CN104478745A - Synthetic method for 4-amino-3-phenylbutyric acid hydrochloride - Google Patents
Synthetic method for 4-amino-3-phenylbutyric acid hydrochloride Download PDFInfo
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- CN104478745A CN104478745A CN201410612409.9A CN201410612409A CN104478745A CN 104478745 A CN104478745 A CN 104478745A CN 201410612409 A CN201410612409 A CN 201410612409A CN 104478745 A CN104478745 A CN 104478745A
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- DAFOCGYVTAOKAJ-UHFFFAOYSA-N NCC(CC(O)=O)c1ccccc1 Chemical compound NCC(CC(O)=O)c1ccccc1 DAFOCGYVTAOKAJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a synthetic method for 4-amino-3-phenylbutyric acid hydrochloride. The synthetic method for 4-amino-3-phenylbutyric acid hydrochloride prepares 4-amino-3-phenylbutyric acid hydrochloride by preparing a first intermediate, a second intermediate, a third intermediate, preparing 4-amino-3-phenylbutyric acid and forming a salt. The synthetic method is a complete technology for synthesizing 4-amino-3-phenylbutyric acid hydrochloride, is simple in technology, high in yield and relatively low in cost, and mainly solves the problems that initial raw materials employed in the prior art are high in price, operation steps are tedious and the production process has large pollution.
Description
Technical field
The present invention relates to a kind of 4-Amino-3-phenylbutyric acid hydrochloride synthetic method.
Background technology
The structural formula of 4-Amino-3-phenylbutyric acid hydrochloride is as follows:
At present; disclosed 3-benzyloxy is as follows the synthetic method of-4-butylaniline hydrochloride: take Metha Amino Phenon as raw material; react through Butyrylation; Fries resets; obtain 2-butyryl radicals-5-butyramidophenol: under the effect of alkali; 2-butyryl-5-butyramidophenol and the effect of halogenation benzyl generate 2-butyryl radicals-5-amide-based small benzyl phenyl ether; then hydrolysis obtains 3-benzyloxy-4-butyryl radicals aniline; eventually pass Huang Min-lon reduction reaction, salify obtains 3-benzyloxy-4-4-butylaniline hydrochloride.The starting raw material price that above technique uses is high, and operation steps is lengthy and tedious, and production process is polluted large.
Summary of the invention
The invention provides a kind of synthetic method of 4-Amino-3-phenylbutyric acid hydrochloride, mainly solve the starting raw material price that existing technique uses high, the lengthy and tedious and heavy-polluted problem of production process of operation steps.
Concrete technical solution of the present invention is as follows:
A synthetic method for 4-Amino-3-phenylbutyric acid hydrochloride, comprises the following steps:
1] the first intermediate is prepared
Phenyl aldehyde and methyl aceto acetate are joined in ethanol, room temperature uses cake filtration after stirring reaction 45 ~ 50h under the catalysis of organic bases, ethanol rinse filter cake is used after filtration completes, dry cake obtains solid, again ethanol filtrate is concentrated into 1/4 of original volume, cold analysis is carried out to concentrated solution, filter alcohol wash, obtain solid, merge twice solid and be the first intermediate; The mol ratio of described phenyl aldehyde, methyl aceto acetate, ethanol is 1:2.5-3:12-15.
2] the second intermediate is prepared
First intermediate is joined in mass concentration 20% sodium hydroxide solution, filter cake is adopted to filter after 85-90 DEG C of stirring reaction 2-2.5h, filtration completes after washing filter cake, merging filtrate also cools, and stirs cooling gained filtrate 3h, drips HCl and regulate pH to 1-2 during stirring, filtration after stirring completes, washing, dry, obtain solid second intermediate; The first described intermediate and the mass ratio of sodium hydroxide solution are 1:1.8-2.0;
3] the 3rd intermediate is prepared
Second intermediate is dissolved in pure solution of acetic anhydride reflux 3 ~ 5h, reflux rear concentrated removing diacetyl oxide and add toluene dissolve, add ammoniacal liquor after having dissolved, under 60-65 DEG C of condition, react 1-1.5h, reacted rear ice bath dropping H
2sO
4regulate pH to 1-2, then solid separated out, the solid of separating out is filtered, washed, dry, obtain solid the 3rd intermediate; The mass ratio of the second described intermediate, pure solution of acetic anhydride, toluene, ammoniacal liquor is 5:1-1.2:0.5-0.8:0.5-0.8;
4] luxuriant and rich with fragrance Buddhist nun's Boot is prepared
It is in 25% sodium hydroxide solution that 3rd intermediate is dissolved in mass concentration, be cooled to-5 DEG C ~ 10 DEG C, in 15-20min, slowly clorox is dripped after having cooled, reaction 1h, then ice bath reaction 0.5 ~ 1.5h is carried out successively, water-bath 0.5 ~ 1.5h, 1-1.5h is reacted under being finally warming up to 60 ~ 80 DEG C of conditions gradually, again cool after having reacted, cool rear ice-water bath and drip salt acid for adjusting pH to 2, stirring at room temperature decolouring 1h, filter, after filtering, ice-water bath hydro-oxidation sodium is 6-7 to pH, cooling and stirring 2h, again filter get Fei Ni Boot and 4-Amino-3-phenylbutyric acid, the mass ratio of the 3rd described intermediate, sodium hydroxide solution, clorox is 1.0:0.8-1.0:1.0-1.1,
5] salify
Be 18% diluted hydrochloric acid dissolution by the mass concentration that adds soluble in water for 4-Amino-3-phenylbutyric acid solid, after dissolving, reconcentration is to dry, adds 95% ethanolic soln heating for dissolving recrystallization, obtains 4-Amino-3-phenylbutyric acid hydrochloride; The mass ratio of described 4-Amino-3-phenylbutyric acid, water, dilute hydrochloric acid, ethanolic soln is 1.0:0.3-0.5:2.0-2.5:2.0-3.0.
