Preparation method of apelisib intermediate 4-methylpyridine compound

Abstract

The invention discloses a preparation method of an apelisib intermediate 4-methylpyridine compound. According to the method, 2-halogen-4-methylpyridine is used as an initiator to prepare the apelisib intermediate 4-methylpyridine compound. 2-halo-4-methylpyridine shown as a compound I is used as an initiator and reacts with 1, 1, 1-trifluoroacetone under the condition of a reducing agent to obtain the 4-methylpyridine compound shown as a compound II, and the method is easy to operate, high in yield and more suitable for industrialization.

Description

[Technical field]

[0001] The present invention relates to the technical field of drug preparation, and in particular to a method for preparing a 4-methylpyridine compound, and in particular to a method for preparing 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine. [Background Technology]

[0002] Apellis is a kinase inhibitor indicated in combination with fulvestrant for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated advanced or metastatic breast cancer in men or postmenopausal women whose disease has progressed during or after treatment with an endocrine-based regimen.

[0003]

[0004] Patent CN106083840A discloses a route for preparing Apelles using 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine:

[0005]

[0006]

[0007] Patent CN106083840A also discloses two methods for synthesizing 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine. Method 1:

[0008]

[0009] The method uses 2-acetyl-4-methylpyridine as the starting material to react with TMSCF3 to introduce a trifluoromethyl group, and then converts the hydroxyl group into a methyl group through a two-step reaction. The starting material and trimethyltrifluoromethylsilane of this route are expensive, the production cost is high, and the final product is obtained by column chromatography, which is not conducive to industrial production.

[0010] Method 2:

[0011]

[0012] Using 2,4-lutidine as the starting material, butyl lithium as the base and methyl iodide as the addition to introduce the dimethyl group, and then the carboxylate is converted into trifluoromethyl through a two-step reaction. The use of hydrogen fluoride will cause serious corrosion to the production equipment. At the same time, sulfur tetrafluoride, a gas with a strong odor, is used. The production personnel need special protective equipment, which will increase the production cost. It is also extremely unfriendly to the environment and is also not conducive to industrial production. [Summary of the invention]

[0013] In order to solve the above problems, the present invention discloses a method for preparing 4-methylpyridine compounds, which are intermediates of Apellis. The method uses 2-halogen-4-methylpyridine as a starting material to prepare 4-methylpyridine compounds. The method has simple operation, high yield and is more suitable for industrialization.

[0014] The present invention discloses the following technical solutions:

[0015] A method for preparing an apellis intermediate 4-methylpyridine compound, using 2-halogen-4-methylpyridine shown in compound I as a starting material, reacting with 1,1,1-trifluoroacetone under a reducing agent condition to obtain a 4-methylpyridine compound shown in compound II, wherein:

[0016]

[0017] X is F, Cl, or Br.

[0018] Further, 2-halogen-4-methylpyridine is dissolved in an organic solvent, and the mass of the organic solvent is 6 times or more than 6 times that of 2-halogen-4-methylpyridine. Preferably, the mass ratio of 2-halogen-4-methylpyridine to the organic solvent is 1:7 to 15, further 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, or 1:15.

[0019] Furthermore, the organic solvent is an ether organic solvent, preferably one or more of methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, methyltetrahydrofuran, isopropyl ether, ethyl ether, and ethylene glycol dimethyl ether.

[0020] Furthermore, the reducing agent is one of n-butyl lithium, isobutyl lithium and sec-butyl lithium; preferably, the organic solvent in which the reducing agent is dissolved includes one of n-hexane, n-pentane, n-butane, cyclohexane and petroleum ether.

[0021] Furthermore, the molar ratio of compound I to 1,1,1-trifluoroacetone is 1:1.5-3, preferably 1:1.5-2.

[0022] A method for preparing 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine comprises the following steps:

[0023] (1) using the 2-halogeno-4-methylpyridine shown in compound I as a starting material, reacting with 1,1,1-trifluoroacetone under reducing agent conditions to obtain a 4-methylpyridine compound shown in compound II;

[0024]

[0025] X is F, Cl, Br;

[0026] (2) the 4-methylpyridine compound represented by compound II is reacted with methanesulfonyl chloride in the presence of a reducing agent to obtain methanesulfonic acid 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propane-2-ester represented by compound III;

[0027]

[0028] (3) Compound III is reacted with trimethylaluminum to obtain 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine

[0029]

[0030] Furthermore, in step (2), the reducing agent is sodium hydride, and the molar ratio of sodium hydride to compound II is 1.5 to 3:1.

[0031] Furthermore, the molar ratio of methanesulfonyl chloride to compound II is 1.5 to 3:1.

