CN113816849A

CN113816849A - Synthesis method of di (4-methyl-2-pentyl) phthalate or stable isotope label thereof

Info

Publication number: CN113816849A
Application number: CN202111182252.7A
Authority: CN
Inventors: 郭会; 胡旭平; 陈武炼
Original assignee: Shanghai Anpu Experimental Technology Co ltd
Current assignee: Shanghai Anpu Experimental Technology Co ltd
Priority date: 2021-10-11
Filing date: 2021-10-11
Publication date: 2021-12-21

Abstract

The invention discloses a method for synthesizing phthalic acid di (4-methyl-2-amyl) ester or a stable isotope label thereof. The synthesis method comprises the steps of firstly utilizing a Steglich esterification reaction, taking phthalic acid or phthalic acid marked by stable isotopes as raw materials, and respectively reacting the raw materials with 4-methyl-2-pentanol under the combined action of a catalyst and a coupling reagent to synthesize the phthalic acid di (4-methyl-2-pentyl) ester or the stable isotope markers thereof. The synthetic method disclosed by the invention is simple and convenient to operate, low in energy consumption, easy to separate and purify the product, high in yield, high in chemical purity and stable isotope abundance which reach more than 98.0%, can be used as an internal standard reagent for detecting phthalate plasticizers, and has good economical efficiency, and the stable isotope cannot be obviously diluted.

Description

Synthesis method of di (4-methyl-2-pentyl) phthalate or stable isotope label thereof

Technical Field

The invention belongs to the technical field of fine chemical synthesis, and particularly relates to a method for synthesizing di (4-methyl-2-pentyl) phthalate or a stable isotope label thereof.

Background

Phthalate is used as plasticizer, mainly for polyvinyl chloride material, which changes the hard plastic into elastic plastic. It is widely used in toys, food packaging materials, blood bags and hoses, vinyl floors and wallpaper, detergents, lubricating oils, personal care products such as nail polish, hair sprays, soaps and shampoos, to name a few hundred products. However, the research shows that the compound plays a role similar to estrogen in human bodies and animal bodies, can interfere endocrine systems and has serious harm to the health of human bodies.

The gas chromatography-mass spectrometry method for 16 phthalic acid esters is specified in the determination of phthalic acid esters in national food safety standards (GB5009.271-2016), and phthalic acid esters labeled with stable isotopes are introduced as internal standards for quantification. The di (4-methyl-2-pentyl) phthalate or the stable isotope label thereof is used as one of 16 phthalate plasticizers, and the synthesis method is not reported in documents, so that the development of the phthalate plasticizer detection industry is seriously restricted, and therefore, the development of the synthesis method of the di (4-methyl-2-pentyl) phthalate or the stable isotope label thereof has important value.

Disclosure of Invention

The invention aims to solve the technical problem of providing a method for synthesizing di (4-methyl-2-pentyl) phthalate or a stable isotope label thereof, which comprises the following specific scheme: by utilizing a Steglich esterification reaction, phthalic acid or stable isotope labeled phthalic acid is taken as a raw material and reacts with 4-methyl-2-pentanol respectively under the combined action of a catalyst and a coupling reagent to synthesize the phthalic acid di (4-methyl-2-pentyl) ester or the stable isotope label thereof.

Further, the stable isotope labeled phthalic acid is phthalic acid-benzene ring-D4 in which four hydrogens on the benzene ring are labeled with deuterium.

Further, the di (4-methyl-2-pentyl) phthalate has the structural formula:

the structural formula of the stable isotope label of the phthalic acid di (4-methyl-2-amyl) ester is as follows:

further, the Steglich esterification process is as follows: adding 4-methyl-2-pentanol, a catalyst, a coupling reagent and a solvent into a reaction device, then adding phthalic acid or phthalic acid-benzene ring-D4, stirring and reacting for 4-8 hours at the temperature of 20-30 ℃, adding acid and acidifying, extracting by using an extracting agent, and then carrying out column chromatography separation and purification to obtain the di (4-methyl-2-pentyl) phthalate or the stable isotope markers thereof.

Further, the molar ratio of the phthalic acid or phthalic acid-benzene ring-D4, the 4-methyl-2-pentanol, the catalyst and the coupling reagent is 1: (2-4): (0.5-1): (2-4).

Further, the catalyst is 4-dimethylaminopyridine or N-hydroxysuccinimide.

Further, the coupling reagent is any one of Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), and 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC).

Further, the solvent is dichloromethane or tetrahydrofuran.

Further, the acid used for acidification is 10-30 wt% of hydrochloric acid or sulfuric acid.

Further, the extraction agent is any one of dichloromethane, chloroform and ethyl acetate.

The invention has the following advantages:

(1) the synthesis method of the invention firstly utilizes the Steglich esterification reaction to synthesize the phthalic acid di (4-methyl-2-pentyl) ester or the stable isotope label thereof, the reaction can be carried out within the temperature range of 20-30 ℃, the heating is not needed, the energy consumption is low, the reaction operation is simple and convenient, the time consumption is short, and the cost is greatly reduced.

(2) The product of the invention is easy to separate and purify, has high yield, and the stable isotope can not be obviously diluted in the reaction and post-treatment processes, and the product marked by the stable isotope at a specific position can be obtained.

(3) The product of the invention has chemical purity and stable isotope abundance of more than 98.0 percent, can be used as an internal standard reagent for detecting phthalate plasticizer, and has high use value and good economic benefit.

Drawings

FIG. 1 shows the NMR spectrum of di (4-methyl-2-pentyl) phthalate obtained in example 1 of the present invention.

FIG. 2 shows the NMR spectrum of stable isotope-labeled di (4-methyl-2-pentyl) phthalate D4 obtained in example 2 of the present invention.

