Production process of fluorouracil

Abstract

The invention relates to the technical field of pharmaceutical engineering, in particular to a fluorouracil production process which specifically comprises the following condensation reaction steps: S1, adding a base catalyst into dichloromethane, and dropwise adding ethyl formate and ethyl fluoroacetate to obtain a mixture, the mass of the dichloromethane is 3-7 times that of the ethyl fluoroacetate, and the molar equivalence ratio of the added base catalyst to the ethyl formate to the ethyl fluoroacetate is (2.5-3.5): 2.5: 1; s2, controlling the temperature of the mixture obtained in S1 to 30-40 DEG C, and continuously stirring to react for 0.5-2 hours to obtain an intermediate state substance; according to the production process of the fluorouracil, provided by the invention, the production cost during mass production can be remarkably reduced, and meanwhile, the quality and the stability of the fluorouracil product are ensured.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a production process of fluorouracil. Background Art

[0002] Fluorouracil (5-fluorouracil, fluorouracil, fluorouracil fluorouracil, fluorouracil fluorouracil) is currently the most widely used anti-tumor small molecule drug, which blocks the conversion of deoxyuridine nucleotide (dUMP) into deoxythymidine nucleotide (dTMP), thereby interfering with the DNA synthesis of cancer cells. In the clinical treatment of cancer, intravenous injection of fluorouracil is an important part of chemotherapy for colorectal cancer.

[0003] There are two synthetic routes of fluorouracil recorded in the existing literature (Zhao Jinlong. 5--Research on the Synthesis Process of Fluorouracil. Master's degree thesis, Wuhan University of Science and Technology, 2012):

[0004] Synthesis route 1: Using uracil as the starting material and fluorine gas diluted with an inert gas as the fluorine source, the corresponding intermediate (5-fluoro-6-ethoxy-5,6-dihydropyrimidine) is generated in an acidic solvent, and then post-processed to obtain fluorouracil. The reaction formula of this route is as follows:

[0005]

[0006] Synthesis route 2: Ethyl fluoroacetate is used as the starting material, which reacts with ethyl formate to generate ethyl fluoroformylacetate potassium enolate, which then reacts with O-methylisourea sulfate to generate the corresponding intermediate (2-methoxy-5-fluorouracil), which is then hydrolyzed with acid to obtain fluorouracil.

[0007]

[0008] Since the fluorine gas used in synthetic route 1 is a highly toxic gas, expensive and highly dangerous, in order to reduce production costs and make the production process more environmentally friendly, safe and controllable, synthetic route 2 can be used as a synthetic route to guide the production process. However, there is no document in the prior art on how to optimize the production process based on synthetic route 2, improve the reaction efficiency, prepare fluorouracil with low impurity content and high stability, and meet the requirements of mass production. Summary of the invention

[0009] In view of the above technical problems, the present invention proposes a production process of fluorouracil, comprising the following condensation reaction steps:

[0010] S1: adding a base catalyst to dichloromethane, and then dropwise adding ethyl formate and ethyl fluoroacetate to obtain a mixture, wherein the base catalyst is any one of sodium methoxide, sodium ethoxide, and potassium ethoxide, the mass of dichloromethane is 3-7 times the mass of ethyl fluoroacetate, and the molar equivalent ratio of the added base catalyst, ethyl formate, and ethyl fluoroacetate is 2.5-3.5:2.5:1;

[0011] S2 controls the temperature of the mixture obtained in S1 to 30-40°C, and continuously stirs and reacts for 0.5-2h to obtain an intermediate substance, wherein the intermediate substance mainly includes the compound C5H6FNaO3, and its chemical formula is as follows:

[0012]

[0013] Furthermore, the method further comprises the following cyclization reaction step:

[0014] S3: adding methanol and O-methylisourea sulfate to the intermediate substance obtained in S2, raising the temperature to 30-60° C., and continuously stirring the reaction for 3-7 hours, wherein the mass of methanol is 4-20 times the mass of ethyl fluoroacetate, and the molar equivalent ratio of the added O-methylisourea sulfate to ethyl fluoroacetate is 0.5-0.7:1;

[0015] S4: The solution after the reaction in S3 is concentrated under reduced pressure to remove the solvent, purified water is added to dissolve and stirred at 80-90°C for 1-2h, and the insoluble matter is filtered out and the filtrate is collected. The filtrate includes the fluorouracil intermediate C5H5FN2O2, and its chemical formula is as follows:

[0016]

[0017] Among them, the mass of purified water is 10-15 times the mass of ethyl fluoroacetate.

[0018] Furthermore, after the cyclization reaction step, a step of preparing a crude fluorouracil product and a refining step are sequentially included, and the step of preparing a crude fluorouracil product specifically includes:

[0019] S5 dissolves the fluorouracil intermediate, adjusts the pH value of the solution to 4.5±0.2, controls the temperature to 0-40°C, stirs and crystallizes for 1-10 hours, filters, washes the filter cake with purified water 1-2 times, and then dries the filter cake at 70-80°C for 4-5 hours to obtain a crude fluorouracil product.

[0020] Furthermore, the base catalyst in S1 is sodium methoxide, and the molar equivalent ratio of sodium methoxide, ethyl acetate and ethyl fluoroacetate is 2.5:2.5:1.

[0021] Furthermore, the mass of dichloromethane in S1 is 4 times the mass of ethyl fluoroacetate.

[0022] Furthermore, in S2, the mixture obtained in S1 is temperature-controlled to 40° C. under reflux conditions, and the reaction is continuously stirred for 0.5.

[0023] Further, S3 adds methanol and O-methylisourea sulfate to the intermediate substance obtained in S2, controls the temperature to 30-50° C., and continues stirring the reaction for 3-4 hours.

