Preparation method of degraded impurities in raltitrexed preparation
Through multi-step reaction optimization of the lytetrexed synthesis process, the problems of high cost, high toxicity and difficult to control poor regional selectivity are solved, and high efficiency, low toxicity and high purity are achieved, which simplifies the operation process And reduce production costs.
Patent Information
- Application Number
- CN202410758165.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-06-13
- Publication Date
- 2024-12-20
AI Technical Summary
There are high cost, high toxic reagents, harsh reaction conditions and difficult-to-control regional selectivity in the synthesis process of letitroxeter, which leads to high production costs and difficult product separation.
Use hydrated hydrogen aldehyde, anhydrous Na2SO4, p-toluidine, concentrated hydrochloric acid, sulfuric acid, methanol, NaOH solution, thioacetamide, anhydrous ethanol, activated carbon, NBS, toluene peroxide, L-glutamic acid, thiophene formaldehyde, Materials such as acetic anhydride, fumed nitric acid, glacial acetic acid, acetone, chromium anhydride, sulfuric acid and iron powder are optimized through multiple steps including oxime compound synthesis, ring formation reaction, quinazoline synthesis, bromination, hydrolysis reaction and other steps. Route to improve yield and remove impurities.
It significantly improves the synthesis yield and impurity removal effect of lytetrexed, simplifies the operation process, reduces the price and toxicity of reagents, avoids the disadvantages of deprotection groups in the strong acid environment in the original process, and improves the synthesis efficiency and product purity.
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Figure CN119161331A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of medicines, and in particular to a method for preparing degradation impurities in a raltitrexed preparation. Background Art
[0002] Raltitrexed is a thymus synthase inhibitor and a quinazoline folate analog. In the body, after being actively taken up by cells, raltitrexed is quickly metabolized by folate-based polyglutamate synthetase into a series of polyglutamic acids. These metabolites have a stronger inhibitory effect on thymus synthase than raltitrexed, thereby inhibiting the synthesis of cellular DNA, and can be retained in cells, exerting an inhibitory effect for a long time. In the treatment of colorectal cancer, the efficacy of raltitrexed is similar to that of fluorouracil, but the former has a low incidence of side effects, a simple method, and is easy for patients to accept.
[0003] In terms of the synthesis process of raltitrexed: reagents such as n-butyl lithium need to be used, which are expensive and toxic, and there are safety hazards; in particular, the reaction needs to be carried out at low temperature (-78°C) and under argon protection, which is harsh and has high production costs, making it difficult to achieve industrial production. In the N-methylation reaction, the regioselectivity is poor, and it is difficult to control the single methylation product, and the single methylation product is difficult to separate. When Boc2O is used to protect the amino group, it is difficult to completely remove the remaining Boc2O in the reaction, and the protecting group needs to be removed in trifluoroacetic acid. Therefore, our method for preparing degraded impurities in raltitrexed preparations solves the above problems. Summary of the invention
[0004] The object of the present invention is to provide a method for preparing degradation impurities in a raltitrexed preparation to solve the problems raised in the above background technology.
[0005] The technical scheme of the present invention is: a preparation method of degradation impurities in a raltitrexed preparation, comprising 117g of hydroaldehyde hydrate, 752g of anhydrous Na2SO4, 70g of p-toluidine, 68ml of concentrated hydrochloric acid, 72g of hydroxylamine hydrochloride, 339ml of concentrated sulfuric acid, 125ml of methanol, 261.7ml of H2O2, 747.8ml of NaOH solution, 20g of thioacetamide, 4785ml of anhydrous ethanol, 32.5g of NaHco, 5g of activated carbon, 25.6g of NBS, 0.32g of benzoyl peroxide, 25.6g of NBS, 3720ml of CHCL, 441g of L-glutamic acid, 542ml of SOCl2, 50g of thiophene carboxaldehyde, 158.3ml of acetic anhydride, 35.6g of fuming nitric acid, 261.5ml of glacial acetic acid, 65.5ml of acetone, 18g of chromic anhydride, 30ml of sulfuric acid, and 200g of iron powder (3.57mol);
[0006] The degradation impurities and preparation process of the raltitrexed preparation include the following steps: synthesis of oxime, cyclization reaction, oxidation reaction of red powder solid, synthesis of quinazoline, bromination, synthesis of L-glutamic acid diethyl ester, nitration, hydrolysis reaction, oxidation reaction of light yellow cotton-like solid, synthesis of aminothiophene-2 and methyl formate, synthesis of N-acetyl, aminothiophene-2 and methyl formate, synthesis of N-acetyl, aminothiophene-2 and methyl formate, synthesis of (N-methyl), aminothiophene-2 and formic acid hydrochloride, synthesis of (N-methyl), aminothiophene-2 and formic acid hydrochloride, synthesis of [N-(2-methyl-4-oxoquinazoline-6-methyl)-N-methyl], aminothiophene-2 and formic acid, synthesis of NI[5-II(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thiophenyl]carbonyl 1-L-glutamic acid dimethyl ester, and synthesis of raltitrexed;
[0007] The synthesis steps of the oxime are as follows:
[0008] Step S1: Add 117g of chloral hydrate and mix with 1308ml of water, stir and add 752g of anhydrous Na2SO4 in portions, heat to 50°C, then add 70g of p-toluidine, 392ml of water, and 57ml of hydrochloric acid, use solid phase precipitation separation method to change the solution conditions so that the solute is separated from the solution in solid form, then add 72g of hydroxylamine hydrochloride and 327ml of water, then quickly heat to 100°C, reflux for 10 minutes, cool to room temperature, filter, and obtain large granular dark brown-red solid, dry for 24 hours, then heat and reflux with 654ml of water for 10 minutes, vigorously stir and cool, filter to obtain small granular solid brown, and dry at room temperature for 24 hours to obtain 88g of oxime.
