A kind of synthetic method of abemaciclib

Abstract

The present invention relates to a method for synthesizing abemaciclib, comprising the following steps: (1) using a compound of formula III as a raw material, adding compounds of formula III-1 and formula II-1, water, a catalyst and a base, and obtaining a compound of formula I through post-treatment and purification; (2) dissolving the compounds of formula I and formula I-1 in a solvent, adding a base, and obtaining a compound abemaciclib; (3) dissolving abemaciclib in a solvent, adding methanesulfonic acid to form a salt, obtaining a crude methanesulfonate, and obtaining abemaciclib methanesulfonate after recrystallization in a solvent; the reaction equation is as follows: The present invention provides a method for synthesizing abemaciclib with low cost, low by-products, high conversion rate, economy and environmental protection, which reduces the use of heavy metal catalysts and phosphine ligands, realizes a two-step reaction by a one-step continuous reaction, reduces post-processing operations, and saves costs.

Description

Technical Field

[0001] The invention relates to a method for preparing abemaciclib mesylate and an intermediate thereof, and belongs to the field of pharmaceutical chemical industry. Background Art

[0002] Breast cancer is the most frequently diagnosed cancer in women and the leading cause of cancer death in women. Its morbidity and mortality rate are both among the top three. Among the numerous protein kinase studies, the study of cyclin-dependent kinase (CDKs) inhibitors is a hot area.

[0003] Abemaciclib (1), chemical name N-[5-[(4-ethyl-1-piperazine)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-1-(1-isopropyl)2-methyl-1H-benzimidazol-6-yl]-2-pyrimidinamine, is an oral effective cyclin-dependent kinase (CDKs) inhibitor developed by Eli Lilly and Company, USA. It targets the CDK4 / 6 cell cycle pathway and has good anti-tumor activity. The drug was approved for marketing by the US FDA on September 28, 2017 for the treatment of advanced or metastatic breast cancer. The trade name is Verzenio, the dosage form is tablets, and the dosage is 50, 100, 150 and 200 mg.

[0004] Eli Lilly's original patent WO2010075074A1 reported a synthesis method of abemaciclib. This route is a convergent route and is Eli Lilly's original research route used in production. It has eight steps and a total yield of 16.4%. The specific route is as follows:

[0005]

[0006] Although this method has readily available raw materials, mild reaction conditions, and low equipment requirements, high-boiling point solvents, heavy metal catalysts, and phosphine ligands are used multiple times in the reaction route, post-processing is difficult and cumbersome, and excessive solid waste and wastewater are generated, making it unsuitable for industrial scale-up production.

[0007] For its key intermediate 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine, existing patents disclose a variety of synthetic routes. The original research patent WO2010075074A1 discloses the following synthetic route:

[0008]

[0009] The synthetic route uses N-ethylpiperazine and 6-bromopyridine-3-carboxaldehyde as raw materials, and obtains 5-(4-ethylpiperazine-1-yl)methyl-2-bromopyridine through reductive amination, and then uses LiHMDS and catalyst Pd2(dba)3 catalyst or liquid ammonia and cuprous oxide to catalyze amination to prepare the compound 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine. Similarly, the synthetic route of the original patent has certain disadvantages. The raw material 6-nitropyridine-3-carboxylic acid used is expensive, the catalytic hydrogenation has high requirements for equipment, LiAlH4 reduction, expensive raw materials, anhydrous and oxygen-free reaction, high equipment requirements, complex operation, low yield, and is not suitable for industrial scale-up production.

[0010] Chinese patent CN108440401A discloses the synthesis route of the key intermediate 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine as follows:

[0011]

[0012] The synthetic route uses N-ethylpiperazine and 2-chloro-5-chloromethylpyridine as raw materials, and obtains the compound 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine through substitution reaction and ammonia water and cuprous oxide amination. Although the raw materials N-ethylpiperazine and 2-chloro-5-chloromethylpyridine used in this method are cheap and easy to obtain, the second step reaction requires high temperature and high pressure reaction, has high requirements for equipment, has strong irritation of ammonia water, low reaction yield, and many by-products, which is not suitable for industrial scale-up production.

