CN105152918A - Preparation method of methoxyphenylacetic acid and intermediate and salt thereof - Google Patents
Preparation method of methoxyphenylacetic acid and intermediate and salt thereof Download PDFInfo
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- CN105152918A CN105152918A CN201510561254.5A CN201510561254A CN105152918A CN 105152918 A CN105152918 A CN 105152918A CN 201510561254 A CN201510561254 A CN 201510561254A CN 105152918 A CN105152918 A CN 105152918A
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Abstract
The invention discloses a preparation method of methoxyphenylacetic acid and intermediate and salt thereof. The invention provides the preparation method of the hydroxyphenylacetic acid salt, and the method is a first method or a second method. The preparation method has the advantages of high yield, high purity, simple operation process, mild reaction conditions, short reaction time, low equipment requirement, catalyst recycling, simple post-processing, environment-friendliness, low production cost, and is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of methoxyphenylacetic acid, its intermediate and salt thereof.
Background technology
Arylacetic acids compounds is widely used in the fields such as medicine, agricultural chemicals, spices and dyestuff, palkoxy benzene acetic acid is current widely used fuel oil additive in the world, is also the necessary intermediate of synthesis of medical sterilant, antiphlogistic, slow convulsion medicine, low-melting point liquid crystal material; Wherein homoanisic acid is the intermediate synthesizing thymoleptic Venlafaxine (Venlafaxine) of new generation, is also the key intermediate of multiple cardiovascular agent such as synthesis puerarin, osajin etc.; Traditional synthetic method makes atom utilization low and serious environment pollution because of regioselectivity.
The method of the homoanisic acid of report synthesis is both at home and abroad as follows at present:
1, cyanide process: general is raw material with p-methoxybenzyl chloride, reacts, obtain PARA METHOXY PHENYL ACETONITRILE with sodium cyanide; Be hydrolyzed again, obtain homoanisic acid.Reaction formula is as follows:
2, Willgerodt-kindler method: this method is often raw material with methyl-phenoxide, carries out Friedel-Crafts reaction, obtains p-methoxy-acetophenone, then react with sulphur and piperazine, obtain homoanisic acid through resetting and being hydrolyzed.Reaction formula is as follows:
, there is Friedel-Crafts with ethyl oxalyl chloride and react in 3, huang-Minlon reduction: the method take methyl-phenoxide as raw material, generates p-methoxy-acetophenone acetoacetic ester, then obtain target product through hydrazine hydrate generation huang-Minlon reaction.Reaction formula is as follows:
4, additive method: synthetic method as not general in amide hydrolysis method, oxo synthesis, trichloroacetic acid method etc.
The deficiency of above-mentioned each reaction is: (1) cyanide process, and market not easily obtains raw material p-methoxybenzyl chloride, expensive; And reaction process uses highly toxic product sodium cyanide, produces hypertoxic sodium cyanide waste water, strict to equipment requirements, environmental pollution is large, and production cost is high, and suitability for industrialized production is difficult to carry out; (2) Willgerodt-kindler method, first the first step Friedel-Crafts reaction has isomers to produce, and is difficult to be separated, causes product purity low; Secondly, during second step reaction, can produce the hydrogen sulfide of hypertoxic cacosmia, yield is not high yet, and strict to equipment requirements equally, environmental pollution is large, and product purity is poor, and production cost is high, and suitability for industrialized production is difficult to carry out; (3) huang-Minlon reduction: ethyl oxalyl chloride is expensive, and the reaction conditions of second step Huang Min-lon reduction is more than 200 DEG C, high to equipment requirements, reaction yield is low, and production cost is high, and suitability for industrialized production is difficult to carry out; (4) additive method, amide hydrolysis method can produce by product 2-benzene sulfur alcohol, and taste cacosmia is incomparable, contaminate environment; Oxo synthesis needs to use expensive catalyzer, and catalyzer easy in inactivation, yield is not high, and production cost is high; Trichloroacetic acid method uses phenyl-selenide, and this material is extremely serious to water pollution, and raw material aubepine not easily obtains; Three's suitability for industrialized production is all difficult to carry out.In sum, above-mentioned synthetic method synthesizes cheap, highly purified homoanisic acid for environmental protection, all inapplicable, or is not easy to suitability for industrialized production.
Meanwhile, contriver retrieves discovery " study on the synthesis of p-hydroxyphenylaceticacid " (Jiang Peihua etc., Speciality Petrochemicals progress, 7th phase, 3 volumes, 53 ~ 56 pages, in July, 2002) describe be hydrolyzed p-chlorobenzyl cyanide for a long time under the condition of High Temperature High Pressure highly basic, obtained p-hydroxyphenylaceticacid.But its reaction conditions is too harsh, is unsuitable for suitability for industrialized production, and yield only 78.1%.
Contriver also finds " synthesis of 1-(4-methoxyl group) phenyl-2-propylamine " (Zhao Dongmei, Chinese Journal of Pharmaceuticals, the 8th phase, 32 volumes, calendar year 2001) describe p-hydroxyphenylaceticacid use dimethyl sulfate methylation of ester, obtained homoanisic acid, yield 98%.But the large and long reaction time of methyl-sulfate consumption, is unsuitable for suitability for industrialized production in this reaction.
Synthesis2010,24,4268-4272 describe the hydrolysis of 2-methyl-oxine and cuprous iodide catalysis PARA NITRO CHLOROBENZENE (PNCB), and yield only 10%, is unsuitable for suitability for industrialized production.
Therefore, this area is in the urgent need to a kind of preparation method of methoxyphenylacetic acid, the method should be reacted with the industrial raw material more easily buied, technique is simple, aftertreatment is easy, and condition is relatively gentle, and environmental pollution is relatively little, and the methoxyphenylacetic acid of higher degree should be able to be obtained with higher yields, simultaneously can industrialization.
Summary of the invention
Technical problem to be solved by this invention is that the preparation method's yield in order to overcome existing methoxyphenylacetic acid is low, purity is low, complex operation, severe reaction conditions, strict to equipment requirements, catalyzer difficulty reclaims, environmental pollution is large, production cost is high, be unsuitable for the defects such as suitability for industrialized production, and provide a kind of methoxyphenylacetic acid, the preparation method of its intermediate and salt thereof, the method yield is high, purity is high, operating procedure is simple, reaction conditions is gentle, reaction times is short, lower to equipment requirements, catalyzer recoverable, aftertreatment is simple, environmental protection, production cost is low, be suitable for suitability for industrialized production.
