CN104961672B - A kind of synthetic method of the tartrate of N (4 luorobenzyl) N (base of 1 methyl piperidine 4) N ' (4 isobutoxy benzyl) urea - Google Patents

Abstract

The invention belongs to the technical field of medicine, and relates to a kind of N- (4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) -N ' -(4-isobutoxybenzyl) urea The synthetic method of tartrate, the present invention is to take 4-hydroxybenzylamine as raw material, obtain N -protecting group-4-isobutoxybenzylamine through amino protection, alkylation reaction, then make key intermediate through deprotection reaction 4-isobutoxybenzylamine, then reacts with phenyl chloroformate to obtain N- (4-isobutoxybenzyl) phenyl carbamate, and finally passes through with another intermediate N- (4-fluorobenzyl )-1-methyl-4-piperidinamine by ammonolysis to N- (4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) -N ' -(4-iso Butoxybenzyl) urea, with tartaric acid salt formation, to obtain N- (4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) -N ' -(4-isobutoxybenzyl base) tartrate of urea. The invention has easy-to-obtain raw materials, simple and mild operation, short production period, high yield, good safety and low cost, and is suitable for industrialized production.

Description

A kind of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxy The synthetic method of the tartrate of benzyl) urea

technical field

The invention belongs to the technical field of medicine, and relates to a kind of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea The synthetic method of tartrate also relates to its intermediate N-protecting group-4-hydroxybenzylamine, N-protecting group-4-isobutoxybenzylamine, 4-isobutoxybenzylamine and N-(4- The synthetic method of isobutoxybenzyl) phenyl carbamate.

Background technique

Parkinson's syndrome (Parkinsonism) is a chronic degenerative disorder of the central nervous system, clinically characterized by certain movement disorders (rest tremor, muscle rigidity, bradykinesia and loss of postural reflexes). It can impair a patient's motor skills, speech, and other functions. Its etiology is still unknown, and it is speculated that it is related to the rapid degeneration of brain cells in the basal ganglia and substantia nigra of the brain, which cannot produce enough neuroguiding substance dopamine (DA) (Friedman, 1991, Goetz et al, 2001).

At present, the number of patients with Parkinson's disease in the world has reached 7 million to 10 million, and China has about 2.6 million, ranking first in the world. More than 40% of people with Parkinson's disease have had a mental illness. Mental illness presents greater challenges in the treatment and care of people with Parkinson's disease. In patients with Parkinson's disease, psychiatric symptoms are the leading cause of hospitalization and significantly increase the risk of death (Weintraub and Stern, 2005; Factor et al, 2003).

Mental diseases, such as schizophrenia and related idiopathic psychosis, the causes of their pathogenesis and the molecular basis of the onset of current antipsychotic drugs have not been fully studied in the medical field, so that the rational design and preparation of drugs for the treatment of psychiatric disorders face great difficulties. Studies have shown that the positive symptoms of mental disorders are related to the hyperactivity of dopamine, and the negative symptoms are related to the increase of central 5-hydroxytryptamine (5-HT) function and the decline of DA function, especially the prefrontal DA function (Romrell et al, 2003) .

Since the pathogenesis of psychiatric diseases is generally believed to be related to excessive dopamine in the brain of patients, the general mechanism of action of antipsychotic drugs is the antagonism of dopamine D2 receptors (Chou et al, 2007; Romrell et al, 2003). Unfortunately, dopamine D2 receptor antagonists, in addition to causing peripheral side effects, can also exacerbate Parkinson's disease in psychiatric patients (Molho and Factor, 1999; Weintraub and Stern, 2005).

Pimavanserin (Pimavanserin) is a patent drug independently developed by Acadia (Acadia) pharmaceutical company, which is used to treat the mental symptoms of Parkinson's disease. Drugs that inhibit body activity rather than dopamine receptors (Herbert Y Meltzer, Roger Mills et al, 2010). Pimavanserin was granted Breakthrough Therapy Certification by the U.S. Food and Drug Administration on September 3, 2014. Arcadia Pharmaceuticals submitted a new drug application for pimavanserin to the FDA in 2014.

In view of the very limited drugs for the treatment of Parkinson's psychiatric symptoms on the market, and all have strong toxic and side effects, it is imminent to develop a kind of low toxicity and good Parkinson's disease psychotropic drugs.

According to the method provided by US20060111399: use 4-hydroxybenzaldehyde as raw material, first carry out alkylation reaction to obtain 4-isobutoxybenzaldehyde, and obtain 4-isobutoxybenzaldehyde oxime through dehydration reaction, and then pass through hydrogen Reduction to obtain the important intermediate 4-isobutoxybenzylamine, react with triphosgene to obtain the intermediate 4-isobutoxybenzyl isocyanate, and finally react with N-(4-fluorobenzyl)-1-methyl- Preparation of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea by ammonolysis of 4-piperidinamine , with tartaric acid to give the tartrate salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea, Overall yield: 15.9%. The synthetic route is represented as follows:

The disadvantages of this route are: the whole route has a long cycle, the yield is not high, and phosgene is used to prepare isocyanate. When phosgene is passed into the reactor, it will exotherm violently, is not easy to operate, and is highly toxic. Once a leak occurs in industry, it will Serious potential safety hazards and environmental pollution are caused.

Contents of the invention

The technical problem to be solved in the present invention is to propose a new N-(4-fluorobenzyl)-N-( A synthetic method for the tartrate of 1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea, the method has short preparation period, high yield, simple post-treatment and high safety high.

The present invention adopts following technical scheme:

Using 4-hydroxybenzylamine as raw material, N-protecting group-4-isobutoxybenzylamine is obtained through amino protection and alkylation reaction, and then the key intermediate 4-isobutoxybenzylamine is obtained through deprotection reaction. Reaction with phenyl chloroformate to obtain N-(4-isobutoxybenzyl) phenyl carbamate, and finally by reacting with another intermediate N-(4-fluorobenzyl)-1-methyl-4- The aminolysis reaction of piperidinamine makes N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea, and Tartaric acid is salified to give the tartrate salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea.

The whole process includes the following steps:

(1) N-protecting group-4-hydroxybenzylamine described in the preparation formula II:

With 4-hydroxybenzylamine (I), protection reagent, acid binding agent according to molar ratio 1:(1.1-2.5):(1.2-3), preferred ratio is 1:(1.2-1.5):(1.5-2), Add it into the solvent, react at -25～60℃, preferably at 0～25℃ for 0.5-24h, after the reaction is terminated, remove the solvent, extract the residue with an extraction reagent, add water to wash the layers, discard the water layer, and remove the solvent , to obtain N-protecting group-4-hydroxybenzylamine.

The solvent used in the above preparation method includes but not limited to dichloromethane, dioxane, tetrahydrofuran, toluene, acetonitrile, chloroform or a mixed solvent of each solvent and water, the preferred solvent is dichloromethane, 4-hydroxybenzylamine and solvent The ratio is 1:2～10(m/v);

Protecting group X is benzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, p-toluenesulfonyl, trityl , 2,4-dimethoxybenzyl, 4-methoxybenzyl or benzyl;

Protecting reagents are benzyl chloroformate, fluorenylmethoxyformyl chloride, di-tert-butyl dicarbonate, 2,2,2-trimethylsilethoxyformyl chloride, ethyl chloroformate, methyl chloroformate, formic acetic anhydride, acetic acid Acid anhydride, p-toluenesulfonyl chloride, triphenylchloromethane, 2,4-dimethoxybenzaldehyde, 2,4-dimethoxybenzyl chloride, 4-methoxybenzaldehyde, 4-methoxybenzyl Chlorine and benzyl chloride (bromide);

The extraction reagent is dichloromethane, ethyl acetate, toluene, dioxane, and the selected reagent is dichloromethane;

The acid-binding agent is sodium bicarbonate, potassium bicarbonate, triethylamine, preferably the acid-binding agent is sodium bicarbonate.

(2) N-protecting group-4-isobutoxybenzylamine shown in the preparation formula III:

The N-protecting group-4-hydroxybenzylamine, bromoisobutane and acid-binding agent are in a molar ratio of 1:(1.2-3):(1.2-3), preferably in a ratio of 1:(1.2-1.5):( 1.5-2), adding to the solvent, reacting for 12-36h at 50-82°C, preferably at a temperature of 55-82°C, after the reaction, remove the solvent, extract the residue with an extraction reagent, wash with alkaline water, discard the water layer, Removal of the solvent affords N-protecting group-4-isobutoxybenzylamine.

The solvent used in the above preparation method includes but not limited to DMF, DMA, ethanol, acetonitrile, preferred solvent: DMF, the ratio of N-protecting group-4-hydroxybenzylamine to solvent is 1:2～10(m/v);

The extraction reagent is dichloromethane, ethyl acetate, toluene, dioxane, and the preferred reagent is dichloromethane;

The acid-binding agent is anhydrous sodium carbonate, anhydrous potassium carbonate, 1,8-diazabicycloundec-7-ene (DBU), and the preferred catalyst is anhydrous potassium carbonate.

(3) 4-isobutoxybenzylamine described in the preparation formula IV:

Add N-protecting group-4-isobutoxybenzylamine and deprotection reagent in a molar ratio of 1:(3-10), preferably 1:(3-4), into the solvent, -25～78°C, preferably React at a temperature of 40-78°C for 3-8 hours to obtain 4-isobutoxybenzylamine.

Described solvent is methanol, ethanol, Virahol, DMF, methylene dichloride, and the preferred solvent is ethanol;

The deprotection reagent is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, hydrazine hydrate, trifluoroacetic acid, hydrochloric acid, preferably alkaline deprotection reagent potassium hydroxide, and acidic deprotection reagent trifluoroacetic acid.

(4) N-(4-isobutoxybenzyl) phenyl carbamate described in the preparation formula V:

4-isobutoxybenzylamine, phenyl chloroformate and acid binding agent according to the molar ratio 1:(1.1-2):(1.2-3), the preferred ratio 1:(1.2-1.3):(1.5-2) , added to the solvent, and reacted at -25 to 60°C, preferably at a temperature of 0 to 25°C, for 1-3h. After the reaction, the solvent was removed, the residue was washed with water, the solid was suction filtered, and recrystallized with a refining reagent to obtain N-( 4-isobutoxybenzyl)phenylcarbamate.

The solvent used in the above-mentioned preparation method includes but not limited to dichloromethane, dioxane, tetrahydrofuran, toluene, methanol, ethanol, isopropanol, acetonitrile, the preferred solvent is dichloromethane, 4-isobutoxybenzylamine and The ratio of solvent is 1:2～8(m/v);

The acid-binding agent is triethylamine, pyridine, sodium bicarbonate, potassium bicarbonate, anhydrous sodium carbonate, anhydrous potassium carbonate, sodium hydroxide, potassium hydroxide, preferably the acid-binding agent is anhydrous potassium carbonate;

The refining reagents are methanol and ethanol, and the preferred reagent is methanol.

