CN104945246A - Preparation method of p-alkoxyphenylacetic acid and intermediate thereof - Google Patents
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- NRPFNQUDKRYCNX-UHFFFAOYSA-N COc1ccc(CC(O)=O)cc1 Chemical compound COc1ccc(CC(O)=O)cc1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 description 1
- PXNJGLAVKOXITN-UHFFFAOYSA-N N#CCc(cc1)ccc1[N+]([O-])=O Chemical compound N#CCc(cc1)ccc1[N+]([O-])=O PXNJGLAVKOXITN-UHFFFAOYSA-N 0.000 description 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N N#CCc1ccccc1 Chemical compound N#CCc1ccccc1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 1
- CSEWAUGPAQPMDC-UHFFFAOYSA-N Nc1ccc(CC(O)=O)cc1 Chemical compound Nc1ccc(CC(O)=O)cc1 CSEWAUGPAQPMDC-UHFFFAOYSA-N 0.000 description 1
- XQXPVVBIMDBYFF-UHFFFAOYSA-N OC(Cc(cc1)ccc1O)=O Chemical compound OC(Cc(cc1)ccc1O)=O XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 1
- YBADLXQNJCMBKR-UHFFFAOYSA-N [O-][N+](c1ccc(CC(O)=O)cc1)=O Chemical compound [O-][N+](c1ccc(CC(O)=O)cc1)=O YBADLXQNJCMBKR-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of p-alkoxyphenylacetic acid and an intermediate thereof. The preparation method of the p-alkoxyphenylacetic acid disclosed as Formula I comprises the following steps: (1) in the presence of alkali, carrying out hydrolytic ring-opening salification reaction on a compound disclosed as Formula II in water; and (2) after the reaction in the step (1) finishes, regulating the pH value of the system to 7-14, carrying out decarboxylation reaction on a compound disclosed as Formula III under the direct action of an oxidizer. The preparation method of the compound disclosed as Formula II comprises the following step: under the catalytic action of alcamine compounds, carrying out condensation reaction on a compound disclosed as Formula IV and hydantoin in water. The preparation method has the advantages of high yield, high purity, mild reaction conditions and environmental protection, and is simple to operate and more suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of a kind of palkoxy benzene acetic acid and intermediate thereof.
Background technology
Homoanisic acid is the intermediate synthesizing thymoleptic Venlafaxine of new generation, is also the intermediate of multiple cardiovascular agent such as synthesis puerarin, osajin etc., is also the key intermediate of synthesis central antitussive Dextromethorphane Hbr simultaneously.About its synthetic method, report both domestic and external mainly contains following several method:
Route 1:
" Liaoning chemical industry " (1993,24(6), P45-46) in report by benzyl cyanide to be starting raw material, to prepare p-hydroxyphenylaceticacid through nitrated, hydrolysis, reduction, diazotization and hydrolysis, then methylate can obtain homoanisic acid to it.This route is early stage synthetic route, and step is more, and by product is many, and loss is large, and the raw material of use is very large to the pollution of environment, and yield is also lower, is 31.7%." Chinese Journal of Pharmaceuticals " (1993,24(6), P276-7) in report process modification for said synthesis route, first para orientation nitration is reduced, diazotization, is placed in acid hydrolysis finally, and preparing p-hydroxyphenylaceticacid total recovery is 28%.
Route 2:
JP57185234,1982 to report with phenol and oxoethanoic acid as starting raw material, prepare parahydroxymandelic acid, are obtaining p-hydroxyphenylaceticacid to its reduction α position hydroxyl.By methylating to it and can obtaining homoanisic acid.This route is the principal synthetic routes preparing p-hydroxyphenylaceticacid the nineties, and reactions steps is few, good product quality, but raw material is more expensive, and cost is higher.
Route 3:
JP58206541,1983 and GB2078718,1982 to report with p-chlorobenzyl cyanide be starting raw material, and through hydrolysis, fragrant hydroxylation prepares p-hydroxyphenylaceticacid, methylates can obtain homoanisic acid to it.In this route, p-chlorobenzyl cyanide raw material is common pesticide intermediate, to be easy to get and cheap, producer is had to adopt this route to produce at present, but the aromatic hydroxylation reaction needed in this route is at highly basic, react under High Temperature High Pressure, very high to equipment requirements, the oxine ketone simultaneously used cannot be reused, and aftertreatment is more loaded down with trivial details.