[0013] Chinese patent CN 107337634A discloses the synthesis route of the key intermediate 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine as follows:

[0014]

[0015] The method uses butadiene nitrile and nitromethane as raw materials, obtains 5-nitro-4-nitromethyl-2,4-pentadiene nitrile through alkaline condensation, then reduces the nitro group through catalytic hydrogenation and cyclizes to obtain 2-amino-5-aminomethylpyridine, and finally, dehydrochlorination and condensation with N,N-dichloroethylethylamine under the action of alkali to obtain the compound 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine. The first step of the method uses nitromethane, which is easy to explode, and is dangerous to store and transport. In addition, the reaction requires high temperature (120°C) and high pressure, and the equipment requirements are high. The last step is the cyclization dehydrochlorination reaction, which has a long reaction time and water extraction during the post-treatment process. Since the product has good water solubility, the extraction treatment is difficult and is not suitable for industrial scale-up production.

[0016] WO2009 / 141386A1 discloses a method for synthesizing 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine:

[0017]

[0018] Using 6-aminonicotinic acid ethyl ester as raw material, Boc protection is first applied, then the ethyl ester is reduced to alcohol with LiAlH4, Ms is added, and then N-alkylation is carried out with N-ethylpiperazine, and finally Boc protection is removed to obtain the compound 5-(4-ethylpiperazin-1-yl)methyl-2-aminopyridine. This method not only has expensive raw materials, but also a long preparation route, which is not suitable for industrial scale-up production. In addition, the addition of protecting groups and then deprotection is not in line with atom economics.

[0019] In view of the deficiencies of the prior art, the present invention provides a method for synthesizing abemaciclib and its intermediates with low cost, low by-products, high conversion rate, economy and environmental protection. Summary of the invention

[0020] The present invention provides a method for synthesizing abemaciclib, which comprises the following steps:

[0021] (1) dissolving the compound of formula III, the compound of formula III-1 and a base in a solvent, adding a palladium catalyst, heating the reaction for a certain time, then adding the compound II-1, a base and a palladium catalyst, heating the reaction for a certain time, and post-treating to obtain a compound of formula I;

[0022] (2) in an organic solvent, the compound of formula I and the compound of formula I-1 are reacted under alkaline conditions for a certain period of time, and then post-treated to obtain the compound abemaciclib;

[0023] (3) dissolving the compound abemaciclib in an organic solvent, adding methanesulfonic acid to carry out a salt-forming reaction to obtain a crude product of abemaciclib mesylate, and then recrystallizing in a recrystallization solvent to obtain abemaciclib mesylate;

[0024] The reaction formula is as follows:

[0025]

[0026] Preferably, the base in step (1) is selected from potassium acetate, sodium carbonate, sodium hydroxide, potassium phosphate, cesium carbonate or potassium carbonate, preferably potassium acetate or sodium carbonate; and the palladium catalyst is selected from Pd(dppf)Cl2.DCM, Pd(dppf)Cl2, Pd2(dba)3 or Pd(PPh3)Cl2.

[0027] Preferably, the alkaline condition in step (2) is selected from potassium tert-butoxide, magnesium tert-butoxide, sodium methoxide, sodium hydride, sodium ethoxide or sodium hydroxide, preferably potassium tert-butoxide, sodium methoxide or sodium hydride.

[0028] More preferably, the step (1) is a one-step continuous reaction, and the reaction intermediate II is not subjected to a post-treatment purification step.

[0029] Further preferably, the solvent in step (1) is selected from one, two or more of dioxane, DMSO, DMF, water, toluene, benzene, methanol, ethanol, and acetonitrile; in terms of mL / g, the volume of the solvent is 3-20 times the mass of the compound of formula III; in terms of mol / mol, the amount of the compound of formula III-1 is 1.1-1.8 times the mass of the compound of formula III; in terms of mol / mol, the amount of the compound of formula II-1 is 1.1-1.6 times the mass of the compound of formula III; in terms of mol / mol, the amount of palladium catalyst is 0.08-0.50 times the mass of the compound of formula III; the reaction temperature is 20°C to 130°C; the reaction time is 4-30 hours;

[0030] The organic solvent in step (2) is selected from methanol, acetonitrile, DMF, tetrahydrofuran, dioxane, toluene, benzene, methanol, ethanol or DMSO; the volume of the organic solvent is 1-30 times the mass of the compound of formula I in mL / g; the base is 1.1-2.3 times the mass of the compound of formula I in mol / mol; the amount of the compound of formula I-1 is 0.9-1.5 times the mass of the compound of formula I in mol / mol; the reaction temperature is -20°C to 120°C; the reaction time is 2-24 hours;

