Preparation method and application of an antiemetic compound

Abstract

The application relates to a preparation method and application of an antiemetic drug compound, and the specific steps are as follows: 1) taking 2-diphenylmethyl quinuclidin-3-one as a starting material, an intermediate 1, (2S)-2-diphenylmethyl quinuclidin-3-one, is obtained through a resolution reaction; the resolution agent 1 is selected from L-glutamic acid; 2) the intermediate 1 and (5-(tert-butyl)-2-methoxyphenyl)methylamine are subjected to condensation hydrolysis reaction and reduction reaction, so as to prepare an intermediate 2, 2-diphenylmethyl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine; 3) the intermediate 2 is subjected to a resolution reaction, so as to prepare maropitant, and the resolution agent 2 is selected from D-(+)-dibenzoyl tartaric acid; 4) maropitant and citric acid are subjected to a salt reaction in a solvent, so as to prepare maropitant citrate, the yield is more than 80%, the optical purity is more than 99% and 98%, and in the resolution reaction process, optical transformation can be achieved, so that the resolution yield is greater than 50%, the reaction yield is greatly improved, and the optical purity of the obtained product can meet the requirements of subsequent preparation and clinical efficacy.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of veterinary medicine, in particular to a preparation method and application of an anti-emetic compound. BACKGROUND

[0002] Maropitant citrate is an effective and selective NK-1 receptor antagonist, which can act on the central nervous system by inhibiting substance P, a key neurotransmitter causing vomiting, and can inhibit peripheral and central vomiting. It is the first drug for preventing and treating severe vomiting and motion sickness in dogs, and is also the first drug approved for marketing for treating canine motion sickness, which has good clinical application value and market prospect.

[0003] The maropitant citrate extracted by the existing synthesis technology has low optical purity, low yield, complex operation, long time consumption, and large solvent amount, and cannot be used for large-scale production. In the Chinese patent CN106977512, synthesis route 1 uses 3-oxoquinuclidine-2-carboxylate and ethylene glycol as starting materials, and maropitant free base is prepared through 5-step reactions such as condensation reaction, Grignard reaction, reductive amination, palladium-carbon catalytic hydrogenation to remove benzyl, and nucleophilic substitution reaction, with a total yield of 21.91%. The key raw material 3-oxoquinuclidine-2-carboxylate is not easy to obtain and is expensive, and experimental verification shows that the reductive amination has many by-products, low yield, and low optical purity, which cannot meet the requirements of industrial production. In the Chinese patent CN109320510, synthesis route starts from (2S)-diphenylmethyl quinuclidine-3-ketone, and maropitant free base is obtained through 3-step reactions such as sodium metal reduction, sulfonate esterification, and nucleophilic substitution reaction, with a total yield of about 10%. The synthesis route has low optical purity, needs column chromatography separation and purification, has harsh reaction conditions, complex operation, long time consumption, low production efficiency, and large solvent amount, and cannot be used for large-scale production. In the patent WO2004035575, synthesis route starts from 3-quinuclidinone, and (2S)-diphenylmethyl quinuclidine-3-ketone is prepared through hydroxyaldehyde condensation, Michael addition, and configuration conversion: (2S)-diphenylmethyl quinuclidine-3-ketone forms an imine with benzylamine, is reduced by palladium-carbon catalytic hydrogenation, is further purified by salting with L-camphor sulfonic acid, the benzyl group is removed by palladium-carbon catalytic hydrogenation, the corresponding imine is formed with 2-methoxy-5-tert-butylbenzaldehyde, and maropitant base is obtained by palladium-carbon catalytic hydrogenation reduction; and finally, the maropitant base is salted with citric acid to obtain the pharmaceutical form of maropitant citrate. The route needs 9-step reactions to achieve, the steps are complicated, 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

[0004] In view of the above technical limitations, on the basis of the existing research, the application provides a preparation method of maropitant citrate, which uses 2-diphenylmethyl quinuclidin-3-one as a starting material, and obtains maropitant citrate through a resolution reaction, a condensation and hydrolysis reaction, a resolution reaction and a salt formation reaction, and the optical purity of the maropitant citrate reaches more than 98%, and the yield reaches 80%, the process is simple, and the maropitant citrate can be generated on a large scale, and the above defects are overcome.

