A method for preparing a palladium catalyst and a method for preparing an all-trans C15 phosphine salt.
By using a palladium catalyst with a pyrazole ring structure to isomerize cis-C15 phosphine salt to all-trans-C15 phosphine salt, the problem of utilizing isomers in the crystallization mother liquor was solved, achieving efficient conversion and preparation of high-purity products, and reducing the production cost of vitamin A acetate.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- WANHUA CHEM GRP CO LTD
- Filing Date
- 2024-12-27
- Publication Date
- 2026-06-30
AI Technical Summary
In the existing technology, there is no effective method to effectively utilize the C15 phosphine salt isomers in the crystallization mother liquor during the production of vitamin A acetate, especially to convert cis-C15 phosphine salts into high-purity all-trans-C15 phosphine salts, thereby reducing production costs.
A palladium catalyst composed of a ligand containing a pyrazole ring structure and palladium is used to isomerize cis-C15 phosphine salt to all-trans-C15 phosphine salt via the Wittig reaction. The catalytic conversion is then carried out under specific conditions using a bispyrazole palladium dichloride catalyst, combined with a crystallization process to obtain high-purity all-trans-C15 phosphine salt.
The C15 phosphine salt isomerization conversion rate reached over 90.0%, the selectivity was over 97%, and the product purity reached over 99.0%, effectively reducing production costs.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis, specifically to a palladium catalyst and its preparation method, and a method for preparing all-trans C15 phosphine salt. Background Technology
[0002] Vitamin A acetate is a fat-soluble vitamin with various physiological functions, including promoting growth and reproduction, maintaining bone, epithelial tissue, vision, and normal secretion of mucous membranes. The molecule of vitamin A acetate contains multiple double bonds, resulting in various isomers, primarily all-trans, 9-cis, 11-cis, and 13-cis. Organisms can most effectively utilize all-trans vitamin A acetate, while cis vitamin A acetate has low bioavailability.
[0003] Industrially, vitamin A acetate is primarily synthesized via the Wittig reaction using C15 phosphine salts and C5 aldehydes as raw materials. During the production of the all-trans C15 phosphine salt, the crystallization mother liquor produced contains unrecovered all-trans C15 phosphine salt and cis C15 phosphine salt isomers. Recovering and utilizing this portion of C15 phosphine salt is an effective way to reduce the production costs of both C15 phosphine salt and vitamin A acetate.
[0004] CN104583223 discloses a method for the thermal isomerization of olefinic C15 phosphine salts to generate [(2Z,4E)-3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)pent-2,4-dienyl]triphenylphosphine salt. This method involves thermal isomerization of a mother liquor containing a mixture of C15 phosphine salt 2E,4E isomers (also known as all-trans C15 phosphine salts), 2Z,4E isomers, and 2E,4Z isomers to obtain a mother liquor with high purity of the 2Z,4E-C15 phosphine salt isomer. The mother liquor after thermal isomerization is then subjected to a Wittig reaction to obtain 9-Z retinol. While the disclosed method effectively utilizes the C15 phosphine salt mixture to obtain the 2Z,4E-C15 phosphine salt, how to utilize this mother liquor to produce the all-trans C15 phosphine salt has not yet been investigated.
[0005] In summary, developing a method for isomerizing cis-C15 phosphonates to generate all-trans-C15 phosphonates, and effectively utilizing the mother liquor from phosphonate crystallization, is an effective way to reduce the production cost of vitamin A acetate. Summary of the Invention
[0006] The purpose of this invention is to provide a palladium catalyst and its preparation method. This catalyst uses pyrazole ligands to coordinate with palladium, which greatly improves the coordination activity of palladium with olefin double bonds, and improves the catalytic conversion rate and selectivity of double bond isomerism.
[0007] This invention also provides a method for preparing all-trans C15 phosphine salts. Using the palladium catalyst prepared by this invention, the isomerization of cis-C15 phosphine salts to trans-C15 phosphine salts can be effectively completed, realizing the recovery and utilization of the C15 isomer in the C15 phosphine salt crystallization mother liquor. This method features high olefin isomerization conversion rate, high selectivity, and high purity of the C15 phosphine salt obtained from crystallization.
[0008] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows:
[0009] First, the present invention relates to a palladium catalyst.
[0010] A ligand-palladium catalyst for catalyzing olefin double bond isomerization, the catalyst comprising a support, palladium chloride, and a ligand; wherein the support is activated carbon, and the ligand contains a pyrazole ring structure.
