CN103113298B - Preparation method of 7-bromo-4-hydroxy-3-quinoline carboxylic acid - Google Patents
Preparation method of 7-bromo-4-hydroxy-3-quinoline carboxylic acid Download PDFInfo
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Abstract
The invention relates to a preparation method of 7-bromo-4-hydroxy-3-quinoline carboxylic acid. The preparation method comprises that hydrochloric acid serves as a catalyst to catalyze 7-bromo-4-hydroxy-3-quinoline carboxylic acid (C1-3) alkyl ester for carrying out hydrolysis reaction, specifically, the preparation method comprises the following steps of: heating and refluxing 7-bromo-4-hydroxy-3-quinoline carboxylic acid (C1-3) alkyl ester, an organic solvent and 1-2 mol/L hydrochloric acid aqueous solution for 0.5-2 hours under stirring, and then filtering and washing filter cake to obtain 7-bromo-4-hydroxy-3-quinoline carboxylic acid. In an embodiment of the invention, 7-bromo-4-hydroxy-3-quinoline carboxylic acid (C1-3) alkyl ester is obtained by condensation and cyclization of m-bromoaniline and (C1-2) alkoxy methylene malonic acid bi(C1-3) alkyl ester. The preparation method is few in side reactions, simple in after-treatment, liable to separate the product, high in yield and high in product purity, so that the preparation method is suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of the bromo-4-hydroxyl of a kind of 7--3-quinoline carboxylic acid, belong to technical field of organic synthesis.
Background technology
7-bromo-4-hydroxyl-3-quinoline carboxylic acid is a kind of important medicine, dyestuff and pesticide intermediate, be mainly used in synthesis antimalarial agent, synthesis textile dyeing auxiliary and hair, fur dyeing agent and in agricultural for the synthesis of the sterilant of vegetables and fruit and sanitas etc.
At present, the method preparing the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid take m-bromoaniline as raw material, obtains product through condensation, cyclisation, hydrolyzed under basic conditions.The product yield of the method is lower, mainly because the hydrolysis of the bromo-4-hydroxyl of final step 7--3-quinoline carboxylic acid ethyl ester is carried out in the basic conditions, creates a lot of by products.Specifically, because the existence of alkali lye, bromine on the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid ethyl ester is removed, what finally obtain is 4, many by products such as 7-dihydroxyl-3-quinoline carboxylic acid, 4,7-dihydroxyl-3-quinoline carboxylic acid ethyl esters, thus cause product yield low, aftertreatment bothers, the not high many drawbacks of product purity.
Therefore, how to reduce the generation of side reaction in hydrolytic process, that improves the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid prepares productive rate, becomes one of 7-bromo-4-hydroxyl-3-quinoline carboxylic acid preparation field technical problem urgently to be resolved hurrily.
Summary of the invention
The object of this invention is to provide the preparation method of the bromo-4-hydroxyl of a kind of 7--3-quinoline carboxylic acid, the method overcome the deficiency of existing technique, decrease secondary generation of answering in Ester hydrolysis process, high yield, the bromo-4-hydroxyl of high-quality 7--3-quinoline carboxylic acid can be obtained.
The invention provides the preparation method of the bromo-4-hydroxyl of a kind of 7--3-quinoline carboxylic acid, it is characterized in that, with hydrochloric acid as the bromo-4-hydroxyl of the 7--3-quinoline carboxylic acid C shown in catalyst following formula (I)
1 ~ 3alkyl ester is hydrolyzed reaction:
Wherein, R
1for methyl, ethyl, n-propyl or sec.-propyl.
