Process for the preparation of folvicicil and intermediates thereof

Abstract

The application discloses a preparation method of fosnetupitant and intermediates thereof, which comprises the following steps: taking an amino thiophene compound II-a as a starting material, generating a chlorinated compound II-d through a plurality of reactions such as urea formation, ring closure and chlorination, then selectively catalytically hydrogenating and removing the chlorine at the C-4 position of the pyrimidine ring to obtain a compound II-e, and then preparing an intermediate compound II through ester hydrolysis and condensation with dimethylamine hydrochloride; taking a compound III-a and a compound III-b as starting materials to generate a substitution reaction to obtain a compound III-c, and then reducing the compound III-c through catalytic hydrogenation to obtain an intermediate compound III; and further generating a Buchwald-Hartwig coupling reaction of the intermediate compound II and the intermediate compound III to obtain a finished product of fosnetupitant. The preparation method can not only reduce the cost, simplify the synthesis route, control each reaction and improve the total yield, but also is more economic and environmental. Meanwhile, the application improves the stability and reliability of the process, and provides a guarantee for industrialized scale production of fosnetupitant.

Description

Technical Field

[0001] This invention belongs to the fields of organic chemistry and medicinal chemistry, specifically relating to methods for preparing voveccidil and its intermediates. More specifically, this invention relates to 7-cyclopentyl- N , N Preparation method of dimethyl-2-((5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)amino)thiopheno[3,2-d]pyrimidine-6-carboxamide (vovecyl) and its intermediates. Background Technology

[0002] CDKs are serine / threonine protein kinases, which are the driving force behind cell cycle and cell proliferation, and are cyclin-dependent kinases. CDKs regulate the initiation, progression, and completion of the mammalian cell cycle and are crucial for cell growth. Most known CDKs, including CDK1 to CDK9, are directly or indirectly involved in cell cycle progression. CDKs directly involved in cell cycle progression, such as CDK1-4 and CDK6, can be classified as G1, S, or G2M phase enzymes.

[0003] Abnormal proliferation is a characteristic of cancer cells, and CDK dysfunction occurs frequently in many solid tumors. This indicates that tumor development is closely related to gene mutations and abnormal regulation of CDKs and their regulatory proteins. Therefore, finding a CDK inhibitor may be an effective anti-cancer therapy.

[0004] Compounds with CDK inhibitory activity are of great significance for the prevention and treatment of cancer. Fovinaciclib citrate, chemically named 7-cyclopentyl- N,N Dimethyl-2-((5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide dicitrate is a Class 1 innovative drug developed by Jinzhou Aohong Pharmaceutical Co., Ltd., marketed under the brand name Futonin. It was approved for marketing in May 2025. This drug is a selective inhibitor of cyclin-dependent kinase 4 / 6 (CDK4 / 6). Its molecular structure is shown in the figure below:

[0005] .

[0006] CDK4 / 6 can form a dimer with cyclin D, leading to phosphorylation of retinoblastoma protein (Rb). This phosphorylation regulates the cell cycle, causing it to transition from the pre-DNA synthesis phase (G1 phase) to the DNA synthesis phase (S phase), thus inducing cell proliferation. Vorvecil citrate selectively inhibits CDK4 / 6 kinase activity, preventing Rb phosphorylation and arresting the cell cycle in the G1 phase, thereby inhibiting tumor cell proliferation. This drug, in combination with fulvestrant, is primarily used to treat hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative recurrent or metastatic breast cancer in adult patients whose disease has progressed after prior endocrine therapy.

[0007] Patent ZL201780028206.7 describes a method for preparing vovichil, and its specific synthetic route is as follows:

[0008]

[0009]

[0010] The method involves preparing compound 1 and compound 2 via two separate routes, then preparing intermediate compound 3 through a coupling reaction, and finally preparing intermediate compound 4 by deprotecting the piperazine ring with trifluoroacetic acid. Finally, compound 4 is reacted with formaldehyde to undergo a reductive methylation reaction to prepare compound I, i.e., voveccidil.

[0011] One route involves the reductive amination of a Boc-protected piperazine with a Cbz-protected piperidinone, followed by Pd / C catalytic hydrogenation deprotection, substitution, and Pd / C catalytic hydrogenation reduction to prepare compound 1. The other route uses a pyrimidinyl-substituted carboxylic acid compound as a starting material, and proceeds through a series of reactions including decarboxylation coupling with an aldehyde compound, hydroxyl oxidation, affinity substitution with a bromide, in-situ intramolecular cyclization, amidation, and oxidation to prepare compound 2.

[0012] However, this preparation method involves a long reaction route, cumbersome operation, and unreliable product yield. It also involves the repeated use of flammable, explosive, and genotoxic materials and reagents, thus failing to meet the needs of industrial production. Summary of the Invention

[0013] This disclosure addresses the shortcomings of existing technologies by further reducing impurities and byproducts in the process, and provides a simple and high-purity method for synthesizing the compound shown in Formula I, namely vovichil and its intermediates.

[0014] One of the objectives of this invention is to provide a method for preparing the compound shown in Formula I, namely vovichil.

