A method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content
By using a combination method of phase transfer catalyst and acid in the aromatization reaction of vitamin B6, the reaction conditions are controlled to reduce the generation of pyrrole ring impurities, and the problem of high impurity content in vitamin B6 products in the prior art is solved, and the purity and yield of the product are improved.
Patent Information
- Application Number
- CN202411810931.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-10
- Publication Date
- 2025-04-01
AI Technical Summary
In the prior art, the pyrrole ring impurity content in the aromatization reaction of vitamin B6 is relatively high, which affects product quality and safety.
The method of reacting the compound of formula I with the action of a phase transfer catalyst and an acid in an organic solvent is used to obtain the compound of formula II, and the formation of pyrrole ring impurities is reduced by controlling the reaction temperature, time and dropwise addition of the acid.
It effectively reduces the content of pyrrole ring impurities in the aromatic compounds of vitamin B6, improves the yield and purity of the product, simplifies the subsequent refining process, and improves the quality of the product.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of chemical synthesis of vitamins, and in particular relates to a method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content. Background Art
[0002] The main commodity form of vitamin B6 is pyridoxine hydrochloride, which is widely used in feed additives, food additives, health products, medicines, etc. Vitamin B6 is a water-soluble vitamin, one of the essential vitamins for the human body. It is a component of certain coenzymes in the human body and participates in a variety of metabolic reactions, especially closely related to amino acid metabolism.
[0003] At present, the oxazole method is widely used in industry to synthesize vitamin B6. This method uses 4-methyl-5-ethoxyoxazole and n-propyl heptacyclic as raw materials, and obtains refined vitamin B6 through Diels-Alder reaction, aromatization reaction, hydrolysis reaction, and purification steps. In the aromatization reaction, the Diels-Alder reaction product is prone to side reactions to generate pyrrole ring impurity structures. The specific mechanism is as follows:
[0004]
[0005] The existing reports on the synthesis of vitamin B6 by the oxazole method are as follows: the aromatization reaction system in the journal document "New Process for the Synthesis of Vitamin B6 by Oxazole Method, Zhou Houyuan, Chinese Journal of Pharmaceutical Industry, 1994" is a Diels-Alder reaction product, ethanol, water, and hydrochloric acid. After the reaction is completed, ethanol and water are distilled off. The document does not mention the content of pyrrole ring impurities in the aromatization step.
[0006] The compound obtained by aromatization reaction is one of the key intermediates of vitamin B6. Its impurity level directly affects the complexity of the refining process and the quality of the product. Impurities in drugs directly affect the safety, effectiveness and stability of products, which are related to the health and life safety of patients. Therefore, reducing the impurity content of pyrrole ring in vitamin B6 aromatization intermediates is of great significance to improving the quality of vitamin B6 drugs. Summary of the invention
[0007] In view of the deficiencies in the prior art, the present invention provides a method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content. The preparation method of the present invention is simple, easy to operate, easy to implement process conditions, energy saving, simple separation process, less wastewater, green, safe and environmentally friendly, high reaction atomic economy, low cost, and suitable for industrial production. The method of the present invention can prepare vitamin B6 aromatic compounds with high selectivity, high yield and purity of the target product, and effectively reduces the content of pyrrole ring impurities in the product.
[0008] The technical solution of the present invention is as follows:
[0009] A method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content, comprising the steps of:
[0010] In an organic solvent, under the action of a phase transfer catalyst and an acid, the compound of formula I is reacted to obtain a compound of formula II; the phase transfer catalyst is one or a combination of two or more of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride;
[0011]
[0012] Among them, in the compound of formula I and the compound of formula II, the substituent R1 is a C1-C4 alkyl group, and R2 is hydrogen or a C1-C4 alkyl group.
[0013] According to the present invention, the organic solvent is preferably selected from one or a combination of dichloromethane, n-heptane, chloroform, ethyl acetate, acetone, methanol, ethanol or ethyl acetate, preferably dichloromethane. The mass of the organic solvent is 4 to 5 times the mass of the compound of formula I.
[0014] Preferably according to the present invention, the phase transfer catalyst is tetrabutylammonium bromide.
[0015] Preferably according to the present invention, the mass of the phase transfer catalyst is 0.1% to 0.3% of the mass of the compound of formula I.
[0016] According to the present invention, the acid is preferably hydrochloric acid, acetic acid, sulfuric acid or ammonium chloride, preferably acetic acid. The molar ratio of the compound of formula I to the acid is 1:0.1-0.3.
