CN107954870A - A kind of preparation method of 4- methylols -3- methoxyphenoxyacetics - Google Patents

A kind of preparation method of 4- methylols -3- methoxyphenoxyacetics Download PDF

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CN107954870A
CN107954870A CN201711059441.9A CN201711059441A CN107954870A CN 107954870 A CN107954870 A CN 107954870A CN 201711059441 A CN201711059441 A CN 201711059441A CN 107954870 A CN107954870 A CN 107954870A
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ethyl acetate
formula
reaction
formoxyl
preparation
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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
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SHANGHAI BIOCOMPOUNDS CHEMLAB CO Ltd
East China Normal University
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SHANGHAI BIOCOMPOUNDS CHEMLAB CO Ltd
East China Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group

Abstract

The invention discloses a kind of preparation method of 4 methylol, 3 methoxyphenoxyacetic, including step：A) starting material 2,4 4-dihydroxy benzaldehydes are occurred nucleophilic substitution with halogenated acetic acids ethyl ester under alkaline reagent effect, obtains formula (I) 2 (4 formoxyl, 3 hydroxyphenoxy) ethyl acetate；B) (4 formoxyl, the 3 hydroxyphenoxy) ethyl acetate of formula (I) 2 obtains formula (II) 2 (4 formoxyl, 3 methoxyphenoxy) ethyl acetate with iodomethane nucleophilic substitution under alkaline reagent effect；C) (4 formoxyl, the 3 methoxyphenoxy) ethyl acetate of formula (II) 2 reacts under go back original reagent effect, obtains formula (III) 2 (4 methylol, 3 methoxyphenoxy) ethyl acetate；D) after formula (III) 2 (4 methylol, 3 methoxyphenoxy) ethyl acetate is hydrolyzed in alkaline conditions, then it is acidified to obtain 3 methoxyphenoxyacetic of target product formula (IV) 4 methylol.Synthetic route of the present invention is short, easy to operate, security is good, product yield is high, quality is high, synthesis cost is low, meets the requirement of industrialized production.

Description

A kind of preparation method of 4- methylols -3- methoxyphenoxyacetics
Technical field
Linking agent (linker) is the reagent in Peptide systhesis, the present invention relates to a kind of preparation of linking agent, specifically It is related to the preparation method of 4- methylol -3- methoxyphenoxyacetics.
Background technology
4- methylol -3- methoxyphenoxyacetics (HMPA) are the analog of 4- methylols-phenoxyacetic acid (HMP), It is common Solid phase peptide synthesis link reagent, its structural formula is：
On the synthetic methods of 4- methylol -3- methoxyphenoxyacetics, there has been no document report.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of preparation side of 4- methylols -3- methoxyphenoxyacetics Method, with 2,4- 4-dihydroxy benzaldehydes cheap and easy to get for raw material, occurs nucleophilic substitution with halogenated acetic acids ethyl ester first, obtains Intermediate (I), then again by methylation reaction, nucleophilic substitution, aldehyde radical reduction reaction, prepare 4- methylols- 3- methoxyphenoxyacetics.This method have synthetic route is short, easy to operate, security is good, product yield is high, quality is high, close Into cost it is low, be easy to the advantages of industrialized production.