(5) Tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea described in the preparation formula VII :

N-(4-fluorobenzyl)-1-methyl-4-piperidinamine, N-(4-isobutoxybenzyl)phenyl carbamate and tartaric acid in a molar ratio of 1:(1.1-1.5) :(0.5-1), preferred ratio 1:(1.2-1.3):(0.5-0.52), the above-mentioned N-(4-fluorobenzyl)-1-methyl-4-piperidinamine and N-(4 - Isobutoxybenzyl) phenyl carbamate is added to the solvent, and the reaction temperature is 25-100°C, preferably 65-78°C, for 3-12h. After the reaction, the temperature drops to 45-40°C, and tartaric acid is added at this temperature Stir the solid for 2-4 hours, stop the reaction and drop to room temperature to crystallize for 5-9 hours, filter with suction, recrystallize with refined reagents, and filter the crystals with suction to obtain the N-(4-fluorobenzyl)-N- Tartrate salt of (1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea.

The solvent used in the above-mentioned preparation method includes but not limited to methanol, ethanol, isopropanol, toluene, acetonitrile, the preferred solvent is ethanol, N-(4-fluorobenzyl)-1-methyl-4-piperidinamine and solvent The ratio is 1:2～10(m/v);

Refining reagents are absolute methanol, absolute ethanol, isopropanol, preferably absolute ethanol.

The whole synthetic route is expressed as follows:

The advantage of the present invention is: N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea designed in the present invention As far as the tartrate synthesis process is concerned, it has the characteristics of easy-to-obtain raw materials, simple operation, high yield, low cost, less three wastes, and high safety, and is suitable for industrial production.

detailed description

The tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea and its intermediate Body N-protecting group-4-hydroxybenzylamine, N-protecting group-4-isobutoxybenzylamine, 4-isobutoxybenzylamine and N-(4-isobutoxybenzyl)carbamate benzene Esters can be carried out as follows:

Embodiment 1, with ethoxycarbonyl as protecting group

1) N-(4-hydroxybenzyl) ethyl carbamate

4-Hydroxybenzylamine (20 g) and sodium bicarbonate (16 g) were added to dichloromethane (100 ml) and stirred at room temperature, and ethyl chloroformate (19.4 g) was added dropwise to in suspension. After the addition was complete, the mixture was stirred at 20°C to 25°C for 2 hours, starting material remaining by TLC. After the reaction was completed, suction filtration was performed to remove excess sodium salt. The filter cake was washed with dichloromethane (50ml x 2). The filtrate was washed with 5% dilute hydrochloric acid (36ml×2), and then washed with water (75ml×2). After separating the layers, the aqueous layer was discarded, and the organic layer was dried. The solvent was recovered under reduced pressure at 30°C to 40°C to obtain a crude red solid (30g), which was washed with toluene (45ml×2). The product was filtered and vacuum-dried at 40°C for 3 hours to obtain a light yellow solid (29.1g), yield 81.1%, mp: 62-64°C, ESI-MS m/z: 196[M+H] ⁺ , 218[M+ Na] ^+.

2) N-(4-isobutoxybenzyl) ethyl carbamate

Dissolve ethyl N-(4-hydroxybenzyl)carbamate (47g) in dimethylformamide (250ml) at 15°C to 25°C, then add anhydrous potassium carbonate (50g) in portions at <30°C , and the suspension was heated to 78°C to 82°C. Isobutane bromide (40 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (100ml×2). The solvent was recovered under reduced pressure, the residue was diluted with dichloromethane (300ml), and the dichloromethane solution was washed with 5% NaOH (50ml×2), then washed with water (100ml×2), the aqueous layer was discarded, and the dichloromethane solution was Recover under reduced pressure at 50°C, add n-hexane (100ml) to the residual solid, heat to 60°C and stir, dissolve the solid and cool to 40°C, add 10g of activated carbon powder, reheat to 60°C and stir for 30 minutes, filter the insoluble matter while it is hot, and the filtrate Cool to 10°C under stirring (crystallization at about 30°C) and let stand for 3 hours, filter the product and wash the filter cake with cold n-hexane (50ml×2), and vacuum dry at 30°C for 5 hours to obtain light yellow flocculent Solid (46.2g), yield 76.6%, mp: 39～40℃, ESI-MS m/z: 252[M+H] ⁺ , 274[M+Na] ^+.

3) 4-isobutoxybenzylamine

Dissolve potassium hydroxide (15g) in ethanol (50ml) at 40°C to 45°C, then add N-(4-isobutoxybenzyl) ethyl carbamate (17g) as a solid, and heat the solution to 78°C Stir for 8 hours and check for remaining starting material by TLC. After the reaction was completed, ethanol was recovered under reduced pressure at 50°C, dichloromethane (75ml) was added to the residue, stirred at room temperature for 10 minutes, the insoluble matter was filtered, and concentrated under reduced pressure at 30°C to obtain 9.9g of oily amino base, yield 82 %, ESI-MS m/z: 180[M+H] ⁺ , 202[M+Na] ^+.

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve 4-isobutoxybenzylamine (5 g) oily liquid which has deprotected group in dichloromethane (10 ml) at room temperature, then add anhydrous potassium carbonate (5 g), and cool the suspension to 0°C to 10°C , and phenyl chloroformate (4.8 g) was added dropwise to the suspension at 0°C to 10°C over 0.5 hours. After the addition was complete, the remaining starting material was detected by TLC. After the reaction, remove the inorganic salts by filtration, wash the filter cake with dichloromethane (30ml*2), wash the filtrate with 10% HCl (100ml*2), separate the layers to obtain an organic layer, wash with water (100ml*2), and dry Finally, the solvent was recovered under reduced pressure at 30°C to obtain a crude white solid (8.1 g), which was added with methanol (10 ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (5ml*2). Vacuum dried at 60°C for 2 hours to obtain 5.9g of pure white solid, yield 71%, mp: 98.2～99.5°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

N-(4-isobutoxybenzyl)phenylcarbamate (14.8g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (10g) were dissolved in the In water ethanol (20ml), heated to reflux and stirred for 3 hours, the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solid (3.38g) was added to the ethanol solution (yield 100%, calculated as piperidinamine) prepared in Example 5 at 40°C to 45°C for 30 minutes, stirred at this temperature for 2 hours, and the The solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (150ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C for 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (16.2g), yield 84.1%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ HNMR(400MHz,CDCl ₃ )δ7.25(dd,J＝8.3,5.7Hz,2H,Ar-H),7.11(dt,J＝8.7 and 4.5Hz,4H ,Ar-H),6.83(d,J=8.6Hz,2H,Ar-H),4.42(s,2H,CH ₂ ),4.19(d,J=5.5Hz,2H,CH ₂ ),4.02(s ,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41–2.29 (m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz, 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35, 115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53; IR (CM ^-1 ): 3425.1,2930.3,1647.6,1383.9,86.9,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,56.3,856.3,856.3,856.3,8.9,8.9. ,732.4.

Embodiment 2, with methoxycarbonyl as protecting group

1) Methyl N-(4-hydroxybenzyl)carbamate

Add 4-hydroxybenzylamine (15g) and sodium bicarbonate (15g) into dichloromethane (90ml) at room temperature (25°C, the same below) and stir, and dichloroformate formaldehyde at -25°C to 0°C for 1 hour The ester (13.8 g) was added dropwise to the suspension. After the addition was complete, the mixture was stirred at -25°C for 2 hours and the remaining starting material was checked by TLC. After the reaction was completed, suction filtration was performed to remove excess sodium salt. The filter cake was washed with dichloromethane (50ml x 2). The filtrate was washed with 5% dilute hydrochloric acid (36ml×2), and then washed with water (75ml×2). After separating the layers, the aqueous layer was discarded, and the organic layer was dried. The solvent was recovered under reduced pressure at 40°C to obtain a red liquid, which was dried under vacuum at 50°C for 3 hours to obtain 23.3g of a red oily liquid, yield: 81%, ESI-MS m/z: 182[M+H] ⁺ , 204[M+Na ] ⁺

2) Methyl N-(4-isobutoxybenzyl)carbamate

Dissolve methyl N-(4-hydroxybenzyl)carbamate (12g) in dimethylacetamide (24ml) at room temperature (25°C), then add anhydrous potassium carbonate (11g) in portions at <30°C , and the suspension was heated to 50°C to 55°C. Isobutane bromide (12 g) was added dropwise to the suspension at 55°C over 2 hours. After the addition was complete, the mixture was stirred at 55° C. for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (50ml×2). The solvent was recovered under reduced pressure. The residue was diluted with dichloromethane (150ml), and the dichloromethane solution was washed with 5% NaOH (30ml×2), then washed with water (50ml×2), the aqueous layer was discarded, and the dichloromethane solution was decompressed at 50°C Recovery, the obtained yellow liquid was vacuum-dried at 50°C for 3 hours to obtain a yellow oily liquid (12.4g), yield: 77.8%, ESI-MS m/z: 238[M+H] ⁺ , 260[M+Na] ⁺

3) 4-isobutoxybenzylamine

Potassium hydroxide (13g) was dissolved in ethanol (40ml) at 40°C to 45°C, then solid methyl N-(4-isobutoxybenzyl)carbamate (14g) was added, and the solution was heated to 78°C Stir for 2 hours and check for remaining starting material by TLC. After the reaction was completed, ethanol was recovered under reduced pressure at 50°C, dichloromethane (60ml) was added to the residue, stirred at room temperature for 10 minutes, the insoluble matter was filtered, washed with water (30ml*2) to separate layers, and the solvent was concentrated under reduced pressure at 30°C. 8.8 g of oily amino base was obtained, the yield was 83%, ESI-MS m/z: 180[M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (8g) deprotected in dioxane (24ml) at room temperature, then add anhydrous sodium carbonate (8g), and cool the suspension to 0°C to 10°C. °C, and phenyl chloroformate (8.4 g) was added dropwise to the suspension at 0 °C to 10 °C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 1 hour, then heated to 60°C and stirred for 1 hour, and the residual starting material was checked by TLC. After the reaction was finished, the inorganic salts were removed by filtration, the filter cake was washed with dioxane (20ml*2), the filtrate was washed with 10% HCl (20ml*2), the layers were separated to obtain an organic layer, washed with water (20ml*2), and washed with water (20ml*2). After drying, the solvent was recovered under reduced pressure at 60°C to obtain a crude white solid (23g), which was added with methanol (30ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (10ml*2). Vacuum dried at 60°C for 2 hours to obtain 10 g of pure white solid, yield 75%, mp: 99.1～99.4°C; ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

N-(4-isobutoxybenzyl)phenyl carbamate (12.9g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (8g) were dissolved in toluene at room temperature (30ml), heated to reflux and stirred for 12 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, a toluene solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea was obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Remove the toluene solvent, add 30ml of absolute ethanol, and add tartaric acid solid (3.24g) into the ethanol solution (yield 100%, calculated as piperidinamine) at 40°C to 45°C for 30 minutes, and stir at this temperature After 2 hours, the solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (150ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C in 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (13.7g), yield 89.4%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ H NMR (400MHz,CDCl ₃ )δ7.25(dd,J＝8.3,5.7Hz,2H,Ar-H),7.11(dt,J＝8.7and4.5Hz, 4H, Ar-H), 6.83 (d, J=8.6Hz, 2H, Ar-H), 4.42 (s, 2H, CH ₂ ), 4.19 (d, J=5.5Hz, 2H, CH ₂ ), 4.02 ( s,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41– 2.29(m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz , 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35 , ^{115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53} ; 780.1, 732.4.

