Preparation method of large-granularity capecitabine

Abstract

The invention discloses a preparation method of large-granularity capecitabine, which is characterized in that 5-flucytosine is used as a starting material, a capecitabine crude product is synthesized through silanization reaction, Silyl-Hilbert-Johnson glycosylation reaction, amidation and hydrolysis reaction in sequence, PS-SnCl4 is used as a condensing agent in the Silyl-Hilbert-Johnson glycosylation reaction, and the capecitabine crude product is synthesized through amidation and hydrolysis reaction. The acylation hydrolysis reaction is carried out in a pipeline reactor; acetone (or butanone or a mixed solvent of acetone and butanone) is adopted as a crystallization solvent for crude product refining, a proper amount of purified water is added for crystallization, and large-particle-size capecitabine with the average particle size being 300 micrometers or above and the bulk density being 0.4 g / mL-0. 5 g / mL is obtained. The method is safe, reliable, economical, environment-friendly, high in quality and high in yield in production, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a method for preparing large-particle capecitabine. Background Art

[0002] Capecitabine is a pyrimidine compound that is non-cytotoxic. It is metabolized to 5-fluorouracil (5-FU) by enzymes in the body, and then exerts anti-tumor effects. It is a new targeted drug for the treatment of breast cancer and colorectal cancer. The drug was developed by Roche and its trade name is "Xeloda". It was approved for marketing in the United States in November 1998. In November 1999, it began to conduct registration clinical trials in China and was marketed as "Xeloda". Its structure is as follows:

[0003]

[0004] At present, there are mainly the following methods for synthesizing capecitabine: (1) Using D-ribose as the raw material, the target compound is obtained through 8 steps of ketalization protection, sulfonylation, reduction, hydrolysis, acetylation, silylation, amidation and hydrolysis. The raw materials of this synthetic route are simple and easy to obtain, but there are many synthetic steps and a long production cycle, which is not suitable for commercialization of the synthetic route. (2) Using 5'-deoxy-5-fluorouridine as the raw material, capecitabine is obtained through benzoyl chloride (BzCl) protection of the hydroxyl group, ketocarbonyl amination, acylation, and then deprotection. This route has obvious advantages and reduces the total number of synthetic steps, but it has a fatal disadvantage. The starting material 5'-deoxy-5-fluorouridine is expensive in the market (the market quotation is more than 2,000 yuan / kg), which is not conducive to industrial production. (3) Using 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine as the starting material (the synthetic method of capecitabine disclosed in patent CN104744537A), capecitabine is prepared through two steps of condensation and hydrolysis. This synthetic route is shorter and has a higher yield. However, the starting material 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine is expensive and difficult to purchase, which seriously limits its industrial production. (4) Using the key intermediates 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose and 5-fluorocytosine as raw materials (such as the synthesis method of capecitabine disclosed in patent CN104478975A), capecitabine is synthesized through silanization, Silyl-Hilbert-Johnson glycosylation, amidation, and hydrolysis. The raw materials of this route are easy to obtain, but the synthesis steps are shorter. However, the reagent tin tetrachloride used in Silyl-Hilbert-Johnson glycosylation is large in size and has a high cost. In addition, a large amount of tin salt is produced in the post-reaction treatment, which places a heavy burden on hazardous waste treatment.

[0005] In addition, the dosage form of capecitabine is an oral solid preparation. When preparing the oral solid preparation of capecitabine, there are certain requirements for the particle size of the capecitabine raw material. Since capecitabine has a relatively low bulk density, the bulk density of the capecitabine currently available on the market is generally around 0.18g / mL to 0.24g / mL, making it difficult to make a large amount of drugs into tablets with consistent weight and ideal hardness. Patent CN102302466A discloses a method for preparing large-particle capecitabine, specifically: dissolving the capecitabine raw material in an organic solvent (preferably butyl acetate) to obtain a clear solution; distilling under reduced pressure until the solution becomes slightly turbid oil; adding n-heptane, stirring and mixing to obtain a suspension; cooling to 0-5°C, centrifuging, filtering, and drying, the average particle size of the capecitabine obtained by this method is 100-200μm. Patent CN102858791A discloses a method for preparing large-sized capecitabine particles, which uses n-pentanol as a crystallization solvent and washes with n-hexane to obtain an average particle size D 90 The capecitabine raw material is 250-350 μm, but the product obtained by this method has poor fluidity and a bulk density of only about 0.20 g / mL (see Figure 6 Other patents such as US2010130734, WO2010065586 and CN103509072A disclose capecitabine D 90 Different preparation methods for capecitabine particles with a particle size of ≤50μm. By consulting the literature, it is found that the particle size of capecitabine particles obtained by the existing crystallization methods is not easy to control and cannot meet the requirements of some customers for D 90 The requirement is to be above 300μm and the bulk density is above 0.30g / mL.