In above-mentioned steps 1, organic bases is piperazine or triethylamine.
The invention has the advantages that:
Invention creates the complete process of a synthesis 4-Amino-3-phenylbutyric acid hydrochloride, technique is simple, and yield is high, and cost is lower.
Accompanying drawing explanation
Fig. 1 is the Liquid Detection figure in example 1 of the present invention;
Fig. 2 is the Liquid Detection figure in example 2 of the present invention.
Embodiment
Synthesis route is as follows:
Example 1
1] preparation of the first intermediate:
Phenyl aldehyde 265g (2.5mol), methyl aceto acetate 812.5g (6.25mol), piperazine 20 grams join in 1000ml (97%) ethanol, room temperature 20 DEG C-25 DEG C stirring reaction 48h filter, with dehydrated alcohol drip washing filter cake, dry, obtain solid 700g, filtrate is concentrated into 1/4 of original volume, cold analysis, filters alcohol wash, again solid 50g, merge twice solid totally 750 grams, productive rate 78%;
2] preparation of the second intermediate:
Intermediate 280g (0.11mol), joining mass concentration is in 20% sodium hydroxide solution (80g sodium hydroxide is dissolved in 320mL water) 400mL, 85-90 DEG C of stirring reaction 2-2.5h, filter, washing filter cake, merging filtrate, cooling filtrate, stirring cooling lower dropping hydrochloric acid 170mL regulates pH to be 1-2, stirs 3h, filter under cooling, washing, drying, obtains solid 360g, productive rate 73%;
3] preparation of the 3rd intermediate:
Intermediate 216g is dissolved in the diacetyl oxide that 60mL mass concentration is 99%, 140 DEG C of backflow 4h, it is 99% diacetyl oxide that 2h adds 20mL mass concentration, concentrated removing diacetyl oxide, add 40ml dry toluene to dissolve, add 40g ammoniacal liquor, 60-65 DEG C of reaction 1-1.5h, cooling, ice-water bath drips the sulfuric acid 10mL of mass concentration 98%.Regulate pH to 1-2, solid is separated out, and filters, washing, dry solid 140g.Productive rate 87%;
4] preparation of luxuriant and rich with fragrance Buddhist nun's Boot:
Intermediate 38g is dissolved in sodium hydroxide solution (16g sodium hydroxide the is dissolved in 50mL water) 30g that mass concentration is 24.2%, cool-5 DEG C---10 DEG C, the effective content dripping chlorine in slow 15-20min is 10% chlorine bleach liquor 40g,-5 DEG C of reaction 1h, ice-water bath reaction 1h, water-bath 1h, heat up 70 DEG C of reaction 1-1.5h gradually, cooling, ice-water bath drips the concentrated hydrochloric acid 20mL adjustment pH to 2 that mass concentration is 37%, stirring at room temperature decolouring 1h, filter, ice-water bath add mass concentration be 24.2% sodium hydroxide be 6-7 to pH, cooling and stirring 2h, filter, water recrystallization get Fei Ni Boot and 4-Amino-3-phenylbutyric acid,
5 salifies
4-Amino-3-phenylbutyric acid solid is dissolved in 20ml water and adds the diluted hydrochloric acid dissolution that mass concentration is 10%, is concentrated into dry, adds the ethanol heating for dissolving recrystallization that 100ml mass concentration is 95%, obtains 4-Amino-3-phenylbutyric acid hydrochloride finished product.
