WO2023174449A1

WO2023174449A1 - Method for preparing n-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide

Info

Publication number: WO2023174449A1
Application number: PCT/CN2023/094292
Authority: WO
Inventors: 岳永力; 沈艳阳; 饶经纬; 鲁飞; 林立; 柯尚峰
Original assignee: 安庆朗坤药业有限公司
Priority date: 2022-03-15
Filing date: 2023-05-15
Publication date: 2023-09-21
Also published as: CN114736154B; CN114736154A

Abstract

Provided is a method for preparing a pharmaceutical intermediate N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide. The method comprises: taking 3-chloro-4-fluoronitrobenzene and 2-pyridinemethanol as raw materials for a substitution reaction under an alkaline condition to generate N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene; then under an acidic condition, performing reduction using iron powder to generate N-(3-chloro-4-(2-pyridylmethoxy)aniline; and then performing a condensation reaction on the N-(3-chloro-4-(2-pyridylmethoxy)aniline and cyanoacetic acid under the condition of a condensing agent to generate the N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide. The method is simple to operate, mild in condition, and suitable for large-scale industrial production.

Description

Preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide

This application is required to be submitted to the China Patent Office on March 15, 2022. The application number is 202210251646.1 and the invention name is “N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoethyl The priority of the Chinese patent application "Method for Preparing Amides", the entire content of which is incorporated into this application by reference.

Technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a preparation method of pharmaceutical intermediate N-(3-chloro-4-(2-pyridinemethoxy)phenyl)-2-cyanoacetamide.

Background technique

N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide (CAS: 915945-31-2) is a HER-2 receptor tyrosine kinase inhibitor Important pharmaceutical intermediates for pyrotinib and pyrotinib maleate. Patent WO2006127205 reports the substitution reaction of 3-chloro-4-nitrobenzene and 2-pyridinemethanol as raw materials, and reduction under zinc powder conditions to generate N-(3-chloro-4-(2-pyridylmethoxy)aniline , and then condensation reaction with ethyl cyanoacetate at high temperature to prepare the synthetic route of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide, but the reaction temperature Higher (120℃-125℃), more impurities, lower yield (<30%), which is not conducive to industrial production. Chinese patent CN108084085A discloses the use of 3-chloro-4-fluoroaniline and cyanoacetic acid for condensation Reaction, and then substitution reaction with 2-pyridinemethanol under strongly alkaline conditions to prepare N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide; but this method The condensation reaction of 3-chloro-4-fluoroaniline and cyanoacetic acid is easy to occur, and the activity of the generated intermediate is greatly reduced when the substitution reaction occurs, and the amide is easy to hydrolyze under alkaline conditions, and the yield is low.

Contents of the invention

In view of the above problems, the present invention provides a preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide, which method uses 3-chloro-4-fluorine Nitrobenzene and 2-pyridinemethanol are used as raw materials, and a substitution reaction occurs under alkaline conditions. After the reaction is completed, suction filtration is performed, the filter cake is beaten in an aqueous solution, and dried after suction filtration to obtain high yield and high purity N-(3 -Chloro-4-(2-pyridylmethoxy)nitrobenzene; N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene) In a mixed solvent of ethanol and water, add acid and reduce Iron powder, after the reaction is completed, filter with suction and discard the filter cake. The filtrate is concentrated under reduced pressure to remove ethanol. After cooling to room temperature, filter with suction and filter the cake. Drying to obtain high yield and high purity N-(3-chloro-4-(2-pyridylmethoxy)aniline; then use N-(3-chloro-4-(2-pyridylmethoxy)aniline and cyanide Acetic acid undergoes a condensation reaction under the action of a condensing agent. After the reaction is completed, filter while it is hot, concentrate the solvent and add water for low-temperature crystallization to obtain the target product N-(3-chloro-4-(2-pyridylmethoxy)benzene. base)-2-cyanoacetamide, this preparation route has mild reaction, high yield, and is easy for industrial production.