[0015] The method for preparing the compound of formula I, i.e., voveccidil, provided by this invention includes the following steps: Under alkaline conditions, in the presence of a palladium catalyst and an organophosphorus ligand, the compound shown in intermediate formula II undergoes a Buchwald–Hartwig coupling reaction with the compound shown in intermediate formula III to give the compound shown in formula I, namely vovichil.

[0016] In the above method, the compound shown in Formula II can specifically be 2-chloro-7-cyclopentyl-N,N-dimethylthiopheno[3,2-d]pyrimidine-6-carboxamide; The compound shown in Formula III can specifically be 5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-amine.(n) hydrate, wherein n is selected from 0 to 2; The molar ratio of the compound shown in Formula II to the compound shown in Formula III can be 1:0.9 to 1.2, specifically 1:1; The alkaline conditions are provided by an alkali, which may be selected from one or more inorganic or organic alkalis. The inorganic alkali may be selected from one or more of NaOH, KOH, Cs2CO3, K2CO3, and Na2CO3. The organic alkali may be selected from one or more of 1,8-diazabicycloundec-7-ene (DBU), tetramethylguanidine, triethylamine, pyridine, N,N-diisopropylethylamine, t-BuOK, t-BuONa, CH3CH2ONa, and CH3ONa, with t-BuONa and Cs2CO3 being preferred. The palladium catalyst can be selected from one of Pd2(dba)3 and Pd(OAc)2, with Pd(OAc)2 being preferred. The organophosphorus ligand may be selected from one or more of Josiphos, BINAP, DIOP, DIPAMP, PPFA, and BPPFA, with BINAP being preferred; The molar ratio of the compound shown in Formula II to the base can be 1:1 to 2, preferably 1:1.2; The molar ratio of the compound shown in Formula II to the palladium catalyst is 1:0.01 to 0.05, preferably 1:0.03; The molar ratio of the compound shown in Formula II to the organophosphorus ligand is 1:0.04 to 0.08, preferably 1:0.06; The Buchwald–Hartwig coupling reaction is carried out in a solvent, which may be selected from dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl isopropyl ketone, methyl isobutyl ketone and toluene, preferably dioxane or tetrahydrofuran; The temperature of the Buchwald–Hartwig coupling reaction can be 60°C to 90°C, preferably 65°C to 75°C; the time can be 3 to 6 hours, preferably 4 hours. The mass-to-volume ratio of the compound shown in Formula II to the reaction solvent can be 20:1 g / L to 65:1 g / L, preferably 30:1 g / L to 50:1 g / L, and more preferably 40:1 g / L.

[0017] In the above method, the compound represented by Formula II is prepared according to the following synthetic route by a method including the following steps:

[0018] (1) In an acidic system, aminothiophene compound II-a reacts with a cyanate reagent to form urea compound II-b; (2) Compound II-b undergoes further cyclization under the action of a base to generate thiophene-pyrimidine compound II-c; (3) Compound II-c reacts with chlorinating agent under the action of acid-binding agent to form chloride II-d; (4) In the presence of an organic base, palladium on carbon is used as a catalyst to selectively catalytically hydrogenate the chlorine at the C-4 position of the pyrimidine ring to obtain compound II-e; (5) Compound II-e undergoes further hydrolysis of the ester group under the action of a base to give compound II-f; (6) Compound II was finally prepared by condensation reaction of compound II-f with dimethylamine hydrochloride under the action of condensing agent and base.

[0019] in: R1 and R2 are each independently selected from C1 to C2. 10 Alkyl groups, preferably C1 to C4 alkyl groups, with methyl, ethyl, propyl or isopropyl being the most preferred.

