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Preparation method of benzyl aryl ether

A benzyl aryl ether and benzyl technology, which is applied in the field of organic compound synthesis, can solve the problems of high content and difficult product purification, and achieves the effects of good economic benefit, high yield and selectivity, and mild reaction conditions

Inactive Publication Date: 2017-02-01
SHANGAI PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] WO2007147491 describes the preparation of 4-(3-fluorobenzyloxy)-benzaldehyde I(X = 3-F), the content of reaction by-product IV (X=3-F) is higher, which brings difficulties for product purification

Method used

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  • Preparation method of benzyl aryl ether
  • Preparation method of benzyl aryl ether
  • Preparation method of benzyl aryl ether

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 3-fluorobenzyl chloride II-1 (X=3-F, Y=-Cl) (50g, 0.34mol), p-hydroxybenzaldehyde III-1 (44.3g, 0.36 mol), acetonitrile 500mL, diisopropylethylamine (49.2g, 0.38mol), sodium iodide (5.18g, 0.034mol), after addition, the reaction solution was heated to 50°C and stirred for 24h. Cool to room temperature, concentrate the reaction solution under reduced pressure, add 500 mL of dichloromethane to the residue, wash the resulting mixed solution with 1M hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution successively, dry the organic phase, and concentrate to obtain a crude product. Recrystallization of isopropyl ether gave 71 g of white solid I-1 (X=3-F), yield 89%, Mp: 42.2-43.5°C, purity 99.7% by HPLC, no impurity IV-1 (X=3-F) was detected 3-F).

[0030] 1 H NMR (CDCl 3 ,400MHz) δ9.89(s,1H),7.84(m,2H),7.37(m,1H),7.17(m,2H),7.05(m,3H),5.15(s,2H).

[0031] 19 F NMR (CDCl 3 ,376.5MHz) δ-112.38(s).

Embodiment 2

[0033] Add 3-fluorobenzyl methanesulfonate II-2 (X=3-F, Y=CH 3 SO 3 -) (69.4g, 0.34mol), p-hydroxybenzaldehyde III-1 (44.3g, 0.36mol), tetrahydrofuran 500mL, triethylamine (38.5g, 0.38mol), sodium iodide (5.18g, 0.034mol), After the addition, the reaction solution was stirred at 20-25°C for 24h. Concentrate the reaction solution under reduced pressure, add 500 mL of dichloromethane to the residue, wash the resulting mixed solution with 1M hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution successively, dry the organic phase, and concentrate to obtain a crude product, which is reconstituted with isopropyl ether. Crystallization gave 70 g of white solid I-1 (X=3-F), yield 87.7%, Mp: 42.5-43.7°C, purity 99.72% by HPLC, no impurity IV-1 (X=3-F) was detected .

[0034] 1 H NMR spectrum and 19 The F NMR spectral data are consistent with Example 1.

Embodiment 3

[0036] Add 3-fluorobenzyl chloride II-1 (X=3-F, Y=-Cl) (25g, 0.17mol), p-hydroxybenzaldehyde III-1 (22.2g, 0.18 mol), methanol 250mL, DBU (28.8g, 0.19mol), sodium iodide (2.59g, 0.017mol), after addition, the reaction solution was stirred at 20-25°C for 24h. Concentrate the reaction solution under reduced pressure, add 250 mL of dichloromethane to the residue, wash the resulting mixed solution with 1M hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution successively, dry the organic phase, and concentrate to obtain a crude product, which is reconstituted with isopropyl ether. Crystallization gave 35.9 g of white solid I-1 (X=3-F), yield 90%, Mp: 42.6-43.8°C, purity 99.79% by HPLC, no impurity IV-1 (X=3-F) was detected ).

[0037] 1 H NMR spectrum and 19 The F NMR spectrum data are consistent with Example 1.

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Abstract

The invention discloses a preparation method of highly-pure benzyl aryl ether 4-(3-fluorobenzyloxy)-benzaldehyde and a derivative thereof. The method is characterized in that the benzyl aryl ether 4-(3-fluorobenzyloxy)-benzaldehyde and the derivative thereof are prepared through condensation of a benzyl derivative and p-hydroxybenzaldehyde in the presence of an organic alkali. The method has the characteristics of mild reaction conditions, simplicity in operation, good reaction selectivity, high product purity, and easy realization of industrial production.

Description

technical field [0001] The present invention relates to a kind of preparation method of benzyl aryl ether and derivative thereof, specifically, relate to the preparation method of 4-(3-fluorobenzyloxy)-benzaldehyde and derivative thereof, belong to the synthesis field of organic compound . Background technique [0002] Benzyl aryl ether 4-(3-fluorobenzyloxy)-benzaldehyde and its derivatives (compounds of general formula I) are important intermediates for the synthesis of Parkinson’s disease treatment drugs safinamide and ralfinamide. In the process of the general formula compound I, there are often dibenzyl-substituted by-products IV to generate, and IV will participate in the follow-up reaction to generate cytotoxic impurities. Therefore, the preparation of the high-purity general formula I compound is the synthesis of safinamide and ralfin Amide key. [0003] [0004] Chinese patent ZL200880120328.X and U.S. patent US20090156678 describe the preparation of I(X = 2-F ...

Claims

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Application Information

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IPC IPC(8): C07C45/64C07C47/575
CPCC07C45/64C07C47/575
Inventor 黄建毕光庆孙珩
Owner SHANGAI PHARMA GRP CO LTD
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