According to a concrete but nonrestrictive embodiment of the present invention, described method comprises: by the bromo-4-hydroxyl of the 7--3-quinoline carboxylic acid C shown in above formula (I)
1 ~ 3alkyl ester, organic solvent and concentration are the aqueous hydrochloric acid of 1-2mol/L, under agitation reflux 0.5-2 hour, after having reacted, filter, and filtrate is concentrated into solid and separates out, merge filter cake, washing leaching cake, obtains the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, the concentration of hydrochloric acid is 1.5mol/L.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid C
1 ~ 3the mol ratio of alkyl ester and hydrochloric acid is 1:3-5.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, reflux 1-1.5 hour.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid C
1 ~ 3alkyl ester is by the alkoxyl group methene dialkyl malonate shown in m-bromoaniline and following formula (II), and through condensation, cyclisation obtains:
Wherein, R
1for methyl, ethyl, n-propyl or sec.-propyl, R
2for methyl or ethyl.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid C
1 ~ 3the preparation method of alkyl ester comprises:
By the alkoxyl group methene dialkyl malonate shown in m-bromoaniline and above formula (II), under agitation slowly heat, when being warming up to 80-130 DEG C, stir 0.5-3 hour, wherein the mol ratio of m-bromoaniline and alkoxyl group methene dialkyl malonate is 1:1-2, after having reacted, is directly concentrated by reaction solution, the thick product purification by column chromatography obtained, obtains dialkyl group (the 3-bromaniline methylene radical) propanedioic acid shown in following formula (III) after drying
Wherein, R
1for methyl, ethyl, n-propyl or sec.-propyl;
Under agitation, inertia high boiling solvent is added in reaction vessel, when being heated to 240-250 DEG C, add dialkyl group (the 3-bromaniline methylene radical) propanedioic acid shown in above formula (III), react 0.5-3 hour at this temperature, after having reacted, be cooled to room temperature, separate out solid, filter, after washing, drying solid, obtain the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid C
1 ~ 3alkyl ester.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, the mol ratio of m-bromoaniline and alkoxyl group methene dialkyl malonate is 1:1.2-1.5.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, m-bromoaniline and alkoxyl group methene dialkyl malonate temperature of reaction control at 90-120 DEG C, stir 1-2 hour.
According to a concrete but nonrestrictive embodiment of the present invention, wherein, inertia high boiling solvent is phenyl ether, biphenyl-biphenyl ether, whiteruss and/or diethyl phthalate.
Beneficial effect of the present invention is mainly reflected in:
1. the present invention adopts hydrochloric acid as the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid (C
1 ~ 3) the esterolytic catalyzer of alkyl, can overcome the deficiency that existing this hydrolysis reaction of technique base catalysis causes by product many, decrease the generation of side reaction in Ester hydrolysis process, thus make product be easy to be separated, aftertreatment is simple, significantly improves and prepares productive rate.
2. a kind of embodiment of the present invention is with m-bromoaniline and (C
1 ~ 2) alkoxyl group methylene malonic acid two (C
1 ~ 3) alkyl ester is raw material, first carries out condensation, then cyclisation, then hydrolysis obtains the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid in acid condition.This synthetic route raw material is easy to get, simple to operate, can obtain high yield, highly purified product.
3. preparation method of the present invention is simple to operate, and whole process contamination is little, is applicable to large-scale industrial production.
Accompanying drawing explanation
Fig. 1 is the H-NMR spectrogram (solvent: DMSO) of the bromo-4-hydroxyl of the 7--3-quinoline carboxylic acid of preparation in embodiment 2.
Embodiment
Provided hereinafter concrete embodiment and further illustrate the present invention, but the present invention is not limited only to following embodiment.
Usually, 7-bromo-4-hydroxyl-3-quinoline carboxylic acid is hydrolyzed by the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid ethyl ester and obtains.According to prior art, this hydrolysis reaction carries out all in the basic conditions, this is because hydrolysis reaction is irreversible in the basic conditions.But because the bromine on bromo-for 7-4-hydroxyl-3-quinoline carboxylic acid ethyl ester easily removes by the alkali lye existed, finally can obtain 4,7-dihydroxyl-3-quinoline carboxylic acid, 4, many by products such as 7-dihydroxyl-3-quinoline carboxylic acid ethyl ester, produce more side reaction, thus cause the problems such as low yield, product purity are not high.Meanwhile, due to the existence of alkali lye, reaction solution pH value is adjusted to acidity by the acid of aftertreatment needs, could separate out product, therefore product post-processing operation trouble.
