Synthesis process of ponatinib key intermediate

Abstract

The invention discloses a synthesis process of a ponatinib key intermediate, which comprises the following steps: taking 2-methyl-3-butyne-2-alcohol and 3-iodo-4-methyl methyl benzoate as raw materials, and carrying out coupling reaction under an alkaline condition to obtain a compound I, namely 3-(3-hydroxy-3-methylbutyl-1-alkynyl)-4-methyl methyl benzoate; and reacting the compound I with sodium hydrogen to remove tert-butyl alcohol so as to obtain a compound II, namely 3-ethynyl-4-methyl benzoate. The synthesis of the ponatinib key intermediate is realized by replacing alkynyl silane with alkynol in a breakthrough manner, the raw materials are wide in source and low in cost, the operation is safe and simple, the purity of the final intermediate reaches 90% or above, and the total yield reaches 60% or above.

Description

Technical Field

[0001] The invention relates to the technical field of waste gas treatment, and in particular to a synthesis process of a key intermediate of Ponatinib. Background Art

[0002] Methyl 3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethyl)-4-methylbenzoate (Compound III) is a pharmaceutical intermediate and is the core structure for preparing ponatinib.

[0003] 3-ethynyl-4-methylbenzoic acid methyl ester (Compound II) is a key intermediate for preparing 3-(2-(imidazo[1,2-b]pyridazine-3-yl)ethyl)-4-methylbenzoic acid methyl ester (Compound III). At present, the domestic patents CN 103664951.(2014) and CN 103664960.(2014) are prepared by the reaction of trimethylethynylsilane and 3-iodo-4-methylbenzoic acid methyl ester, which has the disadvantages of high price, complex post-treatment, low yield (<50%), etc., and cannot meet the requirements of the pharmaceutical industry for quality control and safety of Ponatinib. Therefore, the present invention introduces a preparation method of 3-ethynyl-4-methylbenzoic acid methyl ester (Compound II), which has the advantages of wide material source, low price, high yield, etc., and provides a synthetic research idea for the preparation of this key intermediate (Compound II).

[0004]

[0005] The preparation of prior art compound II is as follows:

[0006] Summary of the invention

[0007] Based on the above deficiencies in the prior art, the technical problem solved by the present invention is that, in view of the fact that 3-ethynyl-4-methylbenzoic acid methyl ester (Compound II) is currently a key intermediate for preparing 3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethyl)-4-methylbenzoic acid methyl ester (Compound III), and domestic patents currently report that Compound II is prepared by the reaction of trimethylethynylsilane and 3-iodo-4-methylbenzoic acid methyl ester. The present invention provides a method for preparing 3-ethynyl-4-methylbenzoic acid methyl ester (Compound II) by using 2-methyl-3-butyn-2-ol and 3-iodo-4-methylbenzoic acid methyl ester, the raw material source is wide and cheap, the operation is safe and simple, the final intermediate purity reaches more than 90%, and the total yield reaches more than 60%.

[0008] In order to solve the above technical problems, the present invention provides a synthesis process of a key intermediate of Ponatinib, wherein the process comprises the following steps: using 2-methyl-3-butyn-2-ol and 3-iodo-4-methylbenzoic acid methyl ester as raw materials for coupling reaction under alkaline conditions to obtain compound I, i.e., 3-(3-hydroxy-3-methylbut-1-ynyl)-4-methylbenzoic acid methyl ester; and compound I is then reacted with sodium hydrogen to remove tert-butyl alcohol to obtain compound II, i.e., 3-ethynyl-4-methylbenzoic acid methyl ester.

[0009] As a preferred embodiment of the above technical solution, the synthesis process of the key intermediate of Ponatinib provided by the present invention further includes some or all of the following technical features:

[0010] As an improvement of the above technical solution, the synthesis process is carried out according to the following chemical reaction equation:

[0011]

[0012] As an improvement of the above technical solution, the specific steps are as follows:

[0013] (1) Add water, K2CO3 / Cs2CO3 / K3PO4, CuI, Ph3P and 10% Pd / C (ligand palladium reagent catalysis) to a DME solution of methyl 3-iodo-4-methylbenzoate, stir at room temperature for 30 to 60 minutes, then add 2-methyl-3-butyn-2-ol, and heat at 80 to 90°C for reaction for 5 to 8 hours; cool the mixture to room temperature, wash and filter on a diatomaceous earth pad with ethyl acetate; dilute the solution with water and extract with ethyl acetate; wash the organic phase with brine, dry the organic phase with anhydrous Na2SO4, and concentrate under reduced pressure; purify the concentrate by column chromatography and crystallization to obtain compound I;

[0014] (2) A dispersion of NaH in mineral oil is added to a stirred solution of compound I in dry toluene; the suspension is slowly distilled until half the volume of milliliters of toluene / acetone mixture is collected; the residue is cooled and concentrated under reduced pressure; the obtained solid is dissolved in ether and the mixture is washed with 1M Na2CO3 solution, water and brine; the organic phase is dried and concentrated under reduced pressure to obtain methyl 3-ethynyl-4-methylbenzoate.

