CN109400470B - Synthesis method of stable isotope labeled diphenyl phthalate - Google Patents
Synthesis method of stable isotope labeled diphenyl phthalate Download PDFInfo
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- CN109400470B CN109400470B CN201811277769.2A CN201811277769A CN109400470B CN 109400470 B CN109400470 B CN 109400470B CN 201811277769 A CN201811277769 A CN 201811277769A CN 109400470 B CN109400470 B CN 109400470B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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Abstract
The invention relates to a synthesis method of stable isotope labeled diphenyl phthalate, which utilizes an organic synthesis method to react stable isotope labeled phthaloyl chloride serving as a raw material with stable isotope labeled sodium phenolate to obtain the stable isotope labeled diphenyl phthalate. After simple separation and purification, the stable isotope labeled diphenyl phthalate prepared by the invention has the chemical purity of more than 99 percent and the isotope abundance of more than 99 percent, can be applied to the fields of biological metabolism and food safety, and has the advantages of good quality and low cost.
Description
Technical Field
The invention relates to the field of stable isotope labeled compounds, in particular to a synthesis method of stable isotope labeled diphenyl phthalate.
Background
Diphenyl phthalate, known by the english name Diphenyl phthalate (DPHP), is a phthalate plasticizer, has good intersolubility with resins, and is widely used in hundreds of products such as toys, food packaging materials, medical blood bags and hoses, vinyl floors and wallpaper, detergents, lubricating oils, personal care products (such as nail polish, hair sprays, soaps, and shampoos).
However, a large number of experiments prove that DPHP has a strong toxic action on reproductive development, generates environmental hormone toxicity on human or animals, is easy to accumulate continuously through a food chain, has adverse effects on a human reproductive system and a genetic system, blocks energy metabolism, causes germ cell damage and generates reproductive genetic toxicity, mainly shows mutagenic, teratogenic and environmental estrogen effects on animals, and can generate anaphylaxis or respiratory diseases on serious human beings to influence the functions of a nervous system. The national ministry of health lists phthalates as non-edible substances that may be illegally added to food and food additives that are easily abusable (batch six), with emphasis on monitoring.
Complex matrix effects in food require detection by stable isotope internal standard methods. Meanwhile, the research on diphenyl phthalate metabolism in the field of biological metabolism also urgently needs stable isotope-labeled diphenyl phthalate products. At present, the synthetic literature of the diphenyl phthalate labeled by stable isotopes is only rarely reported, and the literature of the natural diphenyl phthalate is also less.
Patent JP2010195902 adopts phthalic anhydride, phenol potassium carbonate and the like as raw materials, isobutyl ketone with low flash point (flash point 15.6 ℃) and high price as a solvent, diphenyl phthalate is prepared by high-temperature and two-step reaction, the reaction steps are long, the temperature is high, the solvent is high and the flash point is low, and the generated wastewater is much because neutralization treatment is needed; in the patent, JP2010023676 phthalic anhydride, phenol and the like are used as raw materials, p-toluenesulfonic acid is used as a catalyst, and diphenyl phthalate is prepared by toluene reflux, wherein the yield is only 20%; JP10291964 adopts sodium phthalate, phenol, toluene and phosphorus oxychloride as raw materials to synthesize diphenyl phthalate at high temperature, adopts the highly toxic phosphorus oxychloride in the reaction process, and involves the steps of neutralization, water washing and the like in the reaction, so that the generated wastewater is large. In conclusion, the synthesis method of the natural diphenyl phthalate has low yield or high reaction temperature, uses strong acid, strong base or highly toxic chemicals, and is not suitable for the synthesis of the stable isotope labeled diphenyl phthalate with strict requirements on abundance and purity.
Patent CN104860817A discloses a stable isotope labeled benzyl butyl phthalate and a synthesis method thereof, which takes stable isotope labeled phthalic anhydride as a raw material to react with benzyl alcohol to generate stable isotope labeled benzyl phthalate monobenzyl, and then the stable isotope labeled benzyl phthalate monobenzyl reacts with butanol to obtain stable isotope labeled benzyl butyl phthalate.
Disclosure of Invention
The present invention is directed to solving the above problems and providing a method for synthesizing stable isotope-labeled diphenyl phthalate.