[0031] The organic solvent or recrystallization solvent in step (3) is selected from one, two or more of dichloromethane, methanol, acetone, methyl tert-butyl ether, n-hexane, n-heptane, acetonitrile and dioxane; in terms of mL / g, the volume of the organic solvent in the salt-forming reaction is 3-15 times the mass of abemaciclib; in terms of mol / mol, the amount of methanesulfonic acid is 1.1-1.8 times the mass of abemaciclib; the reaction time is 0.5-6h; in terms of mL / g, the volume of the recrystallization solvent in the recrystallization step is 3-20 times the mass of abemaciclib; the crystallization temperature is -10°C-20°C, and the crystallization time is 1-6h.

[0032] Further preferably, the method comprises the following steps:

[0033] (1) dissolving the compound of formula III and the compound of formula III-1 in a solvent, adding a base and a palladium catalyst, protecting with nitrogen, heating to react, and after the reaction is completed, continuing to add the compound of formula II-1, water, a palladium catalyst and a base, and continuing the reaction, after the reaction is completed, cooling and filtering, removing the solvent, adding water, extracting with dichloromethane, drying, concentrating, and purifying to obtain the compound of formula I;

[0034] (2) dissolving the compound of formula I and the compound of formula I-1 in an organic solvent, adding a base, stirring and reacting, adding water to quench the reaction after the reaction is completed, extracting with dichloromethane, drying, concentrating, and recrystallizing to obtain the compound abemaciclib;

[0035] (3) The compound abemaciclib is dissolved in an organic solvent, and methanesulfonic acid is added to form a salt, and then the solvent is removed by concentration to obtain a crude methanesulfonate, which is then recrystallized in a recrystallization solvent to obtain abemaciclib methanesulfonate.

[0036] The present invention also provides a method for synthesizing a compound of formula I-1:

[0037] (a) dissolving the compound of formula IV in an organic solvent, adding triethylamine and trifluoroacetic anhydride to react to obtain a compound of formula III-2;

[0038] (b) dissolving the compound of formula III-2 in an organic solvent, adding NBS / AIBN or NBS / BPO, reflux reaction, and post-treating to obtain the compound of formula II-2;

[0039] (c) dissolving the compound of formula II-2 and the compound of formula II-3 in an organic solvent, adding a base, refluxing the mixture, and performing a post-treatment recrystallization step to obtain the compound of formula I-1;

[0040] The reaction formula is as follows:

[0041] Preferably, the organic solvent in step (a) is selected from dichloromethane, chloroform, tetrahydrofuran or acetonitrile; and the base in step (c) is selected from potassium carbonate, sodium carbonate or cesium carbonate.

[0042] Further preferably, in step (a), the volume of the organic solvent is 2-15 times the mass of the compound of formula IV in mL / g, the mass of trifluoroacetic anhydride is 1.05-1.4 times the mass of the compound of formula IV in mol / mol, and the amount of the base is 1.1-1.6 times the mass of the compound of formula IV in mol / mol; the reaction temperature is -20°C to the boiling point of the organic solvent, and the reaction time is 0.5-4 hours;

[0043] In step (b), the organic solvent is selected from carbon tetrachloride, chloroform, dichloromethane, acetonitrile, DMF, or dioxane, and the volume of the organic solvent is 1-30 times the mass of the compound of formula III-2 in mL / g. In mol / mol, the mass of NBS is 1.1-2.0 times the mass of the compound of formula III-2; in mol / mol, the mass of AIBN is 0.1-0.5 times the mass of the compound of formula III-2; the reaction temperature is 20°C to the boiling point of the organic solvent; the reaction time is 4-36 hours;

[0044] In step (c), the organic solvent is selected from methanol, acetonitrile, DMF or dioxane; in mL / g, the volume of the organic solvent is 1-15 times the mass of the compound of formula II-2; in mol / mol, the amount of the base is 2.0-2.3 times the amount of the compound of formula II-2, in mol / mol, the mass of the compound of formula II-3 is 1.1-1.5 times the mass of the compound of formula II-2, the reaction temperature is 20°C to the boiling point of the organic solvent, and the reaction time is 0.5-8 hours; the recrystallization solvent is selected from methanol, ethanol, isopropanol, methyl tert-butyl ether, tetrahydrofuran, n-hexane or acetone; in mL / g, the volume of the recrystallization solvent is 1-10 times the mass of the crude compound of formula I-1; the recrystallization temperature is -10°C-0°C, and the recrystallization time is 2-6 hours.