[0020] The acidic system mentioned in step (1) is one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, and formic acid mixed with water, preferably a mixture of acetic acid and water; The cyanate-based reagent is selected from one or more of chlorosulfonyl isocyanate, ammonium cyanate, potassium cyanate, and sodium cyanate, with potassium cyanate being preferred; The molar ratio of compound II-a to the cyanate-based reagent is 1:2 to 6, preferably 1:5; The reaction temperature can be 15–30°C, preferably 25°C; the reaction time can be 3–6 hours, preferably 4 hours. The base in step (2) is selected from one or more of 1,8-diazabicycloundec-7-ene (DBU), tetramethylguanidine, triethylamine, pyridine, N,N-diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, t-BuOK, t-BuONa, CH3CH2ONa, and CH3ONa, preferably CH3CH2ONa and t-BuONa; In step (2), the molar ratio of compound II-b to the base is 1:1 to 4, preferably 1:2; The reaction temperature can be 10–20°C, preferably 15°C; the reaction time can be 2–4 hours, preferably 2 hours. The reaction solvent in step (2) can be selected from one or a mixture of several of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, tert-butanol, methyl isopropyl ketone, and methyl isobutyl ketone, with isopropanol being preferred; The acid-binding agent in step (3) is selected from one or a mixture of several of 1,8-diazabicycloundec-7-ene (DBU), tetramethylguanidine, triethylamine, pyridine, N,N-diisopropylethylamine, N,N-dimethylaniline, and N,N-diethylaniline, preferably triethylamine or N,N-diisopropylethylamine; The chlorinating agent in step (3) is selected from one of thionyl chloride, phosphorus oxychloride, and oxalyl chloride, with phosphorus oxychloride being preferred; The temperature of the reaction in step (3) can be 60℃~100℃, preferably 70℃~80℃; the time can be 6~10h, preferably 8h; The organic base in step (4) is selected from one or more of 1,8-diazabicycloundec-7-ene (DBU), tetramethylguanidine, triethylamine, pyridine, N,N-diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, t-BuOK, t-BuONa, CH3CH2ONa, and CH3ONa, preferably N,N-diisopropylethylamine; The amount of palladium on carbon used in step (4) is 5% to 15% of the mass of compound II-d, preferably 8%; the pressure during catalytic hydrogenation is 0.1 to 1.0 MPa, preferably 0.2 to 0.4 MPa; The temperature of the reaction in step (4) can be 0℃ to 10℃, preferably 5℃; the time can be 6 to 8 hours, specifically 6 hours. The reaction solvent in step (4) can be selected from one or a mixture of several of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate, and isopropyl acetate, with methanol and ethanol being preferred. The alkali mentioned in step (5) is selected from one or more of LiOH, NaOH, KOH, Cs2CO3, K2CO3, and Na2CO3, with NaOH and KOH being preferred; In step (5), the molar ratio of compound II-e to the base is 1:1 to 3, preferably 1:2; The reaction temperature in step (5) can be 10–30°C, preferably 20°C; the reaction time can be 4–6 h, preferably 4 h. The reaction solvent in step (5) is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, tert-butanol, and dioxane and a mixture of water, preferably ethanol or a mixture of methanol and water; The condensing agent in step (6) is selected from one or more of DCC, DIC, EDCI, HBTU, HATU, TBTU, HOBT, DIEA, and DMAP, and is used in combination. EDCI and HOBT are preferred to be used in combination. The base in step (6) is selected from one or more of 1,8-diazabicycloundec-7-ene (DBU), tetramethylguanidine, sodium bis(trimethylsilyl)aminodide, triethylamine, pyridine, N,N-diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, N-methylmorpholine, and 4-dimethylaminopyridine, preferably triethylamine and pyridine; In step (6), the molar ratio of II-f to the base is 1:2 to 5, preferably 1:3; In step (6), the molar ratio of compound II-f to dimethylamine hydrochloride can be 1:1.0 to 1.5, preferably 1:1.1; The reaction temperature in step (6) can be 0–10°C, preferably 5°C; the reaction time can be 2–4 h, preferably 2 h. The reaction solvent in step (6) is selected from one of tetrahydrofuran, dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile, preferably tetrahydrofuran and acetonitrile.

[0021] The compound shown in Formula III was prepared by a method comprising the following steps along the following synthetic route:

[0022] (1) In an organic solvent system, under the action of a base, compound III-a and compound III-b undergo a substitution reaction to give compound III-c; (2) Compound III-c was reduced by pressurized hydrogenation using palladium on carbon as a catalyst to obtain compound III.

[0023] in: n is selected from 0 to 2; R is selected from halogen; In step (1), the molar ratio of compound III-a to compound III-b is 1:1.0 to 1.5, preferably 1:1.3; The organic solvent mentioned in step (1) is one or a mixture of several of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide, preferably dimethyl sulfoxide and N-methylpyrrolidone; More preferably, the mass-to-volume ratio of compound III-a to the organic solvent is 62:1 g / L to 125:1 g / L, preferably 100:1 g / L; More preferably, the base is selected from one or more inorganic or organic bases, wherein the inorganic base is selected from one or more of NaOH, KOH, Cs2CO3, K2CO3, and Na2CO3, and the organic base is selected from one or more of 1,8-diazabicycloundec-7-ene (DBU), tetramethylguanidine, triethylamine, pyridine, N,N-diisopropylethylamine, t-BuOK, t-BuONa, CH3CH2ONa, and CH3ONa, preferably CH3CH2ONa; The temperature of the substitution reaction can be 60-80°C, preferably 70°C; the time can be 8-12 hours, specifically 10 hours. In step (2), the reaction solvent is an alcohol solvent such as methanol, ethanol, isopropanol, or tert-butanol, or an alcohol / water mixed solvent, with ethanol being preferred; More preferably, the amount of palladium on carbon in step (2) is 1% to 10% of the mass of compound III-c, preferably 5%; the pressure during pressurized hydrogenation reduction is 0.1 to 1.0 MPa, preferably 0.3 to 0.4 MPa; In step (2), the mass-to-volume ratio of compound III-c to solvent is 60:1 g / L to 180:1 g / L, preferably 100:1 g / L to 150:1 g / L; In step (2), the reaction temperature is 10℃~40℃, preferably 20℃~30℃; the reaction time can be 4~6h.

[0024] More preferably, step (2) of the above method further includes a step of drying the product obtained after pressurized hydrogenation reduction; The drying process is vacuum drying; The vacuum degree of the drying process is P≤-0.08MPa, the drying time can be 4 to 12 hours, and the drying temperature can be 35℃ to 65℃. Preferably, the drying time is 10 hours and the drying temperature is 40℃ (dihydrate) or the drying time is 6 hours and the drying temperature is 60℃ (anhydrous).