[0024] Furthermore, the mass of methanol in S3 is 4 times the mass of ethyl fluoroacetate, and the molar equivalent ratio of the added O-methylisourea sulfate to ethyl fluoroacetate is 0.5:1.

[0025] Further, in S5, the temperature is controlled to 10-30° C. and the crystallization is stirred for 1-2 hours.

[0026] Furthermore, the refining step comprises:

[0027] S6: The crude fluorouracil is dissolved in purified water at a temperature of 85-95°C, and then activated carbon is added for decolorization for 1 hour. The decolorized solution is filtered and crystallized, and the filtered residue is dried under reduced pressure at 70-80°C for more than 6 hours to obtain the finished fluorouracil.

[0028] The production process of fluorouracil proposed in the present invention can significantly reduce the production cost during mass production, while ensuring the quality and stability of the fluorouracil product. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1-1 : Flow chart of embodiment 5;

[0030] Figure 1-2 : Flow chart of embodiment 5;

[0031] Figure 2 : Flow chart of Example 6;

[0032] Figure 3 : Flow chart of Example 9. DETAILED DESCRIPTION

[0033] The content of the present invention is further illustrated by the following examples, but it should not be construed as limiting the present invention. Without departing from the spirit and essence of the present invention, the modification or replacement of the method, steps or conditions of the present invention all belongs to the scope of the present invention. The main production equipment used in the following examples is shown in Table 1. The output represented by the term "large-scale production" involved in the following examples and test examples is at least 15 kg.

[0034] Table 1. List of main production equipment

[0035]

[0036] Example 1

[0037] In this embodiment, fluorouracil intermediate is prepared by reacting raw material 1 (SM1) ethyl fluoroacetate and raw material 2 (SM2) O-methylisourea sulfate in sequence through a condensation reaction step and a cyclization reaction step. The specific steps are as follows:

[0038] S1: adding a base catalyst to dichloromethane, and then dropwise adding ethyl formate and ethyl fluoroacetate to obtain a mixture, wherein the base catalyst is sodium methoxide, the mass of dichloromethane is 3-7 times the mass of ethyl fluoroacetate, and the molar equivalent ratio of the added base catalyst, ethyl formate and ethyl fluoroacetate is 2.5-3.5:2.5:1;

[0039] S2 controls the temperature of the mixture obtained in S1 to 30-40°C, and continuously stirs and reacts for 0.5-2h to obtain an intermediate substance, wherein the intermediate substance mainly includes the compound C5H6FNaO3, and its chemical formula is as follows:

[0040]

[0041] It should be noted that the intermediate substance is a viscous substance in appearance. In addition to the main compound C5H6FNaO3, it also includes a small amount of water and trace impurities.

[0042] S3: adding methanol and O-methylisourea sulfate to the intermediate substance obtained in S2, raising the temperature to 30-60° C., and continuously stirring the reaction for 3-7 hours, wherein the mass of methanol is 4-20 times the mass of ethyl fluoroacetate, and the molar equivalent ratio of the added O-methylisourea sulfate to ethyl fluoroacetate is 0.5-0.7:1;

[0043] S4: The solution after the reaction in S3 is concentrated under reduced pressure to remove the solvent, purified water is added to dissolve and stirred at 80-90°C for 1-2h, and the insoluble matter is filtered out and the filtrate is collected; wherein the mass of the purified water is 10-15 times the mass of ethyl fluoroacetate; the filtrate includes the fluorouracil intermediate C5H5FN2O2, and its chemical formula is as follows:

[0044]

[0045] In the above steps, S1-2 is a condensation reaction step, and S3-4 is a cyclization reaction step.

[0046] Example 2

[0047] Based on Example 1, the following parameters of S1 were optimized: the molar equivalent ratio of sodium methoxide, ethyl acetate and ethyl fluoroacetate was 2.5:2.5:1. The mass of dichloromethane was 4 times that of ethyl fluoroacetate.

[0048] Example 3

[0049] On the basis of Example 2, the following parameters of S2 were optimized: the mixture obtained in S1 was temperature-controlled to 40° C. under reflux conditions, and the reaction was stirred continuously for 0.5.

[0050] Example 4

[0051] On the basis of Example 3, the following parameters of S3 were optimized: methanol and O-methylisourea sulfate were added to the intermediate substance obtained in S2, the temperature was controlled to 30-50°C, and the reaction was stirred for 3-4 hours. The mass of methanol was 4 times the mass of ethyl fluoroacetate, and the molar equivalent ratio of the added O-methylisourea sulfate to ethyl fluoroacetate was 0.5:1.

[0052] Example 5

[0053] A preferred embodiment process based on embodiment 4 is shown in FIG1 , and the specific steps are as follows:

[0054] Add 180L of dichloromethane and 57.2kg of sodium methoxide to a 1000L enamel reactor, and then slowly add 78.5kg of ethyl formate and 45kg of ethyl fluoroacetate. After the addition is completed, control the temperature to 30-40°C and stir to react for 0.5h to obtain an intermediate substance.

[0055] Add 180 L of methanol and 52.2 kg of O-methylisourea sulfate to the intermediate substance, raise the temperature to 30-50° C. and stir to react for 3-4 hours.

[0056] After the reaction is completed, the solvent is removed by concentrating under reduced pressure below 50°C, 585L of purified water is added, and the solution is stirred to dissolve. The pH of the solution is adjusted to 4.5±0.2 with an appropriate amount of hydrochloric acid, and then the temperature is lowered to 10-30°C, stirred for crystallization for 1-2h, filtered, and the filter cake is collected.

[0057] Add the filter cake and 90L purified water to a 200L enamel reactor, heat to 80-90°C, stir and beat for 2h, cool to 10-30°C, stir and crystallize for 1-2h, filter, and collect the filter cake. Add the filter cake and 90L purified water to a 200L enamel reactor, heat to 80-90°C, stir and beat for 2h, cool to 10-30°C, stir and crystallize for 1-2h, filter, collect the filter cake, and dry under reduced pressure at 70-80°C for not less than 4h to obtain a fluorouracil intermediate.