To achieve these goals, the technical solution adopted by the present invention is：
A kind of preparation method of 4- methylols -3- methoxyphenoxyacetics, comprises the following steps：
(a) 2,4- 4-dihydroxy benzaldehydes are dissolved in the first reaction dissolvent, at ambient temperature, are sent out with halogenated acetic acids ethyl ester Raw nucleophilic substitution, obtains formula (I) 2- (4- formoxyl -3- hydroxyphenoxies) ethyl acetate；
(b) formula (I) 2- (4- formoxyl -3- hydroxyphenoxies) ethyl acetate prepared by step (a) is dissolved in the second reaction In solvent, appropriate alkali is added, nucleophilic substitution occurs with iodomethane, obtains formula (II) 2- (4- formoxyl -3- methoxybenzenes Epoxide) ethyl acetate；
(c) in the 3rd reaction dissolvent, by formula (II) 2- (4- formoxyl -3- methoxyphenoxies) of step (b) preparation Ethyl acetate is reacted with go back original reagent, obtains formula (III) 2- (4- methylol -3- methoxyphenoxies) ethyl acetate；
(d) in the 4th reaction dissolvent, formula (III) 2- (4- methylol -3- methoxyphenoxies) second of step (c) preparation Hydrolysis occurs in alkaline conditions for acetoacetic ester, then is acidified to obtain the 4- methylols -3- methoxyphenoxyacetics, it is tied Structure is as shown in formula (IV) 4- methylol -3- methoxyphenoxyacetics；Shown in reaction process such as route (1)：
Shown in syntheti c route such as formula (1)：
Wherein, in step (a)：
First reaction dissolvent is selected from：N,N-dimethylformamide, dimethyl sulfoxide (DMSO), DMAC N,N' dimethyl acetamide；It is excellent Selection of land, is n,N-Dimethylformamide.
The ratio between mole of the 2,4- 4-dihydroxy benzaldehydes and alkali is 1:1.0~1.5；Preferably, 2, the 4- bis- The ratio between mole of hydroxy benzaldehyde and alkali is 1:1.5；Preferably, alkali is potassium carbonate.
The ratio between mole of the 2,4- 4-dihydroxy benzaldehydes and halogenated acetic acids ethyl ester is 1:1.0~1.5；Preferably, The ratio between mole of the 2,4- 4-dihydroxy benzaldehydes and halogenated acetic acids ethyl ester is 1:1.2；Preferably, halogenated acetic acids ethyl ester is bromine Ethyl acetate.The nucleophilic substitution temperature is 20 DEG C~60 DEG C；Preferably, it is 25 DEG C.
When the time of the nucleophilic substitution is 8~12 small；Preferably, for 12 it is small when.
Preferably, described in step (a) after the completion of nucleophilic substitution, step can also be included：Solvent evaporated, with appropriate Solvent extraction, is washed, dry, is evaporated, and is 1 with ethyl acetate and petroleum ether volume ratio:8 carry out mashing purifying.What extraction used Solvent includes dichloromethane, chloroform, ethyl acetate.
Wherein, in step (b)：
Second reaction dissolvent is dichloromethane, chloroform, toluene, N,N-dimethylformamide, acetonitrile or tetrahydrofuran； Preferably, it is n,N-Dimethylformamide.
The alkali is sodium hydride, Sodamide, sodium methoxide or sodium ethoxide；Preferably, it is sodium hydride.
2- (4- formoxyl -3- hydroxyphenoxies) ethyl acetate and alkali, the ratio between the mole of iodomethane are 1:1.0~ 1.5:1.2~2.0；Preferably, 2- (4- formoxyl -3- hydroxyphenoxies) ethyl acetate and alkali, the mole of iodomethane The ratio between be 1:1.5:2.0.
The nucleophilic substitution temperature is 20 DEG C~25 DEG C；Preferably, it is 25 DEG C.
When the time of the nucleophilic substitution is 5~8 small；Preferably, for 8 it is small when.
Preferably, in step (b), after the completion of the reaction, step is further included：Filter and remove solid, solvent evaporated, with suitable Work as solvent extraction, wash, it is dry, it is evaporated, is 3 with absolute ethyl alcohol and petroleum ether volume ratio:1 mashing.Extract the solvent bag used Include dichloromethane, chloroform, ethyl acetate.
Wherein, in step (c)：
3rd reaction dissolvent is absolute ethyl alcohol or absolute methanol；Preferably, it is absolute ethyl alcohol.
The ratio between mole of 2- (4- methylol -3- methoxyphenoxies) ethyl acetate and go back original reagent is 1:0.6 ~1.0；Preferably, the ratio between mole of 2- (4- methylol -3- methoxyphenoxies) ethyl acetate and go back original reagent is 1:0.6。
The go back original reagent is sodium borohydride or potassium borohydride, it is preferable that is sodium borohydride.