[0015] As an improvement of the above technical solution, in step (1), the column chromatography is an ordinary silica gel column, the column is wet packed and the sample is dry loaded, and the eluent is hexane-ethyl acetate 2:1.

[0016] As an improvement of the above technical solution, the drying in step (2) is carried out by using Na2SO 4 / MgSO4 was used as a desiccant.

[0017] Methyl 3-ethynyl-4-methylbenzoate (Compound II) is a key intermediate for the pharmaceutical synthesis of panatinib. The key point of its synthesis technology lies in the coupling of the alkynyl group. At present, the relevant domestic patents CN 103664951. (2014) and CN 103664960. (2014) report that it is prepared from trimethylethynyl silicon and methyl 3-iodo-4-methylbenzoate. The trimethylethynyl silicon used has the disadvantages of high price, cumbersome post-treatment and low yield. Methyl 3-ethynyl-4-methylbenzoate (Compound II) can be used to prepare methyl 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzoate (Compound III), and methyl 3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethyl)-4-methylbenzoate (Compound III) is the mother core structure for the preparation of panatinib. This patent introduces a method for preparing methyl 3-ethynyl-4-methylbenzoate (Compound II), which has the advantages of wide material sources, low price, and high yield, and is used to meet the requirements of the pharmaceutical industry for quality control and safety of methyl 3-ethynyl-4-methylbenzoate (Compound II).

[0018] The key point of the synthesis of Ponatinib lies in the coupling of the alkynyl group. The present invention uses alkynol instead of alkynyl silane to achieve the synthesis of the key intermediate of Ponatinib. The method for preparing methyl 3-ethynyl-4-methylbenzoate (Compound II) has the following advantages:

[0019] (1) The raw material 2-methyl-3-butyn-2-ol is more widely available, cheaper, and safer to use than trimethylethynyl silicon;

[0020] (2) It provides a synthetic strategy for methyl 3-ethynyl-4-methylbenzoate (Compound II), and provides ideas for the preparation and impurity research of methyl 3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethyl)-4-methylbenzoate (Compound III), which helps in the quality control and safety of ponatinib.

[0021] (3) The purity is greater than 90%, the total yield is higher than 60%, the process operation is simple, and the post-processing is safe and convenient.

[0022] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention, it can be implemented in accordance with the contents of the specification. In order to make the above and other purposes, features and advantages of the present invention more obvious and easy to understand, the following is a detailed description in combination with the preferred embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the drawings of the embodiment are briefly introduced below.

[0024] Figure 1This is the HPLC detection spectrum of compound I obtained in Example 1 of the present invention;

[0025] Figure 2 This is the HPLC detection spectrum of compound II obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0026] The specific implementation modes of the present invention are described in detail below, which is a part of this specification. The principles of the present invention are explained through examples. Other aspects, features and advantages of the present invention will become clear through the detailed description.

[0027] Example 1

[0028] (1) To a solution of methyl 3-iodo-4-methylbenzoate (40.05 g, 145 mmol) in 600 mL of DME (ethylene glycol dimethyl ether) were added water (275 mL), K2CO3 (50.05 g, 362 mmol), CuI (1.1 g, 5.8 mmol), Ph3P (3 g, 11.5 mol) and 10% Pd / C (3.1 g, 2.9 mmol). The resulting mixture was stirred at room temperature for 30 to 60 minutes, then 2-methyl-3-butyn-2-ol (35.5 mL, 362 mmol) was added and heated at 80 to 90°C for 5 to 8 hours. The mixture was cooled to room temperature and filtered on a celite pad after washing with ethyl acetate. The solution was diluted with water (2000 mL) and extracted with ethyl acetate (2 x 1500 mL). The organic phase was washed with brine (650 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: hexane-ethyl acetate 2:1) and crystallization (hexane-ethyl acetate 1:3, 300 mL) to obtain 33.05 g (≥97% GC) of compound Ⅰ (83% yield);

[0029] (2) NaH (400 mg of a 60% dispersion in mineral oil, 10 mmol) was added to a stirred solution of compound I (27.6 g, 119 mmol) in dry toluene (400 ml). The suspension was slowly distilled until about 200 ml of toluene / acetone mixture was collected. The residue was cooled and concentrated under reduced pressure. The solid obtained was dissolved in ether (400 ml) and the mixture was washed with 1M Na2CO3 solution (100 ml), water (60 ml) and brine (100 ml). The organic phase was dried (Na2SO4) and concentrated under reduced pressure to give 12 (≥95% GC, 21.7 g, 84% yield).