[0058] Table 2. List of materials used in the synthesis of fluorouracil intermediates

[0059]

[0060] The yield range of the fluorouracil intermediate in this example is 40-50%.

[0061] Example 6

[0062] Based on Example 5, it also includes Figure 2 The following steps are shown for preparing crude fluorouracil:

[0063] S5 uses the fluorouracil intermediate prepared in Example 5, adjusts the pH value of the fluorouracil intermediate solution to 4.5±0.2, stirs and crystallizes at a temperature of 0-40°C for 1-10 hours, filters, washes the filter cake with purified water 1-2 times, and then dries the filter cake at 70-80°C for 4-5 hours to obtain a crude fluorouracil product.

[0064] Table 3. List of materials used in the synthesis of crude fluorouracil

[0065]

[0066] Example 7

[0067] A preferred embodiment based on Example 6 carried out 3 batches of crude product tests, and the specific steps are as follows:

[0068] Add 27.2 L of purified water and 49.8 L of hydrochloric acid to a 200 L enamel reactor, stir evenly, then add 25.58 kg of fluorouracil intermediate (solution), heat to 40-50 ° C, stir and react for 2-3 hours, and monitor the reaction progress by TLC.

[0069] After the reaction is completed, the temperature is lowered to 0-20°C and stirred for crystallization for 1-2 hours, filtered, the filter cake is washed with an appropriate amount of purified water, the filter cake is collected, and dried under reduced pressure at 70-80°C for 4 hours to obtain crude fluorouracil.

[0070] The three batches of crude fluorouracil prepared had yields of 84.71% to 86.47% and purities of more than 99%, indicating that the preparation process of crude fluorouracil was stable and had good reproducibility.

[0071] Example 8

[0072] Based on Example 7, the method further includes a purification step of the crude fluorouracil product: S6: the crude fluorouracil product is dissolved in purified water at a temperature of 85-95°C, and then activated carbon is added for decolorization for 1 hour. The amount of activated carbon used is 5% of the quality of the crude product. The decolorized solution is filtered and crystallized, and the filtered residue is dried under reduced pressure at 70-80°C for more than 6 hours to obtain a finished fluorouracil product.

[0073] Example 9

[0074] Based on Example 8, a preferred embodiment is Figure 3 As shown, three batches of crude fluorouracil prepared in Example 7 were used to prepare three batches of finished fluorouracil products according to the following purification steps:

[0075] Add 19.92kg of crude fluorouracil and 239L of purified water to a 300L stainless steel reactor, heat to 85-95°C and stir to dissolve (i.e., purified water slurrying process), add 1.0kg of activated carbon (approximately 5% of the quality of crude fluorouracil), and stir to decolorize at 85-95°C for 1h. Filter while hot, transfer the filtrate to a 1000L crystallization tank, cool to 0-10°C and stir to crystallize for 1-2h. Filter, wash the filter cake with an appropriate amount of purified water, collect the filter cake, and dry it under reduced pressure at 70-80°C for not less than 2h to obtain the finished fluorouracil.

[0076] Table 4. List of materials used for crude product refining

[0077]

[0078] The yields of the three batches of fluorouracil products were 78.42% to 80.17%, the purities were all over 99.5%, and the maximum single impurity was less than 0.05%, indicating that the purification process of fluorouracil was stable and reproducible.

[0079] Example 10

[0080] This example is the optimal range of various parameters for preparing fluorouracil intermediates determined based on the above examples 1-5.

[0081] Table 5. Optimal ranges of various parameters of fluorouracil intermediates

[0082]

[0083]

[0084] Test Example 1 Comparative test of condensation reaction solvent types

[0085] In parallel, under nitrogen protection, add 100 ml of toluene, dichloromethane, tetrahydrofuran and 26 g (0.48 mol, 2.5 eq) of sodium methoxide to a 1 L reaction bottle, then add 34.8 g (0.47 mol, 2.5 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate dropwise. After the addition is complete, raise the temperature to 40 °C and stir the reaction (take samples at 0.5 h, 2 h, and 4 h to detect the remaining amount of ethyl fluoroacetate) to obtain an intermediate state.

[0086] The intermediate state was cooled to 0±5°C, 400 ml of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate were added, and the temperature was raised to 60°C and stirred for reaction for 5 h.

[0087] After the reaction is completed, the solvent is removed by vacuum concentration, 260 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The filtrate is weighed and sampled for testing of the content of related substances and fluorouracil intermediates.

[0088] Table 6. Condensation reaction solvent type comparison test results

[0089]

[0090] Analysis of test results: When tetrahydrofuran, toluene and dichloromethane were used as condensation reaction solvents, the ethyl fluoroacetate was completely reacted after 2 hours of reaction. When toluene and dichloromethane were used as condensation reaction solvents, there was no significant difference in the related substances and conversion rate of the obtained fluorouracil intermediates, and toluene was better than tetrahydrofuran. Because toluene is highly toxic and its price is higher than dichloromethane, it is not conducive to large-scale production.

[0091] Therefore, dichloromethane is preferred as the condensation reaction solvent.

[0092] Test Example 2 Comparative test of the amount of solvent used in the condensation reaction

[0093] In parallel, under nitrogen protection, add 60 ml (3 times), 80 ml (4 times), 100 ml (5 times), 120 ml (6 times), 140 ml (7 times) of dichloromethane and 26 g (0.48 mol, 2.5 eq) of sodium methoxide to a 1 L reaction bottle, then add 34.8 g (0.47 mol, 2.5 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate dropwise in sequence. After the addition is complete, raise the temperature to 40°C and stir the reaction (take samples at 0.5 h, 1 h, and 2 h to detect the remaining amount of ethyl fluoroacetate) to obtain an intermediate state.

