CN101445467B - Chemical synthesis method of N-(4-chlorobenzoyl)-tyramine - Google Patents

Chemical synthesis method of N-(4-chlorobenzoyl)-tyramine Download PDF

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CN101445467B
CN101445467B CN 200810163746 CN200810163746A CN101445467B CN 101445467 B CN101445467 B CN 101445467B CN 200810163746 CN200810163746 CN 200810163746 CN 200810163746 A CN200810163746 A CN 200810163746A CN 101445467 B CN101445467 B CN 101445467B
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tyrasamine
chlorobenzene formacyl
chemical synthesis
synthesis process
chlorobenzene
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CN101445467A (en
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邬卫国
张美君
陈晓艳
周志敏
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Abstract

The invention discloses a chemical synthesis method of N-(4-chlorobenzoyl)-tyramine with a structure as shown in formula (I), and the method takes tyramine with a structure as shown in formula (II) and p-chlorobenzoic acid with a structure as shown in formula (II) as raw materials for full reaction to obtain the N-(4-chlorobenzoyl)-tyramine. Compared with the prior art, the raw materials used by the invention are cheap and easy to obtain (eliminating the use of the raw materials prepared by thionyl chloride), the invention basically eliminates the problems of great safety hidden troubles, serious pollution caused by three wastes, and the like of the traditional process and reduces the production cost; meanwhile, the invention has simple and safe operation, reasonable process conditions and high reaction yield, thereby having great implementing value and social and economic benefits.