The reaction temperature is 20 DEG C~25 DEG C；Preferably, it is 25 DEG C.
When the time of the reduction reaction is 2~3 small；Preferably, for 3 it is small when.
Preferably, described in step (c) after the completion of nucleophilic substitution, step is further included：Water is added to system, with appropriate Solvent extraction, is washed with saturated sodium bicarbonate solution, dry, is evaporated, and uses ethyl acetate with petroleum ether volume ratio for 1:3 carry out Mashing purifying.Extracting the solvent used includes dichloromethane, chloroform, ethyl acetate.
Wherein, in step (d)：
4th reaction dissolvent is selected from：The mixed liquor of water and absolute ethyl alcohol mixed liquor, water and absolute methanol；Preferably The mixed liquor of water and absolute ethyl alcohol, volume ratio 1:1.
The ratio between mole of 2- (4- methylol -3- methoxyphenoxies) ethyl acetate and alkaline reagent is 1:1.0 ~1.2；Preferably, the ratio between mole of 2- (4- methylol -3- methoxyphenoxies) ethyl acetate and alkaline reagent is 1: 1.2。
The alkaline reagent is sodium hydroxide or potassium hydroxide；Preferably, it is sodium hydroxide.
The acid reagent is acetic acid, phosphoric acid or hydrochloric acid；Preferably, it is phosphoric acid.
The temperature of the hydrolysis of ester group reaction is 45 DEG C~60 DEG C；Preferably, it is 60 DEG C.
When the time of the hydrolysis of ester group reaction is 3~4 small；Preferably, for 4 it is small when.
The temperature of the acidification reaction is 20 DEG C~25 DEG C；Preferably, it is 25 DEG C.
When the time of the acidification reaction is 3~5 small；Preferably, for 5 it is small when.
Preferably, after the completion of being reacted described in step (d), step is further included：Solvent evaporated, water and acetic acid are added to system Ethyl ester, with phosphoric acid tune pH to 2~3, separates organic phase, dry, is evaporated.Use ethyl acetate with petroleum ether volume ratio for 1:3 into Row mashing purifying.
The beneficial effects of the present invention are：(1) present invention passes through with 2,4- 4-dihydroxy benzaldehydes cheap and easy to get for raw material Nucleophilic displacement of fluorine, methylate, aldehyde radical reduction, the reaction such as hydrolysis of ester group obtain compound 4-hydroxy methyl -3- methoxyphenoxyacetics, Synthetic route is brief, and high income, yield is up to 75%；(2) present invention is not related to the use of expensive reagent, and cost is low；(3) this hair The easy to operate, condition that bright preparation method is related to is easily-controllable, is easy to industrialized production.
Embodiment
With reference to specific examples below, the present invention is described in further detail.Implement the present invention process, condition, Experimental method etc., in addition to the following content specially referred to, is among the general principles and common general knowledge in the art, the present invention does not have Especially limitation content.
Embodiment 1
1.1), 5.0g 2,4- 4-dihydroxy benzaldehydes are dissolved in 20mL n,N-Dimethylformamide, added in single port bottle Enter 7.5g potassium carbonate (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry are pure), add 9.07g bromoacetate (Chinese medicines groups Solution on Chemical Reagents in Shanghai company, chemistry are pure), room temperature reaction.React 12 it is small when, TLC detection raw material the reaction was complete.It is evaporated N, N- diformazans Yl acetamide, adds ethyl acetate, is washed with water, separate organic phase, and anhydrous sodium sulfate drying, is evaporated, using ethyl acetate with Petroleum ether volume ratio is 1:8 carry out mashing purifying.Obtain formula (I) 2- (4- formoxyl -3- hydroxyphenoxies) ethyl acetate 4.96g, yield 69%.
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),11.37(s,1H).
MS(EI):M/z=224.