[0094] The intermediate state was cooled to 0±5°C, 400 ml of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate were added, and the temperature was raised to 60°C and stirred for reaction for 5 h.

[0095] After the reaction is completed, the solvent is removed by vacuum concentration, 260 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The filtrate is weighed and sampled for testing of the content of related substances and fluorouracil intermediates.

[0096] Table 7. Condensation solvent dosage comparison test results

[0097]

[0098]

[0099] Analysis of the test results: when the amount of dichloromethane is 3 to 7 times the amount of ethyl fluoroacetate, there is no significant difference in the related substances in the filtrate before crystallization of the obtained fluorouracil intermediate and the conversion rate of the fluorouracil intermediate; when the amount of condensation reaction solvent is 3 times the amount of ethyl fluoroacetate, the intermediate state obtained by the reaction is very viscous and difficult to stir, which is not conducive to large-scale production operations.

[0100] Therefore, the amount of condensation reaction solvent used is preferably 4 times.

[0101] Test Example 3 Comparative Test of Condensation Reaction Temperature and Time

[0102] In parallel, under nitrogen protection, add 80 ml of dichloromethane and 26 g (0.48 mol, 2.5 eq) of sodium methoxide to a 1 L reaction bottle, then add 34.8 g (0.47 mol, 2.5 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate dropwise in sequence. After the addition, control the temperature to 0°C, 10°C, 20°C, 30°C, and 40°C (reflux) respectively, and stir the reaction for 0.5 h (take samples to detect the remaining amount of ethyl fluoroacetate) to obtain an intermediate state.

[0103] The intermediate state was cooled to 0±5°C, 400 ml of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate were added, and the temperature was raised to 60°C and stirred for reaction for 5 h.

[0104] After the reaction is completed, the solvent is removed by vacuum concentration, 260 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The filtrate is weighed and sampled for testing of the content of related substances and fluorouracil intermediates.

[0105] Table 8. Condensation reaction temperature comparison test results

[0106]

[0107]

[0108] Analysis of experimental results: The condensation reaction was completed for 0.5h at different temperatures with ethyl fluoroacetate. The condensation temperature was 0℃~40℃, and there was no significant difference in the related substances in the filtrate before crystallization of the obtained fluorouracil intermediate. When the reaction temperature was lower than 30℃, the lower the temperature, the lower the conversion rate of the fluorouracil intermediate. When the reaction temperature was 30℃ and 40℃ (reflux), there was no significant difference in the conversion rate of the fluorouracil intermediate.

[0109] The preferred condensation reaction temperature is determined to be 30-40°C (reflux), and the condensation reaction time is 0.5h.

[0110] Test Example 4 Comparative Test on the Dosage of Ethyl Formate

[0111] In parallel, under nitrogen protection, add 80 ml of dichloromethane and 26 g (0.48 mol, 2.5 eq) of sodium methoxide to a 1 L reaction bottle, and then add 14.0 g (0.19 mol, 1.0 eq), 20.9 g (0.28 mol, 1.5 eq), 27.9 g (0.38 mol, 2.0 eq), 34.8 g (0.47 mol, 2.5 eq), 41.9 g (0.57 mol, 3.0 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate dropwise respectively. After the addition is complete, raise the temperature to 30-40 ° C and stir the reaction for 0.5 h (take a sample to detect the remaining amount of ethyl fluoroacetate) to obtain an intermediate substance.

[0112] The intermediate substance was cooled to 0±5°C, 400 ml of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate were added, and the temperature was raised to 60°C and stirred for reaction for 5 h.

[0113] After the reaction is completed, the solvent is removed by vacuum concentration, 260 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The filtrate is weighed and sampled for testing of the content of related substances and fluorouracil intermediates.

[0114] Table 9. Comparative test results of ethyl formate dosage

[0115]

[0116] Analysis of the experimental results: As the amount of ethyl formate increases, the purity and conversion rate of the fluorouracil intermediate also increase. When the amount of ethyl formate increases to 2.5eq, the purity and conversion rate reach the highest. If the amount of ethyl formate continues to increase, the purity and conversion rate of the fluorouracil intermediate will no longer increase.

[0117] The preferred amount of ethyl formate fed is 2.5 eq.

[0118] Experimental Example 5 Comparative Test of Different Types of Bases in the Condensation Reaction Step

[0119] In three parallel batches, 80 ml of dichloromethane and 2.5 eq of three different bases (26 g of sodium methoxide, 32 g of sodium ethoxide and 39.6 g of potassium ethoxide) were added to a 1 L reaction bottle respectively, followed by dropwise addition of 34.8 g (0.47 mol, 2.5 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate. After the addition was complete, the temperature was raised to 30-40°C and stirred for reaction for 1 h (samples were taken at 0.5 h and 1 h to detect the remaining amount of ethyl fluoroacetate) to obtain an intermediate substance.

[0120] At room temperature, 400 ml of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate were added to the above intermediate state, and the temperature was raised to 60° C. and stirred for reaction for 5 h.

[0121] After the reaction is completed, the solvent is removed by vacuum concentration, 260 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The filtrate is weighed and sampled for testing of the content of related substances and fluorouracil intermediates.

[0122] Table 10. Comparative test results of condensation reactions using different types of bases

[0123]

[0124] According to the test results in the above table, sodium methoxide, sodium ethoxide and potassium ethoxide as reaction bases can all make ethyl fluoroacetate react completely; there is no obvious difference in the conversion rate of fluorouracil intermediate and related substances obtained by the reaction of sodium ethoxide and sodium methoxide, and both are better than potassium ethoxide.

[0125] Since the price of sodium ethoxide is about twice that of sodium methoxide, sodium methoxide is preferred.

