Synthetic method for thienopyrimidine derivative and use thereof
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2025-04-30
- Publication Date
- 2026-08-13
Smart Images
Figure PCTCN2025092274-FTAPPB-I100001 
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Figure PCTCN2025092274-FTAPPB-I100003
Abstract
Description
A synthetic method for a thiophene pyrimidine derivative and its application Technical Field
[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for synthesizing thiophene pyrimidine derivatives and their applications. Background Technology
[0002] Epidermal growth factor receptor (EGFR, Erbb1) is involved in the proliferation of both normal and malignant tumor cells. EGFR overexpression has been found to be associated with cancers such as lung cancer, breast cancer, head and neck cancer, and bladder cancer.
[0003] The EGFR family comprises four receptor tyrosine kinases: EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2, ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Tyrosine kinases play a role in signal transduction. They bind ligands to the receptor's ligand-binding domain extracellularly, forming active homodimers or heterodimers, leading to autophosphorylation of EGFR and activation of stopping proteins (Greulich H. Chen, PLoS Med, 2005, 2, e313; Olayioye MA, EMBO J, 2000, 19, 3159-3167). These signals promote cellular processes such as proliferation, protein synthesis, angiogenesis, cell growth, and survival.
[0004] EGFR overexpression is present in approximately 70% of cancer patients (Seymour, LK, Curr Drug Targets, 2001, 2, 117-133). EGFR tyrosine kinase has become a therapeutic target, and several drugs have been developed to inhibit kinase activity and block its signal transduction pathway as ATP competitors, such as the FDA-approved Tarceva, Irressa, and Gilotrif (all 4-amino-quinazoline inhibitors). These drugs have been widely used in patients with EGFR-overexpressing non-small cell lung cancer (NSCLC), including wild-type and active mutation patients (W. Pao, Nat. Rev. Cancer, 2010, 10, 760-774; R. Rosell, Lancet Oncol, 2012, 13, 239-246; NULin, Breast Cancer Res, 2004, 6, 204-210).
[0005] Two common active mutations were found in patients: L858R and E746-A750 deletion. Mechanistic studies suggest that the clinical activity of Tarceva and Iressa in patients with active mutations may be a result of the combined effects of the enhanced binding affinity of the inhibitor to the mutant kinase and the addiction of mutant cells to proto-oncogenes (JA. Engelman, Science, 2007, 316, 1039-1043).
[0006] However, these first- and second-generation inhibitors with a 4-amino-quinazoline core structure are not effective in approximately 50% of patients with relapsed and acquired resistance diseases such as NSCLC. Acquired resistance is caused by mutations in the T790M gate residue (LV. Sequist, Sci Transl Med, 2011, 3, 75ra26; S. Kobayashi, N Engl J Med, 2005, 352, 786-792; W. Pao, PLoS Med, 2005, 2, 373; JA. Engelman, Semin Respir Crit Care Med, 2005, 26, 314-322). This mutation (the second mutation) increases the binding affinity of ATP for EGFR tyrosine kinase and affects the thermodynamic and kinetic binding properties of these formulations (CH. Yun, Proc Natl Acad Sci USA, 2008, 105, 2070-2075; Cancer Cell, 2007, 11, 217-227; M. Azam, Nat Struct Mol Biol, 2008, 15, 1109-1118; TA. Carter, Proc Natl Acad Sci USA, 2005, 102, 11011-11016). The larger methionine side chain in the choke region prevents those drug molecules from interacting with the ATP binding pocket at clinically effective concentrations.
[0007] Second-generation covalent EGFR inhibitors, such as the FDA-approved afatinib and the clinical-tested compound HKI-272, are effective in patients with the T790M mutation. However, the use of afatinib in patients with active mutations is limited due to dose-limiting toxicity that causes inhibition of wild-type EGFR.
[0008] Thiophene pyrimidine derivatives are effective and selective inhibitors of mutant epidermal growth factor receptor (EGFR) tyrosine kinases without affecting wild-type EGFR, thus reducing side effects.
[0009] Existing patent literature (US Patent Publication No. US20150119379A1) discloses a method for synthesizing pyrimidine derivatives, which uses a 2-pentanol / p-toluenesulfonic acid reaction system. Studies have found that this reaction system has the following problems: 1) 2-pentanol is expensive, which leads to high cost of the synthesis method; 2) p-toluenesulfonic acid used in the reaction has one molecule of water of crystallization, which causes a certain amount of hydrolysis byproducts to be generated during the reaction.
[0010] Therefore, there is an urgent need to optimize the existing synthetic methods for thiophene pyrimidine derivatives and find a synthetic route that is low in cost, has readily available raw materials, and reduces byproducts. Summary of the Invention
[0011] To address the shortcomings of existing technologies, the present invention aims to provide a route-optimized, low-cost synthetic method for thiophene pyrimidine derivatives and its applications. This invention optimizes existing synthetic methods for thiophene pyrimidine derivatives, improves reaction conditions, selects inexpensive solvents, significantly reduces reaction costs, and ensures good yields and reproducibility across reaction scales from gram to 10 kg.
[0012] This invention screened the reaction systems disclosed in patent literature (US Patent Publication No. US20150119379A1) and proposed that using a 1-methoxy-2-propanol / methanesulfonic acid system instead of a 2-pentanol / p-toluenesulfonic acid system yields the same conversion and yield under essentially the same reaction time and temperature, while significantly reducing byproducts. This invention selected this solvent because 1-methoxy-2-propanol has a similar main chain structure to 2-pentanol, similar solubility in the reaction mixture, and the same boiling point temperature. Furthermore, 1-methoxy-2-propanol is a commonly used industrial solvent, and compared to 2-pentanol, it is cheaper and more readily available, making it a better alternative. During the screening process, this invention also compared various solvents, including primary alcohols, tertiary alcohols, aprotic polar solvents, nonpolar solvents, and mixed solvent systems. The results show that 1-methoxy-2-propanol has significant advantages.
[0013] Because the 1-methoxy-2-propanol used in this invention has a similar main chain structure, solubility, and boiling point temperature to 2-pentanol, it is not easy to think of replacing the 2-pentanol / p-toluenesulfonic acid system with the 1-methoxy-2-propanol / methanesulfonic acid system. This invention requires pre-screening a sufficient number of systems (the pre-screening should be able to screen out the target system), and then obtaining the optimal conditions through comparison of experimental data.
