阅读说明：本技术 多位取代的二甲氨基苯基乙酸类化合物的合成方法 (Synthesis method of multi-substituted dimethylamino phenyl acetic acid compound ) 是由 汪明中 朱明新 苏道 李金金 于 2020-07-22 设计创作，主要内容包括：本发明涉及一种多位取代的二甲氨基苯基乙酸类化合物的合成方法,包括使式I所示化合物进行甲酯化反应,得式II所示化合物；使式II所示化合物在相转移催化剂和碱性条件下,与N-甲基化试剂进行反应,得式III所示化合物,其中,式I所示化合物的结构式：<Image he="174" wi="423" file="DDA0002595453290000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式II所示化合物的结构式：<Image he="161" wi="448" file="DDA0002595453290000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式III所示化合物的结构式：<Image he="167" wi="414" file="DDA0002595453290000013.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式I、式II中,R<Sub>1</Sub>′为NH<Sub>2</Sub>,R<Sub>2</Sub>为烷基、H中的一种,R<Sub>1</Sub>′、R<Sub>2</Sub>分别为苯环上的对位、邻位、间位取代,且R<Sub>1</Sub>′、R<Sub>2</Sub>不同时在一个位置取代；式III中,R<Sub>1</Sub>为N(CH<Sub>3</Sub>)<Sub>2</Sub>,R<Sub>2</Sub>为烷基、H中的一种,R<Sub>1</Sub>、R<Sub>2</Sub>分别为苯环上的对位、邻位、间位取代,且R<Sub>1</Sub>、R<Sub>2</Sub>不同时在一个位置取代。合成过程中避免使用高度易燃性物质氰基硼氢化钠,安全性好,且反应温和,产物收率高达80％以上。(The invention relates to a synthesis method of a multi-position substituted dimethylamino phenyl acetic acid compound, which comprises the steps of carrying out methyl esterification reaction on a compound shown as a formula I to obtain a compound shown as a formula II; reacting a compound shown in a formula II with an N-methylating agent under the conditions of a phase transfer catalyst and alkali to obtain a compound shown in a formula III, wherein the structural formula of the compound shown in the formula I is as follows: the structural formula of the compound shown in formula II: the structural formula of the compound shown in the formula III: in the formula I and the formula II, R 1 Is' NH 2 ，R 2 Is one of alkyl and H, R 1 ′、R 2 Respectively para, ortho and meta substitution on the benzene ring, and R 1 ′、R 2 Not simultaneously at one position; in the formula III, R 1 Is N (CH) 3 ) 2 ，R 2 Is one of alkyl and H, R 1 、R 2 Respectively para, ortho and meta substitution on the benzene ring, and R 1 、R 2 Not at one position at the same time. In the synthesis process, highly flammable substance sodium cyanoborohydride is avoided, the safety is good, the reaction is mild, and the product yield is up to more than 80%.)

1. A synthetic method of a dimethylamino phenyl acetic acid compound is characterized by comprising the following steps:

(1) carrying out methyl esterification reaction on the compound shown in the formula I to obtain a compound shown in a formula II;

(2) under the protection of inert gas, reacting the compound shown in the formula II with an N-methylating agent under the conditions of a phase transfer catalyst and alkali to obtain the compound shown in the formula III,

the structural formula of the compound shown in the formula I is as follows:

the structural formula of the compound shown in the formula II is as follows:

the formula IIIThe structural formula of the compound is as follows:

in the formula I and the formula II, R is₁Is' NH₂Said R is₂Is one of alkyl with 1-4 carbon atoms and H, R₁′、R₂Are each-CH on a benzene ring₂COOH or-CH₂Para, ortho, meta substitution of the COOMe group, and R₁′、R₂Not simultaneously at one position;

in the formula III, R is₁Is N (CH)₃)₂Said R is₂Is one of alkyl with 1-4 carbon atoms and H, R₁、R₂Are each-CH on a benzene ring₂Para, ortho, meta substitution of the COOH group, and R₁、R₂Not at one position at the same time.

2. The method for synthesizing dimethylaminophenylacetic acid compounds according to claim 1, wherein: in the step (2), the phase transfer catalyst is one or a combination of more of tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride and tetrabutylammonium bisulfate.

3. The method for synthesizing dimethylaminophenylacetic acid compounds according to claim 1, wherein: in the step (2), the N-methylating agent is one or a combination of methyl p-toluenesulfonate, trimethyl phosphate, methyl iodide and formaldehyde.