[0005] The application provides a preparation method of an antiemetic compound, which comprises the following steps:

[0006]

[0007] 1) using 2-diphenylmethyl quinuclidin-3-one (CAS number 32531-66-1) as a starting material, a resolution reaction is performed to obtain an intermediate 1, (2S)-2-diphenylmethyl quinuclidin-3-one; the resolution reaction includes a resolving agent 1, and the resolving agent 1 is selected from L-glutamic acid;

[0008] 2) the intermediate 1 is subjected to a condensation and hydrolysis reaction and a reduction reaction with (5-(tert-butyl)-2-methoxyphenyl)methanamine to prepare an intermediate 2, 2-diphenylmethyl-N-(-5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine;

[0009] 3) the intermediate 2 is subjected to a resolution reaction to prepare maropitant, and the resolution reaction further includes a resolving agent 2 selected from D-(+)-dibenzoyl tartaric acid;

[0010] 4) maropitant and citric acid are subjected to a salt formation reaction in a solvent to prepare maropitant citrate, and the yield is more than 80%.

[0011] Further, in the step 1), the reaction further 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, and preferably is ethanol; and the reaction substrate is selected from acetic acid.

[0012] The molar ratio of the starting material 2-diphenylmethyl quinuclidin-3-one to the resolving agent 1 L-glutamic acid is 1:(1-10), the molar ratio of the starting material 2-diphenylmethyl quinuclidin-3-one to the reaction solvent 1 is 1:(40-60), and the molar ratio of the starting material 2-diphenylmethyl quinuclidin-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 the step 1) is more than 99%, and the resolution yield is greater than 50%.

[0014] Further, in the step 2), the reaction further includes a reaction solvent 2, a condensing agent, a hydrolysis reagent and a reducing agent.

[0015] The 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 reagent is selected from acetic acid;

[0018] The reducing agent is selected from borohydride;

[0019] Preferably,

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

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

[0022] The molar ratio of the intermediate 1 to the condensing agent p-toluenesulfonic acid in step 2) is 1:(1-5);

[0023] The molar ratio of the intermediate 1 to the hydrolysis reagent acetic acid in step 3) is 1:(1-5).

[0024] The molar ratio of the intermediate 1 to the reducing agent borohydride in step 4) is 1:(3-10).

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

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

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

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

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

[0030] Further, the preparation method further comprises a reaction temperature and a reaction time;

[0031] 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] The reaction temperature in step 4) is 40-80℃, and the reaction time is 10-24 hours.

[0035] Further, step 5) is also included, in which the maropitant citrate is refined under the following conditions:

[0036] The maropitant citrate is added with a reaction solvent 4, heated to reflux, hot filtered, and the purified agent is added dropwise to the filtrate. After the dropwise addition is completed, the temperature is lowered, and the product is crystallized under stirring, filtered and dried to obtain the maropitant citrate product.

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

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

[0039] Beneficial effects

[0040] 1. The products obtained by twice splitting in the maropitant citrate synthesis route of the application are verified to have an optical purity of more than 99% and 98%, and can achieve optical conversion in the splitting reaction process, so that the splitting yield can be greater than 50%, the reaction yield is greatly improved, and the optical purity of the obtained product can meet the requirements of subsequent preparation and clinical efficacy.

[0041] 2. The "three wastes" generated in the application 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, which can be recycled.