[0014] This invention provides a thiophene pyrimidine derivative or its stereoisomer, a pharmaceutically acceptable salt, a prodrug, or a solvate, the structure of which is shown in Formula 1:
[0015] The "thiophene pyrimidine derivative" proposed in this invention is a novel structure disclosed for the first time in this invention.
[0016] The present invention also provides a method for synthesizing the thiophene pyrimidine derivative, the method comprising the following steps:
[0017] Step 1: In the presence of aluminum trichloride (AlCl3) and the first solvent, compound 2 reacts with N-methylindole to generate compound 3;
[0018] In the second step, in the presence of the second solvent and methanesulfonic acid (MsOH), compound 3 reacts with 4-fluoro-2-methoxy-5-nitroaniline to generate compound 4;
[0019] In the third step, in the presence of the third solvent and the first base, compound 4 reacts with N,N,N'-trimethylethylenediamine to generate compound 5;
[0020] In the fourth step, in the presence of the fourth solvent, anhydrous potassium carbonate, compound 5 reacts with sodium dithionite, and then reacts in the presence of the fifth solvent, acid, to obtain compound 6;
[0021] Step 5: In the presence of the sixth solvent and the second base, compound 6 reacts with 3-chloropropionyl chloride to generate compound 7; then it reacts with the third base to generate compound 8;
[0022] Step 6: In the seventh solvent, compound 8 reacts with methanesulfonic acid (MeSO3H) to generate compound 1.
[0023] The reaction route of the synthesis method is shown in reaction formula (A):
[0024] In the synthesis method described in this invention, the first step reaction specifically includes the following steps:
[0025] The first solvent and compound 2 were added to the reaction vessel; aluminum trichloride was added at 10±10℃, and then the temperature was raised to 20±5℃ and stirred for 20-40 minutes. N-methylindole was added dropwise to the reaction vessel at 20±5℃. The reaction temperature was raised to 80±5℃ and stirred for 3-5 hours to obtain compound 3. The reaction was monitored by HPLC, and purification was performed after the reaction was complete.
[0026] Preferably, aluminum trichloride is slowly added at 10°C. The temperature is then raised to 20°C and stirred for 30 minutes. N-methylindole is then slowly added dropwise to the reaction vessel at 20°C. The reaction temperature is then raised to 80°C and stirred for 3 hours.
[0027] Specifically, aluminum trichloride participates in the reaction as a Lewis acid;
[0028] Specifically, the first solvent is selected from one or more of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, etc.; preferably, it is ethylene glycol dimethyl ether.
[0029] Specifically, the molar ratio of compound 2, aluminum trichloride, N-methylindole, and the first solvent is 1:(1-2):(1-2):(20-25); preferably, it is 1:1.28:1.08:23.76.
[0030] In the synthesis method described in this invention, the second step reaction specifically includes the following steps:
[0031] The second solvent, compound 3, 4-fluoro-2-methoxy-5-nitroaniline, and methanesulfonic acid were added to a reaction vessel, and the mixture was heated to 115±5℃ and stirred for 19-24 hours. After the reaction was completed, the temperature was lowered to 20±5℃ and stirred for 1-2 hours to obtain compound 4.
[0032] Preferably, the temperature is raised to 115°C and stirred for 20 hours. After the reaction is complete, the temperature is lowered to 20°C and stirred for 1 hour.
[0033] Specifically, the second solvent is selected from one or more of 1-methoxy-2-propanol, 2-pentanol, n-butanol, 2-butanol, isobutanol, 2-methyl-2-butanol, ethylene glycol dimethyl ether, etc.; preferably, it is 1-methoxy-2-propanol.
[0034] Specifically, the molar ratio of compound 3, methanesulfonic acid, 4-fluoro-2-methoxy-5-nitroaniline, and the second solvent is 1; (1-2): (1-2): (45-50); preferably, it is 1:1.33:1.33:48.55.
[0035] In the synthesis method described in this invention, the third reaction step specifically includes the following steps:
[0036] The third solvent, compound 4, N,N,N'-trimethylethylenediamine, and the first base were added to a reaction vessel, and the temperature was raised to 85±5℃ and stirred for 2-4 hours. After the reaction was completed, the reaction temperature was lowered to 10±5℃, and purified water was slowly added dropwise to the reaction vessel and stirred for 1-3 hours to obtain compound 5.
[0037] Preferably, the temperature is raised to 85°C and stirred for 2 hours. After the reaction is complete, the reaction temperature is lowered to 10°C, purified water is slowly added dropwise to the reaction vessel, and the mixture is stirred for 2 hours.
[0038] Specifically, the third solvent, as an organic solvent in the reaction, is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, and 1,4-dioxane; preferably, it is N,N-dimethylacetamide.
[0039] Specifically, the first base acts as a basic reagent in the reaction to neutralize the acid produced during the reaction, and is selected from one or more of N,N-diisopropylethylamine, triethylamine (NEt3), etc.; preferably, it is N,N-diisopropylethylamine;
[0040] Specifically, the molar ratio of compound 4, the first base, the N,N,N'-trimethylethylenediamine, and the third solvent is 1:(3-5):(2-3):(30-35); preferably, it is 1:4.69:2.82:30.79.
[0041] In the synthesis method described in this invention, the fourth step reaction specifically includes the following steps:
[0042] The fourth solvent, compound 5, and anhydrous potassium carbonate were added to the reaction vessel, and the temperature was lowered to 5±5℃. Sodium dithionite was added to the reaction vessel in portions. The temperature was raised to 30±5℃, and the mixture was stirred for 6-10 hours to obtain a crude solution. Then, the organic solvent in the crude solution was replaced with the fifth solvent, and the temperature was lowered to 5-20℃. The acid was slowly added dropwise to the reaction vessel. After the addition was complete, the temperature was raised to 40-60℃, and the mixture was stirred at this temperature for 16-24 hours to obtain compound 6.
[0043] Preferably, the temperature is lowered to 5±5℃. Sodium dithionite is added to the reaction vessel in portions. The temperature is raised to 30±5℃ and stirred for 8 hours to obtain a crude solution. The organic solvent in the crude solution is replaced with anhydrous methanol, and the temperature is lowered to 10±5℃. Concentrated hydrochloric acid is slowly added dropwise to the reaction vessel. After the addition is complete, the temperature is raised to 45±5℃ and stirred for 18 hours to obtain compound 6.