Description

The chemical synthesis process of N-(4-chlorobenzene formacyl)-tyrasamine
Technical field
The present invention relates to the chemical synthesis process of a kind of N-(4-chlorobenzene formacyl)-tyrasamine.
Background technology
N-(4-chlorobenzene formacyl)-tyrasamine, molecular formula: C 15H 14ClNO 2, molecular weight: 275.7, cas number: 41859-57-8, English name: N-(4-Chlorobenzoyl)-tyramine, its structure is suc as formula shown in (I):
It is a kind of important chemical intermediate, has very widely purposes at medicine and the field of chemical synthesis.
The method of prior art one-step synthesis N-(4-chlorobenzene formacyl)-tyrasamine, generally adopting tyrasamine (4-hydroxyphenethylamine) is starting raw material, reacts with the 4-chloro-benzoyl chloride, reaction equation is as follows:
Figure G2008101637469D00012
About this route, the document of having announced at present is as follows:
1. English Patent GB 2; 021; 575; date of publication: on December 5th, 1979; title: α-[4-(4-chlorobenzene formacyl) amino-ethyl phenoxy group]-isobutyric preparation process (Processfor the preparation of α-[4-(4-chlorobenzoyl) aminoethylphenoxy]-isobutyric acid); the reaction process of announcing is as follows: take tyrasamine (4-hydroxyphenethylamine) as starting raw material; at water; alkali (NaOH); methyl alcohol and gac exist lower and 4-chloro-benzoyl chloride generation acylation reaction, get N-(4-chlorobenzoyl) tyrasamine.The problem that this route exists is: complex operation, the complex process (adding first NaOH and gac, rear adding methyl alcohol) of preparation N-(4-chlorobenzoyl) tyrasamine, and productive rate lower (only having 5.6%).
2. European patent EP 582; 441; date of publication: on February 9th, 1994; title: the preparation process of tyrasamine derivative (Process for the preparation of tyraminederivatives); reaction process is as follows: take tyrasamine (4-hydroxyphenethylamine) as starting raw material; at water, with 4-chloro-benzoyl chloride generation acylation reaction, get N-(4-chlorobenzoyl) tyrasamine under the existence of alkali (saleratus) and organic solvent (such as ethyl acetate).
3. document: the synthesising process research of N-para hydroxybenzene ethyl-4-chlorobenzamide (chemistry world, Wu Jie, Ni Peizhou, 42 (5), 276; 2001) route of route described in and patent GB 2,021,575 is consistent, and the difference place is to have replaced methyl alcohol with 95% ethanol.
4. document: single stage method is synthesized N-para hydroxybenzene ethyl-4-chlorobenzamide (fine-chemical intermediate, Wu Jie, 33 (6), 38-39; 2003), in reaction process, use sodium bicarbonate and acetone.
The shortcoming that above route and reaction exist is: for the synthesis of the material 4-chloro-benzoyl chloride of target product difficult the acquisition: 4-chloro-benzoyl chloride cost is higher, if use the ordinary method preparation, must use sulfur oxychloride in reaction process, but sulfur oxychloride (SOCl 2) be chloride reagent, seriously corroded, big for environment pollution, high to equipment requirements; And sulfur oxychloride is the chemical weapons of the strict control of United Nations regulation, thereby, transportation and use must strict control, the conversion unit sealing requirements is high, invests also larger.
Summary of the invention
The object of the invention is to overcome the shortcoming of prior art; a kind of N-chemical synthesis process that (4-chlorobenzene formacyl)-tyrasamine is brand-new is provided, its technique is reasonable, easy and simple to handle, production safety is reliable, raw materials for production be simple and easy to, reaction yield is high, production cost is low.
To achieve these goals, the technical solution used in the present invention is as follows:
A kind of structure is suc as formula the chemical synthesis process of the N-shown in (I) (4-chlorobenzene formacyl)-tyrasamine; be to obtain described N-(4-chlorobenzene formacyl)-tyrasamine suc as formula the Chlorodracylic acid shown in (III) as raw material reacts suc as formula the tyrasamine shown in (II) and structure take structure, its reaction equation can be expressed as:
Figure G2008101637469D00031
Preferred scheme is: take described tyrasamine and described Chlorodracylic acid as raw material, under the effect of catalyzer, fully reaction makes described N-(4-chlorobenzene formacyl)-tyrasamine in organic solvent.
The below is described further technique scheme.
Organic solvent of the present invention is preferably from one of following: dimethylbenzene, toluene, and most preferably dimethylbenzene adds dimethylbenzene, so that the reaction elevation of boiling point, temperature raises, reaction is easily carried out.
The present invention adds catalyzer in reaction system, so that speed of reaction raises, reaction times shortens, and it is one of following that described catalyzer is recommended to be selected from: boric acid, metaboric acid, 4-chlorobenzene boric acid, (2-acetylamino phenyl) boric acid are preferably boric acid or metaboric acid.
Further, described reaction is recommended under the reflux temperature and carries out.
The described reaction times is recommended as 8~12 hours, more preferably 9~10 hours.
Further again, it is 1: 1~1.3 that the present invention recommends the molar ratio of described tyrasamine and described Chlorodracylic acid.
The quality consumption of described organic solvent is generally 8~12 times of described tyrasamine quality.
The quality consumption of described catalyzer is recommended as 9%~12% of described tyrasamine quality.
Further, the present invention is fully obtaining reaction mixture after the reaction, obtains product behind the recovery solvent, preferably adds alcohol and carries out purification process to obtain the higher N-of purity (4-chlorobenzene formacyl)-tyrasamine product in products therefrom.
The alcohol that above-mentioned purification process is used can be selected from the combination of following one or more arbitrary proportions: ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol; Recommendation ethanol.
Described purification process specifically can adopt following method: add alcohol in the product that obtains behind the solvent toward reclaiming, and reflux making beating 1~2 hour, the cooling suction filtration, drying obtains N-(4-chlorobenzene formacyl)-tyrasamine product.
The present invention compared with prior art, its used raw material (having got rid of the raw material that uses sulfur oxychloride to make) cheap and easy to get has fundamentally been eliminated the problems such as the traditional technology potential safety hazard is large, three-waste pollution is serious, and so that production cost reduce; Simultaneously the present invention safety simple to operate, processing condition are reasonable, and reaction yield is high, has larger implementary value and economic results in society.
Embodiment
The below is described further technical scheme of the present invention with specific embodiment, but protection scope of the present invention is not limited to this:
Embodiment 1
Be equipped with in the clean ware mouth flask of water trap at 1000ml, add the 50g tyrasamine, 5g boric acid, the 58g Chlorodracylic acid, dimethylbenzene 460ml, stirring heating refluxes and was with water 9.5 hours; Underpressure distillation dimethylbenzene; Add ethanol 75ml, reflux making beating 1 hour; The cooling suction filtration; Drying obtains target product 95.3g, yield 95.1%.
Embodiment 2
Be equipped with in the clean ware mouth flask of water trap at 1000ml, add the 40g tyrasamine, the 4g metaboric acid, the 50g Chlorodracylic acid, dimethylbenzene 460ml, stirring heating refluxes and was with water 8 hours; Underpressure distillation dimethylbenzene; Add ethanol 75ml, reflux making beating 1 hour; The cooling suction filtration; Drying obtains target product 74.9g, yield 93.4%.
Embodiment 3
Be equipped with in the clean ware mouth flask of water trap at 1000ml, add the 30g tyrasamine, 3g boric acid, the 41g Chlorodracylic acid, dimethylbenzene 420ml, stirring heating refluxes and was with water 12 hours; Underpressure distillation dimethylbenzene; Add ethanol 75ml, reflux making beating 1 hour; The cooling suction filtration; Drying obtains target product 56.9g, yield 94.7%.
Embodiment 4
Be equipped with in the clean ware mouth flask of water trap at 1000ml, add the 50g tyrasamine, 4.5g boric acid, the 58g Chlorodracylic acid, toluene 500ml, stirring heating refluxes and was with water 10 hours; Underpressure distillation dimethylbenzene; Add n-propyl alcohol 100ml, reflux making beating 1 hour; The cooling suction filtration; Drying obtains target product 90.5g, yield 90.8%.
Embodiment 5
Be equipped with in the clean ware mouth flask of water trap at 1000ml, add the 40g tyrasamine, 4g 4-chlorobenzene boric acid, the 50g Chlorodracylic acid, dimethylbenzene 460ml, stirring heating refluxes and was with water 8 hours; Underpressure distillation dimethylbenzene; Add isopropylcarbinol 100ml, reflux making beating 1.5 hours; The cooling suction filtration; Drying obtains target product 71.1g, yield 89.7%.
Embodiment 6
Be equipped with in the clean ware mouth flask of water trap at 1000ml, add the 30g tyrasamine, 3.5g (2-acetylamino phenyl) boric acid, the 41g Chlorodracylic acid, dimethylbenzene 450ml, stirring heating refluxes and was with water 12 hours; Underpressure distillation dimethylbenzene; Add Virahol 100ml, reflux making beating 2 hours; The cooling suction filtration; Drying obtains target product 50.7g, yield 88.3%.
In sum; the chemical synthesis process of N-of the present invention (4-chlorobenzene formacyl)-tyrasamine is reasonable, easy and simple to handle, production safety is reliable, raw materials for production be simple and easy to, reaction yield is high, production cost is low, has larger implementary value and economic results in society.
Need to prove, all documents of mentioning are in the present invention quoted as a reference in this application, just as each piece document is quoted separately as a reference.Should understand in addition, above-described is specific embodiments of the invention and the know-why used, after having read foregoing of the present invention, those skilled in the art can make various changes or modifications and not deviate from spirit of the present invention and scope the present invention, and these equivalent form of values fall within the scope of the invention equally.

