Novel preparation method of ribosilil

Abstract

The invention discloses a novel preparation method of ribosilil. The invention specifically discloses a preparation method of rebosilib, which comprises the following steps: (1) in a solvent, in the presence of alkali and a phase transfer catalyst, carrying out substitution reaction 1 on a compound 4 and a compound 5 to generate a compound 6; and (2) in a solvent, in the presence of an acid, carrying out a protecting group removal reaction on the compound 6 to obtain rebosilil. The preparation method has the advantages of simple operation, mild reaction conditions, cheap and easily available raw materials, no use of a noble metal catalyst, and suitableness for large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of organic compound technology and relates to a new method for preparing reboxil. Background Technology

[0002] Ribociclib succinate, developed by Novartis, is a CDK4 / 6 inhibitor primarily used to treat HR-positive, HER2-negative advanced or metastatic breast cancer. This drug significantly prolongs progression-free survival (PFS) and improves patients' quality of life by selectively inhibiting cancer cell proliferation by blocking cell cycle progression, thus addressing a significant unmet medical need in this subtype of breast cancer.

[0003] Breast cancer is the most common malignant tumor among women in my country and a significant public health issue. Compared to other types of breast cancer, premenopausal advanced breast cancer is often more malignant, has a poorer prognosis, and its incidence is increasing rapidly, making it a major focus in breast cancer treatment. On January 19, 2023, ribociclib was approved by the National Medical Products Administration (NMPA). This approval represents a major breakthrough in breast cancer treatment, ushering in a new era for the treatment of premenopausal breast cancer patients. Therefore, developing a simple and efficient method for preparing ribociclib is undoubtedly of great significance.

[0004] The literature reports the following main synthetic routes for reboxil:

[0005] Method 1:

[0006] The original patent US20120115878 reports a method for synthesizing reboxil as follows: using 5-bromo-2,4-dichloropyrimidine as a starting material, the key nucleus is obtained through nucleophilic substitution, coupling, cyclization, hydrolysis, and oxidation reactions. This nucleus is then coupled with 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester via Buchwald-Hartwig coupling and deBoc protection to generate reboxil. The entire route is lengthy, requiring nine steps (two of which involve pre-fabricating the coupling fragment), with an overall yield of 12%. The use of expensive palladium catalysts twice and the highly toxic sodium cyanide contributes to the high production cost.

[0007]

[0008] Method 2: CN106749259A

[0009] This patent reports the use of 4-chloro-2-(methylthio)pyrimidin-5-carboxaldehyde and N-cyclopentylglycine ethyl ester as raw materials, followed by substitution, dehydration condensation, hydrolysis, acid-amine condensation, oxidation, substitution, and deBoc protection to obtain the final product reboxil. However, N-cyclopentylglycine ethyl ester and 4-chloro-2-(methylthio)pyrimidin-5-carboxaldehyde are expensive and require one or more additional steps in their preparation, making them unsuitable for industrial production.

[0010]

[0011] Method 3: US 2020 / 0339588

[0012] This method improves upon the original patented route, reducing the use of expensive palladium catalysts and highly toxic sodium cyanide. It can obtain reboxil in 7 steps with a yield of 17%, but the yield of the second step is only moderate, and the separation and purification are difficult, resulting in low overall production efficiency.

[0013] Summary of the Invention

[0014] The purpose of this invention is to overcome the shortcomings of existing technologies, such as expensive starting materials, the use of precious metal palladium catalysts and highly toxic chemicals like sodium cyanide, resulting in high production costs, numerous steps, low overall yield, and unsuitability for industrial production. This invention provides a new method for preparing reboxil. The method of this invention is simple to operate, has mild reaction conditions, and uses inexpensive and readily available raw materials, avoiding the use of precious metal catalysts, making it suitable for scale-up production.

[0015] The specific technical solution for achieving the objective of this invention is as follows:

[0016] This invention provides a method for preparing reboxil, comprising the following steps:

[0017] ;

[0018] (1) In a solvent, in the presence of a base and a phase transfer catalyst, compound 4 and compound 5 undergo a substitution reaction 1 to generate compound 6;

[0019] (2) In a solvent, in the presence of an acid, compound 6 undergoes a protecting group removal reaction to give reboxil.

[0020] In some embodiments of the present invention, in the substitution reaction 1, the base is an inorganic base or an organic base; the inorganic base is preferably an alkali metal carbonate, an alkali metal phosphate, or an alkali metal hydride; more preferably potassium carbonate, cesium carbonate, potassium phosphate, or sodium hydride; for example, potassium carbonate or cesium carbonate; the organic base is preferably potassium tert-butoxide, n-butyllithium, diisopropylaminolithium, bis(trimethylsilylaminolithium), 1,8-diazacyclo[5,4,0]undecene-7, or tetramethylguanidine; more preferably bis(trimethylsilylaminolithium).

[0021] In some embodiments of the present invention, in the substitution reaction 1, the solvent is selected from one or more of ether solvents, amide solvents, sulfoxide solvents, and aromatic solvents; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; the amide solvent is preferably N,N-dimethylformamide or N,N-dimethylacetamide; the sulfoxide solvent is preferably dimethyl sulfoxide; and the aromatic solvent is preferably toluene.

[0022] In some embodiments of the present invention, in the substitution reaction 1, when the base is an organic base, the solvent is an ether solvent, preferably tetrahydrofuran; when the base is an inorganic base, the solvent is an amide solvent or a sulfoxide solvent, preferably N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, more preferably N,N-dimethylformamide.