[0009] The cyclization reaction steps are as follows:
[0010] Step S2: Add concentrated sulfuric acid to a 1L three-necked flask and heat it to 50°C, add the oxime in batches, and control the reaction temperature between 60 and 70°C. After the addition, heat it to 80°C, stir for 10 minutes, cool it, add it to ice water, stir it well, change the solution conditions by solid phase separation method, separate the solute from the solution in solid form, filter it, wash it with water, and then wash it with an appropriate amount of methanol, and dry it in an oven at 50°C to obtain 73.5g of red powdery solid;
[0011] The red powder solid oxidation reaction steps are as follows:
[0012] Step S3: add the red powdered solid and NaOH solution into a 3L three-necked flask, stir to dissolve, add 10% H2O2 solution dropwise, keep the reaction temperature below 50°C, stir and react at 85°C for 2 hours, cool, filter, cool the filtrate with ice water to below 10°C, acidify with concentrated hydrochloric acid to pH=3.5-4, change the solution conditions by solid phase precipitation separation method, separate the solute from the solution in solid form, filter with suction, and dry in a 50°C oven to obtain 48.5 orange-yellow solid;
[0013] The quinazoline synthesis steps are as follows:
[0014] Step S4: The orange-yellow solid and thioacetamide were fully ground, mixed and put into a flask, stirred and reacted at 140-160°C for 2 hours, the reactant was first melted and then solidified, after the reaction was completed, the solid was taken out and fully crushed, 250ml of 1% NaHCO3 aqueous solution was added and fully stirred, filtered, washed with water and dried to obtain a dry product, the dry product was added to a 3L three-necked flask, 1500ml of anhydrous ethanol was added, refluxed to dissolve it, 5g of activated carbon was added, refluxed for 15 minutes, filtered, the filtrate was cooled to room temperature, and then refrigerated in a freezer overnight, filtered, washed with anhydrous ethanol three times with 100ml ethanol each time, and dried in a 50°C oven to obtain 24g of light brown solid quinazoline;
[0015] The bromination steps are as follows:
[0016] Step S5: quinazoline, NBS, chloroform, and benzoyl peroxide were sequentially placed in a 1L three-necked flask, and reacted in a 50°C water bath overnight. The reactants began to dissolve and solids precipitated in about 6 hours. After the reaction was completed, the mixture was cooled and refrigerated in a refrigerator for 2 hours. The mixture was filtered, washed with CHCl3, and dried to obtain 13.5 g of a No. 1 off-white solid;
[0017] The synthesis steps of described L-glutamic acid diethyl ester are as follows:
[0018] Step S6: Add L-glutamic acid and anhydrous ethanol to a 5L four-necked bottle, stir, cool in an ice-salt bath, add SOCb dropwise at -10°C, control the temperature not to exceed 0°C, complete the addition, stir at room temperature overnight, the reaction solution is clear and colorless, concentrate under reduced pressure to dryness, and obtain a white solid. Add 1000ml of pure water to the bottle and stir until the material is dissolved. The solution is light yellow, cool with ice water, add K2CO3 to the reaction solution to adjust the pH to 10, control the temperature not to exceed 20°C, stir for 10 minutes, extract the solution three times with CH2Cl2, 700ml each time, wash the organic phase three times with saturated NaCl solution, 500ml each time, add 10gMgSO4 to the organic phase, dry, filter, and concentrate the filtrate to obtain 535g of L-glutamic acid diethyl ester as an oil;
[0019] The steps of the nitrification are as follows:
[0020] Step S7: put thiophene carboxaldehyde and acetic anhydride into a 1L three-necked bottle, stir and mix, cool to 20°C, add a mixed solution of fuming nitric acid and glacial acetic acid (35.6g fuming nitric acid, 261.6ml glacial acetic acid) dropwise, dripping for 2 hours, then heating to react, pouring into ice water after the reaction, precipitating solid, filtering with suction, washing with water to obtain a yellow granular solid with a wet weight of 127g, and drying naturally, transferring the yellow granular solid into a 500ml three-necked bottle, adding 100ml ethanol, heating to raise the temperature, reflux until the product is completely dissolved, cooling, refrigerating in a freezer at room temperature overnight, filtering with suction, washing with cold ethanol, and drying naturally to obtain 55g of a No. 1 light yellow solid;
[0021] The hydrolysis reaction steps are as follows:
[0022] Step S8: Add the light yellow solid, water, ethanol, and sulfuric acid into a 500 ml three-necked flask in sequence, heat and stir, reflux for 2 hours, cool down, and after standing, the lower layer is an oily substance. Add appropriate amount of ice water and stir vigorously until a large amount of cotton-like solid precipitates. Put it in a freezer and freeze it for 1 hour, filter it with suction, and wash it with water to obtain 19.5 g of light yellow cotton-like solid;
[0023] The oxidation reaction steps of the light yellow cotton-like solid are as follows:
[0024] Step S9: Add a light yellow cotton-like solid, acetone, and 65.5 ml of water into a 500 ml three-necked flask, stir, and control the temperature (25-50° C.) to dropwise add a sulfuric acid aqueous solution of chromic anhydride (mixed with 18 g of chromic anhydride, 30 ml of sulfuric acid, and 60 ml of water). After the addition is complete, control the temperature at 50° C. and stir to react for 3 hours. The reaction solution is dark green. After the reaction is completed, cool, precipitate a solid, and dry in an oven at 50° C. to obtain 10 g of a light yellow solid No. 2;
[0025] Step S10: Refining of No. 2 pale yellow solid: 44 g of No. 2 pale yellow solid was put into a 250 ml three-necked flask, 200 ml of methanol was added, stirring and heating, the raw material was dissolved, and the temperature was continued to be raised to reflux, and water was added dropwise, about 100 ml of water was added, and the liquid became turbid, and heating was stopped, cooled (or refrigerated for 1 hour), filtered, and washed with water for 3 times to obtain No. 2 off-white solid;
[0026] The synthesis steps of aminothiophene-2 and methyl formate are as follows:
