Preparation method and application of vomiting arresting drug compound

Abstract

The invention relates to a preparation method and application of a vomiting arresting drug compound, and the specific steps are as follows: 1) taking 2-benzhydrylquinuclidin-3-one as an initial raw material, and carrying out resolution reaction to obtain an intermediate 1: (2S)-2-benzhydrylquinuclidin-3-one; the reaction comprises a resolving agent 1, and the resolving agent 1 is selected from L-glutamic acid; 2) carrying out condensation hydrolysis reaction and reduction reaction on the intermediate 1 and (5-(tert-butyl)-2-methoxyphenyl) methylamine to prepare an intermediate 2: 2-benzhydryl-N-(-5-tert-butyl-2-methoxybenzyl) quinuclide-3-amine; 3) the intermediate 2 is subjected to a resolution reaction to prepare maropitant, and a resolving agent 2 is selected from D-(+)-dibenzoyl tartaric acid; 4) maropitant and citric acid are subjected to a salt forming reaction in a solvent to prepare maropitant citrate, the yield is 80% or above, the optical purity is 99% or above, the optical purity is 98% or above, and optical transformation can be achieved in the resolution reaction process, so that the resolution yield is larger than 50%, the reaction yield is greatly increased, and the method is suitable for industrial production. And the optical purity of the obtained product can meet the requirements of subsequent preparations and clinical efficacy.

Description

Technical Field

[0001] The present invention relates to the technical field of veterinary drugs, and in particular to a preparation method and application of an antiemetic compound. Background Art

[0002] Maropitant citrate is an effective and selective type 1 neurokinin (NK-1) receptor antagonist that can act on the central nervous system by inhibiting substance P (a key neurotransmitter that causes vomiting), and can inhibit peripheral and central vomiting. It is the first drug used to prevent and treat severe vomiting and motion sickness in dogs, and is also the first drug approved for the treatment of canine motion sickness. It has good clinical application value and market prospects.

[0003] The optical purity of Maropitant citrate extracted by existing synthesis technology is low, and the yield is low, and the operation is complicated, and the time consumed is long, and the amount of solvent required is large, and it cannot be used for large-scale production. It is recorded in Chinese patent CN106977512 that synthetic route 1 is based on 3-oxoquinuclidine-2-carboxylate and ethylene glycol as starting materials, and condensation reaction, Grignard reaction, reductive amination, palladium carbon catalytic hydrogenation removal of benzyl, nucleophilic substitution reaction and other 5-step reactions are used to prepare free alkali Maropitant, and the total yield is 21.91%. The key raw material 3-oxoquinuclidine-2-carboxylate of this route is not easy to buy and the price is more expensive. It is verified by experiment that reductive amination, by-products are many, yield is low, and optical purity is low, and industrial production requirements can not be met. According to Chinese patent CN109320510, the synthesis route starts from (2S)-dibenzylquinin-3-one, and the free base maropitant is obtained through three steps of sodium metal reduction, sulfonation, and nucleophilic substitution reaction, with a total yield of about 10%. The optical purity of this synthesis route is low, column chromatography separation and purification are required, the reaction conditions are harsh, the operation is complicated, the time consumption is long, the production efficiency is low, and the amount of solvent required is large, so it cannot be used for large-scale production. According to the patent WO2004035575, the synthetic route starts from 3-quininone, and (2S)-dibenzylquinin-3-one is prepared by aldol condensation, Michael addition, and configuration transformation: (2S)-dibenzylquinin-3-one forms an imine with benzylamine, which is further purified by palladium-carbon catalytic hydrogenation reduction, and further purified by L-camphorsulfonic acid salification, palladium-carbon catalytic hydrogenation to remove the benzyl group, and then forms the corresponding imine with 2-methoxy-5-tert-butylbenzaldehyde, and palladium-carbon catalytic hydrogenation reduction to obtain maropitant base; finally, it is salified with citric acid to obtain a pharmaceutical form of maropitant citrate. This route requires 9 steps of reaction, the steps are cumbersome, the yield is too low, and it is not suitable for industrial production. Therefore, improving the optical purity, yield, and industrialization of maropitant citrate is a direction worth studying at present. Summary of the invention

[0004] In view of the above-mentioned technical limitations, on the basis of existing research, the present invention provides a method for preparing maropitant citrate, using 2-dibenzylquinuclidine-3-one as a starting material, and obtaining maropitant citrate through splitting reaction, condensation hydrolysis reaction, splitting reaction and salt-forming reaction, with an optical purity of more than 98% and a yield of 80%. The process is simple and can be produced on a large scale, thus overcoming the above-mentioned defects.

