 2.48 (s, 1H).
Embodiment 2
[0051] Example 2: Synthesis of methyl 3-(3-thienyl)acrylate (compound 3).
[0052] Dissolve all the solids obtained in the above reaction in 400ml of methanol, stir until dissolved, add 25ml of concentrated sulfuric acid, and heat to reflux overnight. TLC tracked until the raw material disappeared, concentrated to remove methanol, added 200mL ethyl acetate to dissolve, washed with saturated aqueous sodiumcarbonate until neutral, dried over sodiumsulfate, filtered and concentrated to obtain 57g of liquid, which was solid 3-(3-thienyl) after cooling Methyl acrylate, 85% yield in two steps.
Embodiment 3
[0053] Example 3: Synthesis of methyl 3-(3-thienyl)propionate (compound 4).
[0054] Dissolve 52g of 3-(3-thienyl)methyl acrylate (0.3mol) in 1L of methanol, cool down to 0°C, add 78g of hexahydrate and nickelchloride (0.328mol), then add 103g of boron in batches at 0°C Sodiumhydride (2.7mol), the color of the reaction solution turns black, TLC (PE / EA=10 / 1) traces until the reaction is complete, add 3N hydrochloric acid to adjust Ph=6-7, filter with Celite, rinse with methanol, and concentrate to obtain 46g yellow liquid 3-(3-thienyl) methyl propionate, yield 90%. 1 H NMR (300 MHz, DMSO) δ 7.42 (dd, J = 4.9, 3.0 Hz, 1H), 7.20 – 7.08 (m, 1H), 6.98 (dd, J = 4.9, 1.2 Hz, 1H), 3.57 (s, 3H), 2.83 (t, J = 7.5 Hz, 2H), 2.61 (dd, J = 8.0, 7.1 Hz, 2H).
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Abstract
The invention relates to a synthetic process of 4, 5-dihydro-6H-cyclopenta[b]thiophene-6-ketone. The synthetic process comprises the following steps of: with 3-thiophene carbinal as a starting material, carrying out Knoevenagel condensation reaction, esterification and hydrogenation reduction, and finally carrying out ring formation under the action of PPA (phenyl-propanolamine) to obtain a target product. According to the preparation method, the 3-thiophene carbinal is taken as the starting material and is cheap and easily available, so that the production cost is low. The synthetic process is simple and reasonable. The conversion rate is high, and the total yield is increased to 50%. The aftertreatment is convenient and feasible. A part of intermediates do not need to be purified and can be directly used in a next reaction step, so that the aftertreatment process is reduced, simultaneously the technology difficulty and the discharge of pollutants are reduced, and the whole reaction is suitable for large-scale commercial process.
Description
Technical field: [0001] The present invention relates to a preparation method of a compound, in particular to a preparation method of 4,5-dihydro-6H-cyclopenta[b]thiophen-6-one. Background technique: [0002] Cyclopentanonethiophene rings are widely used in medicinal chemistry due to their strong biological activity, but the synthesis of such compounds becomes difficult due to the strain of the thiophene rings. [0003] At present, according to literature reports, there are mainly the following routes for reference to synthesize 4,5-dihydro-6H-cyclopenta[b]thiophen-6-one, but all of them have some shortcomings. [0004] For example, the literature (European Journal of Organic Chemistry. 2004, 4442-4451) uses 3-(3-thienyl)-acrylic acid as the starting material, and under the catalysis of Pd / C, 3-(3-thienyl) is obtained by microwave reaction reduction )-propionic acid, and then ring-closing under the action of phosphoruspentoxide, the total yield of the two-step reaction...
Claims
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