Specifically, this application is implemented through the following technical routes:

A preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide, the preparation steps are as follows:

1) Dissolve 3-chloro-4-fluoronitrobenzene (II) and 2-pyridinemethanol (I) in solvent I, add solid inorganic base, and after a substitution reaction occurs at 30-50°C under alkaline conditions, Perform suction filtration, take the filter cake and beat it in the aqueous solution, suction filtrate again, and obtain N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene (III) after air drying at 60°C;

The solvent I includes at least one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether and toluene, and acetonitrile is preferably used;

The inorganic base includes at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, and potassium hydroxide is preferably used;

The molar ratio of the 2-pyridinemethanol (I) and 3-chloro-4-fluoronitrobenzene (II) is 1.03 to 1.2:1;

The molar ratio of the inorganic base to 3-chloro-4-fluoronitrobenzene (II) is 1.1 to 1.4:1;

2) Dissolve N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene (III) in ethanol aqueous solution, add acid and reduced iron powder at 20-40°C to react, filter after the reaction is completed, and take The filtrate is concentrated under reduced pressure to remove ethanol. After cooling to room temperature, it is suction filtered again. After drying the filter cake, N-(3-chloro-4-(2-pyridylmethoxy)aniline (IV) is obtained;

The volume ratio of ethanol to water in the ethanol aqueous solution is 3 to 5:1.

The acid includes at least one of commercially available hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid, preferably hydrochloric acid is used;

The molar ratio of the acid to the substrate N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene (III) is 2 to 4:1;

The molar ratio of the reduced iron powder to the substrate N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene (III) is 3 to 6:1;

3) Dissolve N-(3-chloro-4-(2-pyridylmethoxy)aniline (IV) and cyanoacetic acid (V) in solvent II, add a condensing agent, and a condensation reaction will occur at 40-70°C. After completion, suction filtration while hot removes solid insoluble matter, and the filtrate is concentrated to obtain a concentrate; after adding an appropriate amount of water to the concentrate, crystallize at 0-10°C to obtain N-(3-chloro-4-(2- Pyridylmethoxy)phenyl)-2-cyanoacetamide (VI);

The solvent II includes at least one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether and toluene, and tetrahydrofuran is preferably used;

The volume to mass ratio (m/v) of the solvent II described in the above steps to the substrate N-(3-chloro-4-(2-pyridylmethoxy)aniline (IV) is 5 to 12:1, and the mass to volume ratio The unit is mL/g.

The molar ratio of the cyanoacetic acid (V) and N-(3-chloro-4-(2-pyridinemethoxy)aniline (IV) is 1.1 to 1.6:1;

The molar ratio of the condensation agent to the substrate N-(3-chloro-4-(2-pyridylmethoxy)aniline (IV) is 1.1 to 1.6:1;

The condensation agent includes dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1,3-diisopropyl At least one of carbodiimides (DIC); the condensation agent used and the urea generated after condensation are soluble in water, preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide is used Imine hydrochloride (EDCI).

The chemical equation involved in the above reaction is as follows:

Compared with the existing preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide, the preparation method provided by the invention has the following beneficial effects:

1) The reaction route of the present invention uses 3-chloro-4-fluoronitrobenzene and 2-pyridinemethanol as raw materials, under alkaline conditions A substitution reaction occurs under the conditions. After the reaction is completed, it is suction filtered. The product in the filter cake has high purity and the filtrate is a single solvent, which is easy to recycle. After the filter cake is slurried with water, the inorganic salts and slight excess alkali in the product are removed; due to N-(3 -Chloro-4-(2-pyridylmethoxy)nitrobenzene has low solubility in organic solvents and water, but has high solubility in mixed solvents of organic solvents and water. The reaction yield is higher than that of 3-chloro-4 reported in WO2006127205 -After the substitution reaction of nitrobenzene and 2-pyridine benzyl alcohol is completed, the crystallization yield by adding water is significantly higher, and the mother liquor is easy to recover.

2) The reducing agent used in N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene is reduced iron powder, which is cheaper, easier to obtain and safer than zinc powder; the solvent used is a mixture of water and ethanol The solvent has a mild reduction temperature; after the reaction is completed, filter with suction, the filtrate is concentrated in ethanol, filter with suction, and the filter cake is dried to obtain N-(3-chloro-4-(2-pyridylmethoxy)aniline, with high purity of 96% above;

3) The condensation agent used in the condensation reaction is DCC, EDCI, DCI, etc. After the condensation is completed, the insoluble matter is removed by suction filtration, and the solvent is concentrated and removed, and water is added for crystallization to obtain N-(3-chloro-4-(2-pyridinemethoxy)) Phenyl)-2-cyanoacetamide; compared with the high-temperature preparation route disclosed in patent WO2006127205, the reaction is milder, and the crystallized solid has higher purity and higher yield.

