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

A kind of synthetic method of the tartrate of N (4 luorobenzyl) N (base of 1 methyl piperidine 4) N ' (4 isobutoxy benzyl) urea Download PDF

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CN104961672B
CN104961672B CN201510259570.7A CN201510259570A CN104961672B CN 104961672 B CN104961672 B CN 104961672B CN 201510259570 A CN201510259570 A CN 201510259570A CN 104961672 B CN104961672 B CN 104961672B
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benzyl
isobutoxy
isobutoxies
luorobenzyls
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CN104961672A (en
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王绍杰
王瀚培
赵龙山
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Hainan Shenzhou Kang Sheng Pharmaceutical Technology Co., Ltd.
Shenyang Pharmaceutical University
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Hainan Shenzhou Kang Sheng Pharmaceutical Technology Co Ltd
Shenyang Pharmaceutical University
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Abstract

The invention belongs to pharmaceutical technology field, it is related to one kindN(4 luorobenzyl)N(base of 1 methyl piperidine 4)N’The synthetic method of the tartrate of (4 isobutoxy benzyl) urea, the present invention is, using 4 hydroxy benzylamines as raw material, to be obtained by amido protecting, alkylation reactionNThe isobutoxy benzylamine of protection group 4, is then made the isobutoxy benzylamine of key intermediate 4, then be made with phenyl chloroformate reaction by deprotection reactionN(4 isobutoxy benzyl) phenyl carbamate, finally by with another intermediateN‑The ammonolysis reaction of the piperidinamine of (4 luorobenzyl) 1 methyl 4 is madeN(4 luorobenzyl)N(base of 1 methyl piperidine 4)N’(4 isobutoxy benzyl) urea, with tartaric acid, is obtainedN(4 luorobenzyl)N(base of 1 methyl piperidine 4)N’The tartrate of (4 isobutoxy benzyl) urea.Raw material of the present invention is easy to get, gentle, with short production cycle, high income simple to operate, security is good, cost is low, be adapted to industrialized production.

Description

A kind of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies Benzyl) urea tartrate synthetic method
Technical field
The invention belongs to pharmaceutical technology field, be related to a kind of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N ' - The synthetic method of the tartrate of (4- isobutoxies benzyl) urea, further relates to its intermediate N-protected base -4- hydroxy benzylamines, N- and protects Protect the synthetic method of base -4- isobutoxies benzylamine, 4- isobutoxies benzylamine and N- (4- isobutoxies benzyl) phenyl carbamate.
Background technology
Parkinson's syndrome (Parkinsonism) is a kind of chronic central nervous system degenerative disorder, with some Dyskinesia (static tremor, myotonia, bradykinesia and attitudinal reflex are lost) is the disease of Clinical symptoms.It can damage trouble Motor skill, language ability and other functions of person.Its cause of disease at present still fail to understand, thus it is speculated that and brain bottom substrate core and Black substance brain cell fast degradation, it is impossible to the enough nerve guiding material dopamines (DA) of manufacture it is relevant (Friedman, 1991, Goetz et al,2001)。
Current whole world parkinsonian's number reaches 7 million to one thousand ten thousand, China about 2,600,000, occupies the world the One.More than 40% parkinsonian once had psychotic disorder.Mental illness to parkinsonian treatment and Tourniquet carrys out bigger challenge.In Parkinsonian, mental symptom is the first cause for causing patient to be in hospital, and it also to suffer from The mortality risk of person significantly increases (Weintraub and Stern, 2005；Factor et al,2003).