[0006] Different solvents have different solubility for capecitabine. In solvents with higher solubility, the movement speed of solute molecules is relatively fast, and it is not easy to form large particles during crystallization; while in solvents with lower solubility, solute molecules are more likely to aggregate and grow to form large particles after collision, so it is necessary to select the refined solvent. At the same time, during the development of the crystallization process, the influence of water on the crystal size and yield is relatively large, so a small amount of water needs to be added to adjust the crystallization process.

[0007] Temperature affects solubility and crystallization rate. Generally speaking, lower temperatures will reduce the solubility of capecitabine, increase supersaturation, increase the driving force for crystallization, and easily form crystals with larger particle sizes.

[0008] Stirring and stirring form are critical in the crystallization process. When the stirring speed is moderate, it is conducive to the uniform dispersion of the solute and the transfer of crystallization heat. However, if the stirring speed is too fast, the probability of collision between crystals will increase, which will easily break the growing crystals and is not conducive to the formation of large particles; while if the stirring speed is too slow, it may lead to excessive local concentration, forming small crystal nuclei, which is also not conducive to the formation of large particles.

[0009] In summary, it is necessary to explore a preparation process for capecitabine with large particles, high bulk density and good fluidity to solve the problems of poor fluidity and low bulk density of the product; at the same time, ensure product quality, simplify the production process, reduce production costs, and be suitable for industrial production requirements. Summary of the invention

[0010] In view of the above problems, the present invention provides a method for preparing large-particle capecitabine. The present invention uses 5-fluorocytosine as a starting material, and synthesizes a crude capecitabine product through silanization reaction, Silyl-Hilbert-Johnson glycosylation reaction, amidation and hydrolysis reaction in sequence, wherein the Silyl-Hilbert-Johnson glycosylation reaction uses PS-SnCl4 as a condensation agent, and the acylation hydrolysis reaction is carried out in a pipeline reactor; the crude product is refined using acetone (or butanone, or a mixed solvent of acetone and butanone) as a crystallization solvent, and an appropriate amount of purified water is added for crystallization, so as to obtain a large-particle capecitabine with an average particle size of more than 300 μm and a bulk density of 0.4 g / mL to 0.5 g / mL. The method is safe and reliable in production, economical and environmentally friendly, high-quality, and high-yield, and is suitable for industrial production.

[0011] The technical scheme of the present invention is: a method for preparing large-particle capecitabine, which uses 5-fluorocytosine as a starting material, synthesizes a crude capecitabine product through silylation reaction, Silyl-Hilbert-Johnson glycosylation reaction, amidation and hydrolysis reaction, and finally obtains a finished capecitabine product through crystallization, wherein:

[0012] The Silyl-Hilbert-Johnson glycosidation reaction uses PS-SnCl4 (resin-loaded SnCl4) as a condensation agent, and PS-SnCl4 can be recycled;

[0013] The amidation and hydrolysis reactions are carried out simultaneously in the pipeline reactor, specifically: the dichloromethane feed liquid of compound IV and n-pentyl chloroformate are used as feed liquid 1, entering the reactor from channel A; the methanol aqueous solution containing sodium hydroxide is used as feed liquid 2, entering the reactor from channel B, and mixing and reacting are carried out in the pipeline reactor;

[0014] The crude product is refined by turbine stirring or turbine disc stirring, and acetone (or butanone, or a mixed solvent of acetone and butanone) is used as a crystallization solvent during the crystallization process, and an appropriate amount of purified water is added for crystallization.

[0015] The overall reaction route is as follows:

[0016]

[0017] Further, the silylation reaction is specifically as follows: 5-fluorocytosine (Compound I) is used as a starting material, toluene is used as a reaction solvent, hexamethyldisilazane and ammonium sulfate are added, the temperature is raised to reflux (110-120°C), reflux reaction is carried out for 2.0-2.5 hours, to obtain a toluene feed solution of Compound II, the temperature is controlled below 60°C, and the reduced pressure distillation is carried out until no fraction flows out, to obtain a light yellow oil-solid mixture (Compound II). The molar ratio of 5-fluorocytosine (Compound I), hexamethyldisilazane and ammonium sulfate in the silylation reaction is 1.0:1.3-1.5:0.01-0.03, and the preferred molar ratio is 1.0:1.3:0.02.

[0018] Furthermore, the Silyl-Hilbert-Johnson glycosidation reaction is specifically as follows: dichloromethane is added to the light yellow oil-solid mixture (compound II) obtained in the previous step, and the mixture is stirred and dissolved, PS-SnCl4 (resin-loaded SnCl4) is added, 5-deoxy-1,2,3-tri-O-acetyl-β-D-ribofuranose (compound III) is added at a temperature of 20 to 30°C, and the temperature is controlled at 20 to 30°C for a heat-retention reaction of 3.0 to 4.0 hours. After the reaction is completed, the mixture is filtered, and the filter cake is rinsed with dichloromethane. The filter cake (PS-SnCl4) is applied to the next batch, and the filtrate is washed with a saturated sodium bicarbonate solution and then dried to obtain a yellow or light yellow liquid (dichloromethane feed solution of compound IV). In the Silyl-Hilbert-Johnson glycosylation reaction, 5-fluorocytosine is used as the benchmark, and the feeding molar ratio of 5-fluorocytosine, PS-SnCl4 (2-3 mmol SnCl4 / g carrier microspheres) and 5-deoxy-1,2,3-tri-O-acetyl-β-D-furanose is 1.0:1.2-1.4:0.95-1.05, and the preferred feeding molar ratio is 1.0:1.3:1.0.