[0017] According to the present invention, the acid is preferably added dropwise to the reaction system at 10-40° C. under inert gas protection and stirring. Preferably, the inert gas is nitrogen or argon.
[0018] Preferably according to the present invention, in the compound of formula I and the compound of formula II, the substituent R1 is ethyl, and R2 is n-propyl or isopropyl.
[0019] According to the present invention, preferably, the reaction temperature is 10-40°C, the reaction time is 1-10 hours, and the reaction is carried out under inert gas protection and stirring conditions. Preferably, the reaction temperature is 20-30°C, the reaction time is 4-6 hours, and the inert gas is nitrogen or argon.
[0020] Preferably according to the present invention, the post-treatment method of the reaction solution obtained by the reaction comprises the steps of adding water to the reaction solution, cooling to 0-5°C, stirring to grow crystals, filtering, and drying to obtain the vitamin B6 aromatic compound.
[0021] According to a preferred embodiment of the present invention, the method for preparing the vitamin B6 aromatic compound with reduced pyrrole ring impurity content comprises the steps of:
[0022] The compound of formula I and the organic solvent are stirred and mixed evenly, a phase transfer catalyst is added, stirred evenly, the temperature is controlled at 10-40°C, the acid is added dropwise under the protection of inert gas and stirring, the temperature is controlled at 10-40°C, the reaction is stirred for 1-10 hours under the protection of inert gas, after the reaction is completed, water is added, the temperature is lowered to 0-5°C, the crystal is grown by stirring, filtered, and dried to obtain the vitamin B6 aromatic compound.
[0023] The aromatization reaction route of the present invention is as follows:
[0024]
[0025] Among them, in the compound of formula I and the compound of formula II, the substituent R1 is a C1-C4 alkyl group, and R2 is hydrogen or a C1-C4 alkyl group.
[0026] Technical features and beneficial effects of the present invention:
[0027] 1. The preparation method of the vitamin B6 key intermediate aromatic compound of the present invention is simple, easy to operate, easy to achieve process conditions, energy saving, simple separation process, small amount of wastewater, green, safe and environmentally friendly, high reaction atomic economy, low cost, and suitable for industrial production.
[0028] 2. The present invention utilizes the effect of phase transfer catalyst to reduce the reaction temperature, reduce the strength of the acid, improve the reaction selectivity, reduce the content of pyrrole ring impurities in the product, and effectively improve the yield and purity of the product.
[0029] 3. The method of the present invention can prepare the key intermediate aromatic compound of vitamin B6 with high selectivity, has high reaction selectivity, high yield and purity of the target product, and effectively reduces the content of pyrrole ring impurities in the product, thereby simplifying the subsequent refining process of vitamin B6 and improving the product quality of vitamin B6.
[0030] 4. The method of the present invention as a whole works together to achieve the excellent effects of the present invention. If the type of organic solvent or the type of catalyst or the amount of catalyst used is not suitable, the yield of the target product will be reduced and the content of pyrrole ring impurities in the product will increase. BRIEF DESCRIPTION OF THE DRAWINGS
[0031] Figure 1 HPLC spectrum of the product prepared in Example 1;
[0032] Figure 2 HPLC spectrum of the product prepared in Example 2;
[0033] Figure 3 HPLC spectrum of the product prepared in Example 3;
[0034] Figure 4 The HPLC spectrum of the product prepared in Comparative Example 1. DETAILED DESCRIPTION
[0035] The present invention is described in detail below with reference to the embodiments, but the present invention is not limited thereto.
[0036] The raw materials and reagents used in the examples are all commercially available products. The yields in the examples are molar yields, unless otherwise specified.
[0037] Example 1
[0038] A method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content, comprising the steps of:
[0039] In a 500mL four-necked flask, first add 50g of the compound of formula I (wherein R1 is ethyl, R2 is 0.186mol of n-propyl), 200g of dichloromethane, stir evenly, then add 0.12g of tetrabutylammonium bromide, stir evenly, and slowly add 1.1g (0.018mol) of glacial acetic acid dropwise with a constant pressure dropping funnel under stirring at 25°C. After the dropwise addition, stir and react for 6h at 25°C, and nitrogen protection is used during the dropwise addition and reaction. After the reaction is completed, add 50g of water, cool to 0-5°C, stir and grow crystals for 1h, filter, and dry to obtain the vitamin B6 aromatic compound.
[0040] The yield of vitamin B6 aromatic compound is 95.2%, the pyrrole ring impurity content is 0.03%, and the purity is 99.93%. Figure 1 shown.