The invention provides a kind of preparation method of hydroxyl phenylacetic acid salt, it is method one or method two;
Described method one comprises the following steps: under the existence of water, alkali and catalyzer, and be hydrolyzed compound 1 reaction, obtains compound 3; Described catalyzer is for such as formula the compound shown in A, or described catalyzer is for such as formula the compound shown in B and cupric salt, or described catalyzer is for such as formula the compound shown in A, such as formula the compound shown in B and cupric salt;
Wherein, X is halogen; M
1for the corresponding positively charged ion of described alkali; R
1, R
2and R
3be hydrogen or C independently
1~ C
6alkyl; R
4, R
5and R
6be hydrogen or C independently
1~ C
6alkyl; R
7, R
8and R
9be hydrogen, nitro or sulfonic group independently; Described-X and-OM
1all in ortho position or contraposition;
Described method two comprises the following steps: under the existence of water, alkali and catalyzer, and be hydrolyzed compound 2 reaction, obtains compound 3 '; Described catalyzer is for such as formula the compound shown in A, or described catalyzer is for such as formula the compound shown in B and cupric salt, or described catalyzer is for such as formula the compound shown in A, such as formula the compound shown in B and cupric salt;
Wherein, X is halogen; M
2for alkalimetal ion and/or TBuA ion; M
3for described M
2with the corresponding positively charged ion of described alkali; R
1, R
2and R
3be hydrogen or C independently
1~ C
6alkyl; R
4, R
5and R
6be hydrogen or C independently
1~ C
6alkyl; R
7, R
8and R
9be hydrogen, nitro or sulfonic group independently; Described-X and-OM
3all in ortho position or contraposition.
In described method one, described halogen is preferably chlorine, bromine or iodine.
In described method one, as described R
1, R
2and R
3be C independently
1~ C
6during alkyl, described C
1~ C
6alkyl is preferably methyl.
In described method one, as described R
4, R
5and R
6be C independently
1~ C
6during alkyl, described C
1~ C
6alkyl is preferably methyl.
In described method one, described alkali can be the alkali of this area routine, preferably for containing alkali hydroxy, is more preferably alkali metal hydroxide and/or 4-n-butyl ammonium hydroxide; Described alkali metal hydroxide can be the alkali metal hydroxide of this area routine, is preferably one or more in sodium hydroxide, potassium hydroxide and cesium hydroxide.
In described method one, the corresponding positively charged ion of described alkali refers to the cationic moiety of alkali, and such as the cationic moiety of sodium hydroxide is sodium ion, and the cationic moiety of TBAH is TBuA ion.
In described method one, the mol ratio of described alkali and described compound 1 can be this area, and such reacts conventional mol ratio, and being preferably 3.0 ~ 6.0, is more preferably 3.5 ~ 4.0.
In described method one, than can be this area, such reacts conventional Molar ratio to the Molar of described water and described compound 1, is preferably 1.0L/mol ~ 2.0L/mol, such as 1.44L/mol.
In described method one, preferably, described alkali and described water add with the form of the aqueous solution of alkali; In the aqueous solution of described alkali, the massfraction of alkali can be the conventional massfraction of such reaction of this area, and being preferably 5% ~ 30%, is more preferably 10% ~ 20%.
In described method one, when described catalyzer is for during such as formula compound shown in A, the mol ratio of described catalyzer and described compound 1 is preferably 0.03 ~ 0.3, is more preferably 0.05 ~ 0.15, such as 0.1.
In described method one, described cupric salt i.e. free copper ion, cupric salt with described formula B compound coordination in water, such as cupric bromide, cupric chloride, copper sulfate, cupric nitrate, neutralized verdigris etc.
In described method one, when described catalyzer for or such as formula the compound shown in B and cupric salt time, the mol ratio of described cupric salt and described compound 1 is preferably 0.05 ~ 0.40, is more preferably 0.1 ~ 0.2, such as 0.15; Described formula B compound and the mol ratio of described cupric salt are preferably 1 ~ 2.
In described method one, the temperature of described hydrolysis reaction can be 50 DEG C ~ 150 DEG C, is preferably 50 DEG C ~ 115 DEG C.When described halogen is chlorine, the temperature of described hydrolysis reaction is preferably 100 DEG C ~ 120 DEG C, such as 105 DEG C ~ 115 DEG C; When described halogen is bromine, the temperature of described hydrolysis reaction is preferably 80 DEG C ~ 120 DEG C, such as 80 DEG C ~ 85 DEG C; When described halogen is iodine, the temperature of described hydrolysis reaction is preferably 50 DEG C ~ 120 DEG C, such as 50 DEG C ~ 55 DEG C.
In described method one, the pressure of described hydrolysis reaction can 0MpaG ~ 1.0MpaG.When described halogen is chlorine, the pressure of described hydrolysis reaction is preferably 0.2MpaG ~ 1.0MpaG, is more preferably 0.4MpaG ~ 0.5MpaG, such as 0.45MpaG ~ 0.48MpaG; When described halogen is bromine or iodine, the pressure of described hydrolysis reaction can be 0MpaG.
In described method one, the process of described hydrolysis reaction can adopt the routine monitoring method (such as TLC, HPLC or NMR) in this area to monitor, for reaction end when generally no longer reacting with compound 1, reaction times is preferably 2h ~ 15h, be more preferably 4h ~ 6h, such as 5h.
In described method one, preferably, after described hydrolysis reaction completes, adjustment reaction solution pH is 7 ~ 8, filters, and reclaims catalyzer; Preferably, (preferred mass mark is the HCl aqueous solution of 36%) is regulated with hydrochloric acid.The catalyzer reclaimed can overlap again to be used in described hydrolysis reaction.When described catalyzer is for during such as formula compound shown in A, the catalyzer of described recovery is for such as formula the compound shown in A; When described catalyzer is for during such as formula the compound shown in B and cupric salt, the catalyzer of described recovery is for such as formula the compound shown in A, such as formula the compound shown in B and cupric salt, and wherein, the content such as formula the compound shown in A is lower.
In described method two, described halogen is preferably chlorine, bromine or iodine.
In described method two, described alkalimetal ion can be the alkalimetal ion of this area routine, is preferably sodium ion and/or potassium ion.
In described method two, if described M
2sodium ion is, then described M with the corresponding positively charged ion of described alkali
3for sodium ion; If described M
2for sodium ion, the corresponding positively charged ion of described alkali is potassium ion, then there is sodium ion and potassium ion in reaction system, described M
3may be sodium ion, also may be potassium ion.
In described method two, preferably, described M
2with described M
3identical.
In described method two, as described R
1, R
2and R
3be C independently
1~ C
6during alkyl, described C
1~ C
6alkyl is preferably methyl.