[0042] 3. The production process route of the application is easy to implement, simple to operate and easy to control under the current fine chemical production conditions. It does not involve column chromatography and high-pressure reaction. The yield is high, the production cost is relatively low, a large amount of time and cost can be saved in actual production, and the economic benefit is good. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 The infrared spectrum of the maropitant citrate prepared in Test Example 1 is prepared;

[0044] Figure 2 The positive source high-resolution mass spectrum of the maropitant citrate prepared in Test Example 1 is prepared;

[0045] Figure 3 The nuclear magnetic hydrogen spectrum of the maropitant citrate prepared in Test Example 1 is prepared.

[0046] DETAILED DESCRIPTION

[0047] For the purpose of making the object, technical solutions and advantages of the present application more clear, the present application is further described in details. However, it should be understood that the description herein is only used to explain the present application and is not intended to limit the scope of the present application.

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting of the present application. The reagents and instruments used herein are commercially available and the characterization means involved are described in the prior art, which will not be described herein.

[0049] For the purpose of further understanding the present application, the present application is further described in details in combination with the best embodiments.

[0050] Embodiment 1

[0051] The present embodiment provides a preparation method of an antiemetic compound:

[0052]

[0053] 1) Synthesis of intermediate 1

[0054]

[0055] 2-dibenzylquinuclidin-3-one as a starting material, the intermediate 1 was obtained by a resolution reaction: (2S)-2-dibenzylquinuclidin-3-one, ethanol as a reaction solvent 1, the molar ratio of 2-dibenzylquinuclidin-3-one to the reaction solvent 1 ethanol was 1: (40-60), the resolution reagent was L-glutamic acid, the molar ratio of 2-dibenzylquinuclidin-3-one to L-glutamic acid was 1: (1-10), the reaction substrate was acetic acid, the molar ratio of 2-dibenzylquinuclidin-3-one to acetic acid was 1: (1-10), the reaction temperature was 50-100℃, and the reaction time was 6-12 hours.

[0056] The optical purity of the product intermediate 1 prepared after the resolution reaction was more than 99%, and the resolution yield was 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-diphenylmethyl-N-(-5-tert-butyl-2-methoxybenzyl)quinuclidin-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 condensing agent p-toluenesulfonic acid is 1:(1-5), the molar ratio of the intermediate 1 to the hydrolysis reagent acetic acid 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 is subjected to resolution reaction to prepare maropitant; the molar ratio of the intermediate 2 to the resolution agent D-(+)-dibenzoyl tartaric acid is 1:(1-10), the reaction temperature is 40-100°C, and the reaction time is 10-20 hours; the optical purity of the prepared product maropitant after the resolution reaction is more than 98%, and the resolution yield is greater than 50%.

[0063] 4) Synthesis of maropitant citrate

[0064]

[0065] Maropitant citrate is prepared by salt reaction of maropitant and citric acid in a solvent, 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) Maropitant citrate is refined under the following conditions:

[0067] Tetrahydrofuran is used as the solvent, the molar ratio of maropitant citrate to the reaction solvent 4-tetrahydrofuran is 1:(40-70), or the amount is 5 ml of tetrahydrofuran per gram of maropitant citrate crude product, heating is refluxed for 1 hour, the temperature is 75-80°C, hot filtration is performed, the purification agent n-heptane is added dropwise to the filtrate, the molar ratio of maropitant citrate to the purification agent n-heptane is 1:(80-150), or the amount is 20 ml of n-heptane per gram of maropitant citrate crude product, after the dropwise addition is completed, the temperature is lowered to 10-15°C, stirring is performed to precipitate crystals, filtration and drying are performed to obtain maropitant citrate pure product.

[0068] Example 2

[0069] The following test example specifically describes the preparation process according to the method of preparing the antiemetic pharmaceutical composition of Example 1.