[0027] Step S11: Add 200.0 g (3.57 mol) of iron powder and 1000 mL of glacial acetic acid to a reaction bottle, stir vigorously, add 173.0 g (0.92 mol) of No. 2 off-white solid in batches, heat to 50° C. and react for 3 h, remove the solvent by vacuum distillation, add 1000 mL of NaHCO 3 saturated solution, extract with dichloromethane, dry with anhydrous Na 7 SO 4, filter, and vacuum distill to obtain 132.2 g (0.84 mol) of the first viscous liquid;
[0028] The synthesis steps of the N-acetyl, aminothiophene-2 and methyl formate are as follows:
[0029] Step S12: 132.2 g (0.84 mol) of the first viscous liquid was dissolved in 1000 mL of glacial acetic acid, 85.9 g (0.84 mol) of acetic anhydride was added dropwise, and the mixture was reacted at room temperature for 24 h. After the solvent was evaporated, 500 mL of petroleum ether was added, and the mixture was refluxed for 15 min. An off-white solid was precipitated after cooling, and 150.9 g (0.76 mol) of the first compound was obtained by filtration;
[0030] The synthesis steps of the (N-methyl) aminothiophene-2 and formate are as follows:
[0031] Step S13: 150.9 g (0.76 mol) of the first compound was dissolved in 500 mL of NN-dimethylformamide (DMF), and 110 g (0.80 mol) of anhydrous K2CO3 and 113.6 g (0.80 mol) of methyl iodide were added in sequence, and the mixture was stirred at 110-120° C. for 5 h, filtered, and the solvent was removed by distillation under reduced pressure. 200 mL of concentrated hydrochloric acid was added, the mixture was refluxed for 12 h, and the solvent was evaporated to dryness. 500 mL of petroleum ether was added, the mixture was refluxed, and cooled to precipitate, to obtain 116.5 g (0.76 mol) of the second compound;
[0032] The synthesis steps of the (N-methyl) aminothiophene-2 and formate are as follows:
[0033] Step S14: Dissolve 150.9 g (0.76 mol) of the second compound in 500 mL of NN-dimethylformamide (DMF), add 110 g (0.80 mol) of anhydrous K2CO3 and 113.6 g (0.80 mol) of methyl iodide in sequence, and stir at 110-120°C for 5 h. Filter, remove the solvent by distillation under reduced pressure, add 200 mL of concentrated hydrochloric acid, reflux for 12 h, evaporate the solvent, add 500 mL of petroleum ether, reflux, and cool to precipitate to obtain 116.5 g (0.54 mol) of the third compound;
[0034] The synthesis steps of [N-(2-methyl-4-oxoquinazoline-6-methyl)-N-methyl], aminothiophene-2 and formic acid are as follows:
[0035] Step S15: 112.4 g (0.54 mol) of the third compound was dissolved in 500 mL of DMF, 3NK2CO3 and 137 g (0.54 mol) of 6-bromomethyl-3,4-dihydro-2-methyl-4-oxoquinazoline were added in sequence, the mixture was reacted at 50° C. for 3 h, then poured into water and filtered to obtain compound A. Compound A was added to 1 N NaOH solution and stirred for 12 h, acidified to pH=4, solid was precipitated, and filtered to obtain 107.0 g (0.32 mol) of the fourth compound;
[0036] The synthesis steps of the NI[5-II(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thiophenyl]carbonyl 1-L-glutamic acid dimethyl ester are as follows:
[0037] Step S16: 107.0 g (0.32 mol) of the fourth compound was dissolved in 3N thionyl chloride, stirred at room temperature for 24 h, the solvent was evaporated under reduced pressure, dichloromethane was added to dissolve, and an equivalent amount of dimethyl L-glutamate and triethylamine were added, stirred at room temperature for 24 h, washed with water, the organic phase was dried over anhydrous Na2SO4, filtered, the solvent was evaporated, excess ethyl acetate was added to reflux, cooled to precipitate solid, filtered with suction, and dried naturally to obtain 134.3 g (0.28 mol) of the fifth compound;
[0038] The synthesis steps of raltitrexed are as follows:
[0039] Step S17: 134.3 g (0.28 mol) of the fifth compound was added to 500 mL of 1 N NaOH solution, cooled in an ice-water bath, naturally heated to room temperature and stirred for reaction for 1 h. After the reaction, the mixture was washed with chloroform, 25 g of activated carbon was added to the aqueous phase for decolorization, and the mixture was filtered with suction. The filtrate was taken, and 1 N hydrochloric acid solution was added dropwise to the filtrate to acidify it to pH = 3, a large amount of solid was precipitated, and stirring was continued for 30 min. The mixture was filtered with suction to obtain 187.3 g of raltitrexed (brown solid);
[0040] Preferably, the oxime is added in five portions, namely 30 g, 25 g, 15 g, 10 g, 5 g and 3 g, and added successively.
[0041] Preferably, the temperature of the dropwise addition of H2O2 is controlled at 40°C.
[0042] Preferably, the temperature of the dropwise addition of H2O2 is controlled at 40°C.
[0043] Preferably, the SOCl2 should be in excess of 20%, and a drying tube is provided on the dropping funnel.
[0044] Preferably, the temperature of the HNO3 insulation reaction does not exceed 60°C.
[0045] Preferably, the CH2Cl2 extraction is performed three times, with 700 ml each time.
[0046] Preferably, when the precipitated solid is added with 100 ml of ice water, the solid is filtered and washed with water three times.
[0047] Preferably, the filtration device is assembled from a Buchner funnel, a filtration bottle, a hose, a vacuum pump, and filter paper.
[0048] Preferably, the mixed solution of fuming nitric acid and glacial acetic acid should be heated to 50-60° C. when being added dropwise, and the reaction time is 5 hours.
[0049] Preferably, the large granular dark brown-red solid is dried at room temperature 16°C.
[0050] Preferably, the large granular dark brown-red solid needs to be dried naturally at room temperature of 16°C.
[0051] The present invention provides a planted flower mosaic medicine through improvement, which has the following improvements and advantages compared with the prior art:
[0052] First, the present invention uses a preparation process to operate 11 main reactions in 8 steps to finally prepare raltitrexed, optimizes the synthesis route, improves the yield and impurity removal effect, and significantly improves the operability, optimizes the reaction conditions of each step, and improves the synthesis yield.
[0053] Secondly, the present invention improves the product yield by optimizing the synthesis process, uses ethyl acetate: petroleum ether = 1:1 (or chloroform: methanol = 10:1) as a developing agent, has a good separation effect, shortens the reaction time, and improves the synthesis efficiency.
