Synthesis method of vitamin B1 pyrimidine intermediate
Through the new synthesis route, the condensation reaction of 3-aminopropionitrile, methyl formate and acemidine was successfully solved by using the condensation reactions of 3-aminopropionitrile, methyl formate and acemidine, and the problems of high pressure, toxic gases and high wastewater volume in the traditional vitamin B1 pyrimidine intermediate synthesis method were successfully solved, achieving an efficient, environmentally friendly and safe production process.
Patent Information
- Application Number
- CN202411452850.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-17
- Publication Date
- 2025-02-28
AI Technical Summary
The synthesis method of traditional vitamin B1 pyrimidine intermediates has problems such as high requirements for high pressure equipment, toxic gas production, large amount of wastewater, high cost and poor environmental protection.
Using a new synthetic route, 3-formylaminopropionitrile was prepared by the reaction of 3-aminopropionitrile and methyl formate under the action of catalyst, and then reacted with triester orthoformate and catalyst, and finally condensed with acetamidine to obtain the vitamin B1 pyrimidine intermediate. This method does not require the use of carcinogenic substances, the reaction conditions are mild, the equipment requirements are low, and the amount of wastewater is generated.
The high yield and high purity of the target products are achieved, the production costs are reduced, environmental protection and safety are improved, and the use and emission of toxic substances are avoided.
Smart Images
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Abstract
Description
Technical Field
[0001] The invention relates to the field of preparation of vitamin B1, and in particular to a method for synthesizing a vitamin B1 pyrimidine intermediate. Background Art
[0002] Vitamin B1, also known as thiamine, is the earliest water-soluble vitamin purified by humans. Its chemical name is 3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-5-(2-hydroxyethyl)-4-methylthiazolium chloride hydrochloride, which has the function of maintaining normal sugar metabolism. Its structural formula is as follows:
[0003]
[0004] Vitamin B1 has multiple physiological functions: promoting growth; aiding digestion, especially the digestion of carbohydrates; improving mental state; maintaining normal activity of nervous tissue, muscles, and heart; and is necessary for human energy metabolism, especially sugar metabolism.
[0005] 4-amino-5-(formamidomethyl)-2-methylpyrimidine is an important intermediate of vitamin B1. There are two main routes, malononitrile and acrylonitrile, according to the starting material selection. Due to the high cost of malononitrile raw materials, domestic industrial routes mostly use acrylonitrile as raw material. First, acrylonitrile and ammonia react with addition, and the addition product 3-aminopropionitrile reacts with sodium in solvent methyl formate with an equivalent amount of sodium methoxide as a base under high pressure. The sodium product and o-chloroaniline react with hydrochloric acid to obtain enamine, and the enamine and free acetamidine condense to obtain 4-amino-5-(formamidomethyl)-2-methylpyrimidine.
[0006]
[0007] However, the above-mentioned traditional synthesis method of 4-amino-5-(formamidomethyl)-2-methylpyrimidine has the following shortcomings: the sodium generation reaction pressure is 3.0-6.0MPa, the equipment requirements are high, the process produces carbon monoxide, the operating environment requirements are high, and the risk factor is large; the sodium generation reaction uses sodium methoxide, usually 1.5-2.0 equivalents, and the production cost is high; the use of carcinogenic o-chloroaniline as an activating group and a leaving group is not conducive to environmental protection, and the recovery rate of o-chloroaniline is low and the cost is high; a large amount of salt-containing wastewater is generated during the reaction, which increases the cost of "three wastes" treatment; the product yield needs to be further improved. Summary of the invention
[0008] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing a vitamin B1 pyrimidine intermediate. The present invention adopts a new synthesis route, has mild reaction conditions, and has low equipment requirements; does not require the use of carcinogenic o-chloroaniline, does not generate toxic gases, generates less wastewater, and is more environmentally friendly and safe; sodium methoxide is only a catalytic amount, and the cost is relatively low; the reaction selectivity is good, and the yield and purity of the target product are high.