[0070] Test Example 1

[0071] A specific preparation method of an antiemetic pharmaceutical composition is as follows:

[0072] 1) Synthesis of intermediate 1

[0073]

[0074] In a 100 mL reaction flask, 60 mL of ethanol was added, followed by 2- diphenylmethyl quinuclidin-3-one 8 g, L-glutamic acid 4 g and acetic acid 3 g. The reaction was stirred and refluxed for 12 h. TLC detection showed that the reaction was complete. The temperature was lowered to 10-15 °C and stirred for 3 h. White solid was precipitated. The solid was filtered and washed with 3 kg of anhydrous ethanol. After drying, intermediate 1 was obtained: 7.2 g, with an optical purity of 99%. The yield was 90%.

[0075] 2) Synthesis of intermediate 2

[0076]

[0077] In a 250 mL reaction flask, 100 mL of toluene was added, followed by intermediate 1: 7.2 g, (5-(tert-butyl)-2-methoxyphenyl)methanamine: 7 g, and p-toluenesulfonic acid 6 g. The temperature was raised to reflux at 110 °C and the reaction was carried out for about 6 h. After the reaction was complete, the temperature was lowered to 0-5 °C and stirred to precipitate. The filtrate was retained. The filtrate was returned to the kettle and desolventized until no fraction appeared. A yellow thick liquid was obtained.

[0078] In a 250 mL reaction flask, 100 mL of tetrahydrofuran was added, followed by the yellow thick liquid. The mixture was stirred for 10 min, followed by the addition of acetic acid 15 g and sodium triacetoxyborohydride 30 g. The mixture was stirred and the temperature was raised to reflux. The reaction was carried out for 24 h. After the reaction was complete, the temperature was lowered to 0-5 °C. The pH of the solution was adjusted to 10-11 with 20% sodium hydroxide solution. The organic phase was separated and retained. The aqueous phase was extracted twice with 119.4 kg of dichloromethane. The organic phases were combined and dried with 4.4 kg of anhydrous magnesium sulfate. The filtrate was returned to the kettle and the solvent was removed. A yellow sticky solid was obtained. Ethyl acetate was added and the mixture was stirred and heated to reflux. After 1 h, the temperature was lowered to 0-5 °C. The mixture was allowed to stand and the crystals were precipitated. The filtrate was filtered and dried to obtain a white solid 9.47 g. The yield was 79.1%.

[0079] 3) Synthesis of maropitant

[0080]

[0081] 100 mL reaction bottle, add 25 ml of ethyl acetate, add intermediate 2 (3.96 g), after adding, 45 °C stirring dissolution. Again add D-(+)-dibenzoyl tartaric acid anhydrous ethanol solution (D-(+)-dibenzoyl tartaric acid 2 g + anhydrous ethanol 5 ml), reflux reaction 12 h, cooling to 0-5 °C stirring 2 h, filtration, the filter cake was washed with 5 ml of ethyl acetate, white solid. White solid, add 50 ml g dichloromethane and 5 ml distilled water, stirring to dissolution. Adjusted to pH = 10-11 with 20% sodium hydroxide solution, liquid-liquid, the water phase was extracted twice with 6 g dichloromethane, combined organic phase, the organic phase was dried with anhydrous magnesium sulfate, suction filtration, the filtrate was concentrated to a large amount of precipitation, cooling to 0-5 °C, stirring 1 h, filtration, the filter cake was dried to obtain white solid maropitant 3.2 g ， Optical purity 98.5%. Yield 81%.

[0082] 4) synthesis of maropitant citrate

[0083]

[0084] 100 L glass lined reaction bottle, add 15 ml of methyl tert-butyl ether, add maropitant (3.2 g), after adding, heating to 40 °C, stirring dissolution, then slowly add citric acid in tetrahydrofuran saturated solution (2 g citric acid), reaction at 60-70 °C for 20 h, after the reaction is complete, cooling to 10-15 °C, stirring 2 h, white solid can be seen precipitation, continue stirring 2 h, suction filtration, to obtain white solid. Dry, to obtain maropitant citrate crude product 4.062 g. Yield 90%.