[0030] Figure 1This is the liquid phase detection spectrum of Compound I of Example 1 of the present invention, and the detection conditions are: wavelength 270.4nm, HC-C18 loading column 4.6*12.5mm, 5μm, flow rate 1mL / min, mobile phase: A: 1% acetic acid; B: acetonitrile: methanol = 65:35; as shown in the figure, the purity of 3-(3-hydroxy-3-methylbut-1-ynyl)-4-methylbenzoic acid methyl ester (Compound I) obtained after column chromatography and crystallization purification is more than 99%.

[0031] Figure 2 This is the liquid phase detection spectrum of compound II in Example 1 of the present invention. As shown in the figure, the purity of 3-ethynyl-4-methylbenzoic acid methyl ester (compound II) obtained after post-treatment, washing, drying and concentration is more than 97%.

[0032] Example 2

[0033] (1) To a solution of methyl 3-iodo-4-methylbenzoate (40.05 g, 145 mmol) in 600 mL of CPME (cyclopentyl methyl ether) were added water (275 mL), Cs2CO3 (117.87 g, 362 mmol), CuI (1.1 g, 5.8 mmol), and tetrakis(triphenylphosphine)palladium (3.4 g, 2.9 mmol). The resulting mixture was stirred at room temperature for 30 to 60 minutes, then 2-methyl-3-butyn-2-ol (35.5 mL, 362 mmol) was added, and the reaction was heated at 80 to 90° C. for 5 to 8 hours. The mixture was cooled to room temperature, washed and filtered on a diatomaceous earth pad with ethyl acetate. The solution was diluted with water (2000 mL) and extracted with ethyl acetate (2×1500 mL). The organic phase was washed with brine (650 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: hexane-ethyl acetate 2:1) and crystallization (hexane-ethyl acetate 1:3, 300 mL) to obtain 30.05 g (≥97% GC) of compound Ⅰ (76% yield);

[0034] (2) NaH (400 mg of a 60% dispersion in mineral oil, 10 mmol) was added to a stirred solution of compound I (27.6 g, 119 mmol) in dry toluene (400 ml). The suspension was slowly distilled until about 200 ml of toluene / acetone mixture was collected. The residue was cooled and concentrated under reduced pressure. The solid obtained was dissolved in ether (400 ml) and the mixture was washed with 2M NaHCO3 solution (100 ml), water (60 ml) and brine (100 ml). The organic phase was dried (Na2SO4) and concentrated under reduced pressure to give 12 (≥95% GC, 20.7 g, 80% yield).

[0035] Example 3

[0036] (1) To a solution of methyl 3-iodo-4-methylbenzoate (40.05 g, 145 mmol) in 600 mL of DME (ethylene glycol dimethyl ether) were added water (275 mL), K3PO4 (53.2 g, 250 mmol), CuI (1.1 g, 5.8 mmol), Ph3P (3 g, 11.5 mol) and 10% barium sulfate supported palladium (3.1 g, 2.9 mmol). The resulting mixture was stirred at room temperature for 30 to 60 minutes, then 2-methyl-3-butyn-2-ol (35.5 mL, 362 mmol) was added and heated at 80 to 90° C. for 5 to 8 hours. The mixture was cooled to room temperature and filtered on a celite pad after washing with ethyl acetate. The solution was diluted with water (2000 mL) and extracted with ethyl acetate (2×1500 mL). The organic phase was washed with brine (650 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: hexane-ethyl acetate 2:1) and crystallization (hexane-ethyl acetate 1:3, 300 mL) to obtain 33.15 g (≥97% GC) of compound Ⅰ (83% yield);

[0037] (2) NaH (400 mg of a 60% dispersion in mineral oil, 10 mmol) was added to a stirred solution of compound I (27.6 g, 119 mmol) in dry toluene (400 ml). The suspension was slowly distilled until about 200 ml of toluene / acetone mixture was collected. The residue was cooled and concentrated under reduced pressure. The solid obtained was dissolved in ether (400 ml) and the mixture was washed with 1M Na2CO3 solution (100 ml), water (60 ml) and brine (100 ml). The organic phase was dried (Na2SO4) and concentrated under reduced pressure to give 12 (≥95% GC, 21.9 g, 84% yield).

