Preparation method of kapasitinib

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a preparation method of kapparetinib, a compound 1 is taken as a substrate and sequentially passes through intermediates 3, 10, 11 and 12 to obtain a compound 6, namely kapparetinib, the process is simple in process, simple and convenient in operation process, convenient in quality control and relatively high in reaction yield, for example, in the process of synthesizing a compound 10 from a compound 3, the yield is high, and the yield is high. The compound 3 can be used for synthesis of a compound 10 in the next step without column chromatography purification after synthesis, a high-purity compound 10 product is obtained, the compound 3 is good in solubility and can rapidly complete reaction in a homogeneous system, the compounds 11 to 6 are synthesized in a one-pot method, separation is not needed, the atom utilization degree is high, the intermediate 11 is in a free state, and the synthesis cost is low. The compound 6 has no trifluoroacetate form, has good dissolvability, can rapidly complete the fourth-step reaction in a homogeneous system, after the intermediate 12 is subjected to protecting group removal, the reaction liquid is high in central control purity, and the high-purity compound 6 can be obtained through subsequent simple pulping.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and specifically discloses a preparation method of capmatinib. Background Art

[0002] Capmatinib is a highly selective c-MET (mesenchymal-epithelial transition factor) inhibitor, mainly used for treating patients with non-small cell lung cancer (NSCLC) carrying MET exon 14 skipping mutation (METex14). The total incidence rate of MET exon 14 skipping mutation in non-small cell lung cancer is 3%-6%, the incidence rate in lung adenocarcinoma is 3%-4%, and the incidence rate in pulmonary sarcomatoid carcinoma can be as high as 22%. Capmatinib (INC280) is an investigational, oral, potent, and selective MET inhibitor, and its inhibitory ability against MET is much stronger than other MET-targeted drugs, such as crizotinib, savolitinib, and tepotinib. Multiple synthetic routes have been proposed in the prior art, but more or less have certain defects. For example: WO2009 / 047563 patent discloses three preparation schemes for compound 6. The first scheme uses 6-chloro-7-azapurine to undergo a nucleophilic substitution reaction with N-Boc-amino-piperidinyl-1,1-carboxylic acid to obtain intermediate 3, and then condenses with (S)-3-amino-3-(4-chlorophenyl)propan-1-ol to obtain intermediate 5. Intermediate 5 is then deprotected to obtain compound 6. Using this route, each step is separated and purified by column chromatography, and in the preparation process of the second amide, due to involving multiple active sites, more impurities may be generated in the reaction. The yield of the last step is only 19.4%, and the atom economy is poor.

[0003] The second synthetic route is to first construct amide compound 8, then deprotect to obtain intermediate 9, and finally intermediate 9 undergoes a nucleophilic substitution reaction with starting material 1 to obtain the target compound 6. Facing the same problems as the first route, the process requires purification by silica gel column chromatography, and the yield of the last step is only increased to 42.5%.

[0004] The third route is to change the amide condensation reagent on the basis of the first route. However, this modification does not significantly improve the advantages of this process route. The cost of the condensation reagent used is high, the industrialization prospect is weak, and the last deprotection and purification require preparative liquid separation, and the yield is only 25.3%, without industrialization prospect.

[0005]

[0006] WO2015 / 181532 patent discloses Figure 4Synthetic route of Compound 6:

[0007] The first step is similar to the aforementioned patent. First, intermediate compound 3 is preferably constructed, and then trifluoroacetic anhydride is used for dehydration condensation to form the trifluoroacetate of the internal anhydride intermediate 9. Finally, ring-opening substitution reaction is carried out with compound 4 to obtain the target compound 6. This patent route simplifies the reaction process. The process route using the internal anhydride intermediate avoids the reaction conditions that require a large amount of condensation reagents in conventional amide condensation and the problem of generating a large amount of impurities in the condensation reaction. However, when preparing compound 9, it is inevitable to generate a salt structure compound with trifluoroacetic acid, which will consume a certain amount of chiral compound 4 during the subsequent reaction with chiral compound 4, resulting in waste of chiral materials. In addition, during the reaction of compound 9 with compound 4, due to the exposed nitrogen atom on the azapurine still having certain basicity and nucleophilic attack ability, this reaction site will form a competitive relationship with the amino group in compound 4, leading to the generation of more impurities, thus increasing the difficulty of subsequent purification and quality control. Summary of the Invention

[0008] In view of the problems existing in the prior art, a first aspect of the present invention provides a preparation method of capesertinib, and the capesertinib has the structure of compound 6. The preparation method includes reacting compound 11 to obtain compound 6, and the reaction steps include:

[0009] (i) After mixing compound 11 with buffer salt, 2-methyltetrahydrofuran, and compound 4, the temperature is controlled for reaction to obtain compound 12; (ii) Removing the protecting group R from compound 12 to obtain compound 6; The R is selected from any one of acetyl, propionyl, and isobutyryl.

