CN115466185A - Preparation method of 6PPD metabolite - Google Patents
Preparation method of 6PPD metabolite Download PDFInfo
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- CN115466185A CN115466185A CN202211129168.3A CN202211129168A CN115466185A CN 115466185 A CN115466185 A CN 115466185A CN 202211129168 A CN202211129168 A CN 202211129168A CN 115466185 A CN115466185 A CN 115466185A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the technical field of drug metabolism, in particular to a preparation method of a 6PPD metabolite. The preparation method provided by the invention comprises the following steps: mixing 4-aminodiphenylamine, diacetone alcohol, an organic solvent and a hydrogenation reagent for reductive amination reaction to obtain a 6PPD metabolite with a structure shown in formula I. The preparation method provided by the invention takes 4-aminodiphenylamine, diacetone alcohol and a hydrogenation reagent as raw materials, and adopts a reasonably designed reaction synthesis route: the reductive amination reaction is carried out by a one-step method, the successful preparation of 6PPD metabolite is realized, the yield is high, a reference substance can be provided for the metabolism mechanism research of 6PPD, the method can be used for researching the metabolic process of the drug in the environment, and the method has great value for the systematic research and risk assessment of 6PPD and the metabolite thereof. The preparation method provided by the invention has the advantages of low preparation cost, strong operability and high safety factor, and can realize industrial production.
Description
Technical Field
The invention relates to the technical field of drug metabolism, in particular to a preparation method of a 6PPD metabolite.
Background
6PPD, namely N- (1,3-dimethylbutyl) -N' -phenyl-p-phenylenediamine, with CAS number of 793-24-8, is a common antiozonant, has excellent effects of resisting oxygen, ozone and flex cracking, is suitable for various synthetic rubbers and natural rubbers, and can also be used as a thermal oxygen stabilizer for polyethylene, polypropylene and acrylic resin.
The main metabolite of 6PPD in rats is 2-methyl-4- ((4- (phenylamino) phenyl) amino) pentan-2-ol, and the chemical structural formula is shown in formula I. At present, data such as environmental behavior and toxicity of 6PPD metabolite are lacked, and an Adam catalyst (PtO) is required to be used in the preparation process of the structure shown in the formula 1 disclosed in the US patent 3388096A 2 ) The manufacturing cost is high, the risk coefficient of the preparation method is high, difficulty is brought to systematic research of 6PPD metabolites, and accuracy of 6PPD risk assessment is affected.
Disclosure of Invention
The invention aims to provide a preparation method of a 6PPD metabolite, which is low in cost, high in yield of the prepared 6PPD metabolite, strong in operability and suitable for industrial production.
In order to achieve the above purpose, the invention provides the following technical scheme:
the invention provides a preparation method of a 6PPD metabolite, which comprises the following steps:
mixing 4-aminodiphenylamine, diacetone alcohol, an organic solvent and a hydrogenation reagent for reductive amination reaction to obtain a 6PPD metabolite with a structure shown in a formula I;
preferably, the hydrogenation reagent comprises one or more of sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.
Preferably, the molar ratio of the hydrogenation reagent to the 4-aminodiphenylamine is (1-2): 1.
Preferably, the molar ratio of the diacetone alcohol to the 4-aminodiphenylamine is (1-2): 1.
Preferably, the temperature of the reductive amination reaction is 10-40 ℃, and the heat preservation time of the reductive amination reaction is 8-24 h.
Preferably, the organic solvent comprises tetrahydrofuran, methanol or dichloromethane.
Preferably, the reductive amination reaction solution is directly obtained after the reductive amination reaction, and the method further comprises the following steps:
adding water to dilute the reductive amination reaction solution to obtain a diluted reaction solution;
mixing and extracting the diluted reaction solution and an organic extractant to obtain an extracted organic phase;
and (3) sequentially washing, drying, removing the organic solvent and carrying out column chromatography on the extracted organic phase to obtain the 6PPD metabolite with the structure shown in the formula I.
Preferably, the organic extractant is ethyl acetate.
Preferably, the eluent used in the column chromatography separation and purification is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1:4.
Preferably, the column chromatography is flash column chromatography.