In described method two, as described R
4, R
5and R
6be C independently
1~ C
6during alkyl, described C
1~ C
6alkyl is preferably methyl.
In described method two, described alkali can be the alkali of this area routine, preferably for containing alkali hydroxy, is more preferably alkali metal hydroxide and/or 4-n-butyl ammonium hydroxide; Described alkali metal hydroxide can be the alkali metal hydroxide of this area routine, is preferably one or more in sodium hydroxide, potassium hydroxide and cesium hydroxide.
In described method two, the corresponding positively charged ion of described alkali refers to the cationic moiety of alkali, and such as the cationic moiety of sodium hydroxide is sodium ion, and the cationic moiety of TBAH is TBuA ion.
In described method two, the mol ratio of described alkali and described compound 2 can be this area, and such reacts conventional mol ratio, and being preferably 3.0 ~ 6.0, is more preferably 3.5 ~ 4.0.
In described method two, than can be this area, such reacts conventional Molar ratio to the Molar of described water and described compound 2, is preferably 1.0L/mol ~ 2.0L/mol, such as 1.44L/mol.
In described method two, preferably, described alkali and described water add with the form of the aqueous solution of alkali; In the aqueous solution of described alkali, the massfraction of alkali can be the conventional massfraction of such reaction of this area, and being preferably 5% ~ 30%, is more preferably 10% ~ 20%.
In described method two, when described catalyzer is for during such as formula compound shown in A, the mol ratio of described catalyzer and described compound 2 is preferably 0.03 ~ 0.3, is more preferably 0.05 ~ 0.15, such as 0.1.
In described method two, described cupric salt i.e. free copper ion, cupric salt with described formula B compound coordination in water, such as cupric bromide, cupric chloride, copper sulfate, cupric nitrate, neutralized verdigris etc.
In described method two, when described catalyzer for or such as formula the compound shown in B and cupric salt time, the mol ratio of described cupric salt and described compound 2 is preferably 0.05 ~ 0.40, is more preferably 0.1 ~ 0.2, such as 0.15; Described formula B compound and the mol ratio of described cupric salt are preferably 1 ~ 2.
In described method two, the temperature of described hydrolysis reaction can be 50 DEG C ~ 150 DEG C, is preferably 50 DEG C ~ 115 DEG C.When described halogen is chlorine, the temperature of described hydrolysis reaction is preferably 100 DEG C ~ 120 DEG C, such as 105 DEG C ~ 115 DEG C; When described halogen is bromine, the temperature of described hydrolysis reaction is preferably 80 DEG C ~ 120 DEG C, such as 80 DEG C ~ 85 DEG C; When described halogen is iodine, the temperature of described hydrolysis reaction is preferably 50 DEG C ~ 120 DEG C, such as 50 DEG C ~ 55 DEG C.
In described method two, the pressure of described hydrolysis reaction can 0MpaG ~ 1.0MpaG.When described halogen is chlorine, the pressure of described hydrolysis reaction is preferably 0.2MpaG ~ 1.0MpaG, is more preferably 0.4MpaG ~ 0.5MpaG, such as 0.45MpaG ~ 0.48MpaG; When described halogen is bromine or iodine, the pressure of described hydrolysis reaction can be 0MpaG.
In described method two, the process of described hydrolysis reaction can adopt the routine monitoring method (such as TLC, HPLC or NMR) in this area to monitor, for reaction end when generally no longer reacting with compound 2, reaction times is preferably 2h ~ 15h, be more preferably 4h ~ 6h, such as 5h.
In described method two, preferably, after described hydrolysis reaction completes, adjustment reaction solution pH is 7 ~ 8, filters, and reclaims catalyzer; Preferably, (preferred mass mark is the HCl aqueous solution of 36%) is regulated with hydrochloric acid.The catalyzer reclaimed can overlap again to be used in described hydrolysis reaction.When described catalyzer is for during such as formula compound shown in A, the catalyzer of described recovery is for such as formula the compound shown in A; When described catalyzer is for during such as formula the compound shown in B and cupric salt, the catalyzer of described recovery is for such as formula the compound shown in A, such as formula the compound shown in B and cupric salt, and wherein, the content such as formula the compound shown in A is lower.
Described method two, also can comprise the following steps: under the existence of water and alkali, be hydrolyzed compound 1 reaction, obtains described compound 2;
Wherein ,-the X in the-X in described compound 1 and described compound 2 is all in ortho position or contraposition.
The condition of the preparation method of compound 2 can be the conventional condition of such reaction of this area, and the present invention is following condition particularly preferably:
In the preparation method of described compound 2, described alkali can be the alkali of this area routine, preferably for containing alkali hydroxy, is more preferably alkali metal hydroxide and/or 4-n-butyl ammonium hydroxide; Described alkali metal hydroxide can be the alkali metal hydroxide of this area routine, is preferably one or more in sodium hydroxide, potassium hydroxide and cesium hydroxide.
In the preparation method of described compound 2, the mol ratio of described alkali and described compound 1 can be this area, and such reacts conventional mol ratio, and being preferably 1.0 ~ 5.0, is more preferably 1.5 ~ 3.0, such as 1.9.
In the preparation method of described compound 2, than can be this area, such reacts conventional Molar ratio to the Molar of described water and described compound 1, is preferably 0.1L/mol ~ 1.0L/mol, such as 0.2L/mol.
In the preparation method of described compound 2, preferably, after described alkali mixes with described water, the compound 1 described in instillation.
In the preparation method of described compound 2, the temperature of described hydrolysis reaction is preferably 100 DEG C ~ 120 DEG C, such as 116 DEG C.
In the preparation method of described compound 2, the process of described hydrolysis reaction can adopt the routine monitoring method (such as TLC, HPLC or NMR) in this area to monitor, for reaction end when generally no longer reacting with compound 1, reaction times is preferably 2h ~ 15h, is more preferably 10h ~ 12h.
In described method two, preferably, after the hydrolysis reaction of described cyano group completes, compound 2 without separation (namely not by compound 2 separation and purification, or, obtain the mixture containing compound 2; The reaction solution of the hydrolysis reaction of such as cyano group carries out simple aftertreatment etc. without the reaction solution of the hydrolysis reaction of aftertreatment, cyano group, obtains the mixture containing compound 2; Described simple aftertreatment can be removing solvent, concentrated, filtration etc.), then carry out the hydrolysis reaction of described halogen atom.
