A preparation method of midanaxine

Abstract

The present invention provides a method for preparing midanacin. This method uses readily available and inexpensive diphenylacetonitrile, 1,2-dibromoethane, and 2-methylimidazole as raw materials, and it is easier to control costs during large-scale production. By adopting the method of continuous feeding in a multi-step conversion through superposition and contraction, the process flow is streamlined and the production cycle is shortened. The purity of the finished product is above 99%, and the overall yield is 78-83%. Compared with the existing process, the material cost can be relatively saved by about 20%-30%. The process uses water and alcohols as solvents, which is more environmentally friendly and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and particularly relates to a preparation method of imidafenacin. Background Art

[0002] Imidafenacin is a novel highly bladder-selective anticholinergic drug of diphenylbutyramide class jointly developed by Ono Pharmaceutical Co., Ltd. and Kyorin Pharmaceutical Co., Ltd. in Japan. It can block the contraction effect of choline on the detrusor muscle and is used for the treatment of overactive bladder. It was approved for marketing in Japan in June 2007. The chemical name of imidafenacin is 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutyramide, and its structural formula is shown as formula (Ⅰ):

[0003]

[0004] Patent CN105399678 reported the following route: Using 2-bromoethyl diphenylacetonitrile and 2-methylimidazole as raw materials, through two-step reactions of substitution and hydrolysis and subsequent recrystallization purification, imidafenacin was obtained, with an overall yield of about 78%. During the scale-up production process, there are problems such as high price of the raw material 2-bromoethyl diphenylethyl and high production cost.

[0005]

[0006] Patent CN103772286 reported the following route: Using 2-bromoethyl diphenylacetonitrile as the raw material, first hydrolyzing, and then carrying out a substitution reaction with 2-methylimidazole to obtain imidafenacin, with an overall yield of about 72% for the two steps. In the actual production process, problems such as high price of the raw material 2-bromoethyl diphenylethyl and high production cost are still encountered.

[0007]

[0008] Patent CN103880751 reported the following route: Reacting 2-methylimidazole with 1,2-dibromoethane to obtain 1-(2-bromoethyl)-2-methyl-imidazole, then carrying out a substitution reaction with diphenylacetonitrile, and after purification by hydrochloric acid salting, continuing the hydrolysis reaction to obtain imidafenacin. The production steps are slightly longer, and the overall yield is about 65%.

[0009]

[0010] Patent CN103319422 reported the following route: Using 2-chloroethyl diphenylacetonitrile and 2-methylimidazole as raw materials, through two-step reactions of substitution and hydrolysis and subsequent recrystallization purification, imidafenacin was obtained, with an overall yield of about 75%. During the scale-up production process, problems such as difficult purchase of the raw material 2-bromoethyl diphenylethyl and high production cost still exist.

[0011] SUMMARY OF THE INVENTION

[0012] Based on the previous research, the present invention further optimizes the production process and controls the production cost, and provides a preparation method of midanaxine.

[0013] The technical solution of the present invention is as follows: A preparation method of midanaxine, comprising the following steps:

[0014]

[0015] a) 2-Methylimidazole, 1,2-dibromoethane, and catalyst A are dissolved in solvent A, and heated for reaction;

[0016] b) Diphenylacetonitrile is added to the reaction system of step a), and further heated for reaction;

[0017] c) After monitoring by TLC that the reaction of diphenylacetonitrile is complete, the temperature is lowered to room temperature, base A and 30% hydrogen peroxide are added, and the temperature is raised for reaction,

[0018] d) After the reaction in step c) is completed, the temperature is lowered to room temperature, the reaction solution is diluted with water, stirred and filtered, and the filter cake is washed with cold solvent B to obtain the crude midanaxine;

[0019] e) The crude midanaxine is recrystallized with isopropanol to obtain the finished midanaxine.

[0020] In some embodiments, the catalyst A in step a) is selected from triethylenediamine.

[0021] In some embodiments, the solvent A in step a) is selected from one or more of water, ethanol, and isopropanol, preferably a mixed solution of ethanol, isopropanol and water, more preferably 50% aqueous ethanol solution or 50% aqueous isopropanol solution.

[0022] In some embodiments, the heating temperature in step a) is 60-70 °C, and the reaction time is 3 h.

[0023] In some embodiments, the molar ratio of the amounts of 2-methylimidazole, 1,2-dibromoethane and catalyst A in step a) is 1:1:2.

[0024] In some embodiments, the volume-mass ratio of solvent A to 2-methylimidazole in step a) is 8:1.

[0025] In some embodiments, the molar ratio of the amounts of diphenylacetonitrile and 2-methylimidazole in step b) is 1:0.85-0.95.

[0026] In some embodiments, the heating temperature in step b) is 90 °C.

[0027] In some embodiments, in step c), base A is selected from potassium hydroxide or sodium hydroxide, preferably potassium hydroxide.

[0028] In some embodiments, in step c), the molar ratio of the amount of base A to 2-methylimidazole is 1:2.

[0029] In some embodiments, in step c), the reaction temperature is 50 - 60 °C and the reaction time is 3 h.

[0030] In some embodiments, in step d), solvent B is selected from ethanol or isopropanol.

[0031] In some embodiments, in step e), the volume-mass ratio of isopropanol to the fed 2-methylimidazole is 2.3:1.