The idiopathic psychoses of psychotic disorder, such as schizophrenia and correlation, its pathogenic factor and existing anti-essence The molecular basis that refreshing disease medicine works, medical field does not study clear completely, so that the reasonability of psychotropic disorders medicine is set Meter and preparation face extreme difficulties.Research shows that the positive symptom of psychotropic disorders is relevant with the hyperactivity of dopamine, negative Symptom is relevant in the raising of maincenter serotonin (5-HT) function and the decline of DA functions especially prefrontal lobe DA functions (Romrell et al,2003)。
Because psychotic disorder pathogenesis is generally acknowledged that it is excessively related to patient's intracerebral dopamine, universal antipsychotic The mechanism of action of disease drug is antagonism (the Chou et al, 2007 of d2 dopamine receptor；Romrell et al,2003). Unfortunately, side effect of the dopamine D 2 receptor antagonists except causing centrum periphery, can also allow the Parkinson of spiritedness disease Family name's sufferer aggravates the state of an illness (Molho and Factor, 1999；Weintraub and Stern,2005).
Mo Fanselin (Pimavanserin) is the patent medicine of Acadia (Acadia) drugmaker independent research, is used In treatment Parkinson's disease mental symptom, this be it is a kind of it is new, can effectively suppress 5-HT2A monoamine receptor activities rather than dopamine The medicine (Herbert Y Meltzer, Roger Mills et al, 2010) that acceptor suppresses.Mo Fanselin was in 2014 9 The moon, 3 food and medicine Surveillance Authority of the Huo U.S. authorized breakthrough sex therapy certification.Drugmaker of Acadia in 2014 to FDA submits the NDA of a Mo Fanselin.
In view of the medicine for the treatment of Parkinson's mental symptom is extremely limited in the market, and all have stronger poison is secondary to make With so developing a kind of low toxicity, eutherapeutic Parkinson's disease antipsychotics are extremely urgent.
The method provided according to US20060111399：Using 4- hydroxy benzaldehydes as raw material, first carry out alkylation reaction and be made 4- isobutoxy benzaldehydes, 4- isobutoxy benzaldoximes are made through dehydration, then by hydrogen reducing obtain it is important in Mesosome 4- isobutoxy benzylamines, intermediate 4- isobutoxy benzyl isocyanate esters are made with triphosgene reaction, finally again with N- (4- Luorobenzyl) obtained N- (4- luorobenzyls)-N- (1- methyl piperidine -4- the bases)-N ' of -1- methyl -4- piperidinamines progress ammonolysis reaction - (4- isobutoxies benzyl) urea, and tartaric acid obtains N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is different Butoxy benzyl) urea tartrate, total recovery：15.9%.The synthetic route is expressed as follows：
The shortcoming of the route is：The whole piece route cycle is long, and yield is not high, and prepares isocyanates, phosgene using phosgene Reactor meeting very exothermic is passed through, it is not easy to operate, and have severe toxicity, and it is industrial once leaking, serious safety can be produced hidden The problems such as trouble and environmental pollution.
The content of the invention
The technical problem to be solved in the present invention be for existing process production cycle length, yield is low, post processing is numerous and diverse, safely Property difference and the problems such as environmental pollution, a kind of new N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutyls of proposition Oxy-benzyl) urea tartrate synthetic method, this method short preparation period, high income, and post processing is simple, security It is high.
The present invention is adopted the following technical scheme that：
Using 4- hydroxy benzylamines as raw material, N-protected base -4- isobutoxy benzylamines are obtained by amido protecting, alkylation reaction, Then key intermediate 4- isobutoxy benzylamines are made by deprotection reaction, then (4- is different with the obtained N- of phenyl chloroformate reaction Butoxy benzyl) phenyl carbamate, finally by the ammonia with another intermediate N (4- luorobenzyls) -1- methyl -4- piperidinamines Solution reaction be made N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea, with tartaric acid into Salt, obtains the tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea.
Whole technique comprises the following steps：
(1) the N-protected base -4- hydroxy benzylamines described in formula II：
By 4- hydroxy benzylamines (I), protection reagent, acid binding agent according to mol ratio 1:(1.1-2.5):(1.2-3), preferred proportion For 1:(1.2-1.5):(1.5-2), is added in solvent, -25~60 DEG C, 0~25 DEG C of reaction 0.5-24h of preferable temperature, reaction After termination, solvent is sloughed, residue is extracted with extraction agent, add water and wash layering, discard water layer, slough solvent, N-protected is made Base -4- hydroxy benzylamines.