[0005] The present invention provides a method for preparing an antiemetic compound, comprising the following steps:

[0006]

[0007] 1) using 2-benzhydrylquinuclidine-3-one (CAS No. 32531-66-1) as a starting material, performing a resolution reaction to obtain an intermediate 1: (2S)-2-benzhydrylquinuclidine-3-one; the reaction includes a resolution agent 1, and the resolution agent 1 is selected from L-glutamic acid;

[0008] 2) Intermediate 1 is subjected to condensation hydrolysis reaction and reduction reaction with (5-(tert-butyl)-2-methoxyphenyl)methylamine to prepare Intermediate 2: 2-diphenylmethyl-N-(-5-tert-butyl-2-methoxybenzyl)quinuclidine-3-amine;

[0009] 3) intermediate 2 undergoes a resolution reaction to prepare maropitant, and the resolution agent 2 is selected from D-(+)-dibenzoyltartaric acid;

[0010] 4) Maropitant and citric acid react in a solvent to form a salt to prepare maropitant citrate, with a yield of more than 80%.

[0011] Furthermore, in step 1), a reaction solvent 1 and a reaction substrate are also included; the reaction solvent 1 is selected from ethanol, toluene, methyl tert-butyl ether, tetrahydrofuran, and dichloromethane, preferably ethanol; the reaction substrate is selected from acetic acid;

[0012] The molar ratio of the raw material 2-dibenzylquinuclidine-3-one to the resolving agent 1L-glutamic acid is 1:(1-10), the molar ratio of the raw material 2-dibenzylquinuclidine-3-one to the reaction solvent 1 is 1:(40-60), and the molar ratio of the raw material 2-dibenzylquinuclidine-3-one to the reaction substrate is 1:(1-10).

[0013] Preferably, the optical purity of the product intermediate 1 prepared after the resolution reaction in step 1) reaches above 99%, and the resolution yield is greater than 50%.

[0014] Furthermore, in step 2), a reaction solvent 2, a condensation agent, a hydrolysis reaction reagent, and a reducing agent are also included;

[0015] Reaction solvent 2 is selected from ethanol, toluene, methyl tert-butyl ether, tetrahydrofuran, dichloromethane, preferably toluene;

[0016] The condensing agent is selected from p-toluenesulfonic acid;

[0017] The hydrolysis reaction reagent is selected from acetic acid;

[0018] The reducing agent is selected from borohydrides;

[0019] Preferably,

[0020] The molar ratio of intermediate 1 to (5-(tert-butyl)-2-methoxyphenyl)methylamine is 1:(1-5);

[0021] The molar ratio of intermediate 1 to reaction solvent 2 is 1:(30-50);

[0022] The molar ratio of intermediate 1 to condensing agent p-toluenesulfonic acid is 1:(1-5);

[0023] The molar ratio of intermediate 1 to hydrolysis reagent acetic acid is 1:(1-5)

[0024] The molar ratio of intermediate 1 to reducing agent borohydride is 1:(3-10).

[0025] Furthermore, in step 3), the molar ratio of intermediate 2 to the resolving agent D-(+)-dibenzoyltartaric acid is 1:(1-10).

[0026] Preferably, the optical purity of the product maropitant prepared after the resolution reaction in step 3) is above 98%, and the resolution yield is greater than 50%.

[0027] Furthermore, in step 4), the reaction solvent 3 is selected from toluene, methyl tert-butyl ether, and dichloromethane, preferably methyl tert-butyl ether;

[0028] The molar ratio of maropitant to reaction solvent 3 is 1:(20-30);

[0029] The molar ratio of maropitant to citric acid is 1:(1-2).