Described " after the hydrolysis reaction of described cyano group completes; compound 2 is without separation; carry out the hydrolysis reaction of described halogen atom again " is preferably " after the hydrolysis reaction of described cyano group completes; the reaction solution of the hydrolysis reaction of cyano group directly carries out the substitution reaction of described halogen atom ", be more preferably " hydrolysis reaction of described cyano group complete after, the reaction solution of the hydrolysis reaction of cyano group directly carries out the substitution reaction of described halogen atom ".
Present invention also offers a kind of preparation method of hydroxyl phenylacetic acid, it comprises the following steps:
(1) method one obtains compound 3 as described above, or method two obtains compound 3 ' as described above;
(2) in water, described compound 3 or compound 3 ' are carried out acidification reaction, obtains compound 5;
Wherein, when described step (1) for described method for the moment ,-OM
1with-OH all in ortho position or contraposition; When described step (1) is for described method two ,-OM
3with-OH all in ortho position or contraposition.
In the preparation method of described hydroxyl phenylacetic acid, the pH of described acidification reaction is preferably 1 ~ 2.
In the preparation method of described hydroxyl phenylacetic acid, described acidification reaction preferably uses hydrochloric acid; Described hydrochloric acid is preferably the HCl aqueous solution that massfraction is 36%.
In the preparation method of described hydroxyl phenylacetic acid, preferably, after the hydrolysis reaction of step (1) completes, reaction solution " without aftertreatment " or simple aftertreatment (such as concentrated, filtration etc.), directly carry out step (2); More preferably, after the hydrolysis reaction of step (1) completes, method with reference to above-mentioned recovery catalyzer reclaims after catalyzer, and reaction solution " without aftertreatment " or simple aftertreatment (such as concentrated, filtration etc.), directly carry out the acidification reaction of step (2).
Present invention also offers a kind of preparation method of methoxyphenylacetic acid salt, it comprises the following steps:
A () as described above method one obtains compound 3, or method two obtains compound 3 ' as described above;
B described compound 3 or compound 3 ', in water, in the presence of base, are carried out substitution reaction with methylating reagent, obtain compound 4 by ();
Wherein, when described step (a) for described method for the moment, described M
4for described M
1with the corresponding positively charged ion of described alkali ,-OM
1with-OCH
3all in ortho position or contraposition; When described step (a) is for described method two, described M
4for described M
3with the corresponding positively charged ion of described alkali ,-OM
3with-OCH
3all in ortho position or contraposition.
In the step (b) of the preparation method of described methoxyphenylacetic acid salt, the corresponding positively charged ion of described alkali refers to the cationic moiety of alkali, the cationic moiety of such as sodium hydroxide is sodium ion, and the cationic moiety of TBAH is TBuA ion.
In the step (b) of the preparation method of described methoxyphenylacetic acid salt, if described M
3(or M
1) and the corresponding positively charged ion of described alkali be sodium ion, then described M
4for sodium ion; If described M
3(or M
1) be sodium ion, the corresponding positively charged ion of described alkali is potassium ion, then there is sodium ion and potassium ion in reaction system, described M
4for sodium ion and potassium ion.
In the step (b) of the preparation method of described methoxyphenylacetic acid salt, preferably, described M
3with described M
4identical, or, described M
1with described M
4identical.
In the step (b) of the preparation method of described methoxyphenylacetic acid salt, than can be this area, such reacts conventional Molar ratio to the Molar of described water and described compound 3 or compound 3 ', be preferably 1.0L/mol ~ 2.0L/mol, such as 1.44L/mol.
In the step (b) of the preparation method of described methoxyphenylacetic acid salt, described alkali can be the alkali of this area routine, preferably for containing alkali hydroxy, is more preferably alkali metal hydroxide and/or 4-n-butyl ammonium hydroxide; Described alkali metal hydroxide can be the alkali metal hydroxide of this area routine, is preferably one or more in sodium hydroxide, potassium hydroxide and cesium hydroxide.
In the step (b) of the preparation method of described methoxyphenylacetic acid salt, the mol ratio of described alkali and described compound 3 or compound 3 ' can be this area, and such reacts conventional mol ratio, is preferably 2 ~ 3.
In the step (b) of the preparation method of described methoxyphenylacetic acid salt, described methylating reagent can be the conventional methylating reagent of such reaction of this area, being preferably one or more in methyl-sulfate, methyl iodide and methyl tosylate, is more preferably methyl-sulfate.
In the step (b) of the preparation method of described methoxyphenylacetic acid salt, the mol ratio of described methylating reagent and described compound 3 or compound 3 ' can be this area, and such reacts conventional mol ratio, being preferably 1 ~ 2, is more preferably 1.2 ~ 1.4, such as 1.24.
In the step (b) of the preparation method of described methoxyphenylacetic acid salt, the temperature of described substitution reaction can be the conventional temperature of such reaction of this area, and being preferably 10 DEG C ~ 100 DEG C, is more preferably 30 DEG C ~ 50 DEG C, such as 40 DEG C.
In the step (b) of the preparation method of described methoxyphenylacetic acid salt, the process of described substitution reaction can adopt the routine monitoring method (such as TLC, HPLC or NMR) in this area to monitor, for reaction end when generally no longer reacting with compound 3 or compound 3 ', reaction times is preferably 2h ~ 10h, be more preferably 3h ~ 5h, such as 3.5h.
In the preparation method of described methoxyphenylacetic acid salt, preferably, after the hydrolysis reaction of step (a) completes, compound 3 or compound 3 ' are without being separated (namely not by compound 3 or compound 3 ' separation and purification, or, obtain the mixture containing compound 3 or compound 3 '; The reaction solution of such as hydrolysis reaction carries out simple aftertreatment etc. without the reaction solution of aftertreatment, hydrolysis reaction, obtains the mixture containing compound 3 or compound 3 '; Described simple aftertreatment can be removing solvent, concentrated, filtration etc.), then carry out the substitution reaction described in step (b);
More preferably, after the hydrolysis reaction of step (a) completes, the method with reference to above-mentioned recovery catalyzer reclaims catalyzer, afterwards, regulates reaction solution pH 13 ~ 14 (preferably to regulate with aqueous sodium hydroxide solution; Described aqueous sodium hydroxide solution is preferably for massfraction is the aqueous sodium hydroxide solution of 30%), compound 3 or compound 3 ' are without being separated (namely not by compound 3 or compound 3 ' separation and purification, or, obtain the mixture containing compound 3 or compound 3 '; The reaction solution of such as hydrolysis reaction carries out simple aftertreatment etc. without the reaction solution of aftertreatment, hydrolysis reaction, obtains the mixture containing compound 3 or compound 3 '; Described simple aftertreatment can be removing solvent, concentrated, filtration etc.), then carry out the substitution reaction described in step (b).