[0045] More preferably, (a) using the compound of formula IV as a raw material, dissolving it in an organic solvent, adding triethylamine and trifluoroacetic anhydride, and stirring; after the reaction is completed, pouring the reaction solution into ice water, extracting, drying, spin drying, and purifying to obtain a compound of formula III-2;

[0046] (b) dissolving the compound of formula III-2 in an organic solvent, adding NBS / AIBN or NBS / BPO, and reflux reaction. After the reaction is completed, adding water to quench the reaction, extracting, drying, spin drying, and purifying to obtain the compound of formula II-2;

[0047] (c) Dissolve the compound of formula II-2 and the compound of formula II-3 in an organic solvent, add a base, and reflux the reaction. After the reaction is completed, filter out the insoluble matter, remove the organic solvent, and obtain a crude solid product. Add an organic solvent, stir and slurry, filter out the solid, and spin-dry the solvent to obtain a crude compound of formula I-1. Add the crude compound of formula I-1 to a recrystallization solvent, heat to dissolve, then cool to precipitate crystals, filter and dry to obtain a compound of formula I-1.

[0048] The Chinese names of the compounds appearing in the above synthetic route are as follows:

[0049] Compound I: 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole;

[0050] Compound II: 4-fluoro-2-methyl-1-(isopropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole; Compound III: 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[D]imidazole;

[0051] Compound I-1: 5-(4-ethylpiperazin-1-yl)methyl-2-aminopyridine;

[0052] Compound II-1: 2,4-dichloro-5-fluoropyrimidine;

[0053] Compound II-2: N-((5-bromomethyl)pyridin-2-yl)-2,2,2-trifluoroacetamide;

[0054] Compound II-3: N-ethylpiperazine;

[0055] Compound III-1: biboric acid pinacol ester;

[0056] Compound III-2: 2,2,2-trifluoro-N-(5-methylpyridin-2-yl)acetamide;

[0057] Compound IV: 2-amino-5-methylpyridine.

[0058] The main reaction route of the present invention is as follows:

[0059]

[0060] The synthesis method of the present invention is compared with the prior art, and the main points are as follows:

[0061]

[0062]

[0063] The beneficial effects of the present invention are:

[0064] 1. In the prior art, the compound shown in Formula I in WO2010075074A1 is synthesized by a two-step method, and a heavy metal catalyst is used in both the two-step methods. In view of the shortcomings of the prior art, the present invention provides a low-cost, low-byproduct, high-conversion, economical and environmentally friendly synthesis method of abemaciclib, which reduces the use of a heavy metal catalyst and a phosphine ligand in one step, saves costs, and is simple to post-process. The two-step reaction is achieved by one-step continuous addition, which reduces post-processing operations and saves costs;

[0065] 2. The present invention also provides a method for synthesizing 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine, an intermediate of Abemaciclib. The method does not use expensive reagents, does not require high temperature, high pressure reaction, irritating reagent ammonia, and harsh conditions for LiAlH4 reduction reaction. The raw materials used are cheap and easy to obtain, the reaction steps are simple to operate, and the yield is high. The noble metal palladium catalytic reaction is avoided, and the synthesis cost is reduced. The reaction docking and detrifluoroacetyl protection are synthesized in one pot, which shortens the reaction steps, avoids contact with water, improves the reaction yield, and is simple to post-process.

[0066] 3. The two-step reaction of the synthesis of abemaciclib in the present invention is optimized into a continuous reaction, and the column purification process is changed to a column brushing and beating process, which shortens the post-processing and saves a lot of manpower, material resources, time and cost;

[0067] 4. The abemaciclib and its intermediate 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine obtained by the preparation method of the present invention have high quality, high conversion rate and high purity. 1 The product was confirmed by H NMR, F spectroscopy and high-resolution mass spectrometry. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 is the proton nuclear magnetic resonance spectrum of abemaciclib;

[0069] Figure 2 is the fluorine NMR spectrum of abemaciclib;

[0070] Figure 3 This is the mass spectrum of abemaciclib;

[0071] Figure 4 It is the hydrogen spectrum of abemaciclib mesylate;

