Method for preparing abelsilib

Abstract

The invention relates to a method for preparing abesilib. The method comprises the following process steps: Miyaura boric acid esterification reaction, Suzuki coupling reaction, substitution, Buchwald-Hartwisting coupling reaction and crystal transformation. The invention provides a novel process synthesis route which is mild in reaction condition, simple to operate, environment-friendly, high in yield and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of raw material drug synthesis and intermediate synthesis, and in particular to a method for preparing abemaciclib. Background Art

[0002] At present, the incidence and mortality of breast cancer in women in the world rank second and third respectively; in my country, breast cancer is the malignant tumor with the highest incidence and fourth highest mortality rate among women, which also means that more and more effective therapeutic drugs are needed for the treatment of breast cancer.

[0003] Abemaciclib is a highly specific dual inhibitor of cell cycle-dependent kinase (CDK4 / 6). It can restore cell cycle control and block tumor cell proliferation by selectively inhibiting cyclin-dependent kinase CDK4 / 6. Its single drug has significant therapeutic effects on metastatic breast cancer. It was granted "Breakthrough Therapy" certification by the US FDA in October 2015, approved for marketing by the US FDA in September 2017, and approved for marketing in my country in 2020. Clinical research results show that abemaciclib is the first and currently the only CDK4 / 6 inhibitor that has achieved prolonged progression-free survival (PFS) in mainly Chinese patients. The launch of this drug can benefit many domestic patients. It is currently being developed for the treatment of various cancers, clinical research is progressing smoothly, and the market prospects are broad.

[0004] There are many literature reports on the synthesis method of Abemaciclib. Patent WO2010075074 uses compound 1 and compound 2 as starting materials, prepares compound 3 by reductive amination reaction, and then reacts with ammonia to obtain compound 4. Compound 5 is dehydrated and condensed under the action of phosphorus oxychloride and triethylamine, and cyclized under the action of potassium tert-butoxide to obtain compound 7, which is then reacted with bis-pennanoyl borate under the action of palladium acetate and cyclohexylphosphine to generate the corresponding compound 8. The borate compound and 2,4-dichloro-5-fluoropyrimidine undergo Suzuki reaction under palladium catalysis to obtain intermediate compound 9. The obtained intermediate compound 4 and compound 9 are reacted with transition metal catalyst tris(dibenzylideneacetone)dipalladium, ligand 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene and cesium carbonate to obtain Abemaciclib. The reaction route is as follows: Figure 1 shown.

[0005] This route is a method of gradually adding functional groups, so there are many reaction steps. In particular, the preparation of compound 9 and its target product often uses precious metal palladium catalysts and other special ligands, making the preparation cost difficult to control. At the same time, in the preparation process of intermediate compound 9 and the target product, there are many situations where "several active functional groups compete for a reaction at the same time", such as the two chlorine atoms and one fluorine atom on the pyrimidine ring in the Suzuki reaction, and one chlorine atom and two fluorine atoms in the intermediate compound 9 in the last step of condensation coupling, which will produce potential side reactions due to poor selectivity, thereby affecting the quality and yield of the product.

[0006] Patent CN110218189 reported that compound 2 was prepared by substitution reaction of compound 1 and isopropylamine, such as Figure 2 As shown, the compound undergoes hydrogenation reduction reaction and cyclization reaction to obtain compound 3, and then undergoes addition reaction with Grignard reagent fluoromethyl magnesium halide to obtain compound 4. In the presence of a base catalyst, compound 4 and N, N-dimethylformamide dimethyl acetal are condensed to obtain compound 5. The intermediate reacts with compound 6 to prepare abemaciclib.

[0007] This route improves the synthesis of compound 5 on the CN104529904 route. The intermediate compound 5 has been patented in China and has been authorized, which cannot be circumvented. The second step reaction conversion rate is low, and the third step uses a fluorine-containing Grignard reagent with a low conversion rate. The material cost of the entire route is high. Summary of the invention

[0008] In view of this, the object of the present invention is to provide a synthetic method for preparing abemaciclib to solve one or more of the above-mentioned prior art problems.