[0044] Specifically, the fourth solvent is selected from one or more of anhydrous ethanol, tetrahydrofuran, N,N-dimethylformamide, and water; preferably, it is a mixed solution of anhydrous ethanol and water.
[0045] Specifically, the acid reacts with the target compound in the reaction to form a hydrochloride salt, which is selected from one or more of concentrated hydrochloric acid, methanesulfonic acid, hydrochloric acid solution, etc.; preferably, it is concentrated hydrochloric acid.
[0046] Specifically, the fifth solvent, as an organic solvent in the salt-forming reaction, is selected from one or more of anhydrous methanol, anhydrous ethanol, tetrahydrofuran, and 1,4-dioxane; preferably, it is anhydrous methanol.
[0047] Specifically, the molar ratio of compound 5, anhydrous potassium carbonate, sodium dithionite, acid, fourth solvent, and fifth solvent is 1; (4-7): (6-9): (10-16): (60-85): (200-205); preferably, it is 1:4:8.51:14.94:62.68:201.42.
[0048] In the synthesis method described in this invention, the fifth step reaction specifically includes the following steps:
[0049] The sixth solvent and compound 6 were added to the reaction vessel. Under nitrogen protection, the temperature was lowered to 0-10°C. The second base was slowly added dropwise at 0-10°C. After the addition was complete, the mixture was stirred at 0-10°C for 20-40 minutes. Then, 3-chloropropionyl chloride was slowly added dropwise at 0-10°C. After the addition was complete, the mixture was stirred at 0-10°C for 1-2 hours to give compound 7. After the reaction was complete, the temperature was raised to 15-25°C, and the third base was added dropwise at 15-25°C. After the addition was complete, the temperature was raised to 50-70°C, and the mixture was stirred for 16-24 hours. The third base was added again at 50-70°C, and the mixture was stirred for 5-8 hours. This process of adding the third base was repeated once more. The reaction yielded compound 8.
[0050] Preferably, under nitrogen protection, the temperature is lowered to 5°C. At 5°C, N,N-diisopropylethylamine is slowly added dropwise. After the addition is complete, the mixture is stirred at 5°C for 30 minutes. Then, 3-chloropropionyl chloride is slowly added dropwise at 5°C. After the addition is complete, the mixture is stirred at 5°C for 1 hour to give compound 7. After the reaction is complete, the temperature is raised to 20°C, and triethylamine is added dropwise at 20°C. After the addition is complete, the temperature is raised to 60°C and stirred for 6 hours.
[0051] Specifically, the sixth solvent is selected from one or more of N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and water; preferably, it is tetrahydrofuran or water.
[0052] Specifically, the second base acts as an organic base in the reaction to neutralize the acid produced during the reaction, and is selected from N,N-diisopropylethylamine, triethylamine, etc.; preferably, it is N,N-diisopropylethylamine.
[0053] Specifically, the third base acts as an organic base in the reaction, serving to remove hydrochloric acid, and is selected from one or more of triethylamine, N,N-diisopropylethylamine, etc.; preferably, it is triethylamine;
[0054] Specifically, the molar ratio of compound 6, the second base, the 3-chloropropionyl chloride, and the sixth solvent is 1:(3-4):(2-3):(70-75); preferably, it is 1:3.17:2.53:72.76.
[0055] Specifically, the molar ratio of compound 7 to the third base is 1:(15-20); preferably, it is 1:19.31.
[0056] In the synthesis method of the present invention, the sixth step reaction includes the following steps:
[0057] The seventh solvent and compound 8 were added to the reaction vessel and washed with acetone. Under nitrogen protection, the temperature was raised to 40-60°C and stirred until the solution was clear. At 40-60°C, an acetone solution of methanesulfonic acid was added dropwise. After the addition was complete, the mixture was washed with acetone, and the eluent was added dropwise to the reaction vessel. The mixture was stirred at 40-60°C for 16-24 hours. The reaction yielded compound 1.
[0058] Preferably, under nitrogen protection, the temperature is raised to 50°C and stirred until the solution is clear. At 50°C, an acetone solution of methanesulfonic acid is added dropwise. After the addition is complete, the dropping vessel is rinsed with acetone, and the rinsing solution is added dropwise to the reaction vessel. The mixture is stirred at 50°C for 24 hours. The reaction yields compound 1.
[0059] Specifically, the seventh solvent is selected from one or more of acetone, tetrahydrofuran, etc.; preferably, it is acetone.
[0060] Specifically, the molar ratio of compound 8, methanesulfonic acid, and the seventh solvent is 1:(1-1.2):(600-650); preferably, it is 1:1:633.36.
[0061] The present invention also provides thiophene pyrimidine derivatives prepared by the synthetic method described above.
[0062] The present invention also provides the use of the thiophene pyrimidine derivatives or stereoisomers thereof, pharmaceutically acceptable salts, prodrugs or solvates as described above, or the synthetic methods as described above, or the use of the thiophene pyrimidine derivatives as described above in the preparation of a medicament for treating diseases caused by abnormal cell proliferation due to overexpression of EGFR.
[0063] The beneficial effects of this invention include: This invention optimizes the synthesis method of thiophene pyrimidine derivatives, and screens the reaction systems in the synthesis method. It was found that when the 1-methoxy-2-propanol / methanesulfonic acid system is used instead of the 2-pentanol / p-toluenesulfonic acid system, the same conversion rate and yield are obtained under essentially the same reaction time and temperature. Under this reaction system, 1) hydrolysis byproducts are reduced; 2) the market price of 1-methoxy-2-propanol is about 1 / 7 that of 2-pentanol. During the screening process, this invention also compared various solvents, including primary alcohols, tertiary alcohols, aprotic polar solvents, nonpolar solvents, and mixed solvent systems. The results show that 1-methoxy-2-propanol has significant advantages.
[0064] Compared with existing technologies, the method for synthesizing thiophene pyrimidine derivatives provided by this invention has the advantages of low cost, readily available raw materials, reduced by-products, convenient operation, and suitability for large-scale production. Detailed Implementation
[0065] The present invention will be further described in detail below with reference to specific embodiments. Except for the contents specifically mentioned below, the processes, conditions, and experimental methods for implementing the present invention are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations.
