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Preparation method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid

A kind of technology of methoxyphenoxyacetic acid and methoxyphenoxyacetic acid, which is applied in the field of preparation of linking agent, and can solve the problem of the synthesis method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid, which has not been reported in the literature and other problems, to achieve the effect of easy industrial production, high yield and easy control of conditions

Inactive Publication Date: 2018-04-24
EAST CHINA NORMAL UNIV +1
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

[0004] There is no literature report about the synthetic method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid

Method used

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  • Preparation method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid
  • Preparation method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid
  • Preparation method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid

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Experimental program
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Effect test

Embodiment 1

[0047] 1.1), dissolve 5.0g of 2,4-dihydroxybenzaldehyde in 20mL of N,N-dimethylformamide in a one-mouth bottle, add 7.5g of potassium carbonate (Sinopharm Group Shanghai Chemical Reagent Company, chemically pure), and then Add 9.07 g of ethyl bromoacetate (Sinopharm Shanghai Chemical Reagent Company, chemically pure), and react at room temperature. The reaction was carried out for 12 hours, and TLC detected that the reaction of the raw materials was complete. Evaporate N,N-dimethylacetamide to dryness, add ethyl acetate, wash with water, separate the organic phase, dry over anhydrous sodium sulfate, evaporate to dryness, use ethyl acetate to petroleum ether volume ratio of 1:8 for beating and purification . 4.96 g of ethyl 2-(4-formyl-3-hydroxyphenoxy)acetate of formula (I) was obtained with a yield of 69%.

[0048] 1H NMR: (400MHz, CDCl3): δ=1.24(t, J=7.1Hz, 3H), 4.22(q, J=7.2Hz, 2H), 4.60(s, 2H), 6.32(d, J=2.0Hz ,1H),6.52(dd,J=8.7,2.2Hz,1H),7.40(d,J=8.7Hz,1H),9.67(s,1H),1...

Embodiment 2

[0060] 2.1) In a single-necked bottle, dissolve 7.0g of ethyl 2-(4-formyl-3-methoxyphenoxy)acetate in 35mL of acetonitrile, drop it into an ice-water bath, and add 1.88g of 60% hydrogenated Sodium, then add 8.88g iodomethane, room temperature reaction. After 8 hours of reaction, TLC detected that the reaction of the raw materials was complete. The solid was removed by suction filtration, the solvent was evaporated to dryness, ethyl acetate was added, washed with water, the organic phase was separated, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by beating with anhydrous ethanol and petroleum ether at a volume ratio of 3:1. 4.83 g of ethyl 2-(4-formyl-3-methoxyphenoxy)acetate of formula (II) was obtained with a yield of 65%.

[0061] 1H NMR: (400MHz, CDCl3): δ=1.24(t, J=7.1Hz, 3H), 3.83(s, 3H), 4.22(q, J=7.1Hz, 2H), 4.61(s, 2H), 6.41 (dd,J=8.7,1.5Hz,1H),6.47(d,J=1.8Hz,1H),7.73(d,J=8.7Hz,1H),10.23(s,1H).

[0062] MS (EI): m / z=238.

[0063] 2.2) I...

Embodiment 3

[0076] 3.1) Dissolve 4.97g of ethyl 2-(4-formyl-3-methoxyphenoxy)acetate in 25mL of absolute ethanol in a single-necked bottle, drop it into an ice-water bath, add 0.47g of sodium borohydride, React at room temperature. The reaction was carried out for 3 hours, and TLC detected that the reaction of the raw materials was complete. Water was added to the system, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried, evaporated to dryness, and purified by beating with a volume ratio of ethyl acetate to petroleum ether of 1:3. 3.75 g of ethyl 2-(4-hydroxymethyl-3-methoxyphenoxy)acetate of formula (III) was obtained with a yield of 75%.

[0077] 1H NMR: (400MHz, CDCl3): δ=1.23(t, J=7.1Hz, 3H), 2.09(t, J=6.4Hz, 1H), 3.77(s, 3H), 4.21(q, J=7.1Hz ,2H),4.54(d,J=4.2Hz,4H),6.31(dd,J=8.2,2.2Hz,1H),6.50(d,J=2.1Hz,1H),7.09(d,J=8.2Hz ,1H).

[0078] MS (EI): m / z=240.

[0079] 3.2) Dissolve 4.97g of ethyl 2-(4-formyl-3-methoxyphenoxy)acetate in 25mL of abs...

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Abstract

The invention discloses a preparation method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid, comprising the steps of a) subjecting the start material 2,4-dihydroxybenzaldehyde and halogenated ethyl acetate to nucleophilic substitution reaction under the action of an alkaline reagent to obtain 2-(4-formyl-3-hydroxyphenoxy)ethyl acetate of formula (I) that is shown in the description; b) subjecting2-(4-formyl-3-hydroxyphenoxy)ethyl acetate of formula (I) and iodomethane to nucleophilic substitution reaction under the action of an alkaline reagent to obtain 2-(4-formyl-3-hydroxyphenoxy)ethyl acetate of formula (II) that is shown in the description; c) allowing 2-(4-formyl-3-hydroxyphenoxy)ethyl acetate of formula (II) to react under the action of a reducing agent to obtain 2-(4-formyl-3-hydroxyphenoxy)ethyl acetate of formula (III) that is shown in the description; d) hydrolyzing 2-(4-formyl-3-hydroxyphenoxy)ethyl acetate of formula (III) under alkaline conditions, and acidifying to obtain 4-hydroxymethyl-3-methoxyphenoxyacetic acid of target product formula (IV) that is shown in the description. The preparation method has a short route, is simple to perform, good in safety, high inproduct yield and product quality, is low in synthetic cost and meets the industrial production requirements.

Description

technical field [0001] A linker is an important reagent in polypeptide synthesis. The invention relates to the preparation of a linker, in particular to a preparation method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid. Background technique [0002] 4-Hydroxymethyl-3-methoxyphenoxyacetic acid (HMPA) is an analogue of 4-hydroxymethyl-phenoxyacetic acid (HMP), and is a commonly used linking reagent for solid-phase peptide synthesis. Its structural formula is: [0003] [0004] There is no literature report about the synthetic method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid. Contents of the invention [0005] The technical problem to be solved by this invention is to provide a kind of preparation method of 4-hydroxymethyl-3-methoxyphenoxyacetic acid, take cheap and easy-to-get 2,4-dihydroxybenzaldehyde as raw material, firstly mix with halogenated Ethyl acetate undergoes a nucleophilic substitution reaction to obtain intermediate (I), and then undergoes steps such...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/31C07C67/30C07C69/712C07C27/02C07C51/09C07C59/70
CPCC07C51/09C07C67/30C07C67/31C07C69/712C07C59/70
Inventor 罗宇周朴李晓林朱皓庭何洋张玉柳占莉吴文萱李倩康立涛杨世琼
Owner EAST CHINA NORMAL UNIV
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