[0072] Figure 5 It is the hydrogen nuclear magnetic resonance spectrum of 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine, an intermediate of abemaciclib;

[0073] Figure 6 This is the mass spectrum of 5-(4-ethylpiperazine-1-yl)methyl-2-aminopyridine, an intermediate of abemaciclib; DETAILED DESCRIPTION

[0074] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

[0075] Example 1

[0076] Compound III (3 g, 11.06 mmol), compound III-1 (3.37 g, 13.28 mmol), potassium acetate (2.17 g, 22.13 mmol) were added to dioxane (45 mL), Pd2(dba)3 (509 mg, 0.89 mmol) was added under nitrogen protection, the mixture was reacted at 100°C for 4 h, cooled to room temperature, II-1 (2.22 g, 13.28 mmol), sodium carbonate (2.35 g, 22.13 mmol), Pd2(dba)3 (509 mg, 0.89 mmol) and H2O (12 mL) were added under nitrogen protection, the mixture was reacted at 100°C for 16 h, cooled to room temperature, filtered, dried by spin drying, water and dichloromethane were added for extraction, dried, dried by spin drying, and slurried after simple brushing on a silica gel pad to obtain 2.7 g of an off-white solid, which was compound I. The two-step yield was 75.6%.

[0077] Example 2

[0078] Compound III (3 g, 11.06 mmol), compound III-1 (5.06 g, 19.91 mmol), potassium acetate (2.17 g, 22.13 mmol) were added to DMF (30 mL), Pd (dppf) Cl2 (805 mg, 1.11 mmol) was added under nitrogen protection, the mixture was reacted at 80°C for 6 h, cooled to room temperature, II-1 (2.03 g, 12.17 mmol), sodium carbonate (2.35 g, 22.13 mmol), Pd (dppf) Cl2 (805 mg, 1.11 mmol) and H2O (12 mL) were added under nitrogen protection, the mixture was reacted at 80°C for 12 h, cooled to room temperature, filtered, extracted with water and dichloromethane, dried, spin-dried, and simply brushed on a silica gel pad and slurried to obtain 2.79 g of an off-white solid, which was compound I. The two-step yield was 77.8%.

[0079] Example 3

[0080] Compound III (3 g, 11.06 mmol), compound III-1 (3.93 g, 15.48 mmol), potassium acetate (2.17 g, 22.13 mmol) were added to acetonitrile (15 mL), Pd(PPh3)Cl2 (856 mg, 1.12 mmol) was added under nitrogen protection, refluxed for 8 h, cooled to room temperature, II-1 (2.58 g, 15.48 mmol), sodium carbonate (2.35 g, 22.13 mmol), Pd(PPh3)Cl2 (856 mg, 1.12 mmol) and H2O (12 mL) were added under nitrogen protection, refluxed for 10 h, cooled to room temperature, filtered, acetonitrile was removed by spin drying, water and dichloromethane were added for extraction, dried, spin dried, and simply brushed on a silica gel pad and slurried to obtain 2.52 g of an off-white solid, which was compound I. The two-step yield was 70.5%.

[0081] Example 4

[0082] Compound I (2.0 g, 6.20 mmol) and compound I-1 (1.23 g, 5.58 mmol) were added to acetonitrile (20 mL), and then potassium tert-butoxide (1.39 g, 12.4 mmol) was added, and the mixture was reacted at 20°C for 16 h. After the reaction was complete, water and dichloromethane were added for extraction, and the mixture was dried, spin-dried, and recrystallized from ethyl acetate to obtain 1.62 g of a light yellow solid, which was the compound Abemaciclib, with a yield of 57.1%. Abemaciclib 1 H NMR (CDCl3, 400MHz)δ:8.44(d,1H),8.39(t,2H),8.25(d,1H),8.20(d,1H),7.80(d,1H),7.69(d,1H),4.71-4.78(m,1H),3.53(s,2H),2.54-2.70(m,11H),1.72(d,6H),1.29(t,2H),1.16(t,3H); (see Appendix Figure 1 ) Abemaciclib fluorine spectrum (CDCl3, 400MHz) δ: 127.96 (1F), 148.11 (1F); (see Appendix Figure 2 )Abemaciclib mass spectrum: (m / z) 507.26 (ESI+) (see Appendix Figure 3 )

[0083] Example 5

[0084] Compound I (2.0 g, 6.20 mmol) and compound I-1 (2.05 g, 9.3 mmol) were added to dioxane (30 mL), and then sodium methoxide (0.74 g, 13.64 mmol) was added. The mixture was reacted at 80° C. for 10 h. After the reaction was complete, water and dichloromethane were added for extraction, dried, spin-dried, and recrystallized from ethyl acetate to obtain 2.36 g of a light yellow solid, which was compound Ab maciclib, with a yield of 75.2%.