[0066] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.
[0067] In all examples shown and discussed herein, any specific values should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.
[0068] Unless otherwise specified, the experimental materials used in the examples are all conventional biochemical reagents.
[0069] Example 1
[0070] first step:
[0071] Experimental procedure:
[0072] 420 kg (4660.4 mol) of dimethyl ethylene glycol ether (DME) and 40 kg (196.1 mol) of compound 2 were added to a reaction vessel. 33.2 kg (251.7 mol) of aluminum trichloride was slowly added at 10 ± 10 °C. The temperature was then raised to 20 ± 5 °C and stirred for 30 minutes. At 20 ± 5 °C, 27.85 kg (212.5 mol) of N-methylindole was slowly added dropwise to the reaction vessel. The reaction temperature was raised to 80 ± 5 °C and stirred for 3 hours. The reaction was monitored by HPLC, and purification was performed after the reaction was complete.
[0073] The reaction temperature was lowered to 20±5℃, and 400 kg of purified water was slowly added dropwise to the reaction vessel, with stirring for 2 hours. The reaction mixture was filtered and washed with 80 kg of purified water to obtain a yellow filter cake, which was set aside. 240 kg of ethyl acetate and 360 kg of purified water were added sequentially to the reaction vessel, followed by the filter cake obtained above. The temperature was controlled at 20±5℃, and stirring was carried out for 2 hours. The mixture was filtered again and washed with 40 kg of purified water and 20 kg of ethyl acetate to obtain a yellow filter cake. The filter cake was vacuum dried at 60±5℃ until constant weight, yielding 53.5 kg of dry product, with a yield of 88.4%. Product purity: 97.0%, content: 96.6%, KF = 0.7%.
[0074] 1 HNMR (400MNz, DMSO) δ8.65(d,1H), δ8.58(d,1H), δ8.50(s,1H), δ7.63(d,2H), δ7.33(d,2H), δ4.02(s,3H).
[0075] Step Two:
[0076] Experimental procedure:
[0077] 736 kg (8166.9 mol) of 1-methoxy-2-propanol, 53 kg (168.2 mol) of compound 3, 41.8 kg (224.7 mol) of 4-fluoro-2-methoxy-5-nitroaniline, and 21.5 kg (224.0 mol) of methanesulfonic acid were added to a reaction vessel. Under nitrogen protection, the mixture was heated to 115 ± 5 °C and stirred for 20 hours. After the reaction was complete, the temperature was lowered to 20 ± 5 °C and stirred for 1 hour. The mixture was filtered and washed with 108 kg of ethyl acetate to obtain a filter cake. 600 kg of ethyl acetate and the filter cake were added to the reaction vessel, and the mixture was stirred at 20 ± 5 °C for 2 hours. The mixture was filtered and washed with 104 kg of ethyl acetate. The filter cake was dried under vacuum at 50 ± 5 °C to obtain 89.15 kg of product. Yield: 75.7%, purity: 88.3%, content: 79.1%.
[0078] 1 HNMR(400MNz, DMSO)δ9.40(s,1H),δ8.83(d,1H),δ8.41(t,3H),δ7.61(d,1 H), δ7.46(t,2H), δ7.45(s,1H), δ7.13(t,2H), δ3.93(t,6H), δ2.39(s,4H).
[0079] Step 3:
[0080] Experimental procedure:
[0081] 438 kg (5027.5 mol) of N,N-dimethylacetamide, 89 kg (163.3 mol) of compound 4, 47 kg (460.0 mol) of N,N,N'-trimethylethylenediamine, and 99 kg (766.0 mol) of N,N-diisopropylethylamine were added to a reactor, and the mixture was heated to 85±5°C and stirred for 2 hours. After the reaction was complete, the reaction temperature was lowered to 10±5°C, and 1336 kg of purified water was slowly added dropwise to the reactor, while stirring for 2 hours. The reaction mixture was centrifuged. The resulting solid was set aside. 712 kg of purified water and the solid obtained from the previous centrifugation step were added to the reactor, and the mixture was stirred at 20±5°C for 2 hours. The liquid was centrifuged. The reactor was rinsed with 180 kg of purified water and centrifuged. 3590 kg of acetonitrile and the solid obtained from the previous centrifugation step were added to the reactor, and the mixture was heated to 75±5°C under nitrogen protection and stirred until dissolved. Under nitrogen protection, the mixture was cooled to 5±5℃ and stirred for 2 hours. The solution was then centrifuged; the reactor was washed with 150 kg of acetonitrile and centrifuged again to obtain a filter cake. The filter cake was vacuum dried at 50±5℃ for 16 hours to obtain 69.9 kg of product. Yield: 100.4%, purity: 98.8%, maximum single impurity: 0.13%, content: 99.0%.
[0082] 1 HNMR(400MNz, CDCl3)δ9.35(s,1H),δ8.66(d,1H),δ7.82(t,1H),δ7.39(s,1H),δ7.35(t,4H),δ6 .69(s,1H), δ4.0(s,3H), δ3.93(s,3H), δ3.25(t,2H), δ2.89(t,3H), δ2.55(t,2H), δ2.27(s,6H).
[0083] Step 4:
[0084] Experimental procedure:
[0085] 188 kg (4080.7 mol) of anhydrous ethanol, 95 kg (5277.8 mol) of purified water, 34.6 kg (65.1 mol) of compound 5, and 36 kg (261.0 mol) of anhydrous potassium carbonate were added to the reaction vessel, and the mixture was cooled to 5 ± 5 °C. 96.4 kg (553.7 mol) of sodium dithionite was added to the reaction vessel in portions. The mixture was heated to 30 ± 5 °C and stirred for 8 hours. After the reaction was complete, the mixture was cooled to 20 ± 5 °C, and 638.6 kg of dichloromethane was added to the reaction vessel, and the mixture was stirred for 2 hours. The mixture was filtered under nitrogen pressure, and the reaction vessel was rinsed with 300 kg of dichloromethane, followed by filtration. The filtrate was transferred to the reaction vessel, 174 kg of purified water was added, the mixture was stirred for 30 minutes, and allowed to stand for 30 minutes. The lower organic layer was transferred to a receiving container. Add 140 kg of dichloromethane to the reactor, stir for 30 minutes, let stand for 30 minutes, transfer the lower organic layer to a receiving container, and combine the dichloromethane phase solutions. Concentrate to 139-174 L by vacuum distillation at 30±10℃. Add 192 kg of anhydrous methanol to the reactor, and concentrate to 139-174 L by vacuum distillation at 40±10℃. Repeat the methanol addition-concentration operation once. Cool to 20±10℃, add 420 kg (13112.7 mol) of anhydrous methanol, and cool to 10±5℃. Slowly add 35 kg (972.8 mol) of concentrated hydrochloric acid dropwise to the reactor. After the addition is complete, raise the temperature to 45±5℃ and maintain the temperature with stirring for 18 hours. After the reaction is complete, maintain the temperature at 45±5℃, discharge the material into a centrifuge, wash with 291.5 kg of anhydrous methanol, and centrifuge again. The filter cake was transferred to a drying oven and vacuum-dried at 30±5℃ for 6 hours. The temperature was then increased to 50±5℃, and vacuum-dried for 24 hours. 32.4 kg of dried solid was obtained, with a purity of 98.1% and a yield of 78.6%.