[0030] Furthermore, the preparation method also includes reaction temperature and reaction time;

[0031] Wherein, in step 1), the reaction temperature is 50-100°C and the reaction time is 6-12 hours;

[0032] In step 2), the reaction temperature is 90-130° C. and the reaction time is 24 hours;

[0033] In step 3), the reaction temperature is 40-100° C. and the reaction time is 10-20 hours;

[0034] In step 4), the reaction temperature is 40-80° C. and the reaction time is 10-24 hours.

[0035] Further, the method further comprises step 5), wherein in step 5), the maropitant citrate is purified under the following purification conditions:

[0036] Add reaction solvent 4 to maropitant citrate, heat to reflux, filter hot, dropwise add purifying agent to the filtrate, cool after completion of dropwise addition, stir to crystallize, filter and dry to obtain pure maropitant citrate;

[0037] The reaction solvent 4 is selected from ethanol, toluene, methyl tert-butyl ether, tetrahydrofuran, and dichloromethane, preferably tetrahydrofuran; and the purifying agent is selected from n-heptane and ethyl acetate.

[0038] Preferably, the molar ratio of maropitant citrate to reaction solvent 4 is 1:(40-70), the molar ratio of maropitant citrate to purification agent is 1:(80-150), the heating reflux temperature is 75-80°C, and the temperature is lowered to 10-15°C after purification.

[0039] Beneficial Effects

[0040] 1. The products obtained by the two splits in the synthesis route of maropitant citrate of the present invention have been verified to have optical purities of 99% and 98% or more, and optical transitions can be achieved during the split reaction process, so the split yield can be greater than 50%, which greatly improves the reaction yield and ensures that the optical purity of the obtained product can meet the requirements of subsequent preparations and clinical efficacy.

[0041] 2. The "three wastes" generated in the present invention are less and easy to handle, and have the advantages of being green and environmentally friendly. The reagents used are ethanol, tetrahydrofuran, tert-butyl methyl ether, dichloromethane, toluene, ethyl acetate and n-heptane, all of which can be recycled.

[0042] 3. Each link of the production process route of the present invention is easy to implement under current fine chemical production conditions, simple to operate and easy to control. No column chromatography or high-pressure reaction is involved. The yield is high, the production cost is relatively low, a lot of time and cost can be saved in actual production, and the economic benefits are good. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 Experimental Example 1 The infrared spectrum of maropitant citrate was prepared;

[0044] Figure 2 Experimental Example 1 Prepared a positive source high-resolution mass spectrum of maropitant citrate;

[0045] Figure 3 Experimental Example 1 The H NMR spectrum of maropitant citrate was prepared.

[0046] Specific implementation method

[0047] In order to make the purpose, technical solution and advantages of the present application more clear, the present application is further described in detail below. However, it should be understood that the description here is only used to explain the present application and is not used to limit the scope of the present application.

[0048] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present application, and the terms used herein in the specification of the present application are only for the purpose of describing specific embodiments and are not intended to limit the present application. The reagents and instruments used herein are all commercially available, and the characterization means involved can refer to the relevant descriptions in the prior art, which will not be repeated herein.

[0049] In order to further understand the present application, the present application is further described in detail below in conjunction with the best embodiment.

[0050] Example 1

[0051] This embodiment provides a method for preparing an antiemetic compound:

[0052]

[0053] 1) Synthesis of intermediate 1

[0054]

[0055] 2-Benzhydrylquinuclidine-3-one is used as a starting material, and a splitting reaction is performed to obtain an intermediate 1: (2S)-2-benzhydrylquinuclidine-3-one. Ethanol is used as a reaction solvent 1, the molar ratio of 2-benzhydrylquinuclidine-3-one to the reaction solvent 1 ethanol is 1: (40-60), the splitting reagent is L-glutamic acid, the molar ratio of 2-benzhydrylquinuclidine-3-one to L-glutamic acid is 1: (1-10), the reaction substrate is acetic acid, the molar ratio of 2-benzhydrylquinuclidine-3-one to acetic acid is 1: (1-10), the reaction temperature is 50-100° C., and the reaction time is 6-12 hours.