[0032] Furthermore, in the step (3), compound III is dissolved in dichloromethane or toluene, and the mass ratio of compound III to the organic solvent is 1:10-20.

[0033] The 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine prepared by the invention is used for preparing apellis.

[0034] Compared with existing technologies:

[0035] 1. The starting material 2-bromo-4-methylpyridine is cheap and easily available.

[0036] 2. The fluorination reagent 1,1,1-trifluoroacetone is cheaper and easier to obtain than other metal fluorination reagents, and is also environmentally friendly.

[0037] 3. There are few reaction steps, easy operation, high yield and relatively low cost.

[0038] 4. The final product is purified by vacuum distillation, which is conducive to industrial production. [Example]

[0039] To further illustrate the technical means and effects of the present invention, the present invention is further described below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention, rather than to limit the present invention.

[0040] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0041] First step reaction:

[0042]

[0043] X is F, Cl, or Br.

[0044] Compound I is dissolved in an organic solvent to prepare a solution of Compound I, and a reducing agent is added to the solution of Compound I, and the mixture is stirred. 1,1,1-trifluoroacetone is added to react to obtain Compound II.

[0045] The mass of the organic solvent for dissolving compound I is 6 times or more than the mass of compound I, and further the mass ratio of compound I to the organic solvent is 1:7 to 15, and further 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15. The organic solvent is an ether organic solvent, and further one or more of methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, methyltetrahydrofuran, isopropyl ether, ethyl ether, and ethylene glycol dimethyl ether.

[0046] The reducing agent is one of n-butyl lithium, isobutyl lithium and sec-butyl lithium.

[0047] The reducing agent is dissolved in an organic solvent and then added dropwise into the solution of compound I. The organic solvent in which the reducing agent is dissolved includes: n-hexane, n-pentane, n-butane, cyclohexane, petroleum ether, etc., including: n-hexane solution of n-butyl lithium, n-hexane solution of isobutyl lithium, n-hexane solution of sec-butyl lithium, cyclohexane solution of n-butyl lithium, cyclohexane solution of isobutyl lithium, cyclohexane solution of sec-butyl lithium, n-pentane solution of n-butyl lithium, n-pentane solution of isobutyl lithium, n-pentane solution of sec-butyl lithium, n-butane solution of n-butyl lithium, n-butane solution of isobutyl lithium, n-butane solution of sec-butyl lithium, etc.

[0048] The solubility of the reducing agent is 2.0-3.0 mol / L, further 2.0 mol / L, 2.5 mol / L, 3.0 mol / L, 3.5 mol / L, 4.0 mol / L.

[0049] The molar ratio of compound I to the reducing agent is: 1:1-1.5, further 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5.

[0050] The molar ratio of compound I to 1,1,1-trifluoroacetone is 1:1.5-3, further 1:1.5-2, further 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.

[0051] The reaction temperature of this step is less than -60°C, further -78°C.

[0052] The reducing agent is dissolved in an organic solution and then added dropwise into the solution of compound I, and stirred at a temperature below -60°C for at least 30 minutes to prepare a mixed solution; after 1,1,1-trifluoroacetone is added to the mixed solution, the mixture is kept warm and stirred for 1 hour, and then the temperature is raised to below 10°C, further to 0-10°C, 20% ammonium chloride solution and ethyl acetate are added, extraction is performed, the pressure is reduced, and concentration is performed to obtain compound II 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol.

[0053] Second step reaction:

[0054]

[0055] Sodium hydride is dissolved in mineral oil to prepare a solution with a mass fraction of 60%. The sodium hydride mineral oil solution is added to tetrahydrofuran, the temperature is controlled at 0-10°C, and the solution of compound II is added dropwise. After the addition is completed, the temperature is raised to 35-45°C, and the reaction is stirred for 4 hours. The temperature is lowered to 20-30°C, and a solution of methanesulfonyl chloride is added dropwise to obtain compound III.

[0056] The molar ratio of sodium hydride to compound II is 1.5 to 3:1, further 2 to 3:1, and is 2:1, 2.5:1, and 3:1.

[0057] The molar ratio of methanesulfonyl chloride to compound II is 1.5 to 3:1, further 2 to 3:1, and is 2:1, 2.5:1, and 3:1.

[0058] Step 3

[0059]

[0060] Compound III is dissolved in an organic solvent, trimethylaluminum solution is added dropwise at -20°C to 0°C, and the reaction is stirred while maintaining the temperature at -20°C to 0°C to prepare compound TM.

[0061] Compound III is dissolved in dichloromethane or toluene, and the mass ratio of compound III to the organic solvent is 1:10-20, further 1:10-15, further 1:10, 1:11, 1:12, 1:13, 1:14, 1:15.