Example 2
1] preparation of the first intermediate:
Phenyl aldehyde 53g (0.5mol), methyl aceto acetate 162.5g (1.25mol), triethylamine 25 grams joins in 200ml95% (97%) ethanol, and room temperature 20 DEG C-25 DEG C stirring reaction 48h filter, with dehydrated alcohol drip washing filter cake, dry. obtain solid 140g, filtrate is concentrated into 1/4, cold analysis, filter alcohol wash, obtain solid 6g, merge twice solid and to obtain 146 grams altogether, productive rate 83%;
2] preparation of the second intermediate:
Intermediate 140g (0.11mol), joins in 20% sodium hydroxide solution (80g sodium hydroxide is dissolved in 320mL water) 400mL, 85-90 DEG C of stirring reaction 2-2.5h, filter, washing filter cake, merging filtrate, cooling filtrate, stirring the lower HCl170mL of dropping of cooling regulates pH to be 1-2, stirs 3h, filter under cooling, washing, drying, obtains solid 190g, productive rate 80%;
3] preparation of the 3rd intermediate:
Intermediate 54g is dissolved in the diacetyl oxide that 60mL mass concentration is 99%, 140 DEG C of backflow 4h, 2h adds the diacetyl oxide that 20mL mass concentration is 99%, concentrated removing diacetyl oxide, add 40ml dry toluene to dissolve, add 40g ammoniacal liquor, 60-65 DEG C of reaction 1-1.5h, cooling, ice-water bath drips the sulfuric acid 10mL that mass concentration is 98%.Regulate pH to 1-2, solid is separated out, and filters, washing, dry solid 50g, productive rate 93%;
4] preparation of luxuriant and rich with fragrance Buddhist nun's Boot:
Intermediate 19g is dissolved in sodium hydroxide solution (16g sodium hydroxide the is dissolved in 50mL water) 15g that mass concentration is 24.2%, cool-5 DEG C---10 DEG C, the effective content dripping chlorine in slow 15-20min is 10% chlorine bleach liquor 40g,-5 DEG C of reaction 1h, ice-water bath reaction 1h, water-bath 1h, heat up 70 DEG C of reaction 1-1.5h gradually, cooling, ice-water bath drips the concentrated hydrochloric acid 10mL adjustment pH to 2 that mass concentration is 37%, stirring at room temperature decolouring 1h, filter, ice-water bath drip mass concentration be 24.2% sodium hydroxide solution be 6-7 to pH, cooling and stirring 2h, filter, water recrystallization get Fei Ni Boot and 4-Amino-3-phenylbutyric acid,
5. salify
4-Amino-3-phenylbutyric acid solid is dissolved in 20ml water and adds 10% diluted hydrochloric acid dissolution, is concentrated into dry, adds 100ml dehydrated alcohol heating for dissolving recrystallization, obtains 4-Amino-3-phenylbutyric acid hydrochloride finished product.
Claims (2)
1. a synthetic method for 4-Amino-3-phenylbutyric acid hydrochloride, is characterized in that, comprises the following steps:
1] the first intermediate is prepared
Phenyl aldehyde and methyl aceto acetate are joined in ethanol, room temperature uses cake filtration after stirring reaction 45 ~ 50h under the catalysis of organic bases, ethanol rinse filter cake is used after filtration completes, dry cake obtains solid, again ethanol filtrate is concentrated into 1/4 of original volume, cold analysis is carried out to concentrated solution, filter alcohol wash, obtain solid, merge twice solid and be the first intermediate; The mol ratio of described phenyl aldehyde, methyl aceto acetate, ethanol is 1:2.5-3:12-15;
2] the second intermediate is prepared
First intermediate is joined in mass concentration 20% sodium hydroxide solution, filter cake is adopted to filter after 85-90 DEG C of stirring reaction 2-2.5h, filtration completes after washing filter cake, merging filtrate also cools, and stirs cooling gained filtrate 3h, drips HCl and regulate pH to 1-2 during stirring, filtration after stirring completes, washing, dry, obtain solid second intermediate; The first described intermediate and the mass ratio of sodium hydroxide solution are 1:1.8-2.0;
3] the 3rd intermediate is prepared
Second intermediate is dissolved in pure solution of acetic anhydride reflux 3 ~ 5h, reflux rear concentrated removing diacetyl oxide and add toluene dissolve, add ammoniacal liquor after having dissolved, under 60-65 DEG C of condition, react 1-1.5h, reacted rear ice bath dropping H