[0025] The technical advantages of this invention are that the preparation method not only effectively reduces costs, simplifies the synthetic route, makes each reaction controllable, and improves the overall yield, but is also more economical and environmentally friendly, making it suitable for industrial-scale production. At the same time, this invention improves the stability and reliability of the process, providing a guarantee for the industrial-scale production of voveccidyl citrate. Attached Figure Description

[0026] Figure 1 This is a synthetic route diagram for the compound vovichil, represented by Formula I in this invention.

[0027] Figure 2 The image shows the NMR spectrum of compound I, namely vovichil.

[0028] Figure 3 This is the mass spectrum of compound I, namely vovichil.

[0029] Figure 4 This is the NMR spectrum of compound II-f.

[0030] Figure 5 This is the mass spectrum of compound II-f.

[0031] Figure 6 This is the NMR spectrum of the intermediate compound of formula II.

[0032] Figure 7 This is the mass spectrum of intermediate compound II.

[0033] Figure 8 This is the NMR spectrum of the intermediate compound of formula III.

[0034] Figure 9 This is the mass spectrum of the intermediate compound of formula III. Detailed Implementation

[0035] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0036] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0037] Example 1: Preparation of the compound shown in Formula I, i.e., voveccidil according to Figure 1 The synthetic route shown is used to prepare the compound represented by Formula I.

[0038] Under nitrogen protection, 450 ml of dioxane was added to the reaction flask, followed by stirring and the addition of 15.49 g (0.05 mol) of compound II, 15.57 g (0.05 mol) of compound III (dihydrate), 19.55 g (0.06 mol) of Cs₂CO₃, 0.34 g (1.5 mmol) of palladium acetate, and 1.87 g (3.0 mmol) of BINAP. After the addition was complete, the temperature was raised to 75 °C and the reaction was maintained at this temperature for 4 h. After the reaction was complete, the system was cooled to ≤35 °C, and 310 ml of purified water was slowly added. After the addition was complete, the reaction solution was cooled to 20 °C and crystallized for at least 2 h. The mixture was filtered through a Buchner funnel, the filter cake was washed with a small amount of purified water, and dried in a vacuum drying oven at 45 °C and a vacuum degree of P ≤ -0.08 MPa for 10 h. 20.63 g of voveczybide, the compound shown in Formula I, was obtained, with a yield of 75.2%.

[0039] Example 2: Preparation of the compound shown in Formula I, i.e., voveccidioline Under nitrogen protection, 348.5 L of tetrahydrofuran was added to a 1000 L glass-lined reactor. Stirring was started, followed by the addition of 13.94 kg (40 mol) of compound II, 11.02 kg (40 mol) of compound III (anhydrous form), 4.61 kg (48 mol) of t-BuONa, 0.27 kg (1.2 mol) of palladium acetate, and 1.50 kg (2.4 mol) of BINAP. After the addition was complete, the temperature was raised to 66 °C and the reaction was maintained for 4 h. After the reaction was complete, the system was cooled to ≤35 °C, and 279 L of purified water was slowly added. After the addition was complete, the reaction solution was cooled to 20 °C and crystallized for at least 2 h. The mixture was centrifuged and filtered. The filter cake was washed with purified water and dried in a vacuum drying oven at 45 °C and a vacuum level of P ≤ -0.08 MPa for 10 h. 17.89 kg of compound I, vovichil, was obtained, with a yield of 81.5%. The NMR spectrum of the compound represented by Formula I, i.e., vovichil, is shown in the figure below. Figure 2 The mass spectra are shown below. Figure 3 .

[0040] Example 3: Preparation of compound II-b

[0041] 1360.11 g of glacial acetic acid was added to a reaction flask, followed by the addition of 136.02 g (0.40 mol) of compound II-a (3-amino-4-cyclopentylthiophene-2,5-dicarboxylic acid diisopropyl ester) under stirring. 162.22 g (2.00 mol) of potassium cyanate was then slowly added. After the addition was complete, the temperature was maintained at 25 °C for 4 h. After the reaction was complete, 2 L of purified water was slowly added, followed by stirring to induce crystallization for 3 h. The system was then cooled to below 10 °C and allowed to crystallize for 2 h. The crystals were filtered through a Buchner funnel, and the filter cake was washed with a small amount of purified water. The mixture was then dried in a vacuum drying oven at 60 °C and a vacuum level of P ≤ -0.08 MPa for 10 h. 123.27 g of compound II-b (3-cyclopentyl-4-ureidothiophene-2,5-dicarboxylic acid diisopropyl ester) was obtained, with a yield of 80.6%.

[0042] Example 4: Preparation of compound II-b

[0043] 450.01 kg of glacial acetic acid was added to a 1000 L glass-lined reactor. While stirring, 45.00 kg (158.8 mol) of compound II-a (3-amino-4-cyclopentylthiophene-2,5-dicarboxylic acid dimethyl ester) was added, followed by slow addition of 64.41 kg (794 mol) of potassium cyanate. After the addition was complete, the temperature was maintained at 25 °C for 4 h. After the reaction was complete, 675 L of purified water was slowly added, followed by stirring to induce crystallization for 3 h. The system was then cooled to below 10 °C and allowed to crystallize for 2 h. The crystals were centrifuged and filtered. The filter cake was washed with purified water and dried in a vacuum drying oven at 60 °C and a vacuum level of P ≤ -0.08 MPa for 10 h. 43.51 kg of compound II-b (3-cyclopentyl-4-ureidothiophene-2,5-dicarboxylic acid dimethyl ester) was obtained, with a yield of 84.0%.

