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Preparation method of 4, 5-dihydro-6H-cyclopenta[b]thiophene-6-ketone

A technology of cyclopentane and thiophene, applied in the field of compound preparation, can solve the problems of difficulty in post-processing, expensive raw materials, complicated products, etc., and achieve the effects of reducing post-processing process, convenient post-processing, and simple synthesis process

Inactive Publication Date: 2013-06-12
YANCHENG INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Yamabe et al. (Journal of Americal Chemical. Society. 2005, 127: 3248-3249) used trimethylsilyl propynyl alcohol derivatives as starting materials for cyclization under the catalysis of transition metal ruthenium 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
[0007] 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
[0008] 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%.

Method used

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  • Preparation method of 4, 5-dihydro-6H-cyclopenta[b]thiophene-6-ketone
  • Preparation method of 4, 5-dihydro-6H-cyclopenta[b]thiophene-6-ketone
  • Preparation method of 4, 5-dihydro-6H-cyclopenta[b]thiophene-6-ketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Synthesis of 3-(3-thienyl)acrylic acid (compound 2).

[0056]45g of 3-thiophenecarboxaldehyde (0.4mol), 50g of malonic acid (0.48) and 48ml of pyridine were added to the reaction flask, heated to 90°C, followed by TLC (PE / EA=3 / 1). After the reaction was completed, the temperature was lowered, the reaction solution was poured into ice water, 2N hydrochloric acid was added to adjust Ph=2-3, 10 ml of petroleum ether was added, stirred for 15-30 minutes, filtered, and rinsed with water to obtain a white solid 3-(3-thienyl) Acrylic acid was used directly in the next reaction. 1 H 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

[0057] Example 2: Synthesis of methyl 3-(3-thienyl)acrylate (compound 3).

[0058] All the solids obtained in the above reaction were dissolved in 400 ml of methanol, stirred until dissolved, 25 ml of concentrated sulfuric acid was added, and heated to reflux overnight. Followed by TLC until the raw material disappeared, concentrated to remove methanol, added 200 mL of ethyl acetate to dissolve, washed with saturated aqueous sodium carbonate solution until neutral, dried over sodium sulfate, filtered and concentrated to obtain 57 g of liquid, which was solid 3-(3-thienyl) after cooling Methyl acrylate, the two-step yield is 85%.

Embodiment 3

[0059] Example 3: Synthesis of methyl 3-(3-thienyl)propionate (compound 4).

[0060] Dissolve 52g 3-(3-thienyl) methyl acrylate (0.3mol) in 1L methanol, cool down to 0°C, add 78g hexahydrate and nickel chloride (0.328mol), and then add 103g boron in batches at 0°C Sodium hydride (2.7mol), the color of the reaction solution turned black, followed by TLC (PE / EA=10 / 1) until the reaction was complete, 3N hydrochloric acid was added to adjust Ph=6-7, filtered through celite, rinsed with methanol, and concentrated to obtain 46g yellow liquid methyl 3-(3-thienyl)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

[0001] Technical field: [0002] The present invention relates to a preparation method of a compound, in particular to a preparation method of 4,5-dihydro-6H-cyclopentano[b]thiophen-6-one. [0003] Background technique: [0004] Cyclopentanonethiophene ring is widely used in medicinal chemistry due to its strong biological activity, and then the synthesis of such compounds is made difficult by the strain of the thiophene ring. [0005] At present, according to the literature reports, there are mainly the following routes for the synthesis of 4,5-dihydro-6H-cyclopentano[b]thiophen-6-one, but they all have some deficiencies. [0006] For example, the literature (Europen Journal of Organic Chemistry. 2004, 4442-4451) uses 3-(3-thienyl)-acrylic acid as a starting material, and under the catalysis of Pd / C, 3-(3-thienyl) is obtained by microwave reaction reduction )-propionic acid, and then close the ring under the action of phosphorus pentoxide. The total yield of the two-s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/78
Inventor 王伟方海林高金荣马玉涛
Owner YANCHENG INST OF TECH
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