阅读说明：本技术 一种稳定同位素标记的3-氯-1，2-丙二醇脂肪酸二酯的合成方法 (Synthetic method of stable isotope labeled 3-chloro-1, 2-propanediol fatty acid diester ) 是由 郭会 陈武炼 于 2019-12-12 设计创作，主要内容包括：本发明公开了一种稳定同位素标记的3-氯-1,2-丙二醇脂肪酸二酯的合成方法。该合成方法包括以下步骤：S1：将稳定同位素标记的环氧氯丙烷水解,制得稳定同位素标记的3-氯-1,2-丙二醇；S2：将稳定同位素标记的3-氯-1,2-丙二醇和脂肪酸酰氯在固定化脂肪酶催化作用下反应,制得3-氯-1,2-丙二醇脂肪酸二酯。本发明的合成工艺条件温和,过程简单,工艺路线短,产品容易分离提纯,产率高,得到的产品化学纯度与稳定同位素丰度均达到99％以上,满足作为定量检测3-氯-1,2-丙二醇脂肪酸二酯的标准试剂的要求；使用价值高、具有良好的经济性。(The invention discloses a synthesis method of stable isotope labeled 3-chloro-1, 2-propylene glycol fatty acid diester. The synthesis method comprises the following steps: s1: hydrolyzing the epoxy chloropropane marked by the stable isotope to prepare 3-chloro-1, 2-propanediol marked by the stable isotope; s2: reacting 3-chloro-1, 2-propanediol marked by stable isotope with fatty acid chloride under the catalysis of immobilized lipase to prepare 3-chloro-1, 2-propanediol fatty acid diester. The synthesis process has mild conditions, simple process, short process route, easy separation and purification of the product and high yield, and the obtained product has chemical purity and stable isotope abundance which both reach more than 99 percent and meets the requirement of serving as a standard reagent for quantitatively detecting the 3-chloro-1, 2-propylene glycol fatty acid diester; high use value and good economical efficiency.)

1. A synthetic method of 3-chloro-1, 2-propanediol fatty acid diester labeled with stable isotope is characterized by comprising the following steps:

s1: hydrolyzing the epoxy chloropropane marked by the stable isotope to prepare 3-chloro-1, 2-propanediol marked by the stable isotope;

s2: reacting 3-chloro-1, 2-propanediol marked by stable isotope with fatty acid chloride under the catalysis of immobilized lipase to prepare 3-chloro-1, 2-propanediol fatty acid diester.

2. The method of synthesis according to claim 1, characterized in that: the procedure of step S1 is as follows: and (2) adding stable isotope labeled epichlorohydrin and water into a reaction container in sequence, reacting for 20-30 hours at the temperature of 90-110 ℃, and removing water by reduced pressure distillation to obtain the stable isotope labeled 3-chloro-1, 2-propanediol.

3. The method of synthesis according to claim 2, characterized in that: the mol ratio of the stable isotope labeled epichlorohydrin to water is 1: 2-1: 4.

4. the method of synthesis according to claim 1, characterized in that: the procedure of step S2 is as follows: adding 3-chloro-1, 2-propanediol labeled by stable isotope, fatty acid chloride and immobilized lipase into a reaction vessel in sequence, reacting for 2-10 hours at the temperature of 25-30 ℃, filtering to remove the immobilized lipase, and carrying out column chromatography to obtain the 3-chloro-1, 2-propanediol fatty acid diester labeled by the stable isotope.

5. The method of synthesis according to claim 4, characterized in that: the mol ratio of the stable isotope labeled 3-chlorine-1, 2-propanediol to the fatty acid chloride is 1: 2.0-1: 3.0; the mass ratio of the stable isotope labeled 3-chloro-1, 2-propanediol to the immobilized lipase is 1: 0.3-1: 0.4.

6. the method of synthesis according to claim 1, characterized in that: the stable isotope labeled epichlorohydrin is epichlorohydrin-D₅。

7. The method of synthesis according to claim 1, characterized in that: the fatty acid chloride is any one of palmitoyl chloride, stearoyl chloride, heptafluorobutyryl chloride and oleoyl chloride.

8. The method of synthesis according to claim 1, characterized in that: the immobilized lipase is one or a mixture of Novozym435, Lipozyme RM IM and Lipozyme TL IM.

9. A stable isotope labeled 3-chloro-1, 2-propanediol fatty acid diester, characterized in that: prepared by the synthesis method according to any one of claims 1 to 8.