[0019] Further, the amidation hydrolysis reaction is carried out in a pipeline reactor (schematic diagram as shown in Figure 1As shown), specifically: the dichloromethane feed liquid of compound IV obtained in the above step and n-pentyl chloroformate are feed liquid 1, which enters the reactor from channel A and is controlled by pump 1; 18-22% methanol aqueous solution containing 8-12% sodium hydroxide is feed liquid 2, which enters the reactor from channel B and is controlled by pump 2. The feed rates of reaction liquid 1 and reaction liquid 2 are controlled by pump 1 and pump 2, and reaction liquid 1 and reaction liquid 2 are mixed and reacted in the pipeline reactor (the residence time of the feed liquid in the pipeline reactor is preferably 1-2 minutes). After the reaction is completed, the mixed feed liquid directly flows into a 0°C-5°C receiving tank, and the aqueous phase is separated into layers, and the aqueous phase is acidified to adjust the pH to 3-5, and then dichloromethane is added to separate layers to obtain an organic phase, and EDTA and purified water are added to the organic phase for washing, and the organic phase is separated into layers to obtain an organic phase, and the organic phase is dried to obtain a dichloromethane feed liquid of crude capecitabine. In the hydrolysis reaction, taking 5-fluorocytosine as a reference, the molar ratio of 5-fluorocytosine, sodium hydroxide and EDTA is 1.0:2.9-3.1:0.04-0.06, and the preferred molar ratio is 1.0:3.0:0.05.

[0020] Furthermore, the crude product is refined as follows: controlling the temperature below 35°C, distilling the dichloromethane feed liquid of the crude capecitabine obtained in the previous step under reduced pressure until no fraction flows out to obtain a yellow oily substance, adding acetone (or butanone, or a mixed solvent of acetone and butanone), heating to 50-60°C to dissolve, adding purified water, then slowly cooling to 35-45°C to grow crystals for 2-4h, continuing to slowly cool to 0-10°C to keep warm for crystallization for 5-8h, filtering and drying to obtain a plate-like crystal capecitabine product. In the crude product refining, based on 5-fluorocytosine, the mass volume ratio of 5-fluorocytosine to the organic solvent (acetone, or butanone, or a mixed solvent of acetone and butanone) is 1:11-13, preferably 1:12; in the crude product refining, the amount of purified water used is 0.9%-1.1% of the volume of the organic solvent (acetone, or butanone, or a mixed solvent of acetone and butanone), preferably 1.0%; in addition, in the crude product refining, the preferred stirring form is turbine stirring or turbine disc stirring.

[0021] Compared with the prior art, the advantages of the present invention are as follows:

[0022] 1. In the literature and patent reports, SnCl4 is usually used as a condensing agent in the Silyl-Hilbert-Johnson glycosidation reaction. The amount of SnCl4 used is large, and a large amount of tin salts will be generated in the post-processing, which has a heavy burden on the treatment of hazardous waste (tin salts). However, the present invention uses PS-SnCl4 (resin-loaded SnCl4) as a condensing agent. After the reaction is completed, PS-SnCl4 can be recovered by filtration, and the recovered PS-SnCl4 can be directly applied to the next batch. It is determined through experiments that a batch of PS-SnCl4 can be continuously applied for 10 to 12 times. Therefore, while effectively reducing the cost, the generation of post-processing hazardous waste is greatly reduced.

[0023] 2. The present invention uses pipeline reaction to react amidation and hydrolysis in a pipeline reactor in a fast contact reaction and fast separation, so that sodium hydroxide plays a dual role of acid binding agent and hydrolysis in the system, avoiding the use of a large amount of pyridine, making the entire reaction cleaner; at the same time, part of methanol is added to the sodium hydroxide aqueous solution to play a role of solubilization, so that liquid A and liquid B are mixed more evenly in the pipeline, which is more conducive to the reaction; if pure methanol sodium hydroxide solution is used as liquid B, more n-amyl chloroformate will be consumed in the pipeline, affecting the reaction. Through pipeline reaction, acylation and hydrolysis are carried out simultaneously, which greatly improves production efficiency and atomic economy, and meets environmentally friendly reaction steps.

[0024] 3. Since capecitabine has poor stability under alkaline conditions, the process byproducts (over-hydrolysis impurities, impurity A) produced under alkaline conditions are not easy to remove during the crude product refining process. The hydrolysis reaction of the present invention is carried out in a pipeline reactor, and the generation of process byproducts of over-hydrolysis impurities (impurity A) is effectively reduced by shortening the contact time between the reactants and the alkali solution (20% methanol aqueous solution containing about 10% sodium hydroxide). Under the process conditions, the impurity A in the crude product is small (within 0.05%), and the impurity A in the finished product can be reduced to within 0.02% after the obtained crude product is crystallized.