4. The method for synthesizing dimethylaminophenylacetic acid compounds according to claim 1, wherein: in the step (2), the phase transfer catalyst is tetrabutylammonium bromide, and the N-methylating agent is methyl p-toluenesulfonate.

5. The method for synthesizing dimethylaminophenylacetic acid compounds according to claim 1, wherein: in the step (2), the alkali adopted in the alkaline condition is one or more of potassium hydroxide and sodium hydroxide, and the used solvent is water.

6. The method for synthesizing dimethylaminophenylacetic acid compounds according to claim 1, wherein: in the step (2), the reaction is carried out at 70-90 ℃ for 4-8 h.

7. The method for synthesizing dimethylaminophenylacetic acid compounds according to claim 1, wherein: in the step (2), the feeding molar ratio of the compound shown in the formula II to the N-methylating agent is 1: 3-5, and the feeding molar ratio of the compound shown in the formula II to the phase transfer catalyst is 1: 0.03-0.05.

8. The method for synthesizing dimethylaminophenylacetic acid compounds according to claim 1, wherein: in the step (2), after the reaction is finished, cooling to 15-35 ℃, extracting with diethyl ether, combining organic phases, drying with anhydrous magnesium sulfate, removing the solvent by rotation, carrying out chromatography purification, and eluting to obtain the compound shown in the formula III.

9. The method for synthesizing dimethylaminophenylacetic acid compounds according to any one of claims 1 to 8, wherein: the methyl esterification reaction is carried out in SOCl₂And methanol.

10. The method for synthesizing dimethylaminophenylacetic acid compounds according to any one of claims 1 to 8, wherein: the methyl esterification is carried out for 10-14 h at 50-70 ℃.

Technical Field

The invention belongs to the technical field of organic compound synthesis, and particularly relates to a synthesis method of a multi-substituted dimethylamino phenyl acetic acid compound.

Background

The multi-position substituted dimethylamino phenyl acetic acid compounds are amino acids of important medical intermediates and are widely applied in the field of medical chemistry. Such as intermediates for compounds such as isotopically derivatized reagents for labeling a range of compounds bearing amino groups or bearing phenolic hydroxyl groups.

The synthesis method of the compound is relatively lacking, and the currently published synthesis method of the amino acid compound is obtained by reacting formaldehyde and phenyl primary amine carboxylic acid under the condition of sodium cyanoborohydride, for example, the synthesis method published in Chinese patent CN109111389 has the following route:

the synthesis steps are as follows: using p-aminophenylacetic acid and NaBH₃CN and CH₂Dissolving p-aminophenylacetic acid in ultrapure water, dissolving with vibration or ultrasonic wave, and adding CH₂O shaking and mixing fully, adding NaBH₃CN, shaking and mixing, controlling the pH value of the solution to be 5 by using formic acid, fixing the volume by using ultrapure water, and reacting for 1h at room temperature to prepare the p-dimethylamino phenylacetic acid.

In the synthesis method, the raw material adopts toxic substance formaldehyde which is irritant and harmful to skin mucosa and is easy to cause cancer. And the high-flammability substance sodium cyanoborohydride is adopted, so the safety is poor, the mixing needs to be assisted by shaking or ultrasonic wave to dissolve, and the operation is complex.

Disclosure of Invention

The invention aims to provide a safe and easy-to-operate synthetic method of dimethylamino phenyl acetic acid compounds with high yield.

In order to achieve the purpose, the invention adopts the technical scheme that:

a synthetic method of dimethylamino phenyl acetic acid compounds comprises the following steps:

(1) carrying out methyl esterification reaction on the compound shown in the formula I to obtain a compound shown in a formula II;

(2) under the protection of inert gas, reacting the compound shown in the formula II with an N-methylating agent under the conditions of a phase transfer catalyst and alkali to obtain the compound shown in the formula III,

the structural formula of the compound shown in the formula I is as follows:

the structural formula of the compound shown in the formula II is as follows:

the structural formula of the compound shown in the formula III is as follows:

in the formula I and the formula II, R is₁Is' NH₂Said R is₂Is one of alkyl with 1-4 carbon atoms and H, R₁′、R₂Are each-CH on a benzene ring₂COOH or-CH₂Para, ortho, meta substitution of the COOMe group, and R₁′、R₂Not simultaneously at one position;

in the formula III, R is₁Is N (CH)₃)₂Said R is₂Is one of alkyl with 1-4 carbon atoms and H, R₁、R₂Are each-CH on a benzene ring₂COPara, ortho, meta substitution of the OH group, and R₁、R₂Not at one position at the same time.

