New preparation process of tasimeltion intermediate
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A technology of tasimelteon and preparation process, which is applied in the field of preparation of synthesizing tasimelteon intermediates, and can solve problems such as inability to enlarge
Active Publication Date: 2016-11-09
苏州莱克施德药业有限公司
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[0003] Regarding the synthesis of tasimelteon intermediate (1R, 2R)-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylic acid, the synthetic method disclosed in the world patent WO9825606 is to use 2,3-dihydro Benzofuran-4 acrylic acid is used as starting material and prosthetic camphorsulfonamide to generate amide, and then under the catalysis of palladium acetate and diazomethane to generate cyclopropyl, this method uses highly toxic and explosive diazomethane as raw material , cannot zoom in
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Embodiment 1
[0021] (compound 2 Synthesis)
[0022] Add pyridine (1.3Kg) and piperidine (50g) into a 10L four-neck flask equipped with a thermometer, mechanical stirring, constant pressure dropping funnel, and tail gas absorption device, stir and heat up to 90-100°C, slowly add 2,3 - Dihydrobenzofuran-4-carbaldehyde (1.0 Kg), then malonic acid (1.5 Kg) was added. Stirring was continued at 90-100°C for 4 hours; then water (4.0 L) was added, and a pyridine / water mixture (2.5 L) was evaporated from the reaction flask under reduced pressure. After cooling to room temperature, the pH of the reaction solution was adjusted to 1 with 37% concentrated hydrochloric acid (4.5Kg), and a large amount of solids were precipitated. Filter, wash twice with 1% hydrochloric acid (3 L each time), and dry under vacuum at 40-50°C to obtain 2,3-dihydrobenzofuran-4-acrylic acid (1.1Kg), with a yield of 85% and a purity of 98%.
[0023] (compound 3 Synthesis)
[0024] compound 2 (1.0Kg), a mixture of toluene...
Embodiment 2
[0032] (compound 2 Synthesis)
[0033] Add pyridine (1.3Kg) and piperidine (50g) into a 10L four-neck flask equipped with a thermometer, mechanical stirring, constant pressure dropping funnel, and tail gas absorption device, stir and heat up to 90-100°C, slowly add 2,3 -Dihydrobenzofuran-4-carbaldehyde (1.0 Kg), then malonic acid (1.8 Kg) was added. Stirring was continued at 90-100°C for 4 hours; then water (4.0 L) was added, and a pyridine / water mixture (2.5 L) was evaporated from the reaction flask under reduced pressure. After cooling to room temperature, the pH of the reaction solution was adjusted to 1 with 37% concentrated hydrochloric acid (4.5Kg), and a large amount of solids were precipitated. Filter, wash twice with 1% hydrochloric acid (3 L each time), and dry under vacuum at 40-50°C to obtain the product (1.2Kg), with a yield of 93% and a purity of 98%.
[0034] (compound 3 Synthesis)
[0035] compound 2 (1.0Kg), a mixture of toluene (1.0kg) and pyridine (30g...
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Abstract
The invention provides a novel preparation technology of a tasimelteon intermediate namely (1R,2R)-(2,3-dihydrobenzofuran-4-yl)cyclopropyl formic acid. The technology comprises the following steps: (1) carrying out reactions between 2,3-dihydrobenzofuran-4-formaldehyde and malonic acid in the presence of piperidine to generate 2,3-dihydrobenzofuran-4-acrylic acid; (2) converting 2,3-dihydrobenzofuran-4-acrylic acid into acyl chloride in the presence of thionyl chloride, then reacting the acyl chloride with L-menthol to generate 2,3-dihydrobenzofuran-4-acrylic acid L-menthol; (3) carrying out reactions between 2,3-dihydrobenzofuran-4-acrylic acid L-menthol and dimethyl sulfur oxide in the presence of sodium hydroxide to generate (1R,2R)-(2,3-dihydrobenzofuran-4-yl)cyclopropyl formic acid L-menthol; (4) hydrolyzing the (1R,2R)-(2,3-dihydrobenzofuran-4-yl)cyclopropyl formic acid L-menthol in the action of a sodium hydroxide water solution so as to obtain the (1R,2R)-(2,3-dihydrobenzofuran-4-yl)cyclopropyl formic acid. The novel preparation technology is developed on the basis of the conventional technologies, and has the advantages of easily-available raw materials, low cost, simple operation, and suitability for industrial massive production.
Description
Technical field: [0001] The invention belongs to the field of medicinal chemistry, and relates to a new preparation process of a tasimelteon intermediate, in particular to a synthesis of a tasimelteon intermediate from 2,3-dihydrobenzofuran-4-carbaldehyde as a starting material The preparation method,. Background technique: [0002] Tasimelteon, the English name is Tasimelteon, the chemical name is (1R-trans)-N-[[2-(2,3-Dihydro-4-benzofuranyl)cyclopropyl]methyl]propanamide, which was developed by Vanda Pharmaceutical Company of the United States A new oral melatonin receptor agonist, launched in the United States in January 2014, with the trade name Hetlioz. Melatonin receptors are thought to be involved in the control of circadian rhythms, but the drug's precise mechanism of action is unknown. The drug has the advantages of small dosage, strong curative effect and good tolerance. [0003] Regarding the synthesis of tasimelteon intermediate (1R, 2R)-(2,3-dihydrobenzofuran...
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