[0025]

[0026] 4. By consulting the literature, it is found that the particle size of capecitabine obtained by the existing crystallization method is not easy to control and cannot meet the requirements of some customers for D 90 The requirement is that the crystal size is above 300 μm and the bulk density is above 0.30 g / mL. The preparation process of the capecitabine plate-like crystals provided by the present invention is simple, and the obtained capecitabine has a large bulk density (0.4 g / mL to 0.5 g / mL), good fluidity, no static electricity, no agglomeration, easy mixing, and is convenient for the preparation of large-dose capecitabine tablets. It is low in cost, high in yield, and suitable for industrial-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is a schematic diagram of a pipeline reactor;

[0028] Figure 2 is the particle size detection spectrum of the capecitabine product of Example 1;

[0029] Figure 3 is the electron microscopic spectrum of the capecitabine product of Example 1;

[0030] Figure 4 is the X-ray powder diffraction pattern of the capecitabine product of Example 1;

[0031] Figure 5 is the reported X-ray powder diffraction pattern of capecitabine;

[0032] Figure 6 It is a picture of turbine stirring;

[0033] Figure 7 It is a picture of turbine disc stirring;

[0034] Figure 8 This is the electron microscopic image of the capecitabine product of Comparative Example 1. Specific embodiments

[0035] The following are embodiments provided by the present invention, which are only intended to further illustrate the technical scheme and technical effects of the present invention, rather than to limit the present invention.

[0036] Embodiment 1:

[0037] (1) Silylation reaction

[0038] Take 10 g of the starting material 5-fluorocytosine, add 100 mL of toluene, 17.50 g of hexamethyldisilazane and 0.20 g of ammonium sulfate, raise the temperature to reflux, and reflux for 2.0 hours to obtain a toluene solution of compound II. Control the temperature below 60°C and distill under reduced pressure until no fraction flows out to obtain a light yellow oil-solid mixture (compound II).

[0039] (2) Silyl-Hilbert-Johnson glycosylation reaction

[0040] To the light yellow oil-solid mixture (Compound II) obtained in the previous step, 150 mL of dichloromethane was added and stirred to dissolve, and 41.96 g of PS-SnCl4 (resin-loaded SnCl4, the content of which was determined to be 2.4 mmol SnCl4 / g carrier microspheres) was added, and the temperature was controlled at 20-30°C, and 20.16 g of 5-deoxy-1,2,3-tri-0-acetyl-BD-furanose (Compound III) was added, and the temperature was controlled at 20-30°C to react for 3.5 hours. After the reaction was completed, the filter was filtered, and the filter cake was rinsed with 20 mL of dichloromethane. The filter cake was the recovered PS-SnCl4, which was applied to the next batch. The filtrate was washed with 80 mL of saturated sodium bicarbonate solution and dried with 5.13 g of anhydrous magnesium sulfate to obtain a yellow or light yellow liquid (dichloromethane feed solution of Compound IV).

[0041] (3) Amidation hydrolysis reaction

[0042] The dichloromethane liquid of compound IV after drying in the above step and 29.55 g of n-pentyl chloroformate are mixed and cooled to -5 to 5°C to obtain liquid 1 (the weight of the liquid is 214.45 g), which enters the reactor from channel A and is controlled by pump 1; 9.3 g of sodium hydroxide is added to 83.7 g of purified water to dissolve, 18.6 g of methanol is added, and the mixture is evenly mixed to obtain reaction liquid 2, which enters the reactor from channel B and is controlled by pump 2. The feed rates of reaction liquid 1 and reaction liquid 2 are controlled by pump 1 and pump 2 (the flow rate ratio of reaction liquid 1 and reaction liquid 2 is about 1.9:1), reaction liquid 1 and reaction liquid 2 are mixed and reacted in the pipeline reactor (the residence time of the feed liquid in the pipeline reactor is preferably 1 to 2 minutes), and after the reaction is completed, the mixed feed liquid directly flows into a 0°C to 5°C receiving tank, and the aqueous phase is separated and separated, and the pH of the aqueous phase is adjusted to 3.5 with 9% hydrochloric acid, and 100 mL of dichloromethane is added to separate and separate to obtain an organic phase, and 1.13 g of EDTA and 60 mL of purified water are added to the organic phase for washing, and the organic phase is separated and separated, and 5.13 g of anhydrous magnesium sulfate is added to the organic phase for drying, and the dichloromethane feed liquid of crude capecitabine is obtained by filtration.