Route 4:
US5149866; 1992 and Synthetic Communications; 2003; 33 (1); P59-63 reports and reacts with sulphur and Uricida by methoxy methyl phenyl ketone; reset and be hydrolyzed and obtain homoanisic acid, wherein p-methoxy-acetophenone is prepared by friedel-crafts acylation primarily of phenylmethylether.This route raw materials cost is lower, but the hydrogen sulfide environmental pollution produced after the aluminum chloride of Friedel-Crafts reaction and Willgerodt-Kindler rearrangement reaction in route is comparatively large, and three-protection design difficulty, yield is also lower.
Summary of the invention
Technical problem to be solved by this invention be overcome that the reaction scheme existed in prior art is long, yield is low, contaminate environment, complex operation be complicated, the high and high in cost of production defect to equipment requirements and provide the preparation method of a kind of palkoxy benzene acetic acid and intermediate thereof.Preparation method's yield of the present invention is high, purity is high, reaction conditions is gentle, simple to operate, environmental protection and be more suitable for suitability for industrialized production.
The invention provides a kind of preparation method such as formula the palkoxy benzene acetic acid shown in I, it comprises the following steps:
(1) in water, in the presence of base, by the open loop salt-forming reaction that is hydrolyzed such as formula the compound shown in II, obtained such as formula the compound shown in III;
(2) after the reaction of step (1) terminates, behind regulation system pH value to 7 ~ 14, reaction system, directly under the effect of oxygenant, carries out decarboxylic reaction by such as formula the compound shown in III, obtained such as formula the palkoxy benzene acetic acid shown in I;
Wherein, R is C
1~ C
4alkyl; M is alkalimetal ion.
Described C
1~ C
4alkyl be preferably methyl, ethyl, propyl group, sec.-propyl or butyl; It is more preferably methyl.Described alkalimetal ion is preferably sodium ion or potassium ion.
In step (1), the method for described hydrolysis salt-forming reaction and condition can be the conventional method of this type of reaction of this area and condition, and the present invention is following condition particularly preferably: described alkali is preferably mineral alkali.Described mineral alkali is preferably one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide and sodium hydride, is more preferably sodium hydroxide and/or potassium hydroxide.The form of all right alkali aqueous solution of described alkali exists, and the mass percent of described alkali aqueous solution is preferably 20% ~ 35%, is more preferably 25% ~ 35%; Described mass percent is refer to that the quality of alkali accounts for the per-cent of alkali aqueous solution total mass.The described mol ratio such as formula the compound shown in II and described alkali is preferably 1:1 ~ 1:10, is more preferably 1:4 ~ 1:6.Described water and the volume mass such as formula the compound shown in II are 2mL/g ~ 10mL/g than preferably.Described hydrolysis salt-forming reaction temperature is preferably 0 ~ 150 DEG C, is more preferably 90 ~ 110 DEG C.The process of described hydrolysis salt-forming reaction can adopt the traditional test methods in this area (as TLC, HPLC or NMR) to monitor, for reaction end time generally to disappear such as formula the compound shown in II, reaction times is preferably 0.5 ~ 5 hour, is preferably 1.5 ~ 3 hours.
In step (1), after described hydrolysis salt-forming reaction terminates, also can through aftertreatment.The method of described aftertreatment and condition are preferably by the reaction solution of hydrolysis salt-forming reaction, regulation system pH value to 7 ~ 14, filter, must such as formula the compound shown in III; Again in water, under the effect of oxygenant, carry out described decarboxylic reaction by such as formula the compound shown in III, obtained such as formula the compound shown in I.Wherein, described regulation system pH value obtains method and condition can be the conventional method of this type of reaction of this area and condition, and the acid of preferred this area routine in the present invention, regulates the pH value in reaction solution to be 7 ~ 14.Described acid is preferably one or more in hydrochloric acid, sulfuric acid and acetic acid, is more preferably hydrochloric acid.Described pH value is preferably 8 ~ 10.
In step (2), the method for described decarboxylic reaction and condition can be the conventional method of this type of reaction of this area and condition, and the present invention is following condition particularly preferably: described oxygenant is preferably hydrogen peroxide.The described mol ratio such as formula the compound shown in III or formula II and oxygenant is preferably 1:0.5 ~ 1:5, is more preferably 1:1 ~ 1:2.Described decarboxylic reaction temperature is preferably 0 ~ 50 DEG C, is more preferably 20 ~ 30 DEG C.The process of described decarboxylic reaction can adopt the traditional test methods in this area (as TLC, HPLC or NMR) to monitor, and for reaction end time generally to disappear such as formula the compound shown in III, the reaction times is preferably 1h ~ 3h hour.