[0044] Example 5: Preparation of compound II-c

[0045] Add 1150 ml of methanol to the reaction flask, and then add 115.02 g (0.35 mol) of compound II-b (3-cyclopentyl-4-ureidothiophene-2,5-dicarboxylic acid dimethyl ester) while stirring. After the addition is complete, maintain the temperature at 15 °C and slowly add 67.28 g (0.70 mol) of t-BuONa. After the addition is complete, maintain the temperature for 2 h. After the reaction is complete, cool the system to 0–10 °C, and slowly add hydrochloric acid to adjust the pH to 6–7. After the addition is complete, stir the reaction solution and heat it to 20–30 °C. Add 460 ml of purified water, and then maintain the temperature for 2 h to allow crystals to precipitate. Filter the solution using a Buchner funnel, rinse the filter cake with a small amount of purified water, and dry it in a vacuum drying oven at 65 °C and a vacuum degree of P ≤ -0.08 MPa for 16 h. 88.32 g of compound II-c (methyl 7-cyclopentyl-2,4-dihydroxythiopheno[3,2-d]pyrimidine-6-carboxylate) was obtained, with a yield of 85.7%.

[0046] Example 6: Preparation of compound II-c

[0047] 420 L of isopropanol was added to a 1000 L glass-lined reactor. Then, 42.01 kg (118.5 mol) of compound II-b (3-cyclopentyl-4-ureidothiophene-2,5-dicarboxylic acid diethyl ester) (prepared according to the method in Example 4, with 3-amino-4-cyclopentylthiophene-2,5-dicarboxylic acid dimethyl ester replaced by 3-amino-4-cyclopentylthiophene-2,5-dicarboxylic acid diethyl ester) was added under stirring. After the addition was complete, the temperature was controlled at 15 °C, and 16.13 kg (237 mol) of sodium ethoxide was slowly added. After the addition was complete, the reaction was maintained at this temperature for 2 h. After the reaction was complete, the system was cooled to 0–10°C, and hydrochloric acid was slowly added to adjust the pH to 6–7. After the addition was complete, the reaction solution was stirred and heated to 20–30°C. 168 L of purified water was added, and the mixture was kept at this temperature for 2 hours to allow crystals to precipitate. The crystals were then centrifuged and filtered. The filter cake was washed with purified water and dried in a vacuum drying oven at 65°C and a vacuum degree of P ≤ -0.08 MPa for 16 hours. Compound II-c (ethyl 7-cyclopentyl-2,4-dihydroxythiopheno[3,2-d]pyrimidine-6-carboxylate) was obtained in 32.18 kg, with a yield of 88.1%.

[0048] Example 7: Preparation of Chloride II-d Add 403.02 g of phosphorus oxychloride to a reaction flask, and while stirring, add 80.60 g (0.25 mol) of compound II-c (7-cyclopentyl-2,4-dihydroxythiopheno[3,2-d]pyrimidine-6-carboxylic acid isopropyl ester). Slowly add 64.63 g (0.50 mol) of N,N-diisopropylethylamine, controlling the temperature to ≤50℃. After the addition is complete, raise the reaction system to 90℃ and maintain the temperature for 8 h. After the reaction is complete, cool the system to 15–30℃ and set aside. Add 645 ml of purified water and 806 ml of n-hexane to another reaction flask, and while stirring, slowly add the above reaction solution to the reaction flask, controlling the temperature to 10–30℃. After completion, maintain the temperature and stir for 30 min, let stand for 30 min, retain the organic phase, extract and wash with saturated sodium bicarbonate solution, extract and wash with saturated sodium chloride solution, and concentrate the organic phase under reduced pressure until no distillate flows out. 80.66 g of chloride II-d (isopropyl 2,4-dichloro-7-cyclopentylthiopheno[3,2-d]pyrimidine-6-carboxylic acid) was obtained, yield: 89.8%.

[0049] Example 8: Preparation of Chloride II-d

[0050] 144.30 kg of phosphorus oxychloride was added to a 300 L glass-lined reactor. While stirring, 28.85 kg (98 mol) of compound II-c (methyl 7-cyclopentyl-2,4-dihydroxythiopheno[3,2-d]pyrimidine-6-carboxylate) was added, followed by slow addition of 19.83 kg (196 mol) of triethylamine. The temperature was controlled to ≤50 °C. After the addition was complete, the reaction system was heated to 75 °C and maintained at this temperature for 8 h. After the reaction was complete, the system was cooled to 15–30 °C for later use. 231 L of purified water and 289 L of n-hexane were added to a 1000 L glass-lined reactor. While stirring, the above reaction solution was slowly added to the reactor, maintaining the temperature at 10–30 °C. After completion, the mixture was stirred at this temperature for 30 min, allowed to stand for 30 min, and the organic phase was retained. The organic phase was extracted and washed with saturated sodium bicarbonate solution and then extracted and washed with saturated sodium chloride solution. The organic phase was concentrated under reduced pressure until no distillate flowed out. 30.15 kg of chloride II-d (methyl 2,4-dichloro-7-cyclopentylthiophene[3,2-d]pyrimidine-6-carboxylate) was obtained, with a yield of 92.9%.