[0085] 5) maropitant citrate was refined

[0086] Take 10 g of maropitant citrate crude product, add 50 ml of tetrahydrofuran, heated to reflux for 1 hour, the temperature at 75-80 °C, hot filtration, drop 200 ml of n-heptane to the filtrate, after the drop is completed, cooling to 10-15 °C, stirring crystallization, filtration and drying, to obtain maropitant citrate pure product 8.9 g. Yield 89%. Characterization data see Figure 1 、 Figure 2 、 Figure 3 .

[0087] Comparative example 1

[0088] A method for preparing maropitant citrate, the steps are as follows:

[0089] 1) synthesis of intermediate 1

[0090]

[0091] 100 mL reaction flask, add 60 ml ethanol, add 2-diphenylmethyl quinuclidin-3-one 8 g, D-tartaric acid 4 g and acetic acid 3 g, stir reaction, reflux reaction 12 h, TLC detection reaction complete, cooling to 10-15 °C, stirring 3 h, white solid precipitated, suction filtration, the solid is washed with 3 kg of anhydrous ethanol, dried, to get intermediate 1: 2.07 g. Yield 25.0%.

[0092] 2) The same as test example 1.

[0093] 3) Synthesis of maropitant

[0094]

[0095] 100 mL reaction flask, add 60 ml ethanol, add 2-diphenylmethyl quinuclidin-3-one 8 g, D-tartaric acid 4 g and acetic acid 3 g, stir reaction, reflux reaction 12 h, TLC detection reaction complete, cooling to 10-15 °C, stirring 3 h, white solid precipitated, suction filtration, the solid is washed with 3 kg of anhydrous ethanol, dried, to get intermediate 1: 2.07 g. Yield 25.0%.

[0096] Comparative example 2

[0097] A method for preparing maropitant citrate, the steps are as follows:

[0098] 1) Synthesis of intermediate 1

[0099]

[0100] 100 mL reaction flask, add 60 ml ethanol, add 2-diphenylmethyl quinuclidin-3-one 8 g, D-tartaric acid 4 g and acetic acid 3 g, stir reaction, reflux reaction 12 h, TLC detection reaction complete, cooling to 10-15 °C, stirring 3 h, white solid precipitated, suction filtration, the solid is washed with 3 kg of anhydrous ethanol, dried, to get intermediate 1: 2.07 g. Yield 25.0%.

[0101] 2) The same as test example 1.

[0102] 3) Synthesis of maropitant

[0103]

[0104] 100ml reaction bottle, add 25ml ethyl acetate, add intermediate 2 (3.96g), after adding, 45℃ stirring to dissolve. Add D-tartaric acid in anhydrous ethanol solution (D-tartaric acid 2g + anhydrous ethanol 5ml), reflux for 12h, cool to 0-5℃ stirring for 2h, filter, filter cake with 5ml ethyl acetate, get white solid. White solid, add 50ml dichloromethane and 5ml distilled water, stirring to dissolve. Adjust pH = 10-11 with 20% sodium hydroxide solution, liquid separation, water phase with 6g dichloromethane extraction twice, combined organic phase, organic phase with anhydrous magnesium sulfate drying, suction filtration, filter the concentrated to a large amount of precipitation, cooling to 0-5℃, stirring for 1h, filter, filter cake drying to get white solid, detection, failed to split. Yield 0%.

[0105] Conclusion

[0106] Example 1-2 proved that the resolution reagent has a great influence on the yield of the resolution reaction. We get unexpected results by changing the resolution reagent. The yield of this application is improved so high, which is caused by the first step and the third step. The normal yield of the resolution reaction will not be greater than 50%, we can achieve optical transformation by trying new resolution reagents, so the resolution yield can be greater than 50%, which greatly improves the reaction yield, and also ensures that the optical purity of the product obtained can meet the requirements of subsequent preparation and clinical efficacy.