In above-mentioned preparation method solvent for use include but is not limited to dichloromethane, dioxane, tetrahydrofuran, toluene, The mixed solvent of acetonitrile, chloroform or each solvent and water, preferred solvent is dichloromethane, and the ratio of 4- hydroxy benzylamines and solvent is 1: 2~10 (m/v)；
Blocking group X be benzyloxycarbonyl group, tablet held before the breast by officials methoxycarbonyl group, tertbutyloxycarbonyl, trimethylsilyl ethoxycarbonyl, methoxycarbonyl group, Carbethoxyl group, formoxyl, acetyl group, p-toluenesulfonyl, trityl, 2,4- dimethoxy-benzyls, 4- methoxy-benzyls or Benzyl；
Protection reagent is benzyl chloroformate, fluorenes methoxycarbonyl chlorine, di-tert-butyl dicarbonate, 2,2,2- trimethyl silicane methylamino ethoxies Acyl chlorides, ethyl chloroformate, methylchloroformate, acetic formic anhydride, acetic anhydride, paratoluensulfonyl chloride, triphenylchloromethane, 2,4- dimethoxies Benzaldehyde, 2,4- dimethoxy-benzyls chlorine, 4-methoxybenzaldehyde, 4- methoxy-benzyls chlorine and chlorine (bromine) benzyl；
The extraction agent is dichloromethane, ethyl acetate, toluene, dioxane, and selected reagent is dichloromethane；
Acid binding agent is sodium acid carbonate, saleratus, triethylamine, and preferably acid binding agent is sodium acid carbonate.
(2) the N-protected base -4- isobutoxy benzylamines shown in formula III：
By N-protected base -4- hydroxy benzylamines, isobutane bromide and acid binding agent according to mol ratio 1:(1.2-3):(1.2-3), It is preferably in a proportion of 1:(1.2-1.5):(1.5-2), is added in solvent, 50~82 DEG C, and 12- is reacted at 55~82 DEG C of preferable temperature 36h, after reaction terminates, sloughs solvent, residue is extracted with extraction agent, is washed with buck, discards water layer, sloughs solvent, is made N-protected base -4- isobutoxy benzylamines.
Solvent for use includes but is not limited to DMF, DMA, ethanol, acetonitrile, preferred solvent in above-mentioned preparation method：DMF, The ratio of N-protected base -4- hydroxy benzylamines and solvent is 1:2~10 (m/v)；
Extraction agent is dichloromethane, ethyl acetate, toluene, dioxane, and preferred reagent is dichloromethane；
Acid binding agent is natrium carbonicum calcinatum, Anhydrous potassium carbonate, the carbon -7- alkene (DBU) of 1,8- diazabicylos 11, preferred catalytic Agent is Anhydrous potassium carbonate.
(3) the 4- isobutoxy benzylamines described in formula IV：
By N-protected base -4- isobutoxies benzylamine and deprotecting regent in molar ratio 1:(3-10), preferred proportion 1:(3- 4), add in solvent, -25~78 DEG C, 3-8h is reacted at 40~78 DEG C of preferable temperature, 4- isobutoxy benzylamines are made.
Described solvent is that methanol, ethanol, isopropanol, DMF, dichloromethane preferred solvent are ethanol；
Deprotecting regent is sodium hydroxide, potassium hydroxide, sodium methoxide, caustic alcohol, sodium hydride, hydrazine hydrate, trifluoroacetic acid, salt Acid, preferably alkaline deprotecting regent potassium hydroxide, acid deprotecting regent trifluoroacetic acid.
(4) N- (4- isobutoxies benzyl) phenyl carbamate described in formula V：
By 4- isobutoxies benzylamine, phenyl chloroformate and acid binding agent according to mol ratio 1:(1.1-2):(1.2-3), preferably compares Example 1:(1.2-1.3):(1.5-2), is added in solvent, -25~60 DEG C, and preferable temperature is reacts 1-3h at 0~25 DEG C, reaction is tied Shu Hou, sloughs solvent, and residue washing, solid suction filtration is recrystallized with refined reagent, obtains N- (4- isobutoxies benzyl) amino first Acid phenenyl ester.