[0038] Methyl 3-ethynyl-4-methylbenzoate (Compound II) is a key intermediate for the pharmaceutical synthesis of panatinib. The key point of its synthesis technology lies in the coupling of the alkynyl group. At present, the relevant domestic patent reports that it is prepared from trimethylethynyl silicon and methyl 3-iodo-4-methylbenzoate. The trimethylethynyl silicon used has the disadvantages of high price, cumbersome post-processing and low yield. Methyl 3-ethynyl-4-methylbenzoate (Compound II) can be used to prepare methyl 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzoate (Compound III), and methyl 3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethyl)-4-methylbenzoate (Compound III) is the core structure for the preparation of panatinib. This patent introduces a method for preparing methyl 3-ethynyl-4-methylbenzoate (Compound II), which has the advantages of wide material sources, low price, and high yield, and is used to meet the requirements of the pharmaceutical industry for quality control and safety of methyl 3-ethynyl-4-methylbenzoate (Compound II).

[0039] The key point in the synthesis of Ponatinib lies in the coupling of the alkynyl group. The present invention uses alkynol instead of alkynylsilane to realize the synthesis of the key intermediate of Ponatinib. The raw material source is wide, the price is lower, and the use is safer. The product purity is greater than 90%, the total yield is higher than 60%, the process operation is simple, and the post-processing is safe and convenient.

[0040] The raw materials listed in the present invention, as well as the upper and lower limits and interval values ​​of the raw materials of the present invention, and the upper and lower limits and interval values ​​of the process parameters (such as temperature, time, etc.) can all realize the present invention, and the embodiments are not listed one by one here.

[0041] The above is only a preferred embodiment of the present invention, which certainly cannot be used to limit the scope of rights of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and changes can be made without departing from the principle of the present invention, and these improvements and changes are also regarded as the protection scope of the present invention.

Claims

1. A synthesis process of a key intermediate of Ponatinib, characterized in that: The process is as follows: using 1 equivalent of 2-methyl-3-butyn-2-ol and 2.0-3.0 equivalents of 3-iodo-4-methylbenzoic acid methyl ester as raw materials, under 2.0-3.0 equivalents of alkaline conditions, coupling reaction is carried out at 80-100° C. for 1-2 hours to obtain compound I, i.e., 3-(3-hydroxy-3-methylbut-1-ynyl)-4-methylbenzoic acid methyl ester; compound I is then reacted with 0.1 equivalent of catalytic amount of sodium hydrogen sulfide by distillation at 100-120° C. to remove tert-butyl alcohol; after distillation to the required volume, compound II, i.e., 3-ethynyl-4-methylbenzoic acid methyl ester, is obtained by post-treatment.

2. The synthesis process of the key intermediate of Ponatinib according to claim 1, characterized in that: The synthesis process is carried out according to the following chemical reaction equation:

3. The synthesis process of the key intermediate of Ponatinib according to claim 1 or 2, characterized in that: The specific steps are as follows: (1) Add water, K2CO3 / Cs2CO3 / K3PO4, CuI, Ph3P and 10% Pd / C to a DME solution of methyl 3-iodo-4-methylbenzoate, stir at room temperature for 30 to 60 minutes, then add 2-methyl-3-butyn-2-ol, and heat at 80 to 90°C for reaction for 5 to 8 hours; cool the mixture to room temperature, wash and filter on a diatomaceous earth pad with ethyl acetate; dilute the solution with water and extract with ethyl acetate; wash the organic phase with brine, dry the organic phase with anhydrous Na2SO4, and concentrate under reduced pressure; purify the concentrate by column chromatography and crystallization to obtain compound I; (2) A dispersion of NaH in mineral oil is added to a stirred solution of compound I in dry toluene; the suspension is slowly distilled until half the volume of milliliters of toluene / acetone mixture is collected; the residue is cooled and concentrated under reduced pressure; the obtained solid is dissolved in ether and the mixture is washed with 1M Na2CO3 solution, water and brine; the organic phase is dried and concentrated under reduced pressure to obtain methyl 3-ethynyl-4-methylbenzoate.

4. The synthesis process of the key intermediate of Ponatinib according to claim 3, characterized in that: In the step (1), the column chromatography is a common silica gel column, the column is wet packed and the sample is dry loaded, and the eluent is hexane-ethyl acetate 2:

1.

5. The synthesis process of the key intermediate of Ponatinib according to claim 3, characterized in that: In step (2), Na2SO4 is used for drying. 4 / MgSO4 was used as a desiccant.

6. The synthesis process of the key intermediate of Ponatinib according to claim 1, characterized in that: The steps described.

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