The invention provides a preparation method of a 6PPD metabolite, which comprises the following steps: mixing 4-aminodiphenylamine, diacetone alcohol, an organic solvent and a hydrogenation reagent for reductive amination reaction to obtain the 6PPD metabolite. The preparation method provided by the invention takes 4-aminodiphenylamine, diacetone alcohol and a hydrogenation reagent as raw materials, and adopts a reasonably designed reaction synthesis route: the method has the advantages that the reductive amination reaction is carried out by a one-step method under the condition that no catalyst is needed, the successful preparation of the 6PPD metabolite with the structure shown in the formula I is realized, the yield is high, a reference substance can be provided for the metabolism mechanism research of the 6PPD, the method can be used for researching the metabolic process of the drug in the environment, and the method has great value in the systematic research and risk assessment of the 6PPD and the metabolite thereof. Meanwhile, the preparation method provided by the invention has the advantages of low preparation cost, strong operability and high safety factor, and can realize industrial production of the 6PPD metabolite with the structure shown in the formula I.
Further, the reductive amination reaction directly obtains a reductive amination reaction solution, and further comprises the following steps: adding water to dilute the reductive amination reaction solution to obtain a diluted reaction solution; mixing and extracting the diluted reaction solution and an organic extractant to obtain an extracted organic phase; and (3) sequentially washing, drying, removing the organic solvent and carrying out column chromatography on the extracted organic phase to obtain the 6PPD metabolite with the structure shown in the formula I. According to the invention, the reductive amination reaction solution is extracted and separated and purified by column chromatography, so that the purity of the 6PPD metabolite with the structure shown in the formula I can be further improved, and a high-purity reference substance is provided for the metabolism mechanism research of 6 PPD. The results of the examples show that the purity of the 6PPD metabolite with the structure shown in the formula I prepared by the invention is more than or equal to 99 percent.
Drawings
FIG. 1 is a synthetic route diagram of a 6PPD metabolite having the structure shown in formula I provided in the examples of the present invention.
Detailed Description
The invention provides a preparation method of a 6PPD metabolite, which comprises the following steps:
mixing 4-aminodiphenylamine, diacetone alcohol, an organic solvent and a hydrogenation reagent for reductive amination reaction to obtain a 6PPD metabolite with a structure shown in a formula I;
in the present invention, all the preparation starting materials/components are commercially available products well known to those skilled in the art unless otherwise specified.
In the present invention, the structural formula of the 4-aminodiphenylamine is shown in formula II:
in the present invention, the hydrogenation reagent preferably includes one or more of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride, and more preferably sodium cyanoborohydride.
In the present invention, the organic solvent preferably includes tetrahydrofuran, methanol or dichloromethane, and more preferably methanol.
In the present invention, the molar ratio of the hydrogenation reagent to the 4-aminodiphenylamine is preferably (1-2): 1, more preferably 1.5.
In the present invention, the molar ratio of diacetone alcohol to 4-aminodiphenylamine is preferably (1-2) to 1, more preferably 1.1.
The invention has no special requirements on the dosage of the organic solvent, and can ensure that the raw materials of the reductive amination reaction are completely dissolved and the reductive amination reaction is smoothly carried out.
In the present invention, the temperature of the reductive amination reaction is preferably 10 to 40 ℃, more preferably 25 ℃.
In the present invention, the incubation time for the amine reduction reaction is preferably 8 to 24 hours, and more preferably 12 hours.
In the present invention, the reductive amination reaction directly obtains a reductive amination reaction solution, and the present invention preferably further comprises the steps of:
adding water to dilute the reductive amination reaction solution to obtain a diluted reaction solution;
mixing and extracting the diluted reaction solution and an organic extractant to obtain an extracted organic phase;
and sequentially washing, drying, removing the organic solvent and carrying out column chromatography on the extracted organic phase to obtain the 6PPD metabolite with the structure shown in the formula I.
In the present invention, the ratio of the volume of the dilution water to the volume of the organic solvent is preferably 1:4.
In the present invention, the organic extractant is preferably ethyl acetate. The extraction times are preferably 3 times, and the ratio of the volume of the ethyl acetate to the volume of the organic solvent in each extraction is preferably 1:1. The invention combines the extracted organic phases obtained each time to obtain the extracted organic phase.
In the present invention, the washing is preferably performed by washing with a saturated saline solution.
In the present invention, the drying is preferably performed using anhydrous sodium sulfate.
In the invention, the specific implementation mode of removing the organic solvent is preferably reduced pressure distillation, and the invention has no special requirements on the specific implementation process of the reduced pressure distillation.
The residue after the removal of the organic solvent is preferably subjected to column chromatography in the present invention.