[0126] Test Example 6 Comparative Test of Methanol and O-Methylisourea Sulfate with and without Cooling Before Feeding

[0127] In parallel, under nitrogen protection, add 80 ml of dichloromethane and 26 g (0.48 mol, 2.5 eq) of sodium methoxide to a 1 L reaction bottle, then add 34.8 g (0.47 mol, 2.5 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate dropwise in sequence. After the addition is complete, heat to 30-40 °C and stir to react for 0.5 h to obtain an intermediate substance.

[0128] In one portion, the intermediate substance was cooled to 0±5°C, 400 ml of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate were added, and the temperature was raised to 60°C and stirred for reaction for 5 h.

[0129] To the other portion, 400 ml of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate were added without cooling, and the temperature was raised to 60° C. and stirred for reaction for 5 h.

[0130] After the reaction is completed, the solvent is removed by vacuum concentration, 260 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The filtrate is weighed and sampled for testing of the content of related substances and fluorouracil intermediates.

[0131] Table 11. Positive and negative comparison test results of cooling conditions

[0132]

[0133] According to the test results in the above table, whether or not to cool before adding methanol and SM2 has no obvious effect on the conversion rate of fluorouracil intermediates and related substances. Considering the simplicity of production operation, it is not necessary to cool before adding methanol and SM2.

[0134] Test Example 7 Comparative test of nitrogen protection conditions and non-nitrogen protection conditions throughout the condensation reaction

[0135] Two parallel experiments were conducted, one of which was carried out under nitrogen protection throughout the condensation reaction step (S1-S2 of Example 1), and the other was carried out without nitrogen protection during the condensation reaction step.

[0136] Add 80 ml of dichloromethane and 26 g (0.48 mol, 2.5 eq) of sodium methoxide to a 1 L reaction bottle, then add 34.8 g (0.47 mol, 2.5 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate dropwise in sequence. After the addition is complete, heat to 30-40 °C and stir to react for 0.5 h to obtain an intermediate substance.

[0137] At room temperature, 400 ml of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate were added to the intermediate substance, and the temperature was raised to 60° C. and stirred for reaction for 5 h.

[0138] After the reaction is completed, the solvent is removed by vacuum concentration, 260 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The filtrate is weighed and sampled for testing of the content of related substances and fluorouracil intermediates.

[0139] Table 12. Positive and negative control test results of nitrogen protection conditions for condensation reaction

[0140]

[0141] According to the test results in the above table, the presence or absence of nitrogen protection has no obvious effect on the conversion rate of the fluorouracil intermediate obtained by the reaction and related substances. Considering the simplicity of production operation, it is preferred not to carry out nitrogen protection during the reaction.

[0142] Experimental Example 8 Comparative Test of Cyclization Reaction Temperature

[0143] In parallel, add 80 ml of dichloromethane and 26 g (0.48 mol, 2.5 eq) of sodium methoxide to a 1 L reaction bottle, then add 34.8 g (0.47 mol, 2.5 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate dropwise in sequence. After the addition is complete, heat to 30-40 °C and stir to react for 0.5 h to obtain an intermediate state.

[0144] At room temperature, add 400 ml of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate to the intermediate state, raise the temperature to 30°C, 40°C, 50°C, 60°C, and 65°C (reflux), respectively, and stir to react for 5 to 6 hours.

[0145] After the reaction is completed, the solvent is removed by vacuum concentration, 260 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The filtrate is weighed and sampled for testing of the content of related substances and fluorouracil intermediates.

[0146] Table 13. Comparative test results of cyclization reaction temperature

[0147]

[0148] According to the test results in the above table, when the cyclization temperature is higher than 50°C, the purity and conversion rate of the obtained fluorouracil intermediate decrease with increasing temperature; when the cyclization temperature is 30°C, 40°C, and 50°C, the purity and conversion rate of the obtained fluorouracil intermediate are the highest, and there is no significant difference.

[0149] The preferred cyclization temperature was determined to be 30-50°C.

[0150] Test Example 9 Comparative Test of Cyclization Reaction Time

[0151] In parallel, add 80 ml of dichloromethane and 26 g (0.48 mol, 2.5 eq) of sodium methoxide to a 1 L reaction bottle, then add 34.8 g (0.47 mol, 2.5 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate dropwise in sequence. After the addition is complete, heat to 30-40 °C and stir to react for 0.5 h to obtain an intermediate state.

[0152] At room temperature, 400 ml of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate were added to the above intermediate state, and the temperature was raised to 40° C. and stirred for reaction for 3 h, 4 h, 5 h, 6 h, and 7 h, respectively.

[0153] After the reaction is completed, the solvent is removed by vacuum concentration, 260 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The filtrate is weighed and sampled for testing of the content of related substances and fluorouracil intermediates.

[0154] Table 14. Comparative test results of cyclization reaction time

[0155]

[0156] According to the test results in the above table, the cyclization reaction time is within 3-7 hours, the reaction is complete, and there is no significant difference in the conversion rate of the obtained fluorouracil intermediate and related substances.

[0157] However, considering the production efficiency, the preferred cyclization reaction time is 3-4 h.

[0158] Test Example 10 Comparative test on the amount of cyclization solvent

[0159] In parallel, add 80 ml of dichloromethane and 26 g (0.48 mol, 2.5 eq) of sodium methoxide to a 1 L reaction bottle, then add 34.8 g (0.47 mol, 2.5 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate dropwise in sequence. After the addition is complete, heat to 30-40 °C and stir to react for 0.5 h to obtain an intermediate state.

[0160] At room temperature, add 80 ml (4 times), 160 ml (8 times), 240 ml (12 times), 320 ml (16 times), 400 ml (20 times) of methanol and 32 g (0.13 mol, 0.7 eq) of O-methylisourea sulfate to the above intermediate state, respectively, raise the temperature to 40°C and stir to react for 3 to 4 hours.