Present invention also offers a kind of preparation method of methoxyphenylacetic acid, it comprises the following steps:
I, the as described above preparation method of methoxyphenylacetic acid salt obtain compound 4;
II, in water, described compound 4 is carried out acidification reaction, obtains compound 6;
Wherein ,-the OCH in described compound 4
3with-the OCH in described compound 6
3all in ortho position or contraposition.
In the preparation method of described methoxyphenylacetic acid, the pH of described acidification reaction is preferably 1 ~ 2.
In the preparation method of described methoxyphenylacetic acid, described acidification reaction preferably uses hydrochloric acid; Described hydrochloric acid is preferably the HCl aqueous solution that massfraction is 36%.
In the preparation method of described methoxyphenylacetic acid, preferably, after the substitution reaction of step I completes, reaction solution " without aftertreatment " or simple aftertreatment (such as concentrated, filtration etc.), directly carry out the acidification reaction of Step II; More preferably, after the substitution reaction of step I completes, use organic solvent washing reaction solution (described organic solvent is preferably toluene) again, afterwards, reaction solution " without aftertreatment " or simple aftertreatment (such as concentrated, filtration etc.), directly carry out the acidification reaction of Step II.
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.
In the present invention, " the corresponding positively charged ion of alkali " refers to the cationic moiety of alkali, and the cationic moiety of such as sodium hydroxide is sodium ion, and the cationic moiety of TBAH is TBuA ion.
In the present invention, compounds X is without separation, and namely not by compounds X separation and purification, or acquisition contains the mixture of compounds X; Such as reaction solution carries out simple aftertreatment etc. without aftertreatment, reaction solution, obtains the mixture containing compounds X; Described simple aftertreatment can be removing solvent, concentrated, filtration etc.
In the present invention, if no special instructions, " pressure " is gauge pressure (unit is MpaG), equals absolute pressure and deducts normal atmosphere (being generally 0.1Mpa).
In the present invention, if no special instructions, described " ortho position " refers to that two substituting groups on phenyl ring are in ortho position, and described " contraposition " refers to that two substituting groups on phenyl ring are in contraposition.
Positive progressive effect of the present invention is: the method yield is high, purity is high, operating procedure is simple, reaction conditions is gentle, the reaction times is short, catalyzer recoverable lower to equipment requirements, aftertreatment are simple, environmental protection, production cost are low, be suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is p-hydroxyphenylaceticacid mass spectrum.
Fig. 2 is homoanisic acid mass spectrum.
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.
" mass content " in following embodiment all with commercial standard in contrast, adopts HPLC to measure reaction solution and obtains.
The preparation of embodiment 1 homoanisic acid
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, adds 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 17.6g (0.05mol) copper 8-quinolinolate, after adding, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 700g, detects to obtain p-hydroxyphenylaceticacid mass content 10.3%, yield 94.5%.As shown in Figure 1, base peak, at m/z107 place, is decarboxylation peak to its mass spectrum.
The preparation of step 2 homoanisic acid
Above-mentioned reaction products therefrom is dropped in 2L vial, be warming up to 30 ~ 40 DEG C, in reaction system, drip 78.1g (0.62mol) methyl-sulfate, keep temperature 30 ~ 40 DEG C, dropwise, insulation 3.5h, it is complete that sampling detects raw material reaction, and reaction solution is cooled to room temperature, with toluene wash reaction solution 2 times, layering, water layer concentrated hydrochloric acid regulates pH value 1 ~ 2, and solid is separated out, and filters, dry, obtaining white solid powder, is homoanisic acid, and solid is weighed to obtain 75.0g, two step total recoverys are 90.3%, purity (HPLC) >=99.0%.As shown in Figure 2, base peak, at m/z121 place, is decarboxylation peak to its mass spectrum.
Embodiment 2
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, adds 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 19.0g (0.05mol) 2-methyl-copper 8-quinolinolate, after adding, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 685g, detects to obtain p-hydroxyphenylaceticacid mass content 10.54%, and yield is 94.6%.
Step 2 is with embodiment 1.
Embodiment 3
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, adds 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 19.0g (0.05mol) 4-methyl-copper 8-quinolinolate, after adding, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 721g, detects to obtain p-hydroxyphenylaceticacid mass content 10.01%, and yield is 94.6%.
Step 2 is with embodiment 1.
Embodiment 4
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 10.9g (0.075mol) oxine, after 12.8g (0.075mol) cupric chloride adds, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 693g, detects to obtain p-hydroxyphenylaceticacid mass content 10.42%, and yield is 94.7%.
Step 2 is with embodiment 1.
Embodiment 5
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 11.9g (0.075mol) 2-methyl-oxine, after 12.8g (0.075mol) cupric chloride adds, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 688g, detects to obtain p-hydroxyphenylaceticacid mass content 10.50%, and yield is 94.7%.
Step 2 is with embodiment 1.
Embodiment 6
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 11.9g (0.075mol) 4-methyl-oxine, after 12.8g (0.075mol) cupric chloride adds, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 712g, detects to obtain p-hydroxyphenylaceticacid mass content 10.14%, and yield is 94.6%.
Step 2 is with embodiment 1.
Embodiment 7
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, the copper 8-quinolinolate that 16.7g (0.0475mol) reclaims, the copper 8-quinolinolate that 0.9g (0.0025mol) is fresh, after adding, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detection raw material reaction is complete, reactor is lowered the temperature, and is adjusted between 7 ~ 8, filtering recovering catalyst with 36% hydrochloric acid by reaction solution pH value.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 738g, and detect to obtain p-hydroxyphenylaceticacid mass content 9.8%, yield is greater than 94.9%.
Step 2 is with embodiment 1.
The preparation of embodiment 8 homoanisic acid
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, adds 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 22.1g (0.05mol) 5-nitro-copper 8-quinolinolate, after adding, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 763g, detects to obtain p-hydroxyphenylaceticacid mass content 9.3%, yield 93.8%.
Step 2 is with embodiment 1.
The preparation of embodiment 9 homoanisic acid
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 25.6g (0.05mol) 5-sulfonic group-copper 8-quinolinolate, after adding, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 747g, detects to obtain p-hydroxyphenylaceticacid mass content 9.5%, yield 93.5%.
Step 2 is with embodiment 1.
Embodiment 10
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 98g (0.5mol) to bromobenzylcyanide, 800g (2mol) 10% sodium hydroxide, 10.9g (0.075mol) oxine, after 12.8g (0.075mol) cupric chloride adds, close still and be warming up to 80 ~ 85 DEG C, keep still pressure at 0MpaG, keep temperature of reaction system between 80 ~ 85 DEG C, reaction 8h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 722g, detects to obtain p-hydroxyphenylaceticacid mass content 10.17%, and yield is 96.6%.