[0041] Example 2
[0042] A method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content, comprising the steps of:
[0043] In a 500mL four-necked flask, first add 50g of the compound of formula I (wherein R1 is ethyl, R2 is n-propyl, 0.186mol), 200g of n-heptane, stir evenly, then add 0.12g of tetrabutylammonium bromide, stir evenly, and slowly add 1.1g (0.018mol) of glacial acetic acid dropwise with a constant pressure dropping funnel under stirring at 25°C. After the dropwise addition, stir and react at 25°C for 6h, and nitrogen protection is used during the dropwise addition and reaction. After the reaction is completed, add 50g of water, cool to 0-5°C, stir and grow crystals for 1h, filter, and dry to obtain the vitamin B6 aromatic compound.
[0044] The yield of vitamin B6 aromatic compound is 94.5%, the pyrrole ring impurity content is 0.31%, and the purity is 99.48%. Figure 2 shown.
[0045] Example 3
[0046] A method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content, comprising the steps of:
[0047] In a 500mL four-necked flask, first add 50g of the compound of formula I (wherein R1 is ethyl, R2 is n-propyl, 0.186mol), 200g of dichloromethane, stir evenly, then add 0.06g of tetrabutylammonium bromide, stir evenly, and slowly add 1.1g (0.018mol) of glacial acetic acid dropwise with a constant pressure dropping funnel under stirring at 25°C. After the dropwise addition, stir and react for 6h at 25°C, and nitrogen protection is used during the dropwise addition and reaction. After the reaction is completed, add 50g of water, cool to 0-5°C, stir and grow crystals for 1h, filter, and dry to obtain the vitamin B6 aromatic compound.
[0048] The yield of vitamin B6 aromatic compound is 96.0%, the pyrrole ring impurity content is 0.06%, and the purity is 99.84%. Figure 3 shown.
[0049] Example 4
[0050] A method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content, comprising the steps of:
[0051] In a 500mL four-necked flask, first add 50g of the compound of formula I (wherein R1 is ethyl, R2 is n-propyl, 0.186mol), 200g of ethanol, stir evenly, then add 0.06g of tetrabutylammonium bromide, stir evenly, and slowly add 1.1g (0.018mol) of glacial acetic acid dropwise with a constant pressure dropping funnel under stirring at 25°C. After the dropwise addition, stir and react for 6h at 25°C, and nitrogen protection is used during the dropwise addition and reaction. After the reaction is completed, add 50g of water, cool to 0-5°C, stir and grow crystals for 1h, filter, and dry to obtain the vitamin B6 aromatic compound.
[0052] The yield of vitamin B6 aromatic compound is 60.0% (ethanol dissolves the aromatic material, resulting in a lower yield), the pyrrole ring impurity content is 0.06%, and the purity is 99.89%.
[0053] Example 5
[0054] A method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content, comprising the steps of:
[0055] In a 500mL four-necked flask, first add 50g of the compound of formula I (wherein R1 is ethyl, R2 is n-propyl, 0.186mol), 200g of dichloromethane, stir evenly, then add 0.06g of benzyltriethylammonium chloride, stir evenly, and slowly add 1.1g (0.018mol) of glacial acetic acid dropwise with a constant pressure dropping funnel under stirring at 25°C. After the dropwise addition, stir and react for 6h at 25°C, and nitrogen protection is used during the dropwise addition and reaction. After the reaction is completed, add 50g of water, cool to 0-5°C, stir and grow crystals for 1h, filter, and dry to obtain the vitamin B6 aromatic compound.
[0056] The yield of the vitamin B6 aromatic compound is 95.5%, the pyrrole ring impurity content is 0.08%, and the purity is 99.85%.
[0057] Example 6
[0058] A method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content, comprising the steps of:
[0059] In a 500mL four-necked flask, first add 50g of the compound of formula I (wherein R1 is ethyl, R2 is n-propyl, 0.186mol), 200g of dichloromethane, stir evenly, then add 0.06g of tetrabutylammonium bromide, stir evenly, and slowly add 2.05g (0.018mol) of 32% hydrochloric acid aqueous solution with a constant pressure dropping funnel under stirring at 25°C. After the dropping is completed, stir and react at 25°C for 6h, and nitrogen protection is used during the dropping and reaction process. After the reaction is completed, add 50g of water, cool to 0-5°C, stir and grow crystals for 1h, filter with suction, and dry to obtain the vitamin B6 aromatic compound.
[0060] The yield of the vitamin B6 aromatic compound is 93.5%, the pyrrole ring impurity content is 0.28%, and the purity is 99.55%.