The present inventor, through studying discovery for a long period of time, is hydrolyzed if change into, in acid condition with hydrochloric acid as the bromo-4-hydroxyl of catalyst 7--3-quinoline carboxylic acid (C
1 ~ 3) alkyl ester hydrolysis, significantly can improve and prepare productive rate, and the product purity obtained is high, quality better, product aftertreatment is more simple, and product is more easily separated, and beneficial effect is very remarkable, and this method has no bibliographical information at present.
The bromo-4-hydroxyl of 7-provided by the invention-3-quinoline carboxylic acid preparation method comprises:
By the bromo-4-hydroxyl of the 7--3-quinoline carboxylic acid (C shown in following formula (I)
1 ~ 3) alkyl ester
Wherein, R
1for methyl, ethyl, n-propyl or sec.-propyl, the aqueous hydrochloric acid being 1-2mol/L with the organic solvent such as dehydrated alcohol or anhydrous methanol and concentration joins in reaction vessel, and wherein the amount of solvent is according to the every gram of bromo-4-hydroxyl of 7--3-quinoline carboxylic acid (C
1 ~ 3) alkyl ester needs the ratio of solvent 25mL to add, the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid (C
1 ~ 3) mol ratio of alkyl ester and hydrochloric acid is 1:3-5, stir and reflux 0.5-2 hour, preferred 1-1.5 hour, there is a large amount of solid phase prods to separate out, after having reacted, filter, filtrate is concentrated into solid to separate out, merge filter cake, with organic solvent washings such as ethanol, methyl alcohol or sherwood oil 2-3 time, finally obtain the bromo-4-hydroxyl of white solid 7--3-quinoline carboxylic acid.
We find through research, and the concentration of hydrochloric has important impact to whole hydrolysis reaction.Under the condition that used catalyst hydrochloric acid total amount (mole number) is certain, as concentration of hydrochloric acid <1mol/L, the yield of product is lower, below 70%, this may be that hydrolysis rate is slow because the concentration of hydrochloric acid is low, it is incomplete that hydrolysis reaction carries out, and is therefore hydrolyzed yield low; Along with the continuation of hydrochloric concentration increases, product yield constantly increases, and when concentration of hydrochloric acid is at 1-2mol/L, product yield can reach more than 90%, and when concentration of hydrochloric acid reaches 1.5mol/L, product yield reaches the highest by 97%; And as concentration of hydrochloric acid >2mol/L, product yield no longer increases, be down to less than 70% on the contrary, this may be because concentration of hydrochloric acid is too high, accelerates product generation reversed reaction, and side reaction generates impurity and causes products collection efficiency to reduce.Therefore, the concentration of hydrochloric is preferably 1.5mol/L.
The bromo-4-hydroxyl of the raw material 7--3-quinoline carboxylic acid (C of said hydrolyzed reaction
1 ~ 3) alkyl ester can obtain from commercial channels, also can with m-bromoaniline and (C
1 ~ 2) alkoxyl group methylene malonic acid two (C
1 ~ 3) alkyl ester is raw material, obtain through condensation, cyclisation.From m-bromoaniline and (C
1 ~ 2) alkoxyl group methylene malonic acid two (C
1 ~ 3) alkyl ester is as follows to the synthetic route of 7-bromo-4-hydroxyl-3-quinoline carboxylic acid:
Wherein, the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid (C
1 ~ 3) preparation process of alkyl ester is as follows:
(1) two (C
1 ~ 3) preparation of alkyl (3-bromaniline methylene radical) propanedioic acid
By the alkoxyl group methene dialkyl malonate shown in m-bromoaniline and following formula (II)
Wherein, R
1for methyl, ethyl, n-propyl or sec.-propyl, R
2for methyl or ethyl, to join in reaction vessel and to stir, wherein m-bromoaniline and (C
1 ~ 2) alkoxyl group methylene malonic acid two (C
1 ~ 3) mol ratio of alkyl ester can be 1:1-2, preferred 1:1.2-1.5; Slow heating, when temperature of reaction rises to 80 DEG C-130 DEG C, when preferable reaction temperature rises to 90 DEG C-120 DEG C, stirs 0.5-3 hour, preferably stirs 1-2 hour; After having reacted, directly concentrated by reaction solution, remove out the alcohol that reaction generates, the thick product purification by column chromatography obtained, obtains dialkyl group (the 3-bromaniline methylene radical) propanedioic acid shown in following formula (III) after drying
Wherein, R
1for methyl, ethyl, n-propyl or sec.-propyl.