[0107] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modifications, equivalent replacements or improvements made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing an antiemetic compound, characterized in that, Includes the following steps: 1) Starting from 2-diphenylmethylquinine-3-one, intermediate 1 was obtained by resolution reaction: (2S)-2-diphenylmethylquinine-3-one; the reaction included resolving agent 1, which was selected from L-glutamic acid; It also includes reaction solvent 1 and reaction substrate; reaction solvent 1 is selected from ethanol, toluene, methyl tert-butyl ether, tetrahydrofuran, and dichloromethane; reaction substrate is selected from acetic acid; The molar ratio of the raw material 2-diphenylmethylquinine-3-one to the resolving agent 1L-glutamic acid is 1:(1-10), the molar ratio of the raw material 2-diphenylmethylquinine-3-one to the reaction solvent 1 is 1:(40-60), and the molar ratio of the raw material 2-diphenylmethylquinine-3-one to the reaction substrate is 1:(1-10). After the resolution reaction, the optical purity of intermediate 1 of the product prepared reached over 99%, and the resolution yield was greater than 50%. 2) Intermediate 1 undergoes condensation hydrolysis and reduction reactions with (5-(tert-butyl)-2-methoxyphenyl)methylamine to prepare intermediate 2: 2-diphenylmethyl-N-(-5-tert-butyl-2-methoxybenzyl)quinine-3-amine; 3) Intermediate 2 undergoes a resolution reaction to prepare maropistan, which also includes resolving agent 2 selected from D-(+)-dibenzoyl tartaric acid; 4) Maropitan citrate was prepared by salt formation reaction of maropitan and citric acid in a solvent, with a yield of over 80%.

2. The preparation method according to claim 1, characterized in that, In step 1), the reaction solvent 1 is ethanol.

3. The preparation method according to claim 1, characterized in that, Step 2) also includes reaction solvent 2, condensing agent, hydrolysis reaction reagent, and reducing agent; The reaction solvent 2 is selected from ethanol, toluene, methyl tert-butyl ether, tetrahydrofuran, and dichloromethane; The condensing agent is selected from p-toluenesulfonic acid; The reagent for the hydrolysis reaction is selected from acetic acid; The reducing agent is selected from borohydrides.

4. The preparation method according to claim 3, characterized in that, In step 2), the reaction solvent 2 is toluene.

5. The preparation method according to claim 3, characterized in that, In step 2), 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 acetic acid, the reagent for the hydrolysis reaction, is 1:(1-5). The molar ratio of intermediate 1 to reducing agent borohydride is 1:(3-10).

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

7. The preparation method according to claim 6, characterized in that, The product maropistane prepared after the resolution reaction in step 3) has an optical purity of over 98% and a resolution yield of over 50%.

8. The preparation method according to claim 1, characterized in that, Step 4) also includes reaction solvent 3 selected from toluene, methyl tert-butyl ether, and dichloromethane; The molar ratio of maropistan to reaction solvent 3 is 1:(20-30); The molar ratio of maropitane to citrate is 1:(1-2).

9. The preparation method according to claim 8, characterized in that, The reaction solvent 3 is methyl tert-butyl ether.

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

11. The preparation method according to claim 1, characterized in that, It also includes step 5), In step 5): Maropitan citrate is purified under the following conditions: Maropitam citrate was added to reaction solvent 4, heated to reflux, hot filtered, and a purifying agent was added dropwise to the filtrate. After the addition was complete, the mixture was cooled, stirred to precipitate crystals, filtered, and dried to obtain pure maropitam citrate. The reaction solvent 4 is selected from ethanol, toluene, methyl tert-butyl ether, tetrahydrofuran, and dichloromethane; the purifying agent is selected from n-heptane and ethyl acetate.

12. The preparation method according to claim 11, characterized in that, The reaction solvent 4 is tetrahydrofuran.

13. The preparation method according to claim 11, characterized in that, The molar ratio of maropistan citrate to the reaction solvent is 1:(40-70), and the molar ratio of maropistan citrate to the purifying agent is 1:(80-150). The heating reflux temperature is 75-80℃, and the temperature is lowered to 10-15℃ after purification.

Images