[0085] Example 6

[0086] Compound I (2.0 g, 6.20 mmol) and compound I-1 (1.50 g, 6.82 mmol) were added to tetrahydrofuran (10 mL), and then sodium hydride (0.27 g, 11.16 mmol) was added, and the mixture was refluxed for 20 h. After the reaction was complete, water and dichloromethane were added for extraction, and the mixture was dried, spin-dried, and recrystallized from ethyl acetate to obtain 2.32 g of a light yellow solid, which was the compound Abemaciclib, with a yield of 73.8%. Abemaciclib Mesylate 1H NMR (CD3OD, 400 MHz) δ: 8.81 (d, 1H), 8.48 (d, 1H), 8.28-8.33 (m, 2H), 8.07 (d, 1H), 7.54 (d, 1H), 5.01-5.08 (m, 1H), 3.82 (s, 2H), 3.20-3.25 (m, 11H), 2.86 (s, 2H), 2.61 (s, 9H), 1.71 (d, 6H), 1.27 (t, 3H) (see Appendix Figure 4 ).

[0087] Example 7

[0088] Abemaciclib (200 mg, 0.39 mmol) was added to dichloromethane (2.4 mL), and then methanesulfonic acid (56.9 mg, 0.59 mmol) was added, and the mixture was reacted at 20°C for 2 h. The mixture was spin-dried, and methyl tert-butyl ether (2 mL) was added. The mixture was stirred at 20°C for 2 h, and then filtered to obtain 230 mg of a light yellow solid, which is the compound Abemaciclib Mesylate, with a yield of 96.7%.

[0089] Example 8

[0090] Abemaciclib (2.0 g, 3.9 mmol) was added to methanol (30 mL), and then methanesulfonic acid (412.2 mg, 4.29 mmol) was added, and the mixture was refluxed for 1 h. The mixture was spin-dried, and n-hexane (15 mL) was added. The mixture was stirred at 0°C for 4 h, and then filtered to obtain 2.36 g of a light yellow solid, which is the compound Abemaciclib Mesylate, with a yield of 99.2%.

[0091] Example 9

[0092] Abemaciclib (2.0 g, 3.9 mmol) was added to acetonitrile (8 mL), and then methanesulfonic acid (674.6 mg, 7.02 mmol) was added, and the mixture was refluxed for 6 h, and then dried by rotation. n-heptane (6 mL) was added, and the mixture was stirred at -5°C for 1 h, and then filtered to obtain 2.32 g of a light yellow solid, which is the compound Abemaciclib Mesylate, with a yield of 97.5%.

[0093] Example 10

[0094] The compound 2-amino-5-methylpyridine (IV) (5.0 g, 46.2 mmol) and triethylamine (5.15 g, 50.8 mmol) were dissolved in dichloromethane (50 mL), cooled to 0°C in an ice-water bath, and trifluoroacetic anhydride (10.2 g, 48.5 mmol) was added dropwise. The mixture was then heated to reflux for 1 h. The reaction was detected to be complete, and the reaction solution was poured into ice water for quenching. After extraction, drying, and spin drying, the intermediate (III-2) (8.7 g) was obtained with a yield of 92.2%.

[0095] Embodiment 11

[0096] The compound 2-amino-5-methylpyridine (IV) (5.0 g, 46.2 mmol) and triethylamine (7.47 g, 73.9 mmol) were dissolved in dichloromethane (75 mL), cooled to 0°C in an ice-water bath, trifluoroacetic anhydride (11.64 g, 55.4 mmol) was added dropwise, the temperature was maintained at 0°C, and the reaction was allowed to proceed for 4 h. The reaction was detected to be complete, and the reaction solution was poured into ice water to quench. After extraction, drying and spin drying, the intermediate (III-2) (8.89 g) was obtained with a yield of 94.2%.