Example 3, using tert-butoxycarbonyl as a protecting group

1) N-(4-hydroxybenzyl)-tert-butyl carbamate

4-Hydroxybenzylamine (20g) and potassium bicarbonate (22g) were added to tetrahydrofuran (60ml) and water (15ml) at room temperature and stirred, di-tert-butyl dicarbonate (46.1 g) dropwise into the suspension. After the addition was complete, the mixture was stirred at 20°C to 25°C for 24 hours, starting material remaining by TLC. After the reaction was complete, the solid was filtered with suction, the filter cake was washed with tetrahydrofuran (30ml×2), the solid was washed with 5% dilute hydrochloric acid (36ml×2), the solid was filtered, washed with water (50ml×2), and filtered with suction. The solid was dried under vacuum at 60°C for 5 hours to obtain 14.7g of off-white powder, yield: 72.1%, mp: 105-107°C, ESI-MS m/z: 224[M+H] ⁺ , 246[M+Na] ⁺

2) tert-butyl N-(4-isobutoxybenzyl)carbamate

Dissolve N-(4-hydroxybenzyl)-tert-butyl carbamate (25g) in tetrahydrofuran (75ml) at room temperature, then add anhydrous potassium carbonate (23g) in portions at <30°C, and dissolve the suspension Heat to 60°C. Bromoisobutane (23 g) was added dropwise to the suspension at 60°C over 2 hours. After the addition was complete, the mixture was stirred at 60°C-65°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (50ml×2). The solvent was recovered under reduced pressure. Pour the residual liquid into 100ml of water, filter the precipitated solid with suction, wash the filter cake with 5% NaOH (30ml×2), then wash with water (30ml×2), and add toluene (60ml) to the solid to be heated to 60°C and stir to dissolve, then Cool to 10°C to 15°C under stirring and let stand for 10 hours, filter the precipitated pale yellow crystals, wash with cold toluene (15ml*2), and vacuum dry at 45°C for 5 hours to obtain brown flaky crystals (19.7g ), yield: 70.1%, mp: 59～61℃, ESI-MS m/z: 280[M+H] ⁺ , 302[M+Na] ⁺

3) 4-isobutoxybenzylamine

Dissolve 20 g of tert-butyl N-(4-isobutoxybenzyl) carbamate in dichloromethane (200 ml) at room temperature, then add trifluoroacetic acid (160 ml) dropwise to the solution at -25-0°C After the dropwise addition was completed, it was stirred at room temperature for 3 hours, and the remaining raw materials were detected by TLC. After the reaction was completed, the pH of the solution was adjusted to alkaline, and the layers were washed with water (50ml*2), and concentrated under reduced pressure at 30°C to obtain 9.6g of oily amino base, with a yield of 74%, ESI-MS m/z: 180[ M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (12 g) deprotected at room temperature in toluene (40 ml), then add triethylamine (9 g), and cool the suspension to 0° C. to 10° C. Phenyl chloroformate (14.6 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 3 hours, the remaining starting material was checked by TLC. After the reaction, remove triethylamine hydrochloride by filtration, wash the filter cake with toluene (30ml*2), wash the filtrate with 10% HCl (30ml*2), separate the layers to obtain the organic layer, wash with water (20ml*2), After drying, the solvent was recovered under reduced pressure at 60°C to obtain a crude white solid (18 g), which was added with ethanol (30 ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (10ml*2). Vacuum dried at 60°C for 2 hours to obtain 14.4g white solid pure product, yield 78%, mp: 98.6～99.1°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

Dissolve N-(4-isobutoxybenzyl)phenyl carbamate (21g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (12g) in isopropyl Alcohol (24ml), heated to reflux and stirred for 8 hours, the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solid (5.68g) was added to the isopropanol solution (100% yield, calculated as piperidinamine) prepared in Example 5 at 60°C to 65°C for 30 minutes, stirred at this temperature for 2 hours, A white solid precipitated out, and the solution was cooled to 20°C to 25°C and allowed to stand at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold isopropanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (80ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C in 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (20.1g), yield 87%, mp: 135.5-137.5°C (document 133-135°C), ESI-MSm/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ,ESI-MS m/z:428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ )δ7.25 (dd, J＝8.3 ,5.7Hz,2H,Ar-H),7.11(dt,J＝8.7and 4.5Hz,4H,Ar-H),6.83(d,J＝8.6Hz,2H,Ar-H),4.42(s,2H , CH ₂ ), 4.19 (d, J=5.5Hz, 2H, CH ₂ ), 4.02 (s, 1H, CH), 3.70 (d, J=6.5Hz, 2H, CH ₂ ), 2.98 (d, J= 11.1Hz, 2H, CH ₂ ), 2.56–2.46 (m, 1H, NH), 2.41–2.29 (m, 4H, CH ₂ ), 1.99 (dp, J＝13.3, 6.6Hz, 2H, CH ₂ ), 1.73 (q, J=12.3Hz, 2H, CH ₂ ), 1.51 (d, J=11.4Hz, 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ )δ174.99,162.58,160.18,157.95,137.27,133.44,128.86,128.78,128.63,115.35,115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53；IR(cm ^-1 ):3425.1, 2930.3, 1693.3, 1647.6, 1383.9, 1263.9, 1074.3, 856.6, 834.2, 780.1, 732.4.

Embodiment 4, with acetyl group as protecting group

1) N-(4-hydroxybenzyl)acetamide

4-Hydroxybenzylamine (25g) and sodium bicarbonate (31g) were added to toluene (50ml) and stirred at room temperature, and acetic anhydride (29.1g) was added dropwise to the suspension at 0°C to 20°C over 1 hour. After the addition was complete, the mixture was stirred at 20°C to 25°C for 0.5 hours and the remaining starting material was checked by TLC. After the reaction was completed, the solid was suction filtered, the filter cake was washed with dichloromethane (25ml×2), the solid was washed with 5% dilute hydrochloric acid (45ml×2), the pH was adjusted to 3-4, the solid was filtered, and water (40ml ×2) washing to obtain a white solid. Vacuum dried at 60°C for 5 hours to obtain 32.7g of white solid, yield: 81.2%, mp: 135～137°C, ESI-MS m/z: 166[M+H] ⁺ , 188[M+Na] ⁺

2) N-(4-isobutoxybenzyl)acetamide

N-(4-Hydroxybenzyl)acetamide (10 g) was dissolved in acetonitrile (30 ml) at room temperature, then anhydrous sodium carbonate (11 g) was added in portions at <30 °C, and the suspension was heated to 78 °C to 82°C. Isobutane bromide (12 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess sodium salt, and the filter cake was washed with dichloromethane (50ml×2). The solvent was recovered under reduced pressure. Pour the residual liquid into 100ml of water, filter the precipitated solid with suction, wash the filter cake with 5% NaOH (30ml×2), and then wash with water (30ml×2) to obtain the solid, add toluene (60ml) and heat to 60°C for 30 minutes, The filtrate was cooled to 15°C to 20°C under stirring and allowed to stand for 5 hours. The precipitated pale yellow crystals were filtered, washed with cold toluene (15ml*2), and dried in vacuo at 45°C for 5 hours to obtain a pale yellow solid (7.75 g), yield: 50.3%, mp: 53～55℃, ESI-MS m/z: 222[M+H] ⁺ , 244[M+Na] ⁺

3) 4-isobutoxybenzylamine

Dissolve hydrazine hydrate (80ml) in methanol (100ml) at room temperature, then add N-(4-isobutoxybenzyl)acetamide (10g) solid, the solution is heated to reflux temperature and stirred for 8 hours, detected by TLC Raw material remaining. After the reaction was completed, the solvent was recovered under reduced pressure at 80°C, dichloromethane (80ml) was added to the residue, washed with water (30ml*2), and then concentrated under reduced pressure at 30°C to obtain 5.3g of oily amino base with a yield of 65 %, ESI-MS m/z: 180[M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (15 g) deprotected at room temperature in tetrahydrofuran (75 ml), then add sodium bicarbonate (15 g), and cool the suspension to 0° C. to 10° C., and in Phenyl chloroformate (19.6 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 1 hour, then heated to 60°C and stirred for 10 hours, and the residual starting material was checked by TLC. After the reaction, remove the inorganic salt by filtration, wash the filter cake with tetrahydrofuran (30ml*2), wash the filtrate with 10% HCl (50ml*2), separate the layers to obtain the organic layer, wash with water (20ml*2), and after drying, The solvent was recovered under reduced pressure at 60°C to obtain a crude white solid (25 g), which was added with methanol (50 ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (20ml*2). Vacuum dried at 60°C for 2 hours to obtain 15.8g of pure white solid, yield 62%, mp: 97.8～98.5°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

Dissolve N-(4-isobutoxybenzyl)phenyl carbamate (37.7g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (20g) in methanol at room temperature (60ml), heated to reflux and stirred for 6 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solid (4.5 g) was added to the methanol solution (yield 100%, calculated as piperidine amine) prepared in Example 5 at 40°C to 45°C for 30 minutes, stirred at this temperature for 2 hours, and the The solution was cooled to 0°C and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (20ml*2). The crude product was obtained, and the wet product was heated to reflux with anhydrous methanol (150ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C for 1 hour, and stood at this temperature for 24 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (28.2g), yield 62%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ H NMR (400MHz,CDCl ₃ )δ7.25(dd,J＝8.3,5.7Hz,2H,Ar-H),7.11(dt,J＝8.7and 4.5Hz, 4H, Ar-H), 6.83 (d, J=8.6Hz, 2H, Ar-H), 4.42 (s, 2H, CH ₂ ), 4.19 (d, J=5.5Hz, 2H, CH ₂ ), 4.02 ( s,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41– 2.29(m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz , 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35 , ^{115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53} ; 780.1, 732.4.