(2) the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid (C
1 ~ 3) preparation of alkyl ester
Under agitation, in reaction vessel, add inertia high boiling solvent as phenyl ether, biphenyl-biphenyl ether, whiteruss, diethyl phthalate etc., preferably use phenyl ether, wherein the amount of solvent is according to 1g bis-(C
1 ~ 3) alkyl (3-bromaniline methylene radical) propanedioic acid needs the ratio of inertia high boiling solvent amount 5mL to add; When being heated to 240 DEG C-250 DEG C, then add two (C of (1) step generation
1 ~ 3) alkyl (3-bromaniline methylene radical) propanedioic acid, react 0.5-3 hour at this temperature, preferred reaction 1-2 hour, after having reacted, be cooled to room temperature, adularescent solid is separated out, and filters, by organic solvent washings such as the solid dehydrated alcohol, methyl alcohol or the ether that obtain 2-3 time, after drying, obtain the bromo-4-hydroxyl of white solid powder 7--3-quinoline carboxylic acid (C
1 ~ 3) alkyl ester.
And then, use the bromo-4-hydroxyl of hydrochloric acid catalysis 7--3-quinoline carboxylic acid (C according to the method described above
1 ~ 3) alkyl ester hydrolysis obtain the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid.This with m-bromoaniline and (C
1 ~ 2) alkoxyl group methylene malonic acid two (C
1 ~ 3) alkyl ester is raw material, through condensation, cyclisation, then hydrolysis obtains the synthetic route of the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid in presence of hydrochloric acid, has raw material and is easy to get, simple operation and other advantages, and the product yield obtained is high, purity is high, be applicable to large-scale industrial production.
Below in conjunction with specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.
Above and the experimental technique used in following embodiment if no special instructions, be ordinary method.
Above and material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.
Embodiment 1
The preparation of the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid
By commercially available for bromo-for analytical pure 7-4-hydroxyl-3-quinoline carboxylic acid ethyl ester 28.7g(), anhydrous methanol 720mL and 1mol/L aqueous hydrochloric acid 147mL joins in reaction flask, stir and reflux 1.5h, a large amount of solid phase prods is had to separate out, after having reacted, filter, filtrate is concentrated into solid to separate out, merge filter cake methanol wash 3 times, the bromo-4-hydroxyl of white solid 7--3-quinoline carboxylic acid 22.7g is obtained after drying, calculated yield is 87.5%, and obtaining the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid purity by Agilent1100 liquid chromatograph is 99.0%.
Embodiment 2
(1) preparation of diethyl (3-bromaniline methylene radical) propanedioic acid
Analytical pure m-bromoaniline 30g, analytical pure diethyl ethoxymethylenemalonate 49g are joined in reaction flask, stirs, slowly heat, when temperature of reaction rises to 110 DEG C, stir 1.5h; After having reacted, reaction solution is directly concentrated, remove out the ethanol that reaction generates, the thick product purification by column chromatography obtained, diethyl (3-bromaniline methylene radical) propanedioic acid 56.1g is obtained after drying, calculated yield is 94%, and obtaining diethyl (3-bromaniline methylene radical) propanedioic acid purity by Agilent1100 liquid chromatograph is 99.0%.