[0043] (4) Refining of crude products

[0044] The stirring mode of this step is turbine stirring (such as Figure 6 As shown), the temperature was controlled below 35°C, and the dichloromethane feed liquid of the crude capecitabine obtained in the previous step was distilled under reduced pressure until no fraction flowed out, and a yellow oil (about 27.45g) was obtained. 120g of acetone was added, and the temperature was raised to 50-60°C to dissolve, and 1.20g of purified water was added, and the temperature was slowly lowered to 35-40°C for crystallization for 3h, and the temperature was slowly lowered to 0-10°C for crystallization for 7h. After the crystallization was completed, it was filtered and dried to obtain 18.16g of plate-like crystals of capecitabine finished product, and the total yield was 65.23%. The purity was 99.89% by HPLC, and impurity A was not detected; the average particle size was measured by Mastersizer 3000 laser particle size analyzer using Malvem laser diffraction method, and the average particle size was 723μm, see Figure 2 , observed under an electron microscope, it is a relatively thick plate-like crystal. Figure 3 The bulk density test result is 0.44 g / mL, and the X-ray powder diffraction pattern test result is consistent with the reported capecitabine crystal form. Figure 4 , Figure 5 .

[0045] The sample of Example 1 was placed under 40°C ± 2°C / 75% ± 5% RH for 6 months. Samples were taken at the end of the 1st, 2nd, 3rd and 6th month to test various stability indicators. The results are shown in the following table:

[0046] Table 1 Product stability test results

[0047]

[0048] By comparing and analyzing the changes in the data at each stability inspection point, it was found that after the samples were subjected to accelerated testing for 6 months, no significant changes were observed in the various inspection indicators compared with those at day 0.

[0049] Embodiment 2:

[0050] (1) Silylation reaction

[0051] Take 10 g of the starting material 5-fluorocytosine, add 90 mL of toluene, 16.25 g of hexamethyldisilazane and 0.10 g of ammonium sulfate, raise the temperature to reflux, and reflux for 2.0 hours to obtain a toluene solution of compound II. Control the temperature below 60°C and distill under reduced pressure until no fraction flows out to obtain a light yellow oil-solid mixture (compound II).

[0052] (2) Silyl-Hilbert-Johnson glycosylation reaction

[0053] To the light yellow oil-solid mixture (Compound II) obtained in the previous step, 140 mL of dichloromethane was added, stirred and dissolved, and the recovered PS-SnCl4 obtained in Example 1 was added, and the temperature was controlled at 20-30°C. 19.15 g of 5-deoxy-1,2,3-tri-0-acetyl-BD-furanose (Compound III) was added, and the temperature was controlled at 20-30°C to keep the reaction for 3.5 hours. After the reaction was completed, it was filtered, and the filter cake was rinsed with 20 mL of dichloromethane. The filter cake was the recovered PS-SnCl4, which was applied to the next batch. The filtrate was washed with 70 mL of saturated sodium bicarbonate solution and dried with 4.66 g of anhydrous magnesium sulfate to obtain a yellow or light yellow liquid (dichloromethane feed solution of Compound IV).

[0054] (3) Amidation hydrolysis reaction

[0055] The dichloromethane liquid of compound IV after drying in the above step and 29.01 g of n-pentyl chloroformate are mixed and cooled to -5 to 5°C to obtain liquid 1 (the weight of the liquid is 220.33 g), which enters the reactor from channel A and is controlled by pump 1; 9.01 g of sodium hydroxide is added to 81.22 g of purified water to dissolve, 18.05 g of methanol is added, and the mixture is evenly mixed to obtain reaction liquid 2, which enters the reactor from channel B and is controlled by pump 2. The feed rates of reaction liquid 1 and reaction liquid 2 are controlled by pump 1 and pump 2 (the flow rate ratio of reaction liquid 1 and reaction liquid 2 is about 2.0:1), reaction liquid 1 and reaction liquid 2 are mixed and reacted in the pipeline reactor (the residence time of the feed liquid in the pipeline reactor is preferably 1 to 2 minutes), and after the reaction is completed, the mixed feed liquid directly flows into a 0°C to 5°C receiving tank, and the aqueous phase is separated by stratification, the pH of the aqueous phase is adjusted to 3.5 with 9% hydrochloric acid, and 90 mL of dichloromethane is added, and the organic phase is separated by stratification, 0.91 g EDTA and 50 mL purified water are added to the organic phase for washing, and the organic phase is separated by stratification, 4.66 g of anhydrous magnesium sulfate is added to the organic phase for drying, and the dichloromethane feed liquid of crude capecitabine is obtained by filtration.

[0056] (4) Refining of crude products

[0057] The stirring form of this step is turbine disc stirring (such as Figure 7 As shown), the temperature was controlled below 35°C, and the dichloromethane feed liquid of the crude capecitabine obtained in the previous step was distilled under reduced pressure until no fraction flowed out, and a yellow oil (about 27.89g) was obtained. 120g of butanone was added, and the temperature was raised to 50-60°C to dissolve, and 1.08g of purified water was added, and the temperature was slowly lowered to 35-40°C for crystallization for 3h, and the temperature was slowly lowered to 0-10°C for crystallization for 7h. After the crystallization was completed, the plate-like crystals of capecitabine were filtered and dried to obtain 17.96g of finished product, and the total yield was 64.51%. The purity was 99.91% by HPLC, and impurity A was not detected; the average particle size was measured by Mastersizer 3000 laser particle size analyzer using Malvem laser diffraction method, and the bulk density was 0.42g / mL.