1.2), 5.0g 2,4- 4-dihydroxy benzaldehydes are dissolved in 20mL n,N-Dimethylformamide, added in single port bottle Enter 7.5g potassium carbonate (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry are pure), add 7.26g bromoacetate (Chinese medicines groups Solution on Chemical Reagents in Shanghai company, chemistry are pure), room temperature reaction.React 12 it is small when, TLC detection raw material the reaction was complete.It is evaporated N, N- diformazans Base formamide, adds ethyl acetate, is washed with water, separate organic phase, and anhydrous sodium sulfate drying, is evaporated, using ethyl acetate with Petroleum ether volume ratio is 1：8 carry out mashing purifying.Formula (I) 2- (4- formoxyl -3- hydroxyphenoxies) ethyl acetate 5.7g is obtained, Yield is 70%.
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),11.37(s,1H).
MS(EI):M/z=224.
1.3), 5.0g 2,4- 4-dihydroxy benzaldehydes are dissolved in 20mL n,N-Dimethylformamide, added in single port bottle Enter 7.5g potassium carbonate (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry are pure), add 5.35g ethyl chloroacetate (Chinese medicines groups Solution on Chemical Reagents in Shanghai company, chemistry are pure), it is warming up to 50~60 DEG C.React 12 it is small when, TLC detection raw material the reaction was complete.It is evaporated N, Dinethylformamide, adds ethyl acetate, is washed with water, and separates organic phase, anhydrous sodium sulfate drying, is evaporated, using acetic acid Ethyl ester is 1 with petroleum ether volume ratio：8 carry out mashing purifying.Obtain formula (I) 2- (4- formoxyl -3- hydroxyphenoxies) acetic acid second Ester 5.03g, yield 62%.
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),11.37(s,1H).
MS(EI):M/z=224.
1.4) 5.0g 2,4- 4-dihydroxy benzaldehydes are dissolved in 20mL n,N-Dimethylformamide in single port bottle, added 5.49g triethylamines (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry are pure), add 7.26g bromoacetates (in Chinese medicines group Extra large chemical reagents corporation, chemistry are pure), room temperature reaction.React 12 it is small when, TLC detection raw material the reaction was complete.It is evaporated N, N- dimethyl Formamide, adds ethyl acetate, is washed with water, and separates organic phase, anhydrous sodium sulfate drying, is evaporated, using ethyl acetate and stone Oily ether volume ratio is 1:8 carry out mashing purifying.Formula (I) 2- (4- formoxyl -3- hydroxyphenoxies) ethyl acetate 5.28g is obtained, Yield is 65%.
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),11.37(s,1H).
MS(EI):M/z=224.
Embodiment 2
2.1) in single port bottle, 7.0g 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate is dissolved in 35mL acetonitriles In, fall into ice-water bath, 60% sodium hydrides of 1.88g are added portionwise, add 8.88g iodomethane, react at room temperature.It is small to react 8 When, the reaction was complete for TLC detections raw material.Filter and remove solid, solvent evaporated, adds ethyl acetate, be washed with water, separate organic Phase, anhydrous sodium sulfate drying, is evaporated, and uses absolute ethyl alcohol with petroleum ether volume ratio for 3:1 carries out mashing purifying.Obtain formula (II) 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate 4.83g, yield 65%.
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).
MS(EI):M/z=238.
2.2) in single port bottle, 7.0g 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate is dissolved in 35mL N, In dinethylformamide, fall into ice-water bath, 60% sodium hydrides of 1.88g are added portionwise, add 5.33g iodomethane, room temperature Reaction.React 8 it is small when, TLC detection raw material the reaction was complete.Filter and remove solid, be evaporated n,N-Dimethylformamide, add acetic acid Ethyl ester, is washed with water, and separates organic phase, and anhydrous sodium sulfate drying, is evaporated, and uses absolute ethyl alcohol with petroleum ether volume ratio for 3:1 Carry out mashing purifying.Obtain formula (II) 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate 5.13g, yield 69%.
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).
MS(EI):M/z=238.