[0010] In some specific embodiments of the preparation method of capesertinib proposed in the first aspect, the specific method for removing the protecting group R from compound 12 is that compound 12 is deprotected in an aqueous solution of a base to obtain compound 6.

[0011] In some specific embodiments of the preparation method of capesertinib proposed in the first aspect, in some specific preferred embodiments of the preparation method of capesertinib proposed in the first aspect, the base is any one of sodium hydroxide and potassium hydroxide. In some further preferred embodiments of the preparation method of capesertinib proposed in the first aspect, the pH of the aqueous solution of the base is 11.

[0012] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, the buffer salt is selected from an aqueous solution of any one or a combination of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium acetate, acetate buffer, sodium citrate, citrate buffer, ammonia, ammonium chloride, sodium bicarbonate, and sodium carbonate buffer.

[0013] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, the temperature of temperature control is 5 - 25 °C.

[0014] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, the molar ratio of compound 11 to compound 4 in the feed is 5:(4 - 6).

[0015] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, the molar amount of compound 11 fed per 1 L of 2 - methyltetrahydrofuran is 0.28 - 0.32 mol.

[0016] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, the molar amount of compound 4 fed per 1 L of 2 - methyltetrahydrofuran is 0.2 - 0.3 mol.

[0017] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, the molar amount of buffer salt fed per 1 L of 2 - methyltetrahydrofuran is 0.3 - 0.6 mol.

[0018] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, the synthesis method of compound 11 includes , adding trifluoroacetic anhydride to the mixture of compound 10 and an organic solvent to obtain compound 11, as shown in the formula: , where R is selected from any one of acetyl, propionyl, and isobutyryl.

[0019] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, 0.20 - 0.25 mol of compound 10 is mixed with per 1 L of organic solvent to obtain a mixture.

[0020] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, the organic solvent is selected from any one or a mixture of dichloromethane, chloroform, DMF, toluene, and methanol.

[0021] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, the way of adding trifluoroacetic anhydride is by dropwise addition.

[0022] In specific embodiments of the preparation method of capmatinib proposed in some first aspects, the synthesis method of compound 10 includes , mix the compound 3 with an organic solvent, a base, and N,N-dimethyl-4-pyridinamine, add an acylating agent, and carry out the reaction while controlling the temperature to obtain the compound 10, as shown in the formula: , where R is selected from any one of acetyl, propionyl, and isobutyryl.

[0023] In specific embodiments of the preparation method of capesertinib proposed in some first aspects, the organic solvent is selected from any one or a combination of acetonitrile, toluene, dichloromethane, and tetrahydrofuran.

[0024] In specific embodiments of the preparation method of capesertinib proposed in some first aspects, 0.28 - 0.32 mol of the compound 3 is mixed with every 1 L of the organic solvent.

[0025] In specific embodiments of the preparation method of capesertinib proposed in some first aspects, the base is selected from any one or a combination of triethylamine, methylamine, ethylamine, N-methylmorpholine, and tetramethylammonium hydroxide.

[0026] In specific embodiments of the preparation method of capesertinib proposed in some first aspects, 1.0 - 1.1 mol of the base is mixed with every 1 L of the organic solvent.

[0027] In specific embodiments of the preparation method of capesertinib proposed in some first aspects, the molar ratio of the compound 3 to N,N-dimethyl-4-pyridinamine in the feed is (3 - 4):1.

[0028] In specific embodiments of the preparation method of capesertinib proposed in some first aspects, the temperature for controlling the temperature is 45 - 55 °C.

[0029] In specific embodiments of the preparation method of capesertinib proposed in some first aspects, the synthesis method of the compound 3 includes, , mix the compound 1, the compound 2, a base, water, and an organic solvent, and carry out the reaction while controlling the temperature to obtain the compound 3, as shown in the formula: .