[0061] Comparative Example 1
[0062] A method for preparing a vitamin B6 aromatic compound comprises the following steps:
[0063] In a 500mL four-necked flask, first add 50g of the compound of formula I (wherein R1 is ethyl, R2 is n-propyl, 0.186mol) and 50g of ethanol and stir evenly, then slowly add dilute hydrochloric acid (1.69g of 30wt% hydrochloric acid + 150g of water) with a constant pressure dropping funnel under stirring at 50°C. After the addition is complete, stir and react at 50°C for 8h, then at 60°C for 3h. Nitrogen protection is used during the addition and reaction. After the reaction is completed, the system is distilled under reduced pressure until there is no ethanol in the system, and it is directly used for the next step reaction.
[0064] The yield of vitamin B6 aromatic compound is 90%, the pyrrole ring impurity content is 0.97%, and the purity is 98.39%. Figure 4 shown.
[0065] Comparative Example 2
[0066] A method for preparing a vitamin B6 aromatic compound comprises the following steps:
[0067] In a 500mL four-necked flask, first add 50g of the compound of formula I (wherein R1 is ethyl, R2 is n-propyl, 0.186mol) and 200g of dichloromethane, stir evenly, and slowly add 1.1g (0.018mol) of glacial acetic acid dropwise with a constant pressure dropping funnel under stirring at 25°C. After the addition is complete, stir and react at 25°C for 6h, and nitrogen protection is used during the addition and reaction. After the reaction is completed, add 50g of water, cool to 0-5°C, stir and grow crystals for 1h, filter, and dry to obtain the vitamin B6 aromatic compound.
[0068] The yield of vitamin B6 aromatic compound is 85.5%, the content of pyrrole ring impurity is 0.48%, and the purity is 98.45%.
Claims
1. A method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content, comprising the steps of: In an organic solvent, under the action of a phase transfer catalyst and an acid, the compound of formula I is reacted to obtain a compound of formula II; the phase transfer catalyst is one or a combination of two or more of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride; in, In the compounds of formula I and formula II, the substituent R1 is a C1-C4 alkyl group, and R2 is hydrogen or a C1-C4 alkyl group.
2. The method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content according to claim 1, characterized in that: The organic solvent is selected from one or a combination of dichloromethane, n-heptane, chloroform, ethyl acetate, acetone, methanol, ethanol or ethyl acetate, preferably dichloromethane; the mass of the organic solvent is 4 to 5 times the mass of the compound of formula I.
3. The method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content according to claim 1, characterized in that: The phase transfer catalyst is tetrabutylammonium bromide.
4. The method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content according to claim 1, characterized in that: The mass of the phase transfer catalyst is 0.1% to 0.3% of the mass of the compound of formula I.
5. The method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content according to claim 1, characterized in that: The acid is hydrochloric acid, acetic acid, sulfuric acid or ammonium chloride, preferably acetic acid; the molar ratio of the compound of formula I to the acid is 1:0.1-0.
3.
6. The method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content according to claim 1, characterized in that: The acid is added dropwise to the reaction system at 10-40° C. under inert gas protection and stirring; preferably, the inert gas is nitrogen or argon.
7. The method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content according to claim 1, characterized in that: In the compound of formula I and formula II, the substituent R1 is ethyl, and R2 is n-propyl or isopropyl.
8. The method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content according to claim 1, characterized in that: The reaction temperature is 10-40°C, the reaction time is 1-10 hours, and the reaction is carried out under inert gas protection and stirring conditions; preferably, the reaction temperature is 20-30°C, the reaction time is 4-6 hours, and the inert gas is nitrogen or argon.
9. The method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content according to claim 1, characterized in that: The post-treatment method of the reaction liquid obtained by the reaction comprises the steps of adding water to the reaction liquid, cooling to 0-5°C, stirring to grow crystals, filtering, and drying to obtain the vitamin B6 aromatic compound.
10. The method for preparing a vitamin B6 aromatic compound with reduced pyrrole ring impurity content according to claim 1, characterized in that: Includes steps: The compound of formula I and the organic solvent are stirred and mixed evenly, a phase transfer catalyst is added, stirred evenly, the temperature is controlled at 10-40°C, the acid is added dropwise under the protection of inert gas and stirring, the temperature is controlled at 10-40°C, the reaction is stirred for 1-10 hours under the protection of inert gas, after the reaction is completed, water is added, the temperature is lowered to 0-5°C, the crystal is grown by stirring, filtered, and dried to obtain the vitamin B6 aromatic compound.