In step (2), after described decarboxylic reaction terminates, preferably through aftertreatment.The method of described aftertreatment and condition are preferably after being mixed with sodium sulfite solution by the reaction solution of decarboxylic reaction, and being mixed to pH value with acid is 1 ~ 3, separate out solid, filter, dry, must such as formula the compound shown in I.Wherein, it is used that the mass percent of described sodium sulfite solution can be this area routine, and preferably for mass percent is the sodium sulfite solution of 5%, described mass percent is refer to that the quality of S-WAT accounts for the per-cent of sodium sulfite solution total mass.Described acid is preferably one or more in hydrochloric acid, sulfuric acid and acetic acid, and be more preferably hydrochloric acid, the massfraction of described acid can be described in the routine of this area, as long as the pH value of reaction system can be regulated to be 1 ~ 3.
Described such as formula the compound shown in I, preferably purified process.The method of described purifying and condition can be method and the condition of this area purifying routine, are preferably recrystallization.The method of described recrystallization preferably comprises the following steps: after mixing with water such as formula the compound shown in I, crystallization.
The described preparation method such as formula the palkoxy benzene acetic acid shown in I, it also can comprise the following steps: in water further, under the effect of catalyzer, carry out condensation reaction by such as formula the compound shown in IV and glycolylurea, obtained described such as formula the compound shown in II;
Wherein, R is C
1~ C
4alkyl.
Wherein, the method for described condensation reaction and condition can be the conventional method of this type of reaction of this area and condition, and the present invention is following condition particularly preferably: described catalyzer is preferably alcamine compound.Described alcamine compound is preferably α-amino isopropyl alcohol and/or thanomin.The described mol ratio such as formula the compound shown in IV and described glycolylurea is preferably 1:1 ~ 1:2, is more preferably 1:1 ~ 1:1.2.The described mol ratio such as formula the compound shown in IV and described catalyzer is preferably 1:0.1 ~ 1:1.5, is more preferably 1:0.3 ~ 1:1.Described water and the volume mass such as formula the compound shown in IV are 5mL/g ~ 20mL/g than preferably, are more preferably 8mL/g ~ 15mL/g.The temperature of described reaction is preferably 0 ~ 150 DEG C, is more preferably 90 ~ 110 DEG C.The process of described condensation reaction can adopt the traditional test methods in this area (as TLC, HPLC or NMR) to monitor, and for reaction end time generally to disappear such as formula the compound shown in IV, the reaction times is preferably 0.5 ~ 10 hour.
Wherein, after described condensation reaction terminates, preferably through aftertreatment.Method and the condition of described aftertreatment preferably comprise the following steps: by the reacting liquid filtering of condensation reaction, obtain mother liquor, filter cake washes with water, dry, obtain such as formula the compound shown in II.Described mother liquor can be applied mechanically to lower batch reaction at least three times.
Such as formula a preparation method for the compound shown in II, it comprises the following steps: in water, under the catalysis of alcamine compound, carries out condensation reaction by such as formula the compound shown in IV and glycolylurea, obtained such as formula the compound shown in II; The described mol ratio such as formula the compound shown in IV and described catalyzer is 1:0.1 ~ 1:1.5;
Wherein, R is C
1~ C
4alkyl, the method for described condensation reaction and condition ditto described in.
In the present invention, described such as formula the compound shown in I, its synthetic route is preferably as follows:
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is:
Preparation method's reaction conditions of the present invention is gentle, simple to operate, environmental protection, cost are low, and the yield of target compound is high, purity is also high, is applicable to industrialized production.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Embodiment 1 is such as formula the preparation of the compound shown in II
Aubepine (13.6g is added in 250mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed, 0.1mol), glycolylurea (10.1g, 0.1mol), deionized water 150mL and thanomin (3g, 0.05mol), under strong stirring, by room temperature to 95 DEG C, raw material dissolves gradually, just yellow solid is had constantly to separate out afterwards, after reaction 4h, TLC monitors, raw material primitive reaction is complete, be cooled to room temperature, filter, and after washing filter cake with water, dry, obtain intermediate formula II 20.1g of yellow solid, yield 92%, mother liquor can overlap the preparation of using next batch intermediate formula II.