Claims (9)

1. a structure is suc as formula the chemical synthesis process of the N-shown in (I) (4-chlorobenzene formacyl)-tyrasamine, it is characterized in that described synthetic method is under the effect of catalyzer, obtain described N-(4-chlorobenzene formacyl)-tyrasamine suc as formula the Chlorodracylic acid shown in (III) as raw material reacts suc as formula the tyrasamine shown in (II) and structure take structure;
Figure FSB00000863063900011
Described catalyzer is selected from: boric acid, metaboric acid, 4-chlorobenzene boric acid, (2-acetylamino phenyl) boric acid.
2. the chemical synthesis process of N-as claimed in claim 1 (4-chlorobenzene formacyl)-tyrasamine; it is characterized in that described synthetic method is as raw material take described tyrasamine and described Chlorodracylic acid; under the effect of catalyzer; fully reaction in organic solvent; make described N-(4-chlorobenzene formacyl)-tyrasamine
It is one of following that wherein said catalyzer is selected from: boric acid, metaboric acid, 4-chlorobenzene boric acid, (2-acetylamino phenyl) boric acid.
3. the chemical synthesis process of N-as claimed in claim 2 (4-chlorobenzene formacyl)-tyrasamine is characterized in that described organic solvent is dimethylbenzene or toluene.
4. the chemical synthesis process of N-as claimed in claim 2 (4-chlorobenzene formacyl)-tyrasamine is characterized in that described reaction carried out 8~12 hours under reflux temperature.
5. such as the chemical synthesis process of the described N-of one of claim 1~4 (4-chlorobenzene formacyl)-tyrasamine, the molar ratio that it is characterized in that described tyrasamine and described Chlorodracylic acid is 1: 1~1.3.
6. such as the chemical synthesis process of the described N-of one of claim 2~4 (4-chlorobenzene formacyl)-tyrasamine, the quality consumption that it is characterized in that described catalyzer is 9%~12% of described tyrasamine quality.
7. such as the chemical synthesis process of the described N-of one of claim 2~4 (4-chlorobenzene formacyl)-tyrasamine, the quality consumption that it is characterized in that described organic solvent is 8~12 times of described tyrasamine quality.
8. such as the chemical synthesis process of the described N-of one of claim 2~4 (4-chlorobenzene formacyl)-tyrasamine; it is characterized in that fully obtaining reaction mixture after the reaction; add alcohol in the product that obtains behind the reaction mixture recovery solvent and carry out purification process to obtain the higher N-of purity (4-chlorobenzene formacyl)-tyrasamine product, described alcohol is selected from the combination of following one or more arbitrary proportions: ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol.
9. the chemical synthesis process of N-as claimed in claim 8 (4-chlorobenzene formacyl)-tyrasamine; it is characterized in that the following method of the concrete employing of described purification process: add alcohol in the product that obtains behind the solvent toward reclaiming; reflux making beating 1~2 hour; the cooling suction filtration; drying obtains N-(4-chlorobenzene formacyl)-tyrasamine product.
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CN108849863A (en) * 2018-06-22 2018-11-23 河北联兴佳垚农业科技有限公司 Degerming medical fluid for gemmule yulan root
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EP0582441A1 (en) * 1992-08-02 1994-02-09 Chemagis Ltd. Processes for the preparation of tyramine derivatives
CN1935779A (en) * 2006-10-20 2007-03-28 贵州省中国科学院天然产物化学重点实验室 N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative, and its preparing method and use

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US4370495A (en) * 1978-05-12 1983-01-25 Boehringer Mannheim Gmbh Process for the preparation of α-[4-(4-chlorobenzoylaminoethyl)-phenoxy]-isobutyric acid
EP0582441A1 (en) * 1992-08-02 1994-02-09 Chemagis Ltd. Processes for the preparation of tyramine derivatives
CN1935779A (en) * 2006-10-20 2007-03-28 贵州省中国科学院天然产物化学重点实验室 N-(N-benzoyl-phenylalanyl)-phenylalanine dipeptide derivative, and its preparing method and use

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