Step 2 is with embodiment 1.
Embodiment 11
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 121.5g (0.5mol) to iodobenzene acetonitrile, 800g (2mol) 10% sodium hydroxide, 10.9g (0.075mol) oxine, after 12.8g (0.075mol) cupric chloride adds, close still and be warming up to 50 ~ 55 DEG C, keep still pressure at 0MpaG, keep temperature of reaction system between 50 ~ 55 DEG C, reaction 7h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 755g, detects to obtain p-hydroxyphenylaceticacid mass content 9.79%, and yield is 97.3%.
Step 2 is with embodiment 1.
The preparation of embodiment 12 O-methoxy toluylic acid
The preparation of step 1 o-hydroxy phenylacetic acid sodium salt solution
1L autoclave pressure, adds 76g (0.5mol) adjacent chlorobenzene acetonitrile, 800g (2mol) 10% sodium hydroxide, 17.6g (0.05mol) copper 8-quinolinolate, after adding, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is o-hydroxy phenylacetic acid sodium salt solution, and weigh solution 759g, detects to obtain o-hydroxy phenylacetic acid mass content 9.5%, yield 95.0%.
The preparation of step 2 O-methoxy toluylic acid
Above-mentioned reaction products therefrom is dropped in 2L vial, be warming up to 30 ~ 40 DEG C, in reaction system, drip 78.1g (0.62mol) methyl-sulfate, keep temperature 30 ~ 40 DEG C, dropwise, insulation 3.5h, it is complete that sampling detects raw material reaction, and reaction solution is cooled to room temperature, with toluene wash reaction solution 2 times, layering, water layer concentrated hydrochloric acid regulates pH value 1 ~ 2, and solid is separated out, and filters, dry, obtaining white solid powder, is O-methoxy toluylic acid, and solid is weighed to obtain 74.7g, two step total recoverys are 90.0%, purity (HPLC) >=99.0%.
The preparation of embodiment 13 homoanisic acid
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, adds 85.3g (0.5mol) 4-Chlorophenylacetic acid, 800g (2mol) 10% sodium hydroxide, 17.6g (0.05mol) copper 8-quinolinolate, after adding, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 706g, detects to obtain p-hydroxyphenylaceticacid mass content 9.7%, yield 90.1%.
Step 2 is with embodiment 1.
Reference example 1 is with reference to " study on the synthesis of p-hydroxyphenylaceticacid " (Jiang Peihua etc., Speciality Petrochemicals is in progress, the 7th phase, 3 volumes, 53 ~ 56 pages, in July, 2002)
In 500mL four-hole boiling flask, add p-chlorobenzyl cyanide 150g, under agitation condition, be heated to 100 DEG C, start to drip 30% sodium hydroxide solution (75g sodium hydroxide is dissolved in 180mL distilled water).Control rate of addition, temperature of reaction remains on 116 DEG C, makes reaction solution produce a large amount of backflow, reaction times 10 ~ 12h.When the ammonia of releasing is less, stopped reaction.Obtained 4-Chlorophenylacetic acid sodium, yield 98%.
Comparative example 1
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 6.75g (0.05mol) cupric chloride, after adding, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, sampling detects, p-hydroxyphenylaceticacid HPLC (A%)=23%, 4-Chlorophenylacetic acid HPLC (A%)=54%, p-chlorobenzyl cyanide HPLC (A%)=15%, reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 736g, detects to obtain p-hydroxyphenylaceticacid mass content 1.84%, yield 17.8%.
Comparative example 2
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 10.9g (0.075mol) oxine, after 7.5g (0.075mol) cuprous chloride adds, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, p-hydroxyphenylaceticacid HPLC (A%)=13%, 4-Chlorophenylacetic acid HPLC (A%)=57%, p-chlorobenzyl cyanide HPLC (A%)=23%, reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 723g, detects to obtain p-hydroxyphenylaceticacid mass content 3.65%, and yield is 34.7%.
Comparative example 3
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 76g (0.5mol) p-chlorobenzyl cyanide, 800g (2mol) 10% sodium hydroxide, 12.1g (0.075mol) oxine-N-oxide compound, after 12.8g (0.075mol) cupric chloride adds, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detection reaction transformation efficiency 44%, reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 734g, detects to obtain p-hydroxyphenylaceticacid mass content 3.85%, and yield is 37.2%.
Comparative example 4
The preparation of step 1 p-hydroxyphenylaceticacid sodium salt solution
1L autoclave pressure, add 98g (0.5mol) to bromobenzylcyanide, 800g (2mol) 10% sodium hydroxide, 10.9g (0.075mol) oxine, after 7.5g (0.075mol) cuprous chloride adds, close still and be warming up to 105 ~ 115 DEG C, keep still pressure at 0.45 ~ 0.48MpaG, keep temperature of reaction system between 105 ~ 115 DEG C, reaction 5h, detects raw material reaction complete, and reactor is lowered the temperature, with 36% hydrochloric acid, reaction solution pH value is adjusted between 7 ~ 8, filtering recovering catalyst.Mother liquor 30%NaOH regulates PH to 13 ~ 14, and obtaining scarlet transparent liquid, is p-hydroxyphenylaceticacid sodium salt solution, and weigh solution 744g, detects to obtain p-hydroxyphenylaceticacid mass content 8.65%, and yield is 84.7%.
Claims (11)
1. a preparation method for hydroxyl phenylacetic acid salt, it is method one or method two;
Described method one comprises the following steps: under the existence of water, alkali and catalyzer, and be hydrolyzed compound 1 reaction, obtains compound 3; Described catalyzer is for such as formula the compound shown in A, or described catalyzer is for such as formula the compound shown in B and cupric salt, or described catalyzer is for such as formula the compound shown in A, such as formula the compound shown in B and cupric salt;
Wherein, X is halogen; M
1for the corresponding positively charged ion of described alkali; R
1, R
2and R
3be hydrogen or C independently
1~ C
6alkyl; R
4, R
5and R
6be hydrogen or C independently
1~ C
6alkyl; R
7, R
8and R
9be hydrogen, nitro or sulfonic group independently; Described-X and-OM
1all in ortho position or contraposition;
Described method two comprises the following steps: under the existence of water, alkali and catalyzer, and be hydrolyzed compound 2 reaction, obtains compound 3 '; Described catalyzer is for such as formula the compound shown in A, or described catalyzer is for such as formula the compound shown in B and cupric salt, or described catalyzer is for such as formula the compound shown in A, such as formula the compound shown in B and cupric salt;
Wherein, X is halogen; M
2for alkalimetal ion and/or TBuA ion; M
3for described M
2with the corresponding positively charged ion of described alkali; R
1, R
2and R
3be hydrogen or C independently
1~ C
6alkyl; R
4, R
5and R
6be hydrogen or C independently
1~ C
6alkyl; R
7, R
8and R
9be hydrogen, nitro or sulfonic group independently; Described-X and-OM
3all in ortho position or contraposition.