[0056] After the resolution reaction is completed, the optical purity of the product intermediate 1 prepared reaches more than 99%, and the resolution yield is greater than 50%.

[0057] 2) Synthesis of Intermediate 2

[0058]

[0059] The intermediate 1 is subjected to condensation hydrolysis reaction with (5-(tert-butyl)-2-methoxyphenyl)methylamine to prepare the intermediate 2: 2-benzhydryl-N-(-5-tert-butyl-2-methoxybenzyl)quinuclidine-3-amine; the molar ratio of the intermediate 1 to (5-(tert-butyl)-2-methoxyphenyl)methylamine is 1:(1-5), the molar ratio of the intermediate 1 to the reaction solvent 2 toluene is 1:(30-50), the molar ratio of the intermediate 1 to the condensation agent p-toluenesulfonic acid is 1:(1-5), the molar ratio of the intermediate 1 to the hydrolysis reaction reagent acetic acid reactant is 1:(1-5), the molar ratio of the intermediate 1 to the reducing agent borohydride is 1:(3-10), the reaction temperature is 90-130°C, and the reaction time is 24 hours.

[0060] 3) Synthesis of Maropitant

[0061]

[0062] The intermediate 2 undergoes a splitting reaction to prepare maropitant, the molar ratio of the intermediate 2 to the splitting agent D-(+)-dibenzoyltartaric acid is 1:(1-10), the reaction temperature is 40-100° C., and the reaction time is 10-20 hours; after the splitting reaction is completed, the optical purity of the product maropitant prepared is above 98%, and the splitting yield is greater than 50%.

[0063] 4) Synthesis of Maropitant Citrate

[0064]

[0065] Maropitant citrate is prepared by reacting maropitant and citric acid in a solvent to form a salt, and the yield is more than 80%. The molar ratio of maropitant to the reaction solvent 3-methyl tert-butyl ether is 1:(20-30), the molar ratio of maropitant to citric acid is 1:(1-2), the reaction temperature is 40-80°C, and the reaction time is 10-24 hours.

[0066] 5) Refining maropitant citrate under the following refining conditions:

[0067] Tetrahydrofuran is used as a solvent, the molar ratio of maropitant citrate to the reaction solvent 4 tetrahydrofuran is 1: (40-70), or the dosage is per gram of crude maropitant citrate / 5 ml of tetrahydrofuran, heating and reflux for 1 hour at a temperature of 75-80° C., hot filtration, and dropwise addition of a purifying agent n-heptane to the filtrate, the molar ratio of maropitant citrate to the purifying agent n-heptane is 1: (80-150) or the dosage is per gram of crude maropitant citrate / 20 ml of n-heptane. After the dropwise addition is completed, the temperature is lowered to 10-15° C., stirred for crystallization, filtered and dried to obtain pure maropitant citrate.

[0068] Example 2

[0069] According to the method for preparing the antiemetic pharmaceutical composition in Example 1, the following test example specifically introduces the preparation process.

[0070] Test Example 1

[0071] A specific preparation method of an antiemetic drug composition, the specific steps are as follows:

[0072] 1) Synthesis of intermediate 1

[0073]

[0074] In a 100mL reaction bottle, add 60ml of ethanol, 8g of 2-benzhydrylquinuclidine-3-one, 4g of L-glutamic acid and 3g of acetic acid, stir and react, reflux for 12h, TLC detection reaction is complete, cool to 10-15℃, stir for 3h, white solid precipitates, filter, wash the solid with 3kg of anhydrous ethanol, dry, and obtain intermediate 1: 7.2g, optical purity 99%, yield 90%.