[0097] Example 12

[0098] The compound 2-amino-5-methylpyridine (IV) (5.0 g, 46.2 mmol) and triethylamine (6.54 g, 64.7 mmol) were dissolved in acetonitrile (20 mL), cooled to 0°C in an ice-water bath, trifluoroacetic anhydride (12.61 g, 60.1 mmol) was added dropwise, and then the temperature was raised to reflux and the reaction was carried out for 0.5 h. The reaction was detected to be complete, and the reaction solution was poured into ice water to quench. After extraction, drying and spin drying, the intermediate (III-2) (8.78 g) was obtained with a yield of 93.0%.

[0099] Example 13

[0100] The intermediate (III-2) (2.0 g, 9.8 mmol) and AIBN (160 mg, 0.98 mmol) were dissolved in carbon tetrachloride (40 mL) and protected by nitrogen. NBS (1.88 g, 10.78 mmol) was added and refluxed for 4 h. After the reaction was complete, the temperature was cooled to room temperature and saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, dried, spin-dried and purified to obtain 2.22 g of the intermediate (II-2) with a yield of 80%.

[0101] Embodiment 14

[0102] The intermediate (III-2) (2.0 g, 9.8 mmol) and AIBN (320 mg, 1.96 mmol) were dissolved in dichloromethane (20 mL), and NBS (2.62 g, 14.7 mmol) was added under nitrogen protection. The reaction was refluxed for 24 h. After the reaction was complete, the temperature was cooled to room temperature, saturated sodium bicarbonate solution was added to quench, and the mixture was extracted with dichloromethane. After drying, spin drying, and purification, 2.36 g of the intermediate (II-2) was obtained, with a yield of 85%.

[0103] Embodiment 15

[0104] The intermediate (III-2) (2.0 g, 9.8 mmol) and AIBN (804 mg, 4.9 mmol) were dissolved in carbon tetrachloride (50 mL) and protected by nitrogen. NBS (3.14 g, 17.6 mmol) was added and refluxed for 10 h. After the reaction was complete, the temperature was cooled to room temperature and saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, dried, spin-dried and purified to obtain 2.46 g of the intermediate (II-2) with a yield of 88.7%.

[0105] Example 16

[0106] The intermediate (II-2) (5.0 g, 17.6 mmol) and the intermediate (II-3) (2.22 g, 19.4 mmol) were dissolved in methanol (50 mL), and potassium carbonate (5.59 g, 40.5 mmol) was added. The temperature was raised to reflux and the reaction was carried out for 1 h. After the reaction was complete, the temperature was lowered, the filter was filtered, and the filter cake was rinsed with methanol. The organic phases were combined and the solvent was dried to obtain a crude product (6.5 g). The crude product was dissolved in methyl tert-butyl ether (20 mL), the temperature was raised to reflux to dissolve, and the temperature was slowly lowered to 10°C. Crystallization was carried out for 2 h, and the mixture was filtered, rinsed, and the filter cake was dried to obtain pure compound I-1 (3.5 g) with a yield of 90.2%.

[0107] Embodiment 17

[0108] The intermediate (II-2) (5.0 g, 17.6 mmol) and the intermediate (II-3) (3.01 g, 26.4 mmol) were dissolved in acetonitrile (15 mL), and potassium carbonate (4.87 g, 35.2 mmol) was added. The temperature was raised to reflux and the reaction was carried out for 4 hours. After the reaction was complete, the temperature was lowered, the filter was filtered, and the filter cake was rinsed with acetonitrile. The organic phases were combined and the solvent was dried to obtain a crude product (6.6 g). The crude product was dissolved in acetone (25 mL), the temperature was raised to reflux to dissolve, and the temperature was slowly lowered to 0°C. Crystallization was carried out for 6 hours, and the mixture was filtered, rinsed, and the filter cake was dried to obtain pure compound I-1 (3.66 g) with a yield of 94.3%.