Technical Field

The invention relates to a synthesis method of stable isotope labeled 3-chloro-1, 2-propylene glycol fatty acid diester, belonging to the technical field of fine chemical synthesis.

Background

The 3-chloro-1, 2-propanediol fatty acid diester is one of chloropropanol esters, which are a carcinogenic substance newly found in foods, especially refined vegetable oils. Chloropropanol ester releases free chloropropanol by the action of intestinal pancreatic lipase, which has reproductive toxicity and neurotoxicity and can cause renal tumors; therefore, the attention on chloropropanol ester is higher and higher at home and abroad, and the quantitative detection on trace chloropropanol ester in food is more and more important.

Stable isotope Dilution Mass spectrometry (idms) (isotope Dilution Mass spectrometry) is a newly developed baseline quantitative method for measuring trace and trace amounts of organic substances. When the method is used for the quantitative detection of chloropropanol ester, stable isotope internal standard is required, and because the price of stable isotope labeling raw materials is expensive, the cost is high, the production process is difficult to realize, and how to ensure that stable isotope atoms cannot fall off in the production process, the product purification is ensured to have great technical difficulty, and the synthetic method of the stable isotope labeled 3-chloro-1, 2-propylene glycol fatty acid diester is not reported in documents.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a synthesis method of 3-chloro-1, 2-propanediol fatty acid diester labeled by stable isotope, which can be used as a standard reagent for quantitatively detecting the 3-chloro-1, 2-propanediol fatty acid diester; and the preparation process is simple, the product is easy to separate and purify, and the obtained product has high chemical purity and isotopic abundance.

The technical scheme adopted by the invention for solving the technical problems is to provide a synthesis method of stable isotope labeled 3-chloro-1, 2-propanediol fatty acid diester, which comprises the following steps: s1: hydrolyzing the epoxy chloropropane marked by the stable isotope to prepare 3-chloro-1, 2-propanediol marked by the stable isotope; s2: reacting 3-chloro-1, 2-propanediol marked by stable isotope with fatty acid chloride under the catalysis of immobilized lipase to prepare 3-chloro-1, 2-propanediol fatty acid diester.

Further, the step S1 process is as follows: and (2) adding stable isotope labeled epichlorohydrin and water into a reaction container in sequence, reacting for 20-30 hours at the temperature of 90-110 ℃, and removing water by reduced pressure distillation to obtain the stable isotope labeled 3-chloro-1, 2-propanediol.

Further, the mol ratio of the stable isotope labeled epichlorohydrin to water is 1: 2-1: 4.

further, the step S2 process is as follows: adding 3-chloro-1, 2-propanediol labeled by stable isotope, fatty acid chloride and immobilized lipase into a reaction vessel in sequence, reacting for 2-10 hours at the temperature of 25-30 ℃, filtering to remove the immobilized lipase, and carrying out column chromatography to obtain the 3-chloro-1, 2-propanediol fatty acid diester labeled by the stable isotope.

Further, the molar ratio of the stable isotope labeled 3-chloro-1, 2-propanediol to the fatty acid chloride is 1: 2.0-1: 3.0; the mass ratio of the stable isotope labeled 3-chloro-1, 2-propanediol to the immobilized lipase is 1: 0.3-1: 0.4.

further, the stable isotope labeled epichlorohydrin is epichlorohydrin-D₅。

Further, the fatty acid chloride is any one of palmitoyl chloride, stearoyl chloride, heptafluorobutyryl chloride, and oleoyl chloride.

Further, the immobilized lipase is one of Novozym435, Lipozyme RM IM and Lipozyme TL IM or a mixture thereof.

The invention also provides a stable isotope labeled 3-chloro-1, 2-propylene glycol fatty acid diester for solving the technical problems, which is prepared by the synthesis method.

The invention has the following advantages:

(1) the invention has the advantages of mild synthesis process conditions, simple process, short process route and high yield.

(2) The product of the invention is easy to separate and purify, the chemical purity and the stable isotope abundance of the product both reach more than 99 percent, and the requirement of a standard reagent for quantitatively detecting the 3-chloro-1, 2-propylene glycol fatty acid diester can be fully met.

(3) The invention has high use value and good economical efficiency.