In above-mentioned preparation method solvent for use include but is not limited to dichloromethane, dioxane, tetrahydrofuran, toluene, Methanol, ethanol, isopropanol, acetonitrile, preferred solvent is dichloromethane, and the ratio of 4- isobutoxies benzylamine and solvent is 1:2~8 (m/v)；
Acid binding agent be triethylamine, pyridine, sodium acid carbonate, saleratus, natrium carbonicum calcinatum, Anhydrous potassium carbonate, sodium hydroxide, Potassium hydroxide, preferably acid binding agent are Anhydrous potassium carbonate；
Refined reagent is methanol, ethanol, and preferred reagent is methanol.
(5) N- described in formula VII (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) The tartrate of urea：
By N- (4- luorobenzyls) -1- methyl -4- piperidinamines, N- (4- isobutoxies benzyl) phenyl carbamates and tartaric acid According to mol ratio 1:(1.1-1.5):(0.5-1), preferred proportion 1:(1.2-1.3):(0.5-0.52), by above-mentioned N- (4- fluorine benzyls Base) -1- methyl -4- piperidinamines and N- (4- isobutoxies benzyl) phenyl carbamate added in solvent, and 25~100 DEG C, preferably Temperature is 65~78 DEG C of reaction 3-12h, and after reaction terminates, temperature is down to 45~40 DEG C, and the stirring of tartaric acid solid is added under the temperature 2-4 hours, reaction stopped and is down to room temperature crystallization 5-9 hours, suction filtration, was recrystallized with exquisite reagent, by crystal suction filtration, and institute is made State the tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea.
Solvent for use includes but is not limited to methanol, ethanol, isopropanol, toluene, acetonitrile in above-mentioned preparation method, preferably molten Agent is ethanol, and the ratio of N- (4- luorobenzyls) -1- methyl -4- piperidinamines and solvent is 1:2~10 (m/v)；
Refined reagent is absolute methanol, absolute ethyl alcohol, isopropanol, preferred reagent absolute ethyl alcohol.
Whole piece synthetic route is expressed as follows：
The advantage of the invention is that：N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N ' designed by the present invention - For the tartrate synthesis technique of (4- isobutoxies benzyl) urea, it is easy to get with raw material, easy to operate, yield is higher, cost The relatively low, three wastes are less, it is safe the characteristics of, be adapted to industrial production.
Embodiment
The present invention N- to be synthesized (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) Tartrate and its intermediate N protection group -4- hydroxy benzylamines, N-protected base -4- isobutoxies benzylamine, the 4- isobutoxies of urea Benzylamine and N- (4- isobutoxies benzyl) phenyl carbamate can follow these steps to carry out：
Embodiment 1, blocking group is made with carbethoxyl group
1) N- (4- hydroxybenzyls) urethanes
4- hydroxy benzylamines (20g) and sodium acid carbonate (16g) are added to stirring in dichloromethane (100ml) in room temperature, 0 DEG C ethyl chloroformate (19.4g) is added drop-wise in suspension with 1 hour to 20 DEG C.After addition terminates, by the mixture at 20 DEG C Stirred 2 hours to 25 DEG C, starting material left is detected with TLC.After the completion of reaction, carry out suction filtration to remove excessive sodium salt.With two Chloromethanes (50ml × 2) washs filter cake.Filtrate is washed with 5% watery hydrochloric acid (36ml × 2), then is washed with water (75ml × 2), layering After discard water layer, organic layer is dried.30 DEG C to 40 DEG C are recovered under reduced pressure solvent, obtain red solid crude product (30g), solid toluene (45ml × 2) are washed.Product is filtered, 40 DEG C of vacuum drying 3h obtain faint yellow solid (29.1g), yield 81.1%, mp: 62~64 DEG C, ESI-MS m/z:196[M+H]+,218[M+Na]+.