[0011] Preferably, the ligand containing the pyrazole ring structure is a pyrazole or an alkyl / halogen-substituted pyrazole, such as 3-methylpyrazole, 4-methylpyrazole, 3-ethylpyrazole, 4-ethylpyrazole, 3-chloropyrazole, 4-chloropyrazole, 3-bromopyrazole, 4-bromopyrazole, etc., with methyl-substituted pyrazoles being more preferred.
[0012] Preferably, based on the total weight of the catalyst, the catalyst has a palladium chloride loading of 2-5%, a ligand loading of 2-10%, and the remainder is activated carbon.
[0013] The present invention also provides a method for preparing the catalyst. The method includes:
[0014] Palladium chloride and ligands were dissolved in DMF at 60-90℃ and stirred until homogeneous. Activated carbon was added and stirred until homogeneous again. The mixture was impregnated for 2-4 hours. The activated carbon was then removed and dried to obtain the bispyrazole palladium dichloride catalyst.
[0015] This invention also relates to the application of the above-mentioned catalyst in the preparation of all-trans C15 phosphine salts.
[0016] A method for preparing an all-trans C15 phosphine salt, comprising:
[0017] In an inert atmosphere, the C15 phosphine salt mother liquor, bispyrazole palladium dichloride catalyst, and a first organic solvent are mixed in a reaction vessel and reacted. After the reaction is complete, the first organic solvent is removed, a second organic solvent is added, and the mixture is cooled to crystallize, thereby obtaining the high-purity all-trans C15 phosphine salt.
[0018]
[0019] The C15 phosphine salt mother liquor refers to the crystallization mother liquor obtained after industrial production and crystallization of all-trans C15 phosphine salt, and its components after concentration treatment, including 25-35% all-trans phosphine salt, 40-50% cis phosphine salt isomer, and solvent.
[0020] Preferably, in the phosphine salt structure, X- is selected from fluoride ions, chloride ions, bromide ions, iodide ions, nitrate ions, or sulfite ions.
[0021] Preferably, the mass of the Pd(II) catalyst fed is 0.5-5% of the mass of the phosphine salt mother liquor fed.
[0022] Preferably, the first organic solvent is selected from toluene, xylene, n-hexane, n-heptane, cyclohexane, 1,4-dioxane, tetrahydrofuran, or a mixture of at least two of these compounds.
[0023] Preferably, the mass ratio of the first organic solvent to the phosphine salt mother liquor is (5-10):1.
[0024] Preferably, the reaction temperature is 30-60℃ and the reaction time is 2-4h.
[0025] Preferably, the reaction pressure is 0.05-2.0 MPa.
[0026] Preferably, the reaction is carried out under stirring conditions.
[0027] Preferably, the stirring speed is 50-1000 rpm.
[0028] Preferably, after the reaction is completed, a post-processing operation is also included:
[0029] Preferably, the post-processing includes solvent removal and crystallization operations;
[0030] Preferably, the crystallization temperature is -5 to 50°C, more preferably 5 to 10°C;
[0031] Preferably, the crystallization is carried out in a second organic solvent;
[0032] Preferably, the second organic solvent is selected from methanol, ethanol, isopropanol, ethylene glycol, ethyl acetate, or a mixture of at least two of these compounds.
[0033] Preferably, the mass ratio of the second organic solvent to the desolventized material is (1-10):1, more preferably 5-8:1.
[0034] Through the above technical solution, the present invention has the following beneficial effects:
[0035] The bispyrazole palladium dichloride catalyst prepared in this invention is used for the cis-trans isomerization reaction of C15 phosphine salts, exhibiting both high conversion rate and high selectivity. Catalytic isomerization of a mixed mother liquor of C15 phosphine salts is then performed, followed by crystallization to obtain the all-trans 15 phosphine salt.
[0036] The catalytic isomerization reaction has a conversion rate of over 90.0% and a selectivity of over 97%. The all-trans C15 phosphine salt has a high analytical purity of over 99.0%. Detailed Implementation
[0037] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention.
[0038] Analysis method:
[0039] High-performance liquid chromatography (HPLC) system: Agilent LC-1200; Chromatography workstation data processing system: Chomatopac C-RIA. Chromatographic conditions: mobile phase: methanol / water = 4 / 1 (v / v); detection temperature: 40℃; flow rate: 1 mL / min; wavelength: 260 nm. External standard method was used for qualitative and quantitative analysis of the product composition.