[0054] Thirdly, the present invention uses acetic anhydride to protect the 5-amino group of the intermediate 4, and the protecting group can be removed in hydrochloric acid, so the reaction conditions are mild, the reagents are cheap, and the toxicity is low. The disadvantage of route 3 using Boc2O to protect and remove the protecting group in a strong acid environment of trifluoroacetic acid is avoided, especially the process of condensing the N-methylated product with NBS, hydrolyzing, chlorinating, and then condensing with L-glutamic acid diethyl ester. The intermediate can be subjected to the next step reaction without purification, which greatly simplifies the post-treatment process, reduces the labor intensity, and significantly improves the yield. BRIEF DESCRIPTION OF THE DRAWINGS
[0055] The present invention will be further explained below in conjunction with the accompanying drawings and embodiments:
[0056] Figure 1 is the reaction equation for the synthesis of the oxime compound of the present invention;
[0057] Figure 2 is the reaction equation of the cyclization reaction of the present invention;
[0058] Figure 3 is the reaction equation of the red powdery solid oxidation reaction of the present invention;
[0059] Figure 4 It is the reaction equation for the synthesis of quinazoline of the present invention;
[0060] Figure 5 is the reaction equation for the bromination of the present invention;
[0061] Figure 6 It is the reaction equation for the synthesis of L-glutamic acid diethyl ester of the present invention;
[0062] Figure 7 is the reaction equation of nitration of the present invention;
[0063] Figure 8 is the reaction equation of the hydrolysis reaction of the present invention;
[0064] Fig. 9 is the reaction equation for the oxidation reaction of the light yellow cotton-like solid of the present invention;
[0065] Fig.10 is the reaction equation of aminothiophene-2 of the present invention and methyl formate;
[0066] Fig.11 It is the reaction equation for the synthesis of N-acetyl, aminothiophene-2 and methyl formate of the present invention;
[0067] Fig.12 It is the reaction equation for the synthesis of (N-methyl)aminothiophene-2 and formate of the present invention;
[0068] Fig.13 is the reaction equation for the synthesis of aminothiophene-2, methyl formate and aminobenzoic acid of the present invention;
[0069] Fig.14 It is the reaction equation for the synthesis of (N-methyl)aminothiophene-2 and formate of the present invention;
[0070] Fig.15 It is the reaction equation for the synthesis of [N-(2-methyl-4-oxoquinazoline-6-methyl)-N-methyl], aminothiophene-2 and formic acid of the present invention;
[0071] Fig.16 is the reaction equation for the synthesis of NI[5-II(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thiophenyl]carbonyl 1-L-glutamic acid dimethyl ester of the present invention;
[0072] Fig.17 It is the reaction equation for the synthesis of raltitrexed of the present invention. DETAILED DESCRIPTION
[0073] The present invention is described in detail below, and the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0074] The present invention provides a method for preparing degraded impurities in a raltitrexed preparation by improvement. The technical solution of the present invention is:
[0075] like Figure 1 - Fig.17 As shown, a method for preparing degradation impurities in a raltitrexed preparation includes 117g of hydroformaldehyde, 752g of anhydrous Na2SO4, 70g of p-toluidine, 68ml of concentrated hydrochloric acid, 72g of hydroxylamine hydrochloride, 339ml of concentrated sulfuric acid, 125ml of methanol, 261.7ml of H2O2, 747.8ml of NaOH solution, 20g of thioacetamide, 4785ml of anhydrous ethanol, 32.5g of NaHCO3, 5g of activated carbon, 25.6g of NBS, 0.32g of benzoyl peroxide, 25.6g of NBS, 3720ml of CHCL, 441g of L-glutamic acid, 542ml of SOCl2, 50g of thiophene carboxaldehyde, 158.3ml of acetic anhydride, 35.6g of fuming nitric acid, 261.5 of glacial acetic acid, 65.5ml of acetone, 18g of chromic anhydride, 30ml of sulfuric acid, and 200g of iron powder (3.57mol);
[0076] The degradation impurities and preparation process of the raltitrexed preparation include the following steps: synthesis of oxime, cyclization reaction, oxidation reaction of red powder solid, synthesis of quinazoline, bromination, synthesis of L-glutamic acid diethyl ester, nitration, hydrolysis reaction, oxidation reaction of light yellow cotton-like solid, synthesis of aminothiophene-2 and methyl formate, synthesis of N-acetyl, aminothiophene-2 and methyl formate, synthesis of N-acetyl, aminothiophene-2 and methyl formate, synthesis of (N-methyl), aminothiophene-2 and formic acid hydrochloride, synthesis of (N-methyl), aminothiophene-2 and formic acid hydrochloride, synthesis of [N-(2-methyl-4-oxoquinazoline-6-methyl)-N-methyl], aminothiophene-2 and formic acid, synthesis of NI[5-II(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thiophenyl]carbonyl 1-L-glutamic acid dimethyl ester, and synthesis of raltitrexed;
[0077] The synthesis steps of the oxime are as follows:
[0078] Step S1: Add 117g of chloral hydrate and mix with 1308ml of water, stir and add 752g of anhydrous Na2SO4 in portions, heat to 50°C, then add 70g of p-toluidine, 392ml of water, and 57ml of hydrochloric acid, use solid phase precipitation separation method to change the solution conditions so that the solute is separated from the solution in solid form, then add 72g of hydroxylamine hydrochloride and 327ml of water, then quickly heat to 100°C, reflux for 10 minutes, cool to room temperature, filter, and obtain large granular dark brown-red solid, dry for 24 hours, then heat and reflux with 654ml of water for 10 minutes, vigorously stir and cool, filter to obtain small granular solid brown, and dry at room temperature for 24 hours to obtain 88g of oxime.
[0079] The cyclization reaction steps are as follows:
[0080] Step S2: Add concentrated sulfuric acid to a 1L three-necked flask and heat it to 50°C, add the oxime in batches, and control the reaction temperature between 60 and 70°C. After the addition, heat it to 80°C, stir for 10 minutes, cool it, add it to ice water, stir it well, change the solution conditions by solid phase separation method, separate the solute from the solution in solid form, filter it, wash it with water, and then wash it with an appropriate amount of methanol, and dry it in an oven at 50°C to obtain 73.5g of red powdery solid;
[0081] The red powder solid oxidation reaction steps are as follows:
[0082] Step S3: add the red powdered solid and NaOH solution into a 3L three-necked flask, stir to dissolve, add 10% H2O2 solution dropwise, keep the reaction temperature below 50°C, stir and react at 85°C for 2 hours, cool, filter, cool the filtrate with ice water to below 10°C, acidify with concentrated hydrochloric acid to pH=3.5-4, change the solution conditions by solid phase precipitation separation method, separate the solute from the solution in solid form, filter with suction, and dry in a 50°C oven to obtain 48.5 orange-yellow solid;
[0083] The synthesis steps of quinazoline are as follows:
[0084] Step S4: The orange-yellow solid and thioacetamide were fully ground, mixed and put into a flask, stirred and reacted at 140-160°C for 2 hours, the reactant was first melted and then solidified, after the reaction was completed, the solid was taken out and fully crushed, 250ml of 1% NaHCO3 aqueous solution was added and fully stirred, filtered, washed with water and dried to obtain a dry product, the dry product was added to a 3L three-necked flask, 1500ml of anhydrous ethanol was added, refluxed to dissolve it, 5g of activated carbon was added, refluxed for 15 minutes, filtered, the filtrate was cooled to room temperature, and then refrigerated in a freezer overnight, filtered, washed with anhydrous ethanol three times with 100ml ethanol each time, and dried in a 50°C oven to obtain 24g of light brown solid quinazoline;
[0085] The bromination steps are as follows:
[0086] Step S5: quinazoline, NBS, chloroform, and benzoyl peroxide were sequentially placed in a 1L three-necked flask, and reacted in a 50°C water bath overnight. The reactants began to dissolve and solids precipitated in about 6 hours. After the reaction was completed, the mixture was cooled and refrigerated in a refrigerator for 2 hours. The mixture was filtered, washed with CHCl3, and dried to obtain 13.5 g of a No. 1 off-white solid;
[0087] The synthesis steps of L-glutamic acid diethyl ester are as follows:
[0088] Step S6: Add L-glutamic acid and anhydrous ethanol to a 5L four-necked bottle, stir, cool in an ice-salt bath, add SOCb dropwise at -10°C, control the temperature not to exceed 0°C, complete the addition, stir at room temperature overnight, the reaction solution is clear and colorless, concentrate under reduced pressure to dryness, and obtain a white solid. Add 1000ml of pure water to the bottle and stir until the material is dissolved. The solution is light yellow, cool with ice water, add K2CO3 to the reaction solution to adjust the pH to 10, control the temperature not to exceed 20°C, stir for 10 minutes, extract the solution three times with CH2Cl2, 700ml each time, wash the organic phase three times with saturated NaCl solution, 500ml each time, add 10gMgSO4 to the organic phase, dry, filter, and concentrate the filtrate to obtain 535g of L-glutamic acid diethyl ester as an oil;
[0089] The steps of nitrification are as follows:
[0090] Step S7: put thiophene carboxaldehyde and acetic anhydride into a 1L three-necked bottle, stir and mix, cool to 20°C, add a mixed solution of fuming nitric acid and glacial acetic acid (35.6g fuming nitric acid, 261.6ml glacial acetic acid) dropwise, dripping for 2 hours, then heating to react, pouring into ice water after the reaction, precipitating solid, filtering with suction, washing with water to obtain a yellow granular solid with a wet weight of 127g, and drying naturally, transferring the yellow granular solid into a 500ml three-necked bottle, adding 100ml ethanol, heating to raise the temperature, reflux until the product is completely dissolved, cooling, refrigerating in a freezer at room temperature overnight, filtering with suction, washing with cold ethanol, and drying naturally to obtain 55g of a No. 1 light yellow solid;
[0091] The hydrolysis reaction steps are as follows:
[0092] Step S8: Add the light yellow solid, water, ethanol, and sulfuric acid into a 500 ml three-necked flask in sequence, heat and stir, reflux for 2 hours, cool down, and after standing, the lower layer is an oily substance. Add appropriate amount of ice water and stir vigorously until a large amount of cotton-like solid precipitates. Put it in a freezer and freeze it for 1 hour, filter it with suction, and wash it with water to obtain 19.5 g of light yellow cotton-like solid;
[0093] The oxidation reaction steps of the light yellow cotton-like solid are as follows:
[0094] Step S9: Add a light yellow cotton-like solid, acetone, and 65.5 ml of water into a 500 ml three-necked flask, stir, and control the temperature (25-50° C.) to dropwise add a sulfuric acid aqueous solution of chromic anhydride (mixed with 18 g of chromic anhydride, 30 ml of sulfuric acid, and 60 ml of water). After the addition is complete, control the temperature at 50° C. and stir to react for 3 hours. The reaction solution is dark green. After the reaction is completed, cool, precipitate a solid, and dry in an oven at 50° C. to obtain 10 g of a light yellow solid No. 2;
[0095] Step S10: Refining of No. 2 pale yellow solid: 44 g of No. 2 pale yellow solid was put into a 250 ml three-necked flask, 200 ml of methanol was added, stirring and heating, the raw material was dissolved, and the temperature was continued to be raised to reflux, and water was added dropwise, about 100 ml of water was added, and the liquid became turbid, and heating was stopped, cooled (or refrigerated for 1 hour), filtered, and washed with water for 3 times to obtain No. 2 off-white solid;
[0096] The synthesis steps of aminothiophene-2 and methyl formate are as follows:
[0097] Step S11: Add 200.0 g (3.57 mol) of iron powder and 1000 mL of glacial acetic acid to a reaction bottle, stir vigorously, add 173.0 g (0.92 mol) of No. 2 off-white solid in batches, heat to 50° C. and react for 3 h, remove the solvent by vacuum distillation, add 1000 mL of NaHCO 3 saturated solution, extract with dichloromethane, dry with anhydrous Na 7 SO 4, filter, and vacuum distill to obtain 132.2 g (0.84 mol) of the first viscous liquid;
[0098] The synthesis steps of N-acetyl, aminothiophene-2 and methyl formate are as follows:
[0099] Step S12: 132.2 g (0.84 mol) of the first viscous liquid was dissolved in 1000 mL of glacial acetic acid, 85.9 g (0.84 mol) of acetic anhydride was added dropwise, and the mixture was reacted at room temperature for 24 h. After the solvent was evaporated, 500 mL of petroleum ether was added, and the mixture was refluxed for 15 min. An off-white solid was precipitated after cooling, and 150.9 g (0.76 mol) of the first compound was obtained by filtration;