[0161] After the reaction is completed, the solvent is removed by vacuum concentration, 260 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The filtrate is weighed and sampled for testing of the content of related substances and fluorouracil intermediates.

[0162] Table 15. Comparative test results of cyclization solvent dosage

[0163]

[0164] Analysis of test results: Within the range of process parameters investigated, there was no significant difference in the conversion rate of the fluorouracil intermediate and related substances obtained by the reaction.

[0165] Taking production cost into consideration, the amount of cyclization solvent (methanol) is preferably 4 times the amount of ethyl fluoroacetate.

[0166] Test Example 11 Comparative test on the dosage of raw material O-methylisourea sulfate (SM2)

[0167] Add 80 ml of dichloromethane and 26 g (0.48 mol, 2.5 eq) of sodium methoxide into a reaction flask, and then dropwise add 35.5 g (0.48 mol, 2.5 eq) of ethyl formate and 20 g (0.19 mol, 1.0 eq) of ethyl fluoroacetate. After the addition is complete, heat to 30-40°C and stir to react for 0.5 h to obtain an intermediate substance.

[0168] Add 80 ml of methanol and the amount of O-methylisourea sulfate (SM2) described in the table below, raise the temperature to 30-50° C. and stir to react for 3 h-4 h.

[0169] The solvent was removed by concentration under reduced pressure, 260 ml of purified water was added, and after stirring to dissolve, a small amount of insoluble matter was filtered out, the filtrate was weighed and sampled to detect the content of related substances and fluorouracil intermediates.

[0170] Table 16. Comparative test results of O-methylisourea sulfate (SM2) dosage

[0171]

[0172] Analysis of experimental results: When the feeding amount of O-methylisourea sulfate (SM2) is 0.5eq, 0.6eq, and 0.7eq, the purity and conversion rate of the fluorouracil intermediate obtained by the reaction are the highest, and there is no significant difference; when the amount of SM2 is continued to increase to 0.8eq, 0.9eq, and 1.0eq, the second ring-closure reaction site of the intermediate substance reacts with the excess SM2 and the ring-closure reaction cannot be carried out, so the purity and conversion rate of the fluorouracil intermediate decrease with the increase in dosage.

[0173] Preferably, the feeding amount of O-methylisourea sulfate (SM2) is 0.5 eq.

[0174] Experimental Example 12 Comparative Test on Crystallization Temperature and Crystallization Time in the Preparation of Fluorouracil Crude Product

[0175] Add 400 ml of dichloromethane and 127 g (2.35 mol, 2.5 eq) of sodium methoxide to a 3 L reaction bottle, then add 174 g (2.35 mol, 2.5 eq) of ethyl formate and 100 g (0.94 mol, 1.0 eq) of ethyl fluoroacetate dropwise in sequence. After the addition is complete, heat to 30-40 °C and stir to react for 0.5 h to obtain an intermediate state.

[0176] At room temperature, 400 ml of methanol and 116 g (0.47 mol, 0.5 eq) of O-methylisourea sulfate were added to the above intermediate state, and the temperature was raised to 40° C. and stirred for reaction for 3 to 4 hours.

[0177] After the reaction was completed, the solvent was removed by concentration under reduced pressure, 1300 ml of purified water was added, stirred to dissolve, filtered to remove insoluble matter, and the filtrate was collected.

[0178] The filtrate was divided into 5 equal parts, the pH value was adjusted to 4.5±0.2 with appropriate amount of hydrochloric acid, the temperature was controlled to 0℃, 10℃, 20℃, 30℃, 40℃ respectively, and stirred for crystallization for 10 hours (the mother liquor of crystallization was taken every 2 hours to detect the content of fluorouracil intermediate), filtered, the filter cake was washed with purified water (10ml×2), the filter cake was collected, dried at 60℃ for 5 hours, samples were taken for inspection of related substances and contents, and the test results were examined twice.

[0179] Table 17-1. Results of investigation on crystallization temperature and time (first investigation on crystallization mother liquor)

[0180]

[0181]

[0182] Table 17-2. Results of investigation on crystallization temperature and time (crystallization mother liquor of the second investigation experiment)

[0183]

[0184]

[0185] Table 18. Crystallization temperature and time investigation results

[0186]

[0187] Analysis of test results:

[0188] ① Within the range of process parameter investigation, when the crystallization temperature was 10-30°C, there was no significant difference in the content of fluorouracil intermediates in the crystallization mother liquor. When the crystallization temperature was further lowered to 0°C, there was no significant decrease in the content of fluorouracil intermediates in the mother liquor.

[0189] ② When the crystallization temperature is 0-40°C, there is no significant difference in the content of the final fluorouracil intermediate dry solid and related substances;

[0190] ③ According to the results of the second crystallization mother liquor, the fluorouracil intermediate has been completely precipitated after 1 hour of crystallization. If the crystallization time is further extended, the content of the fluorouracil intermediate in the mother liquor will no longer decrease;

[0191] ④ According to the above test results, the content of fluorouracil intermediates obtained under various parameters is low. Through theoretical analysis, the reason for the low content is that a large amount of sodium salt will be produced during the reaction and remain in the product, resulting in a low content of fluorouracil intermediates. Therefore, it is necessary to add a refining process to remove the salt in the fluorouracil intermediate.

[0192] The preferred crystallization temperature is 10-30°C (close to room temperature), and the crystallization time is controlled at 1-2h.

[0193] Experimental Example 13 Comparative test of purification steps under different conditions

[0194] Add 160 ml of dichloromethane and 52 g (0.95 mol, 2.5 eq) of sodium methoxide to a 1 L reaction bottle, then add 70.4 g (0.95 mol, 2.5 eq) of ethyl formate and 40 g (0.38 mol, 1.0 eq) of ethyl fluoroacetate dropwise in sequence. After the addition is complete, heat to 30-40 °C and stir to react for 0.5 h to obtain an intermediate state.