Embodiment 5, with formyl as protecting group

1) N-(4-hydroxybenzyl) formamide

4-Hydroxybenzylamine (20g) and sodium bicarbonate (27g) were added to toluene (60ml) at room temperature and stirred, and fresh formic anhydride (21.5g) was added dropwise to the suspension at 0°C to 20°C for 1 hour . After the addition was complete, the mixture was stirred at 20°C to 25°C for 2 hours, then heated to 60°C and stirred for 1 hour, starting material remaining by TLC. After the reaction was completed, suction filtration was performed to remove excess sodium salt. The filter cake was washed with toluene (30ml x 2). The filtrate was washed with 5% dilute hydrochloric acid (35ml×2), and the layers were washed with water (45ml×2), and the organic layer was dried. The solvent was recovered under reduced pressure at 30°C to 40°C to obtain a red oil, which was left at 20°C to 25°C for 3 hours to obtain a yellow solid, which was filtered and washed with dichloromethane (30ml), dried under vacuum at 60°C for 3 hours to obtain a pale yellow solid 20.6 g, yield: 60.0%, mp: 122～124℃, ESI-MS m/z: 152[M+H] ⁺ , 174[M+Na] ⁺

2) N-(4-isobutoxybenzyl) formamide

Dissolve N-(4-hydroxybenzyl)formamide (12g) in dimethylformamide (50ml) at room temperature, then add anhydrous potassium carbonate (15g) in portions at <30°C, and dissolve the suspension Heat to 78°C to 82°C. Isobutane bromide (17 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (20ml×2). Dimethylformamide was recovered under reduced pressure. Pour the residual liquid into 100ml of water, filter the precipitated solid with suction, wash the filter cake with 5% NaOH (30ml×2), then wash with water (30ml×2), and add acetonitrile (50ml) to heat to 80°C to dissolve the solid and stir for 30 Minutes, the solution was cooled to 15°C to 20°C under stirring and allowed to stand for 5 hours, the precipitated white crystals were filtered, washed with cold toluene (15ml*2), and dried in vacuum at 45°C for 5 hours to obtain a white powder solid ( 13.9g), yield: 70.0%, mp: 78～81℃, ESI-MS m/z: 208[M+H] ⁺ ,230[M+Na] ⁺

3) 4-isobutoxybenzylamine

Dissolve sodium hydroxide (20g) in ethanol (40ml) at 40°C to 45°C, then add N-(4-isobutoxybenzyl)formamide (19g) as a solid, and stir the solution at room temperature for 5 hours , The remaining starting material was detected by TLC. After the reaction was completed, ethanol was recovered under reduced pressure at 50°C, dichloromethane (75ml) was added to the residue, stirred at room temperature for 10 minutes, the insoluble matter was filtered, and then concentrated under reduced pressure at 30°C to obtain 12.3g of oily amino base, yield 75%, ESI-MS m/z: 180[M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (13g) deprotected in dichloromethane (65ml) at room temperature, then add anhydrous potassium carbonate (15g), and cool the suspension to -25°C to 0 °C, and phenyl chloroformate (18.1 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was cooled to -25°C and stirred for 2.5 hours, starting material remaining by TLC. After the reaction, the inorganic salts were removed by filtration, the filter cake was washed with DCM (25ml*2), the filtrate was washed with 10% HCl (20ml*2), the layers were separated to obtain an organic layer, washed with water (20ml*2), and after drying, The solvent was recovered under reduced pressure at 30°C to obtain a crude white solid (23g), which was added with methanol (50ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (20ml*2). Vacuum dried at 60°C for 2 hours to obtain 18g white solid pure product, yield 83%, mp: 98.2～99.5°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

Dissolve N-(4-isobutoxybenzyl)phenyl carbamate (30.3g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (15g) in ethanol at room temperature (60ml), heated to reflux and stirred for 3 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solid (9.12g) was added to the ethanol solution (yield 100%, calculated as piperidinamine) prepared in Example 5 at 40°C to 45°C for 30 minutes, stirred at this temperature for 2 hours, and the The solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (150ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C in 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (26g), yield 90%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ )δ7.25 (dd, J＝8.3, 5.7Hz, 2H, Ar-H), 7.11 (dt, J＝8.7 and 4.5Hz, 4H ,Ar-H),6.83(d,J=8.6Hz,2H,Ar-H),4.42(s,2H,CH ₂ ),4.19(d,J=5.5Hz,2H,CH ₂ ),4.02(s ,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41–2.29 (m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz, 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35, 115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53; IR (CM ^-1 ): 3425.1,2930.3,1647.6,1383.9,86.9,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,56.3,856.3,856.3,856.3,8.9,8.9. ,732.4.

Embodiment 6, using benzyloxycarbonyl as protecting group

1) Benzyl N-(4-hydroxybenzyl)carbamate

4-Hydroxybenzylamine (10g) and triethylamine (14g) were added to acetonitrile (40ml) and stirred at room temperature, and benzyl chloroformate (22.2g) was added dropwise to the suspension at 0°C to 20°C for 1 hour middle. After the addition was complete, the mixture was stirred at 35°C to 40°C for 2 hours, and the remaining starting material was checked by TLC. After the reaction was completed, suction filtration was performed to remove excess triethylamine hydrochloride. The solvent was removed under reduced pressure, and the residual solid was diluted with dichloromethane (20ml×2). The filtrate was washed with 5% dilute hydrochloric acid (25ml×2) to adjust the acidity, and then washed with water (30ml×2). After separating the layers, the water layer was discarded, and the organic layer was dried. The solvent was recovered under reduced pressure at 30°C to 40°C to obtain a red solid. The solid was filtered with suction, washed with toluene, and dried under vacuum at 40°C for 5 hours to obtain 11.7 g of a white solid. Yield: 77.8%. mp:50～51℃ESI-MS m/z:258[M+H] ⁺ ,280[M+Na] ⁺

2) Benzyl N-(4-isobutoxybenzyl)carbamate

Benzyl N-(4-hydroxybenzyl)carbamate (18g) was dissolved in dimethylformamide (90ml) at room temperature, then anhydrous potassium carbonate (19g) was added in portions at <30°C, and the The suspension was heated to 78°C to 82°C. Isobutane bromide (14 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (50ml×2). Dimethylformamide was recovered under reduced pressure. The residue was diluted with dichloromethane (150ml), the dichloromethane solution was washed with 5% NaOH (30ml×2), then water (50ml×2), the aqueous layer was discarded, and the dichloromethane solution was decompressed at 50°C Recover, add methanol (60ml) to the residual solid and heat to 60°C and stir, dissolve the solid and cool to 50°C, add 8g of activated carbon powder, reheat to 60°C and stir for 30 minutes, filter the insoluble matter while it is hot, and cool the filtrate to 15°C under stirring ℃ to 20 ℃ (crystallization at about 25 ℃) and standing for 5 hours, the product was filtered and the filter cake was washed with cold methanol (25ml×2), and vacuum-dried at 30 ℃ for 5 hours to obtain a yellow solid (14.7g). Yield: 83.4%, mp: 38～39℃, ESI-MS m/z: 314[M+H] ⁺ ,336[M+Na] ⁺

3) 4-isobutoxybenzylamine

Add N-(4-isobutoxybenzyl)benzyl carbamate (5g) and 5% Pd-C (0.3g) into (30ml) ethanol and pass through hydrogen, stir at room temperature for 5 hours, and detect with TLC Raw material remaining. After the reaction was completed, the palladium carbon was filtered, and then concentrated under reduced pressure at 50°C to obtain 2.3 g of oily amino base, with a yield of 63%, ESI-MS m/z: 180[M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (11g) deprotected in dichloromethane (65ml) at room temperature, then add anhydrous potassium carbonate (13g), and cool the suspension to 0°C to 10°C , and phenyl chloroformate (13.4 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 1 hour, starting material remained by TLC. After the reaction, the inorganic salts were removed by filtration, the filter cake was washed with DCM (30ml*2), the filtrate was washed with 10% HCl (40ml*2), the layers were separated to obtain an organic layer, washed with water (30ml*2), and after drying, The solvent was recovered under reduced pressure at 30°C to obtain a crude white solid (19 g), which was added with methanol (30 ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (20ml*2). Vacuum dried at 60°C for 2 hours to obtain 15.4g white solid pure product, yield 84%, mp: 98.2～99.5°C, ESI-MS m/z: 300[M+H] ⁺ ,322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

Dissolve N-(4-isobutoxybenzyl)phenyl carbamate (16.3g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (11g) in ethanol at room temperature (55ml), heated to reflux and stirred for 3 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solid (7.43g) was added to the ethanol solution (yield 100%, calculated as piperidinamine) prepared in Example 5 at 40°C to 45°C for 30 minutes, stirred at this temperature for 2 hours, and the The solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (100ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C in 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (19.3g), yield 91%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ HNMR(400MHz,CDCl ₃ )δ7.25(dd,J＝8.3,5.7Hz,2H,Ar-H),7.11(dt,J＝8.7 and 4.5Hz,4H ,Ar-H),6.83(d,J=8.6Hz,2H,Ar-H),4.42(s,2H,CH ₂ ),4.19(d,J=5.5Hz,2H,CH ₂ ),4.02(s ,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41–2.29 (m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz, 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35, 115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53; IR (CM ^-1 ): 3425.1,2930.3,1647.6,1383.9,86.9,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,56.3,856.3,856.3,856.3,8.9,8.9. ,732.4.