[0086] 1 HNMR (400MNz, MeOD) δ8.57(s,1H), δ8.40(d,1H), δ7.66(d,1H), δ7.57(d,1H), δ7.50(d,1H), δ7.41(s,1 H), δ7.26(t,2H), δ4.02(s,3H), δ3.94(s,3H), δ3.55(t,2H), δ3.49(t,2H), δ2.94(s,6H), δ2.86(s,3H).
[0087] Step 5:
[0088] Experimental procedure:
[0089] 290 kg (4081.6 mol) of tetrahydrofuran, 322 kg (17888.9 mol) of purified water, and 32.15 kg (56.1 mol) of compound 6 were added to a reaction vessel. Under nitrogen protection, the mixture was cooled to 5°C. At 5°C, 23 kg (178.0 mol) of N,N-diisopropylethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred at 5°C for 30 minutes. At 5°C, 18 kg (141.8 mol) of 3-chloropropionyl chloride was slowly added dropwise. After the addition was complete, the mixture was stirred at 5°C for 1 hour. After the reaction was complete, the temperature was raised to 20±5°C, and 93 kg (919.1 mol) of triethylamine was added dropwise at 20±5°C. After the addition was complete, the temperature was raised to 60±5°C and stirred for 20 hours. At 60±5°C, 8.3 kg (82.0 mol) of triethylamine was added, and the mixture was stirred for 6 hours. This process of adding triethylamine was repeated once. After the reaction was complete, the temperature was lowered to 25±5℃, and the mixture was allowed to stand for 30 minutes to separate the aqueous phase. 1600 kg of purified water was added dropwise over approximately 2 hours. After the addition was complete, the temperature was lowered to 10±5℃, and the mixture was stirred for 6 hours. The reaction solution was transferred to a centrifuge and centrifuged. The reaction vessel was rinsed with 322 kg of purified water and centrifuged again. The filter cake was dried under vacuum at 55±5℃ for 24 hours. 26.2 kg of dried solid was obtained, with a purity of 98.6% and an abundance of 97.3%.
[0090] Under nitrogen protection, 640 kg of tetrahydrofuran and 18.25 kg of crude compound 8 were added to a reactor. The mixture was stirred at 15±5℃ for ≥0.5 h until dissolved. The solution was filtered through a filter filled with 42 kg of silica gel (200–300 mesh) impregnated with 38 kg of tetrahydrofuran, and the reactor and filter cake were washed with 80 kg of tetrahydrofuran. The filtrate was collected. Under nitrogen protection, the mixture was concentrated under reduced pressure to 99–117 L at a controlled temperature of ≤50℃. The temperature was raised to 65±5℃ and stirred for 0.5 h. The reaction mixture was gradually cooled to 10±5℃ over 3 h and stirred at 10±5℃ for 2 h. The reaction compound was transferred to a centrifuge and centrifuged. The reactor and filter cake were washed with 16 kg of tetrahydrofuran and centrifuged again. The collected wet filter cake was transferred to a drying oven and dried under vacuum at 50±5℃ for 16 h to obtain 13.10 kg of dried solid. Yield: 52.81%, Purity: 99.8%.
[0091] 1 HNMR(400MNz, CDCl3)δ10.10(s,1H),δ9.80(s,1H),δ8.60(d,1H),δ8.18(s,1H),δ7.79(d,1H),δ7.69(s,1H),δ7.49(s,1H),δ7.38(s, 1H), δ7.26(s,1H), δ6.81(s,1H), δ6.33(t,2H), δ5.66(d,1H), δ3.90(d,6H), δ2.88(t,2H), δ2.71(s,3H), δ2.26(t,8H), δ2.86(s,3H).
[0092] Step 6:
[0093] Experimental procedure:
[0094] 206 kg (3546.8 mol) of acetone and 3.09 kg (5.6 mol) of compound 8 were added to a reaction vessel, and the reaction vessel was rinsed with 26 kg (447.6 mol) of acetone. Under nitrogen protection, the temperature was raised to 50±5℃ and stirred until the solution was clear. At 50±5℃, a solution of methanesulfonic acid (0.534 kg, 5.6 mol) in 62 kg of acetone was added dropwise. After the addition was complete, the dropping vessel was rinsed with 5 kg of acetone, and the rinsing solution was added dropwise to the reaction vessel. The mixture was stirred at 50±5℃ for 24 hours. The reaction solution was filtered through a filter at 50±5℃, and the reaction vessel was rinsed with 5 kg of acetone. The rinsing solution was transferred to a filter and filtered to obtain crude compound 1.
[0095] 121 kg of acetone and 3.3 kg of crude compound 1 were added to a reaction vessel, and the reaction vessel was rinsed with 5.5 kg of acetone. The temperature was raised to 50±5℃ and stirred for 6 hours. The mixture was then filtered through a filter at 50±5℃. The reaction vessel was rinsed with 26 kg of acetone, and the rinsing liquid was transferred to a filter for further filtration. The filter cake was transferred to an oven and purged with nitrogen for 4 hours. The temperature was raised to 25-35℃ and vacuum dried for 8 hours. Finally, it was vacuum dried at 45-55℃ for 30 hours. 3.2 kg of product was obtained, with a purity of 99.9% and a yield of 88.3%.