[0023] In some embodiments of the present invention, in the substitution reaction 1, the phase transfer catalyst is a quaternary ammonium salt phase transfer agent or a quaternary phosphate salt phase transfer agent; the quaternary ammonium salt phase transfer agent is preferably tetrabutylammonium halide; more preferably tetra-n-butylammonium iodide, tetra-n-butylammonium bromide or tetra-n-butylammonium chloride; for example, tetra-n-butylammonium bromide; the quaternary phosphate salt phase transfer catalyst is preferably triphenylmethylphosphine halide or tetraphenylphosphine halide; for example, triphenylmethylphosphine bromide or tetraphenylphosphine bromide.

[0024] In some embodiments of the present invention, in the substitution reaction 1, the molar volume ratio of compound 4 to the solvent is 0.1-1 mol / L; preferably 0.2-0.6 mol / L; for example, 0.2 mol / L or 0.4 mol / L.

[0025] In some embodiments of the present invention, in the substitution reaction 1, the molar ratio of compound 5 to compound 4 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1.

[0026] In some embodiments of the present invention, in the substitution reaction 1, the molar ratio of the base to the compound 4 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1.

[0027] In some embodiments of the present invention, in the substitution reaction 1, the molar ratio of the phase transfer catalyst and the compound 4 is (0.02-0.3):1; preferably (0.05-0.15):1; for example, 0.1:1.

[0028] In some embodiments of the present invention, the temperature of the substitution reaction 1 is a conventional reaction temperature for such reactions in the art; preferably 0-120°C. o C; more preferably 90-110 o C; for example, 100 o C.

[0029] In some embodiments of the present invention, the duration of the substitution reaction 1 is the conventional reaction time for such reactions in the art, typically ending when the raw materials disappear or the product no longer increases; preferably 12-48 h; more preferably 18-30 h; for example 24 h.

[0030] In some embodiments of the present invention, the substitution reaction 1 further includes the following post-processing steps: after the reaction is completed, the mixture is cooled to room temperature, water and ethyl acetate are added respectively, the mixture is stirred and separated, the aqueous phase is extracted with ethyl acetate, the combined organic layers are washed successively with water and saturated sodium chloride to remove the solvent, and compound 6 is obtained.

[0031] In some embodiments of the present invention, in the protecting group removal reaction, the solvent is selected from one or more of halogenated hydrocarbon solvents, ester solvents, ketone solvents, alcohol solvents, ether solvents, aromatic solvents, and nitrile solvents; the halogenated hydrocarbon solvent is preferably dichloromethane, the ester solvent is preferably ethyl acetate, the ketone solvent is preferably acetone, the alcohol solvent is preferably methanol or ethanol, the ether solvent is preferably tetrahydrofuran or 1,4-dioxane, the aromatic solvent is preferably toluene, and the nitrile solvent is preferably acetonitrile; preferably, it is a halogenated hydrocarbon solvent, ester solvent, or aromatic solvent, preferably dichloromethane, ethyl acetate, or toluene.

[0032] In some embodiments of the present invention, in the protecting group removal reaction, the acid is hydrochloric acid, hydrobromic acid, trifluoromethanesulfonic acid, or p-toluenesulfonic acid; preferably hydrochloric acid or trifluoromethanesulfonic acid; more preferably, the hydrochloric acid is added in the form of a 5M hydrochloric acid solution.

[0033] In some embodiments of the present invention, the acid is added dropwise in the protecting group removal reaction.

[0034] In some embodiments of the present invention, in the protecting group removal reaction, the molar volume ratio of compound 6 to the solvent is 0.1-1 mol / L; preferably 0.2-0.6 mol / L; for example, 0.4 mol / L.

[0035] In some embodiments of the present invention, in the protecting group removal reaction, the molar ratio of the acid to the compound 6 is (2-8):1; preferably (4-6):1; for example, 5:1.

[0036] In some embodiments of the present invention, the amount of compound 6 is determined by the amount of compound 4 used in the aforementioned substitution reaction 1, wherein in the protecting group removal reaction, the molar volume ratio of compound 4 to the solvent is 0.1-1 mol / L; preferably 0.2-0.6 mol / L; for example 0.4 mol / L.

[0037] In some embodiments of the present invention, in the protecting group removal reaction, the molar ratio of the acid to the compound 4 is (2-8):1; preferably (4-6):1; for example, 5:1.

[0038] In some embodiments of the present invention, the time for the removal of the protecting group is the conventional reaction time for such reactions in the art, usually ending when the raw material disappears or the product no longer increases; preferably 0.5-6 h; more preferably 1-3 h; for example 2 h.

[0039] In some embodiments of the present invention, the temperature of the protecting group removal reaction is the conventional reaction temperature for such reactions in the art; preferably 0-60°C. o C; more preferably 10-40 o C; for example, 20-30 o C.

[0040] In some embodiments of the present invention, the protecting group removal reaction further includes the following post-processing steps: adjusting the pH to 7±0.5 with saturated sodium hydroxide solution, extracting with ethyl acetate, combining the organic layers, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, recrystallizing the crude product with ethyl acetate and n-hexane, filtering, and drying the filter cake under vacuum to obtain reboxil.

[0041] In some embodiments of the present invention, the method for preparing reboxil further includes the following step: in a solvent, in the presence of an oxidant, compound 3 undergoes an oxidation reaction to generate compound 4;

[0042] .

[0043] In some embodiments of the present invention, in the oxidation reaction, the solvent is an alcohol solvent, an ether solvent, an amide solvent, a sulfoxide solvent, or a nitrile solvent; the alcohol solvent is preferably methanol or ethanol, the ether solvent is preferably tetrahydrofuran or 1,4-dioxane, the amide solvent is preferably N,N-dimethylformamide or N,N-dimethylacetamide, the sulfoxide solvent is preferably dimethyl sulfoxide, and the nitrile solvent is preferably acetonitrile; preferably, the solvent is a nitrile solvent, such as acetonitrile.