[0075] 2) Synthesis of Intermediate 2

[0076]

[0077] In a 250mL reaction bottle, add 100ml toluene, intermediate 1: 7.2g, (5-(tert-butyl)-2-methoxyphenyl)methylamine: 7g, and p-toluenesulfonic acid 6g, heat to reflux 110℃, react for about 6h, after the reaction is complete, cool to 0-5℃, stir to precipitate, filter, and retain the filtrate. Return the filtrate to the kettle for desolventization until no fraction appears, and obtain a yellow viscous liquid.

[0078] In a 250mL reaction bottle, add 100ml tetrahydrofuran, add yellow viscous liquid, stir for 10min, add acetic acid 15g, sodium triacetoxyborohydride 30g, stir and heat to reflux, react for 24h, after TLC detection, cool to 0-5℃, adjust the solution pH to 10-11 with 20% sodium hydroxide solution, separate, retain the organic phase, extract the aqueous phase twice with 119.4kg dichloromethane, combine the organic phases, add 4.4kg anhydrous magnesium sulfate to dry, filter, return the filtrate to the kettle, remove the solvent, and obtain a yellow viscous solid. Add ethyl acetate, stir and dissolve, heat to reflux, cool to 0-5℃ for 1h, stand for crystallization, filter, and dry the filter cake to obtain 9.47g of off-white solid. Yield 79.1%.

[0079] 3) Synthesis of Maropitant

[0080]

[0081] In a 100mL reaction bottle, add 25ml of ethyl acetate and intermediate 2 (3.96g). After the addition is complete, stir at 45°C to dissolve. Then add anhydrous ethanol solution of D-(+)-dibenzoyltartaric acid (2g of D-(+)-dibenzoyltartaric acid + 5ml of anhydrous ethanol), reflux for 12h, cool to 0-5°C and stir for 2h, filter, and wash the filter cake with 5ml of ethyl acetate to obtain a white solid. Add 50mlg of dichloromethane and 5ml of distilled water to the white solid and stir until dissolved. Adjust pH to 10-11 with 20% sodium hydroxide solution, separate the liquids, extract the aqueous phase twice with 6g of dichloromethane, combine the organic phases, add anhydrous magnesium sulfate to the organic phases, dry them, filter with suction, return the filtrate to the kettle and concentrate until a large amount of precipitation occurs, cool to 0-5°C, stir for 1h, filter, and dry the filter cake to obtain 3.2g of white solid maropitant. ， Optical purity: 98.5%. Yield: 81%.

[0082] 4) Synthesis of Maropitant Citrate

[0083]

[0084] In a 100L glass-lined reaction bottle, add 15ml of methyl tert-butyl ether and maropitant (3.2g). After the addition is complete, heat to 40°C, stir to dissolve, and then slowly add a saturated tetrahydrofuran solution of citric acid (2g citric acid). React at 60-70°C for 20h. After the reaction is complete, cool to 10-15°C and stir for 2h. White solid precipitates. Continue stirring for 2h, filter and obtain a white solid. Dry to obtain 4.062g of crude maropitant citrate. Yield 90%.

[0085] 5) Purification of Maropitant Citrate

[0086] Take 10g of crude maropitant citrate, add 50ml of tetrahydrofuran, heat and reflux for 1 hour at 75-80°C, filter hot, add 200ml of n-heptane to the filtrate, cool to 10-15°C after the addition is complete, stir to crystallize, filter and dry to obtain 8.9g of pure maropitant citrate. Yield 89%. Characterization data see Figure 1 , Figure 2 , Figure 3 .

[0087] Comparative Example 1

[0088] A method for preparing maropitant citrate, comprising the following steps:

[0089] 1) Synthesis of intermediate 1

[0090]

[0091] In a 100mL reaction bottle, add 60ml of ethanol, 8g of 2-benzhydrylquinuclidine-3-one, 4g of D-tartaric acid and 3g of acetic acid, stir and react, reflux for 12h, TLC detection reaction is complete, cool to 10-15℃, stir for 3h, white solid precipitates, filter, wash the solid with 3kg of anhydrous ethanol, dry, and obtain intermediate 1: 2.07g, yield 25.0%.

[0092] 2) Same as Test Example 1.