[0100] The synthesis steps of (N-methyl), aminothiophene-2 and formate are as follows:
[0101] Step S13: 150.9 g (0.76 mol) of the first compound was dissolved in 500 mL of NN-dimethylformamide (DMF), and 110 g (0.80 mol) of anhydrous K2CO3 and 113.6 g (0.80 mol) of methyl iodide were added in sequence, and the mixture was stirred at 110-120° C. for 5 h, filtered, and the solvent was removed by distillation under reduced pressure. 200 mL of concentrated hydrochloric acid was added, the mixture was refluxed for 12 h, and the solvent was evaporated to dryness. 500 mL of petroleum ether was added, the mixture was refluxed, and cooled to precipitate, to obtain 116.5 g (0.76 mol) of the second compound;
[0102] The synthesis steps of (N-methyl), aminothiophene-2 and formate are as follows:
[0103] Step S14: Dissolve 150.9 g (0.76 mol) of the second compound in 500 mL of NN-dimethylformamide (DMF), add 110 g (0.80 mol) of anhydrous K2CO3 and 113.6 g (0.80 mol) of methyl iodide in sequence, and stir at 110-120°C for 5 h. Filter, remove the solvent by distillation under reduced pressure, add 200 mL of concentrated hydrochloric acid, reflux for 12 h, evaporate the solvent, add 500 mL of petroleum ether, reflux, and cool to precipitate to obtain 116.5 g (0.54 mol) of the third compound;
[0104] The synthesis steps of [N-(2-methyl-4-oxoquinazoline-6-methyl)-N-methyl], aminothiophene-2 and formic acid are as follows:
[0105] Step S15: 112.4 g (0.54 mol) of the third compound was dissolved in 500 mL of DMF, 3NK2CO3 and 137 g (0.54 mol) of 6-bromomethyl-3,4-dihydro-2-methyl-4-oxoquinazoline were added in sequence, the mixture was reacted at 50° C. for 3 h, then poured into water and filtered to obtain compound A. Compound A was added to 1 N NaOH solution and stirred for 12 h, acidified to pH=4, solid was precipitated, and filtered to obtain 107.0 g (0.32 mol) of the fourth compound;
[0106] The synthesis steps of NI[5-II(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thiophenyl]carbonyl 1-L-glutamic acid dimethyl ester are as follows:
[0107] Step S16: 107.0 g (0.32 mol) of the fourth compound was dissolved in 3N thionyl chloride, stirred at room temperature for 24 h, the solvent was evaporated under reduced pressure, dichloromethane was added to dissolve, and an equivalent amount of dimethyl L-glutamate and triethylamine were added, stirred at room temperature for 24 h, washed with water, the organic phase was dried over anhydrous Na2SO4, filtered, the solvent was evaporated, excess ethyl acetate was added to reflux, cooled to precipitate solid, filtered with suction, and dried naturally to obtain 134.3 g (0.28 mol) of the fifth compound;
[0108] The synthesis steps of raltitrexed are as follows:
[0109] Step S17: 134.3 g (0.28 mol) of the fifth compound was added to 500 mL of 1 N NaOH solution, cooled in an ice-water bath, naturally heated to room temperature and stirred for reaction for 1 h. After the reaction, the mixture was washed with chloroform, 25 g of activated carbon was added to the aqueous phase for decolorization, and the mixture was filtered with suction. The filtrate was taken, and 1 N hydrochloric acid solution was added dropwise to the filtrate to acidify it to pH = 3, a large amount of solid was precipitated, and stirring was continued for 30 min. The mixture was filtered with suction to obtain 187.3 g of raltitrexed (brown solid);
[0110] Furthermore, the oxime compound is added in five portions, namely 30 g, 25 g, 15 g, 10 g, 5 g, and 3 g, and added successively. The portioned addition can make the reaction rate more stable and avoid excessively violent reaction caused by adding a large amount of oxime compound at one time, thereby helping to better control the reaction process.
[0111] Furthermore, the temperature of H2O2 dripping is controlled at 40°C, which not only helps to ensure the reaction and drying effects, but also improves safety and energy saving, while protecting the equipment.
[0112] Furthermore, SOCl2 should be in excess of 20%. A drying tube is provided on the dropping funnel. The drying tube can maintain the purity of the dropped SOCl2 by removing moisture and other impurities in the air, which helps to reduce the reaction interference caused by impurities, thereby improving the reaction efficiency and the quality of the product.
[0113] Furthermore, the temperature of the HNO3 insulation reaction does not exceed 60°C. HNO3 may react with other substances in a more complex manner at a higher temperature to generate unwanted by-products. The possibility of these side reactions can be greatly reduced, thereby ensuring that the main reaction can proceed smoothly and the product is purer.
[0114] Furthermore, the CH2Cl2 extraction is performed three times, and each time with 700 ml. Through multiple extractions, it can be ensured that the target compound or component is more completely extracted from the original mixture. Using a fixed volume (such as 700 ml) of dichloromethane each time can ensure the consistency of the conditions and operations of each extraction, thereby improving the overall extraction efficiency and repeatability.
[0115] Furthermore, when the solid is precipitated, 100 ml of ice water needs to be added, filtered and washed three times. The temperature of ice water is relatively low, which helps to lower the temperature of the solution, thereby accelerating the crystallization of the solute at low temperature. Low temperature can reduce the solubility of the solute in the solution, making it easier to precipitate in the form of a solid.
[0116] Furthermore, the filtration device is assembled from a Buchner funnel, a filtration bottle, a hose, a vacuum pump, and filter paper. Since the vacuum pump can significantly reduce the pressure in the filtration bottle, the filtration process is accelerated, greatly improving work efficiency.
[0117] Furthermore, the mixed solution of fuming nitric acid and glacial acetic acid should be heated to 50-60° C., and the reaction time is 5 hours. The temperature range of 50-60° C. may be the optimal reaction temperature for the reaction, which can ensure that the reaction reaches a higher conversion rate within 5 hours.
[0118] Furthermore, the large granular dark brown-red solid is dried at room temperature of 16° C. Natural drying at a relatively low and constant room temperature helps prevent thermal stress or structural changes in the large granular dark brown-red solid caused by temperature changes, thereby ensuring its stability.
[0119] The above description enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.