[0044] In some embodiments of the present invention, the oxidant in the oxidation reaction is a conventional oxidant for such reactions in the art; for example, potassium persulfate double salt.

[0045] In some embodiments of the present invention, in the oxidation reaction, the potassium persulfate double salt is added in the form of an aqueous solution; the volume ratio of water to solvent is preferably 1:1; more preferably, the aqueous solution is added dropwise; and the temperature at which the aqueous solution is added is preferably 0-15 °C.

[0046] In some embodiments of the present invention, in the oxidation reaction, the molar volume ratio of compound 3 to the solvent is 0.1-1 mol / L; preferably 0.2-0.5 mol / L; for example, 0.32 mol / L.

[0047] In some embodiments of the present invention, in the oxidation reaction, the molar ratio of the oxidant to the compound 3 is (2-8):1; preferably (4-6):1; for example, 5:1.

[0048] In some embodiments of the present invention, the temperature of the oxidation reaction is the conventional reaction temperature for such reactions in the art; preferably 0-40°C. o C; more preferably 0-25 °C.

[0049] In some embodiments of the present invention, the oxidation reaction time is the conventional reaction time for such reactions in the art, usually ending when the raw materials disappear or the products no longer increase; preferably 2-12 h; more preferably 4-6 h; for example 5 h.

[0050] In some embodiments of the present invention, the oxidation reaction further includes the following post-processing steps: concentration under reduced pressure to remove acetonitrile, extraction with ethyl acetate, combining the organic layers, washing with saturated brine, drying with anhydrous sodium sulfate, and concentration under reduced pressure to obtain a crude product; adding tetrahydrofuran and n-hexane to the crude product for recrystallization to obtain compound 4.

[0051] In some embodiments of the present invention, the method for preparing reboxil further includes the following step: in a solvent, compound 2 undergoes an aminolysis reaction with dimethylamine to generate compound 3;

[0052] .

[0053] In some embodiments of the present invention, in the aminolysis reaction, the solvent is selected from one or more of the following: halogenated hydrocarbon solvents, ester solvents, ketone solvents, alcohol solvents, ether solvents, amide solvents, sulfoxide solvents, and nitrile solvents; the halogenated hydrocarbon solvent is preferably dichloromethane, the ester solvent is preferably ethyl acetate, the ketone solvent is preferably acetone, the alcohol solvent is preferably methanol or ethanol, the ether solvent is preferably tetrahydrofuran or 1,4-dioxane, the amide solvent is preferably N,N-dimethylformamide or N,N-dimethylacetamide, the sulfoxide solvent is preferably dimethyl sulfoxide, and the nitrile solvent is preferably acetonitrile; preferably, it is an alcohol solvent, such as methanol or ethanol.

[0054] In some embodiments of the present invention, in the aminolysis reaction, the dimethylamine is added in the form of a dimethylamine methanol solution; the dimethylamine methanol solution is preferably a 2M dimethylamine methanol solution.

[0055] In some embodiments of the present invention, during the aminolysis reaction, the temperature of the dimethylamine methanol solution is controlled at 0-10 °C. o C is added.

[0056] In some embodiments of the present invention, in the aminolysis reaction, the molar volume ratio of compound 2 to the solvent is 0.5-3 mol / L; preferably 1-2 mol / L; for example, 1.3 mol / L.

[0057] In some embodiments of the present invention, in the aminolysis reaction, the molar ratio of the dimethylamine and the compound 2 is (1-2):1; preferably (1-1.5):1; for example, 1.1:1.

[0058] In some embodiments of the present invention, the temperature of the aminolysis reaction is the conventional reaction temperature for such reactions in the art; preferably 0-40°C. o C; more preferably 20-30 o C.

[0059] In some embodiments of the present invention, the time for the aminolysis reaction is the conventional reaction time for such reactions in the art, usually ending when the raw materials disappear or the product no longer increases; preferably 8-32 h; more preferably 12-20 h; for example 16 h.

[0060] In some embodiments of the present invention, the aminolysis reaction further includes the following post-processing steps: concentrating to obtain a crude product, adding tetrahydrofuran to the crude product and slurrying to obtain compound 3.

[0061] In some embodiments of the present invention, the method for preparing reboxil further includes the following step: in a solvent, in the presence of a base, compound 1 undergoes a substitution reaction 2 with bromocyclopentane to generate compound 2;

[0062] .

[0063] In some embodiments of the present invention, in the substitution reaction 2, the solvent is selected from one or more of ether solvents, nitrile solvents, amide solvents, sulfoxide solvents, and aromatic solvents; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane, the nitrile solvent is preferably acetonitrile, the amide solvent is preferably N,N-dimethylformamide or N,N-dimethylacetamide, the sulfoxide solvent is preferably dimethyl sulfoxide, and the aromatic solvent is preferably toluene; preferably, the solvent is an amide solvent or an ether solvent, preferably N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide, more preferably N,N-dimethylformamide.

[0064] In some embodiments of the present invention, in the substitution reaction 2, the base is an inorganic base or an organic base; the inorganic base is preferably an alkali metal carbonate, an alkali metal phosphate, or an alkali metal hydride; more preferably, it is potassium carbonate, cesium carbonate, potassium phosphate, or sodium hydride; the organic base is preferably potassium tert-butoxide, n-butyllithium, diisopropylaminolithium, bis(trimethylsilylaminolithium), triethylamine, N,N-diisopropylethylamine, 1,8-diazacyclo[5,4,0]undecene-7, pyridine, piperidine, quinoline, or tetramethylguanidine; preferably, the base is an inorganic base; preferably potassium carbonate or cesium carbonate; for example, potassium carbonate.