[0009] To achieve the above object, the present invention provides a method for preparing abemaciclib, comprising the following steps:

[0010] Under a nitrogen atmosphere, stir toluene, add compound e, compound i, potassium carbonate, tert-amyl alcohol, XantPhos, replace with nitrogen three times, add Pd2(dba)3, heat to 100-110°C, keep warm for 4h±10mins, monitor the reaction of the raw materials by TLC, cool to 60-70°C, add water, separate the layers, collect the organic phase, concentrate, precipitate the solid, filter to obtain the product, dry in vacuo at 50-60°C for 8h, and obtain the abemaciclib;

[0011] Wherein, the structural formula of the compound e is as follows:

[0012]

[0013] The structural formula of the compound i is as follows:

[0014]

[0015] In some embodiments, the compound i is obtained by the following steps: stirring water under nitrogen atmosphere, adding sodium carbonate, stirring at 20-30°C to dissolve, adding toluene, compound h and bistriphenylphosphine palladium dichloride; heating to 70-80°C, dripping a toluene ethanol solution of compound g, and completing the dripping after 2-3 hours; keeping at 70-80°C for 2h±5mins, and monitoring the complete reaction of the raw materials by TLC. Cooling to 65-70°C, standing, separating, adding toluene to the aqueous phase, extracting, combining the organic phases, cooling to 30-40°C, precipitating a solid, filtering, and vacuum drying at 50-60°C for 8h to obtain the compound i;

[0016] Wherein, the structural formula of the compound h is as follows:

[0017]

[0018] The structural formula of the compound g is as follows:

[0019]

[0020] In some embodiments, the compound g is obtained by the following steps: stirring toluene under a nitrogen atmosphere, adding compound f, biphenylphosphine palladium dichloride and diboric acid pinacol ester and potassium acetate; replacing with nitrogen three times, adding bistriphenylphosphine palladium dichloride; heating to 100-110° C., keeping the temperature for reaction for 12 h±10 mins, monitoring by TLC, and when the raw materials react completely, cooling to 20-30° C., filtering, adding ethanol, stirring at 20-30° C. for 30±5 mins for standby use, to obtain a solution of compound g;

[0021] The structural formula of the compound f is as follows:

[0022]

[0023] In some embodiments, the compound e is obtained by the following steps:

[0024] Under a helium atmosphere, mix sodium carbonate and water, add compound b and compound a, raise the temperature to 60-70°C, keep the temperature for 4h±10mins, and monitor the complete reaction of the raw materials by TLC. Cool down to 30-40°C, concentrate under reduced pressure until no obvious liquid flows out, cool down to 25-35°C, add toluene, separate the liquids, add toluene to the aqueous phase for extraction, combine the organic phases, and concentrate under reduced pressure until no obvious liquid flows out to obtain compound c;

[0025] Toluene was added to the compound c, and the mixture was stirred under a nitrogen atmosphere. A THF solution of RuPhos and LiHMDS was added, and the mixture was replaced with nitrogen three times. The oxygen content was detected by an oxygen content detector to be below 500 ppm. Pd(PhCN)2Cl2 was quickly added, and the mixture was heated to 70-80°C and kept warm for reaction for 2h±5mins. After TLC monitoring, the reaction of the raw materials was complete. The mixture was cooled to 25-35°C, and an aqueous sodium sulfite solution was added dropwise. The temperature was controlled at 25-35°C until the addition was complete. The mixture was stirred for 30±5mins, and the mixture was allowed to stand for separation. Toluene was added to the aqueous phase for extraction, and the organic phases were combined to obtain a compound d.

[0026] Add methanol to the organic phase compound d, replace with nitrogen three times, heat to 65-70°C, keep warm for reaction for 8h±10mins, monitor the reaction of the raw materials by GC, cool to 30-40°C, and concentrate under reduced pressure until no obvious liquid flows out; add ethyl acetate, heat to 65-70°C, stir to dissolve, add activated carbon, keep warm and stir for 1h±5mins; filter, cool to 30-40°C, concentrate under reduced pressure to 2-3V, heat to 70-80°C, keep warm and stir for 30±5smin, cool to 20-30°C, keep warm and stir for 30±5mins, filter, and vacuum dry at 50-60°C for 8h to obtain compound e;

[0027] Wherein, the structural formula of the compound a is as follows:

[0028]

[0029] The structural formula of the compound b is as follows:

[0030]

[0031] The structural formula of the compound C is as follows:

[0032]

[0033] The structural formula of the compound d is as follows:

[0034]

[0035] The structural formula of the compound e is as follows:

[0036]

[0037] Compared with the prior art, the beneficial effects of the present invention are:

[0038] The invention provides a novel process synthesis route with mild reaction conditions, simple operation, environmental friendliness, high yield and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 A synthetic route for preparing abemaciclib in the background technology of the present invention;

[0040] Figure 2 A synthetic route for preparing abemaciclib in the background technology of the present invention;

[0041] Figure 3 The present invention provides a synthetic route for preparing abemaciclib in one embodiment. DETAILED DESCRIPTION

[0042] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0043] Example:

[0044] Preparation of compound c:

[0045] Under nitrogen, sodium carbonate (21.26g, 0.65eq) and water (150.0g) were added to a 2000mL three-necked flask, and the mixture was stirred to dissolve. Compound b (42.3g, 1.2eq) and compound a (50.0g, 1.0eq) were added, and the temperature was raised to 60-70℃, and the reaction was kept warm for 4h±10mins. The reaction of the raw materials was monitored by TLC to be complete. The temperature was lowered to 30-40℃, and the mixture was concentrated under reduced pressure until no obvious liquid flowed out. The temperature was lowered to 25-35℃, and toluene (218g) was added, and the liquids were separated. The aqueous phase was extracted with 130.8g of quinoline (130.8g), and the organic phases were combined and concentrated under reduced pressure until no obvious liquid flowed out to obtain compound c.

[0046] Preparation of compound d:

[0047] Add toluene (305.20 g) to the reaction bottle of compound c in the previous step, stir under nitrogen, add RuPhos (2.19 g, 1.5% eq) and LiHMDS THF solution (300.45 g, 1.1 eq), replace with nitrogen three times, oxygen content is detected by oxygen content detector to be below 500 ppm, quickly add Pd(PhCN)2Cl2 (0.90 g, 0.75% eq), heat to 70-80°C, keep warm for 2h±5mins, TLC monitoring, the raw material reaction is complete; cool to 25-35°C, add 350.00 g sodium sulfite aqueous solution (350.0 g), control the temperature at 25-35°C, and add the solution in about 1 hour. Keep warm and stir for 30±5mins, let stand, separate, add toluene (190.0 g) to the aqueous phase for extraction, combine the organic phases to obtain compound d.

[0048] Preparation of compound e:

[0049] Add methanol (55.60g) to the organic phase, replace with nitrogen three times, heat to 65-70℃, keep warm for 8h±10mins, monitor the reaction of raw materials by GC, cool to 30-40℃, and concentrate under reduced pressure until no obvious liquid flows out. Add ethyl acetate (189.42g), heat to 65-70℃, stir to dissolve, add Egret activated carbon (3.51g), keep warm and stir for 1h±5mins; filter, cool to 30-40℃, concentrate under reduced pressure to 2-3V, heat to 70-80℃, keep warm and stir for 30±5smin, cool to 20-30℃, keep warm and stir for 30±5mins, filter, vacuum dry at 50-60℃ for 8h, and obtain product: 36.75g, yield: 54.0%.

[0050] Preparation of compound g:

[0051] Under nitrogen, add toluene (400.0 g) to a 1000 mL four-necked bottle, stir, add compound f (100.00 g, 1.0 eq), biboric acid pinacol ester (98.34 g, 1.05 eq) and potassium acetate (54.29 g, 1.5 eq). Replace with nitrogen three times, add bistriphenylphosphine palladium dichloride (3.11 g, 1.2% eq). Heat to 100-110°C, keep warm for 12h±10mins, monitor by TLC, the raw material reacts completely, cool to 20-30°C, filter, add ethanol (78.9 g), stir at 20-30°C for 30±5mins for standby use, and obtain a solution of compound g.

[0052] Preparation of compound i:

[0053] Under nitrogen, add water (300.0g) to a 2000mL four-necked bottle, stir, add sodium carbonate (78.18g, 2.0eq), stir at 20-30℃ until dissolved, add toluene (261.6g), compound h (86.2g, 1.4eq) and bistriphenylphosphine palladium dichloride (1.81g, 2.0%eq); heat to 70-80℃, dropwise add toluene ethanol solution of compound g, dropwise addition is completed in about 2-3h; keep at 70-80℃ for 2h±5mins, TLC monitors the reaction of the raw material, cool to 65-70℃, stand, separate, add toluene (174.4g) to the aqueous phase, extract, combine the organic phases, cool to 30-40℃, precipitate solids, filter, vacuum dry at 50-60℃ for 8h, obtain product: 90.3g, yield 88%.

[0054] Preparation of compound j:

[0055] Under nitrogen, add toluene (679.60g) to a 2000mL four-necked bottle, stir, add compound e (68.95g, 1.01eq), compound i (100.0g, 1.0eq), potassium carbonate (85.65g, 2.0eq), tert-amyl alcohol (80.50g), XantPhos (2.15g, 0.012eq), replace with nitrogen three times, add Pd2(dba)3 (1.70g, 0.006eq), heat to 100-110℃, keep warm for 4h±10mins, TLC monitors the complete reaction of the raw materials. Cool to 60-70℃, add water (300.0g), separate, collect the organic phase, concentrate to about 2 volumes, precipitate solid, filter to obtain the product, dry in vacuum at 50-60℃ for 8h, obtain product: 130.0g, yield: 82.8%.