[0009] The technical solution of the present invention is as follows:
[0010] A method for synthesizing a vitamin B1 pyrimidine intermediate comprises the steps of:
[0011] (1) Under the action of catalyst A, 3-aminopropionitrile and methyl formate react to obtain 3-formylaminopropionitrile;
[0012] (2) In solvent A, in the presence of catalyst B, 3-formylaminopropionitrile and orthoformate triester are reacted to obtain N-(2-cyano-3-alkoxyallyl)formamide;
[0013] (3) In solvent B, N-(2-cyano-3-alkoxyallyl)formamide and acetamidine are reacted by condensation to obtain a vitamin B1 pyrimidine intermediate.
[0014] Preferably, in step (1), the molar ratio of 3-aminopropionitrile to methyl formate is 1:1.0-2.0, preferably 1:1.1-1.5. Methyl formate is both a reaction substrate and a reaction solvent.
[0015] Preferably according to the present invention, in step (1), the molar ratio of 3-aminopropionitrile to catalyst A is 1:0.05-0.5, preferably 1:0.1-0.3.
[0016] According to the preferred embodiment of the present invention, in step (1), catalyst A is a solid lower sodium alcoholate, preferably sodium methoxide, sodium ethoxide or sodium isopropoxide, particularly preferably sodium methoxide.
[0017] Preferably, according to the present invention, in step (1), the reaction is a normal pressure reaction, the reaction temperature is 0-30°C, the reaction time is 0.5-5h, and the reaction is carried out under stirring conditions; preferably, the reaction temperature is 0-15°C, and the reaction time is 4h.
[0018] Preferably, in step (1), the post-treatment method of the reaction solution obtained by the reaction is: adding an acid dropwise to the reaction solution to adjust the pH of the system to neutral, then filtering, and concentrating the filtrate under reduced pressure to obtain 3-formylaminopropionitrile.
[0019] Preferably, in step (2), solvent A is an aprotic solvent, preferably one or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, dioxane, n-hexane, n-heptane or cyclohexane, particularly preferably tetrahydrofuran; the volume ratio of the molar amount of 3-formylaminopropionitrile to the solvent A is 1-5 mol / L, preferably 2.5 mol / L.
[0020] According to the preferred embodiment of the present invention, in step (2), catalyst B is a Lewis acid, preferably one or a combination of two of ferric chloride, ferrous chloride, aluminum chloride, zinc chloride, zinc bromide, cupric chloride, cuprous chloride or titanium tetrachloride; the molar ratio of 3-formylaminopropionitrile to catalyst B is 1:0.01-0.2, preferably 1:0.03.
[0021] Preferably according to the present invention, in step (2), the orthoformate triester is trimethyl orthoformate, triethyl orthoformate or triisopropyl orthoformate, preferably trimethyl orthoformate.
[0022] Preferably according to the present invention, in step (2), the molar ratio of 3-formylaminopropionitrile to orthoformate triester is 1:1.0-2.0, preferably 1:1.25.
[0023] Preferably, according to the present invention, in step (2), the reaction temperature is 30-80°C, the reaction time is 3-10h, and the reaction is carried out under stirring; preferably, the reaction temperature is 70°C, and the reaction time is 5h.
[0024] Preferably, in step (2), the post-treatment method of the reaction solution obtained by the reaction is as follows: the reaction solution is concentrated under reduced pressure, cooled to 0-5° C., filtered, the filter cake is washed with tetrahydrofuran, and vacuum dried to obtain N-(2-cyano-3-methoxyallyl)formamide.
[0025] Preferably, in step (3), solvent B is a lower aliphatic alcohol, preferably one or a combination of two or more of methanol, ethanol, isopropanol, n-propanol or n-butanol, particularly preferably methanol; and the mass ratio of N-(2-cyano-3-alkoxyallyl)formamide to solvent B is 1:0.5-1:5, preferably 1:3.
[0026] Preferably according to the present invention, in step (3), the molar ratio of N-(2-cyano-3-alkoxyallyl)formamide to acetamidine is 1:1.1-2.0, preferably 1:1.66.