[0065] In some embodiments of the present invention, when the base in the substitution reaction 2 is an inorganic base, the substitution reaction 2 is carried out in the presence of a phase transfer catalyst; the phase transfer catalyst is a quaternary ammonium salt phase transfer agent or a quaternary phosphate salt phase transfer agent; the quaternary ammonium salt phase transfer agent is preferably tetrabutylammonium halide; more preferably tetra-n-butylammonium iodide, tetra-n-butylammonium bromide or tetra-n-butylammonium chloride; for example, tetra-n-butylammonium bromide; the quaternary phosphate salt phase transfer catalyst is preferably triphenylmethylphosphine halide or tetraphenylphosphine halide; for example, triphenylmethylphosphine bromide or tetraphenylphosphine bromide.

[0066] In some embodiments of the present invention, in the substitution reaction 2, the molar volume ratio of compound 1 to solvent is 0.2-2 mol / L; preferably 0.6-1.2 mol / L; for example 0.9 mol / L.

[0067] In some embodiments of the present invention, in the substitution reaction 2, the molar ratio of the bromocyclopentane and the compound 1 is (1-2):1; preferably (1-1.5):1; for example, 1.2:1.

[0068] In some embodiments of the present invention, in the substitution reaction 2, the molar ratio of the base to the compound 1 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1.

[0069] In some embodiments of the present invention, in the substitution reaction 2, the molar ratio of the phase transfer catalyst to the compound 1 is (0.02-0.3):1; preferably (0.05-0.15):1; for example, 0.1:1.

[0070] In some embodiments of the present invention, the substitution reaction 2 is carried out in an inert gas environment; preferably, it is carried out under nitrogen.

[0071] In some embodiments of the present invention, the temperature of the substitution reaction 2 is a conventional reaction temperature for such reactions in the art; preferably 60-100°C. o C; more preferably 90-100 o C; for example, 100 o C.

[0072] In some embodiments of the present invention, the duration of the substitution reaction 2 is the conventional reaction time for such reactions in the art, typically ending when the raw materials disappear or the product no longer increases; preferably 3-12 h; more preferably 4-8 h; for example 6 h.

[0073] In some embodiments of the present invention, the substitution reaction 2 further includes the following post-processing steps: cooling to room temperature, adding saturated ammonium chloride to quench the reaction, then adding water and ethyl acetate, stirring and separating the liquid, extracting the aqueous phase with ethyl acetate, combining the organic layers and washing with water and saturated sodium chloride in sequence to remove the solvent and obtain the crude product, and then performing column chromatography with ethyl acetate and n-hexane to obtain compound 2.

[0074] This invention provides a method for preparing compound 2, which includes the following steps:

[0075] In a solvent and in the presence of a base, compound 1 undergoes a substitution reaction 2 with bromocyclopentane to generate compound 2.

[0076] .

[0077] In some embodiments of the present invention, the reaction conditions for the substitution reaction 2 are as described above.

[0078] The present invention provides a method for preparing compound 3, which includes the following steps: in a solvent, compound 2 undergoes an aminolysis reaction with dimethylamine to generate compound 3;

[0079] .

[0080] In some embodiments of the present invention, the reaction conditions for the aminolysis reaction are as described above.

[0081] The present invention provides a method for preparing compound 6, which includes the following steps: in a solvent, in the presence of a base and a phase transfer catalyst, compound 4 and compound 5 undergo a substitution reaction 1 to generate compound 6;

[0082] .

[0083] In some embodiments of the present invention, the reaction conditions for substitution reaction 1 are as described above.

[0084] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0085] The reagents and raw materials used in this invention are all commercially available.

[0086] This invention has one or more of the following positive and progressive effects:

[0087] (1) Simple operation with few steps;

[0088] (2) The reaction conditions are mild;

[0089] (3) Raw materials are inexpensive and readily available;

[0090] (4) Avoid using precious metal catalysts;

[0091] (5) Suitable for large-scale production;

[0092] (6) High total yield. Detailed Implementation

[0093] The present invention will be further described in detail below with reference to specific embodiments. However, the scope of protection of the present invention is not limited to these embodiments. All variations and advantages that can be conceived by those skilled in the art without departing from the subject matter and scope of the invention are included in the present invention and are protected by the appended claims. The processes, conditions, reagents, experimental methods, etc., for carrying out the present invention, except as specifically mentioned below, are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations.

[0094] In addition, the purity of the product was determined by HPLC (area normalization method).

[0095] Example 1: Preparation of methyl 7-cyclopentyl-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (compound 2)

[0096] Under nitrogen atmosphere, methyl 2-(methylthioalkyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (compound 1) (1.0 mmol, 223.3 mg), potassium carbonate (1.5 mmol, 207.3 mg), and bromocyclopentane (1.2 mmol, 178.8 mg) were added sequentially to the reaction vessel, followed by anhydrous DMF (1.1 mL). The mixture was heated to 100 °C and stirred for 6 hours. The reaction was cooled to room temperature, and 3.0 mL of saturated ammonium chloride was added to quench the reaction. Subsequently, 3.0 mL of water and 6.0 mL of ethyl acetate were added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (5.0 x 2 mL), and the combined organic layers were washed sequentially with water (10.0 x 2 mL) and saturated sodium chloride (20.0 mL). The solvent was removed by rotational evaporation to obtain the crude product. Column chromatography with ethyl acetate and n-hexane gave compound 2 (201.0 mg, 69% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3): 8.86 (s, 1H), 7.06 (s, 1H), 4.88-4.76 (m, 1H), 3.90 (s, 3H), 2.62 (s, 3H), 2.51-2.40 (m, 2H), 2.06-2.00 (m,4H), 1.71-1.68 (m,2H).