2) N- (4- isobutoxies benzyl) urethanes
N- (4- hydroxybenzyls) urethanes (47g) is dissolved in dimethylformamide in 15 DEG C to 25 DEG C In (250ml), Ran Hou<30 DEG C are added portionwise Anhydrous potassium carbonate (50g), and the suspension are heated into 78 DEG C to 82 DEG C.In 78 DEG C to 82 DEG C were added drop-wise to isobutane bromide (40g) in suspension with 2 hours.Addition terminate after, by the mixture 78 DEG C- 82 DEG C are stirred 24 hours, and surplus stock is detected by TLC.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, taken out Filter washs filter cake to remove excessive sylvite with dichloromethane (100ml × 2).Solvent, residue dichloromethane is recovered under reduced pressure (300ml) is diluted, and dichloromethane solution is washed with 5%NaOH (50ml × 2), and then water (100ml × 2) is washed, water layer discarded, Dichloromethane solution is recovered under reduced pressure at 50 DEG C, and residual solid adds n-hexane (100ml) and is heated to 60 DEG C of stirrings, solid dissolving After be cooled to 40 DEG C, add 10g active carbon powders, be reheated to 60 DEG C and stir 30 minutes, insoluble matter is filtered while hot, filtrate exists 10 DEG C (about crystallizations at 30 DEG C) are cooled under stirring and 3 hours are stood, product is filtered and washed with cold n-hexane (50ml × 2) Filter cake is washed, 30 DEG C are dried in vacuo 5 hours, obtain faint yellow fluffy solid (46.2g), yield 76.6%, mp:39~40 DEG C, ESI-MS m/z:252[M+H]+,274[M+Na]+.
3) 4- isobutoxies benzylamine
Potassium hydroxide (15g) is dissolved in ethanol (50ml) in 40 DEG C to 45 DEG C, N- (4- isobutoxy benzyls are then added Base) urethanes (17g) solid, solution is heated to 78 DEG C and stirred 8 hours, starting material left is detected with TLC.Reaction is completed Afterwards, 50 DEG C are recovered under reduced pressure ethanol, and dichloromethane (75ml) is added in residue, are stirred at room temperature 10 minutes, filter insoluble matter, It is concentrated under reduced pressure in 30 DEG C, obtains oily amino bases 9.9g, yield 82%, ESI-MS m/z:180[M+H]+, 202 [M+Na]+.
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (5g) oily liquids for sloughing protection group is dissolved in dichloromethane (10ml) in room temperature, so Addition Anhydrous potassium carbonate (5g), 0 DEG C to 10 DEG C is cooled to by suspension afterwards, and 0 DEG C to 10 DEG C with 0.5 hour by chloro-carbonic acid benzene Ester (4.8g) is added drop-wise in the suspension.After addition terminates, starting material left is detected by TLC.After reaction terminates, nothing is removed by filtration Machine salt, filter cake is washed with dichloromethane (30ml*2), and filtrate is washed with 10%HCl (100ml*2), and layering obtains organic layer water (100ml*2) is washed, and after drying, 30 DEG C are recovered under reduced pressure solvent, obtains white solid (8.1g) crude product, adds methanol (10ml) Backflow is heated to all to dissolve to solid within about 0.5 hour.The solution is cooled to 10 DEG C with about 1 hour and 5 hours are stood.Will production Thing is filtered, and washs filter cake with cold methanol (5ml*2).It is dried in vacuo 2 hours in 60 DEG C, obtains 5.9g white solid sterlings, is received Rate 71%, mp:98.2~99.5 DEG C, ESI-MS m/z:300[M+H]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (14.8g) and N- (4- luorobenzyls) -1- methyl -4- Piperidinamine (10g) is dissolved in absolute ethyl alcohol (20ml), is heated to flowing back and is stirred 3 hours, and surplus stock N- is detected with TLC (4- luorobenzyls) -1- methyl -4- piperidinamines.Reaction terminate after, produce N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases) - The alcoholic solution of N '-(4- isobutoxies benzyl) urea.