Tepotinib intermediate and preparation method thereof

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses a preparation method of tepotinib, which comprises the following steps: synthesizing a novel compound 12 as an intermediate by using a cheap raw material compound 1 as an initial raw material, synthesizing an intermediate compound 13 through the intermediate compound 12, and finally obtaining a tepotinib intermediate compound 7. Through synthesis of a new intermediate compound 12, a new high-yield path is obtained, the synthesis mode is cheap in raw material and simple to operate, after the compound 13 is prepared by taking the compound 12 as a substrate, a compound 7 can be synthesized in the next step without refining the compound 12 into a pure compound 13, the use of precious metal palladium is saved, and the cost is reduced. According to the technical scheme, the atom utilization rate is high, the production cost is remarkably reduced, repeatability is good, and large-scale production is easy to achieve.

Description

Technical Field

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

[0002] Tepotinib is a targeted anti-cancer drug, first developed by German pharmaceutical company Merck, and is specifically used to treat non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutation (METex14). As the world's first approved highly selective MET inhibitor, it was first launched in Japan in March 2020. On February 3, 2021, the FDA accelerated the approval of tepotinib for marketing. So far, it has been fully approved in more than 30 countries and regions around the world, and its efficacy and safety have been verified in the real world. WO2010078897A1 reported two synthesis methods, specifically as follows: (1) Preparation method one:

[0003] This route uses compound 3-(6-oxo-1,6-dihydro-3-pyridazinyl)benzonitrile (1. CAS: 52240-08-1) as the starting material, undergoes nucleophilic substitution with 5-bromo-2-[3-(chloromethyl)phenyl]pyrimidine (2, CAS: 1100598-50-2) to synthesize compound 3, then undergoes Miyaura borylation reaction to obtain compound 4, then undergoes oxidative hydrolysis with sodium perborate to obtain compound 5, then undergoes Mistnobu reaction with compound 6 to obtain compound 7, and finally obtains the target product tepotinib under the action of formaldehyde formic acid. The starting material compound 2 of this route has a relatively high market price (7700 yuan per 5 grams), which is not conducive to large-scale production. The bromine to hydroxyl requires Miyaura borylation oxidation reaction. The use of peroxides makes large-scale production risky, the reaction efficiency is low, and the Mistnobu reaction has poor repeatability and relatively low yield. (2) Preparation method two:

[0004] Method two uses methyl 3-(5-hydroxypyrimidin-2-yl)benzoate (8, CAS: 1092568-87-0) as the starting material, undergoes Mistnobu reaction with compound 6 to obtain compound 9, compound 9 is obtained under the action of DIBAL-H to obtain compound 10, and finally undergoes Mistnobu reaction with compound 1 again to obtain compound tepotinib. The starting material 8 of this route is relatively expensive, with a market price of 20,000 yuan per gram, which is not suitable for large-scale production. Moreover, there are two Mistnobu reactions in the reaction process, and it is very difficult to remove the triphenylphosphine added during the reaction and the generated triphenylphosphine oxide, bringing great difficulties to purification, with poor repeatability and relatively low yield. SUMMARY OF THE INVENTION

[0005] To solve the problems existing in the prior art, a first aspect of the present invention provides a tepotinib intermediate of formula 12, or its isotope substitute, tautomer, stereoisomer, crystal form: .

[0006] A second aspect of the present invention provides a method for synthesizing a tepotinib intermediate of formula 12, comprising: Dissolve compound 1 in an organic solvent, add a base and compound 11, control the temperature for reaction to obtain a compound of formula 12; .

[0007] In some embodiments of the method for synthesizing the tepotinib intermediate of formula 12 according to the second aspect, the organic solvent is selected from one or a combination of THF, 1,4-dioxane, CH 3 CN, DCM, DMF.

[0008] In some embodiments of the method for synthesizing the tepotinib intermediate of formula 12 according to the second aspect, the base is selected from one or a combination of sodium carbonate, cesium carbonate, sodium bicarbonate, triethylamine, DIPEA.

[0009] In some embodiments of the method for synthesizing the tepotinib intermediate of formula 12 according to the second aspect, the temperature for temperature control is 40-90 °C. In some embodiments, the temperature for temperature control is 50 °C. In some embodiments, the temperature for temperature control is 60 °C. In some embodiments, the temperature for temperature control is 70 °C. In some embodiments, the temperature for temperature control is 80 °C.