Claims
1. A method for preparing degradation impurities in a raltitrexed preparation, comprising 117 g of hydroaldehyde hydrate, 752 g of anhydrous Na2SO4, 70 g of p-toluidine, 68 ml of concentrated hydrochloric acid, 72 g of hydroxylamine hydrochloride, 339 ml of concentrated sulfuric acid, 125 ml of methanol, 261.7 ml of H2O2, 747.8 ml of NaOH solution, 20 g of thioacetamide, 4785 ml of anhydrous ethanol, 32.5 g of NaHCO3, 5 g of activated carbon, 25.6 g of NBS, 0.32 g of toluoyl peroxide, 25.6 g of NBS, 3720 ml of CHCl, 441 g of L-glutamic acid, 542 ml of SOCl2, 50 g of thiophene carboxaldehyde, 158.3 ml of acetic anhydride, 35.6 g of fuming nitric acid, 261.5 ml of glacial acetic acid, 65.5 ml of acetone, 18 g of chromic anhydride, 30 ml of sulfuric acid, and 200 g of iron powder (3.57 mol); The degradation impurities in the raltitrexed preparation and the preparation method thereof comprise the following steps: Synthesis of oximes, cyclization reaction, oxidation reaction of red powdered solids, synthesis of quinazoline, bromination, synthesis of diethyl L-glutamate, nitration, hydrolysis reaction, oxidation reaction of light yellow cotton-like solids, synthesis of aminothiophene-2 and methyl formate, synthesis of N-acetyl aminothiophene-2 and methyl formate, synthesis of N-acetyl aminothiophene-2 and methyl formate, synthesis of (N-methyl) aminothiophene-2 and formic acid hydrochloride, synthesis of (N-methyl) aminothiophene-2 and formic acid hydrochloride, synthesis of [N-(2-methyl-4-oxoquinazoline-6-methyl)-N-methyl] aminothiophene-2 and formic acid, synthesis of NI[5-II(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thienyl]carbonyl 1-L-glutamic acid dimethyl ester, synthesis of raltitrexed; The synthesis steps of the oxime are as follows: Step S1: 117 g of chloral hydrate was added and mixed with 1308 ml of water. After stirring, 752 g of anhydrous Na2SO4 was added in portions and heated to 50°C. Then, 70 g of p-toluidine, 392 ml of water, and 57 ml of hydrochloric acid were added. The solution conditions were changed by solid phase precipitation separation so that the solute was separated from the solution in solid form. Then, 72 g of hydroxylamine hydrochloride and 327 ml of water were added. The mixture was then rapidly heated to 100°C, refluxed for 10 minutes, cooled to room temperature, and filtered to obtain a large granular dark brown-red solid. The solid was dried for 24 hours, then heated to reflux with 654 ml of water for 10 minutes, cooled with vigorous stirring, and filtered to obtain a small granular brown solid. The solid was dried at room temperature for 24 hours to obtain 88 g of oxime. The cyclization reaction steps are as follows: Step S2: Add concentrated sulfuric acid to a 1L three-necked flask and heat to 50°C, add the oxime in batches, and control the reaction temperature between 60 and 70°C. After the addition, heat to 80°C, stir for 10 minutes, let cool, add to ice water, stir well, change the solution conditions by solid phase precipitation separation method, separate the solute from the solution in solid form, filter, wash with water, and then wash with an appropriate amount of methanol, and dry in a 50°C oven to obtain 73.5g of red powdery solid; The red powdery solid oxidation reaction steps are as follows: Step S3: Add the red powdered solid and NaOH solution into a 3 L three-necked flask, stir to dissolve, add 10% H2O2 solution dropwise, maintain the reaction temperature below 50°C, stir and react at 85°C for 2 hours, let cool, filter, cool the filtrate with ice water to below 10°C, acidify with concentrated hydrochloric acid to pH = 3.5-4, change the solution conditions by solid phase precipitation separation method to separate the solute from the solution in solid form, filter with suction, and dry in a 50°C oven to obtain 48.5g of orange-yellow solid; The quinazoline synthesis steps are as follows: Step S4: The orange-yellow solid and thioacetamide were fully ground, mixed and put into a flask, and stirred at 140-160°C for 2 hours. The reactant was first melted and then solidified. After the reaction was completed, the solid was taken out and fully crushed, 250ml of 1% NaHCO3 aqueous solution was added and fully stirred, filtered, washed with water and dried to obtain a dry product, which was added to a 3L three-necked flask, 1500ml of anhydrous ethanol was added, refluxed to dissolve it, 5g of activated carbon was added, refluxed for 15 minutes, filtered, and the filtrate was cooled to room temperature, then refrigerated in a freezer overnight, filtered, washed three times with 100ml of ethanol each time, and dried in a 50°C oven to obtain 24g of quinazoline as a light brown solid; The bromination steps are as follows: Step S5: Quinazoline, NBS, chloroform, and benzoyl peroxide were sequentially added to a 1 L three-necked flask and reacted in a 50°C water bath overnight. The reactants began to dissolve and solids precipitated in about 6 hours. After the reaction was completed, the mixture was cooled and refrigerated in a refrigerator for 2 hours. The mixture was filtered, washed with CHCl3, and dried to obtain 13.5 g of an off-white solid No.
1. The synthesis steps of described L-glutamic acid diethyl ester are as follows: Step S6: Add L-glutamic acid and anhydrous ethanol to a 5L four-necked flask, stir, and cool in an ice-salt bath. Add SOCb dropwise at -10°C, controlling the temperature not to exceed 0°C. After the addition is complete, stir at room temperature overnight. The reaction solution becomes clear and colorless. Concentrate under reduced pressure to dryness to obtain a white solid. Add 1000ml of pure water to the flask and stir until the material dissolves. The solution is light yellow and cooled with ice water. Add K2CO3 to the reaction solution to adjust the pH to 10. Control the temperature not to exceed 20°C and stir for 10 minutes. Extract the solution with CH2Cl2 and wash the organic phase three times with saturated NaCl solution, washing 500ml of the organic phase each time. Add 10gMgSO4 to the organic phase for drying. Filter and concentrate the filtrate to obtain 535g of L-glutamic acid diethyl ester as an oil. The steps of the nitrification are as follows: Step S7: Thiophene carboxaldehyde and acetic anhydride were placed in a 1L three-necked flask and stirred to mix. The mixture was cooled to 20°C, and a mixed solution of fuming nitric acid and glacial acetic acid (35.6 g of fuming nitric acid and 261.6 ml of glacial acetic acid) was added dropwise. The mixture was dripped over 2 hours, and then heated to react. After the reaction, the mixture was poured into ice water to precipitate a solid, filtered, and washed with water to obtain a yellow granular solid with a wet weight of 127 g. The solid was naturally dried. The yellow granular solid was transferred to a 500 ml three-necked flask, 100 ml of ethanol was added, and the mixture was heated and refluxed until the product was completely dissolved. The mixture was cooled and refrigerated in a freezer at room temperature overnight. The mixture was filtered, washed with cold ethanol, and naturally dried to obtain 55 g of a light yellow solid No.
1. The hydrolysis reaction steps are as follows: Step S8: Add the light yellow solid, water, ethanol, and sulfuric acid in a 500 ml three-necked flask in sequence, heat with stirring, reflux for 2 hours, cool, and allow to stand until the lower layer is an oily substance. Add appropriate amount of ice water and stir vigorously until a large amount of cotton-like solid precipitates. Place in a freezer and freeze for 1 hour, filter, and wash with water to obtain 19.5 g of light yellow cotton-like solid. The oxidation reaction steps of the light yellow cotton-like solid are as follows: Step S9: Add a light yellow cotton-like solid, acetone, and 65.5 ml of water to a 500 ml three-necked flask, stir, and control the temperature (25-50°C). Then, dropwise add a sulfuric acid aqueous solution of chromic anhydride (mixed with 18 g of chromic anhydride, 30 ml of sulfuric acid, and 60 ml of water). After the addition is complete, control the temperature to 50°C and stir for 3 hours. The reaction solution turns dark green. After the reaction is complete, cool, precipitate a solid, and dry in a 50°C oven to obtain 10 g of light yellow solid No.