[0062] The concentration of the trimethylaluminum solution is 0.5-1.5 mol / L, further 1.0 mol / L.

[0063] Example 1

[0064] 1,1,1-Trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol

[0065]

[0066] Example 1-1

[0067] Add 100.00g of 2-bromo-4-methylpyridine and 1000.00g of tetrahydrofuran to a 5L four-necked flask. Under nitrogen protection, control the temperature to <-60°C, add 244ml of 2.5mol / L n-butyl lithium n-hexane solution dropwise, complete the addition, stir for 30 minutes, control the temperature to <-60°C, add 97.70g of 1,1,1-trifluoroacetone dropwise, complete the addition, keep warm and stir for 1 hour, then raise the temperature. Control the temperature to <10°C, add 1000.00g of 20% ammonium chloride aqueous solution, and add 1500.00g of ethyl acetate. Let stand, separate, and concentrate the organic phase under reduced pressure to obtain 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol (compound b), weighing 95.50g, with a yield of 80.00%.

[0068] Example 1-2

[0069] Add 100.00g of 2-bromo-4-methylpyridine and 2000.00g of cyclopentyl methyl ether to a 5L four-necked flask. Under nitrogen protection, control the temperature to <-60°C, add 244ml of 2.5mol / L n-butyl lithium n-hexane solution dropwise, complete the addition, stir for 30 minutes, control the temperature to <-60°C, add 97.70g of 1,1,1-trifluoroacetone dropwise, complete the addition, keep warm and stir for 1 hour, then raise the temperature. Control the temperature to <10°C, add 1000.00g of 20% ammonium chloride aqueous solution. Let stand, separate, and concentrate the organic phase under reduced pressure to obtain 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol (compound b), weighing 90.90g, with a yield of 76.21%.

[0070] Examples 1-3

[0071] According to the reaction steps of Examples 1-1 and 1-2, using different reaction reagents, conditions, ratios, etc., the yields obtained are as follows:

[0072]

[0073] Example 2

[0074] 1,1,1-Trifluoro-2-(4-methylpyridin-2-yl)propan-2-methanesulfonate

[0075]

[0076] Example 2-1

[0077] Under nitrogen protection, add 1425.00g of tetrahydrofuran and 37.04g of sodium hydride solution (60% sodium hydride dissolved in mineral oil) to a 5L four-necked flask. Control the temperature at 0-10°C, and drop 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol (Compound II) (95.00g) dissolved in 200ml of tetrahydrofuran. After the addition is complete, raise the reaction temperature to 40°C and stir at 40°C for 4 hours, then cool down. Control the temperature at 20-30°C, drop 106.08g of methylsulfonyl chloride dissolved in 100ml of tetrahydrofuran, and stir at 40°C for 4 hours. Control the temperature at <10°C, add 1000.00g of water to quench, and add 1000.00g of ethyl acetate. After standing, the organic phase was separated into layers. The upper organic phase was washed with 1000.00 g of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to produce a beige solid. The solution was refluxed in 600 ml of n-heptane and 225 ml of ethyl acetate. After hot filtration on a sintered funnel, the product crystallized at 0°C. After filtration, the filter cake was washed with 8:3 cold heptane / ethyl acetate (3×100 ml) and dried at 50°C to constant weight, thereby producing 118.00 g of methanesulfonic acid 1,1,1-trifluoro-2-(4-methylpyridin-2-yl) propan-2-ester (compound c), with a yield of 90.00%.

[0078] Example 2-2

[0079] Under nitrogen protection, add 1425.00g of tetrahydrofuran and 27.78g of sodium hydride solution (60% sodium hydride dissolved in mineral oil) to a 5L four-necked flask. Control the temperature at 0-10°C, and drop 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol (compound b) (95.00g) dissolved in 200ml of tetrahydrofuran. After the addition is complete, raise the reaction temperature to 40°C and stir at 40°C for 4 hours, then cool down. Control the temperature at 20-30°C, drop 79.56g of methylsulfonyl chloride dissolved in 100ml of tetrahydrofuran, and stir at 40°C for 4 hours. Control the temperature at <10°C, add 1000.00g of water to quench, and add 1000.00g of ethyl acetate. After standing, the organic phase was separated into layers. The upper organic phase was washed with 1000.00 g of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to produce a beige solid. Dissolved in 600 ml of n-heptane and 225 ml of ethyl acetate under reflux. After hot filtration on a sintered funnel, the product crystallized at 0°C. After filtration, the filter cake was washed with 8:3 cold heptane / ethyl acetate (3×100 ml) and dried at 50°C to constant weight, thereby producing 120.00 g of methanesulfonic acid 1,1,1-trifluoro-2-(4-methylpyridin-2-yl) propan-2-ester (compound c), with a yield of 91.49%.