[0010] In some embodiments of the method for synthesizing the tepotinib intermediate of formula 12 according to the second aspect, the molar ratio of the feed of compound 1 to the base is 1:(1.5-2.5). In some embodiments, the molar ratio of the feed of compound 1 to the base is 1:1.8. In some embodiments, the molar ratio of the feed of compound 1 to the base is 1:2.0. In some embodiments, the molar ratio of the feed of compound 1 to the base is 1:2.2.

[0011] In some embodiments of the method for synthesizing the tepotinib intermediate of formula 12 according to the second aspect, 0.9 - 1.1 mol of compound 1 is added to every 1 L of the organic solvent. In some embodiments, 1.0 mol of compound 1 is added to every 1 L of the organic solvent.

[0012] The third aspect of the present invention provides a synthesis of a tepotinib intermediate compound of formula 13, comprising: Compound 12 , in an inert atmosphere, dissolving the compound 12, a first base and bis(pinacolato)diboron in an organic solvent, adding dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II), and heating to the reaction temperature to obtain compound 13; .

[0013] In some specific embodiments of the synthesis of the tepotinib intermediate compound of formula 13 according to the third aspect, the first base is selected from any one or a combination of potassium acetate, sodium acetate, triethylamine, and DIPEA.

[0014] In some specific embodiments of the synthesis of the tepotinib intermediate compound of formula 13 according to the third aspect, the inert atmosphere is selected from any one or a combination of a nitrogen atmosphere and an argon atmosphere.

[0015] In some specific embodiments of the synthesis of the tepotinib intermediate compound of formula 13 according to the third aspect, every 1 mL of water is mixed with 1.2 - 1.6 mmol of compound 13. In some embodiments, every 1 mL of water is mixed with 1.3 mmol of compound 13. In some embodiments, every 1 mL of water is mixed with 1.4 mmol of compound 13. In some embodiments, every 1 mL of water is mixed with 1.5 mmol of compound 13.

[0016] In some specific embodiments of the synthesis of the tepotinib intermediate compound of formula 13 according to the third aspect, the second base is selected from any one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, and DIPEA.

[0017] In some specific embodiments of the synthesis of the tepotinib intermediate compound of formula 13 according to the third aspect, the first temperature is 80 - 120 °C. In some embodiments, the first temperature is 90 °C. In some embodiments, the first temperature is 100 °C. In some embodiments, the first temperature is 100 °C.

[0018] In some specific examples of the synthesis of the intermediate compound of tepotinib of formula 13 described in the third aspect, the feeding ratio of compound 13 to the base is 1:(1.5 - 2.5). In some examples, the feeding ratio of compound 13 to the base is 1:1.7. In some examples, the feeding ratio of compound 13 to the base is 1:2.0. In some examples, the feeding ratio of compound 13 to the base is 1:2.2.

[0019] In some specific examples of the synthesis of the intermediate compound of tepotinib of formula 13 described in the third aspect, the second temperature is 65 - 100 °C. In some examples, the second temperature is 75 °C. In some examples, the second temperature is 85 °C. In some examples, the second temperature is 95 °C.

[0020] In some specific examples of the synthesis of the intermediate compound of tepotinib of formula 13 described in the third aspect, the inert atmosphere is one of nitrogen or argon atmospheres.

[0021] In some specific examples of the synthesis of the intermediate compound of tepotinib of formula 13 described in the third aspect, the base is selected from any one or a combination of potassium acetate, sodium acetate, triethylamine, and DIPEA.

[0022] In some specific examples of the synthesis of the intermediate compound of tepotinib of formula 13 described in the third aspect, the organic solvent is selected from one or more of toluene, ethylene glycol dimethyl ether, 1,4 - dioxane, and tetrahydrofuran.

[0023] In some specific examples of the synthesis of the intermediate compound of tepotinib of formula 13 described in the third aspect, the reaction temperature is 90 - 110 °C.