[0027] Preferably, in step (3) of the present invention, the reaction conditions are as follows: the reaction temperature is 60-85°C, the reaction is carried out under stirring conditions, the solvent B is evaporated during the reaction, and the reaction is continued with stirring for 3-5 hours after the evaporation is completed.
[0028] Preferably, in step (3) of the present invention, the post-treatment method of the reaction solution obtained by the reaction is as follows: add solvent B to the reaction solution, stir and cool to 0-10°C, filter, wash the filter cake with solvent B, and vacuum dry to obtain the vitamin B1 pyrimidine intermediate.
[0029] Preferably, according to the present invention, the method for synthesizing the vitamin B1 pyrimidine intermediate comprises the steps of:
[0030] (1) 3-aminopropionitrile and methyl formate are mixed, cooled to 0-15° C., catalyst A is slowly added, and the temperature is controlled at 0-30° C. and stirred at normal pressure for 0.5-5 h; glacial acetic acid is added dropwise to neutralize to pH 7, filtered, and concentrated under reduced pressure to obtain 3-formylaminopropionitrile;
[0031] (2) Add 3-formylaminopropionitrile to solvent A, add orthoformate triester and catalyst B under stirring, heat to 30-80° C., reflux and stir for 3-10 hours, cool to room temperature after the reaction is completed, concentrate under reduced pressure, cool to 0-5° C., filter, wash the filter cake with solvent A, and vacuum dry to obtain N-(2-cyano-3-alkoxyallyl)formamide;
[0032] (3) Mix the solvent B solution of free acetamidine and N-(2-cyano-3-alkoxyallyl)formamide, raise the temperature to 60-85°C and stir to react, evaporate the solvent B while reacting, and continue to keep the temperature and stir for 3-5 hours after evaporating the solvent B. After the reaction is completed, add solvent B, stir and cool to 0-10°C, filter, wash the filter cake with solvent B, and vacuum dry to obtain vitamin B1 pyrimidine intermediate.
[0033] The synthesis process route of the present invention is as follows:
[0034]
[0035] The technical features and beneficial effects of the present invention are as follows:
[0036] 1. In the process of preparing 3-formylaminopropionitrile by reacting 3-aminopropionitrile with methyl formate of the present invention, the reaction conditions are mild, the reaction is under normal pressure, the equipment requirements are low, no toxic gas carbon monoxide is generated, it is more environmentally friendly and safe, the sodium alcoholate used is only a catalytic amount, and the cost is significantly reduced.
[0037] 2. The method of the present invention does not need to use carcinogenic o-chloroaniline, avoids the residue of toxic substances in vitamin B1, and substantially improves the quality and safety of the product. At the same time, the operator avoids contact with toxic substances and avoids the discharge of toxic substances, which is more environmentally friendly and meets the requirements of green chemical development. The method of the present invention generates less salt-containing wastewater, is green and environmentally friendly, and has low cost.
[0038] 3. The method of the present invention is a new route for synthesizing vitamin B1 pyrimidine intermediates, with high reaction selectivity, few side reactions, and a total yield of the target product of 80%-85% with high purity, which is significantly higher than the yield of 65%-70% of the traditional sodium substitution reaction route, and the economic benefits are significantly improved. DETAILED DESCRIPTION
[0039] The present invention is further described below in conjunction with specific examples. The experimental methods used in the examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the examples, unless otherwise specified, can all be obtained from commercial sources.
[0040] Example 1
[0041] A method for synthesizing a vitamin B1 pyrimidine intermediate comprises the steps of:
[0042] Step 1:
[0043] 70.0 g (1 mol) of 3-aminopropionitrile and 78.0 g (1.3 mol) of methyl formate were added to the reaction bottle, cooled to 0-15°C, and 5.4 g (0.1 mol) of sodium methoxide were slowly added. After the addition, the reaction temperature increased significantly, and the temperature was controlled at 10-15°C and stirred at normal pressure for 4 hours. Glacial acetic acid was added dropwise to neutralize the sodium methoxide to a pH of 7, and the sodium acetate was filtered to remove the excess methyl formate and the generated methanol. The product 3-formylaminopropionitrile was obtained with a purity of 96.7% and a yield of 97.8%. The oil was directly used for the next step reaction.