The purpose of the invention is realized by the following technical scheme:
a method for synthesizing stable isotope labeled diphenyl phthalate comprises the following steps of reacting stable isotope labeled phthalic acid dichloride with stable isotope labeled sodium phenolate to prepare the stable isotope labeled diphenyl phthalate, wherein the structural formula of the stable isotope labeled diphenyl phthalate is as follows:
wherein at least one of a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p, q, r, s, t, u, v, w, x is independently13C. D, or18Labeling with an O isotope;
at a position of13C is labeled or unlabeled;
at the position b is13One or two of C label, D label or non-label;
at the position c is13One or two of C label, D label or non-label;
at d is13One or two of C label, D label or non-label;
at the position e is13One or two of C label, D label or non-label;
at f is13C is labeled or unlabeled;
at g is13C is labeled or unlabeled;
at h is18O-label or non-label;
at the position i is18O-label or non-label;
at j is13C is labeled or unlabeled;
at k is13One or two of C label, D label or non-label;
at the position l is13One or two of C label, D label or non-label;
m is13One or two of C label, D label or non-label;
n is13One or two of C label, D label or non-label;
at o is13One or two of C label, D label or non-label;
at p is13C is labeled or unlabeled;
at q is18O-label or non-label;
at the r position is18O-label or non-label;
at s is13C is labeled or unlabeled;
at t is13One or two of C label, D label or non-label;
at the u position is13One or two of C label, D label or non-label;
at v is13One or two of C mark and D markMarking or non-marking;
at w is13One or two of C label, D label or non-label;
the reaction temperature of the stable isotope labeled phthaloyl chloride and the stable isotope labeled sodium phenolate is-50-200 ℃, the reaction time is 1-4h, and the preferable reaction temperature is 20-60 ℃.
The mol ratio of the stable isotope labeled phthaloyl chloride to the stable isotope labeled sodium phenolate is 1: 1.5-5, and the preferable molar ratio is 1: 2 to 4.
After the stable isotope labeled phthaloyl chloride and the stable isotope labeled sodium phenolate react, the reaction product is washed and dried.
The stable isotope labeled phthaloyl chloride is phthaloyl chloride-D4Phthalic chloride-18O2Or phthaloyl chloride-13C8。
The stable isotope labeled sodium phenolate is sodium phenolate-D5Or sodium phenoxide-18O。
The stable isotope labeled diphenyl phthalate is obtained by adopting cheap and easily-obtained stable isotope labeled phthalic acid chloride and sodium phenolate in the next step without the action of a solvent and a catalyst, has short reaction step, high yield, no need of strong alkali as a catalyst, no waste alkali generation, environmental protection, mild reaction conditions and high yield and atom utilization rate, is a synthesis method suitable for the stable isotope labeled diphenyl phthalate, provides a metabolic standard product for the metabolism research of the diphenyl phthalate in the field of biological metabolism, and provides a standard reagent for more accurate quantitative detection of the diphenyl phthalate, thereby effectively providing services for the field of biological metabolism and the field of food safety.
The invention has the following advantages:
1. the method adopts a synthesis method, has the advantages of cheap and easily-obtained raw materials, simple reaction process, mild conditions, no solvent, no waste acid, greenness, environmental protection, high yield and high utilization rate of stable isotope atoms.
2. The product of the invention is easy to separate and purify, the chemical purity of the product is more than 99 percent, and the isotopic abundance is more than 99 percent.
3. The invention has good economical efficiency and use value.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the present invention is not limited thereto in any way.
Example 1
Stable isotope labeled diphenyl phthalate-D4The preparation method comprises the following steps:
in a 250mL three-necked flask, 20.7g of phthaloyl chloride-D was added4Adding 24.4g of sodium phenolate in batches under stirring, controlling the temperature at 50 ℃ after the addition to react for 2 hours, stopping the reaction, washing with trace water and drying to obtain 31.5g of diphenyl phthalate-D4White solid, yield 97.5%, GC detection, purity 99.5%; mass spectrum detection, abundance 99.5 atom% D.
Example 2
Stable isotope labeled diphenyl phthalate-D10The preparation method comprises the following steps:
10.2g of phthaloyl chloride was added to a 250mL three-necked flask, and sodium phenolate-D was added in portions with stirring512.5g, controlling the temperature to 30 ℃ after the addition, reacting for 3 hours, stopping the reaction, washing with trace water and drying to obtain 15.7g diphenyl phthalate-D10White solid, yield 95.7%, GC detection, purity 99.5%; mass spectrum detection, abundance 99.6 atom% D.