[0051] Example 9: Preparation of compound II-e

[0052] Add 690 ml of methanol to the hydrogenation reactor, and then add 69.05 g (0.20 mol) of chloride II-d (ethyl 2,4-dichloro-7-cyclopentylthiophene[3,2-d]pyrimidine-6-carboxylate) while stirring. N,N31.02 g (0.24 mol) of diisopropylethylamine and 5.52 g (5% by mass) palladium on carbon were added to a hydrogenation reactor and pressurized to 0.2–0.4 MPa. The reaction was carried out at 5°C for 6 hours. After the reaction was completed, the palladium on carbon was removed by filtration. The filtrate was cooled to 0–10°C, and hydrochloric acid was slowly added to adjust the pH to 5–6. After the addition was complete, the reaction solution was stirred and heated to 60–70°C. 828 ml of purified water was added. After the water addition was complete, the temperature was slowly lowered to 10–20°C and crystallized for 2 hours. The mixture was filtered through a Buchner funnel, and the filter cake was washed with a small amount of purified water. The mixture was then dried in a vacuum drying oven at 45°C and a vacuum degree of P ≤ -0.08 MPa for 8 hours. Compound II-e (ethyl 2-chloro-7-cyclopentylthiopheno[3,2-d]pyrimidine-6-carboxylate) was obtained, with a yield of 82.6%.

[0053] Example 10: Preparation of compound II-e

[0054] Add 288 L of ethanol to the hydrogenation reactor, and then add 28.74 kg (80 mol) of chloride II-d (2,4-dichloro-7-cyclopentylthiophene[3,2-d]pyrimidine-6-carboxylic acid isopropyl ester) while stirring. N,N 12.41 kg (96 mol) of diisopropylethylamine and 2.30 kg (5% palladium on carbon) were added to a hydrogenation reactor and pressurized to 0.2–0.4 MPa. The reaction was carried out at 5°C for 6 hours. After the reaction was completed, the palladium on carbon was removed by filtration. The filtrate was cooled to 0–10°C, and hydrochloric acid was slowly added to adjust the pH to 5–6. After the addition was complete, the reaction solution was stirred and heated to 60–70°C. 345 L of purified water was added. After the water addition was complete, the temperature was slowly lowered to 10–20°C and crystallized for 2 hours. The mixture was centrifuged and filtered. The filter cake was washed with purified water and dried in a vacuum drying oven at 45°C and a vacuum degree of P ≤ -0.08 MPa for 8 hours. 22.14 kg of compound II-e (2-chloro-7-cyclopentylthiopheno[3,2-d]pyrimidine-6-carboxylic acid isopropyl ester) was obtained, with a yield of 85.2%.

[0055] Example 11, Preparation of compound II-f

[0056] 265 ml of methanol and 133 ml of purified water were added to a reaction flask. 44.52 g (0.15 mol) of compound II-e (methyl 2-chloro-7-cyclopentylthiopheno[3,2-d]pyrimidine-6-carboxylate) (prepared according to the method of Example 10) was added while stirring. The temperature was maintained at 20 °C, and 16.82 g (0.30 mol) of potassium hydroxide was slowly added. The reaction was maintained at this temperature for 4 h. After the reaction was complete, the system was cooled to 0–10 °C, and 445 ml of purified water was added. Hydrochloric acid was then slowly added to adjust the pH to 2–3. The reaction was maintained at this temperature and stirred for 2 h. The mixture was filtered through a Buchner funnel, and the filter cake was washed with a small amount of purified water. The mixture was then dried in a vacuum drying oven at 55 °C and a vacuum level of P ≤ -0.08 MPa for 10 h. 37.12 g of compound II-f was obtained, with a yield of 87.5%. The NMR spectrum of compound II-f is shown below. Figure 4 The mass spectra are shown below. Figure 5 .

[0057] Example 12, Preparation of compound II-f

[0058] 117 L of ethanol and 58.5 L of purified water were added to a 500 L glass-lined reactor. While stirring, 19.50 kg (62.8 mol) of compound II-e (ethyl 2-chloro-7-cyclopentylthiophene[3,2-d]pyrimidine-6-carboxylate) was added. The temperature was maintained at 20 °C, and 5.02 kg (125.5 mol) of sodium hydroxide was slowly added. The reaction was maintained at this temperature for 4 h. After the reaction was complete, the system was cooled to 0–10 °C, and 195 L of purified water was added. Hydrochloric acid was then slowly added to adjust the pH to 2–3. The mixture was stirred and maintained at this temperature for 2 h. The mixture was centrifuged and filtered. The filter cake was washed with purified water and dried in a vacuum drying oven at 55 °C and a vacuum level of P ≤ -0.08 MPa for 10 h. 16.07 kg of compound II-f was obtained, with a yield of 90.5%.