[0080] Example 3

[0081] 4-Methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine

[0082]

[0083] Example 3-1

[0084] Under nitrogen protection, add 100.00 g of 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propane-2-methanesulfonate (Compound C) and 1.5 L of dichloromethane into a 5 L four-necked flask. Control the temperature at -20°C to 0°C, and dropwise add 1 mol / L trimethylaluminum (solvent: n-hexane).

[0085] 1059ml, add dropwise, keep warm and stir for 2 hours. Control the temperature at 0-10℃, add 1000.00g saturated sodium bicarbonate aqueous solution to quench the reaction system. Filter through diatomaceous earth, let stand and stratify, concentrate the lower organic phase under reduced pressure and distill to obtain 42.90g of 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine (Compound 1), with a yield of 60.00%, as a colorless oil.

[0086] Example 3-2

[0087] Under nitrogen protection, add 100.00 g of 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propane-2-methanesulfonate (Compound C) and 1.5 L of toluene into a 5 L four-necked flask. Control the temperature at -20°C to 0°C, and dropwise add 1 mol / L trimethylaluminum (solvent: n-hexane).

[0088] 1059ml, add dropwise, keep warm and stir for 2 hours. Control the temperature at 0-10℃, add 1000.00g saturated sodium bicarbonate aqueous solution to quench the reaction system. Filter through diatomaceous earth, let stand and stratify, concentrate the upper organic phase under reduced pressure and distill to obtain 39.33g of 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine (Compound 1), with a yield of 55.00%, as a colorless oil.

[0089] The applicant declares that the present invention illustrates the detailed method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed method, that is, it does not mean that the present invention must rely on the above-mentioned detailed method to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing apellis intermediate 4-methylpyridine compound, characterized in that: Using 2-halogen-4-methylpyridine shown in compound I as a starting material, under reducing agent conditions, it reacts with 1,1,1-trifluoroacetone to obtain a 4-methylpyridine compound shown in compound II, wherein: X is F, Cl, or Br.

2. The method for preparing an apellis intermediate 4-methylpyridine compound according to claim 1, characterized in that: The 2-halogen-4-methylpyridine is dissolved in an organic solvent, and the mass of the organic solvent is 6 times or more than 6 times that of the 2-halogen-4-methylpyridine. Preferably, the mass ratio of 2-halogen-4-methylpyridine to the organic solvent is 1:7 to 15, further 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, or 1:

15.

3. The method for preparing an apellis intermediate 4-methylpyridine compound according to claim 2, characterized in that: The organic solvent is an ether organic solvent, preferably one or more of methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, dioxane, methyltetrahydrofuran, isopropyl ether, ethyl ether, and ethylene glycol dimethyl ether.

4. The method for preparing an apellis intermediate 4-methylpyridine compound according to claim 3, characterized in that: The reducing agent is one of n-butyl lithium, isobutyl lithium and sec-butyl lithium; preferably, the organic solvent in which the reducing agent is dissolved includes one of n-hexane, n-pentane, n-butane, cyclohexane and petroleum ether.

5. The method for preparing an apellis intermediate 4-methylpyridine compound according to claim 4, characterized in that: The molar ratio of compound I to 1,1,1-trifluoroacetone is 1:1.5-3, preferably 1:1.5-2.

6. A method for preparing 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine, characterized in that: The following steps are involved: (1) using the 2-halogeno-4-methylpyridine shown in compound I as a starting material, reacting with 1,1,1-trifluoroacetone under reducing agent conditions to obtain a 4-methylpyridine compound shown in compound II; X is F, Cl, Br; (2) the 4-methylpyridine compound represented by compound II is reacted with methanesulfonyl chloride in the presence of a reducing agent to obtain methanesulfonic acid 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propane-2-ester represented by compound III; (3) Compound III is reacted with trimethylaluminum to obtain 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine 7. A method for preparing 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine according to claim 6, characterized in that: In the step (2), the reducing agent is sodium hydride, and the molar ratio of sodium hydride to compound II is 1.5 to 3:

1.

8. A method for preparing 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine according to claim 7, characterized in that: The molar ratio of methanesulfonyl chloride to compound II is 1.5-3:

1.

9. The method for preparing 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine according to claim 8, characterized in that: In the step (3), compound III is dissolved in dichloromethane or toluene, and the mass ratio of compound III to the organic solvent is 1:10-20.

10. 4-Methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine prepared according to claims 6 to 9 for use in the preparation of Apelles.

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