[0195] At room temperature, add 160 ml of methanol and 46.8 g (0.19 mol, 0.5 eq) of O-methylisourea sulfate to the above intermediate state, raise the temperature to 30-50° C. and stir to react for 3-4 h.

[0196] After the reaction is completed, the solvent is removed by decompression concentration, 520 ml of purified water is added, stirred and dissolved, filtered, insoluble matter is removed, and the filtrate is collected. The pH value of the filtrate is adjusted to 4.5±0.2 with an appropriate amount of hydrochloric acid, cooled to 10-30°C, stirred and crystallized for 1-2 hours, filtered, the filter cake is weighed, and divided into 2 parts. One part is dried at 60°C for 5 hours. Add 40 ml of purified water to the other filter cake, heat to 80°C, stir thoroughly for 2 hours, cool to 10-30°C, stir and crystallize for 1-2 hours, filter, collect the filter cake, and dry at 60°C for 5 hours.

[0197] Table 19. Comparative test of purification steps under different conditions

[0198]

[0199] This experiment found that after using purified water to heat up and fully pulp, the content of the obtained fluorouracil intermediate was significantly increased, and the content of impurity H was significantly reduced, so it is necessary to add a purified water pulping step.

[0200] Experimental Example 14 Comparative test on drying temperature in the step of preparing crude fluorouracil

[0201] Add 800 ml of dichloromethane and 256 g (4.73 mol, 2.5 eq) of sodium methoxide to a 5 L reaction bottle, then add 350 g (4.73 mol, 2.5 eq) of ethyl formate and 200 g (1.89 mol, 1.0 eq) of ethyl fluoroacetate dropwise in sequence. After the addition is complete, heat to 30-40 °C and stir to react for 0.5 h to obtain an intermediate state.

[0202] At room temperature, add 800 ml of methanol and 234 g (0.95 mol, 0.5 eq) of O-methylisourea sulfate to the above intermediate state, raise the temperature to 40° C. and stir to react for 3-4 h.

[0203] After the reaction is completed, the solvent is removed by decompression and concentration, and 2600 ml of purified water is added. After stirring and dissolving, the insoluble matter is removed and the filtrate is collected. The pH value of the filtrate is adjusted to 4.5±0.2 with an appropriate amount of hydrochloric acid, cooled to 10-30°C, stirred and crystallized for 1-2 hours, filtered, and the filter cake is collected. The filter cake and 400 ml of purified water are heated to 80°C, stirred for 2 hours, cooled to 10-30°C, stirred and crystallized for 1-2 hours, filtered, and the filter cake is collected. The filter cake is divided into 10 portions by weight and dried at 40°C, 50°C, 60°C, 70°C, and 80°C, respectively. Two portions of the filter cake are placed at each temperature, and the weight is monitored every 1 hour until the weight no longer decreases. After drying, samples are taken for inspection of related substances.

[0204] Table 20. Results of drying temperature comparison test

[0205]

[0206]

[0207] Note: The relative retention time of impurity H is about 0.58, and the relative retention time of impurity I is about 1.24.

[0208] Analysis of test results:

[0209] ①The higher the drying temperature, the shorter the time required to dry to constant weight;

[0210] ② Within the parameter investigation range, different drying temperatures have no effect on the related substances of fluorouracil intermediates.

[0211] The preferred drying temperature is 70-80°C, and the tentative drying time is not less than 4 hours.

[0212] Experimental Example 15 Comparative test on drying time in the step of preparing crude fluorouracil

[0213] Take 10g of fluorouracil intermediate, dry it at 80℃ for 30h, and take samples every 5h to detect related substances and their contents.

[0214] Table 21. Drying time parameter comparison test results

[0215]

[0216] According to the test results in the above table: When the fluorouracil intermediate is dried for 30 hours at the determined highest drying temperature, there is no obvious change in the related substances.

[0217] Fluorouracil Fluorouracil intermediates are dried at 80°C for 30h with stable quality. Larger yields require longer drying times. The final drying time is determined based on production.

[0218] Test Example 16 Comparative test on the effect of impurity removal by refining process

[0219] In this test example, a comparative experiment was designed to investigate: the effect of the rework refining process on the removal of impurity H; the fluorouracil intermediates before and after refining were used to prepare crude products according to the crude product process, and to compare whether the fluorouracil crude products with qualified impurity D content could be obtained before and after the refining of the fluorouracil intermediates. The operation is as follows:

[0220] ① Take 100g of fluorouracil intermediate, add 200ml of purified water, heat to 80℃, stir thoroughly for 2h, then cool to 10-30℃, stir and crystallize for 1-2h, filter, collect the filter cake, dry at 80℃ for 4h to obtain the reworked refined product of fluorouracil intermediate, and take samples to detect related substances.

[0221] ② Add fluorouracil intermediate reprocessed refined product to the reaction bottle, add 3 times 25% hydrochloric acid, heat to 40-50°C and stir to react for 2-3h. After the reaction is completed, cool to 10-30°C, stir and crystallize for 1-2h, filter, wash the filter cake with appropriate amount of purified water, collect the filter cake, dry it at 70-80°C for 2h to obtain the crude product, and take samples to detect related substances.

[0222] Table 22. Results of the investigation on the reprocessing and refining of fluorouracil intermediates (comparison of reprocessing and refining of fluorouracil intermediates)

[0223]

[0224] Table 23. Results of reprocessing and refining of fluorouracil intermediates (crude product)

[0225]

[0226]

[0227] Analysis of the test results: The content of impurity I can be effectively reduced through the refining process of the fluorouracil intermediate. The content of impurity D in the crude fluorouracil product obtained by using the fluorouracil intermediate with an impurity I content of less than 0.2% is less than 0.1%. Therefore, in order to effectively ensure the quality of the fluorouracil finished product, the content of impurity I (impurity D precursor) in the fluorouracil intermediate should be controlled below 0.2%.