Embodiment 2 is such as formula the preparation of the compound shown in II
Aubepine (13.6g is added in 250mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed, 0.1mol), glycolylurea (10.1g, 0.1mol), deionized water 68mL and α-amino isopropyl alcohol (7.5g, 0.1mol), under strong stirring, by room temperature to 150 DEG C, raw material dissolves gradually, just yellow solid is had constantly to separate out afterwards, after reaction 4h, TLC monitors, and raw material primitive reaction is complete, be cooled to room temperature, filter, and after washing filter cake with water, dry, obtain intermediate formula II 17.5g of yellow solid, yield 80%.
Embodiment 3 is such as formula the preparation of the compound shown in II
Aubepine (13.6g is added in 250mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed, 0.1mol), glycolylurea (20.2g, 0.2mol), deionized water 272mL and thanomin (1.83g, 0.03mol), under strong stirring, by room temperature to 100 DEG C, raw material dissolves gradually, just yellow solid is had constantly to separate out afterwards, after reaction 10h, TLC monitors, and raw material still has a small amount of unreacted complete, be cooled to room temperature, filter, and after washing filter cake with water, dry, obtain intermediate formula II 17.8g of yellow solid, yield 82%.
Embodiment 4 is such as formula the preparation of the compound shown in III
In 50mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed; add intermediate formula II (4.36g prepared by embodiment 1; 0.02mol), deionized water 20mL; nitrogen protection, then adds sodium hydroxide (3.2g, the 0.08mol) solution being dissolved in 10mL deionized water; be heated to 150 DEG C of reactions; after 3h, stopped reaction, is cooled to room temperature; about regulating pH value to 8; stirring is spent the night, and has a large amount of white solid to separate out, and filters; wash with methanol aqueous solution; drying, obtains white solid 3.36g, yield 78%.
Embodiment 5 is such as formula the preparation of the compound shown in III
In 50mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed, add intermediate formula II (4.36g, 0.02mol), deionized water 25mL prepared by embodiment 2; nitrogen protection, then adds potassium hydroxide (5.6g, the 0.1mol) solution being dissolved in 10mL deionized water; be heated to 90 DEG C of reactions, after 4h, stopped reaction; be cooled to room temperature, about regulating pH value to 8, stirring is spent the night; there is a large amount of white solid to separate out, filter, wash with methanol aqueous solution; drying, obtains white solid 3.50g, yield 81%.
Embodiment 6 is such as formula the preparation of the compound shown in III
In 50mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed; add intermediate formula II (4.36g prepared by embodiment 3; 0.02mol), deionized water 43.6mL; nitrogen protection, then adds sodium hydroxide (4g, the 0.1mol) solution being dissolved in 10mL deionized water; be heated to 110 DEG C of reactions; after 2h, stopped reaction, is cooled to room temperature; about regulating pH value to 10; stirring is spent the night, and has a large amount of white solid to separate out, and filters; wash with methanol aqueous solution; drying, obtains white solid 3.33g, yield 77%.
Embodiment 7 is such as formula the preparation of the compound shown in III
In 50mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed; add intermediate formula II (4.36g prepared by embodiment 3; 0.02mol), deionized water 10mL; nitrogen protection, then adds potassium hydroxide (4.48g, the 0.08mol) solution being dissolved in 10mL deionized water; be heated to 100 DEG C of reactions; after 3h, stopped reaction, is cooled to room temperature; about regulating pH value to 8; stirring is spent the night, and has a large amount of white solid to separate out, and filters; wash with methanol aqueous solution; drying, obtains white solid 3.20g, yield 74%.
The preparation of embodiment 8 homoanisic acid
In 50mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed, add the intermediate formula III (2.16g that embodiment 4 states preparation, 0.01mol), deionized water 20mL, solution is muddy, slowly 30% hydrogen peroxide (1.7g is dripped in 25 DEG C, 0.015mol), bubble is constantly had to emerge, temperature raises, control temperature is no more than 30 DEG C, after 3h, solution is clarified substantially, TLC monitoring reacts completely, with the sodium sulfite solution of 5%, remove excessive hydrogen peroxide, then pH value to 1 ~ 2 are regulated with 8N HCl, a large amount of flaxen solid is had to separate out, filter, drying obtains 1.4g homoanisic acid crude product, yield 85%, use water recrystallizing and refining, obtain white solid 1.1g, yield 66%.HPLC testing product purity is 99.12%.