[0024] In some specific examples of the synthesis of the intermediate compound of tepotinib of formula 13 described in the third aspect, the molar ratio of the base to compound 12 in the feeding is (2.5 - 3.5):1. In some examples, the molar ratio of the base to compound 12 in the feeding is 2.7:1. In some examples, the molar ratio of the base to compound 12 in the feeding is 2.9:1. In some examples, the molar ratio of the base to compound 12 in the feeding is 3.1:1.

[0025] In some specific examples of the synthesis of the intermediate compound of tepotinib of Formula 13 described in the third aspect, the molar amount of Compound 12 charged per 1 L of organic solvent is 0.35 to 0.45 mol. In some examples, the molar amount of Compound 12 charged per 1 L of organic solvent is 0.37 mol. In some examples, the molar amount of Compound 12 charged per 1 L of organic solvent is 0.39 mol. In some examples, the molar amount of Compound 12 charged per 1 L of organic solvent is 0.41 mol.

[0026] The fourth aspect of the present invention provides a synthesis of the intermediate compound of tepotinib of Formula 7, including: Compound 12 , in an inert atmosphere, dissolving Compound 12, a first base, and bis(pinacolato)diboron in an organic solvent, adding dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II), and heating to the reaction temperature to obtain a mixture including Compound 13; Under an inert atmosphere, mixing the mixture including Compound 13 with water, a second base, and Compound 14, and heating to react to obtain Compound 7; .

[0027] In some specific examples of the synthesis of the intermediate compound of tepotinib of Formula 7 described in the fourth aspect, the first base is selected from any one or a combination of potassium acetate, sodium acetate, triethylamine, and DIPEA.

[0028] In some specific examples of the synthesis of the intermediate compound of tepotinib of Formula 7 described in the fourth aspect, the inert atmosphere is selected from any one or a combination of a nitrogen atmosphere and an argon atmosphere.

[0029] In some specific examples of the synthesis of the intermediate compound of tepotinib of Formula 7 described in the fourth aspect, 1.2 to 1.6 mmol of Compound 13 is mixed with each 1 mL of water. In some examples, 1.3 mmol of Compound 13 is mixed with each 1 mL of water. In some examples, 1.4 mmol of Compound 13 is mixed with each 1 mL of water. In some examples, 1.5 mmol of Compound 13 is mixed with each 1 mL of water.

[0030] In some specific examples of the synthesis of the intermediate compound of tepotinib of Formula 7 described in the fourth aspect, the second base is selected from any one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, and DIPEA.

[0031] In some specific examples of the synthesis of the intermediate compound of tepotinib of Formula 7 described in the fourth aspect, the temperature is raised to 80 to 120 °C. In some examples, the temperature is raised to 90 °C. In some examples, the temperature is raised to 100 °C. In some examples, the temperature is raised to 110 °C.

[0032] In some specific examples of the synthesis of the tepotinib intermediate compound of formula 7 described in the fourth aspect, the feeding ratio of compound 13 to the base is 1:(1.5 - 2.5). In some examples, the feeding ratio of compound 13 to the base is 1:1.9. In some examples, the feeding ratio of compound 13 to the base is 1:2.1. In some examples, the feeding ratio of compound 13 to the base is 1:2.3.

[0033] The fifth aspect of the present invention provides an isotope substitute, or a tautomer, stereoisomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate of the tepotinib intermediate of formula 12.

[0034] All the medicaments used in the present invention are purchased from the open and legal market and are not further purified.

[0035] In some examples of the present invention, "room temperature" is 0 - 40 °C. In some examples, "room temperature" is 5 - 35 °C. In some examples, "room temperature" is 10 - 30 °C. In some examples, "room temperature" is 15 - 25 °C. In some examples, "room temperature" is 20 °C.

[0036] Both the first base and the second base in the present invention are bases, and the use of the first base and the second base is only a distinction in terms of code names.

[0037] In Examples 1 - 1, 2, and 2 - 1 of the present invention, reflux reactions are used, so the temperature is about the boiling point of the solvent.

[0038] Examples 1 and 2 of the present invention can be stably carried out in a variety of different solvents.