[0040] Raw material source:
[0041] C15 phosphine salt mother liquor: This is the mother liquor obtained from the industrial crystallization of all-trans C15 phosphine salt from Wanhua Chemical, which is concentrated to form the phosphine salt mother liquor described herein. In the examples and comparative examples, its composition includes 30% C15 all-trans phosphine salt, 45% C15 cis phosphine salt, and X- represents chloride ions.
[0042] Example 1
[0043] Preparation of the catalyst bis(3-methylpyrazole)palladium dichloride:
[0044] Palladium chloride and 3-methylpyrazole ligand were dissolved in DMF at 60℃ and stirred until homogeneous. Activated carbon was added and stirred until homogeneous again. The mixture was impregnated for 4 hours. The activated carbon was then removed and dried to obtain bis(3-methylpyrazole)palladium dichloride catalyst. The loading of palladium chloride was 2% and the loading of ligand was 5% by weight of the total catalyst.
[0045] Preparation of all-trans C15 phosphonium salts:
[0046] Under nitrogen atmosphere, 100 g of C15 phosphine salt mother liquor and 2 g of bis(3-methylpyrazole)palladium dichloride were added to a flask, followed by 500 g of toluene as organic solvent. The reaction system was heated to 40 °C and reacted at 400 rpm for 2 h. After the reaction was completed, samples were taken for analysis. The conversion rate of cis-phosphine salt to all-trans C15 phosphine salt was 93%, with a selectivity of 98%. The reaction solution was desolventized, and 375 g of methanol was added. Crystallization was carried out at 5 °C, and after drying, all-trans C15 phosphine salt crystals were obtained. The product purity was 99.3% when analyzed by high-performance liquid chromatography.
[0047] Example 2
[0048] Preparation of the catalyst bis(4-methylpyrazole)palladium dichloride:
[0049] Palladium chloride and 4-methylpyrazole ligand were dissolved in DMF at 60℃ and stirred until homogeneous. Activated carbon was added and stirred until homogeneous again. The mixture was impregnated for 4 hours. The activated carbon was then removed and dried to obtain bis(4-methylpyrazole)palladium dichloride catalyst. The loading of palladium chloride was 5% and the loading of ligand was 10% by weight of the total catalyst.
[0050] Preparation of all-trans C15 phosphonium salts:
[0051] Under nitrogen atmosphere, 100 g of C15 phosphine salt mother liquor and 4 g of bis(4-methylpyrazole)palladium dichloride were added to a flask, followed by 500 g of hexane as organic solvent. The reaction system was heated to 50 °C and reacted at 400 rpm for 4 h. After the reaction was completed, samples were taken for analysis. The conversion rate of cis-phosphine salt to all-trans C15 phosphine salt was 95%, with a selectivity of 99%. The reaction solution was desolventized, and 400 g of ethanol was added. Crystallization was carried out at 5 °C, and after drying, all-trans C15 phosphine salt crystals were obtained. The product purity was 99.5% when analyzed by high-performance liquid chromatography.
[0052] Example 3
[0053] Preparation of the catalyst bis(4-chloropyrazole)palladium dichloride:
[0054] Palladium chloride and 4-chloropyrazole ligand were dissolved in DMF at 70℃ and stirred until homogeneous. Activated carbon was added and stirred until homogeneous again. The mixture was impregnated for 3 hours. The activated carbon was then removed and dried to obtain bis(4-chloropyrazole)palladium dichloride catalyst. The loading of palladium chloride was 3% and the loading of ligand was 6% by weight of the total catalyst.
[0055] Preparation of all-trans C15 phosphonium salts:
[0056] Under nitrogen atmosphere, 100 g of C15 phosphine salt mother liquor and 1 g of bis(4-chloropyrazole)palladium dichloride were added to a flask, followed by 500 g of xylene, an organic solvent. The reaction system was heated to 60 °C and reacted at 400 rpm for 3 h. After the reaction was completed, samples were taken for analysis. The conversion rate of cis-phosphine salt to all-trans C15 phosphine salt was 90%, with a selectivity of 97%. The reaction solution was desolventized, and 400 g of methanol was added. Crystallization was carried out at 5 °C, and after drying, all-trans C15 phosphine salt crystals were obtained. The product purity was 99.4% when analyzed by high-performance liquid chromatography.