2.3) in single port bottle, 7.0g 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate is dissolved in 35mL N, In dinethylformamide, fall into ice-water bath, 60% sodium hydrides of 1.88g are added portionwise, add 8.88g iodomethane, room temperature Reaction.React 8 it is small when, TLC detection raw material the reaction was complete.Filter and remove solid, be evaporated n,N-Dimethylformamide, add acetic acid Ethyl ester, is washed with water, and separates organic phase, and anhydrous sodium sulfate drying, is evaporated, and uses absolute ethyl alcohol with petroleum ether volume ratio for 3:1 Carry out mashing purifying.Obtain formula (II) 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate 5.65g, yield 76%.
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).
MS(EI):M/z=238.
2.4) in single port bottle, 7.0g 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate is dissolved in 35mL N, In dinethylformamide, fall into ice-water bath, 1.83g Sodamides are added portionwise, add 8.88g iodomethane, react at room temperature. React 8 it is small when, TLC detection raw material the reaction was complete.Filter and remove solid, be evaporated n,N-Dimethylformamide, add ethyl acetate, It is washed with water, separates organic phase, anhydrous sodium sulfate drying, is evaporated, and uses absolute ethyl alcohol with petroleum ether volume ratio for 3:1 is beaten Slurry purifying.Obtain formula (II) 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate 5.49g, yield 74%.
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).
MS(EI):M/z=238.
2.5) in single port bottle, 7.0g 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate is dissolved in 35mL N, In dinethylformamide, fall into ice-water bath, 2.53g sodium methoxides are added portionwise, add 8.88g iodomethane, react at room temperature. React 8 it is small when, TLC detection raw material the reaction was complete.Filter and remove solid, be evaporated n,N-Dimethylformamide, add ethyl acetate, It is washed with water, separates organic phase, anhydrous sodium sulfate drying, is evaporated, and uses absolute ethyl alcohol with petroleum ether volume ratio for 3:1 is beaten Slurry purifying.Obtain formula (II) 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate 4.90g, yield 66%.
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).
MS(EI):M/z=238.
Embodiment 3
3.1) that 4.97g 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate is dissolved in 25mL in single port bottle is anhydrous In ethanol, fall into ice-water bath, add 0.47g sodium borohydrides, room temperature reaction.React 3 it is small when, TLC detection raw material the reaction was complete. Water is added to system, is extracted with ethyl acetate, is washed with saturated sodium bicarbonate solution, it is dry, it is evaporated, using ethyl acetate and stone Oily ether volume ratio is 1:3 carry out mashing purifying.Obtain formula (III) 2- (4- methylol -3- methoxyphenoxies) ethyl acetate 3.75g, yield 75%.
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)
MS(EI):M/z=240.
3.2) that 4.97g 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate is dissolved in 25mL in single port bottle is anhydrous In ethanol, fall into ice-water bath, add 0.79g sodium borohydrides, room temperature reaction.React 3 it is small when, TLC detection raw material the reaction was complete. Water is added to system, is extracted with ethyl acetate, is washed with saturated sodium bicarbonate solution, it is dry, it is evaporated, using ethyl acetate and stone Oily ether volume ratio is 1:3 carry out mashing purifying.Obtain formula (III) 2- (4- methylol -3- methoxyphenoxies) ethyl acetate 3.7g, yield 74%.
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)
MS(EI):M/z=240.
3.3) that 4.97g 2- (4- formoxyl -3- methoxyphenoxies) ethyl acetate is dissolved in 25mL in single port bottle is anhydrous In methanol, fall into ice-water bath, add 0.47g sodium borohydrides, room temperature reaction.React 3 it is small when, TLC detection raw material the reaction was complete. Water is added to system, is extracted with ethyl acetate, is washed with saturated sodium bicarbonate solution, it is dry, it is evaporated, using ethyl acetate and stone Oily ether volume ratio is 1:3 carry out mashing purifying.Obtain formula (III) 2- (4- methylol -3- methoxyphenoxies) ethyl acetate 3.7g, yield 74%.
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)
MS(EI):M/z=240.