[0058] Embodiment 3:

[0059] (1) Silylation reaction

[0060] Take 10 g of the starting material 5-fluorocytosine, add 110 mL of toluene, 18.75 g of hexamethyldisilazane and 0.31 g of ammonium sulfate, raise the temperature to reflux, and reflux for 2.0 hours to obtain a toluene solution of compound II. Control the temperature below 60°C and distill under reduced pressure until no fraction flows out to obtain a light yellow oil-solid mixture (compound II).

[0061] (2) Silyl-Hilbert-Johnson glycosylation reaction

[0062] To the light yellow oil-solid mixture (Compound II) obtained in the previous step, 160 mL of dichloromethane was added, stirred and dissolved, and the recovered PS-SnCl4 obtained in Example 2 was added, and the temperature was controlled at 20-30°C, and 21.17 g of 5-deoxy-1,2,3-tri-0-acetyl-BD-furanose (Compound III) was added, and the temperature was controlled at 20-30°C and kept warm for 3.5 hours. After the reaction was completed, it was filtered, and the filter cake was rinsed with 20 mL of dichloromethane. The filter cake was the recovered PS-SnCl4, which was applied to the next batch. The filtrate was washed with 90 mL of saturated sodium bicarbonate solution and dried with 5.59 g of anhydrous magnesium sulfate to obtain a yellow or light yellow liquid (dichloromethane feed solution of Compound IV).

[0063] (3) Amidation hydrolysis reaction

[0064] The dichloromethane liquid of compound IV after drying in the above step and 29.55 g of n-pentyl chloroformate are mixed and cooled to -5 to 5°C to obtain liquid 1 (the weight of the liquid is 219.10 g), which enters the reactor from channel A and is controlled by pump 1; 9.60 g of sodium hydroxide is added to 86.40 g of purified water to dissolve, 19.20 g of methanol is added, and the mixture is evenly mixed to obtain reaction liquid 2, which enters the reactor from channel B and is controlled by pump 2. The feed rates of reaction liquid 1 and reaction liquid 2 are controlled by pump 1 and pump 2 (the flow rate ratio of reaction liquid 1 and reaction liquid 2 is about 1.9:1), reaction liquid 1 and reaction liquid 2 are mixed and reacted in the pipeline reactor (the residence time of the feed liquid in the pipeline reactor is preferably 1 to 2 minutes), and after the reaction is completed, the mixed feed liquid directly flows into a 0°C to 5°C receiving tank, and the aqueous phase is separated into layers, the pH of the aqueous phase is adjusted to 3.5 with 9% hydrochloric acid, and 110mL of dichloromethane is added to separate layers to obtain an organic phase, 0.91g EDTA and 70mL purified water are added to the organic phase for washing, and the organic phase is separated into layers, 5.59g anhydrous magnesium sulfate is added to the organic phase for drying, and the dichloromethane feed liquid of crude capecitabine is obtained by filtration.

[0065] (4) Refining of crude products

[0066] The stirring mode of this step is turbine stirring, the temperature is controlled below 35°C, the dichloromethane feed liquid of the crude capecitabine obtained in the previous step is distilled under reduced pressure until no fraction flows out, and a yellow oil (about 27.44g) is obtained, 60g of butanone and 60g of acetone are added, the temperature is raised to 50-60°C to dissolve, 1.32g of purified water is added, the temperature is slowly lowered to 35-40°C for crystallization for 3h, and the temperature is slowly lowered to 0-10°C for crystallization for 7h. After the crystallization is completed, the plate-like crystals of capecitabine are filtered and dried to obtain 18.55g of finished product, and the total yield is 66.63%. The purity of the product is 99.90% by HPLC, and impurity A is not detected; the average particle size is 688μm and the bulk density is 0.43g / mL by Malvem laser diffraction method and Mastersizer 3000 laser particle size analyzer.

[0067] Comparative Example 1: Prepared using frame stirring according to the method of Example 1

[0068] (1) Silylation reaction

[0069] Take 10 g of the starting material 5-fluorocytosine, add 100 mL of toluene, 17.50 g of hexamethyldisilazane and 0.20 g of ammonium sulfate, raise the temperature to reflux, and reflux for 2.0 hours to obtain a toluene solution of compound II. Control the temperature below 60°C and distill under reduced pressure until no fraction flows out to obtain a light yellow oil-solid mixture (compound II).

[0070] (2) Silyl-Hilbert-Johnson glycosylation reaction

[0071] To the light yellow oil-solid mixture (Compound II) obtained in the previous step, 150 mL of dichloromethane was added and stirred to dissolve, and 41.96 g of PS-SnCl4 (resin-loaded SnCl4, the content of which was determined to be 2.4 mmol SnCl4 / g carrier microspheres) was added, and the temperature was controlled at 20-30°C, and 20.15 g of 5-deoxy-1,2,3-tri-0-acetyl-BD-furanose (Compound III) was added, and the temperature was controlled at 20-30°C to keep the reaction for 3.5 hours. After the reaction was completed, the filter was filtered, and the filter cake was rinsed with 20 mL of dichloromethane. The filter cake was the recovered PS-SnCl4, which was applied to the next batch. The filtrate was washed with 80 mL of saturated sodium bicarbonate solution and dried with 5.13 g of anhydrous magnesium sulfate to obtain a yellow or light yellow liquid (dichloromethane feed solution of Compound IV).