[0056] The novel process synthesis route provided by the embodiment of the present invention has mild reaction conditions, simple operation, environmental friendliness, high yield, and is suitable for industrial production.

[0057] Finally, it should be noted that: technicians in this industry should understand that the present invention is not limited to the above-mentioned implementation cases. The above-mentioned embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which shall fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing abemaciclib, characterized in that: The following steps are involved: Under a nitrogen atmosphere, stir toluene, add compound e, compound i, potassium carbonate, tert-amyl alcohol, XantPhos, replace with nitrogen three times, add Pd2(dba)3, heat to 100-110°C, keep warm for 4h±10mins, monitor the reaction of the raw materials by TLC, cool to 60-70°C, add water, separate the layers, collect the organic phase, concentrate, precipitate the solid, filter to obtain the product, dry in vacuo at 50-60°C for 8h, and obtain the abemaciclib; Wherein, the structural formula of the compound e is as follows: The structural formula of the compound i is as follows:

2. The method according to claim 1, characterized in that The compound i is obtained by the following steps: stirring water under nitrogen atmosphere, adding sodium carbonate, stirring at 20-30°C to dissolve, adding toluene, compound h and bistriphenylphosphine palladium dichloride; heating to 70-80°C, dripping toluene ethanol solution of compound g, dripping for 2-3 hours; keeping at 70-80°C for 2h±5mins, monitoring the reaction of raw materials by TLC. Cooling to 65-70°C, standing, separating, adding toluene to the aqueous phase, extracting, combining the organic phases, cooling to 30-40°C, precipitating solids, filtering, and vacuum drying at 50-60°C for 8h to obtain the compound i; Wherein, the structural formula of the compound h is as follows: The structural formula of the compound g is as follows:

3. The method according to claim 2, characterized in that The compound g is obtained by the following steps: stirring toluene under a nitrogen atmosphere, adding compound f, bipyraclostrobin and potassium acetate; replacing with nitrogen three times, adding bistriphenylphosphine palladium dichloride; heating to 100-110° C., keeping the temperature for reaction for 12 h±10 mins, monitoring by TLC, cooling to 20-30° C., filtering, adding ethanol, stirring at 20-30° C. for 30±5 mins for standby use, and obtaining a solution of compound g; The structural formula of the compound f is as follows:

4. The method according to claim 1, characterized in that The compound e is obtained by the following steps: Under a helium atmosphere, mix sodium carbonate and water, add compound b and compound a, raise the temperature to 60-70°C, keep the temperature for 4h±10mins, and monitor the complete reaction of the raw materials by TLC. Cool down to 30-40°C, concentrate under reduced pressure until no obvious liquid flows out, cool down to 25-35°C, add toluene, separate the liquids, add toluene to the aqueous phase for extraction, combine the organic phases, and concentrate under reduced pressure until no obvious liquid flows out to obtain compound c; Toluene was added to the compound c, and the mixture was stirred under a nitrogen atmosphere. A THF solution of RuPhos and LiHMDS was added, and the mixture was replaced with nitrogen three times. The oxygen content was detected by an oxygen content detector to be below 500 ppm. Pd(PhCN)2Cl2 was quickly added, and the mixture was heated to 70-80°C and kept warm for reaction for 2h±5mins. After TLC monitoring, the reaction of the raw materials was complete. The mixture was cooled to 25-35°C, and an aqueous sodium sulfite solution was added dropwise. The temperature was controlled at 25-35°C until the addition was complete. The mixture was stirred for 30±5mins, and the mixture was allowed to stand for separation. Toluene was added to the aqueous phase for extraction, and the organic phases were combined to obtain a compound d. Add methanol to the organic phase compound d, replace with nitrogen three times, heat to 65-70°C, keep warm for reaction for 8h±10mins, monitor the reaction of the raw materials by GC, cool to 30-40°C, and concentrate under reduced pressure until no obvious liquid flows out; add ethyl acetate, heat to 65-70°C, stir to dissolve, add activated carbon, keep warm and stir for 1h±5mins; filter, cool to 30-40°C, concentrate under reduced pressure to 2-3V, heat to 70-80°C, keep warm and stir for 30±5smin, cool to 20-30°C, keep warm and stir for 30±5mins, filter, and vacuum dry at 50-60°C for 8h to obtain compound e; Wherein, the structural formula of the compound a is as follows: The structural formula of the compound b is as follows: The structural formula of the compound c is as follows: The structural formula of the compound d is as follows: The structural formula of the compound e is as follows:

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