Description of the drawings

Figure 1 is a high performance liquid chromatogram of intermediate III prepared in Example 1;

Figure 2 is a high performance liquid chromatogram of intermediate IV prepared in Example 2;

Figure 3 is a high performance liquid chromatogram of the target product VI prepared in Example 3;

Figure 4 is a 1H-NMR pattern of the target product intermediate VI prepared in Example 3;

Figure 5 is a high performance liquid chromatogram of the target product VI prepared in Example 4.

Detailed ways

Unless otherwise stated, the raw materials and reagents used in the following examples are all commercially available.

The raw materials 3-chloro-4-fluoronitrobenzene (II) and 2-pyridinemethanol (I) were purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.; cyanoacetic acid (V) was purchased from Shanghai McLean Biochemical Technology Co., Ltd.; reduced iron The powder was purchased from Xilong Science Co., Ltd.

Example 1

Add 1000mL acetonitrile, 34.3g (0.314mol) 2-pyridinemethanol (I) into the 3000mL reaction bottle, stir, add 21.0g (0.375mol) potassium hydroxide, 52.7g (0.30mol) 3-chloro-4-fluoronitro Benzene (II), raise the temperature to 40°C, keep the reaction for more than 24 hours, and detect by TLC (ethyl acetate: n-hexane = 1:1, raw material 3-Chloro-4-fluoronitrobenzene (almost no residue)), after the reaction is completed, cool to 5°C, keep stirring (100 rpm, the same below) for more than 2 hours, filter with suction, beat the filter cake with 200 mL of water and pump again Filter, and the filter cake is blast dried at 60°C for more than 12 hours to obtain 76.2g of light yellow solid N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene, with a yield of 96.0%. High-performance liquid phase detection of Purity 96.47%. (LC conditions: Agilent 1260 infinity II, WondaSil C18 Superb (4.6×250mm, 5um), mobile phase: sodium dihydrogen phosphate buffer, triethylamine to adjust pH to 6.1, wavelength 233nm, column temperature 35 ℃, flow rate 1.0mL/min, the same below), the liquid chromatogram is shown in Figure 1.

Example 2

Add 616 mL ethanol and 154 mL water to the 2000 mL reaction bottle. After stirring, an ethanol aqueous solution is obtained. Add 77 g (0.29 mol) N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene prepared in Example 1, 29 mL). Hydrochloric acid with a concentration of 37% was heated to 30°C, and 81.4g (1.45mol) reduced iron powder was slowly added. After stirring for 1 hour, TLC detected (ethyl acetate: n-hexane = 1:1, the raw material for this step is N-(3 -Chloro-4-(2-pyridylmethoxy)nitrobenzene (III) with almost no residue), after the reaction is completed, cool to room temperature, filter with suction, wash the filter cake with a little ethanol, discard the filter cake, and use the filtrate rotary evaporator Basically no liquid flows out under reduced pressure at 50°C. Concentrate to a viscous state, then add 300mL of water, stir and crystallize at 5°C for more than 1 hour, filter with suction, and blast dry the filter cake at 60°C for more than 12 hours to obtain a tan solid N-(3- 61.8g of chloro-4-(2-pyridylmethoxy)aniline (IV), yield 90.9%, purity 97.08%. Liquid chromatogram of the obtained 3-chloro-4-(pyridylmethoxy)aniline As shown in Figure 2 (chromatographic parameters are the same as Example 1).

Example 3

Add 70 mL tetrahydrofuran, 7.0 g (0.03 mol) N-(3-chloro-4-(2-pyridylmethoxy)aniline (IV) prepared in Example 2, and 3.0 g (0.035 mol) cyanoacetic acid into the 250 mL reaction bottle. , 7.2g (0.035mol) dicyclohexylcarbodiimide, heated to 66°C and incubated for 1 hour, then TLC detected (ethyl acetate: n-hexane = 1:1, the raw material for this step is 3-chloro-4-(pyridinemethyl) There is almost no residue of oxy)aniline (IV), the same below). After the reaction is completed, filter while it is hot. The filtrate is cooled to room temperature. Concentrate under reduced pressure at 40°C on a rotary evaporator until almost no liquid flows out. Add 140 mL of aqueous solution to the concentrate. , keep stirring at 5℃ to crystallize for more than 2h, filter with suction, wash the filter cake with a little ethyl acetate, take a sample for NMR detection, and blast dry the filter cake at 60℃ for more than 12h to get brown solid N-(3-chloro-4-( 4.5g of 2-pyridylmethoxy)phenyl)-2-cyanoacetamide (VI), the yield is 52.1%, and the purity is 96.60%. Its liquid chromatography is shown in Figure 3, and its 1H-NMR chart is shown in Figure 3. As shown in 4, the NMR spectrum was confirmed to be the target product N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetyl Amine(VI).