[0072] (3) Amidation hydrolysis reaction

[0073] The dichloromethane liquid of compound IV after drying in the above step and 29.12 g of n-pentyl chloroformate are mixed and cooled to -5 to 5°C to obtain liquid 1 (the weight of the liquid is 209.18 g), which enters the reactor from channel A and is controlled by pump 1; 9.3 g of sodium hydroxide is added to 84.0 g of purified water to dissolve, 18.6 g of methanol is added, and the mixture is evenly mixed to obtain reaction liquid 2 (10% sodium hydroxide in 20% methanol aqueous solution), which enters the reactor from channel B and is controlled by pump 2. The feed rates of reaction liquid 1 and reaction liquid 2 are controlled by pump 1 and pump 2 (the flow rate ratio of reaction liquid 1 and reaction liquid 2 is about 1.9:1), reaction liquid 1 and reaction liquid 2 are mixed and reacted in the pipeline reactor (the residence time of the feed liquid in the pipeline reactor is preferably 1-2 min), and after the reaction is completed, the mixed feed liquid directly flows into a 0°C-5°C receiving tank, and the aqueous phase is separated and layered. The pH of the aqueous phase is adjusted to 3.5 with 9% hydrochloric acid, and 100 mL of dichloromethane is added to separate and the organic phase is separated. 1.13 g EDTA and 60 mL purified water are added to the organic phase for washing, and the organic phase is separated and layered. 5.12 g anhydrous magnesium sulfate is added to the organic phase for drying, and the dichloromethane feed liquid of crude capecitabine is obtained by filtration.

[0074] (4) Refining of crude products

[0075] The stirring form of this step is frame stirring, and the temperature is controlled below 35°C. The dichloromethane feed liquid of the crude capecitabine obtained in the previous step is distilled under reduced pressure until no fraction flows out, and a yellow oil (about 27.11g) is obtained. 120g of acetone is added, and the temperature is raised to 50-60°C to dissolve. 1.20g of purified water is added, and the temperature is slowly lowered to 35-40°C for crystallization for 3h, and the temperature is slowly lowered to 0-10°C for crystallization for 7h. After the crystallization is completed, it is filtered and dried to obtain 17.98g of the finished capecitabine product with flake agglomeration, and the total yield is 64.58%. The average particle size is 182μm and the bulk density is 0.22g / mL measured by Malvem laser diffraction method through Mastersizer 3000 laser particle size analyzer. The electron microscope spectrum is shown in Figure 8 .

[0076] The results show that compared with the turbine stirring or turbine disc stirring methods of Examples 1-3 of the present invention, the frame stirring method adopted in Comparative Example 1 significantly reduces the average particle size and bulk density of the finished capecitabine product.

[0077] Comparative Example 2: Using n-pentanol n-heptane turbine disc stirring

[0078] According to the operation of Example 1, prepare the dichloromethane feed solution of crude capecitabine

[0079] The stirring mode of this step is disc stirring, and the temperature is controlled below 35°C. The dichloromethane feed liquid of the crude capecitabine obtained in the previous step is distilled under reduced pressure until no fraction flows out, and a yellow oil (about 27.11g) is obtained. 60g of n-pentanol is added, and the temperature is raised to 50-60°C to dissolve, and the temperature is slowly lowered to 35-40°C, and 40g of n-heptane is slowly added. The crystal is grown for 3h, and the temperature is slowly lowered to 0-10°C, and 20g of n-heptane is added dropwise. The crystal is kept warm for 3h. After the crystallization is completed, it is filtered and dried to obtain 16.0g of the finished capecitabine product of needle-shaped powder, and the total yield is 57.5%. The average particle size is 45μm and the bulk density is 0.20g / mL measured by Malvem laser diffraction method through Mastersizer 3000 laser particle size analyzer.

[0080] The results show that compared with Examples 1-3 of the present invention using acetone (or butanone, or a mixed solvent of acetone and butanone) for crystallization, Comparative Example 2 using n-pentanol and n-heptane for crystallization, the yield of the finished capecitabine product is reduced, and the average particle size and bulk density are significantly reduced.

[0081] Comparative Example 3: Using ethyl acetate turbine disc stirring

[0082] According to the operation of the example, the crude dichloromethane feed solution was prepared

[0083] The stirring form of this step is disc stirring, and the temperature is controlled below 35°C. The dichloromethane feed liquid of the crude capecitabine obtained in the previous step is distilled under reduced pressure until no fraction flows out, and a yellow oil (about 27.11g) is obtained. 120g of ethyl acetate is added, and the temperature is raised to 50-60°C to dissolve, and the temperature is slowly lowered to 40-45°C. 0.05g of seed crystals are added to grow crystals for 3h, and the temperature is slowly lowered to 0-10°C, and the temperature is kept for crystallization for 3h. After the crystallization is completed, it is filtered and dried to obtain 16.2g of the finished capecitabine product in the form of needle-shaped powder, and the total yield is 58.2%. The average particle size is 32μm and the bulk density is 0.19g / mL measured by Malvem laser diffraction method through Mastersizer 3000 laser particle size analyzer.