[0032] Advantages of the present invention: The purpose of the present invention is to use more cheap and readily available diphenylacetonitrile, 1,2-dibromoethane and 2-methylimidazole as raw materials, and prepare midanax through a condensation process. The production process is more concise and smooth, the production cost is further reduced, and the solvents used are water and alcohols, which is more environmentally friendly. Specific Embodiments

[0033] The following examples can enable those skilled in the art in this specialty to understand the present invention more comprehensively, but do not limit the present invention within the scope of the described examples.

[0034] Example 1 Preparation of Intermediate 1 and Crude Midanax

[0035] Into a 1 L three-necked flask, 2-methylimidazole (30.0 g, 365.38 mmol), 1,2-dibromoethane (68.6 g, 365.38 mmol), triethylenediamine (DABCO, 82.0 g, 730.76 mmol) and 50% aqueous ethanol solution (400 mL) were added. The temperature was raised to 60 - 70 °C. After reacting for 3 h, diphenylacetonitrile (67.0 g, 347.11 mmol) was added, and the temperature was further raised to 90 °C. After monitoring by TLC that the diphenylacetonitrile reaction was complete, it was cooled to room temperature. KOH (40.9 g, 730.76 mmol) and 30% hydrogen peroxide (10 mL) were added, and the temperature was raised to 50 - 60 °C. After reacting for 3 h, it was cooled to room temperature. The reaction solution was diluted with water (200 mL), stirred for 30 minutes and then filtered. The filter cake was washed with cold ethanol (50 mL) to obtain crude midanax.

[0036] Purification of Midanax

[0037] The above crude midanax was recrystallized with isopropanol (700 mL) to obtain the finished product of midanax, a white solid, 92.0 g, with a purity of 99.87% and a yield of 83% (calculated based on the fed amount of diphenylacetonitrile).

[0038] Example 2 Preparation of Intermediate 1 and Crude Midamor

[0039] Into a 1 L three-necked flask, add 2-methylimidazole (50.0 g, 608.97 mmol), 1,2-dibromoethane (114.4 g, 608.97 mmol), triethylenediamine (DABCO, 136.6 g, 1.22 mol) and 50% isopropyl alcohol aqueous solution (400 mL). Heat the mixture to 60 - 70 °C. After reacting for 3 h, add diphenylacetonitrile (105.9 g, 548.07 mmol), and further heat to 90 °C. After monitoring by TLC that the reaction of diphenylacetonitrile is complete, cool to room temperature, add NaOH (48.5 g, 1.22 mol) and 30% hydrogen peroxide (10 mL), heat to 50 - 60 °C, react for 3 h, then cool to room temperature. Dilute the reaction solution with water (200 mL), stir for 30 minutes and then filter. Wash the filter cake with cold isopropyl alcohol (50 mL) to obtain crude Midamor.

[0040] Purification of Midamor

[0041] The above crude Midamor was recrystallized with isopropyl alcohol (1150 mL) to obtain the finished product of Midamor, a white solid, 136.5 g, with a purity of 99.88% and a yield of 78% (calculated based on the feeding amount of diphenylacetonitrile).

[0042] The present invention uses cheap and easily available diphenylacetonitrile, 1,2-dibromoethane and 2-methylimidazole as raw materials, and it is easier to control costs in large-scale production; adopts the method of continuous feeding in a series of multi-step conversions to streamline the process flow and shorten the production cycle; the purity of the finished product is above 99%, and the overall yield is 78 - 83%; compared with the existing process, the material cost can be saved by about 20% - 30%; the process uses water and alcohols as solvents, which is more environmentally friendly; it is suitable for industrial production.

Claims

1. A preparation method of midanaxine, comprising the following steps: a) 2-Methylimidazole, 1,2-dibromoethane and catalyst A are dissolved in solvent A, and heated for reaction; b) Diphenylacetonitrile is added to the reaction system of step a), and further heated for reaction; c) After monitoring by TLC that diphenylacetonitrile has completely reacted, the temperature is lowered to room temperature, alkali A and 30% hydrogen peroxide are added, and the temperature is raised for reaction, d) After the reaction in step c) is completed, the temperature is lowered to room temperature, the reaction solution is diluted with water, stirred and filtered, and the filter cake is washed with cold solvent B to obtain the crude midanaxine; e) The crude midanaxine is recrystallized with isopropanol to obtain the finished midanaxine; In step a), the catalyst A is selected from triethylenediamine; the solvent A is selected from 50% ethanol aqueous solution or 50% isopropanol aqueous solution; in step a), the heating temperature is 60-70 °C, and the reaction time is 3 h; in step a), the molar ratio of the amounts of 2-methylimidazole, 1,2-dibromoethane and catalyst A is 1:1:2, and the volume-mass ratio of solvent A to 2-methylimidazole in step a) is 8:1; In step b), the molar ratio of the amounts of diphenylacetonitrile and 2-methylimidazole is 1:0.85-0.95; the heating temperature in step b) is 90 °C, In step c), the alkali A is selected from potassium hydroxide or sodium hydroxide; in step c), the molar ratio of the amounts of alkali A and 2-methylimidazole is 1:2; in step c), the reaction temperature is 50-60 °C, and the reaction time is 3 h; In step d), the solvent B is selected from ethanol or isopropanol; In step e), the volume-mass ratio of isopropanol to the fed 2-methylimidazole is 2.3:1.

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