[0057] Comparative Example 1
[0058] No Pd(II) catalyst was added; direct heating was used instead.
[0059] Under nitrogen atmosphere, 100 g of C15 phosphine salt mother liquor was added to a flask, followed by 500 g of hexane, an organic solvent. The reaction system was heated to 40 °C and reacted for 4 h with a stirring speed of 400 rpm. After the reaction was completed, a sample was taken for high performance liquid chromatography analysis. The ratio of cis phosphine salt to all-trans C15 phosphine salt did not change.
[0060] Comparative Example 2
[0061] Without adding Pd(II) catalyst, the reaction temperature was increased to 100℃.
[0062] Under nitrogen atmosphere, 100 g of C15 phosphine salt mother liquor was added to a flask, followed by 500 g of hexane, an organic solvent. The reaction system was heated to 100 °C and reacted for 4 h at a stirring speed of 400 rpm. After the reaction was completed, a sample was taken for high performance liquid chromatography analysis. The ratio of cis phosphine salt to all-trans C15 phosphine salt did not change.
[0063] Comparative Example 3
[0064] Di(triphenylphosphine) palladium dichloride (purchased from Merck) was added as a catalyst.
[0065] Under nitrogen atmosphere, 100 g of C15 phosphine salt mother liquor and 2 g of bis(triphenylphosphine)palladium dichloride were added to a flask, followed by 500 g of hexane organic solvent. The reaction system was heated to 40 °C and reacted at a stirring speed of 400 rpm for 4 h. After the reaction was completed, a sample was taken for high performance liquid chromatography analysis. The ratio of cis-phosphine salt to all-trans-C15 phosphine salt did not change.
Claims
1. A palladium catalyst, the catalyst comprising a support, palladium chloride and a ligand; wherein, The support is activated carbon, and the ligand contains a pyrazole ring structure.
2. The catalyst according to claim 1, characterized in that, The ligand containing the pyrazole ring structure is selected from pyrazoles and alkyl / halogen substituted pyrazoles, such as 3-methylpyrazole, 4-methylpyrazole, 3-ethylpyrazole, 4-ethylpyrazole, 3-chloropyrazole, 4-chloropyrazole, 3-bromopyrazole, and 4-bromopyrazole.
3. Catalyst according to claim 1 or 2, characterized in that Based on the total weight of the catalyst, the catalyst contains 2-5% palladium chloride, 2-10% ligands, and the remainder is activated carbon.
4. Process for the preparation of a catalyst according to any one of claims 1 to 3, characterized in that, include: Palladium chloride and ligands were dissolved in DMF at 60-90℃ and stirred until homogeneous. Activated carbon was added and stirred until homogeneous again. The mixture was impregnated for 2-4 hours. The activated carbon was then removed and dried to obtain the catalyst.
5. A method of preparing an all-trans C15 phosphonium salt, characterized by, include: In an inert atmosphere, the C15 phosphine salt mother liquor, catalyst, and first organic solvent are reacted in a reactor. After the reaction is complete, the first organic solvent is removed, a second organic solvent is added, and the mixture is cooled to crystallize, thereby obtaining all-trans C15 phosphine salt. The catalyst is the catalyst described in any one of claims 1-3.
6. The method of claim 5, wherein, The mass of the catalyst fed is 0.5-5% of the mass of the C15 phosphine salt mother liquor fed.
7. The method of claim 5, wherein, The first organic solvent is selected from toluene, xylene, n-hexane, n-heptane, cyclohexane, 1,4-dioxane, tetrahydrofuran, or a mixture of at least two of these compounds; Preferably, the mass ratio of the first organic solvent to the C15 phosphine salt mother liquor is (5-10):
1.
8. The method of claim 5, wherein, The reaction temperature is 30-60℃, the reaction time is 2-4h, and the reaction is carried out under stirring conditions. Preferably, the stirring speed is 50-1000rpm.
9. The method of claim 5, wherein, The crystallization temperature is -5 to 50°C, preferably 5 to 10°C.
10. The method of claim 5, wherein, The second organic solvent is selected from methanol, ethanol, isopropanol, ethylene glycol, ethyl acetate, or a mixture of at least two of these compounds; Preferably, the mass ratio of the second organic solvent to the desolventized material is (1-10):1, more preferably 5-8:1.