Detailed Description

The invention is further described in the following examples, which should not be construed as limiting the invention.

The method commonly used for synthesizing phthalic acid esters is Fischer esterification, namely an acid-catalyzed esterification method, but experiments show that when the acid-catalyzed esterification method is used for synthesizing the di (4-methyl-2-pentyl) phthalate, only a mono-esterified product can be obtained due to steric hindrance, and the di (4-methyl-2-pentyl) phthalate cannot be obtained. Because there are many phthalate diesters, some documents report that the phthalate diester structure can be synthesized by Fischer esterification without the influence of steric hindrance, but the applicant finds that the steric hindrance is caused and only the mono-esterified product can be obtained after synthesis experiments and actual operations. From the experimental results, it should be noted that when phthalic acid has two carboxyl groups, both of which are reactive sites, and 4-methyl-2-pentanol is reacted with one of the carboxyl sites, two esterified structures cannot be obtained because the steric structure of 4-methyl-2-pentanol occupies a large space and hinders the reaction at the other site. The Steglich esterification reaction, namely DCC/DMAP catalytic esterification reaction, has a very good effect on the esterification reaction with large steric hindrance, so that the invention utilizes the Steglich esterification reaction to synthesize the di (4-methyl-2-pentyl) phthalate or the stable isotope marker thereof.

Example 1

The synthesis of di (4-methyl-2-pentyl) phthalate is as follows:

4-methyl-2-pentanol (15mmol, 2mL), DMAP (4mmol, 489mg), DIC (13mmol, 1.64g) and 20mL of dichloromethane are sequentially added into a reaction device, phthalic acid (5.4mmol, 897mg) is added, stirring reaction is carried out for 4 hours at the temperature of 20-30 ℃, 10 wt% of hydrochloric acid is added for acidification, a product is extracted from water by dichloromethane, after the dichloromethane is removed by reduced pressure rotary evaporation, column chromatography separation and purification are carried out, the di (4-methyl-2-pentyl) phthalate is obtained with the yield of 89%, and the chemical purity of the obtained product can reach more than 98.0%.

The product obtained in the example is used in CDCl₃Dissolving, detecting by Bruke-400M nuclear magnetic resonance apparatus to obtain nuclear magnetic resonance hydrogen spectrum, and as shown in figure 1, indicating that the product structure is di (4-methyl-2-pentyl) phthalate.

Example 2

The synthesis of stable isotope deuterium-labeled di (4-methyl-2-pentyl) phthalate-D4 was as follows:

4-methyl-2-pentanol (20mmol, 2.5mL), DMAP (5mmol, 610mg), DCC (15mmol, 3.1g) and 30mL of dichloromethane are sequentially added into a reaction device, phthalic acid-benzene ring-D4 (5.4mmol, 918mg) is added, stirring reaction is carried out at 20-30 ℃ for 6 hours, 15 wt% of sulfuric acid is added for acidification, ethyl acetate is used for extracting a product from water, after ethyl acetate is removed by reduced pressure rotary evaporation, column chromatography separation and purification are carried out, the stable isotope labeled di (4-methyl-2-pentyl) phthalate-D4 is obtained with the yield of 85%, and the chemical purity and the stable isotope abundance of the obtained product both reach more than 98.0%.

The product obtained in the example is used in CDCl₃Dissolving, detecting by Bruke-400M nuclear magnetic resonance apparatus to obtain nuclear magnetic resonance hydrogen spectrum, and as shown in figure 2, indicating that the product structure is phthalic acid di (4-methyl-2-amyl) ester-D4.

Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. A method for synthesizing phthalic acid di (4-methyl-2-pentyl) ester or a stable isotope label thereof is characterized in that phthalic acid or the stable isotope labeled phthalic acid is used as a raw material to react with 4-methyl-2-pentanol respectively under the combined action of a catalyst and a coupling reagent by a Steglich esterification reaction to synthesize the phthalic acid di (4-methyl-2-pentyl) ester or the stable isotope label thereof.

2. The method of synthesis of claim 1, wherein the stable isotope labeled phthalic acid is phthalic acid-phenyl ring-D4 with four hydrogens on the phenyl ring labeled with deuterium.

3. The method of synthesis according to claim 1, wherein the bis (4-methyl-2-pentyl) phthalate has the formula:

4. the method of synthesis according to claim 1, characterized in that: the Steglich esterification procedure was as follows: adding 4-methyl-2-pentanol, a catalyst, a coupling reagent and a solvent into a reaction device, then adding phthalic acid or phthalic acid-benzene ring-D4, stirring and reacting for 4-8 hours at the temperature of 20-30 ℃, adding acid and acidifying, extracting by using an extracting agent, and then carrying out column chromatography separation and purification to obtain the di (4-methyl-2-pentyl) phthalate or the stable isotope markers thereof.

5. The synthesis method according to claim 4, characterized in that the molar ratio of phthalic acid or phthalic acid-phenyl ring-D4, 4-methyl-2-pentanol, catalyst, coupling reagent is 1: (2-4): (0.5-1): (2-4).

6. The synthesis method according to claim 4, wherein the catalyst is 4-dimethylaminopyridine or N-hydroxysuccinimide.

7. The synthetic method of claim 4, wherein the coupling reagent is any one of Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), and 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC).

8. The synthesis method according to claim 4, wherein the solvent is dichloromethane or tetrahydrofuran.

9. The synthesis method according to claim 4, wherein the acid used for acidification is 10-30 wt% hydrochloric acid or sulfuric acid.

10. The synthesis method according to claim 4, wherein the extraction agent is any one of dichloromethane, chloroform and ethyl acetate.