In the present invention, the eluent used in the column chromatography is preferably a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is preferably 1:4. In the present invention, the column chromatography is preferably flash column chromatography.
According to the invention, the 6PPD metabolite with the structure shown in the formula I is obtained after the eluent obtained by column chromatography is dried.
In the present invention, the 6PPD metabolite having the structure shown in formula I is a red oily liquid.
In order to further illustrate the present invention, the following detailed description of the technical solutions provided by the present invention is made with reference to the accompanying drawings and examples, but they should not be construed as limiting the scope of the present invention.
Example 1
A6 PPD metabolite having the structure shown in formula I was prepared according to the scheme shown in FIG. 1:
4-aminodiphenylamine (1.84g, 10.00mmol) and diacetone alcohol (1.28g, 11.00mmol) were dissolved in methanol (20 mL), and sodium cyanoborohydride (0.94g, 15.00mmol) was added and reacted at 25 ℃ for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (20 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to remove the solvent and leave a residueThe product was purified by flash column chromatography (v: v =1:4, ethyl acetate/petroleum ether) to give a red oily liquid, a 6PPD metabolite of formula I, i.e.: 2-methyl-4- ((4- (phenylamino) phenyl) amino) pentan-2-ol, 2.07g, yield 73%). 1 H NMR(600MHz,Chloroform-d)δ7.25–7.17(m,2H),7.08–6.97(m,2H),6.95–6.87(m,2H),6.85–6.79(m,1H),6.79–6.66(m,2H),3.90–3.72(m,1H),1.73–1.63(m,2H),1.35(s,3H),1.27(s,3H),1.16(d,J＝6.2Hz,3H).HRMS(ESI)C 18 H 25 N 2 O + [M+H] + Calcd for 285.1961, found 285.1967.Hplc, 99.72% (λ =280nm, t R ＝12.18min).
Example 2
A6 PPD metabolite having the structure shown in formula I was prepared according to the scheme shown in FIG. 1:
4-aminodiphenylamine VIII (1.84g, 10.00mmol) and diacetone alcohol (1.16g, 10.00mmol) were dissolved in tetrahydrofuran (20 mL), and then sodium borohydride (0.38g, 10.00mmol) was added to react at 10 ℃ for 24 hours. After the reaction is finished, water (5 mL) is added for dilution, ethyl acetate (20 mL multiplied by 3) is used for extraction, saturated salt solution is used for washing, anhydrous sodium sulfate is dried, the solvent is evaporated under reduced pressure, and the residue is separated and purified by flash column chromatography (1:4 ethyl acetate/petroleum ether) to obtain a red oily liquid which is the 6PPD metabolite with the structure shown in the formula I: 2-methyl-4- ((4- (phenylamino) phenyl) amino) pentan-2-ol, 1.56g, yield 55%).
Example 3
A6 PPD metabolite having the structure shown in formula I was prepared according to the scheme shown in FIG. 1: after 4-aminodiphenylamine VIII (1.84g, 10.00mmol) and diacetone alcohol (2.32g, 20.00mmol) were dissolved in methylene chloride (20 mL), sodium triacetoxyborohydride (4.24g, 20.00mmol) was added and the reaction was carried out at 40 ℃ for 8 hours. After the reaction is finished, water (5 mL) is added for dilution, ethyl acetate (20 mL multiplied by 3) is used for extraction, saturated salt solution is used for washing, anhydrous sodium sulfate is dried, the solvent is evaporated under reduced pressure, and the residue is separated and purified by flash column chromatography (1:4 ethyl acetate/petroleum ether) to obtain a red oily liquid which is the 6PPD metabolite with the structure shown in the formula I: 2-methyl-4- ((4- (phenylamino) phenyl) amino) pentan-2-ol, 1.19g, yield 42%).
In conclusion, the preparation method of the 6PPD metabolite with the structure shown in the formula I, provided by the invention, has the advantages of reasonable design, strong operability and high yield, and can realize industrial production. The purity of the 6PPD metabolite with the structure shown in the formula I prepared by the invention is more than or equal to 99%, the high-purity reference substance can be provided for the metabolism mechanism research of 6PPD, the high-purity reference substance can be used for researching the metabolic process of the drug in the environment, and the high-purity reference substance has great value on the systematic research and risk evaluation of 6PPD and the metabolite thereof. Meanwhile, the preparation method provided by the invention has the advantages of low preparation cost, strong operability and high safety factor, and can realize industrial production of the 6PPD metabolite with the structure shown in the formula I.