[0096] 1 HNMR (400MNz, DMSO) δ10.12(s,1H), δ8.89(s,1H), δ8.52(d,1H), δ8.32(s,1H ), δ8.26(d,1H), δ8.19(s,1H), δ7.53(d,1H), δ7.31(d,1H), δ7.27(t,1H), δ7. 13(t,1H),δ7.05(s,1H),δ6.41(t,1H),δ6.21(t,1H),δ5.73(t,1H),δ3.96(s ,3H), δ3.82(s,3H), δ2.90(t,2H), δ2.74(s,3H), δ2.32(t,2H), δ2.21(s,6H).
[0097] Example 2: Screening and comparison of reaction solvents / catalysts for compounds 3 to 4
[0098] 1. Reaction formula:
[0099] 2. Screening and comparison experiments of solvents / catalysts for the reaction of compounds 3 to 4
[0100] The reaction mechanism of 2-chloropyrimidine (compound 3) with aniline in the presence of a protic acid (methanesulfonic acid) is as follows: First, the lone pair electrons of the pyrimidine nitrogen atom combine with a proton to form a pyrimidine salt. This enhances the electrophilic activity of the carbon at the 2-position adjacent to the pyrimidine nitrogen atom, which is easily attacked by the lone pair electrons of the aniline nitrogen atom. After proton and chloride ion departure and aromatization, the salt of compound 4 is obtained.
[0101] Based on the reaction mechanism, and considering that the salt formed by compound 3 under protic acid conditions has good solubility in polar solvents, which is beneficial to the reaction, polar solvents are preferred in the solvent screening process of this invention.
[0102] This invention first compares two types of polar solvents: aprotic polar solvents (THF, DMSO, DMF, NMP, etc.) and protic solvents (MeOH, EtOH, iPrOH). During the experiment, it was found that the reaction achieved better results in protic solvents, considering both reaction rate and conversion rate, as well as impurities. This may be due to the following two reasons: (1) the reaction has better solubility in protic solvents; (2) in protic solvents, the large number of protons surrounding the pyrimidine salt disperses the electron cloud density of the pyrimidine ring, further enhancing the electrophilicity of the carbon at the 2-position adjacent to the nitrogen atom of the pyrimidine, which is more conducive to the attack of nucleophiles (nitrogen of aniline).
[0103] This invention also reveals that the reaction requires a relatively high temperature to achieve complete conversion. This may be because the shielding effect of protic acids (salt formation) forces the weaker nucleophilic aniline to overcome a higher reaction energy barrier.
[0104] Accordingly, this invention selects n-butanol, isobutanol, and 2-butanol, which have higher boiling points, as reaction solvents. It was found that the reaction in n-butanol and isobutanol solvents produced more corresponding alcohol substitution byproducts, while the reaction in 2-butanol solvent only detected trace amounts of alcohol substitution byproducts. This is because primary alcohols have less steric hindrance, and when used as solvents, the alcohol is in large excess, causing the oxygen atom in the alcohol to compete with the nitrogen in aniline for attack on the 2-carbon. 2-Butanol, being a secondary alcohol, exhibits steric hindrance, resulting in lower levels of 2-butanol substitution byproducts, which can be completely removed during post-treatment purification.
[0105] When using 2-butanol as a solvent, it was found that the complete conversion required a long reaction time. The initial reaction rate was comparable to that of n-butanol, but the final 10% often required a longer time, presumably because the reaction rate decreased with decreasing substrate concentration. Therefore, this invention selects 2-pentanol, which has a higher boiling point, as a solvent, increasing the temperature to provide higher energy and accelerate the reaction, resulting in satisfactory results.
[0106] 2-Pentanol is an expensive solvent, which significantly increases the cost of preparing the target compound. Therefore, this invention seeks a cheaper solvent alternative.
[0107] Ultimately, after comparison, this invention selected 1-methoxy-2-propanol, which has a similar skeleton structure to 2-pentanol, as the solvent. The reasons are as follows: (1) This solvent is widely used as a solvent, dispersant, and diluent, and is also used as a fuel antifreeze, extractant, etc. It is inexpensive and has a reliable supply; (2) The solubility of this solvent in the reaction substrate is comparable to that of 2-butanol or 2-pentanol, which meets the prerequisite for complete conversion; (3) The boiling point of this solvent is high enough to meet the requirement of increasing the temperature to accelerate the reaction conversion; (4) As a secondary alcohol, the solvent substitution byproducts formed in the reaction are reduced by 65% compared to 2-pentanol, which meets the requirements for process impurity control.
[0108] 2.1 Summary table of screening experiment data
[0109] 2.2 Summary Table Data Analysis:
[0110] According to the experimental data in the table, the yield of n-butanol was 58%, with a degradation rate of 29%; the yield of 2-butanol was 73%, with a degradation rate of 6%; the yield of isobutanol was 65%, with a degradation rate of 2%; the yield of 2-pentanol was 73%, with a degradation rate of 10%; the yield of 1-methoxy-2-propanol was 75%, with a degradation rate of 3.5%, and the other solvents either did not react or had very low yields. Comparison revealed that: (1) the reaction yields were similar and relatively high when using 2-pentanol or 1-methoxy-2-propanol as solvents; (2) fewer degradation products were generated when using isobutanol or 1-methoxy-2-propanol as solvents, and the yield of isobutanol was lower; (3) the commercial price of 1-methoxy-2-propanol was also lower, about 1 / 7 the price of 2-pentanol. In summary, 1-methoxy-2-propanol has a clear advantage.