Embodiment 4
4.1) in single port bottle by 3g 2- (4- methylol -3- methoxyphenoxies) ethyl acetate be dissolved in 20mL mix it is molten (V (absolute methanol) in agent：V (water)=1:1) 0.6g sodium hydroxides, are added, are warming up to back flow reaction.React 4 it is small when, TLC inspection Surveying raw material, the reaction was complete.Solvent evaporated, adds water and ethyl acetate to system, with phosphoric acid tune pH to 2~3, separates organic phase, do It is dry, it is evaporated.Use ethyl acetate with petroleum ether volume ratio for 1:3 carry out mashing purifying.Obtain formula (IV) 4- methylol -3- methoxies Phenoxyl acetic acid 1.94g, yield 73%.
1H NMR:(400MHz,DMSO-d6):δ=3.74 (s, 3H), 4.39 (s, 2H), 4.64 (s, 2H), 4.82 (s, 1H), 6.44 (dd, J=8.3,2.1Hz, 1H), 6.52 (d, J=2.1Hz, 1H), 7.21 (d, J=8.3Hz, 1H)
MS(EI):M/z=212.
4.2) in single port bottle by 3g 2- (4- methylol -3- methoxyphenoxies) ethyl acetate be dissolved in 20mL mix it is molten (V (absolute ethyl alcohol) in agent：V (water)=1:1) 0.6g sodium hydroxides, are added, are warming up to back flow reaction.React 4 it is small when, TLC inspection Surveying raw material, the reaction was complete.Solvent evaporated, adds water and ethyl acetate to system, with phosphoric acid tune pH to 2~3, separates organic phase, do It is dry, it is evaporated.Use ethyl acetate with petroleum ether volume ratio for 1:3 carry out mashing purifying.Obtain formula (IV) 4- methylol -3- methoxies Phenoxyl acetic acid 2.0g, yield 75%.
1H NMR:(400MHz,DMSO-d6):δ=3.74 (s, 3H), 4.39 (s, 2H), 4.64 (s, 2H), 4.82 (s, 1H), 6.44 (dd, J=8.3,2.1Hz, 1H), 6.52 (d, J=2.1Hz, 1H), 7.21 (d, J=8.3Hz, 1H)
MS(EI):M/z=212.
4.3) in single port bottle by 3g 2- (4- methylol -3- methoxyphenoxies) ethyl acetate be dissolved in 20mL mix it is molten (V (absolute ethyl alcohol) in agent：V (water)=1:1) 0.5g sodium hydroxides, are added, are warming up to back flow reaction.React 4 it is small when, TLC inspection Surveying raw material, the reaction was complete.Solvent evaporated, adds water and ethyl acetate to system, with phosphoric acid tune pH to 2~3, separates organic phase, do It is dry, it is evaporated.Use ethyl acetate with petroleum ether volume ratio for 1:3 carry out mashing purifying.Obtain formula (IV) 4- methylol -3- methoxies Phenoxyl acetic acid 1.78g, yield 67%.
1H NMR:(400MHz,DMSO-d6):δ=3.74 (s, 3H), 4.39 (s, 2H), 4.64 (s, 2H), 4.82 (s, 1H), 6.44 (dd, J=8.3,2.1Hz, 1H), 6.52 (d, J=2.1Hz, 1H), 7.21 (d, J=8.3Hz, 1H)
MS(EI):M/z=212.
In conclusion the method for preparing 4- methylol -3- methoxyphenoxyacetics of the present invention has synthetic route letter It is short, easy to operate, cost is low, yield is high, is easy to the advantages of industrialized production.
The protection content of the present invention is not limited to above example.Without departing from the spirit and scope of the invention, originally Field technology personnel it is conceivable that change and advantage be all included in the present invention, and using appended claims as protect Protect scope.