(2) preparation of the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid ethyl ester
Under agitation, phenyl ether 280mL is added in reaction flask, when being heated to 240 DEG C, add diethyl (3-bromaniline methylene radical) the propanedioic acid 56.1g of above-mentioned preparation again, reaction solution heating 2h at this temperature, after having reacted, be cooled to room temperature, adularescent solid is separated out, filter, by the solid absolute ethanol washing that obtains 3 times, after drying, obtain white solid powder 7-bromine 4-hydroxyl-3-quinoline carboxylic acid ethyl ester 43.7g, calculated yield is 90%, and obtaining 7-bromine 4-hydroxyl-3-quinoline carboxylic acid ethyl ester purity by Agilent1100 liquid chromatograph is 98.3%.
(3) preparation of the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid
Bromo-for the 7-of above-mentioned preparation 4-hydroxyl-3-quinoline carboxylic acid ethyl ester 43.7g, dehydrated alcohol 1100mL and 1.5mol/L aqueous hydrochloric acid 150mL are joined in reaction flask, stir and reflux 1h, a large amount of solid phase prods is had to separate out, after having reacted, filter, filtrate is concentrated into solid to separate out, merge filter cake washing with alcohol 3 times, white solid 7-bromine 4-hydroxyl-3-quinoline carboxylic acid 38g is obtained after drying, calculated yield is 96.1%, and obtaining 7-bromine 4-hydroxyl-3-quinoline carboxylic acid purity by Agilent1100 liquid chromatograph is 99.2%.Fig. 1 is the H-NMR spectrogram (solvent: DMSO) of the bromo-4-hydroxyl of the 7--3-quinoline carboxylic acid of preparation.
Embodiment 3-6
The difference of embodiment 3-6 and embodiment 2 is that concentration of hydrochloric acid and volume are as shown in table 1 below, and all in the same manner as in Example 1, the productive rate obtained is listed respectively in Table 1 for other step and condition.
Table 1
| ? | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 |
| Aqueous hydrochloric acid volume (mL) | 281 | 188 | 125 | 94 |
| Concentration of hydrochloric acid (mol/L) | 0.8 | 1.2 | 1.8 | 2.4 |
| Productive rate (%) | 67.5% | 94.2% | 95.1% | 65.2% |
As can be seen from embodiment 2-6, under the condition that total mole dosage of hydrochloric is certain, when concentration of hydrochloric acid is 1-2mol/L, product yield is higher, can reach more than 90%.
Embodiment 7
(1) preparation of dimethyl (3-bromaniline methylene radical) propanedioic acid
Analytical pure m-bromoaniline 15g, analytical pure oxyethyl group methene dimethyl malonate 23g are joined in reaction flask, stirs, slowly heat, when temperature of reaction rises to 120 DEG C, stir 2h; After having reacted, reaction solution is directly concentrated, remove out the ethanol that reaction generates, the thick product purification by column chromatography obtained, product dimethyl (3-bromaniline methylene radical) propanedioic acid 25.5g is obtained after drying, calculated yield is 93%, and obtaining dimethyl (3-bromaniline methylene radical) propanedioic acid purity by Agilent1100 liquid chromatograph is 99.0%.
(2) preparation of the bromo-4-hydroxyl of 7--3-Quinolinecarboxylic acid methyl ester
Under agitation, phenyl ether 130mL is added in reaction flask, when being heated to 250 DEG C, add dimethyl-(3-bromaniline methylene radical) propanedioic acid 25.5g of above-mentioned preparation again, reaction solution heating 1h at this temperature, after having reacted, be cooled to room temperature, adularescent solid is separated out, filter, the solid anhydrous diethyl ether obtained is washed 3 times, the bromo-4-hydroxyl of white solid powder 7--3-Quinolinecarboxylic acid methyl ester 20.4g is obtained after drying, calculated yield is 89%, obtaining the bromo-4-hydroxyl of 7--3-Quinolinecarboxylic acid methyl ester purity by Agilent1100 liquid chromatograph is 98.2%.