Embodiment 7, with Wat methoxycarbonyl as protecting group

1) Wat methyl N-(4-hydroxybenzyl) carbamate

4-Hydroxybenzylamine (15g) and sodium bicarbonate (23g) were added to dioxane (75ml) and stirred at room temperature, and fluorenylmethoxycarbonyl chloride (53.6g) was added dropwise at 0°C to 20°C for 1 hour added to the suspension. After the addition was complete, the mixture was stirred at 20°C to 25°C for 2 hours, then warmed up to 50°C and stirred for 1 hour, and the residual starting material was detected by TLC. After the reaction was completed, suction filtration was performed to remove excess sodium salt. The filter cake was washed with dioxane (30ml x 2). The filtrate was washed with 5% dilute hydrochloric acid (30ml×2), and the layers were washed with water (50ml×2), and the organic layer was dried. Recover the solvent under reduced pressure at 60°C to 80°C, dilute the residual solid with ethanol (30ml) and pour it into 300ml of water, filter the precipitated solid with suction and wash the filter cake with ethylene glycol (50ml*2), and dry it in vacuum at 60°C for 3h. Obtained 17.1g of white solid, yield: 85.7%, mp: 144～146℃, ESI-MS m/z: 346[M+H] ⁺ , 368[M+Na] ⁺

2) Wat methyl N-(4-isobutoxybenzyl) carbamate

Benzyl N-(4-hydroxybenzyl)carbamate (12 g) was dissolved in dimethylformamide (70 ml) at room temperature, then anhydrous potassium carbonate (19 g) was added in portions at <30° C., and the The suspension was heated to 78°C to 82°C. Isobutane bromide (14 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (30ml×2). Dimethylformamide was recovered under reduced pressure. The residue was diluted with dichloromethane (300ml), the dichloromethane solution was washed with 5% NaOH (25ml×2), and the layers were washed with water (50ml×2), the aqueous layer was discarded, and the solvent was reduced at 50-60°C. Pressure recovery, add isopropyl ether (20ml) to the residual solid and heat to 60°C and stir, the solid dissolves and cool to 50°C, add 1g of activated carbon powder, reheat to 60°C and stir for 30 minutes, filter the insoluble matter while it is hot, and the filtrate is stirred Cooled to 15°C to 20°C and left to stand for 10 hours, the product was filtered and the filter cake was washed with cold isopropyl ether (5ml×2), dried in vacuo at 60°C for 5 hours to obtain a light yellow solid (7.4g), yield: 84.7 ％,mp:138～139℃,ESI-MSm/z:402[M+H] ⁺ ,424[M+Na] ⁺

3) 4-isobutoxybenzylamine

Dissolve N-(4-isobutoxybenzyl)methyl carbamate (3g) and 20% piperidinamine (15ml) in dimethylformamide (10ml), stir at room temperature for 3 hours, and use TLC Check raw material remaining. After the reaction was completed, the solvent was removed, dichloromethane (10ml*2) was added, washed with water (5ml*2), the solvent was removed to obtain 0.82g of oily amino base, the yield was 52%, ESI-MS m/z: 180[ M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (10g) deprotected in dichloromethane (60ml) at room temperature, then add anhydrous potassium carbonate (12g), and cool the suspension to 0°C to 10°C , and phenyl chloroformate (15.7 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 1 hour, starting material remained by TLC. After the reaction, remove the inorganic salt by filtration, wash the filter cake with DCM (30ml*2), wash the filtrate with 10% HCl (25ml*2), separate the layers to obtain the organic layer, wash with water (20ml*2), after drying, The solvent was recovered under reduced pressure at 30°C to obtain a crude white solid (20 g), which was added with methanol (30 ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (10ml*2). Vacuum dried at 60°C for 2 hours to obtain 13.4g white solid pure product, yield 80%, mp: 98.2～99.5°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

N-(4-isobutoxybenzyl)phenyl carbamate (21g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (13g) were dissolved in ethanol ( 80ml), heated to reflux and stirred for 3 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solid (4.39g) was added to the ethanol solution (yield 100%, calculated as piperidinamine) prepared in Example 5 at 40°C to 45°C for 30 minutes, stirred at this temperature for 2 hours, and the The solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (120ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C in 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (22g), yield 88%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ )δ7.25 (dd, J＝8.3, 5.7Hz, 2H, Ar-H), 7.11 (dt, J＝8.7 and 4.5Hz, 4H ,Ar-H),6.83(d,J=8.6Hz,2H,Ar-H),4.42(s,2H,CH ₂ ),4.19(d,J=5.5Hz,2H,CH ₂ ),4.02(s ,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41–2.29 (m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz, 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35, 115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53; IR (CM ^-1 ): 3425.1,2930.3,1647.6,1383.9,86.9,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,56.3,856.3,856.3,856.3,8.9,8.9. ,732.4.

Example 8, using trimethylsilylethoxycarbonyl as a protecting group

1) N-(4-hydroxybenzyl)carbamate-(2,2,2-trimethylsilyl)ethyl ester

4-Hydroxybenzylamine (15g) and sodium bicarbonate (25g) were added to dichloromethane (90ml) at room temperature and stirred, and 2,2,2-trimethylsilyl ethyl Oxoformyl chloride (38.6 g) was added dropwise to the suspension. After the addition was complete, the mixture was stirred at 20°C to 25°C for 12 hours, starting material remaining by TLC. After the reaction was completed, suction filtration was performed to remove excess sodium salt. The filter cake was washed with dichloromethane (45ml x 2). The filtrate was washed with 5% dilute hydrochloric acid (15ml×2), and then washed with water (70ml×2). After separating the layers, the aqueous layer was discarded, and the organic layer was dried. The solvent was recovered under reduced pressure at 30°C to 40°C, and dried under vacuum at 40°C for 5 hours to obtain 14.8g of red liquid, yield: 61.5%, ESI-MS m/z: 268[M+H] ⁺ , 290[M+ Na] ⁺

2) N-(4-isobutoxybenzyl)carbamate-(2,2,2-trimethylsilyl)ethyl ester

Dissolve N-(4-hydroxybenzyl)carbamate-(2,2,2-trimethylsilyl)ethyl ester (11g) in dimethylformamide (66ml) at room temperature, and then Anhydrous potassium carbonate (13 g) was added portionwise and the suspension was heated to 78°C to 82°C. Isobutane bromide (11 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (50ml×2). Dimethylformamide was recovered under reduced pressure. The residue was diluted with dichloromethane (150ml), the dichloromethane solution was washed with 5% NaOH (30ml×2), then water (50ml×2), the aqueous layer was discarded, and the dichloromethane solution was decompressed at 50°C Recovered and dried under vacuum at 40°C for 5 hours to obtain a brown oily liquid (7.1g), yield: 83.3%, ESI-MS m/z: 324[M+H] ⁺ , 346[M+Na] ⁺

3) 4-isobutoxybenzylamine

Dissolve N-(4-isobutoxybenzyl)carbamate-(2,2,2-trimethylsilyl)ethyl ester (5g) and tetrabutylammonium fluoride (7.3g) in tetrahydrofuran (50ml ), the solution was stirred at room temperature for 12 hours, and the remainder of the reaction raw material was detected by TLC. After the reaction was completed, the solvent was recovered under reduced pressure, the residual liquid was extracted with dichloromethane (15ml*2), the layers were washed with water (50ml*2), the water layer was discarded, and the solvent was removed to obtain 2.1g of oily amino base, the yield 68%, ESI-MS m/z: 180[M+H] ⁺ ,202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve 4-isobutoxybenzylamine (25g) oily liquid which has been deprotected in dichloromethane (150ml) at room temperature, then add anhydrous potassium carbonate (33g), and cool the suspension to 0°C to 10°C , and phenyl chloroformate (41.4 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 1 hour, starting material remained by TLC. After the reaction, the inorganic salts were removed by filtration, the filter cake was washed with DCM (30ml*2), the filtrate was washed with 10% HCl (100ml*2), the layers were separated to obtain an organic layer, washed with water (100ml*2), and after drying, The solvent was recovered under reduced pressure at 30°C to obtain a crude white solid (45 g), which was added with methanol (60 ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (20ml*2). Vacuum dried at 60°C for 2 hours to obtain 33g white solid pure product, yield 79%, mp: 98.2～99.5°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

Dissolve N-(4-isobutoxybenzyl)phenyl carbamate (22.6g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (14g) in ethanol at room temperature (100ml), heated to reflux and stirred for 3 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solid (5.2 g) was added to the ethanol solution (yield 100%, calculated as piperidinamine) prepared in Example 5 at 40°C to 45°C for 30 minutes, stirred at this temperature for 2 hours, and the The solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (120ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C in 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (24.8g), yield 92%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ HNMR(400MHz,CDCl ₃ )δ7.25(dd,J＝8.3,5.7Hz,2H,Ar-H),7.11(dt,J＝8.7 and 4.5Hz,4H ,Ar-H),6.83(d,J=8.6Hz,2H,Ar-H),4.42(s,2H,CH ₂ ),4.19(d,J=5.5Hz,2H,CH ₂ ),4.02(s ,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41–2.29 (m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz, 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35, 115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53; IR (CM ^-1 ): 3425.1,2930.3,1647.6,1383.9,86.9,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,56.3,856.3,856.3,856.3,8.9,8.9. ,732.4.

Embodiment 9, using p-toluenesulfonyl as protecting group

1) N-(4-hydroxybenzyl)-N-(4-methylphenyl)sulfonamide

4-Hydroxybenzylamine (10g) and sodium bicarbonate (25g) were added to tetrahydrofuran (90ml) at room temperature and stirred, and p-toluenesulfonyl chloride (38.6g) was added dropwise to the suspension at 0°C to 20°C for 1 hour middle. After the addition was complete, the mixture was stirred at 20°C to 25°C for 10 hours, then warmed up to 50°C and stirred for 2 hours, and the remaining starting material was detected by TLC. After the reaction was completed, suction filtration was performed to remove excess sodium salt. The filter cake was washed with tetrahydrofuran (40ml×2). The filtrate was washed with 5% dilute hydrochloric acid (10ml×2), and the layers were washed with water (40ml×2), and the organic layer was dried. The solvent was recovered under reduced pressure at 60°C to 80°C, and dried in vacuum at 60°C for 3 hours to obtain 10 g of yellow oily liquid, yield: 68.9%, ESI-MS m/z: 278[M+H] ⁺ , 300[M+Na ] ⁺

2) N-(4-isobutoxybenzyl)-N-(4-methylphenyl)sulfonamide

N-(4-hydroxybenzyl)-N-(4-methylphenyl)sulfonamide liquid (13g) was dissolved in dimethylformamide (65ml) at room temperature, and then added in portions at <30°C without Potassium carbonate water (16 g) and the suspension heated to 78°C to 82°C. Isobutane bromide (14 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (50ml×2). Dimethylformamide was recovered under reduced pressure. The residue was diluted with dichloromethane (100ml), washed with 5% NaOH (50ml×2), washed with water (100ml×2), and the water layer was discarded. The solvent was recovered under reduced pressure at 50-60°C, and the Vacuum drying at 60°C for 5 hours gave light brown oily liquid (9.4g), yield: 80.1%, ESI-MS m/z: 334[M+H] ⁺ , 356[M+Na] ⁺

