Preparation method of N-[2-(phenylmethyl) phenyl]-2-chloroacetamide

Abstract

The invention provides a novel method for preparing an epinastine intermediate N-[2-(phenyl methyl) phenyl]-2-chloroacetamide. The method mainly comprises the following steps: by taking 2-aminobenzophenone as an initial raw material, firstly reducing and then acylating, and carrying out reduction reaction on carbonyl of 2-aminobenzophenone to methylene under the catalysis of RaneyNi by taking water as a proton source. The method has the advantages that RaneyNi is recycled and reused, the organic solvent can be recycled and reused, hydrogen and a hydrogenation kettle are not needed, introduction of a high-boiling-point solvent and a toxic reagent is avoided, and the method is easy and convenient to operate, mild in reaction condition, short in reaction time, low in cost, small in pollution, high in product yield and purity and suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a method for preparing an epinastine intermediate N-[2-(phenylmethyl)phenyl]-2-chloroacetamide. Background Art

[0002] Epinastine's chemical name is 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine (III). This product is an antihistamine, a histamine H receptor antagonist, highly selective and affinity for H1 receptors, and has a stronger anti-allergic effect than traditional drugs. It is mainly used in the treatment of I allergic rhinitis, dermatitis, eczema, urticaria and bronchial asthma, etc. It has strong action, significant efficacy and good safety. The drug was developed by Boehringer Ingelheim and Sankyo in Japan and was launched in Japan in 1994 under the trade name Alesion, becoming a second-generation antihistamine and a drug with a very promising development prospect. N-[2-(phenylmethyl)phenyl]-2-chloroacetamide (I) is an important intermediate in the synthesis of epinastine.

[0003]

[0004] The method for preparing N-[2-(phenylmethyl)phenyl]-2-chloroacetamide reported in current open patents and literature data mainly contains the following:

[0005] In the Japanese invention patent JP2004292364, the carbonyl group of the starting material 2-aminobenzophenone is reduced to methylene by using hydrazine hydrate under alkaline conditions. The hydrazine hydrate used in this method is highly toxic and causes certain harm to the health of the operator. Excessive hydrazine hydrate and excessive strong alkaline wastewater seriously pollute the environment. At the same time, a high boiling point solvent needs to be introduced as a reaction solvent, which makes it difficult to recycle the solvent. In addition, the required reaction temperature is high, the reaction time is long, the energy consumption is high, the synthesis cost is increased, and its industrial production is limited.

[0006] In Chinese patent CN103012408, the carbonyl group of the starting material 2-aminobenzophenone is reduced to methylene, and a silane reagent is used as a reducing agent. The reduction reaction of this method uses a silane reagent and trifluoroacetic acid as a reaction solvent. This process uses a large amount of silane reagent, but the reaction is not thorough, the post-processing process is cumbersome, the yield is low, and the price of silane reagent is high. Trifluoroacetic acid corrodes the equipment greatly, which greatly increases the production cost and brings a series of complex problems to the management and maintenance of the equipment, which is not conducive to its industrialization. Another method is to first reduce the carbonyl group to a hydroxyl group with sodium borohydride, and then use a silane reagent to reduce it to a methylene group. This synthesis method has a cumbersome process, a low product yield, and the price of sodium borohydride is expensive, which greatly limits its industrial production.

[0007] The intermediate patent CN105061246 reduces the carbonyl group of the starting material 2-aminobenzophenone to methylene by a modified Clemmensen method, using dry chlorinated gas to react with zinc without using mercury salts, which avoids mercury pollution to the environment to a certain extent. However, a large amount of zinc mud is difficult to filter and recycle, which increases the cost and pollutes the environment. In addition, dry hydrogen chloride is used in the reaction, which is not conducive to transportation. The system also needs to be dry. Too much water will result in incomplete reaction, and there will be a lot of residual raw materials, and it is useless to extend the time.

[0008] The above-mentioned synthesis method of reducing carbonyl to methylene has many problems, which are not conducive to industrial production. Therefore, a new technical solution is currently needed, which can not only obtain higher yield and purity, but also reduce production costs, while reducing the generation of "three wastes", meet environmental protection requirements, and be suitable for industrial large-scale production. Summary of the invention

[0009] In order to overcome the deficiencies in the above process, the present invention aims to provide a novel method for preparing N-[2-(phenylmethyl)phenyl]-2-chloroacetamide, an important intermediate of epinastine.