[0093] 3) Synthesis of Maropitant

[0094]

[0095] In a 100mL reaction bottle, add 25ml of ethyl acetate and intermediate 2 (3.96g). After the addition is complete, stir and dissolve at 45°C. Then add anhydrous ethanol solution of L-camphorsulfonic acid (2g of L-camphorsulfonic acid + 5ml of anhydrous ethanol), reflux for 12h, cool to 0-5°C and stir for 2h, filter, and wash the filter cake with 5ml of ethyl acetate to obtain a white solid. Add 50mlg of dichloromethane and 5ml of distilled water to the white solid and stir until dissolved. Adjust pH to 10-11 with 20% sodium hydroxide solution, separate the liquids, extract the aqueous phase twice with 6g of dichloromethane, combine the organic phases, add anhydrous magnesium sulfate to the organic phases, dry them, filter with suction, return the filtrate to the kettle and concentrate until a large amount of precipitation occurs, cool to 0-5°C, stir for 1h, filter, and dry the filter cake to obtain 1.22g of white solid maropitant. The yield is 31.0%.

[0096] Comparative Example 2

[0097] A method for preparing maropitant citrate, comprising the following steps:

[0098] 1) Synthesis of intermediate 1

[0099]

[0100] In a 100mL reaction bottle, add 60ml of ethanol, 8g of 2-benzhydrylquinuclidine-3-one, 4g of L-camphorsulfonic acid and 3g of acetic acid, stir and react, reflux for 12h, TLC detection reaction is complete, cool to 10-15℃, stir for 3h, white solid precipitates, filter, wash the solid with 3kg of anhydrous ethanol, dry, and obtain intermediate 1: 3.68g, yield 44.5%.

[0101] 2) Same as Test Example 1.

[0102] 3) Synthesis of Maropitant

[0103]

[0104] In a 100mL reaction bottle, add 25ml of ethyl acetate and intermediate 2 (3.96g). After the addition is complete, stir at 45°C to dissolve. Then add anhydrous ethanol solution of D-tartaric acid (2g D-tartaric acid + 5ml anhydrous ethanol), reflux for 12h, cool to 0-5°C and stir for 2h, filter, wash the filter cake with 5ml ethyl acetate to obtain a white solid. Add 50mlg dichloromethane and 5ml distilled water to the white solid and stir until dissolved. Adjust pH to 10-11 with 20% sodium hydroxide solution, separate the liquids, extract the aqueous phase twice with 6g dichloromethane, combine the organic phases, add anhydrous magnesium sulfate to the organic phases and dry them, filter with suction, return the filtrate to the kettle and concentrate until a large amount of precipitation occurs, cool to 0-5°C, stir for 1h, filter, and dry the filter cake to obtain a white solid. After testing, it cannot be separated. The yield is 0%.

[0105] in conclusion

[0106] Comparative Examples 1-2 prove that the splitting reagent has a great influence on the yield of the splitting reaction. We obtained unexpected results by changing the splitting reagent. The yield of the present application is so high, specifically caused by the first and third steps. The normal yield of the splitting reaction will not be greater than 50%. By trying new splitting reagents, we can achieve optical transformation, so the splitting yield can be greater than 50%, which greatly improves the reaction yield and ensures that the optical purity of the obtained product can meet the requirements of subsequent preparations and clinical efficacy.

[0107] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing an antiemetic compound, characterized in that: The steps include: 1) using 2-benzhydrylquinuclidine-3-one as a starting material, performing a resolution reaction to obtain an intermediate 1: (2S)-2-benzhydrylquinuclidine-3-one; the reaction includes a resolution agent 1, and the resolution agent 1 is selected from L-glutamic acid; 2) Intermediate 1 is subjected to condensation hydrolysis reaction and reduction reaction with (5-(tert-butyl)-2-methoxyphenyl)methylamine to prepare Intermediate 2: 2-diphenylmethyl-N-(-5-tert-butyl-2-methoxybenzyl)quinuclidine-3-amine; 3) intermediate 2 undergoes a resolution reaction to prepare maropitant, and the resolution agent 2 is selected from D-(+)-dibenzoyltartaric acid; 4) Maropitant and citric acid react in a solvent to form a salt to prepare maropitant citrate, with a yield of more than 80%.