[0097] Example 2: Preparation of methyl 7-cyclopentyl-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (compound 2)

[0098] Under nitrogen atmosphere, methyl 2-(methylthioalkyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (compound 1) (100 mmol, 22.3 g), potassium carbonate (150 mmol, 20.7 g), TBAB (10 mmol, 3.2 g), and bromocyclopentane (120 mmol, 17.8 g) were added sequentially to the reaction vessel, followed by anhydrous DMF (110 mL). The mixture was heated to 100 °C and stirred for 6 hours. The reaction was then cooled to room temperature, and 100 mL of saturated ammonium chloride was added to quench the reaction. Subsequently, 300 mL of water and 300 mL of ethyl acetate were added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (100 x 2 mL), and the combined organic layers were washed sequentially with water (100 x 2 mL) and saturated sodium chloride (200 mL). The solvent was removed by rotary evaporation to obtain the crude product. Recrystallization from ethyl acetate and n-hexane gave compound 2 as a yellow solid (26.5 g, yield 91%, purity 99.1%). 1H NMR (400 MHz, CDCl3): 8.86 (s,1H), 7.06 (s, 1H), 4.88-4.76 (m, 1H), 3.90 (s, 3H), 2.62 (s, 3H), 2.51-2.40(m, 2H), 2.06-2.00 (m, 4H), 1.71-1.68 (m, 2H).

[0099] Example 3: Preparation of 7-cyclopentyl-N,N-dimethyl-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (compound 3)

[0100] Compound 2 (91 mmol, 26.5 g) was added to the reaction vessel, followed by 20 mL of methanol. The vessel was then cooled to approximately 0°C using an ice bath, and a dimethylamine methanol solution was added. (50 mL, 2 M). The reaction was stirred at room temperature for 16 h after natural heating, then stopped and concentrated under reduced pressure to obtain the crude product. Tetrahydrofuran was added to the crude product and the mixture was slurried to give a pale yellow solid compound 3 (24.4 g, yield 88%, purity 98.9%). 1 H NMR (400 MHz, CDCl3): 8.74 (s, 1H), 6.45 (s, 1H), 4.85-4.76 (m, 1H), 3.14 (d, J = 16.0 Hz, 6H), 2.61 (s, 3H), 2.54-2.45 (m, 2H), 2.09-2.02 (m, 4H), 1.69-1.67 (m, 2H).

[0101] Example 4: Preparation of 7-cyclopentyl-N,N-dimethyl-2-(methanesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (compound 4)

[0102] Compound 3 (80 mmol, 24.4 g) and 250 mL of acetonitrile were added to a reaction flask, and stirring was started. Potassium persulfate double salt (400 mmol, 123.0 g) dissolved in 250 mL of water was added dropwise while maintaining a temperature <15 °C. After the addition was complete, the temperature was naturally raised to room temperature, and the reaction continued for approximately 5 h. The reaction was stopped, and the acetonitrile was removed by concentration under reduced pressure. The mixture was extracted with ethyl acetate (50 x 3 mL), and the organic layers were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Tetrahydrofuran and n-hexane were added to the crude product, and recrystallization gave compound 4 (25.6 g, 95% yield, 99.5% purity), a yellow solid. 1H NMR (400 MHz, CDCl3): 8.74(s, 1H), 6.45 (s, 1H), 4.85-4.76 (m, 1H), 3.12 (s, 6H), 2.97 (s, 3H), 2.54-2.45 (m, 2H), 2.09-2.02 (m, 4H), 1.69-1.67 (m, 2H).

[0103] Example 5: Preparation of reboxil

[0104] Compound 4 (76 mmol, 25.6 g), cesium carbonate (114 mmol, 37.1 g), TBAB (7.6 mmol, 2.5 g), and 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (compound 5) (114 mmol, 31.7 g) were added sequentially to the reaction flask, followed by 180 mL of DMF. The mixture was heated to 100 °C and reacted for approximately 24 h. After cooling to room temperature, 200 mL of water and ethyl acetate were added, respectively. The mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (50 x 3 mL). The combined organic layers were washed sequentially with water (50 x 2 mL) and saturated sodium chloride (100 mL). The solvent was removed by rotary evaporation to obtain compound 6. 200 mL of toluene was added, stirring was started, and hydrochloric acid solution (5.0 M, 76 mL) was added dropwise. The reaction was continued with stirring at room temperature for two hours. The pH was adjusted to approximately 7 using saturated sodium hydroxide solution, and the extract was extracted with ethyl acetate (100 x 3 mL). The organic layers were combined and washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from ethyl acetate and n-hexane, filtered, and the filter cake was dried under vacuum to obtain a pale yellow solid, reboxil (26.8 g, two-step yield 81%, purity 99.6%). 1 H NMR (400 MHz, CDCl3): 8.69 (s, 1H), 8.36-8.34 (d, J = 8.0 Hz, 1H), 8.01-8.00 (m, 1H), 7.84 (s, 1H), 7.34-7.31 (m, 1H), 6.44 (s, 1H), 4.81-4.75 (m, 1H), 3.16-3.06 (m, 14H), 2.59-2.57 (m, 2H), 2.09-2.03 (m, 4H), 1.70-1.64 (m, 2H), 1.25 (s, 1H).