Detailed Description

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

The invention provides a synthesis method of stable isotope labeled 3-chloro-1, 2-propylene glycol fatty acid diester, which comprises the following steps:

s1: sequentially adding stable isotope labeled epichlorohydrin and water into a reaction container, reacting for 20-30 hours at the temperature of 90-110 ℃, and removing water by reduced pressure distillation to obtain stable isotope labeled 3-chloro-1, 2-propanediol; the mol ratio of the stable isotope labeled epichlorohydrin to water is 1: 2-1: 4, saving the water consumption under the condition of ensuring the complete hydrolysis reaction, and simultaneously reducing the treatment time after the reaction;

s2: reacting 3-chloro-1, 2-propanediol marked by stable isotope and fatty acid chloride under the catalytic action of immobilized lipase to prepare 3-chloro-1, 2-propanediol fatty acid diester; the mol ratio of the stable isotope labeled 3-chlorine-1, 2-propanediol to the fatty acid chloride is 1: 2.0-1: 3.0, the proportion range can ensure that the 3-chlorine-1, 2-propylene glycol marked by the stable isotope completely reacts, fully obtain the 3-chlorine-1, 2-propylene glycol fatty acid diester marked by the stable isotope, and simultaneously save the dosage of fatty acid chloride; the mass ratio of the stable isotope labeled 3-chloro-1, 2-propanediol to the immobilized lipase is 1: 0.3-1: 0.4, the using amount of the catalyst is saved under the condition of ensuring the catalytic effect.

Example 1

Adding epoxy chloropropane-D into a reaction container₅(10mmol, 975mg) and water (30mmol, 6mL) at 100 deg.C for 24 hours, and removing water by reduced pressure distillation to give 3-chloro-1, 2-propanediol-D₅。

Example 2

Adding 3-chloro-1, 2-propanediol-D into a reaction vessel₅(9.0mmol, 1.0g), palmitoyl chloride (25 mmol)6.9g), Novozym435 immobilized lipase (300mg), reacting at 25-30 ℃ for 2.5 hours, filtering to remove the immobilized lipase, washing a filter cake with n-hexane, concentrating the filtrate, and performing column chromatography to obtain 3-chloro-1, 2-propanediol palmitate diester-D₅The yield was 60%.

Example 3

Adding 3-chloro-1, 2-propanediol-D into a reaction vessel₅(9.0mmol, 1.0g), palmitoyl chloride (25mmol, 6.9g), Lipozyme RM IM immobilized lipase (300mg), reacting at 25-30 ℃ for 4 hours, filtering to remove the immobilized lipase, washing a filter cake with n-hexane, concentrating the filtrate, and performing column chromatography to obtain 3-chloro-1, 2-propanediol palmitate diester-D₅The yield was 65%.

Example 4

Adding 3-chloro-1, 2-propanediol-D into a reaction vessel₅(9.0mmol, 1.0g), palmitoyl chloride (25mmol, 6.9g), Lipozyme TL IM immobilized lipase (300mg), reacting at the temperature of 25-30 ℃ for 3 hours, filtering to remove the immobilized lipase, washing a filter cake with n-hexane, concentrating the filtrate, and performing column chromatography to obtain 3-chloro-1, 2-propanediol palmitate diester-D₅The yield was 62%.

Example 5

Adding 3-chloro-1, 2-propanediol-D into a reaction vessel₅(9.0mmol, 1.0g), palmitoyl chloride (25mmol, 6.9g), immobilized lipase (300 mg: 100mg Novozym435, 100mg lipozyme RM IM, 100mg lipozyme TL IM), reacting at 25-30 ℃ for 2 hours, filtering to remove the immobilized lipase, washing filter cake with n-hexane, concentrating the filtrate, and performing column chromatography to obtain 3-chloro-1, 2-propanediol palmitate diester-D₅The yield was 65%.

Example 6

A process for producing 3-chloro-1, 2-propanediol fatty acid diester-D of example₅The specific production steps of the synthesis method of (3) are the same as those in any one of examples 2 to 5, except that the fatty acid chloride is stearoyl chloride.

Example 7

A process for producing 3-chloro-1, 2-propanediol fatty acid diester-D of example₅The specific preparation steps of the synthetic method of (1) and examples 2 to 5Any of (a) and (b) are the same except that the fatty acid chloride is heptafluorobutyryl chloride.

Example 8

This example, a method for producing a 3-chloro-1, 2-propanediol fatty acid diester, D₅The specific production steps of the synthesis method of (3) are the same as those in any one of examples 2 to 5, except that the fatty acid chloride is oleoyl chloride.

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.