[0030] In specific embodiments of the preparation method of capesertinib proposed in some first aspects, 0.75 - 0.85 L of the organic solvent is mixed with every 1 L of water.

[0031] In specific embodiments of the preparation method of capesertinib proposed in some first aspects, 2.2 - 2.8 mol of the base is mixed with every 1 L of water.

[0032] In specific embodiments of the preparation method of capesertinib proposed in some first aspects, the base is selected from any one or a combination of sodium bicarbonate, sodium carbonate, triethylamine, cesium carbonate, and sodium hydroxide.

[0033] In specific embodiments of the method for preparing capesertinib proposed in some first aspects, the temperature of temperature control is 80 - 90 °C.

[0034] In specific embodiments of the method for preparing capesertinib proposed in some first aspects, the organic solvent is selected from any one or a combination of acetonitrile, dichloromethane, chloroform, and toluene.

[0035] In specific embodiments of the method for preparing capesertinib proposed in some first aspects, 1 L of water is mixed with 0.55 - 0.60 mol of Compound 1.

[0036] In specific embodiments of the method for preparing capesertinib proposed in some first aspects, the molar ratio of Compound 1 to Compound 2 in the feed is 1:(0.8 - 1.2).

[0037] In specific embodiments of the method for preparing capesertinib proposed in some first aspects, after temperature-controlled reaction, the mixed solution is subjected to trituration to obtain a crystal form.

[0038] All the medicaments used in the present invention are purchased from publicly legal markets and are not further purified.

[0039] "Room temperature" in the present invention is 5 - 45 °C, 10 - 40 °C in some embodiments, 15 - 35 °C in some embodiments, 20 - 30 °C in some embodiments, and 25 °C in some embodiments.

[0040] Advantages of the present invention: The preparation process of the present invention is simple in process, convenient in operation, easy for crystallization and purification, convenient for quality control, and has a relatively high reaction yield. For example, in the process of synthesizing Compound 10 from Compound 3, Compound 3 can be used for the next-step synthesis of Compound 10 without column chromatography purification after synthesis, and a high-purity Compound 10 product can be obtained. Compound 3 has good solubility and can complete the reaction quickly in a homogeneous system. Compounds 11 to 6 can be synthesized by a one-pot method without separation, with high atom utilization. Moreover, Intermediate 11 is in a free state without the form of trifluoroacetate salt, has good solubility, and can complete the fourth-step reaction quickly in a homogeneous system. After the deprotection of Intermediate 12, the purity control in the reaction solution is high, and the target compound with high purity can be obtained by simple trituration and washing subsequently. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Showing the 1H NMR data of Compound 3; Figure 2 Showing the 1H NMR data of Compound 10; Figure 3 Showing the 1H NMR data of Compound 6; Figure 4 Showing the X-ray powder diffraction pattern - Crystal Form B of Compound 6; Figure 5 Showing polymorph B of DSC-compound 6; Detailed implementation mode

[0042] To enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further elaborate on the present invention in detail.

[0043] Overview of the test scheme of the present invention: , where R is selected from any one of acetyl, propionyl, and isobutyryl; First step: Using 6-chloro-7-azapurine and N-Boc-amino-piperidinyl-1,1-carboxylic acid as substrates, 1,4-dioxane and water as reaction solvents, and sodium bicarbonate as a base reagent; Second step: Using acetic anhydride, propionic anhydride, or isobutyric anhydride as acylating reagents, acetonitrile as the reaction solvent, triethylamine as the base reagent, and 4-(dimethylamino)pyridine as the catalyst, preferably isobutyric anhydride as the acylating reagent; Third step: Using trifluoroacetic anhydride as a condensation reagent, dichloromethane as the reaction solvent, and methyl tert-butyl ether as the crystallization solvent; Fourth step: Using (S)-3-amino-3-(4-chlorophenyl)propan-1-ol as a ring-opening reagent, 2-methyltetrahydrofuran as the reaction solvent, and dipotassium hydrogen phosphate and potassium dihydrogen phosphate as base reagents; Fifth step: Using an aqueous sodium hydroxide solution as the base reagent and 2-methyltetrahydrofuran as the reaction solvent.