3) 4-isobutoxybenzylamine

Add N-(4-isobutoxybenzyl)-N-(4-methylphenyl)sulfonamide (0.25g) to sodium naphthol (15ml, naphthol 2g, sodium 1g) at -78°C THF (20ml) and stirred at this temperature for 10 hours under nitrogen protection. After the reaction is complete, add water (5ml) to terminate the reaction, remove the solvent under reduced pressure, add water (5ml), and extract with ethyl acetate (10ml*2), then wash with saturated brine (10ml*2), dry and reduce pressure The solvent was recovered to obtain 0.09g of oily amino base, yield: 59%, ESI-MS m/z: 180[M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (21g) deprotected in dichloromethane (120ml) at room temperature, then add anhydrous potassium carbonate (29g), and cool the suspension to 0°C to 10°C , and phenyl chloroformate (36.6 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 1 hour, starting material remained by TLC. After the reaction, the inorganic salts were removed by filtration, the filter cake was washed with DCM (30ml*2), the filtrate was washed with 10% HCl (100ml*2), the layers were separated to obtain an organic layer, washed with water (100ml*2), and after drying, The solvent was recovered under reduced pressure at 30°C to obtain a crude white solid (45g), which was added with methanol (75ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (20ml*2). Vacuum dried at 60°C for 2 hours to obtain 28.4g white solid pure product, yield 81%, mp: 98.2～99.5°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

Dissolve N-(4-isobutoxybenzyl)phenyl carbamate (25.9g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (16g) in ethanol at room temperature (120ml), heated to reflux and stirred for 3 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solids (6.49 g) were added to the ethanol solution (yield 100%, calculated as piperidinamine) prepared in Example 5 at 40°C to 45°C for 30 minutes, stirred at this temperature for 2 hours, and the The solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (130ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C for 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (26.2g), yield 85%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ HNMR(400MHz,CDCl ₃ )δ7.25(dd,J＝8.3,5.7Hz,2H,Ar-H),7.11(dt,J＝8.7 and 4.5Hz,4H ,Ar-H),6.83(d,J=8.6Hz,2H,Ar-H),4.42(s,2H,CH ₂ ),4.19(d,J=5.5Hz,2H,CH ₂ ),4.02(s ,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41–2.29 (m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz, 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35, 115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53; IR (CM ^-1 ): 3425.1,2930.3,1647.6,1383.9,86.9,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,56.3,856.3,856.3,856.3,8.9,8.9. ,732.4.

Embodiment 10, using trityl as protecting group

1) N-(4-hydroxybenzyl)-tritylamine

4-Hydroxybenzylamine (12g) and triethylamine (22g) were added to chloroform (60ml) and stirred at room temperature, and a chloroform solution of triphenylchloromethane (57.1g) was added dropwise at 0°C to 20°C for 1 hour added to the suspension. After the addition was complete, the mixture was stirred at 20°C to 25°C for 10 hours, then warmed up to 40°C and stirred for 2 hours, and the remaining starting material was detected by TLC. After the reaction was completed, suction filtration was performed to remove triethylamine salt. The filter cake was washed with chloroform (30ml x 2). The layers were washed with water (50ml×2), and the organic layer was dried. The solvent was recovered under reduced pressure at 60°C to 80°C, the solid was washed with n-hexane (50ml*2), the light yellow powder was filtered, and vacuum-dried at 60°C for 3h to obtain 10.5g. Yield: 66.8%, mp: 182～184℃, ESI-MS m/z: 366[M+H] ⁺ , 388[M+Na] ⁺

2) N-(4-isobutoxybenzyl)-tritylamine

N-(4-hydroxybenzyl)-tritylamine (15 g) was dissolved in dimethylformamide (120 ml) at room temperature, then anhydrous potassium carbonate (14 g) was added in portions at <30° C., and The suspension was heated to 78°C to 82°C. Isobutane bromide (14 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (50ml×2). Dimethylformamide was recovered under reduced pressure. The residue was diluted with ethanol (50ml), then poured into water (200ml), filtered the precipitated solid, added 5% NaOH (50ml×2) to wash, and then washed with water (80ml×2), and the solid was vacuum-dried at 60°C for 5 hours , to obtain white powder (8.1g), yield: 78.3%, mp: 141～143℃, ESI-MS m/z: 422[M+H] ⁺ , 444[M+Na] ⁺

3) 4-isobutoxybenzylamine

Dissolve 8 g of N-(4-isobutoxybenzyl)-tritylamine in tetrahydrofuran (50 ml) at room temperature, then add glacial acetic acid (40 ml) dropwise to the solution at 0-20°C, dropwise After the addition was complete, it was heated to 40° C. and stirred for 4 hours, and the remaining raw material was detected by TLC. After the reaction was completed, the pH of the solution was adjusted to alkaline at 0-25°C, and the layers were washed with water (25ml*2), and the solvent was concentrated under reduced pressure at 30°C to obtain 3.1g of oily amino base, with a yield of 79%, ESI- MS m/z: 180[M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (14g) deprotected in dichloromethane (120ml) at room temperature, then add anhydrous potassium carbonate (22g), and cool the suspension to 0°C to 10°C , and phenyl chloroformate (14.6 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 1 hour, starting material remained by TLC. After the reaction, the inorganic salts were removed by filtration, the filter cake was washed with DCM (30ml*2), the filtrate was washed with 10% HCl (100ml*2), the layers were separated to obtain an organic layer, washed with water (100ml*2), and after drying, The solvent was recovered under reduced pressure at 30°C to obtain a crude white solid (25 g), which was added with methanol (40 ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (20ml*2). Vacuum dried at 60°C for 2 hours to obtain 19.4g white solid pure product, yield 83%, mp: 98.2～99.5°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

Dissolve N-(4-isobutoxybenzyl)phenyl carbamate (15.8g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (9g) in ethanol at room temperature (70ml), heated to reflux and stirred for 3 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solid (3.95 g) was added to the ethanol solution (yield 100%, calculated as piperidinamine) prepared in Example 5 at 40°C to 45°C for 30 minutes, stirred at this temperature for 2 hours, and the The solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (150ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C in 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (14.5g), yield 84.2%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ HNMR(400MHz,CDCl ₃ )δ7.25(dd,J＝8.3,5.7Hz,2H,Ar-H),7.11(dt,J＝8.7 and 4.5Hz,4H ,Ar-H),6.83(d,J=8.6Hz,2H,Ar-H),4.42(s,2H,CH ₂ ),4.19(d,J=5.5Hz,2H,CH ₂ ),4.02(s ,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41–2.29 (m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz, 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35, 115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53; IR (CM ^-1 ): 3425.1,2930.3,1647.6,1383.9,86.9,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,56.3,856.3,856.3,856.3,8.9,8.9. ,732.4.

Example 11, using 2,4-dimethoxybenzyl as a protecting group

1) N-(4-hydroxybenzyl)-N-(2,4-dimethoxy)benzylamine

4-Hydroxybenzylamine (15g) and 2,4-dimethoxybenzaldehyde (10g) were dissolved in dichloromethane (50ml) at room temperature, and sodium triacetylborohydride (17g) was dissolved at 0-15°C The suspension was added in portions. After the addition was complete, it was stirred at 20-25°C for 12 hours, and the remaining starting material was checked by TLC. After the reaction, filter the insoluble matter and wash the filter cake with dichloromethane (20ml*2), add sodium hydroxide (3g-5g) at 0-20°C to adjust the pH from 10 to 12, then wash with water (100ml*2) After the organic layer was dried, the solvent was removed under reduced pressure at 40°C, and the solvent was dried under vacuum at 60°C for 2 hours to obtain 17g of brown oil, yield: 77.5%, ESI-MS m/z: 244[M+H] ⁺ , 266[M+ Na] ⁺

2) N-(4-isobutoxybenzyl)-N-(2,4-dimethoxy)benzylamine

Dissolve N-(4-hydroxybenzyl)-N-(2,4-dimethoxy)benzylamine (12 g) in dimethylformamide (90 ml) at room temperature, then batchwise at <30°C Anhydrous potassium carbonate (18 g) was added and the suspension was heated to 78°C to 82°C. Isobutane bromide (17 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (30ml×2). Dimethylformamide was recovered under reduced pressure. The residue was diluted with dichloromethane (100ml), washed with 5% NaOH (50ml x 2), washed with water (50ml x 2), solvent removed and vacuum dried at 60°C for 5 hours to give a black oily liquid (9.3g) , Yield: 75.1%, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

3) 4-isobutoxybenzylamine

Dissolve 3 g of N-(4-isobutoxybenzyl)-N-(2,4-dimethoxy)benzylamine in tetrahydrofuran (30ml) at room temperature, and then dissolve hydrochloric acid (6ml ) was added dropwise to the solution, heated to reflux temperature and stirred for 8 hours after the dropwise addition was completed, and the remaining raw materials were detected by TLC. After the reaction was completed, the solvent was removed under reduced pressure, dichloromethane (10ml) was added, the pH of the solution was adjusted to alkaline at 0-25°C, the layers were washed with water (20ml*2), and the solvent was concentrated under reduced pressure at 30°C. 1.4 g of oily amino base was obtained, the yield was 68%, ESI-MS m/z: 180[M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (18g) deprotected in dichloromethane (140ml) at room temperature, then add anhydrous potassium carbonate (35g), and cool the suspension to 0°C to 10°C , and phenyl chloroformate (23.5 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 1 hour, starting material remained by TLC. After the reaction, the inorganic salts were removed by filtration, the filter cake was washed with DCM (30ml*2), the filtrate was washed with 10% HCl (100ml*2), the layers were separated to obtain an organic layer, washed with water (100ml*2), and after drying, The solvent was recovered under reduced pressure at 30°C to obtain a crude white solid (30 g), which was added with methanol (50 ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (20ml*2). Vacuum dried at 60°C for 2 hours to obtain 25.6g of pure white solid, yield 85%, mp: 98.2～99.5°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

Dissolve N-(4-isobutoxybenzyl)phenylcarbamate (17.5g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (10g) in ethanol at room temperature (80ml), heated to reflux and stirred for 3 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solid (4.05g) was added to the ethanol solution prepared in Example 5 (yield 100%, calculated as piperidinamine) at 40°C to 45°C for 30 minutes, stirred at this temperature for 2 hours, and the The solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (150ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C in 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (15.6g), yield 84%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ HNMR(400MHz,CDCl ₃ )δ7.25(dd,J＝8.3,5.7Hz,2H,Ar-H),7.11(dt,J＝8.7 and 4.5Hz,4H ,Ar-H),6.83(d,J=8.6Hz,2H,Ar-H),4.42(s,2H,CH ₂ ),4.19(d,J=5.5Hz,2H,CH ₂ ),4.02(s ,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41–2.29 (m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz, 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35, 115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53; IR (CM ^-1 ): 3425.1,2930.3,1647.6,1383.9,86.9,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,56.3,856.3,856.3,856.3,8.9,8.9. ,732.4.