Claims (6)

1. a kind of preparation method of 4- methylols -3- methoxyphenoxyacetics, it is characterised in that comprise the following steps：
(a) 2,4- 4-dihydroxy benzaldehydes are added in the first reaction dissolvent, is sent out under alkaline reagent effect with halogenated acetic acids ethyl ester Raw nucleophilic substitution, obtains formula (I) 2- (4- formoxyl -3- hydroxyphenoxies) ethyl acetate；Wherein, 2, the 4- dihydroxy Benzaldehyde and alkali, the ratio between the mole of halogenated acetic acids ethyl ester are 1:1.0~1.5:1.0~1.5；Reaction temperature is 20 DEG C~60 DEG C, when the reaction time is 8~12 small；
(b) formula (I) 2- (4- formoxyl -3- hydroxyphenoxies) ethyl acetate prepared by step (a) is dissolved in the second reaction dissolvent In, alkali is added, nucleophilic substitution is carried out with iodomethane, obtains formula (II) 2- (4- formoxyl -3- methoxyphenoxies) acetic acid Ethyl ester；Wherein, the ratio between mole of 2- (4- formoxyl -3- hydroxyphenoxies) ethyl acetate and alkali, iodomethane is 1:1.0 ~1.5:1.2~2.0；Reaction temperature is 20 DEG C~25 DEG C, when the reaction time is 5~8 small；
(c) in the 3rd reaction dissolvent, by formula (II) 2- (4- formoxyl -3- methoxyphenoxies) acetic acid of step (b) preparation Ethyl ester is reacted with go back original reagent, obtains formula (III) 2- (4- methylol -3- methoxyphenoxies) ethyl acetate；2- (the 4- hydroxyls Methyl -3- methoxyphenoxies) the ratio between the mole of ethyl acetate and go back original reagent is 1:0.6~1.0；Reaction temperature is 20 DEG C ~25 DEG C, when the reaction time is 2~4 small；
(d) in the 4th reaction dissolvent, formula (III) 2- (4- methylol -3- methoxyphenoxies) acetic acid second of step (c) preparation Hydrolysis occurs in alkaline conditions for ester, then is acidified to obtain the 4- methylols -3- methoxyphenoxyacetics, its structure is such as Shown in formula (IV)；Wherein, the ratio between mole of 2- (4- methylol -3- methoxyphenoxies) ethyl acetate and alkaline reagent For 1:1.0~1.5；Hydrolysis of ester group reaction temperature is 45 DEG C~60 DEG C, when the reaction time is 3~4 small；Acidification reaction temperature is 20 DEG C~25 DEG C, when the acidification reaction time is 3~5 small；Shown in specific syntheti c route such as formula (1)：
2. the preparation method of 4- methylols -3- methoxyphenoxyacetics according to claim 1, it is characterised in that step Suddenly in (a), the alkali is potassium carbonate or triethylamine；The halogenated acetic acids ethyl ester is ethyl chloroacetate or bromoacetate.
3. the preparation method of 4- methylols -3- methoxyphenoxyacetics according to claim 1, it is characterised in that step Suddenly in (b), the alkali is sodium hydride, Sodamide, sodium methoxide or sodium ethoxide.
4. the preparation method of 4- methylols -3- methoxyphenoxyacetics according to claim 1, it is characterised in that step Suddenly in (c), the go back original reagent is sodium borohydride or potassium borohydride.
5. the preparation method of 4- methylols -3- methoxyphenoxyacetics according to claim 1, it is characterised in that step Suddenly in (d), the alkaline reagent is sodium hydroxide or potassium hydroxide；The acid reagent is acetic acid, phosphoric acid or hydrochloric acid.
6. the preparation method of 4- methylols -3- methoxyphenoxyacetics according to claim 1, it is characterised in that institute It is N,N-dimethylformamide, dimethyl sulfoxide (DMSO) or DMAC N,N' dimethyl acetamide to state the first reaction dissolvent；Second reaction dissolvent is Dichloromethane, chloroform, toluene, N,N-dimethylformamide, acetonitrile or tetrahydrofuran；3rd reaction dissolvent is absolute ethyl alcohol or nothing Water methanol；4th reaction dissolvent is water and absolute ethyl alcohol mixed liquor, the mixed liquor of water and absolute methanol；Its volume ratio is 1:1.
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