[0105] Example 6: Preparation of Compound 6

[0106] Compound 4 (1.0 mmol, 336.4 mg), cesium carbonate (1.5 mmol, 488.7 mg), TBAB (0.1 mmol, 32.2 mg), and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (compound 5) (1.5 mmol, 417.5 mg) were added sequentially to the reaction flask, followed by 5 mL of DMF. The mixture was heated to 100 °C and reacted for approximately 24 h. After cooling to room temperature, 10 mL of water and ethyl acetate were added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (10 x 3 mL). The combined organic layers were washed sequentially with water (10 x 2 mL) and saturated sodium chloride (10 mL). The solvent was removed by rotary evaporation to obtain the crude product, which was then subjected to column chromatography (dichloromethane / methanol = 50 / 1 to 20 / 1) to give the brownish-yellow solid product compound 6 (475.9 mg, yield 89%).

[0107] Example 7: Preparation of Compound 6

[0108] Compound 4 (1.0 mmol, 336.4 mg), potassium carbonate (1.5 mmol, 207.3 mg), TBAB (0.1 mmol, 32.2 mg), and 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (compound 5) (1.5 mmol, 417.5 mg) were added sequentially to the reaction flask, followed by 5 mL of DMF. The mixture was heated to 100 °C and reacted for approximately 24 h. After cooling to room temperature, 10 mL of water and ethyl acetate were added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (10 x 3 mL). The combined organic layers were washed sequentially with water (10 x 2 mL) and saturated sodium chloride (10 mL). The solvent was removed by rotary evaporation to obtain the crude product, which was then subjected to column chromatography (dichloromethane / methanol = 50 / 1 to 20 / 1) to give the brownish-yellow solid product compound 6 (363.6 mg, yield 68%).

[0109] Comparative Example 1: Preparation of Compound 6

[0110] Under nitrogen protection, tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid (compound 5) (3.0 mmol, 835.1 mg) and 10 mL of anhydrous THF were added sequentially to the reaction flask. The mixture was then cooled to 0 °C, and LiHMDS (3.6 mmol, 3.6 mL) was added dropwise. After the addition was complete, the reaction was stirred for 0.5 h. Then, compound 4 (1.0 mmol, 336.4 mg) was added, and the mixture was allowed to warm naturally to room temperature for approximately 4 h. Once the temperature stabilized, 10 mL of saturated ammonium chloride solution was added to quench the reaction. 10 mL of ethyl acetate was added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (10 x 2 mL). After combining the organic layers, the solvent was removed by rotary evaporation to obtain the crude product. Column chromatography (dichloromethane / methanol = 50 / 1 to 20 / 1) yielded the brownish-yellow solid product compound 6 (251.3 mg, 47% yield).

[0111] Comparative Example 2: Preparation of Compound 6

[0112] Compound 4 (1.0 mmol, 336.4 mg), potassium carbonate (1.5 mmol, 207.3 mg), and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (compound 5) (1.5 mmol, 417.5 mg) were added sequentially to the reaction flask, followed by 5 mL of DMF. The mixture was heated to 100 °C and reacted for approximately 24 h. After cooling to room temperature, 10 mL of water and ethyl acetate were added, and the mixture was stirred and separated. The aqueous phase was extracted with ethyl acetate (10 x 3 mL). The combined organic layers were washed sequentially with water (10 x 2 mL) and saturated sodium chloride (10 mL). The solvent was removed by rotation to obtain the crude product, which was then subjected to column chromatography (dichloromethane / methanol = 50 / 1 to 20 / 1) to give the brownish-yellow solid product compound 6 (208.5 mg, yield 39%).

Claims

1. A method for preparing reboxil, comprising the following steps: ； (1) In a solvent, in the presence of a base and a phase transfer catalyst, compound 4 and compound 5 undergo a substitution reaction 1 to generate compound 6; (2) In a solvent, in the presence of an acid, compound 6 undergoes a protecting group removal reaction to give reboxil.

2. The preparation method according to claim 1, characterized in that, Meet one or more of the following conditions: (1) In the substitution reaction 1, the solvent is selected from one or more of ether solvents, amide solvents, sulfoxide solvents and aromatic solvents; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane; the amide solvent is preferably N,N-dimethylformamide or N,N-dimethylacetamide; the sulfoxide solvent is preferably dimethyl sulfoxide; the aromatic solvent is preferably toluene; (2) In the substitution reaction 1, the base is an inorganic base or an organic base; the inorganic base is preferably an alkali metal carbonate, an alkali metal phosphate, or an alkali metal hydride; more preferably potassium carbonate, cesium carbonate, potassium phosphate, or sodium hydride; for example, potassium carbonate or cesium carbonate; the organic base is preferably potassium tert-butoxide, n-butyllithium, diisopropylaminolithium, bis(trimethylsilylaminolithium), 1,8-diazacyclo[5,4,0]undecene-7, or tetramethylguanidine; (3) In the substitution reaction 1, the phase transfer catalyst is a quaternary ammonium salt phase transfer agent or a quaternary phosphate salt phase transfer agent; the quaternary ammonium salt phase transfer agent is preferably tetrabutylammonium halide; more preferably tetra-n-butylammonium iodide, tetra-n-butylammonium bromide or tetra-n-butylammonium chloride; for example, tetra-n-butylammonium bromide; the quaternary phosphate salt phase transfer catalyst is preferably triphenylmethylphosphine halide or tetraphenylphosphine halide; for example, triphenylmethylphosphine bromide or tetraphenylphosphine bromide; (4) In the substitution reaction 1, the molar volume ratio of compound 4 to the solvent is 0.1-1 mol / L; preferably 0.2-0.6 mol / L; for example, 0.2 mol / L or 0.4 mol / L; (5) In the substitution reaction 1, the molar ratio of compound 5 and compound 4 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1; (6) In the substitution reaction 1, the molar ratio of the base to the compound 4 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1; (7) In the substitution reaction 1, the molar ratio of the phase transfer catalyst to the compound 4 is (0.02-0.3):1; preferably (0.05-0.15):1; for example, 0.1:1; (8) The temperature of the substitution reaction 1 is 0-120°C. o C; preferably 90-110 o C; for example, 100 o C; (9) The duration of the substitution reaction 1 is 12-48 h; preferably 18-30 h; for example, 24 h; (10) The substitution reaction 1 further includes the following post-processing steps: after the reaction is completed, cool to room temperature, add water and ethyl acetate respectively, stir and separate the liquid, extract the aqueous phase with ethyl acetate, combine the organic layers and wash with water and saturated sodium chloride in sequence to remove the solvent, and obtain compound 6. Preferably, in the substitution reaction 1, the base is an inorganic base; when the base is an inorganic base, the solvent is preferably an amide solvent or a sulfoxide solvent; more preferably N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; for example, N,N-dimethylformamide.