Example 12, using 4-methoxybenzyl as protecting group

1) N-(4-hydroxybenzyl)-N-(4-methoxy)benzylamine

Dissolve 4-hydroxybenzylamine (18g) and 4-methoxybenzaldehyde (20.5g) in dichloromethane (50ml) at room temperature (25°C, the same below), and dissolve triacetylboron at 0-15°C Sodium hydride (31 g) was added to the suspension in portions. After the addition was complete, it was stirred at 20-25°C for 12 hours, and the remaining starting material was checked by TLC. After the reaction, the insoluble matter was filtered and the filter cake was washed with dichloromethane (20ml*2), the filtrate was adjusted to PH to 2 to 3 with 20% HCl aqueous solution (50ml*2), and sodium hydroxide ( 3g-5g) adjust the pH from 10 to 12, then wash the layers with water (100ml*2), remove the solvent under reduced pressure at 40°C after the organic layer is dried, and dry in vacuum at 60°C for 2 hours to obtain 27.4g of bright yellow solid, yield: 75.7% ,mp:179～179.5℃,ESI-MS m/z:274[M+H] ⁺ ,296[M+Na] ⁺

2) N-(4-isobutoxybenzyl)-N-(4-methoxy)benzylamine

Dissolve N-(4-hydroxybenzyl)-N-(4-dimethoxy)benzylamine (15g) in absolute ethanol (135ml) at room temperature, then add anhydrous carbonic acid in batches at <30°C Potassium (21 g), and the suspension was heated to 78°C to 82°C. Isobutane bromide (21 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 24 hours and the remaining starting material was checked by TLC. After the reaction was completed, the suspension was cooled to 20°C to 30°C, suction filtered to remove excess potassium salt, and the filter cake was washed with dichloromethane (30ml×2). Dimethylformamide was recovered under reduced pressure. The residue was diluted with ethanol (30ml), then poured into water (150ml), and the precipitated solid was filtered, washed with 5% NaOH (50ml×2) and then washed with water (50ml×2), the solid was suction-filtered and dried at 60 Vacuum drying at ℃ for 5 hours to obtain dark yellow powder (6.9g), yield: 50.1%, mp: 122～124℃, ESI-MS m/z: 330[M+H] ⁺ , 352[M+Na] ⁺

3) 4-isobutoxybenzylamine

Dissolve 6 g of N-(4-isobutoxybenzyl)-N-(4-methoxy)benzylamine in dichloromethane (60ml) at room temperature, and then dissolve trifluoroacetic acid at -25-0°C (48ml) was added dropwise into the solution, and after the dropwise addition was completed, it was turned to room temperature and stirred for 5 hours, and the remaining raw materials were detected by TLC. After the reaction was completed, adjust the pH of the solution to alkaline at 0-25°C, wash the layers with water (20ml*2), and concentrate under reduced pressure at 30°C to obtain 3.4g of oily amino base with a yield of 77%, ESI-MS m/z: 180[M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (15g) deprotected in dichloromethane (120ml) at room temperature, then add anhydrous potassium carbonate (34g), and cool the suspension to 0°C to 10°C , and phenyl chloroformate (23.5 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 1 hour, starting material remained by TLC. After the reaction, the inorganic salts were removed by filtration, the filter cake was washed with DCM (30ml*2), the filtrate was washed with 10% HCl (100ml*2), the layers were separated to obtain an organic layer, washed with water (100ml*2), and after drying, The solvent was recovered under reduced pressure at 30°C to obtain a crude white solid (30 g), which was added with methanol (50 ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (20ml*2). Vacuum dried at 60°C for 2 hours to obtain 21.3g of pure white solid, yield 85%, mp: 98.2～99.5°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

N-(4-isobutoxybenzyl)phenyl carbamate (10g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (7g) were dissolved in ethanol ( 50ml), heated to reflux and stirred for 8 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Tartaric acid solid (2.25g) was added to the ethanol solution (yield 100%, calculated as piperidinamine) prepared in Example 5 at 40°C to 45°C for 30 minutes, stirred at this temperature for 2 hours, and the The solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (80ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C in 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (13g), yield 82.8%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ )δ7.25 (dd, J＝8.3, 5.7Hz, 2H, Ar-H), 7.11 (dt, J＝8.7 and 4.5Hz, 4H ,Ar-H),6.83(d,J=8.6Hz,2H,Ar-H),4.42(s,2H,CH ₂ ),4.19(d,J=5.5Hz,2H,CH ₂ ),4.02(s ,1H,CH),3.70(d,J=6.5Hz,2H,CH ₂ ),2.98(d,J=11.1Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41–2.29 (m,4H,CH ₂ ),1.99(dp,J=13.3,6.6Hz,2H,CH ₂ ),1.73(q,J=12.3Hz,2H,CH ₂ ),1.51(d,J=11.4Hz, 2H, CH ₂ ), 0.97 (d, J=6.7Hz, 6H, CH ₃ ); ¹³ C NMR (400MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35, 115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53; IR (CM ^-1 ): 3425.1,2930.3,1647.6,1383.9,86.9,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,856.3,56.3,856.3,856.3,856.3,8.9,8.9. ,732.4.

Example 13, using benzyl as protecting group

1) N-(4-hydroxybenzyl)benzylamine

4-Hydroxybenzylamine (10g) and sodium bicarbonate (20g) were added to dichloromethane (100ml) at room temperature and stirred, and benzyl bromide (34.8g) was added dropwise to the suspension at 0°C to 20°C for 1 hour in the liquid. After the addition was complete, the mixture was stirred at 20°C to 25°C for 5 hours, and the remaining starting material was checked by TLC. After the reaction was completed, suction filtration was performed to remove excess sodium salt. The filter cake was washed with methyl chloride (50ml x 2). The filtrate was washed with 5% dilute hydrochloric acid (20ml×2), and the layers were washed with water (70ml×2), and the organic layer was dried. The solvent was recovered under reduced pressure at 60°C, the residue was added toluene (100ml) and heated to 80°C with stirring to dissolve, cooled to 20°C for 5 hours, and vacuum dried at 60°C for 3h to obtain 9.1g of white solid. Yield: 73.3%, mp: 99～100℃, ESI-MSm/z: 214[M+H] ⁺ , 236[M+Na] ⁺

2) N-(4-isobutoxybenzyl)benzylamine

Dissolve N-(4-hydroxybenzyl)benzylamine (15g) in dimethylformamide (150ml) at room temperature, then add diazabicyclo (DBU, 29g) in portions at <30°C, and The suspension was heated to 78°C to 82°C. Isobutane bromide (29 g) was added dropwise to the suspension at 78°C to 82°C over 2 hours. After the addition was complete, the mixture was stirred at 78°C-82°C for 36 hours and the remaining starting material was checked by TLC. After the reaction was completed, dimethylformamide was recovered under reduced pressure. The residue was diluted with dichloromethane (30ml), washed with 5% dilute hydrochloric acid (100ml×2), washed with water (30ml×2), washed with 5% NaOH (50ml×2) in dichloromethane solution, and then washed with water (30ml ×2) Wash and separate layers, discard the water layer, recover the solvent under reduced pressure at 50-60°C, add ethanol (40ml) to the residual solid and heat to 60°C and stir, cool to room temperature after the solid dissolves and let stand for 10 hours, the crystal Filter and wash the filter cake with cold isopropyl ether (10ml×2), and vacuum-dry at 60°C for 5 hours to obtain light yellow powder (12.5g), yield: 70.8%, mp: 71～73°C, ESI-MS m/z :280[M+H] ⁺ ,302[M+Na] ⁺

3) 4-isobutoxybenzylamine

Add 8 g of N-(4-isobutoxybenzyl) benzylamine and 5% Pd-C (0.5 g) into ethanol (60 ml) and stir at room temperature, and stir with hydrogen gas at room temperature for 5 hours, and detect with TLC Raw material remaining. After the reaction was completed, palladium carbon was recovered by filtration, and the solvent was recovered under reduced pressure to obtain 5.1 g of free base, with a yield of 78%, ESI-MS m/z: 180[M+H] ⁺ , 202[M+Na] ⁺

4) Phenyl N-(4-isobutoxybenzyl)carbamate

Dissolve the oily liquid of 4-isobutoxybenzylamine (30g) deprotected in dichloromethane (120ml) at room temperature, then add anhydrous potassium carbonate (34g), and cool the suspension to 0°C to 10°C , and phenyl chloroformate (31 g) was added dropwise to the suspension at 0°C to 10°C over 1 hour. After the addition was complete, the mixture was moved to 20°C to 25°C and stirred for 1 hour, starting material remained by TLC. After the reaction, the inorganic salts were removed by filtration, the filter cake was washed with DCM (30ml*2), the filtrate was washed with 10% HCl (100ml*2), the layers were separated to obtain an organic layer, washed with water (100ml*2), and after drying, The solvent was recovered under reduced pressure at 30°C to obtain a crude white solid (45g), which was added to methanol (180ml) and heated to reflux for about 0.5 hours until the solid was completely dissolved. The solution was cooled to 10°C over about 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold methanol (20ml*2). Vacuum dried at 60°C for 2 hours to obtain 38g white solid pure product, yield 76%, mp: 98.5～99.2°C, ESI-MS m/z: 300[M+H] ⁺ , 322[M+Na] ⁺ .

5) N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-isobutoxybenzyl)urea

Dissolve N-(4-isobutoxybenzyl)phenyl carbamate (20g) and N-(4-fluorobenzyl)-1-methyl-4-piperidinamine (13.5g) in ethanol at room temperature (100ml), heated to reflux and stirred for 3 hours, and the remaining raw material N-(4-fluorobenzyl)-1-methyl-4-piperidinamine was detected by TLC. After the reaction, the alcohol solution of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea is obtained.

6) Preparation of tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea

Add tartaric acid solids (4.5 g) to the ethanol solution (yield 100%, calculated as piperidinamine) prepared in Example 5 at 40°C to 45°C for 30 minutes, stir at this temperature for 2 hours, and the The solution was cooled to 30°C to 35°C, the product crystallized at about 34°C, the suspension was stirred at this temperature for 30 minutes, then cooled to 0°C over 1 hour and allowed to stand for 5 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). The obtained crude product and the wet product were heated to reflux with absolute ethanol (150ml) and stirred for 2 hours, then the solution was cooled to 25°C to 30°C in 1 hour, and stood at this temperature for 3 hours. The product was filtered and the filter cake was washed with cold ethanol (20ml*2). Vacuum dried at 45°C for 8 hours to obtain pure white solid (27.8g), yield 84.8%, mp: 135.5-137.5°C (document 133-135°C), ESI-MS m/z: 428[M+H] ⁺ ,450[M+Na] ⁺ ; ¹ HNMR(400MHz,CDCl ₃ )δ7.25(dd,J＝8.3,5.7Hz,2H,Ar-H),7.11(dt,J＝8.7 and 4.5 Hz,4H ,Ar-H),6.83(d,J=8.6 Hz,2H,Ar-H),4.42(s,2H,CH ₂ ),4.19(d,J=5.5 Hz,2H,CH ₂ ),4.02(s ,1H,CH),3.70(d,J=6.5 Hz,2H,CH ₂ ),2.98(d,J=11.1 Hz,2H,CH ₂ ),2.56–2.46(m,1H,NH),2.41–2.29 (m,4H,CH ₂ ),1.99(dp,J=13.3,6.6 Hz,2H,CH ₂ ),1.73(q,J=12.3 Hz,2H,CH ₂ ),1.51(d,J=11.4 Hz, 2H, CH ₂ ), 0.97 (d, J=6.7 Hz, 6H, CH ₃ ); ¹³ C NMR (400 MHz, CDCl ₃ ) δ174.99, 162.58, 160.18, 157.95, 137.27, 133.44, 128.86, 128.78, 128.63, 115.35 , ^{115.14,114.54,74.23,72.37,54.39,51.69,49.07,44.57,43.58,28.97,28.18,19.53} ; 780.1, 732.4.