2. The preparation method according to claim 1, characterized in that: In step 1), it also includes a reaction solvent 1 and a reaction substrate; the reaction solvent 1 is selected from ethanol, toluene, methyl tert-butyl ether, tetrahydrofuran, and dichloromethane, preferably ethanol; the reaction substrate is selected from acetic acid; Preferably, the molar ratio of the raw material 2-dibenzylquinuclidine-3-one to the resolving agent 1L-glutamic acid is 1:(1-10), the molar ratio of the raw material 2-dibenzylquinuclidine-3-one to the reaction solvent 1 is 1:(40-60), and the molar ratio of the raw material 2-dibenzylquinuclidine-3-one to the reaction substrate is 1:(1-10).

3. The preparation method according to claim 2, characterized in that: After the resolution reaction in step 1) is completed, the optical purity of the product intermediate 1 prepared is above 99%, and the resolution yield is greater than 50%.

4. The preparation method according to claim 1, characterized in that: Step 2) further comprises a reaction solvent 2, a condensation agent, a hydrolysis reaction reagent, and a reducing agent; Reaction solvent 2 is selected from ethanol, toluene, methyl tert-butyl ether, tetrahydrofuran, dichloromethane, preferably toluene; The condensing agent is selected from p-toluenesulfonic acid; The hydrolysis reaction reagent is selected from acetic acid; The reducing agent is selected from borohydrides; Preferably, The molar ratio of intermediate 1 to (5-(tert-butyl)-2-methoxyphenyl)methylamine is 1:(1-5); The molar ratio of intermediate 1 to reaction solvent 2 is 1:(30-50); The molar ratio of intermediate 1 to condensing agent p-toluenesulfonic acid is 1:(1-5); The molar ratio of intermediate 1 to hydrolysis reagent acetic acid is 1:(1-5) The molar ratio of intermediate 1 to reducing agent borohydride is 1:(3-10).

5. The preparation method according to claim 1, characterized in that: In step 3), the molar ratio of intermediate 2 to the resolving agent D-(+)-dibenzoyltartaric acid is 1:(1-10).

6. The preparation method according to claim 5, characterized in that: After the resolution reaction in step 3), the optical purity of the product maropitant prepared is above 98%, and the resolution yield is greater than 50%.

7. The preparation method according to claim 1, characterized in that: In step 4), the reaction solvent 3 is selected from toluene, methyl tert-butyl ether, and dichloromethane, preferably methyl tert-butyl ether; The molar ratio of maropitant to reaction solvent 3 is 1:(20-30); The molar ratio of maropitant to citric acid is 1:(1-2).

8. The preparation method according to claim 1, characterized in that: The preparation method also includes reaction temperature and reaction time; Wherein, in step 1), the reaction temperature is 50-100°C and the reaction time is 6-12 hours; In step 2), the reaction temperature is 90-130° C. and the reaction time is 24 hours; In step 3), the reaction temperature is 40-100° C. and the reaction time is 10-20 hours; In step 4), the reaction temperature is 40-80° C. and the reaction time is 10-24 hours.

9. The preparation method according to claim 1, characterized in that: Also includes step 5), In step 5), maropitant citrate is purified under the following conditions: Add reaction solvent 4 to maropitant citrate, heat to reflux, filter hot, dropwise add purifying agent to the filtrate, cool after the dropwise addition is complete, stir to crystallize, filter and dry to obtain pure maropitant citrate; The reaction solvent 4 is selected from ethanol, toluene, methyl tert-butyl ether, tetrahydrofuran, and dichloromethane, preferably tetrahydrofuran; and the purifying agent is selected from n-heptane and ethyl acetate.

10. The preparation method according to claim 9, characterized in that: The molar ratio of maropitant citrate to the reaction solvent 4 is 1:(40-70), the molar ratio of maropitant citrate to the purification agent is 1:(80-150), the heating reflux temperature is 75-80°C, and the temperature is lowered to 10-15°C after purification.

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