The preparation of embodiment 9 homoanisic acid
In 50mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed, add the intermediate formula II (4.36g of preparation, 0.02mol), deionized water 20mL, nitrogen protection, then sodium hydroxide (the 4g being dissolved in 10mL deionized water is added, 0.1mol) solution, be heated to 100 DEG C of reactions, after 2h, stopped reaction, be cooled to room temperature, about adjust ph to 10, stirring is spent the night, a large amount of white solid is had to separate out, without separation, in 25 DEG C, slow dropping 30% hydrogen peroxide (3.4g, 0.03mol), bubble is constantly had to emerge, temperature raises, control temperature is no more than 30 DEG C, after 3h, solution is clarified substantially, TLC monitoring reacts completely, with the sodium sulfite solution of 5%, remove excessive hydrogen peroxide, then pH value to 1 ~ 2 are regulated with 8N HCl, a large amount of flaxen solid is had to separate out, filter, crude product is used water recrystallizing and refining, obtain white solid 1.73g, two step yields 52%.HPLC testing product purity is 99.46%.
The preparation of embodiment 10 homoanisic acid
In 50mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed, add the intermediate formula II (4.36g of preparation, 0.02mol), deionized water 20mL, nitrogen protection, then sodium hydroxide (2g is added, 0.05mol), be heated to 100 DEG C of reactions, after 2h, stopped reaction, be cooled to room temperature, about adjust ph to 7, stirring is spent the night, a large amount of white solid is had to separate out, without separation, in 25 DEG C, slow dropping 30% hydrogen peroxide (4.5g, 0.04mol), bubble is constantly had to emerge, temperature raises, control temperature is no more than 30 DEG C, after 3h, solution is clarified substantially, TLC monitoring reacts completely, with the sodium sulfite solution of 5%, remove excessive hydrogen peroxide, then pH value to 1 ~ 2 are regulated with 8N HCl, a large amount of flaxen solid is had to separate out, filter, crude product is used water recrystallizing and refining, obtain white solid 1.71g, two step yields 52%.HPLC testing product purity is 99.50%.
Embodiment 11 is such as formula the preparation of the compound shown in II
4-butoxybenzaldehyde (17.8g is added in 250mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed, 0.1mol), glycolylurea (10.1g, 0.1mol), deionized water 150mL and thanomin (3g, 0.05mol), under strong stirring, by room temperature to 95 DEG C, raw material dissolves gradually, just yellow solid is had constantly to separate out afterwards, after reaction 4h, TLC monitors, raw material primitive reaction is complete, be cooled to room temperature, filter, and after washing filter cake with water, dry, obtain intermediate formula II 23.2g of yellow solid, yield 89%, mother liquor can overlap the preparation of using next batch intermediate formula II.
The preparation of embodiment 124-butyl phenyl ether acetic acid
In 50mL tri-mouthfuls of reaction flasks that agitator and thermometer are housed, add the intermediate formula II (5.2g of preparation, 0.02mol), deionized water 20mL, nitrogen protection, then potassium hydroxide (the 5.6g being dissolved in 10ml deionized water is added, 0.1mol) solution, be heated to 110 DEG C of reactions, after 2h, stopped reaction, be cooled to room temperature, about regulating pH value to 14, in 25 DEG C, slow dropping 30% hydrogen peroxide (3.4g, 0.03mol), bubble is constantly had to emerge, temperature raises, control temperature is no more than 30 DEG C, after 3h, solution is clarified substantially, TLC monitoring reacts completely, with the sodium sulfite solution of 5%, remove excessive hydrogen peroxide, then pH value to 1 ~ 2 are regulated with 8N HCl, a large amount of flaxen solid is had to separate out, filter, crude product is used water recrystallizing and refining, obtain white solid 2.0g, two step yields 49%.HPLC testing product purity is 99.23%.
Claims (12)
1., such as formula a preparation method for the palkoxy benzene acetic acid shown in I, it is characterized in that, it comprises the following steps:
(1) in water, in the presence of base, by the open loop salt-forming reaction that is hydrolyzed such as formula the compound shown in II, obtained such as formula the compound shown in III;
(2) after the reaction of step (1) terminates, behind regulation system pH value to 7 ~ 14, reaction system, directly under the effect of oxygenant, carries out decarboxylic reaction by such as formula the compound shown in III, obtained such as formula the palkoxy benzene acetic acid shown in I;
Wherein, R is C
1~ C
4alkyl; M is alkalimetal ion.
2. preparation method as claimed in claim 1, is characterized in that, described C
1~ C
4alkyl be methyl, ethyl, propyl group, sec.-propyl or butyl; And/or described alkalimetal ion is sodium ion or potassium ion.