[0111] 3. Scale-up synthesis of compound 4:
[0112] 1) 2-Pentanol / p-Toluenesulfonic Acid
[0113] 7.5 L of 2-pentanol was added to a 10 L reactor equipped with mechanical stirring and reflux condensation. Compound 3 (1000 g, 3.34 mol, 1.00 eq.), 4-fluoro-2-methoxy-5-nitroaniline (782 g, 4.20 mol, 1.26 eq.), and p-toluenesulfonic acid monohydrate (798 g, 4.2 mol, 1.26 eq.) were added separately with stirring. The resulting suspension was heated to reflux in an oil bath at 130 °C (internal temperature 106-115 °C), and the reaction changed from a brown suspension to a brown semi-dissolved state. After 6 hours of reaction, TLC showed that the reaction was not yet complete. The reaction mixture was cooled to room temperature (15 °C) under nitrogen protection and stirred overnight. The next day, the suspension was reheated to reflux and stirred for about 6 hours, and the reaction was complete. The reaction mixture was cooled to room temperature (~20 °C), and a yellow-green solid precipitated. The mixture was filtered through a Buchner funnel, and the filter cake was collected to give 2.4 kg (wet) of crude compound 4. The crude product was suspended in 1 L of ethyl acetate and stirred overnight at room temperature, then purified by slurry extraction. The suspension was filtered through a Buchner funnel, and the filter cake was washed with a small amount (~150 mL) of ethyl acetate. The filter cake was collected and dried under vacuum at 50 °C for 5 hours to give 1.4 kg of dark green solid powder. NMR analysis revealed that compound 4 was a p-toluenesulfonate. The yield was 79%, and the purity was 90%.
[0114] 2) 1-Methoxy-2-propanol / Methanesulfonic acid
[0115] In a 5L reactor equipped with mechanical stirring and condensation, 3L of 1-methoxy-2-propanol was added. Compound 3 (200g, 0.67mol), 4-fluoro-2-methoxy-5-nitroaniline (156g, 0.84mol), and methanesulfonic acid (81g, 0.84mol) were added separately with stirring. The resulting suspension was heated to reflux in an oil bath at 135°C (internal temperature 113°C), and the brown suspension became a semi-dissolved solution. After 6 hours, LCMS showed only 71% conversion of compound 3. The reaction mixture was cooled to room temperature (~15°C) under nitrogen protection and stirred overnight. The next day, the reaction mixture was heated to reflux and stirred for about 6 hours; LCMS showed that compound 3 reached 97% conversion. The reaction mixture was slowly cooled to ~25°C with stirring. During the cooling process, a yellow-green solid gradually precipitated, and the mixture gradually became viscous, making stirring difficult. The solution was diluted with 2.5 L of ethyl acetate, and the resulting suspension was stirred for another 2 hours. The mixture was then filtered through a Buchner funnel, and the filter cake was washed with 200 mL of ethyl acetate. The filter cake was collected and dried under vacuum at 50 °C for 5 hours to give 310 g of the dark green methanesulfonate of compound 4. The yield was 77%, and the purity was 91%.
[0116] 4. Summary of screening results: Methanesulfonic acid / 1-methoxy-2-propanol
[0117] 4.1 Using methanesulfonic acid instead of p-toluenesulfonic acid monohydrate as a catalyst, equivalent conversion and yield were obtained in alcohol solvents (2-pentanol, 2-butanol, or 1-methoxy-2-propanol) to p-toluenesulfonic acid monohydrate.
[0118] 4.21-Methoxy-2-propanol has a similar main chain structure to 2-pentanol, similar solubility in reaction mixtures, and the same boiling point temperature. Moreover, 1-methoxy-2-propanol is a commonly used industrial solvent, and compared to 2-pentanol, it is cheaper and more readily available, making it a better alternative to 2-pentanol.
[0119] 4.3 Using alcohols as solvents:
[0120] I. Using low-boiling-point alcohols as solvents (such as 2-butanol and 2-methyl-2-butanol) results in very slow reaction conversion and low conversion rates. Attempts to increase the conversion rate by extending the reaction time lead to the formation of more byproducts (hydrolysis products or alcoholysis products of chlorine atoms).
[0121] II. Primary alcohol solvents (such as n-butanol) lead to the formation of more alcoholysis byproducts.
[0122] III. Tertiary alcohol solvents (such as 2-methyl-2-butanol) have poor solubility in the reaction mixture, leading to agglomeration of the reaction solid mixture, making stirring difficult and resulting in low reaction conversion.
[0123] IV. Secondary alcohols (such as 2-pentanol, 2-butanol, or 1-methoxy-2-propanol) have better reaction conversion, fewer hydrolysis byproducts, and higher yields.
[0124] 4.4 Using aprotic polar solvents:
[0125] The reaction is significantly less effective in aprotic polar solvents than in alcohol solvents. For example, the reaction does not proceed at all in DMF; in DMSO, the main product is the hydrolysis of chlorine atoms; and in ethylene glycol dimethyl ether, dioxane, or diethylene glycol dimethyl ether, the conversion rate is very low.
[0126] 4.5 Use nonpolar solvents
[0127] When nonpolar solvents (toluene, xylene, or dichlorobenzene) are used as solvents, even at higher temperatures, the reaction solid mixture agglomerates with only trace conversion, due to the low solubility of the reaction mixture.
[0128] 4.6 Using mixed solvents
[0129] Attempts were made to use mixed solvents (such as 2-butanol / toluene, 2-butanol / xylene) in the hope of removing water from TsOH through azeotropic reaction of the solvents to reduce the formation of hydrolysis byproducts, but the conversion rate was very low.
[0130] 4.7 Replacing p-toluenesulfonic acid monohydrate with methanesulfonic acid yields a similar conversion rate and produces fewer hydrolysis byproducts.
[0131] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
[0132] As used in this invention, the terms "comprising" and "including" are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.
[0133] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.
[0134] The scope of protection of this invention is not limited to the above embodiments. Any variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of this invention are included in this invention and are protected by the appended claims.
Claims
1. A thiophene pyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, prodrug, or solvate, characterized in that, The structure of the thiophene pyrimidine derivative is shown in Formula 1:
2. A method for synthesizing a thiophene pyrimidine derivative, characterized in that, The synthesis method includes the following steps: Step 1: In the presence of aluminum trichloride and the first solvent, compound 2 reacts with N-methylindole to generate compound 3; In the second step, in the presence of the second solvent and methanesulfonic acid, compound 3 reacts with 4-fluoro-2-methoxy-5-nitroaniline to generate compound 4; In the third step, in the presence of the third solvent and the first base, compound 4 reacts with N,N,N'-trimethylethylenediamine to generate compound 5; In the fourth step, in the presence of the fourth solvent, anhydrous potassium carbonate, compound 5 reacts with sodium dithionite; then, in the presence of the fifth solvent, an acid, compound 6 is generated. Step 5: In the sixth solvent, compound 6 reacts with 3-chloropropionyl chloride to form compound 7; then it reacts with the third base to form compound 8; Step 6: In the seventh solvent, compound 8 reacts with methanesulfonic acid to form compound 1; The reaction process along the route is shown in reaction formula (A): Reaction formula (A).
