Synthesis method of 2,3-dihydro-1-benzofuran-4-carbaldehyde

A technology of benzofuran and tetrahydrofuran, which is applied in the field of two-step synthesis of 2,3-dihydro-1-benzofuran-4-carbaldehyde and tasimelteon, can solve the problems of low selectivity, danger, and unknown Reporting and other issues, to achieve high yield and selectivity, mild reaction conditions, less by-products

Active Publication Date: 2017-04-26
富乐马鸿凯(大连)医药有限公司
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Problems solved by technology

[0015] Above-mentioned documents all adopt the method for multi-step conversion to prepare DHBFCA, and productive rate is low, and selectivity is low
Furthermore, performing the entire process often requires performing hazardous reactions or using hazardous reagents, or at very high or very low temperatures
These factors make these methods unsuitable for large-scale industrial application
[0016] In addition, so far, no synthetic method for converting 4-halo-2,3-dihydrobenzofuran represented by general formula (II) into DHBFCA

Method used

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  • Synthesis method of 2,3-dihydro-1-benzofuran-4-carbaldehyde

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preparation example Construction

[0033] The invention provides a method for synthesizing 2,3-dihydro-1-benzofuran-4-carbaldehyde with high conversion rate and good selectivity, which is suitable for industrial scale production. In particular, according to the method of the present invention, DHBFCA can be prepared from 2-(2',6'-dihalophenyl)ethanol (formula (II) ) as the starting substrate is economically and conveniently obtained by Ullman-Bouveault coupling reaction.

[0034] According to one embodiment of the present invention, the present invention provides a method for synthesizing 2,3-dihydro-1-benzofuran-4-carbaldehyde represented by formula (I), comprising: a) adding an alkali metal compound and Cu( I) in the presence of a catalyst, the compound of general formula (II) is subjected to an intramolecular cyclization reaction to produce a compound of general formula (III); and b) the compound of general formula (III) is reacted with magnesium and formula R 3 CONR 1 R 2 The compound of (IV) is reacted ...

preparation example 1

[0054] Preparation Example 1: Preparation of 4-chloro-2,3-dihydrobenzofuran

[0055] Under nitrogen protection, 250 g of 2,6-dichlorophenethyl alcohol, 6.46 g of CuCl and 5.75 g of ethyl acetate were mixed with 7.5 L of tetrahydrofuran. 104.43 g of NaH were added in portions while maintaining the temperature below 70 °C. The resulting mixture was stirred at 70°C for 18 hours. The mass fraction of the starting material in the reaction system was controlled by gas chromatography to 4 dry. The above dried mixture was filtered, and the filter cake was washed with 100 mL of heptane. The filtrates were combined, and 80 g of silica gel was added to the combined filtrates. After fully stirring, filter, and wash the filter cake with 100mL heptane, and then combine the filtrates. The solvent was removed at 40-45°C. 220 g of oily product, ie crude extract of 4-chloro-2,3-dihydrobenzofuran, was obtained with a yield of 109% and a purity of 89%.

[0056] Pass this intermediate throug...

preparation example 2

[0058] Preparation Example 2: Preparation of 2,3-dihydro-1-benzofuran-4-carbaldehyde

[0059] Under nitrogen protection, 46.8g of Mg and 220g of the oil obtained in Preparation Example 1 were mixed in 1.1L of tetrahydrofuran. Add 100 mL of 4-chloro-2,3-dihydrobenzofuran Grignard reagent previously prepared by conventional methods as an initiator. The resulting mixture was heated to reflux and stirred for 18 hours. The reaction is terminated when the mass fraction of the starting materials in the reaction system is detected to be <0.2% by gas chromatography, and the mixture is cooled to a temperature below 20°C.

[0060] In another 3 L flask, 133.51 g of DMF and 660 mL of THF were added. Add the Grignard reagent dropwise to the above step (residual Mg does not transfer with the solution), and keep the temperature below 35°C. After the dropwise addition was complete, the resulting mixture was stirred at room temperature for 3-4 hours. Cool the mixture to a temperature below ...

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Abstract

The invention relates to a synthesis method of 2,3-dihydro-1-benzofuran-4-carbaldehyde. The formula of 2,3-dihydro-1-benzofuran-4-carbaldehyde can be shown in the formula (I). The synthesis method comprises the steps of making a compound shown in the formula (II) be subjected to intramolecular cyclization reaction so as to produce a compound shown in the formula (III) under the existence of alkali metal compounds and Cu(1); making the compound shown in the formula (III) be subjected to reaction together with magnesium and a compound shown in the formula R3CONR1R2(IV) so as to obtain the compound shown in the formula (I). According to the synthesis method of 2,3-dihydro-1-benzofuran-4-carbaldehyde, reaction conditions are mild, procedures are simple, byproducts are few, and thus the synthesis method of 2,3-dihydro-1-benzofuran-4-carbaldehyde is suitable for being applied to large scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing 2,3-dihydro-1-benzofuran-4-carbaldehyde (DHBFCA), in particular to a two-step method for synthesizing 2,3-dihydro-1-benzofuran-4 - formaldehyde method, and the 2,3-dihydro-1-benzofuran-4-carbaldehyde product system obtained by synthesis can be directly used in the synthesis of tasimelteon without separation and purification treatment. Background technique [0002] Tasimelteon (N-[[(1R,2R)-2-(2,3-dihydro-4-benzofuryl)cyclopropyl]methyl]-propionamide) is used to treat complete A dual MT1 / MT2 melatonin agonist for non-24-hour sleep-wake cycle disorder in blind patients is the first FDA-approved psychiatric drug for the treatment of this disorder. Data from earlier trials showed that tasimelteon advanced the melatonin circadian cycle by up to 5 hours at the beginning of administration. Associated with these effects were improved overall sleep performance, reduced sleep latency, and reduced rapid eye move...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79
CPCC07D307/79
Inventor 孙利权赵新俊冯言枢高汉荣法布里斯·科尼利雷纳托·卡尼沃蒂
Owner 富乐马鸿凯(大连)医药有限公司
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