3. preparation method as claimed in claim 1, it is characterized in that, in step (1), described alkali exists with the form of alkali aqueous solution, and the mass percent of described alkali aqueous solution is 2% ~ 20%; Described mass percent is refer to that the quality of alkali accounts for the per-cent of alkali aqueous solution total mass.
4. preparation method as claimed in claim 3, it is characterized in that, the mass percent of described alkali aqueous solution is 5% ~ 15%; Described mass percent is refer to that the quality of alkali accounts for the per-cent of alkali aqueous solution total mass.
5. the preparation method as described in any one of Claims 1 to 4, is characterized in that, in step (1), described alkali is mineral alkali; And/or the described mol ratio such as formula the compound shown in II and described alkali is 1:1 ~ 1:10; And/or described hydrolysis salt-forming reaction temperature is 0 ~ 150 DEG C.
6. preparation method as claimed in claim 5, is characterized in that described mineral alkali is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide and sodium hydride; And/or the described mol ratio such as formula the compound shown in II and described alkali is 1:4 ~ 1:6; Described hydrolysis salt-forming reaction temperature is 90 ~ 110 DEG C.
7. preparation method as claimed in claim 1, it is characterized in that, in step (2), described oxygenant is hydrogen peroxide; And/or the described mol ratio such as formula the compound shown in III or formula II and oxygenant is 1:0.5 ~ 1:5; And/or described decarboxylic reaction temperature is 0 ~ 50 DEG C.
8. preparation method as claimed in claim 7, it is characterized in that, the described mol ratio such as formula the compound shown in III or formula II and oxygenant is 1:1 ~ 1:2; And/or described decarboxylic reaction temperature is 20 ~ 30 DEG C.
9. preparation method as claimed in claim 1, it is characterized in that, the described preparation method such as formula the palkoxy benzene acetic acid shown in I, it also comprises the following steps: in water further, under the effect of catalyzer, condensation reaction is carried out by such as formula the compound shown in IV and glycolylurea, obtained described such as formula the compound shown in II;
Wherein, R is C
1~ C
4alkyl.
10. preparation method as claimed in claim 9, it is characterized in that, described catalyzer is alcamine compound; And/or the described mol ratio such as formula the compound shown in IV and described glycolylurea is 1:1 ~ 1:2; And/or the described mol ratio such as formula the compound shown in IV and described catalyzer is 1:0.1 ~ 1:1.5; And/or the temperature of described condensation reaction is 0 ~ 150 DEG C.
11. preparation methods as claimed in claim 10, it is characterized in that, described alcamine compound is α-amino isopropyl alcohol and/or thanomin; And/or the described mol ratio such as formula the compound shown in IV and described glycolylurea is 1:1 ~ 1:1.2; And/or the described mol ratio such as formula the compound shown in IV and described catalyzer is 1:0.3 ~ 1:1; And/or the temperature of described condensation reaction is 90 ~ 110 DEG C.
12. 1 kinds of preparation methods such as formula the compound shown in II, is characterized in that comprising the following steps: in water, under the catalysis of alcamine compound, carry out condensation reaction by such as formula the compound shown in IV and glycolylurea, obtained such as formula the compound shown in II; The described mol ratio such as formula the compound shown in IV and described catalyzer is 1:0.1 ~ 1:1.5;
Wherein, R is C
1~ C
4alkyl, the method for described condensation reaction and condition are as described in any one of claim 9 ~ 11.
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| CN110627639A (en) * | 2019-09-25 | 2019-12-31 | 福安药业集团重庆博圣制药有限公司 | Preparation method of ketophenylalanine calcium |
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| JP2001316325A (en) * | 2000-05-08 | 2001-11-13 | Tosoh Corp | Method for producing alkali metal 2-naphthylpyruvate |
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| JP2001316325A (en) * | 2000-05-08 | 2001-11-13 | Tosoh Corp | Method for producing alkali metal 2-naphthylpyruvate |
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| CRISTIANA M. L. DI GIURO ET AL.: "Chiral Hydroxylation at the Mononuclear Nonheme Fe(II) Center of 4-(S) Hydroxymandelate Synthase – A Structure-Activity Relationship Analysis", 《PLOS ONE》 * |
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| CN110627639A (en) * | 2019-09-25 | 2019-12-31 | 福安药业集团重庆博圣制药有限公司 | Preparation method of ketophenylalanine calcium |
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