(3) preparation of the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid
Bromo-for the 7-of above-mentioned preparation 4-hydroxyl-3-Quinolinecarboxylic acid methyl ester 20.4g, dehydrated alcohol 510mL and 2mol/L aqueous hydrochloric acid 60mL are joined in reaction flask, stir and reflux 1h, a large amount of solid phase prods is had to separate out, after having reacted, filter, filtrate is concentrated into solid to separate out, merge filter cake washing with alcohol 3 times, the bromo-4-hydroxyl of white solid 7--3-quinoline carboxylic acid 13.2g is obtained after drying, calculated yield is 68%, and obtaining the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid purity by Agilent1100 liquid chromatograph is 99.1%.
Embodiment 8
(1) preparation of diethyl (3-bromaniline methylene radical) propanedioic acid
Analytical pure m-bromoaniline 40g, analytical pure methoxyl group methene diethyl malonate 70.5g are joined in reaction flask, stirs, slowly heat, when temperature of reaction rises to 110 DEG C, stir 2h; After having reacted, reaction solution is directly concentrated, remove out the methyl alcohol that reaction generates, the thick product purification by column chromatography obtained, product diethyl (3-bromaniline methylene radical) propanedioic acid 74g is obtained after drying, calculated yield is 93%, and obtaining diethyl (3-bromaniline methylene radical) propanedioic acid purity by Agilent1100 liquid chromatograph is 99.3%.
(2) preparation of the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid ethyl ester
Under agitation, phenyl ether 370mL is added in reaction flask, when being heated to 240 DEG C, add diethyl (3-bromaniline methylene radical) the propanedioic acid 74g of above-mentioned preparation again, reaction solution heating 1h at this temperature, after having reacted, be cooled to room temperature, adularescent solid is separated out, filter, by the solid absolute ethanol washing that obtains 3 times, after drying, obtain the bromo-4-hydroxyl of white solid powder 7--3-quinoline carboxylic acid ethyl ester 56.4g, calculated yield is 88%, and obtaining the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid ethyl ester purity by Agilent1100 liquid chromatograph is 98.1%.
(3) preparation of the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid
Bromo-for the 7-of above-mentioned preparation 4-hydroxyl-3-quinoline carboxylic acid ethyl ester 56.4g, dehydrated alcohol 1400mL and 1.2mol/L aqueous hydrochloric acid 241mL are joined in reaction flask, stir and reflux 1h, a large amount of solid phase prods is had to separate out, after having reacted, first filter, filtrate is concentrated into solid to separate out, merge filter cake washing with alcohol 3 times, the bromo-4-hydroxyl of white solid 7--3-quinoline carboxylic acid 48.1g is obtained after drying, calculated yield is 94.2%, and obtaining the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid purity by Agilent1100 liquid chromatograph is 99.3%.
Comparative example
Method according to above-described embodiment 8 (1) step and (2) step synthesizes the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid ethyl ester.
Below with art methods synthesis 7-bromine 4-hydroxyl-3-quinoline carboxylic acid:
By the bromo-4-hydroxyl of the 7--3-quinoline carboxylic acid ethyl ester 10g of preparation, dehydrated alcohol 200ml and 10% aqueous sodium hydroxide solution 100ml joins in reaction flask, after first at room temperature stirring 30min, reflux, after having reacted, ethanol in reaction solution is steamed, then water layer removing impurity is extracted with ethyl acetate, the PH of water layer is regulated to be about 6 with the hydrochloric acid of 1mol/L, solid is had to generate, filter, by the solid washing with alcohol that obtains 3 times, the bromo-4-hydroxyl of white solid 7--3-quinoline carboxylic acid 6.1g is obtained after drying, calculated yield is 67%, obtaining product purity by Agilent1100 liquid chromatograph is 98.2%.
By comparing with above-described embodiment 8, can find out that the present invention uses hydrochloric acid catalysis Ester hydrolysis instead, being hydrolyzed in the basic conditions than prior art, product yield improves about 40%, and product purity is apparently higher than the product purity of prior art, and product aftertreatment is simpler.Therefore, prepare the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid by method of the present invention, beneficial effect is very remarkable.
Below be only embody rule example of the present invention, protection scope of the present invention is not constituted any limitation.The technical scheme that all employing equivalents or equivalence are replaced and formed, all drops within rights protection scope of the present invention.