[0044] Example 1

[0045] Mix compound 1 (0.64 mol), compound 2 (0.64 mol), sodium bicarbonate (2.87 mol), water (1.1 L), and acetonitrile (0.9 L) in a three-necked flask. Control the external temperature at 85 o °C, stir the reaction for 24 hours, after the proportion of compound 2 in the in-process control is less than 2%, cool down to 25 o °C, add ethyl acetate (0.5 L × 2) to the reaction kettle for extraction and liquid separation twice, concentrate the aqueous phase under reduced pressure to about 0.3 L, and then adjust the pH value to 4 with 6M hydrochloric acid. Filter, wash with cold water, and dry to obtain solid compound 3 with a yield of 80.3%, which can be directly used for the next step of the reaction.

[0046] Example 2

[0047] Compound 3 (0.37 mol) was mixed with acetonitrile (1.2 L) in a three-necked flask. Subsequently, triethylamine (1.3 mol) and N,N-dimethyl-4-pyridinamine (0.11 mol) were added to the reaction flask in sequence. Stirring was started, and isobutyric anhydride (0.19 mol) was added dropwise under the condition of controlling the temperature at 50 o °C. After the reaction was completed, the temperature was lowered to 25 o °C, and the pH value was adjusted to about 4 with dilute hydrochloric acid. Filtration was carried out, and the filter cake was washed twice with cold water. The filter cake was then slurried with ethanol, filtered, and dried to obtain Compound 10 with a yield of 80.1%.

[0048] Table 1: Data of the screening examples for protecting groups Example 3

[0049] Compound 10 (0.3 mol) and dichloromethane (1.3 L) were added to a 2 L reaction flask. Under stirring, trifluoroacetic anhydride (0.4 mol) was slowly added dropwise to the reaction flask. After the reaction was completed, the reaction solution was concentrated to 0.2 L, and then methyl tert-butyl ether (0.3 L) was added. Filtration and drying gave Compound 11 with a yield of 95.0%, which could be directly used for the next reaction step.

[0050] Example 4

[0051] Compound 11 (0.25 mol), potassium dihydrogen phosphate (0.2 mol), dipotassium hydrogen phosphate (0.2 mol) and 2-methyltetrahydrofuran (0.8 L) were added to the reaction kettle. The temperature was controlled at 5°C, and Compound 4 (0.2 mol) was added to the reaction kettle and stirred for 2 hours. Then, the temperature was raised to 25°C, and the reaction was continued to stir for about 5 hours. After the proportion of Compound 11 was less than 1% monitored by TLC, it could directly enter the next operation step.

[0052] Example 5

[0053] Water (0.5 L) was added to the above reaction solution, and the pH was adjusted to about 11 with 6% sodium hydroxide while controlling the temperature at 25 oStir the reaction for 4 hours. After the proportion of intermediate compound 12 is less than 0.5% as monitored by on-site control, let it stand for liquid separation, and then extract the aqueous phase with 2-methyltetrahydrofuran (0.8 L). Combine the organic phases, and wash the combined organic phases with saturated brine (0.4 L). Finally, concentrate the organic phase under reduced pressure to obtain the crude product of target compound 6. The crude product is slurried with acetonitrile (0.4 L) at 25 °C, and then filtered to obtain the purified compound 6 (polymorph B). The two-step yield is 90%, and the liquid-phase purity is 99.5%.

[0054] 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.46 (d, 1H), 8.12 (s,1H), 7.43 – 7.25 (m, 4H), 7.16 (dd, 1H), 6.58 (dd, 1H), 4.87 (q, 1H), 4.57(t, 1H), 4.50 – 4.26 (m, 2H), 3.67 – 3.45 (m, 2H), 3.38 (m, 2H), 2.17 (s,2H), 2.04 – 1.73 (m, 4H), 1.41 (dd, 2H). m / z (ESI+) (M+H)+ = 429。

[0055] Example 6 The single crystal diffraction experiment after the slurrying in Example 5 has the following characteristic peaks, and the crystal form of the compound is polymorph B.

[0056] Table 2: Ten X-ray powder diffraction peaks of polymorph B of compound 6 For the single crystal of compound 6 prepared in Example 5 of the present invention, referring to the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) Q1A(R2) guideline, stability experiments were carried out under the conditions of 40 °C / 75% RH and 25 °C / 60% RH. The purity and crystal form did not change on the 29th day compared with the 0th day. The results show that the crystal form of the present invention is chemically stable under high temperature and high humidity.