2sO
4regulate pH to 1-2, then solid separated out, the solid of separating out is filtered, washed, dry, obtain solid the 3rd intermediate; The mass ratio of the second described intermediate, pure solution of acetic anhydride, toluene, ammoniacal liquor is 5:1-1.2:0.5-0.8:0.5-0.8;
4] luxuriant and rich with fragrance Buddhist nun's Boot is prepared
It is in 25% sodium hydroxide solution that 3rd intermediate is dissolved in mass concentration, be cooled to-5 DEG C ~ 10 DEG C, in 15-20min, slowly clorox is dripped after having cooled, reaction 1h, then ice bath reaction 0.5 ~ 1.5h is carried out successively, water-bath 0.5 ~ 1.5h, 1-1.5h is reacted under being finally warming up to 60 ~ 80 DEG C of conditions gradually, again cool after having reacted, cool rear ice-water bath and drip salt acid for adjusting pH to 2, stirring at room temperature decolouring 1h, filter, after filtering, ice-water bath hydro-oxidation sodium is 6-7 to pH, cooling and stirring 2h, again filter get Fei Ni Boot and 4-Amino-3-phenylbutyric acid, the mass ratio of the 3rd described intermediate, sodium hydroxide solution, clorox is 1.0:0.8-1.0:1.0-1.1,
5] salify
Be 18% diluted hydrochloric acid dissolution by the mass concentration that adds soluble in water for 4-Amino-3-phenylbutyric acid solid, after dissolving, reconcentration is to dry, adds 95% ethanolic soln heating for dissolving recrystallization, obtains 4-Amino-3-phenylbutyric acid hydrochloride; The mass ratio of described 4-Amino-3-phenylbutyric acid, water, dilute hydrochloric acid, ethanolic soln is 1.0:0.3-0.5:2.0-2.5:2.0-3.0.
2. the synthetic method of 4-Amino-3-phenylbutyric acid hydrochloride according to claim 1, is characterized in that: in described step 1, organic bases is piperazine or triethylamine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107151234A (en) * | 2017-05-15 | 2017-09-12 | 重庆康刻尔制药有限公司 | A kind of preparation method of isradipine impurity I |
| CN107188808A (en) * | 2017-05-22 | 2017-09-22 | 江苏斯威森生物医药工程研究中心有限公司 | A kind of synthetic method of the phenylbutyric acid hydrochloride of 4 amino 3 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2166497C1 (en) * | 2000-02-25 | 2001-05-10 | Специальное конструкторско-технологическое бюро "Технолог" Санкт-Петербургского государственного технологического института (технического университета) | Method of preparing 3-phenyl-4-aminobutyric acid or 3-phenyl-4-aminobutyric acid chlorohydrate |
| CN101033195A (en) * | 2007-04-17 | 2007-09-12 | 安徽省郎溪县科联实业有限公司 | Method of preparing 4-amino-3-phenyl butyric hydrochloride |
| CN102115450A (en) * | 2009-12-30 | 2011-07-06 | 上海新浦化工厂有限公司 | Preparation method for 4-amino-3-phenylbutyric acid |
| CN103232356A (en) * | 2013-05-15 | 2013-08-07 | 天津聚德科技有限公司 | Technology for preparing 3-phenyl-4-aminobutyric acid hydrochloride |
-
2014
- 2014-11-03 CN CN201410612409.9A patent/CN104478745A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2166497C1 (en) * | 2000-02-25 | 2001-05-10 | Специальное конструкторско-технологическое бюро "Технолог" Санкт-Петербургского государственного технологического института (технического университета) | Method of preparing 3-phenyl-4-aminobutyric acid or 3-phenyl-4-aminobutyric acid chlorohydrate |
| CN101033195A (en) * | 2007-04-17 | 2007-09-12 | 安徽省郎溪县科联实业有限公司 | Method of preparing 4-amino-3-phenyl butyric hydrochloride |
| CN102115450A (en) * | 2009-12-30 | 2011-07-06 | 上海新浦化工厂有限公司 | Preparation method for 4-amino-3-phenylbutyric acid |
| CN103232356A (en) * | 2013-05-15 | 2013-08-07 | 天津聚德科技有限公司 | Technology for preparing 3-phenyl-4-aminobutyric acid hydrochloride |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107151234A (en) * | 2017-05-15 | 2017-09-12 | 重庆康刻尔制药有限公司 | A kind of preparation method of isradipine impurity I |
| CN107188808A (en) * | 2017-05-22 | 2017-09-22 | 江苏斯威森生物医药工程研究中心有限公司 | A kind of synthetic method of the phenylbutyric acid hydrochloride of 4 amino 3 |
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Application publication date: 20150401 |