[0059] Example 13: Preparation of intermediate compound II

[0060] Add 85 ml of acetonitrile to the reaction flask, and add 34.01 g (0.12 mol) of compound II-f while stirring. Maintain the temperature at 5 °C, then add 26.84 g (0.14 mol) of EDCI, 18.91 g (0.14 mol) of HOBT, and 12.72 g (0.156 mol) of dimethylamine hydrochloride. Then slowly add 23.73 g (0.30 mol) of pyridine. Maintain the temperature for 2 h after the addition is complete. After the reaction is complete, maintain the temperature at 0–20 °C, add 272 ml of purified water and 272 ml of ethyl acetate, and stir for 30 min. Let stand for 30 min, retain the organic phase, and extract and wash with saturated sodium carbonate solution and saturated sodium chloride solution. Concentrate the organic phase under reduced pressure until no distillate flows out. Then add 204 ml of anhydrous ethanol to the concentrate, stir and heat to 75 °C, maintain the temperature and stir for 1 h, then slowly cool to 0–5 °C and stir to induce crystallization for 2 h. The mixture was filtered through a Buchner funnel, the filter cake was washed with a small amount of anhydrous ethanol, and then dried in a vacuum drying oven at 55°C and a vacuum level of P ≤ -0.08 MPa for 4 hours. 33.09 g of intermediate compound II was obtained, with a yield of 89.0%. The NMR spectrum of intermediate compound II is shown below. Figure 6 The mass spectra are shown below. Figure 7 .

[0061] Example 14: Preparation of intermediate compound II

[0062] Add 37.5 L of tetrahydrofuran to a 500 L glass-lined reactor, then add 15.00 kg (53 mol) of compound II-f while stirring. Maintain the temperature at 5 °C, then add 12.19 kg (63.6 mol) of EDCI, 8.59 kg (63.6 mol) of HOBT, and 4.75 kg (58.3 mol) of dimethylamine hydrochloride. Then slowly add 16.09 kg (159 mol) of triethylamine. Maintain the temperature for 2 h after the addition is complete. After the reaction is complete, maintain the temperature at 0–20 °C, add 120 L of purified water and 120 L of ethyl acetate. After completion, maintain the temperature and stir for 30 min, let stand for 30 min, retain the organic phase, extract and wash with saturated sodium carbonate solution, and extract and wash with saturated sodium chloride solution. Concentrate the organic phase under reduced pressure until no distillate flows out. Then add 90 L of anhydrous ethanol to the concentrate, stir and heat to 75 °C, maintain the temperature and stir for 1 h, then slowly cool to 0–5 °C and stir to induce crystallization for 2 h. Centrifugal filtration was performed, and the filter cake was washed with anhydrous ethanol. The cake was then dried in a vacuum drying oven at 55°C and a vacuum level of P ≤ -0.08 MPa for 4 hours. 15.06 kg of intermediate compound II was obtained, with a yield of 91.7%.

[0063] Example 15: Preparation of Compound III-c

[0064] Add 400 ml of dimethyl sulfoxide to the reaction flask, and while stirring, add 40.01 g (0.22 mol) of compound III-a and 45.00 g (0.28 mol) of compound III-b (5-chloro-2-nitropyridine). Maintain the temperature at 10–30 °C, and add 60.72 g (0.44 mol) of K₂CO₃. After the addition is complete, slowly raise the temperature to 70 °C and maintain the reaction temperature for 10 h. After the reaction is complete, cool the system to 10–30 °C, and slowly add 400 ml of purified water. After the addition is complete, stir to allow crystals to precipitate for 2 h. Filter through a Buchner funnel, rinse the filter cake with a small amount of purified water, and dry in a vacuum drying oven at 60 °C and a vacuum level of P ≤ -0.08 MPa for 10 h. Obtain 49.27 g of compound III-c, yield: 73.3%.

[0065] Example 16: Preparation of Compound III-c

[0066] 145 L of N-methylpyrrolidone was added to a 500 L glass-lined reactor. While stirring, 14.51 kg (79 mol) of compound III-a and 20.85 g (102.7 mol) of compound III-b (5-bromo-2-nitropyridine) were added. The temperature was controlled at 10–30 °C. Then, 10.75 kg (158 mol) of CH3CH2ONa was added. After the addition was complete, the reaction system was slowly heated to 70 °C and maintained at this temperature for 10 h. After the reaction was complete, the system was cooled to 10–30 °C, and 145 L of purified water was slowly added. After the addition was complete, the mixture was stirred to allow crystallization to occur for 2 h. The mixture was filtered through a Buchner funnel, and the filter cake was washed with purified water. The mixture was then dried in a vacuum drying oven at 60 °C and a vacuum level of P ≤ -0.08 MPa for 10 h. 18.32 kg of compound III-c was obtained, with a yield of 75.9%.