Example 3
Stable isotope labeled diphenyl phthalate-18O2-a carbonyl preparation process comprising the steps of:
5.1g phthaloyl chloride-18O2Adding 6.5g of sodium phenolate in batches under stirring, controlling the temperature at 40 ℃ after the addition to react for 2.5 hours, stopping the reaction, washing with trace water and drying to obtain 7.7g of diphenyl phthalate-18O2White solid, yield 94.8%, GC detection, purity 99.6%; mass spectrum detection, the abundance is 99.4 atom%18O。
Example 4
Stable isotope labeled diphenyl phthalate-18O2-a process for the preparation of an ester group, the process comprising the steps of:
5.1g of phthaloyl chloride is added into a 250mL three-neck flask, and sodium phenoxide is added in batches under stirring18O6.8g, after the addition, the temperature is controlled at 40 ℃ for reaction for 3 hours, the reaction is stopped, and 7.5g diphenyl phthalate-containing material is obtained after trace water washing and drying18O2White solid, yield 93.2%, GC detection, purity 99.5%; mass spectrum detection, the abundance is 99.4 atom%18O。
Example 5
Stable isotope labeled diphenyl phthalate-13C8The preparation method comprises the following steps:
mixing a mixture of 1: 2.1 Stable isotope labeling phthalic acid dichloride-13C8Mixing with phenol, controlling the temperature at 60 ℃, and reacting for 1 hour to obtain diphenyl phthalate13C8。
Example 6
Stable isotope labeled diphenyl phthalate-D14The preparation method comprises the following steps:
mixing a mixture of 1: 2.2 phthaloyl chloride-D4With sodium phenolate-D5Mixing, controlling the temperature to be 20 ℃, and reacting for 4 hours to obtain diphenyl phthalate-D14。
Example 7
Stable isotope labeled diphenyl phthalate-D5The preparation method comprises the following steps:
mixing a mixture of 1: 1 o-phthaloyl chloride and sodium phenolate are mixed, the temperature is controlled at 25 ℃ to react for 1 hour, and then equimolar sodium phenolate-D is added5Reacting for 2 hours at the temperature of 30 ℃ to obtain diphenyl phthalate-D5。
Example 8
Stable isotope labeled diphenyl phthalate-D14 13C20 18O4Preparation methodThe method comprises the following steps:
mixing a mixture of 1: 2.2 phthaloyl chloride-D4 13C8 18O2With sodium phenolate-D5 13C6 18Mixing O, controlling the temperature to 35 ℃, and reacting for 4 hours to obtain diphenyl phthalate-D14 13C20 18O4。
Claims (3)
1. A method for synthesizing stable isotope labeled diphenyl phthalate is characterized in that stable isotope labeled diphenyl phthalate is prepared by reacting stable isotope labeled phthalic acid chloride with stable isotope labeled sodium phenolate, wherein the stable isotope labeled diphenyl phthalate has the following structural formula:
wherein at least one of a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p, q, r, s, t, u, v, w, x is independently13C. D, or18Labeling with an O isotope;
the reaction temperature of the stable isotope labeled phthaloyl chloride and the stable isotope labeled sodium phenolate is 20-60 ℃, and the reaction time is 1-4 h;
the mol ratio of the stable isotope labeled phthaloyl chloride to the stable isotope labeled sodium phenolate is 1: 1.5 to 5;
the stable isotope labeled phthaloyl chloride is phthaloyl chloride-D4Phthalic chloride-18O2Or phthaloyl chloride-13C8；
The stable isotope labeled sodium phenolate is sodium phenolate-D5Or sodium phenoxide-18O。
2. The method for synthesizing stable isotope labeled diphenyl phthalate according to claim 1, wherein the molar ratio of the stable isotope labeled phthaloyl chloride to the stable isotope labeled sodium phenolate is 1: 2 to 4.
3. The method according to claim 1, wherein the reaction product is washed with water and dried.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10291964A (en) * | 1997-04-21 | 1998-11-04 | Kyodo Yakuhin Kk | Production of diphenyl phthalate |
| CA2714076A1 (en) * | 2010-03-13 | 2011-09-13 | Muroran Institute Of Technology | Modifier for aromatic polyester and aromatic polyester resin composition comprising the same |
| CN104860817A (en) * | 2015-04-10 | 2015-08-26 | 上海化工研究院 | Stable isotope labeled benzyl butyl phthalate and synthesis method thereof |
-
2018
- 2018-10-30 CN CN201811277769.2A patent/CN109400470B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10291964A (en) * | 1997-04-21 | 1998-11-04 | Kyodo Yakuhin Kk | Production of diphenyl phthalate |
| CA2714076A1 (en) * | 2010-03-13 | 2011-09-13 | Muroran Institute Of Technology | Modifier for aromatic polyester and aromatic polyester resin composition comprising the same |
| CN104860817A (en) * | 2015-04-10 | 2015-08-26 | 上海化工研究院 | Stable isotope labeled benzyl butyl phthalate and synthesis method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Aromatic Rearrangements in the Benzene Series.Part 3.Rearrangement of lsotopically Labelled Phenyl Benzoates:lntermolecularity of the ortho- Directed Rearrangement.Criteria for Determining the Intra-/Inter-molecularity of Aromatic Rearrangements;Ian M. Dawson et al.;《Journal of the Chemical Society-Perkin Transaction II》;19850101(第10期);第1601-1606页 * |
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