[0010] A method for preparing N-[2-(phenylmethyl)phenyl]-2-chloroacetamide comprises adding an acid binding agent under an organic solvent condition and carrying out the following acylation steps:

[0011]

[0012] Further, for the intermediate II-2-aminobenzophenone, the amount of chloroacetyl chloride used is 1.00-1.30 equivalents, preferably 1.10 equivalents.

[0013] Furthermore, the acid binding agent is selected from one or more of triethylamine, pyridine, N,N-diisopropylethylamine and bicyclic amidine, and the amount of triethylamine used is 1.05-1.35 equivalents, preferably 1.15 equivalents, for the substrate 2-aminobenzophenone.

[0014] Furthermore, the organic solvent is selected from one or more of dichloromethane, dichloroethane, chloroform, toluene, methyl tert-ether and ethyl acetate, and the amount of dichloromethane used is 1.0-5.0 equivalents, preferably 1.5 equivalents, for the substrate 2-aminobenzophenone.

[0015] Furthermore, the reaction time of the acylation step is 3-7h or 4h.

[0016] In the embodiment of the present invention, the intermediate II is prepared by the following reduction reaction steps:

[0017]

[0018] The reaction temperature of the reduction reaction is 50-70°C or 60-65°C, and the reaction time is 3-12h or 6h 。

[0019] Furthermore, the reduction reaction is carried out under polar solvent conditions, and the polar solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol, dioxane and N,N-dimethylformamide.

[0020] Furthermore, the polar solvent is isopropanol, and water and isopropanol form a mixed solvent, the mass ratio of water:isopropanol is 1:0.5-7, preferably 1:3; the mass ratio of 2-aminobenzophenone:mixed solvent is 1:3-10, preferably 1:4.

[0021] Furthermore, the weight ratio of the raw material SM to the wet RaneyNi is 1:0.3-2 or 1:0.6.

[0022] The embodiment of the present invention also provides a method for preparing N-[2-(phenylmethyl)phenyl]-2-chloroacetamide, and the reaction steps are as follows:

[0023]

[0024] Using 2-aminobenzophenone as the starting material, under the catalysis of RaneyNi and water as a proton source, the intermediate II is reduced to intermediate Ⅱ, and then chloroacetyl chloride is added for acylation to obtain intermediate Ⅰ.

[0025] Water and isopropanol form a mixed solvent, the mass ratio of water to isopropanol is 1:0.5-7 or 1:3; the mass ratio of 2-aminobenzophenone to the mixed solvent is 1:3-10 or 1:4; the weight ratio of SM to wet RaneyNi is 1:0.3-2 or 1:0.6; the reaction time of the reduction reaction is 3-12h or 6h;

[0026] For the intermediate II-2-aminobenzophenone, the amount of chloroacetyl chloride used is 1.00-1.30 equivalents or 1.10 equivalents; for the substrate 2-aminobenzophenone, the amount of triethylamine used is 1.05-1.35 equivalents or 1.15 equivalents; for the substrate 2-aminobenzophenone, the amount of dichloromethane used is 1.0-5.0 equivalents or 1.5 equivalents; the reaction time of the acylation step is 3-7h or 4h.

[0027] The present invention has the following advantages:

[0028] (1) 2-aminobenzophenone is used as the starting material, which is first reduced and then acylated, and water is used as the proton source. No hydrogen is required, no pressure is required, the reaction conditions are mild, the equipment requirements are reduced, no hydrogenation kettle is required, and an ordinary enamel kettle can be used to complete the reaction. In addition, the reaction time is shortened, the post-treatment process is greatly simplified, and the introduction of toxic substances and high-boiling point solvents is avoided, the energy consumption is reduced, and industrial production is facilitated.

[0029] (2) The method of the present invention is environmentally friendly to the extreme. The RaneyNi and organic solvents used can be recycled and reused, which minimizes the emission of "three wastes" and achieves green production and environmental protection. The process conditions are more in line with environmental protection requirements and are conducive to industrial production.