3. The preparation method according to claim 1, characterized in that, Meet one or more of the following conditions: (1) In the protecting group removal reaction, the solvent is selected from one or more of the following: haloalkanes, esters, ketones, alcohols, ethers, aromatics, and nitriles; the haloalkanes are preferably dichloromethane, the esters are preferably ethyl acetate, the ketones are preferably acetone, the alcohols are preferably methanol or ethanol, the ethers are preferably tetrahydrofuran or 1,4-dioxane, the aromatics are preferably toluene, and the nitriles are preferably acetonitrile; preferably haloalkanes, esters, or aromatics, and preferably dichloromethane, ethyl acetate, or toluene; (2) In the protecting group removal reaction, the acid is hydrochloric acid, hydrobromic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid; preferably hydrochloric acid or trifluoromethanesulfonic acid; more preferably, the hydrochloric acid is added in the form of a 5M hydrochloric acid solution; (3) In the protecting group removal reaction, the acid is added dropwise; (4) In the protecting group removal reaction, the molar volume ratio of compound 6 to the solvent is 0.1-1 mol / L; preferably 0.2-0.6 mol / L; for example, 0.4 mol / L; (5) In the protecting group removal reaction, the molar ratio of the acid to the compound 6 is (2-8):1; preferably (4-6):1; for example, 5:1; (6) The temperature of the protecting group removal reaction is 0-60°C. o C; preferably 10-40 o C; for example, 20-30 o C; (7) The time for the removal of the protecting group is 0.5-6 h; preferably 1-3 h; for example, 2 h; (8) The protecting group removal reaction further includes the following post-processing steps: adjusting the pH to 7±0.5 with saturated sodium hydroxide solution, extracting with ethyl acetate, combining the organic layers, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product, recrystallizing the crude product with ethyl acetate and n-hexane, filtering, and drying the filter cake under vacuum to obtain reboxil; Preferably, the preparation method satisfies one or two of the following conditions: (1) In the protecting group removal reaction, the molar volume ratio of compound 4 to the solvent is 0.1-1 mol / L; preferably 0.2-0.6 mol / L; for example, 0.4 mol / L; (2) In the protecting group removal reaction, the molar ratio of the acid and the compound 4 is (2-8):1; preferably (4-6):1; for example, 5:

1.

4. The preparation method according to claim 1, characterized in that, The method for preparing ripocid includes the following steps: in a solvent, in the presence of an oxidizing agent, compound 3 undergoes an oxidation reaction to generate compound 4; ； Preferably, the preparation method satisfies one or more of the following conditions: (1) In the oxidation reaction, the solvent is an alcohol solvent, an ether solvent, an amide solvent, a sulfoxide solvent, or a nitrile solvent; the alcohol solvent is preferably methanol or ethanol, the ether solvent is preferably tetrahydrofuran or 1,4-dioxane, the amide solvent is preferably N,N-dimethylformamide or N,N-dimethylacetamide, the sulfoxide solvent is preferably dimethyl sulfoxide, and the nitrile solvent is preferably acetonitrile; preferably, the solvent is a nitrile solvent; (2) In the oxidation reaction, the oxidant is potassium persulfate double salt; the potassium persulfate double salt is preferably added in the form of an aqueous solution; the volume ratio of water to solvent is preferably 1:1; preferably, the aqueous solution is added dropwise; the temperature at which the aqueous solution is added is preferably 0-15 ℃. (3) In the oxidation reaction, the molar volume ratio of compound 3 to solvent is 0.1-1 mol / L; preferably 0.2-0.5 mol / L; for example, 0.32 mol / L; (4) In the oxidation reaction, the molar ratio of the oxidant to the compound 3 is (2-8):1; preferably (4-6):1; for example, 5:1; (5) The temperature of the oxidation reaction is 0-40°C. o C; preferably 0-25 ℃; (6) The oxidation reaction takes 2-12 h; preferably 4-6 h; for example 5 h; (7) The oxidation reaction also includes the following post-processing steps: acetonitrile is removed by vacuum concentration, extracted with ethyl acetate, the organic layers are combined, washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product; tetrahydrofuran and n-hexane are added to the crude product for recrystallization to obtain compound 4.