2. Step S10: Refining the No. 2 pale yellow solid: 44 g of the No. 2 pale yellow solid was placed in a 250 ml three-necked flask, 200 ml of methanol was added, and the mixture was stirred and heated until the raw material dissolved. The temperature was continued to be raised to reflux, and water was added dropwise. When about 100 ml of water was added, the liquid became turbid. The heating was stopped, and the mixture was cooled (or refrigerated for 1 hour), filtered, and washed with water 3 times to obtain the No. 2 off-white solid. The synthesis steps of aminothiophene-2 and methyl formate are as follows: Step S11: Add 200.0 g (3.57 mol) of iron powder and 1000 mL of glacial acetic acid to a reaction flask, stir vigorously, add 173.0 g (0.92 mol) of No. 2 off-white solid in batches, heat to 50°C and react for 3 h, remove the solvent by distillation under reduced pressure, add 1000 mL of a saturated NaHCO3 solution, extract with dichloromethane, dry with anhydrous Na7SO4, filter, and distill under reduced pressure to obtain 132.2 g (0.84 mol) of a first viscous liquid; The synthesis steps of the N-acetyl, aminothiophene-2 and methyl formate are as follows: Step S12: 132.2 g (0.84 mol) of the first viscous liquid was dissolved in 1000 mL of glacial acetic acid, 85.9 g (0.84 mol) of acetic anhydride was added dropwise, and the mixture was reacted at room temperature for 24 h. After evaporating the solvent, 500 mL of petroleum ether was added, and the mixture was refluxed for 15 min. The mixture was cooled to precipitate an off-white solid, which was filtered to obtain 150.9 g (0.76 mol) of the first compound; The synthesis steps of the (N-methyl) aminothiophene-2 and formate are as follows: Step S13: 150.9 g (0.76 mol) of the first compound was dissolved in 500 mL of NN-dimethylformamide (DMF), and 110 g (0.80 mol) of anhydrous K2CO3 and 113.6 g (0.80 mol) of iodomethane were added in sequence. The mixture was stirred at 110-120°C for 5 h, filtered, and the solvent was removed by distillation under reduced pressure. 200 mL of concentrated hydrochloric acid was added, the mixture was refluxed for 12 h, and the solvent was evaporated to dryness. 500 mL of petroleum ether was added, the mixture was refluxed, and cooled to precipitate, to obtain 116.5 g (0.76 mol) of the second compound. The synthesis steps of the (N-methyl) aminothiophene-2 and formate are as follows: Step S14: Dissolve 150.9 g (0.76 mol) of the second compound in 500 mL of NN-dimethylformamide (DMF), then add 110 g (0.80 mol) of anhydrous K2CO3 and 113.6 g (0.80 mol) of iodomethane, stirring at 110-120°C for 5 h. Filter and remove the solvent by distillation under reduced pressure. Add 200 mL of concentrated hydrochloric acid and reflux for 12 h, then evaporate the solvent to dryness. Add 500 mL of petroleum ether and reflux, then cool to precipitate, to obtain 116.5 g (0.54 mol) of the third compound. The synthesis steps of [N-(2-methyl-4-oxoquinazoline-6-methyl)-N-methyl], aminothiophene-2 and formic acid are as follows: Step S15: 112.4 g (0.54 mol) of the third compound was dissolved in 500 mL of DMF, and 3NK2CO3 and 137 g (0.54 mol) of 6-bromomethyl-3,4-dihydro-2-methyl-4-oxoquinazoline were added in sequence. The mixture was reacted at 50° C. for 3 h, poured into water, and filtered to obtain compound A. Compound A was added to 1 N NaOH solution and stirred for 12 h. The mixture was acidified to pH 4, and a solid was precipitated. The solid was filtered to obtain 107.0 g (0.32 mol) of the fourth compound. The synthesis steps of the NI[5-II(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thiophenyl]carbonyl 1-L-glutamic acid dimethyl ester are as follows: Step S16: 107.0 g (0.32 mol) of the fourth compound was dissolved in 3N thionyl chloride, stirred at room temperature for 24 h, and the solvent was evaporated under reduced pressure. Dichloromethane was added to dissolve the mixture, and an equivalent amount of dimethyl L-glutamate and triethylamine were added. The mixture was stirred at room temperature for 24 h, washed with water, and the organic phase was dried over anhydrous Na2SO4. After filtering, the solvent was evaporated, and excess ethyl acetate was added and refluxed. The solid was cooled to precipitate, filtered, and dried naturally to obtain 134.3 g (0.28 mol) of the fifth compound. The synthesis steps of described raltitrexed are as follows: Step S17: 134.3 g (0.28 mol) of the fifth compound was added to 500 mL of 1N NaOH solution, cooled in an ice-water bath, naturally warmed to room temperature, and stirred for 1 h. After the reaction, the solution was washed with chloroform, 25 g of activated carbon was added to the aqueous phase for decolorization, and the solution was filtered with suction. The filtrate was taken and 1N hydrochloric acid solution was added dropwise to the filtrate to acidify it to pH = 3. A large amount of solid precipitated. The solution was stirred for 30 min and filtered with suction to obtain 187.3 g of raltitrexed (brown solid).
2. The method for preparing degraded impurities in a raltitrexed preparation according to claim 1, wherein: The oxime compound is added in five portions, namely 30 g, 25 g, 15 g, 10 g, 5 g and 3 g, and is added successively.
3. The method for preparing degraded impurities in a raltitrexed preparation according to claim 1, wherein: The temperature was controlled at 40°C during the dropwise addition of H2O2.
4. The method for preparing degraded impurities in a raltitrexed preparation according to claim 1, wherein: The SOCl2 should be in excess of 20%, and the dropping funnel is provided with a drying tube.
5. The method for preparing degraded impurities in a raltitrexed preparation according to claim 1, wherein: The temperature of the HNO3 insulation reaction does not exceed 60°C.
6. The method for preparing degraded impurities in a raltitrexed preparation according to claim 1, wherein: The CH2Cl2 extraction was performed three times, with 700 ml each time.
7. The method for preparing degraded impurities in a raltitrexed preparation according to claim 1, wherein: When the precipitated solid was added with 100 ml of ice water, filtered and washed three times with water.
8. The method for preparing degraded impurities in a raltitrexed preparation according to claim 1, wherein: The suction filtration device is assembled from a Buchner funnel, a suction filtration bottle, a hose, an air pump, and filter paper.
9. The method for preparing degraded impurities in a raltitrexed preparation according to claim 1, wherein: The mixed solution of fuming nitric acid and glacial acetic acid should be heated to 50-60° C. when being added dropwise, and the reaction time is 5 hours.
10. The method for preparing degraded impurities in a raltitrexed preparation according to claim 1, characterized in that: The large granular dark brown-red solid was air-dried at room temperature (16°C).