[0057] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing capasitinib, wherein the capasitinib has the structure of compound 6, , characterized in that, The preparation method comprises reacting compound 11 to obtain compound 6, which comprises the following reaction steps: ； (i) Compound 11 is mixed with a buffer salt, 2-methyltetrahydrofuran and compound 4, and the mixture is reacted under temperature control to obtain compound 12; (ii) compound 12 is deprotected to obtain compound 6; The R is selected from any one of acetyl, propionyl and isobutyryl.

2. The method for preparing capasitinib according to claim 1, characterized in that: The specific method of deprotecting the protecting group R of the compound 12 is to deprotect the compound 12 in an aqueous solution of alkali to obtain the compound 6. Preferably, the alkali is any one of sodium hydroxide and potassium hydroxide. More preferably, the pH of the aqueous solution of the alkali is 11.

3. The method for preparing capasitinib according to any one of claims 1 or 2, characterized in that: The buffer salt is selected from any one or a combination of aqueous solutions of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium acetate, acetate buffer, sodium citrate, citric acid buffer, ammonia, ammonium chloride, sodium bicarbonate, and sodium carbonate buffer, and / or the temperature of the temperature control is 5~25°C, and / or the feeding molar ratio of compound 11 to compound 4 is 5:(4~6), and / or the feeding molar amount of compound 11 per 1L of 2-methyltetrahydrofuran is 0.28~0.32 mol, and / or the feeding molar amount of compound 4 per 1L of 2-methyltetrahydrofuran is 0.2~0.3 mol, and / or the feeding molar amount of the buffer salt per 1L of 2-methyltetrahydrofuran is 0.3~0.6 mol.

4. The method for preparing capasitinib according to any one of claims 1 to 3, characterized in that: The synthesis method of the compound 11 comprises: , trifluoroacetic anhydride is added to the mixture of the compound 10 and the organic solvent to obtain the compound 11, as shown in the formula: , wherein R is selected from any one of acetyl, propionyl and isobutyryl.

5. The method for preparing capasitinib according to claim 4, characterized in that: Each 1L of the organic solvent is mixed with 0.20-0.25mol of compound 10 to obtain a mixture, and / or the organic solvent is selected from any one of dichloromethane, chloroform, DMF, toluene, and methanol or a mixture thereof, and / or the adding method of trifluoroacetic anhydride is dropwise addition.

6. The method for preparing capasitinib according to any one of claims 4 or 5, characterized in that: The synthesis method of the compound 10 comprises: , the compound 3 is mixed with an organic solvent, a base, and N,N-dimethyl-4-pyridinamine, an acylating agent is added, and the temperature is controlled to react to obtain a compound 10, as shown in the formula: , wherein R is selected from any one of acetyl, propionyl and isobutyryl.

7. The method for preparing capasitinib according to claim 6, characterized in that: The organic solvent is selected from any one or a combination of acetonitrile, toluene, dichloromethane, and tetrahydrofuran, and / or, each 1L of the organic solvent is mixed with 0.28-0.32 mol of compound 3, and / or, the base is selected from any one or a combination of triethylamine, methylamine, ethylamine, N-methylmorpholine, and tetramethylammonium hydroxide, and / or, each 1L of the organic solvent is mixed with 1.0-1.1 mol of the base, and / or, the molar ratio of the compound 3 and N,N-dimethyl-4-pyridinamine is (3-4):1, and / or, the temperature of the temperature control is 45-55°C.

8. The method for preparing capasitinib according to any one of claims 6 or 7, characterized in that: The synthesis method of compound 3 comprises: , the compound 1, the compound 2, a base, water and an organic solvent are mixed and reacted under temperature control to obtain a compound 3, as shown in the formula: 。 9. The method for preparing capasitinib according to claim 8, characterized in that: Each 1L of water is mixed with 0.75-0.85L of organic solvent, and / or each 1L of water is mixed with 2.2-2.8mol of base, and / or the base is selected from any one or a combination of sodium bicarbonate, sodium carbonate, triethylamine, cesium carbonate, and sodium hydroxide, and / or the temperature of the temperature control is 80-90°C.

10. The method for preparing capasitinib according to any one of claims 8 or 9, characterized in that: The organic solvent is selected from any one or a combination of acetonitrile, dichloromethane, chloroform, and toluene, and / or, each 1L of water is mixed with 0.55-0.60 mol of compound 1, and / or, the molar ratio of compound 1 to compound 2 is 1:(0.8-1.2), and / or, after the temperature-controlled reaction, the mixed solution is slurried to obtain a crystalline form.

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