[0109] Embodiment 18

[0110] The intermediate (II-2) (5.0 g, 17.6 mmol) and the intermediate (II-3) (2.61 g, 22.9 mmol) were added to DMF (40 mL) and potassium carbonate (5.10 g, 36.9 mmol) was added. The temperature was raised to reflux and the reaction was carried out for 6 h. After the reaction was complete, the temperature was lowered, the filter was filtered, the filter cake was rinsed with DMF, the organic phases were combined, and the solvent was dried to obtain a crude product (6.8 g). The crude product was dissolved in isopropanol (10 mL), the temperature was raised to reflux to dissolve, and the temperature was slowly lowered to 0 ° C. Crystallization was carried out for 4 h, and the mixture was filtered, rinsed, and the filter cake was dried to obtain pure compound I-1 (3.60 g) with a yield of 92.8%. The intermediate (I-1) 1 H NMR (CDCl3, 400 MHz) δ: 7.96 (d, 1H), 7.28-7.43 (m, 2H), 6.48 (d, 1H), 4.41 (s, 1H), 3.38 (s, 1H), 2.31-2.47 (m, 10H), 1.07 (t, 3H) (see Appendix Figure 5 ); intermediate (I-1) mass spectrum: (m / z) 221.03 (ESI+) (see Appendix Figure 6 ).

Claims

1. A method for synthesizing a compound of formula I-1: The method comprises the following steps: (a) dissolving the compound of formula IV in an organic solvent, adding triethylamine and trifluoroacetic anhydride to react to obtain a compound of formula III-2; (b) dissolving the compound of formula III-2 in an organic solvent, adding NBS / AIBN or NBS / BPO, reflux reaction, and post-treating to obtain the compound of formula II-2; (c) dissolving the compound of formula II-2 and the compound of formula II-3 in an organic solvent, adding a base, refluxing the mixture, and performing a post-treatment recrystallization step to obtain the compound of formula I-1; The reaction formula is as follows: Wherein, the organic solvent in step (a) is selected from dichloromethane, chloroform, tetrahydrofuran or acetonitrile; the base in step (c) is selected from potassium carbonate, sodium carbonate or cesium carbonate; wherein in step (a), the volume of the organic solvent is 2-15 times the mass of the compound of formula IV in mL / g; the molar number of trifluoroacetic anhydride is 1.05-1.4 times the molar number of the compound of formula IV, and the molar number of the base is 1.1-1.6 times the molar number of the compound of formula IV; the reaction temperature is from -20°C to the boiling point of the organic solvent, and the reaction time is 0.5-4 hours; wherein in step (b), the organic solvent is selected from carbon tetrachloride, chloroform, dichloromethane, acetonitrile, DMF, or dioxane, and the volume of the organic solvent is 1-30 times the mass of the compound of formula III-2 in mL / g; the molar number of NBS is 1.1-2.0 times the molar number of the compound of formula III-2; the molar number of AIBN is 0.1-0.5 times the molar number of the compound of formula III-2; the reaction temperature is 20°C to the boiling point of the organic solvent; and the reaction time is 4-36 hours; In the step (c), the organic solvent is selected from methanol, acetonitrile, DMF or dioxane; the volume of the organic solvent is 1-15 times the mass of the compound of formula II-2 in mL / g; the molar number of the base is 2.0-2.3 times the molar number of the compound of formula II-2, the molar number of the compound of formula II-3 is 1.1-1.5 times the molar number of the compound of formula II-2, the reaction temperature is 20°C to the boiling point of the organic solvent, and the reaction time is 0.5-8 hours; the recrystallization solvent is selected from methanol, ethanol, isopropanol, methyl tert-butyl ether, tetrahydrofuran, n-hexane or acetone; the volume of the recrystallization solvent is 1-10 times the mass of the crude compound of formula I-1 in mL / g; the recrystallization temperature is -10°C-0°C, and the recrystallization time is 2-6 hours.

2. The synthesis method according to claim 1, characterized in that (a) using a compound of formula IV as a raw material, dissolving it in an organic solvent, adding triethylamine and trifluoroacetic anhydride, and stirring; after the reaction is completed, pouring the reaction solution into ice water, extracting, drying, spin drying, and purifying to obtain a compound of formula III-2; (b) dissolving the compound of formula III-2 in an organic solvent, adding NBS / AIBN or NBS / BPO, and reflux reaction. After the reaction is completed, adding water to quench the reaction, extracting, drying, spin drying, and purifying to obtain the compound of formula II-2; (c) Dissolve the compound of formula II-2 and the compound of formula II-3 in an organic solvent, add a base, and reflux the reaction. After the reaction is completed, filter out the insoluble matter, remove the organic solvent, and obtain a crude solid product. Add an organic solvent, stir and slurry, filter out the solid, and spin-dry the solvent to obtain a crude compound of formula I-1. Add the crude compound of formula I-1 to a recrystallization solvent, heat to dissolve, then cool to precipitate crystals, filter and dry to obtain a compound of formula I-1.

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