[0039] Advantages of the invention: The present invention uses the cheap raw material compound 1 as the starting material to synthesize a new compound 12 as an intermediate, and then obtains the compound tepotinib through a high - yield route. The synthesis method of the present invention has cheap raw materials and simple operations. After obtaining compound 13 using compound 12 as the substrate, it is not necessary to refine it into pure compound 13, and the next - step synthesis of compound 7 can be carried out, saving the use of precious metal palladium, significantly reducing the production cost, having a high route yield, good repeatability, and being easy to scale up production. Description of the drawings

[0040] Figure 1 It is the H - spectrum NMR data of compound 12; Figure 2 It is the H - spectrum NMR data of compound 7. Detailed implementation manners

[0041] 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 for a more detailed description of the present invention.

[0042] The present invention designs a new method for synthesizing the intermediate of tepotinib as follows: Step 1: Using commercially available 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (Compound 1) as the starting material, Compound 12 is obtained through nucleophilic substitution with Compound 11:

[0043] Step 2: Compound 12 undergoes a boration reaction to obtain Compound 13:

[0044] Step 3: Compound 13 is mixed and reacted with Compound 14, sodium carbonate, and water to obtain Compound 7.

[0045]

[0046] Example 1 Step 1: Synthesis of Compound 12

[0047] Dissolve Compound 1 (507.6 mmol, 1.0 eq.) in 500 mL of an organic solvent (DMF), add a base (potassium carbonate, 1015.2 mmol, 2.0 eq.) and m-bromobenzyl bromide (609.1 mmol, 1.2 eq.). After the addition is complete, control the temperature at 80 °C in an oil bath, heat and stir for 6 hours. It is confirmed by LCMS that the raw materials have completely reacted. After cooling, add 2500 mL of water to the reaction system, extract three times with ethyl acetate (500 mL), combine the organic phases, wash three times with saturated brine (500 mL), dry the organic phase with anhydrous sodium sulfate, filter by suction, and then concentrate to obtain a crude product as a pale yellow solid. The crude product is purified by pulping with PE / EA = 10:1 to obtain Compound 12 (pale yellow solid, 86% yield).

[0048] 1 H NMR (400 MHz, CDCl 3) δ 8.10 (t, J = 1.8 Hz, 1H), 8.02 (dt, J = 8.0,1.6 Hz, 1H), 7.77 – 7.66 (m, 2H), 7.65 – 7.57 (m, 2H), 7.43 (ddt, J = 6.7,3.9, 1.7 Hz, 2H), 7.23 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 9.7 Hz, 1H), 5.38(s, 2H),LCMS: (M+H) + ; m / z=366.28, 368.06; Example 1-1 For the base and organic solvent in Example 1, the oil bath temperature was replaced as shown in Table 1, and the yield test of Compound 12 was carried out, as shown in Table 1: Table 1: Example 2 Step 2: Synthesize Compound 13

[0049] At room temperature, Compound 12 (20.0 mmol, 1.0 eq.), the first base (potassium acetate, 60.0 mmol, 3.0eq.) and bis(pinacolato)diboron (26.0 mmol, 1.3 eq.) were dissolved in the first organic solvent (1,4-dioxane, 7 volumes, 51 mL). After evacuating and replacing with nitrogen three times, 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (0.4 mmol, 2mol%) was added. Under nitrogen protection, the temperature was gradually raised to the first reaction temperature (100 °C). After 2 hours, LCMS detected that the raw materials disappeared, and a mixed solution containing Intermediate 13 was obtained. LCMS: (M+H) + ; m / z=414.23; Step 3: Synthesize Compound 7

[0050] The intermediate 13 mixture obtained in Step 2 of Example 2 was cooled to room temperature, and water (13 mL), a second base (sodium carbonate, 40.0 mmol, 2.0 eq.), and Compound 14 (22.0 mmol, 1.1 eq.) were added. After evacuating and replacing with nitrogen three times, the reaction solution was heated to the second reaction temperature (100 °C) and stirred under reflux for 2 hours. LCMS detection showed that the raw materials were completely converted. After cooling to room temperature, ice water (50 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (100 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain Compound 7 (light gray solid, and the total yield of Steps 2 and 3 was 82%).