[0030] (3) The process is safe and easy to operate, with a short reaction cycle, low production cost, and little environmental pollution. It is an environmentally friendly synthesis method. In addition, the product yield and purity are high, the quality is stable and controllable, and it is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present application and, together with the description, serve to explain the principles of the present application.

[0032] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

[0033] Figure 1 The reaction process of Example 1 (Synthesis II) HPLC spectrum: starting material 9.720min (ketone) - transition state 5.196min (alcohol) - product 10.495min (methylene).

[0034] Figure 2 This is the HPLC spectrum of the product (I) of Example 1. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0036] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments may be combined with each other. The present invention will be described in detail below with reference to specific embodiments.

[0037] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0038] Example 1

[0039] In a reaction bottle equipped with a mechanical stirrer, a thermometer and a reflux tube, add 20g (0.101mol) of raw material 2-aminobenzophenone, 20g of water and 60g of isopropanol, add 12g of wet weight RaneyNi, and then heat to 60-65°C for 6 hours. The raw material 2-aminobenzophenone in the HPHC control is ≤0.2%, and the intermediate state (alcohol) is ≤0.2% (attached Figure 1 The corresponding peak positions of raw materials, intermediates and products are given), otherwise the reaction continues. If the reaction is qualified, the temperature is lowered by about 30 degrees, filtered, RaneyNi is recovered for reuse, the mother liquor is concentrated under reduced pressure to concentrate isopropanol, the isopropanol is recovered for reuse, 20g of water is used to evaporate isopropanol, 30g of dichloromethane is added, the dichloromethane layer is separated, 11.84g (0.117mol) of triethylamine is added, the temperature is lowered to 5-10℃, 12.60g (0.112mol) of chloroacetyl chloride is slowly added dropwise, the reaction is maintained at 5-10℃ for 30min, and the reaction is continued at room temperature for 4h, HPLC raw material II≤0.2%; washed with water, evaporated to dryness, 60g of 95% ethyl is added for purification, suction filtered, and dried to obtain 22.5g of off-white to white solid, with a yield of 85.5%, HPLC purity of 99.6%, and a maximum single impurity of 0.1642% (see attached Figure 2 ), melting point 116.9-119.0℃. HPLC detection conditions are as follows: chromatographic column: C18250mm*4.6mm*5um; mobile phase: water: acetonitrile: methanol = 40:60:3; wavelength: 214nm; column temperature 40℃; flow rate: 1.0ml / min; running time: 25min; injection volume: 5ul; main peak retention time is about 7.49min.

[0040] Embodiment 2:

[0041] In a reaction bottle equipped with a mechanical stirrer, a thermometer and a reflux tube, add 20 g (0.101 mol) of raw material 2-aminobenzophenone, 20 g of water and 60 g of ethanol, add 12 g of wet weight RaneyNi, and then raise the temperature to 60-65 degrees to react for 7 hours. The raw material 2-aminobenzophenone is controlled to be ≤0.2% by HPLC, and the intermediate state is ≤0.2%. Otherwise, continue the reaction. The reaction was qualified, the temperature was lowered by about 30 degrees, filtered, RaneyNi was recovered for reuse, the mother liquor was concentrated under reduced pressure to ethanol, the ethanol was recovered for reuse, ethanol was evaporated with 20g water, 30g dichloromethane was added, the dichloromethane layer was separated, 11.84g (0.117mol) of triethylamine was added, the temperature was lowered to 5-10℃, 12.60g (0.112mol) of chloroacetyl chloride was slowly added dropwise, the reaction was maintained at 5-10℃ for 30min, and the reaction was continued at room temperature for 4h, HPLC raw material II≤0.2%; washed with water, evaporated to dryness, 60g 95% ethyl was added for purification, filtered, and dried to obtain 20.0g of white solid, with a yield of 76.0%, HPLC purity of 96.8%, and a melting point of 116.3-118.8℃.