2. preparation method as claimed in claim 1, it is characterized in that, in described method one, described halogen is chlorine, bromine or iodine;
And/or, in described method one, as described R
1, R
2and R
3be C independently
1~ C
6during alkyl, described C
1~ C
6alkyl is methyl;
And/or, in described method one, as described R
4, R
5and R
6be C independently
1~ C
6during alkyl, described C
1~ C
6alkyl is methyl;
And/or in described method one, described alkali is alkali metal hydroxide and/or 4-n-butyl ammonium hydroxide;
And/or in described method one, the mol ratio of described alkali and described compound 1 is 3.0 ~ 6.0;
And/or in described method one, described water is 1.0L/mol ~ 2.0L/mol with the Molar ratio of described compound 1;
And/or in described method one, described alkali and described water add with the form of the aqueous solution of alkali;
And/or in described method one, when described catalyzer is for during such as formula compound shown in A, the mol ratio of described catalyzer and described compound 1 is 0.03 ~ 0.3;
And/or in described method one, described cupric salt is one or more in cupric bromide, cupric chloride, copper sulfate, cupric nitrate and neutralized verdigris;
And/or, in described method one, when described catalyzer for or such as formula the compound shown in B and cupric salt time, the mol ratio of described cupric salt and described compound 1 is 0.05 ~ 0.40; Described formula B compound and the mol ratio of described cupric salt are 1 ~ 2;
And/or in described method one, the temperature of described hydrolysis reaction is 50 DEG C ~ 150 DEG C;
And/or in described method one, the pressure of described hydrolysis reaction is 0MpaG ~ 1.0MpaG;
And/or in described method one, the reaction times of described hydrolysis reaction is 2h ~ 15h;
And/or in described method one, adjustment reaction solution pH is 7 ~ 8 after described hydrolysis reaction completes, filter, reclaim catalyzer;
And/or in described method two, described halogen is chlorine, bromine or iodine;
And/or in described method two, described alkalimetal ion is sodium ion and/or potassium ion;
And/or, in described method two, described M
2with described M
3identical;
And/or, in described method two, as described R
1, R
2and R
3be C independently
1~ C
6during alkyl, described C
1~ C
6alkyl is methyl;
And/or, in described method two, as described R
4, R
5and R
6be C independently
1~ C
6during alkyl, described C
1~ C
6alkyl is methyl;
And/or in described method two, described alkali is alkali metal hydroxide and/or 4-n-butyl ammonium hydroxide;
And/or in described method two, the mol ratio of described alkali and described compound 2 is 3.0 ~ 6.0;
And/or in described method two, described water is 1.0L/mol ~ 2.0L/mol with the Molar ratio of described compound 2;
And/or in described method two, described alkali and described water add with the form of the aqueous solution of alkali;
And/or in described method two, when described catalyzer is for during such as formula compound shown in A, the mol ratio of described catalyzer and described compound 2 is 0.03 ~ 0.3;
And/or in described method two, described cupric salt is one or more in cupric bromide, cupric chloride, copper sulfate, cupric nitrate and neutralized verdigris;
And/or, in described method two, when described catalyzer for or such as formula the compound shown in B and cupric salt time, the mol ratio of described cupric salt and described compound 2 is 0.05 ~ 0.40; Described formula B compound and the mol ratio of described cupric salt are 1 ~ 2;
And/or in described method two, the temperature of described hydrolysis reaction is 50 DEG C ~ 150 DEG C;
And/or in described method two, the pressure of described hydrolysis reaction is 0MpaG ~ 1.0MpaG;
And/or in described method two, the reaction times of described hydrolysis reaction is 2h ~ 15h;
And/or in described method two, adjustment reaction solution pH is 7 ~ 8 after described hydrolysis reaction completes, filter, reclaim catalyzer.
3. preparation method as claimed in claim 2, is characterized in that, in described method one, described alkali metal hydroxide is one or more in sodium hydroxide, potassium hydroxide and cesium hydroxide;
And/or in described method one, the mol ratio of described alkali and described compound 1 is 3.5 ~ 4.0;
And/or in described method one, in the aqueous solution of described alkali, the massfraction of alkali is 5% ~ 30%;
And/or in described method one, when described catalyzer is for during such as formula compound shown in A, the mol ratio of described catalyzer and described compound 1 is 0.05 ~ 0.15;
And/or, in described method one, when described catalyzer for or such as formula the compound shown in B and cupric salt time, the mol ratio of described cupric salt and described compound 1 is 0.1 ~ 0.2;
And/or in described method one, the temperature of described hydrolysis reaction is 50 DEG C ~ 115 DEG C;
And/or in described method one, when described halogen is chlorine, the temperature of described hydrolysis reaction is 100 DEG C ~ 120 DEG C;
And/or in described method one, when described halogen is bromine, the temperature of described hydrolysis reaction is 80 DEG C ~ 120 DEG C;
And/or in described method one, when described halogen is iodine, the temperature of described hydrolysis reaction is 50 DEG C ~ 120 DEG C;
And/or in described method one, when described halogen is chlorine, the pressure of described hydrolysis reaction is 0.4MpaG ~ 0.5MpaG;
And/or in described method one, when described halogen is bromine or iodine, the pressure of described hydrolysis reaction is 0MpaG;
And/or in described method one, the reaction times of described hydrolysis reaction is 4h ~ 6h;
And/or in described method two, described alkali metal hydroxide is one or more in sodium hydroxide, potassium hydroxide and cesium hydroxide;
And/or in described method two, the mol ratio of described alkali and described compound 2 is 3.5 ~ 4.0;
And/or in described method two, in the aqueous solution of described alkali, the massfraction of alkali is 5% ~ 30%;
And/or in described method two, when described catalyzer is for during such as formula compound shown in A, the mol ratio of described catalyzer and described compound 2 is 0.05 ~ 0.15;
And/or, in described method two, when described catalyzer for or such as formula the compound shown in B and cupric salt time, the mol ratio of described cupric salt and described compound 2 is 0.1 ~ 0.2;
And/or in described method two, the temperature of described hydrolysis reaction is 50 DEG C ~ 115 DEG C;
And/or in described method two, when described halogen is chlorine, the temperature of described hydrolysis reaction is 100 DEG C ~ 120 DEG C;
And/or in described method two, when described halogen is bromine, the temperature of described hydrolysis reaction is 80 DEG C ~ 120 DEG C;
And/or in described method two, when described halogen is iodine, the temperature of described hydrolysis reaction is 50 DEG C ~ 120 DEG C;
And/or in described method two, when described halogen is chlorine, the pressure of described hydrolysis reaction is 0.4MpaG ~ 0.5MpaG;
And/or in described method two, when described halogen is bromine or iodine, the pressure of described hydrolysis reaction is 0.1MpaG;
And/or in described method two, the reaction times of described hydrolysis reaction is 4h ~ 6h.