3. The synthesis method as described in claim 2, characterized in that, The first step reaction specifically includes the following steps: The first solvent and compound 2 were added to a reaction vessel; aluminum trichloride was added at 10±10℃, and then the temperature was raised to 20±5℃ and stirred for 20-40 minutes; N-methylindole was added dropwise to the reaction vessel at 20±5℃; the reaction temperature was raised to 80±5℃ and stirred for 3-5 hours to obtain compound 3; the reaction was monitored by HPLC, and purification was performed after the reaction was completed. And / or, the second step reaction specifically includes the following steps: The second solvent, compound 3, 4-fluoro-2-methoxy-5-nitroaniline, and methanesulfonic acid were added to a reaction vessel, heated to 115±5℃, and stirred for 19-24 hours. After the reaction was completed, the temperature was lowered to 20±5℃ and stirred for 1-2 hours to obtain compound 4. And / or, the third step reaction specifically includes the following steps: The third solvent, compound 4, N,N,N'-trimethylethylenediamine and the first base were added to a reaction vessel, heated to 85±5℃, and stirred for 2-4 hours. After the reaction was completed, the reaction temperature was lowered to 10±5℃, purified water was slowly added dropwise to the reaction vessel, and stirred for 1-3 hours to obtain compound 5. And / or, the fourth step reaction specifically includes the following steps: The fourth solvent, compound 5, and anhydrous potassium carbonate are added to a reaction vessel, and the temperature is lowered to 5±5℃. Sodium dithionite is added to the reaction vessel in portions. The temperature is raised to 30±5℃, and the mixture is stirred for 6-10 hours to obtain a crude solution. Then, the organic solvent in the crude solution is replaced with the fifth solvent, and the temperature is lowered to 5-20℃. The acid is slowly added dropwise to the reaction vessel. After the addition is complete, the temperature is raised to 40-60℃, and the mixture is stirred and maintained at this temperature for 16-24 hours to obtain compound 6. And / or, the fifth step reaction specifically includes the following steps: The sixth solvent and compound 6 were added to a reaction vessel; under nitrogen protection, the temperature was lowered to 0-10°C; the second base was slowly added dropwise at 0-10°C; after the addition was complete, the mixture was stirred at 0-10°C for 20-40 minutes; the 3-chloropropionyl chloride was slowly added dropwise at 0-10°C; after the addition was complete, the mixture was stirred at 0-10°C for 1-2 hours to obtain compound 7; after the reaction was complete, the temperature was raised to 15-25°C, and the third base was added dropwise at 15-25°C; after the addition was complete, the temperature was raised to 50-70°C, and the mixture was stirred for 16-24 hours; the third base was added again at 50-70°C, and the mixture was stirred for 5-8 hours; the addition of the third base was repeated once; the reaction yielded compound 8. And / or, the sixth step reaction includes the following steps: The seventh solvent and compound 8 are added to the reaction vessel and rinsed with acetone; under nitrogen protection, the temperature is raised to 40-60°C and stirred until the solution is clear; at 40-60°C, an acetone solution of methanesulfonic acid is added dropwise; after the addition is complete, the mixture is rinsed with acetone and the rinsing solution is added to the reaction vessel. Stirring at 40-60℃ for 16-24 hours; the reaction yields compound 1.
4. The synthesis method as described in claim 3, characterized in that, The first solvent is selected from one or more of ethylene glycol monomethyl ether and ethylene glycol dimethyl ether; and / or, the molar ratio of compound 2, aluminum trichloride, N-methylindole, and the first solvent is 1; (1-2):(1-2):(20-25).
5. The synthesis method as described in claim 3, characterized in that, The second solvent is selected from one or more of 1-methoxy-2-propanol, 2-pentanol, n-butanol, 2-butanol, isobutanol, 2-methyl-2-butanol, and ethylene glycol dimethyl ether; and / or, the molar ratio of compound 3, methanesulfonic acid, 4-fluoro-2-methoxy-5-nitroaniline, and the second solvent is 1; (1-2):(1-2):(45-50).
6. The synthesis method according to claim 3, characterized in that, The third solvent, used as an organic solvent in the reaction, is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, and 1,4-dioxane; and / or, the first base is selected from one or more of N,N-diisopropylethylamine and triethylamine; and / or, the molar ratio of compound 4, the first base, the N,N,N'-trimethylethylenediamine, and the third solvent is 1:(3-5):(2-3):(30-35).
7. The synthesis method according to claim 3, characterized in that, The fourth solvent is selected from one or more of anhydrous ethanol, tetrahydrofuran, N,N-dimethylformamide, and water; and / or, the fifth solvent is selected from one or more of anhydrous methanol, anhydrous ethanol, tetrahydrofuran, and 1,4-dioxane; and / or, the acid is selected from one or more of concentrated hydrochloric acid, methanesulfonic acid, and hydrochloric acid solution; and / or, the molar ratio of compound 5, anhydrous potassium carbonate, sodium dithionite, the acid, the fourth solvent, and the fifth solvent is 1; (4-7):(6-9):(10-16):(60-85):(200-205).
8. The synthesis method as described in claim 3, characterized in that, The sixth solvent is selected from one or more of N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and water; and / or, the second base is selected from one of N,N-diisopropylethylamine and triethylamine; and / or, the third base is selected from one or more of triethylamine and N,N-diisopropylethylamine; and / or, the molar ratio of compound 6, the second base, the 3-chloropropionyl chloride, and the sixth solvent is 1:(3-4):(2-3):(70-75); and / or, the molar ratio of compound 7 and the third base is 1:(15-20); and / or, the seventh solvent is selected from one or more of acetone and tetrahydrofuran; and / or, the molar ratio of compound 8, the methanesulfonic acid, and the seventh solvent is 1:(1-1.2):(600-650).
9. Thiophene pyrimidine derivatives prepared by the synthetic method according to any one of claims 2-8.
10. The use of the thiophene pyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, prodrug or solvate as described in claim 1, or the synthetic method as described in any one of claims 2-8, or the use of the thiophene pyrimidine derivative as described in claim 9 in the preparation of a medicament for treating diseases caused by abnormal cell proliferation due to overexpression of EGFR.