[0228] The refining process of fluorouracil intermediate can effectively remove impurity I. In order to effectively ensure the quality of the finished product, the content of impurity I in the fluorouracil intermediate should be controlled below 0.2%. When the content of impurity I in the fluorouracil intermediate exceeds 0.2%, rework should be carried out.

[0229] Example 6

[0230] By scaling up production, small-scale test, pilot test and large-scale production were carried out to investigate the stability of the process. Compared with Example 5, the specific changed parameter conditions are shown in the following table.

[0231] Table 24. Summary of major changes in production process during scale-up

[0232]

[0233]

[0234]

[0235] The tests of the main production batches are summarized as follows:

[0236] Table 25. Summary of test data of fluorouracil finished product

[0237]

[0238]

[0239] Test Example 17 Stability Evaluation Test The sample information for the stability test is shown in Table 26.

[0240] Table 26. Stability test sample information

[0241]

[0242] Table 27. Results of the investigation on the influencing factors of stability test

[0243]

[0244]

[0245] Conclusion: According to the quality standard of fluorouracil, the pilot batch samples (batch number: 191001) were subjected to accelerated (40℃±2℃, 75%RH±5%) and long-term (30℃±2℃, 65%RH±5%) stability tests. After 6 months of accelerated and 24 months of long-term stability tests, the test results of each item were in line with the quality standard requirements; the three batches of validation batch samples (batch numbers: 210801, 210802, 210803) were subjected to accelerated (40℃±3℃, 75%RH±5%) and long-term (30℃±2℃, 65%±5%) stability tests. After 6 months of accelerated and 9 months of long-term stability tests, the test results of each item were in line with the quality standard requirements.

[0246] Although the present invention has been described in detail above by general description, specific implementation methods and experiments, it is obvious to those skilled in the art that some modifications or improvements can be made to the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all belong to the scope of protection claimed by the present invention.

Claims

1. A production process of fluorouracil, characterized in that: The method comprises the following condensation reaction steps: S1: adding a base catalyst to dichloromethane, and then dropwise adding ethyl formate and ethyl fluoroacetate to obtain a mixture, wherein the base catalyst is any one of sodium methoxide, sodium ethoxide, and potassium ethoxide, the mass of dichloromethane is 3-7 times the mass of ethyl fluoroacetate, and the molar equivalent ratio of the added base catalyst, ethyl formate, and ethyl fluoroacetate is 2.5-3.5:2.5:1; S2 controls the temperature of the mixture obtained in S1 to 30-40°C, and continuously stirs and reacts for 0.5-2h to obtain an intermediate substance, which mainly includes the compound C5H6FNaO3, and its chemical formula is as follows:

2. The production process of fluorouracil according to claim 1, characterized in that: The method further comprises the following cyclization reaction step: S3: adding methanol and O-methylisourea sulfate to the intermediate substance obtained in S2, raising the temperature to 30-60° C., and continuously stirring the reaction for 3-7 hours, wherein the mass of methanol is 4-20 times the mass of ethyl fluoroacetate, and the molar equivalent ratio of the added O-methylisourea sulfate to ethyl fluoroacetate is 0.5-0.7:1; S4: The solution after the reaction in S3 is concentrated under reduced pressure to remove the solvent, purified water is added to dissolve and stirred at 80-90°C for 1-2h, and the insoluble matter is filtered out and the filtrate is collected. The filtrate includes the fluorouracil intermediate C5H5FN2O2, and its chemical formula is as follows: Among them, the mass of purified water is 10-15 times the mass of ethyl fluoroacetate.

3. The production process of fluorouracil according to claim 2, characterized in that: After the cyclization reaction step, the method further includes a step of preparing a crude fluorouracil product and a refining step, wherein the step of preparing a crude fluorouracil product specifically includes: S5 dissolves the fluorouracil intermediate, adjusts the pH value of the solution to 4.5±0.2, controls the temperature to 0-40°C, stirs and crystallizes for 1-10 hours, filters, washes the filter cake with purified water 1-2 times, and then dries the filter cake at 70-80°C for 4-5 hours to obtain a crude fluorouracil product.

4. The production process of fluorouracil according to claim 1, characterized in that: The base catalyst in S1 is sodium methoxide, and the molar equivalent ratio of sodium methoxide, ethyl acetate and ethyl fluoroacetate is 2.5:2.5:

1.

5. The production process of fluorouracil according to claim 1, characterized in that: The mass of S1 dichloromethane is 4 times the mass of ethyl fluoroacetate.

6. The production process of fluorouracil according to claim 1, characterized in that: S2: The mixture obtained in S1 is temperature controlled to 40° C. under reflux conditions, and the reaction is continued by stirring for 0.

5.

7. The production process of fluorouracil according to claim 2, characterized in that: S3: adding methanol and O-methylisourea sulfate to the intermediate substance obtained in S2, controlling the temperature to 30-50° C., and continuously stirring the reaction for 3-4 hours.

8. The production process of fluorouracil according to claim 2, characterized in that: The mass of methanol in S3 is 4 times the mass of ethyl fluoroacetate, and the molar equivalent ratio of added O-methylisourea sulfate to ethyl fluoroacetate is 0.5:

1.

9. The production process of fluorouracil according to claim 3, characterized in that: In S5, the temperature is controlled to 10-30°C and stirred for crystallization for 1-2h.

10. The production process of fluorouracil according to claim 3, characterized in that: The refining step comprises: S6: The crude fluorouracil is dissolved in purified water at a temperature of 85-95°C, and then activated carbon is added for decolorization for 1 hour. The decolorized solution is filtered and crystallized, and the filtered residue is dried under reduced pressure at 70-80°C for more than 6 hours to obtain the finished fluorouracil.

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