4. preparation method as claimed in claim 1, it is characterized in that, described method two is further comprising the steps of: under the existence of water and alkali, be hydrolyzed compound 1 reaction, obtains described compound 2;
Wherein ,-the X in the-X in described compound 1 and described compound 2 is all in ortho position or contraposition.
5. a preparation method for hydroxyl phenylacetic acid, it comprises the following steps:
(1) compound 3 is obtained according to the method one according to any one of Claims 1 to 4, or, obtain compound 3 ' according to the method two according to any one of Claims 1 to 4;
(2) in water, described compound 3 or compound 3 ' are carried out acidification reaction, obtains compound 5;
Wherein, when described step (1) for described method for the moment ,-OM
1with-OH all in ortho position or contraposition; When described step (1) is for described method two ,-OM
3with-OH all in ortho position or contraposition.
6. a preparation method for methoxyphenylacetic acid salt, it comprises the following steps:
A () obtains compound 3 according to the method one according to any one of Claims 1 to 4, or, obtain compound 3 ' according to the method two according to any one of Claims 1 to 4;
B described compound 3 or compound 3 ', in water, in the presence of base, are carried out substitution reaction with methylating reagent, obtain compound 4 by ();
Wherein, when described step (a) for described method for the moment, described M
4for described M
1with the corresponding positively charged ion of described alkali ,-OM
1with-OCH
3all in ortho position or contraposition; When described step (a) is for described method two, described M
4for described M
3with the corresponding positively charged ion of described alkali ,-OM
3with-OCH
3all in ortho position or contraposition.
7. preparation method as claimed in claim 6, it is characterized in that, in the step (b) of the preparation method of described methoxyphenylacetic acid salt, the Molar of described water and described compound 3 or compound 3 ' is than being 1.0L/mol ~ 2.0L/mol;
And/or, in the step (b) of the preparation method of described methoxyphenylacetic acid salt, described M
3with described M
4identical;
And/or, in the step (b) of the preparation method of described methoxyphenylacetic acid salt, described M
1with described M
4identical;
And/or in the step (b) of the preparation method of described methoxyphenylacetic acid salt, described alkali is alkali metal hydroxide and/or 4-n-butyl ammonium hydroxide;
And/or in the step (b) of the preparation method of described methoxyphenylacetic acid salt, the mol ratio of described alkali and described compound 3 or compound 3 ' is 2 ~ 3;
And/or in the step (b) of the preparation method of described methoxyphenylacetic acid salt, described methylating reagent is one or more in methyl-sulfate, methyl iodide and methyl tosylate;
And/or in the step (b) of the preparation method of described methoxyphenylacetic acid salt, the mol ratio of described methylating reagent and described compound 3 or compound 3 ' is 1 ~ 2;
And/or in the step (b) of the preparation method of described methoxyphenylacetic acid salt, the temperature of described substitution reaction is 10 DEG C ~ 100 DEG C;
And/or in the step (b) of the preparation method of described methoxyphenylacetic acid salt, the reaction times of described substitution reaction is 2h ~ 10h.
8. preparation method as claimed in claim 7, is characterized in that, in the step (b) of the preparation method of described methoxyphenylacetic acid salt, described alkali metal hydroxide is one or more in sodium hydroxide, potassium hydroxide and cesium hydroxide;
And/or in the step (b) of the preparation method of described methoxyphenylacetic acid salt, described methylating reagent is methyl-sulfate;
And/or in the step (b) of the preparation method of described methoxyphenylacetic acid salt, the mol ratio of described methylating reagent and described compound 3 or compound 3 ' is 1.2 ~ 1.4;
And/or in the step (b) of the preparation method of described methoxyphenylacetic acid salt, the temperature of described substitution reaction is 30 DEG C ~ 50 DEG C;
And/or in the step (b) of the preparation method of described methoxyphenylacetic acid salt, the reaction times of described substitution reaction is 3h ~ 5h.
9. preparation method as claimed in claim 6, is characterized in that, after the hydrolysis reaction of described step (a) completes, described compound 3 or compound 3 ' without separation, then carry out the substitution reaction described in described step (b).
10. preparation method as claimed in claim 9, is characterized in that, after the hydrolysis reaction of described step (a) completes, regulates reaction solution pH to be 7 ~ 8, filters, reclaim catalyzer; Afterwards, regulate reaction solution pH to be 13 ~ 14, described compound 3 or compound 3 ' without separation, then carry out the substitution reaction described in described step (b).
The preparation method of 11. 1 kinds of methoxyphenylacetic acids, it comprises the following steps:
I, obtain compound 4 according to the preparation method of the methoxyphenylacetic acid salt according to any one of claim 6 ~ 10;
II, in water, described compound 4 is carried out acidification reaction, obtains compound 6;
Wherein ,-the OCH in described compound 4
3with-the OCH in described compound 6
3all in ortho position or contraposition.
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| CN101830793A (en) * | 2010-05-13 | 2010-09-15 | 中科院广州化学有限公司 | Method for preparing hydroxyl-substituted phenylacetic acid compound |
| CN102643192A (en) * | 2012-03-29 | 2012-08-22 | 常熟市新港农产品产销有限公司 | Preparation method of methoxyphenylacetic acid |
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| CN101830793A (en) * | 2010-05-13 | 2010-09-15 | 中科院广州化学有限公司 | Method for preparing hydroxyl-substituted phenylacetic acid compound |
| CN102643192A (en) * | 2012-03-29 | 2012-08-22 | 常熟市新港农产品产销有限公司 | Preparation method of methoxyphenylacetic acid |
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| 张智泉等: ""对溴苯乙酸合成研究进展"", 《化学工业与工程》 * |
| 赵冬梅等: ""1- (4-甲氧基)苯基-2-丙胺的合成"", 《中国医药工业杂志》 * |
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