Example 4

Add 470 mL tetrahydrofuran to the 1000 mL reaction flask, stir, and add 46.9 g (0.20 mol) of N-(3-chloro-4-(2-pyridylmethoxy)aniline (IV) prepared in Example 2 to the reaction flask, 23.8 g (0.28mol) cyanoacetic acid, 53.7g (0.28mol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, complete the addition, heat to 66°C and incubate for 1 hour, TLC After detection and reaction, filter while hot, cool the filtrate to room temperature, and concentrate the filtrate under reduced pressure using a rotary evaporator at 40°C until almost no liquid flows out. Add 470mL of water, stir at 5°C for more than 2 hours, filter with suction, and wash the filter cake with a little ethanol. , the filter cake was air-dried at 60°C for more than 12 hours to obtain 42.3g of brown solid N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide (VI), with a yield of 73.5%, and the purity is 99.25%. Its liquid chromatography is shown in Figure 5.

It can be seen that using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) as the condensation agent significantly improves the yield and purity compared with dicyclohexylcarbodiimide (DCC).

The above-mentioned specific embodiments further describe the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above-mentioned are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

A preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide, which is characterized in that the steps are as follows:

1) Dissolve 3-chloro-4-fluoronitrobenzene and 2-pyridinemethanol in solvent I, add an inorganic base, and after a substitution reaction occurs at 30-50°C, suction filter; take the filter cake, beat it, suction filter again, and dry. Finally, N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene is obtained;

The solvent I includes at least one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether and toluene;

The inorganic base used includes at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate;

2) Dissolve the N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene obtained in step 1) in an aqueous ethanol solution, add acid and reduced iron powder, filter after the reaction is completed, and take the filtrate to reduce Concentrate under pressure to remove ethanol, filter again with suction, and dry the filter cake to obtain N-(3-chloro-4-(2-pyridylmethoxy)aniline;

The acid includes at least one of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid;

3) Dissolve N-(3-chloro-4-(2-pyridylmethoxy)aniline and cyanoacetic acid obtained in step 2) in solvent II, add a condensing agent to perform a condensation reaction, and filter with suction after the condensation reaction is completed. Take the filtrate and concentrate; add water to the concentrate and crystallize at 0-10°C to obtain N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide;

The solvent II includes at least one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether and toluene;

The condensation agent includes dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1,3-diisopropylcarbodiimide. of at least one.
The preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide according to claim 1, characterized in that, in step 1), the inorganic base The molar ratio to 3-chloro-4-fluoronitrobenzene is 1.1~1.4:1.
The preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide according to claim 1 or 2, characterized in that in step 1), the The molar ratio of 2-pyridinemethanol and 3-chloro-4-fluoronitrobenzene is 1.03 to 1.2:1.
The preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide according to claim 1, characterized in that, in step 2), the ethanol aqueous solution , the volume ratio of ethanol to water It is 3~5:1.
The preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide according to claim 1, characterized in that in step 2), the acid and The molar ratio of N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene is 2 to 4:1.
The preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide according to claim 1 or 5, characterized in that in step 2), the The molar ratio of reduced iron powder to N-(3-chloro-4-(2-pyridylmethoxy)nitrobenzene is 3 to 6:1.
The preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide according to claim 1, characterized in that in step 3), the solvent II The volume to mass ratio with N-(3-chloro-4-(2-pyridylmethoxy)aniline is 5 to 12:1, and the unit of the mass to volume ratio is mL/g.
The preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide according to claim 1, characterized in that, in step 3), the cyano group The molar ratio of acetic acid to N-(3-chloro-4-(2-pyridylmethoxy)aniline is 1.1 to 1.6:1.
The preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide according to claim 1, 7 or 8, characterized in that, in step 3), The molar ratio of the condensation agent to N-(3-chloro-4-(2-pyridylmethoxy)aniline is 1.1 to 1.6:1.
The preparation method of N-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide according to claim 1, 7 or 8, characterized in that, in step 3), The temperature of the condensation reaction is 40-70°C.