[0044] Step 2:
[0045] The 3-formylaminopropionitrile obtained in the previous step was added to 400 ml of tetrahydrofuran, and 132.5 g (1.25 mol) of trimethyl orthoformate and 4.1 g (0.03 mol) of anhydrous zinc chloride were added under stirring. The temperature was raised to 70° C. and refluxed with stirring for 5 h. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was concentrated under reduced pressure until about 250 ml remained. The temperature was lowered to 0-5° C., filtered, and the filter cake was washed with a small amount of tetrahydrofuran. The mixture was dried in vacuo to obtain N-(2-cyano-3-methoxyallyl)formamide with a purity of 98.2% and a yield of 94.5%.
[0046] Step 3:
[0047] A methanol solution of 96.5 g (1.66 mol) of free acetamidine (wherein the methanol content is 300 g, and the methanol solution of free acetamidine is obtained by fully mixing acetamidine hydrochloride and sodium methoxide methanol solution to free them, cooling, filtering and desalting) is added to a reaction bottle, and N-(2-cyano-3-methoxyallyl)formamide obtained in step 2 is added to the reaction solution, and the temperature is raised to 60-65°C and stirred for reaction, and methanol is evaporated while reacting. After the methanol is evaporated, the temperature is kept warm and stirred for 5 hours. After the reaction is completed, 138 g of methanol is added, and the temperature is lowered to 0-10°C with stirring, and filtered. The filter cake is washed with a small amount of methanol, and dried in a vacuum at 40-50°C for 2 hours to obtain a vitamin B1 pyrimidine intermediate with a liquid phase purity of 98.9% and a yield of 90.2%.
[0048] The total yield of the three-step reaction was 83.4%.
[0049] Example 2-Example 6
[0050] A method for synthesizing a vitamin B1 pyrimidine intermediate is as described in Example 1, except that in step 2, the Lewis acid anhydrous zinc chloride is replaced with the Lewis acid in Table 1 below in the same molar amount; the other steps and conditions are the same as in Example 1. The single-step yield data of step 2 is shown in Table 1 below.
[0051] Table 1 Yield data
[0052] Example Lewis acid Yield Example 2 Ferrous chloride 90.1％ Example 3 Zinc bromide 94.3％ Example 4 Cuprous chloride 92.7％ Example 5 Titanium Tetrachloride 85.2％ Example 6 Aluminum chloride 85.0％
[0053] Examples 7-12
[0054] A method for synthesizing a vitamin B1 pyrimidine intermediate is as described in Example 1, except that in step 2, the solvent tetrahydrofuran is replaced with the same volume of the solvent in Table 2 below; the other steps and conditions are the same as in Example 1. The single-step yield data of step 2 is shown in Table 2 below.
[0055] Table 2 Yield data
[0056] Example Solvents Yield Example 7 2-Methyltetrahydrofuran 93.3％ Example 8 Toluene 92.2％ Example 9 Xylene 90.6％ Example 10 n-Hexane 93.9％ Embodiment 11 n-Heptane 93.1％ Example 12 Cyclohexane 93.6％
Claims
1. A method for synthesizing a vitamin B1 pyrimidine intermediate, comprising the steps of: (1) Under the action of catalyst A, 3-aminopropionitrile and methyl formate react to obtain 3-formylaminopropionitrile; (2) In solvent A, in the presence of catalyst B, 3-formylaminopropionitrile and orthoformate triester are reacted to obtain N-(2-cyano-3-alkoxyallyl)formamide; (3) In solvent B, N-(2-cyano-3-alkoxyallyl)formamide and acetamidine are reacted by condensation to obtain a vitamin B1 pyrimidine intermediate.
2. The method for synthesizing the vitamin B1 pyrimidine intermediate according to claim 1, characterized in that: In step (1), one or more of the following conditions are included: i. The molar ratio of 3-aminopropionitrile to methyl formate is 1:1.0-2.0, preferably 1:1.1-1.5; ii. The molar ratio of 3-aminopropionitrile to catalyst A is 1:0.05-0.5, preferably 1:0.1-0.3; iii. Catalyst A is a solid lower sodium alcoholate, preferably sodium methoxide, sodium ethoxide or sodium isopropoxide, particularly preferably sodium methoxide.