[0042] Embodiment 3:

[0043] In a reaction bottle equipped with a mechanical stirrer, a thermometer and a reflux tube, add 20g (0.101mol) of raw material 2-aminobenzophenone, 20g of water and 60g of n-butanol, add 12g of wet weight RaneyNi, then raise the temperature to 60-65 degrees to react for 8 hours. The raw material 2-aminobenzophenone in HPHC is controlled to be ≤0.2%, and the intermediate state is ≤0.2%, otherwise continue the reaction. The reaction was qualified, the temperature was lowered by about 30 degrees, filtered, RaneyNi was recovered for reuse, the mother liquor was concentrated under reduced pressure to obtain n-butanol, the n-butanol was recovered for reuse, 20g of water was used to evaporate n-butanol, 60g of dichloromethane was added, the dichloromethane layer was separated, 11.84g (0.117mol) of triethylamine was added, 11.84g (0.117mol) of triethylamine was added, the temperature was lowered to 5-10°C, 12.60g (0.112mol) of chloroacetyl chloride was slowly added dropwise, the reaction was maintained at 5-10°C for 30min, and the reaction was continued at room temperature for 4h, HPLC raw material II ≤ 0.2%; washed with water, evaporated to dryness, 60g of 95% ethyl was added for purification, suction filtered, and dried to obtain 21.1g of white solid, which was intermediate I, with a yield of 80.1%, HPLC purity of 97.1%, and a melting point of 116.5-118.8°C.

[0044] Embodiment 4:

[0045] In a reaction bottle equipped with a mechanical stirrer, a thermometer and a reflux tube, add 20g (0.101mol) of raw material 2-aminobenzophenone, 20g of water and 60g of methanol, add 12g of wet weight RaneyNi, and then raise the temperature to 60-65 degrees to react for 8 hours. The raw material 2-aminobenzophenone is controlled to be ≤0.2% in HPHC, and the intermediate state is ≤0.2%, otherwise continue the reaction. The reaction was qualified, the temperature was lowered by about 30 degrees, filtered, RaneyNi was recovered for reuse, the mother liquor was concentrated under reduced pressure to methanol, methanol was recovered for reuse, 20g of water was used to evaporate methanol, 60g of dichloromethane was added, the dichloromethane layer was separated, 11.84g (0.117mol) of triethylamine was added, the temperature was lowered to 5-10℃, 12.60g (0.112mol) of chloroacetyl chloride was slowly added dropwise, maintained at 5-10℃ for 30min, and continued to react at room temperature for 4h, HPLC raw material II≤0.2%; washed with water, evaporated to dryness, 60g of 95% ethyl was added for purification, filtered, and dried to obtain 20.0g of white solid, with a yield of 76.0%, HPLC purity of 97.2%, and a melting point of 116.5-118.8℃.

[0046] Embodiment 5:

[0047] In a reaction bottle equipped with a mechanical stirrer, a thermometer and a reflux tube, add 20g (0.101mol) of raw material 2-aminobenzophenone, 20g of water and 60g of dioxane, add 12g of wet weight RaneyNi, and then heat to 60-65 degrees to react for 6 hours. The raw material 2-aminobenzophenone is controlled to be ≤0.2% in HPHC, and the intermediate state is ≤0.2%, otherwise continue the reaction. The reaction was qualified, the temperature was lowered by about 30 degrees, filtered, RaneyNi was recovered for reuse, the mother liquor was concentrated under reduced pressure to obtain dioxane, dioxane was recovered for reuse, dioxane was evaporated with 20g water, 60g dichloromethane was added, the dichloromethane layer was separated, 11.84g (0.117mol) triethylamine was added, the temperature was lowered to 5-10℃, 12.60g (0.112mol) chloroacetyl chloride was slowly added dropwise, the temperature was maintained at 5-10℃ for 30min, and the reaction was continued at room temperature for 4h, HPLC raw material II ≤ 0.2%; washed with water, evaporated to dryness, 60g 95% ethyl was added for purification, suction filtered, dried, and 19.6g white solid was obtained, the yield was 74.4%, the HPLC purity was 98.1%, and the melting point was 116.7-118.9℃.