5. The preparation method according to claim 4, characterized in that, The method for preparing reboxil also includes The process includes the following steps: In a solvent, compound 2 undergoes an aminolysis reaction with dimethylamine to generate compound 3; ； Preferably, the preparation method satisfies one or more of the following conditions: (1) In the aminolysis reaction, the solvent is selected from one or more of the following: haloalkanes, esters, ketones, alcohols, ethers, amides, sulfoxides, and nitriles; the haloalkanes are preferably dichloromethane, the esters are preferably ethyl acetate, the ketones are preferably acetone, the alcohols are preferably methanol or ethanol, the ethers are preferably tetrahydrofuran or 1,4-dioxane, the amides are preferably N,N-dimethylformamide or N,N-dimethylacetamide, the sulfoxides are preferably dimethyl sulfoxide, and the nitriles are preferably acetonitrile; preferably an alcohol, such as methanol or ethanol. (2) In the aminolysis reaction, the dimethylamine is added in the form of a dimethylamine methanol solution; the dimethylamine methanol solution is preferably a 2M dimethylamine methanol solution; more preferably, the temperature of the dimethylamine methanol solution is controlled at 0-10°C. o C is added; (3) In the aminolysis reaction, the molar volume ratio of compound 2 to the solvent is 0.5-3 mol / L; preferably 1-2 mol / L; for example, 1.3 mol / L; (4) In the aminolysis reaction, the molar ratio of the dimethylamine and the compound 2 is (1-2):1; preferably (1-1.5):1; for example, 1.1:1; (5) The temperature of the aminolysis reaction is 0-40°C. o C; preferably 20-30 o C; (6) The time for the aminolysis reaction is 8-32 h; preferably 12-20 h; for example, 16 h; (7) The aminolysis reaction further includes the following post-processing steps: concentrating to obtain a crude product, adding tetrahydrofuran to the crude product and slurrying to obtain compound 3.

6. The preparation method according to claim 5, characterized in that, The method for preparing ribocidide further includes the following steps: in a solvent, in the presence of a base, compound 1 undergoes a substitution reaction 2 with bromocyclopentane to generate compound 2; ； Preferably, the preparation method satisfies one or more of the following conditions: (1) In the substitution reaction 2, the solvent is selected from one or more of ether solvents, nitrile solvents, amide solvents, sulfoxide solvents and aromatic solvents; the ether solvent is preferably tetrahydrofuran or 1,4-dioxane, the nitrile solvent is preferably acetonitrile, the amide solvent is preferably N,N-dimethylformamide or N,N-dimethylacetamide, the sulfoxide solvent is preferably dimethyl sulfoxide, and the aromatic solvent is preferably toluene; preferably, the solvent is an amide solvent or an ether solvent, preferably N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, more preferably N,N-dimethylformamide; (2) In the substitution reaction 2, the base is an inorganic base or an organic base; the inorganic base is preferably an alkali metal carbonate, an alkali metal phosphate, or an alkali metal hydride; more preferably potassium carbonate, cesium carbonate, potassium phosphate, or sodium hydride; the organic base is preferably potassium tert-butoxide, n-butyllithium, diisopropylaminolithium, bis(trimethylsilylaminolithium), triethylamine, N,N-diisopropylethylamine, 1,8-diazacyclo[5,4,0]undecene-7, pyridine, piperidine, quinoline, or tetramethylguanidine; preferably, the base is an inorganic base; preferably potassium carbonate or cesium carbonate; for example, potassium carbonate; (3) In the substitution reaction 2, the molar volume ratio of compound 1 to solvent is 0.2-2 mol / L; preferably 0.6-1.2 mol / L; for example, 0.9 mol / L; (4) In the substitution reaction 2, the molar ratio of the bromocyclopentane and the compound 1 is (1-2):1; preferably (1-1.5):1; for example, 1.2:1; (5) In the substitution reaction 2, the molar ratio of the base to the compound 1 is (1-2):1; preferably (1.2-1.8):1; for example, 1.5:1; (6) In the substitution reaction 2, the molar ratio of the phase transfer catalyst to the compound 1 is (0.02-0.3):1; preferably (0.05-0.15):1; for example, 0.1:1; (7) The substitution reaction 2 is carried out in an inert gas environment; preferably under nitrogen. (8) The temperature of the substitution reaction 2 is 60-100°C. o C; preferably 90-100 o C; for example, 100 o C; (9) The duration of the substitution reaction 2 is 3-12 h; more preferably 4-8 h; for example 6 h; (10) The substitution reaction 2 further includes the following post-processing steps: cooling to room temperature, adding saturated ammonium chloride to quench the reaction, then adding water and ethyl acetate, stirring and separating the liquid, extracting the aqueous phase with ethyl acetate, combining the organic layers and washing with water and saturated sodium chloride in sequence, removing the solvent to obtain the crude product, and then performing column chromatography with ethyl acetate and n-hexane to obtain compound 2.

7. The preparation method according to claim 6, characterized in that, In the substitution reaction 2, when the base is an inorganic base, the substitution reaction is carried out in the presence of a phase transfer catalyst; the phase transfer catalyst is a quaternary ammonium salt phase transfer agent or a quaternary phosphate salt phase transfer agent; the quaternary ammonium salt phase transfer agent is preferably tetrabutylammonium halide; more preferably tetra-n-butylammonium iodide, tetra-n-butylammonium bromide or tetra-n-butylammonium chloride; for example, tetra-n-butylammonium bromide; the quaternary phosphate salt phase transfer catalyst is preferably triphenylmethylphosphine halide or tetraphenylphosphine halide; for example, triphenylmethylphosphine bromide or tetraphenylphosphine bromide.

8. A method for preparing compound 2, comprising the following steps: In a solvent and in the presence of a base, compound 1 undergoes a substitution reaction 2 with bromocyclopentane to generate compound 2. ； Preferably, the reaction conditions for the substitution reaction 2 are as described in claim 6 or 7.

9. A method for preparing compound 3, comprising the following steps: In a solvent, compound 2 undergoes an aminolysis reaction with dimethylamine to generate compound 3; ； Preferably, the reaction conditions for the aminolysis reaction are as described in claim 5.

10. A method for preparing compound 6, comprising the following steps: In a solvent, in the presence of a base and a phase transfer catalyst, compound 4 undergoes a substitution reaction 1 with compound 5 to generate compound 6; ； Preferably, the reaction conditions for the substitution reaction 1 are as described in claim 2.

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