Although the above embodiments have been described in detail, they are only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and all of the embodiments belong to the protection scope of the present invention.
Claims (10)
1. A method for preparing a 6PPD metabolite, comprising the steps of:
mixing 4-aminodiphenylamine, diacetone alcohol, an organic solvent and a hydrogenation reagent for reductive amination reaction to obtain a 6PPD metabolite with a structure shown in a formula I;
2. the method of claim 1, wherein the hydrogenation reagent comprises one or more of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.
3. The process according to claim 1 or 2, wherein the molar ratio of the hydrogenation reagent to the 4-aminodiphenylamine is (1-2): 1.
4. The preparation method according to claim 1, wherein the molar ratio of the diacetone alcohol to the 4-aminodiphenylamine is (1-2): 1.
5. The method according to claim 1, wherein the temperature of the reductive amination reaction is 10 to 40 ℃, and the holding time of the reductive amination reaction is 8 to 24 hours.
6. The method of claim 1, wherein the organic solvent comprises tetrahydrofuran, methanol, or dichloromethane.
7. The method according to claim 1 or 5, wherein the reductive amination directly obtains a reductive amination reaction solution, further comprising the steps of:
adding water to dilute the reductive amination reaction solution to obtain a diluted reaction solution;
mixing and extracting the diluted reaction solution and an organic extractant to obtain an extracted organic phase;
and (3) sequentially washing, drying, removing the organic solvent and carrying out column chromatography on the extracted organic phase to obtain the 6PPD metabolite with the structure shown in the formula I.
8. The method of claim 7, wherein the organic extractant is ethyl acetate.
9. The preparation method of claim 7, wherein the eluent used in the column chromatography is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1:4.
10. The method of claim 7 or 9, wherein the column chromatography is flash column chromatography.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3388096A (en) * | 1964-09-21 | 1968-06-11 | Firestone Tire & Rubber Co | Nu-2-(4-hydroxy-4-methylpentyl)-nu'-phenyl-para-phenylenediamine |
| US3424713A (en) * | 1966-02-21 | 1969-01-28 | Firestone Tire & Rubber Co | Rubber stabilized with a mixture of p-phenylenediamines |
| US20060258887A1 (en) * | 2005-05-16 | 2006-11-16 | Korea Kumho Petrochemical Co., Ltd. | Method for preparing 4-aminodiphenylamine |
| WO2021003295A1 (en) * | 2019-07-02 | 2021-01-07 | Regeneron Pharmaceuticals, Inc. | Modulators of hsd17b13 and methods of use thereof |
| CN114054057A (en) * | 2021-10-26 | 2022-02-18 | 中石化南京化工研究院有限公司 | Preparation method and evaluation method of catalyst for synthesizing age resister 6PPD (p-phenylene sulfide) sulfide precious metal |
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- 2022-09-16 CN CN202211129168.3A patent/CN115466185A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3388096A (en) * | 1964-09-21 | 1968-06-11 | Firestone Tire & Rubber Co | Nu-2-(4-hydroxy-4-methylpentyl)-nu'-phenyl-para-phenylenediamine |
| US3424713A (en) * | 1966-02-21 | 1969-01-28 | Firestone Tire & Rubber Co | Rubber stabilized with a mixture of p-phenylenediamines |
| US20060258887A1 (en) * | 2005-05-16 | 2006-11-16 | Korea Kumho Petrochemical Co., Ltd. | Method for preparing 4-aminodiphenylamine |
| WO2021003295A1 (en) * | 2019-07-02 | 2021-01-07 | Regeneron Pharmaceuticals, Inc. | Modulators of hsd17b13 and methods of use thereof |
| CN114054057A (en) * | 2021-10-26 | 2022-02-18 | 中石化南京化工研究院有限公司 | Preparation method and evaluation method of catalyst for synthesizing age resister 6PPD (p-phenylene sulfide) sulfide precious metal |
Non-Patent Citations (2)
| Title |
|---|
| A. E. OBERSTER ET AL.: "Syntheses of novel substituted p-phenylenediamines", 《CANADIAN JOURNAL OF CHEMISTRY》, vol. 45, no. 3, pages 195 - 201 * |
| 吴结华: "新型橡胶防老剂6PPD合成催化剂", 《工业催化》, vol. 20, no. 7, pages 43 - 45 * |
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