Claims (9)
1. the bromo-4-hydroxyl of a 7--3-quinoline carboxylic acid's preparation method, is characterized in that, with hydrochloric acid as the bromo-4-hydroxyl of the 7--3-quinoline carboxylic acid C shown in catalyst following formula (I)
1 ~ 3alkyl ester is hydrolyzed reaction:
Wherein, R
1for methyl, ethyl, n-propyl or sec.-propyl, the method comprises:
By the bromo-4-hydroxyl of the 7--3-quinoline carboxylic acid C shown in above formula (I)
1 ~ 3alkyl ester, organic solvent and concentration are the aqueous hydrochloric acid of 1-2mol/L, under agitation reflux 0.5-2 hour, after having reacted, filter, and filtrate is concentrated into solid and separates out, merge filter cake, washing leaching cake, obtains the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid.
2. method according to claim 1, wherein, the concentration of hydrochloric acid is 1.5mol/L.
3. method according to claim 1, wherein, the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid C
1 ~ 3the mol ratio of alkyl ester and hydrochloric acid is 1:3-5.
4. method according to claim 1, wherein, reflux 1-1.5 hour.
5. according to method arbitrary in claim 1-4, wherein, the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid C
1 ~ 3alkyl ester is by the alkoxyl group methene dialkyl malonate shown in m-bromoaniline and following formula (II), and through condensation, cyclisation obtains:
Wherein, R
1for methyl, ethyl, n-propyl or sec.-propyl, R
2for methyl or ethyl.
6. method according to claim 5, wherein, the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid C
1 ~ 3the preparation method of alkyl ester comprises:
By the alkoxyl group methene dialkyl malonate shown in m-bromoaniline and above formula (II), under agitation slowly heat, when being warming up to 80-130 DEG C, stir 0.5-3 hour, wherein the mol ratio of m-bromoaniline and alkoxyl group methene dialkyl malonate is 1:1-2, after having reacted, is directly concentrated by reaction solution, the thick product purification by column chromatography obtained, obtains dialkyl group (the 3-bromaniline methylene radical) propanedioic acid shown in following formula (III) after drying
Wherein, R
1for methyl, ethyl, n-propyl or sec.-propyl;
Under agitation, inertia high boiling solvent is added in reaction vessel, when being heated to 240-250 DEG C, add dialkyl group (the 3-bromaniline methylene radical) propanedioic acid shown in above formula (III), react 0.5-3 hour at this temperature, after having reacted, be cooled to room temperature, separate out solid, filter, after washing, drying solid, obtain the bromo-4-hydroxyl of 7--3-quinoline carboxylic acid C
1 ~ 3alkyl ester.
7. method according to claim 6, wherein, the mol ratio of m-bromoaniline and alkoxyl group methene dialkyl malonate is 1:1.2-1.5.
8. method according to claim 6, wherein, m-bromoaniline and alkoxyl group methene dialkyl malonate temperature of reaction control at 90-120 DEG C, stir 1-2 hour.
9. method according to claim 6, wherein, inertia high boiling solvent is phenyl ether, biphenyl-biphenyl ether, whiteruss and/or diethyl phthalate.
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|---|---|---|---|---|
| CN1062905A (en) * | 1991-01-01 | 1992-07-22 | 唐良平 | 4-hydroxyl-7-chloro-quinolinic acid synthetic method |
| US20130225524A1 (en) * | 2010-11-05 | 2013-08-29 | Deping Chai | Chemical Compounds |
| CN102070524A (en) * | 2011-01-12 | 2011-05-25 | 无锡好芳德药业有限公司 | Method for preparing 3-cyano-4-halogenated quinoline derivatives |
| CN102219736B (en) * | 2011-04-13 | 2012-12-19 | 杰达维（上海）医药科技发展有限公司 | Preparation method for 8-quinolinecarboxylic ester and 8-quinolinecarboxylic acid |
| CN102702098A (en) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesis of 6-methoxyl-1, 2, 3, 4 tetrahydroquinoline-5 methyl ester carboxylate |
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