Claims (14)

1. a synthetic method of the tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea, It is characterized in that: 4-hydroxybenzylamine is used as raw material, N-protecting group-4-hydroxybenzylamine is obtained through amino protection, and N-protecting group-4-isobutoxybenzylamine is obtained through alkylation reaction, and then through The deprotection reaction makes 4-isobutoxybenzylamine, then reacts with phenyl chloroformate to make N-(4-isobutoxybenzyl) phenyl carbamate, and finally reacts with N-(4-fluorobenzyl N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4- Isobutoxybenzyl) urea, salified with tartaric acid to give N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxy benzyl) urea tartrate, the protecting group is benzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, p-toluenesulfonyl, trityl, 2,4-dimethoxybenzyl, 4-methoxybenzyl or benzyl. 2. A kind of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 The synthetic method of tartrate is characterized in that, comprises the steps: (1) N-protecting group-4-hydroxybenzylamine described in the preparation formula II: Using 4-hydroxybenzylamine as raw material, it is prepared by protecting the amino group with a protecting reagent. The protective reagents are benzyl chloroformate, fluorenylmethoxyformyl chloride, di-tert-butyl dicarbonate, 2,2,2-trimethylsilylethoxyformyl chloride, ethyl chloroformate, methyl chloroformate, methyl ethyl anhydride, acetic anhydride, p-toluenesulfonyl chloride, triphenylchloromethane, 2,4-dimethoxybenzaldehyde, 2,4-dimethoxybenzyl chloride, 4-methoxybenzaldehyde, 4-methoxybenzaldehyde Oxybenzyl chloride, benzyl chloride or benzyl bromide; (2) N-protecting group-4-isobutoxybenzylamine shown in the preparation formula III: Prepared by alkylation reaction of N-protecting group-4-hydroxybenzylamine and bromoisobutane; (3) 4-isobutoxybenzylamine described in the preparation formula IV: N-protecting group-4-isobutoxybenzylamine, obtained by removing the amino protecting group; (4) N-(4-isobutoxybenzyl) phenyl carbamate described in the preparation formula V: N-protecting group-4-isobutoxybenzylamine, prepared by reacting with phenyl chloroformate after deprotecting the amino group; (5) Tartrate of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea described in the preparation formula VII : N-(4-isobutoxybenzyl) phenyl carbamate, with another intermediate N-(4-fluorobenzyl)-1-methyl-4-piperidinamine, reacts with tartaric acid by aminolysis salt made; Wherein, in steps (1) and (2), X is benzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, p-toluenesulfonyl, trityl, 2,4-dimethoxybenzyl, 4-methoxybenzyl or benzyl. 3. The synthetic method of N-(4-isobutoxybenzyl) phenyl carbamate is characterized in that, with 4-hydroxybenzylamine as raw material, N-protecting group-4-hydroxybenzylamine is obtained through amino protection treatment , and then carry out alkylation reaction with bromoisobutane to obtain N-protecting group-4-isobutoxybenzylamine, then deprotect the amino group to obtain 4-isobutoxybenzylamine, and then react with phenyl chloroformate be made of. 4. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate or the synthetic method of N-(4-isobutoxybenzyl) phenyl carbamate according to claim 3, is characterized in that, protecting reagent is ethyl chloroformate. 5. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate or the synthetic method of N-(4-isobutoxybenzyl) phenyl carbamate described in claim 3, is characterized in that, described N-protecting group-4-hydroxybenzylamine Prepared by the following method: add 4-hydroxybenzylamine, protective reagent, and acid-binding agent into the solvent according to the molar ratio of 1:(1.1-2.5):(1.2-3), react at -25～60°C for 0.5-24h, Obtain N-protecting group-1-(4-hydroxybenzyl)amine; the solvent is dichloromethane, dioxane, tetrahydrofuran, toluene, acetonitrile, chloroform or a mixed solvent of each solvent and water, acid-binding agent For sodium bicarbonate, potassium bicarbonate, triethylamine. 6. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate or the synthetic method of N-(4-isobutoxybenzyl) phenyl carbamate described in claim 3, is characterized in that, described N-protecting group-4-hydroxybenzylamine Prepared by the following method: add 4-hydroxybenzylamine, protective reagent, acid-binding agent: molar ratio 1:(1.1-1.2):1.5 into the solvent, react at 0-25°C for 0.5-24h, and obtain N-protecting group -1-(4-hydroxybenzyl)amine; the solvent is dichloromethane; the acid-binding agent is sodium bicarbonate. 7. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate or the synthetic method of N-(4-isobutoxybenzyl) phenyl carbamate described in claim 3, is characterized in that, N-protecting group-4-isobutoxybenzylamine Prepared by: Add N-protecting group-4-hydroxybenzylamine, bromoisobutane and acid-binding agent into the solvent at a molar ratio of 1:(1.2-3):(1.2-3), and react at 50-82°C for 12- 36h, after the reaction, the solvent was washed with alkaline water, the water layer was discarded, and the solvent was removed to obtain N-protecting group-4-isobutoxybenzylamine; the solvents were: DMF, DMA, ethanol, acetonitrile, Tetrahydrofuran; acid binding agent is anhydrous sodium carbonate, anhydrous potassium carbonate, DBU. 8. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate or the synthetic method of N-(4-isobutoxybenzyl) phenyl carbamate described in claim 3, is characterized in that, N-protecting group-4-hydroxybenzylamine, bromine Substituted isobutane and acid-binding agent are added into the solvent according to the molar ratio of 1:(1.2-1.5):(1.5-2), and reacted for 12-36 hours at 55-82°C. After the reaction, the solvent is washed with alkaline water and discarded. The aqueous layer was removed from the solvent to obtain N-protecting group-4-isobutoxybenzylamine; the solvent was DMF; the acid-binding agent was anhydrous potassium carbonate. 9. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate or the synthetic method of N-(4-isobutoxybenzyl) phenyl carbamate described in claim 3, is characterized in that, 4-isobutoxybenzylamine is prepared by the following method: Add N-amino-protecting group-1-(4-isobutoxybenzyl)amine and deprotection reagent into the solvent at a molar ratio of 1:(3-10), and react at -25～80°C for 3-8h, Obtain 4-isobutoxybenzylamine, described solvent is methanol, ethanol, isopropanol, DMF, methylene chloride; Deprotection reagent is sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, hydrazine hydrate , trifluoroacetic acid, hydrochloric acid. 10. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate or the synthetic method of N-(4-isobutoxybenzyl) phenyl carbamate according to claim 3, is characterized in that, N-amino protecting group-1-(4-isobutyl Oxybenzyl) amine and deprotection reagent according to molar ratio 1: (3-4), add in solvent, react 3-8h at 50～80 ℃, obtain 4-isobutoxybenzylamine, described solvent is ethanol; the deprotection reagent is potassium hydroxide or trifluoroacetic acid. 11. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate or the synthetic method of N-(4-isobutoxybenzyl) phenyl carbamate described in claim 3, is characterized in that, N-(4-isobutoxybenzyl) amino Phenyl formate is prepared by the following method: Add 4-isobutoxybenzylamine, phenyl chloroformate and acid-binding agent into the solvent according to the molar ratio of 1:(1.1-2):(1.2-3), react at -25～60°C for 0.5-3h, and react After the end, the solvent is removed, the residue is washed with water, and the solid is suction filtered to obtain N-(4-isobutoxybenzyl)phenyl carbamate. The solvent is dichloromethane, dioxane, tetrahydrofuran, Toluene, methanol, ethanol, isopropanol, acetonitrile; acid binding agent is triethylamine, sodium bicarbonate, potassium bicarbonate, anhydrous sodium carbonate, anhydrous potassium carbonate, sodium hydroxide, potassium hydroxide. 12. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate or the synthetic method of N-(4-isobutoxybenzyl) phenyl carbamate described in claim 3, is characterized in that, 4-isobutoxybenzylamine, chloroformic acid benzene The ester and the acid-binding agent are added into the solvent according to the molar ratio of 1:(1.1-2):(1.2-3), and react at -25～60°C for 0.5-3h. After the reaction is completed, the solvent is removed, the residue is washed with water, and the solid is extracted Filter to obtain N-(4-isobutoxybenzyl) phenyl carbamate, the solvent is dichloromethane, and the acid-binding agent is anhydrous potassium carbonate. 13. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate is characterized in that, N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea The tartrate salt is prepared by the following method: N-(4-fluorobenzyl)-1-methyl-4-piperidinamine, N-(4-isobutoxybenzyl)phenyl carbamate and tartaric acid in a molar ratio of 1:(1.1-1.5) : (0.5-1), adding the above-mentioned piperidinamine and phenyl carbamate into the solvent, reacting at 25-100°C for 3-12h, after the reaction, the temperature dropped to 40°C, adding tartaric acid solid at this temperature and stirring for 2 hours, The reaction was stopped and dropped to room temperature for crystallization, suction filtration, and the N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxy benzyl) urea tartrate; The solvent is absolute methanol, absolute ethanol, isopropanol, toluene or acetonitrile. 14. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea as claimed in claim 1 or 2 The synthetic method of tartrate is characterized in that, N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-isobutoxybenzyl)urea The tartrate salt is prepared by the following method: N-(4-fluorobenzyl)-1-methyl-4-piperidinamine, N-(4-isobutoxybenzyl)phenyl carbamate and tartaric acid in a molar ratio of 1:(1.2-1.3) : (0.5-0.52), the above-mentioned piperidine amine and phenyl carbamate are added in the solvent, and the temperature is 65～78° C. for 3-12 hours. Hours, the reaction was stopped and dropped to room temperature for crystallization, suction filtration to obtain the N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-iso butoxybenzyl) urea tartrate; the solvent is absolute ethanol.