[0048] Embodiment 6:

[0049] In a reaction bottle equipped with a mechanical stirrer, a thermometer and a reflux tube, add 20g (0.101mol) of raw material 2-aminobenzophenone, 20g of water and 60g of DMF, add 12g of wet weight RaneyNi, and then raise the temperature to 60-65 degrees to react for 7 hours. The raw material 2-aminobenzophenone is controlled to be ≤0.2% in HPHC, and the intermediate state is ≤0.2%, otherwise continue the reaction. The reaction was qualified, the temperature was lowered by about 30 degrees, filtered, RaneyNi was recovered for reuse, the mother liquor was concentrated under reduced pressure to DMF, DMF was recovered for reuse, DMF was evaporated with 20g water, 60g dichloromethane was added, the dichloromethane layer was separated, 11.84g (0.117mol) of triethylamine was added, the temperature was lowered to 5-10℃, 12.60g (0.112mol) of chloroacetyl chloride was slowly added dropwise, the reaction was maintained at 5-10℃ for 30min, and the reaction was continued at room temperature for 4h, HPLC raw material II≤0.2%; washed with water, evaporated to dryness, 60g 95% ethyl was added for purification, filtered, and dried to obtain 18.2g of white solid, with a yield of 69.5%, HPLC purity of 98.8%, and a melting point of 116.7-119.0℃.

[0050] The embodiments described above are part of the embodiments of the present invention, rather than all of the embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention claimed for protection, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. A method for preparing N-[2-(phenylmethyl)phenyl]-2-chloroacetamide, characterized in that: Under organic solvent conditions, an acid binding agent is added to carry out the following acylation steps:

2. The preparation method according to claim 1, characterized in that: For the intermediate II-2-aminobenzophenone, the amount of chloroacetyl chloride used is 1.00-1.30 equivalents or 1.10 equivalents.

3. The preparation method according to claim 2, characterized in that: The acid binding agent is selected from one or more of triethylamine, pyridine, N,N-diisopropylethylamine and bicyclic amidine, and the amount of triethylamine used is 1.05-1.35 equivalents or 1.15 equivalents for the substrate 2-aminobenzophenone.

4. The preparation method according to claim 3, characterized in that: The organic solvent is selected from one or more of dichloromethane, dichloroethane, chloroform, toluene, methyl tert-ether and ethyl acetate, and the amount of dichloromethane used is 1.0-5.0 equivalents or 1.5 equivalents for the substrate 2-aminobenzophenone.

5. The preparation method according to claim 4, characterized in that: The reaction time of the acylation step is 3-7h or 4h.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The intermediate II is prepared by the following reduction reaction steps: The reaction temperature of the reduction reaction is 50-70°C or 60-65°C, and the reaction time is 3-12h or 6h 。 7. The preparation method according to claim 6, characterized in that: The reduction reaction is carried out under polar solvent conditions, and the polar solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol, dioxane and N,N-dimethylformamide.

8. The preparation method according to claim 7, characterized in that: The polar solvent is isopropanol, and water and isopropanol form a mixed solvent, the mass ratio of water:isopropanol is 1:0.5-7 or 1:3; the mass ratio of 2-aminobenzophenone:mixed solvent is 1:3-10 or 1:

4.

9. The preparation method according to claim 6, characterized in that: The weight ratio of SM to wet RaneyNi is 1:0.3-2 or 1:0.

6.

10. A method for preparing N-[2-(phenylmethyl)phenyl]-2-chloroacetamide, characterized in that: The reaction steps are as follows: Using 2-aminobenzophenone as the starting material, under the catalysis of RaneyNi and water as a proton source, the intermediate II is reduced to intermediate Ⅱ, and then chloroacetyl chloride is added for acylation to obtain intermediate Ⅰ. Water and isopropanol form a mixed solvent, the mass ratio of water to isopropanol is 1:0.5-7 or 1:3; the mass ratio of 2-aminobenzophenone to the mixed solvent is 1:3-10 or 1:4; the weight ratio of SM to wet RaneyNi is 1:0.3-2 or 1:0.6; the reaction time of the reduction reaction is 3-12h or 6h; For the intermediate II-2-aminobenzophenone, the amount of chloroacetyl chloride used is 1.00-1.30 equivalents or 1.10 equivalents; for the substrate 2-aminobenzophenone, the amount of triethylamine used is 1.05-1.35 equivalents or 1.15 equivalents; for the substrate 2-aminobenzophenone, the amount of dichloromethane used is 1.0-5.0 equivalents or 1.5 equivalents; the reaction time of the acylation step is 3-7h or 4h.

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