3. The method for synthesizing the vitamin B1 pyrimidine intermediate according to claim 1, characterized in that: In step (1), one or more of the following conditions are included: i. The reaction is carried out under normal pressure, the reaction temperature is 0-30°C, the reaction time is 0.5-5h, and the reaction is carried out under stirring; preferably, the reaction temperature is 0-15°C, and the reaction time is 4h; ii. The post-treatment method of the reaction solution obtained by the reaction is: adding an acid dropwise to the reaction solution to adjust the pH of the system to neutral, then filtering, and concentrating the filtrate under reduced pressure to obtain 3-formylaminopropionitrile.
4. The method for synthesizing the vitamin B1 pyrimidine intermediate according to claim 1, characterized in that: In step (2), solvent A is an aprotic solvent, preferably one or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, dioxane, n-hexane, n-heptane or cyclohexane, particularly preferably tetrahydrofuran; the volume ratio of the molar amount of 3-formylaminopropionitrile to solvent A is 1-5 mol / L, preferably 2.5 mol / L.
5. The method for synthesizing the vitamin B1 pyrimidine intermediate according to claim 1, characterized in that: In step (2), catalyst B is a Lewis acid, preferably one or a combination of two of ferric chloride, ferrous chloride, aluminum chloride, zinc chloride, zinc bromide, cupric chloride, cuprous chloride or titanium tetrachloride; the molar ratio of 3-formylaminopropionitrile to catalyst B is 1:0.01-0.2, preferably 1:0.
03.
6. The method for synthesizing the vitamin B1 pyrimidine intermediate according to claim 1, characterized in that: In step (2), the orthoformate triester is trimethyl orthoformate, triethyl orthoformate or triisopropyl orthoformate, preferably trimethyl orthoformate.
7. The method for synthesizing the vitamin B1 pyrimidine intermediate according to claim 1, characterized in that: In step (2), the molar ratio of 3-formylaminopropionitrile to orthoformate triester is 1:1.0-2.0, preferably 1:1.
25.
8. The method for synthesizing the vitamin B1 pyrimidine intermediate according to claim 1, characterized in that: In step (2), one or more of the following conditions are included: i. The reaction temperature is 30-80°C, the reaction time is 3-10h, and the reaction is carried out under stirring; preferably, the reaction temperature is 70°C, and the reaction time is 5h; ii. The post-treatment method of the reaction solution obtained by the reaction is as follows: the reaction solution is concentrated under reduced pressure, cooled to 0-5° C., filtered, the filter cake is washed with tetrahydrofuran, and vacuum dried to obtain N-(2-cyano-3-methoxyallyl)formamide.
9. The method for synthesizing the vitamin B1 pyrimidine intermediate according to claim 1, characterized in that: In step (3), one or more of the following conditions are included: i. Solvent B is a lower aliphatic alcohol, preferably one or a combination of two or more of methanol, ethanol, isopropanol, n-propanol or n-butanol, particularly preferably methanol; the mass ratio of N-(2-cyano-3-alkoxyallyl)formamide to solvent B is 1:0.5-1:5, preferably 1:3; ii. The molar ratio of N-(2-cyano-3-alkoxyallyl)formamide to acetamidine is 1:1.1-2.0, preferably 1:1.
66.
10. The method for synthesizing the vitamin B1 pyrimidine intermediate according to claim 1, characterized in that: In step (3), one or more of the following conditions are included: i. The reaction conditions are as follows: the reaction temperature is 60-85°C, the reaction is carried out under stirring, the solvent B is evaporated during the reaction, and the stirring reaction is continued for 3-5 hours after the evaporation is completed; ii. The post-treatment method of the reaction solution is as follows: add solvent B to the reaction solution, stir and cool to 0-10°C, filter, wash the filter cake with solvent B, and vacuum dry to obtain vitamin B1 pyrimidine intermediate.