Preferably, the compound of formula III is:

2- (4- (dimethylamino) phenyl) acetic acid having the formula:

2- (4- (dimethylamino) -3-methylphenyl) acetic acid having the formula:

2- (4- (dimethylamino) -2-methylphenyl) acetic acid having the formula:

2- (3- (dimethylamino) phenyl) acetic acid having the formula:

2- (3- (dimethylamino) -2-methylphenyl) acetic acid having the formula:

2- (3- (dimethylamino) -4-methylphenyl) acetic acid having the formula:

2- (2- (dimethylamino) phenyl) acetic acid having the formula:

2- (2- (dimethylamino) -5-methylphenyl) acetic acid having the formula:

2- (2- (di)Methylamino) -3-methylphenyl) acetic acid having the formula:

2- (2- (dimethylamino) -6-methylphenyl) acetic acid having the formula:or

2- (2- (dimethylamino) -4-methylphenyl) acetic acid having the formula:

according to some embodiments of the invention, in step (1), the methyl esterification reaction is performed in SOCl₂And methanol.

According to some embodiments of the invention, in the step (1), the methyl esterification is carried out at 50-70 ℃ for 10-14 h.

According to some embodiments of the invention, in the step (2), the phase transfer catalyst is one or a combination of tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride and tetrabutylammonium bisulfate. Preferably, the phase transfer catalyst is tetrabutylammonium bromide.

According to some embodiments of the invention, in the step (2), the N-methylating agent is one or more of methyl p-toluenesulfonate, trimethyl phosphate, methyl iodide and formaldehyde. Preferably, the N-methylating agent is methyl p-toluenesulfonate.

According to some preferred embodiment aspects of the invention, in step (2), the phase transfer catalyst is tetrabutylammonium bromide and the N-methylating agent is methyl p-toluenesulfonate. The method adopts tetrabutylammonium bromide as a phase transfer catalyst and methyl p-toluenesulfonate as an N-methylation reagent, and has the advantages of safe and efficient reaction, easy operation, mild reaction conditions, convenient operation, low synthesis cost and the like.

According to some embodiments of the present invention, in step (2), the alkali used in the alkaline condition is one or more of potassium hydroxide and sodium hydroxide, and the solvent used is water.

According to some embodiments of the invention, in the step (2), the reaction is carried out at 70-90 ℃ for 4-8 h.

According to some embodiments of the invention, in the step (2), the feeding molar ratio of the compound represented by the formula II to the N-methylating agent is 1: 3-5, and the feeding molar ratio of the compound represented by the formula II to the phase transfer catalyst is 1: 0.03-0.05.

According to some implementation aspects of the invention, in the step (2), after the reaction is finished, the reaction product is cooled to 15 to 35 ℃, ether is extracted, organic phases are combined, dried by anhydrous magnesium sulfate, solvent is removed by spinning, and the compound shown in the formula III is prepared by chromatography purification and elution.

In the invention, the synthesis method has the following synthesis route:

the synthesis method of the multi-position substituted xylyl acetic acid compound is applied to the fields of synthesis and medicinal chemistry.

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

the synthesis method takes multi-position substituted aminophenylacetic acid as a starting material, firstly carries out methyl esterification on the starting material, and then reacts with an N-methylating reagent under the conditions of a phase transfer catalyst and alkalinity to prepare the multi-position substituted dimethylamino phenylacetic acid compound, avoids using highly flammable substance sodium cyanoborohydride in the synthesis process, has good safety and mild reaction, and has the product yield of more than 80 percent.

Detailed Description

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following examples are provided only to further illustrate the present invention and are not meant to limit the scope of the present invention in any way.

The starting materials may be obtained from commercial sources or prepared by methods known in the art or according to the methods described herein.

The structure of the compound is determined by nuclear magnetic resonance¹H-NMR)、(¹³C-NMR and/or Mass Spectrometry (MS). NMR was measured using a Bruker ACF-400(400MHz) nuclear magnetic resonance apparatus using heavy water as a solvent (D)₂O) or deuterated dimethyl sulfoxide (DMSO-D)₆) And TMS is an internal standard. The column chromatography adopts 200-mesh silica gel (produced by Qingdao ocean chemical plant) of 300 meshes.