[0051] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (s, 2H), 8.38 (d, J = 2.3 Hz, 2H),8.31 – 8.21 (m, 2H), 8.18 (d, J = 9.8 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.72(t, J = 7.9 Hz, 1H), 7.49 (d, J = 4.9 Hz, 2H), 7.17 (d, J = 9.7 Hz, 1H), 5.45(s, 2H), 4.06 (d, J = 6.4 Hz, 2H), 3.98 (d, J = 12.5 Hz, 2H), 2.75 (s, 2H),1.98 (s, 1H), 1.85 – 1.68 (m, 2H), 1.40 (s, 9H), 1.17 (qd, J = 12.6, 4.6 Hz,2H). Example 2-1 Replace the first base, the first organic solvent, and the first reaction temperature in Step 2 of Example 2, and the second base and the second reaction temperature in Step 3 with the content in Table 2, and test the total yield of the two steps.

[0052] Table 2: a: The catalyst is Pd(PPh 3 ) 2 Cl 2 ; b: Pd(OAc) 2 , PPh 3 In Example 2 and Example 2-1, using compound 12 as a substrate, compound 7 (CAS: 1103506-80-4) was obtained through an intermediate compound 13 in a two-step method. By replacing different bases and organic solvents, good results can be achieved, and the technical solution has strong adaptability.

[0053] 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 tepotinib intermediate of formula 12, such as: 。 2. A method for synthesizing a tepotinib intermediate of formula 12, comprising: Dissolve compound 1 in an organic solvent, add a base and compound 11, and react under controlled temperature to obtain a compound of formula 12; 。 3. The method for synthesizing the intermediate of Tepotinib of formula 12 according to claim 2, characterized in that: The organic solvent is selected from one or a combination of THF, 1,4-dioxane, CH3CN, DCM, and DMF, and / or the base is selected from one or a combination of sodium carbonate, cesium carbonate, sodium bicarbonate, triethylamine, and DIPEA, and / or the temperature of the temperature control is 40-90°C.

4. A method for synthesizing a tepotinib intermediate of formula 12 according to any one of claims 2 or 3, characterized in that: The molar ratio of the compound 1 to the base is 1:(1.5-2.5), and / or, 0.9-1.1 mol of the compound 1 is added to every 1 L of the organic solvent.

5. A synthesis of a tepotinib intermediate compound of formula 13, comprising: Compound 12 , dissolving the compound 12, the first base and the diboric acid pinacol ester in an organic solvent in an inert atmosphere, adding 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, and heating to a first temperature to obtain a compound 13; 。 6. The synthesis of the intermediate compound of Tepotinib of formula 13 according to claim 4, characterized in that: The inert atmosphere is one of nitrogen or argon atmosphere, and / or the base is selected from any one or a combination of potassium acetate, sodium acetate, triethylamine, DIPEA, and / or the organic solvent is selected from one or more of toluene, ethylene glycol dimethyl ether, 1,4-dioxane, and tetrahydrofuran.

7. The synthesis of the intermediate compound of formula 13 of Tepotinib according to any one of claims 5 or 6, characterized in that: The first temperature is 90-110° C., and / or the molar ratio of the base to the compound 12 is (2.5-3.5):1, and / or the molar amount of the compound 12 per 1 L of organic solvent is 0.35-0.45 mol.

8. A synthesis of a tepotinib intermediate compound of formula 7, comprising: Compound 12 , dissolving the compound 12, the first base and the diboric acid pinacol ester in an organic solvent in an inert atmosphere, adding 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, and heating to a first temperature to obtain a mixed solution including the compound 13; Under an inert atmosphere, the mixed solution including compound 13 is mixed with water, a second base, and compound 14, and the mixture is heated to a second temperature to react, thereby obtaining compound 7; 。 9. The synthesis of the intermediate compound of Tepotinib of formula 7 according to claim 8, characterized in that: The first base is selected from any one or a combination of potassium acetate, sodium acetate, triethylamine, and DIPEA, and / or the inert atmosphere is selected from any one or a combination of nitrogen atmosphere and argon atmosphere, and / or each 1 mL of water is mixed with 1.2 to 1.6 mmol of compound 13, and / or the second base is selected from any one or a combination of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, and DIPEA, and / or the first temperature is 80 to 120°C, and / or the feed ratio of the compound 13 to the base is 1:(1.5 to 2.5), and / or the second temperature is 65 to 100°C.

10. An isotopic substitution of a tepotinib intermediate of formula 12, or a tautomer, stereoisomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate.

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