[0067] Example 17: Preparation of intermediate compound III

[0068] 460 ml of methanol was added to a hydrogenation reactor. While stirring, 46.00 g (0.15 mol) of compound III-c and 2.30 g of 10% palladium on carbon were added. Hydrogen gas was introduced into the reactor and pressurized to 0.3–0.4 MPa. The reaction was carried out at 20–30 °C for 5 hours. After the reaction was complete, the palladium on carbon was removed by filtration. The filtrate was cooled to 0–10 °C, and 230 ml of purified water was slowly added. After the water addition was complete, the mixture was kept at this temperature for 4 hours to allow crystals to precipitate. The mixture was filtered through a Buchner funnel, and the filter cake was washed with a small amount of purified water. The mixture was then dried in a vacuum drying oven at 40 °C and a vacuum level of P ≤ -0.08 MPa for 10 hours. 34.69 g of intermediate compound III (dihydrate) was obtained, with a yield of 74.3%. The NMR spectrum of intermediate compound III is shown below. Figure 8 The mass spectra are shown below. Figure 9 .

[0069] Example 18: Preparation of intermediate compound III

[0070] 170 L of ethanol was added to a hydrogenation reactor, followed by 17.00 kg (55.7 mol) of compound III-c and 0.85 kg of 10% palladium on carbon under stirring. Hydrogen gas was introduced into the reactor to pressurize it to 0.3–0.4 MPa, and the reaction was carried out at 20–30 °C for 5 hours. After the reaction was complete, the palladium on carbon was removed by filtration. The filtrate was cooled to 0–10 °C, and 85 L of purified water was slowly added. After the water addition was complete, the mixture was kept at this temperature for 4 hours to allow crystals to precipitate. The mixture was then centrifuged and filtered. The filter cake was washed with purified water and dried in a vacuum drying oven at 60 °C and a vacuum level of P ≤ -0.08 MPa for 6 hours. 11.94 kg of anhydrous intermediate III compound was obtained, with a yield of 77.9%.

[0071] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. A method for preparing the compound of formula I, namely voveccidil, comprising the following steps: Under alkaline conditions, in the presence of a palladium catalyst and an organophosphorus ligand, the compound shown in intermediate formula II undergoes a Buchwald–Hartwig coupling reaction with the compound shown in intermediate formula III to give the compound shown in formula I, namely vovichil. 。 2. The method according to claim 1, characterized in that, The compound shown in Formula II is 2-chloro-7-cyclopentyl-N,N-dimethylthiopheno[3,2-d]pyrimidine-6-carboxamide; The compound shown in Formula III is 5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-amine (n) hydrate, wherein n is selected from 0 to 2; The molar ratio of the compound shown in Formula II to the compound shown in Formula III is 1:0.9 to 1.

2.

3. The method according to claim 1, characterized in that, The alkaline conditions are provided by a base, which is selected from one or more inorganic or organic bases; The inorganic base is selected from one or more of NaOH, KOH, Cs2CO3, K2CO3, and Na2CO3; The organic base is selected from one or more of 1,8-diazabicycloundec-7-ene (DBU), tetramethylguanidine, triethylamine, pyridine, N,N-diisopropylethylamine, t-BuOK, t-BuONa, CH3CH2ONa, and CH3ONa; The palladium catalyst is selected from one of Pd2(dba)3 and Pd(OAc)2; The organophosphorus ligand is selected from one or more of Josiphos, BINAP, DIOP, DIPAMP, PPFA, and BPPFA.

4. The method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula II to the base is 1:1 to 2: The molar ratio of the compound shown in Formula II to the palladium catalyst is 1:0.01 to 0.05; The molar ratio of the compound shown in Formula II to the organophosphorus ligand is 1:0.04 to 0.

08.

5. The method according to claim 1, characterized in that, The Buchwald–Hartwig coupling reaction was carried out at a temperature of 60°C to 90°C for 3 to 6 hours.

6. The method according to claim 1, characterized in that, The Buchwald–Hartwig coupling reaction is carried out in a solvent selected from at least one of dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl isopropyl ketone, methyl isobutyl ketone, and toluene.

7. The method according to claim 1, characterized in that, The compound shown in Formula II was prepared by a method comprising the following steps along the following synthetic route: (1) In an acidic system, aminothiophene compound II-a reacts with a cyanate reagent to form urea compound II-b; (2) Compound II-b undergoes further cyclization under the action of a base to generate thiophene-pyrimidine compound II-c; (3) Compound II-c reacts with chlorinating agent under the action of acid-binding agent to form chloride II-d; (4) In the presence of an organic base, palladium on carbon is used as a catalyst to selectively catalytically hydrogenate the chlorine at the C-4 position of the pyrimidine ring to obtain compound II-e; (5) Compound II-e undergoes further hydrolysis of the ester group under the action of a base to give compound II-f; (6) Compound II was finally prepared by condensation reaction of compound II-f with dimethylamine hydrochloride under the action of condensing agent and base; Among them, R1 and R2 are each independently selected from C1 to C2. 10 Alkyl groups.

8. The method according to claim 1, characterized in that, The compound shown in Formula III was prepared by a method comprising the following steps along the following synthetic route: (1) In an organic solvent system, under the action of a base, compound III-a and compound III-b undergo a substitution reaction to give compound III-c; (2) Compound III-c was reduced by pressurized hydrogenation using palladium on carbon as a catalyst to obtain compound III; in: n is selected from 0 to 2; R is selected from halogens.

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