[0084] The results show that compared with Examples 1-3 of the present invention which use acetone (or butanone, or a mixed solvent of acetone and butanone) for crystallization, Comparative Example 3 uses ethyl acetate + seed crystals for crystal cultivation, and the yield of the finished capecitabine product is reduced, and the average particle size and bulk density are significantly reduced.

Claims

1. A method for preparing large-particle capecitabine, which uses 5-fluorocytosine as a starting material, synthesizes a crude capecitabine product through silanization reaction, Silyl-Hilbert-Johnson glycosylation reaction, amidation and hydrolysis reaction, and finally obtains a finished capecitabine product through crystallization, wherein: The Silyl-Hilbert-Johnson glycosidation reaction uses PS-SnCl4 as a condensation agent, and the PS-SnCl4 is recycled and reused; The amidation and hydrolysis reactions are carried out simultaneously in the pipeline reactor, specifically: the dichloromethane feed liquid of compound IV and n-pentyl chloroformate are used as feed liquid 1, entering the reactor from channel A; the methanol aqueous solution containing sodium hydroxide is used as feed liquid 2, entering the reactor from channel B, and mixing and reacting are carried out in the pipeline reactor; The crude product is refined by turbine stirring or turbine disc stirring, and acetone, butanone, or a mixed solvent of acetone and butanone is used as a crystallization solvent during the crystallization process, and purified water is added for crystallization; 2. The method for preparing large-particle capecitabine according to claim 1, characterized in that: The silylation reaction is specifically as follows: using 5-fluorocytosine as a starting material, using toluene as a reaction solvent, adding hexamethyldisilazane and ammonium sulfate, heating to reflux, and reacting under reflux for 2.0 to 2.5 hours to obtain a toluene feed solution of compound II, controlling the temperature to be below 60° C. and performing reduced pressure distillation until no fraction flows out to obtain compound II.

3. The method for preparing large-particle capecitabine according to claim 1, characterized in that: The Silyl-Hilbert-Johnson glycosidation reaction is specifically as follows: Compound II is added to dichloromethane and stirred to dissolve, PS-SnCl4 is added, 5-deoxy-1,2,3-tri-O-acetyl-β-D-ribofuranose is added at a temperature controlled at 20 to 30°C, the temperature is controlled at 20 to 30°C and the reaction is kept warm for 3.0 to 4.0 hours, after the reaction is completed, the filter is filtered, the filter cake is rinsed with dichloromethane, the filter cake PS-SnCl4 is applied to the next batch, the filtrate is washed with a saturated sodium bicarbonate solution and then dried to obtain a dichloromethane feed solution of compound IV.

4. The method for preparing large-particle capecitabine according to claim 1, characterized in that: The content of SnCl4 in the PS-SnCl4 is 2-3 mmol / g.

5. The method for preparing large-particle capecitabine according to claim 1, characterized in that: The amidation hydrolysis reaction is carried out in a pipeline reactor, specifically: the dichloromethane feed liquid of compound IV and n-pentyl chloroformate are used as feed liquid 1, which enter the reactor from channel A and are controlled by pump 1; 18-22% methanol aqueous solution containing 8-12% sodium hydroxide is used as feed liquid 2, which enters the reactor from channel B and is controlled by pump 2; reaction liquid 1 and reaction liquid 2 are mixed and reacted in the pipeline reactor.

6. The method for preparing large-particle capecitabine according to claim 5, characterized in that: After the reaction is completed, the mixed liquid flows directly into a 0°C to 5°C receiving tank, and the aqueous phase is separated into layers. The aqueous phase is acidified to adjust the pH to 3 to 5, and then dichloromethane is added to separate layers to obtain an organic phase. EDTA and purified water are added to the organic phase for washing, and the organic phase is separated into layers. The organic phase is dried to obtain a dichloromethane feed liquid of crude capecitabine.

7. The method for preparing large-particle capecitabine according to claim 6, characterized in that: The crude product refining specifically comprises: controlling the temperature below 35°C, distilling the dichloromethane feed liquid of the crude capecitabine under reduced pressure until no fraction flows out to obtain a yellow oily substance, adding acetone, butanone or a mixed solvent of acetone and butanone, heating to 50-60°C to dissolve, adding purified water, then slowly cooling to 35-45°C to grow crystals for 2-4h, continuing to slowly cool to 0-10°C to keep warm for crystallization for 5-8h, filtering and drying after the crystallization is completed to obtain a plate-like crystal capecitabine finished product.

8. The method for preparing large-particle capecitabine according to claim 7, characterized in that: In the crude product refining, the amount of purified water used is 0.9% to 1.1% of the volume of the mixed solvent.

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