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (3.38g) was added to the ethanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled to 30 DEG C to 35 DEG C, product is about 34 DEG C of crystallizations, the suspension is stirred 30 minutes, be then cooled to 0 DEG C with 1 hour and stand 5 hours at this temperature. The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Obtain crude product, wet product absolute ethyl alcohol (150ml) heating To flowing back and stirring 2 hours, solution is then cooled to 25 DEG C to 30 DEG C with 1 hour, 3 hours are stood in this temperature.Filtering should Product, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (16.2g), Yield 84.1%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR(400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2),4.02(s, 1H, CH), 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH), 2.41–2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2), 1.51 (d, J=11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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 2, blocking group is made with methoxycarbonyl group
1) N- (4- hydroxybenzyls) methyl carbamate
4- hydroxy benzylamines (15g) and sodium acid carbonate (15g) are added to dichloromethane (90ml) in room temperature (25 DEG C, similarly hereinafter) Methylchloroformate (13.8g), was added drop-wise in suspension by middle stirring at -25 DEG C to 0 DEG C with 1 hour.After addition terminates, this is mixed Compound is stirred 2 hours at -25 DEG C, and starting material left is detected with TLC.After the completion of reaction, carry out suction filtration to remove excess sodium Salt.Filter cake is washed with dichloromethane (50ml × 2).Filtrate is washed with 5% watery hydrochloric acid (36ml × 2), then is washed with water (75ml × 2) Wash, water layer is discarded after layering, organic layer is dried.40 DEG C are recovered under reduced pressure solvent, obtain red liquid, and 50 DEG C of vacuum drying 3h are obtained To red oil 23.3g, yield:81%, ESI-MS m/z:182[M+H]+,204[M+Na]+
2) N- (4- isobutoxies benzyl) methyl carbamate
N- (4- hydroxybenzyls) methyl carbamates (12g) are dissolved in dimethyl acetamide (24ml) in room temperature (25 DEG C) In, Ran Hou<30 DEG C are added portionwise Anhydrous potassium carbonate (11g), and the suspension are heated into 50 DEG C to 55 DEG C.In 55 DEG C with 2 Isobutane bromide (12g) is added drop-wise in suspension by hour.After addition terminates, the mixture is stirred 24 hours at 55 DEG C, led to Cross TLC detection surplus stocks.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, suction filtration is carried out to remove excessive sylvite, Filter cake is washed with dichloromethane (50ml × 2).Solvent is recovered under reduced pressure.Residual solution is diluted with dichloromethane (150ml), with 5% NaOH (30ml × 2) washs dichloromethane solution, and then water (50ml × 2) is washed, water layer discarded, and dichloromethane solution is at 50 DEG C Under be recovered under reduced pressure, obtained yellow liquid 50 DEG C be dried in vacuo 3 hours, obtain yellow oily liquid (12.4g), yield： 77.8%, ESI-MS m/z:238[M+H]+,260[M+Na]+
3) 4- isobutoxies benzylamine
Potassium hydroxide (13g) is dissolved in ethanol (40ml) in 40 DEG C to 45 DEG C, N- (4- isobutoxy benzyls are then added Base) methyl carbamate (14g) solid, solution is heated to 78 DEG C and stirred 2 hours, starting material left is detected with TLC.Reaction is completed Afterwards, 50 DEG C are recovered under reduced pressure ethanol, and dichloromethane (60ml) is added in residue, are stirred at room temperature 10 minutes, filter insoluble matter, (30ml*2) layering is washed, in 30 DEG C of solvents that are concentrated under reduced pressure, oily amino bases 8.8g, yield 83%, ESI-MS m/z is obtained: 180[M+H]+,202[M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (8g) oily liquids for sloughing protection group is dissolved in dioxane (24ml) in room temperature, so Addition natrium carbonicum calcinatum (8g), 0 DEG C to 10 DEG C is cooled to by suspension afterwards, and 0 DEG C to 10 DEG C with 1 hour by phenyl chloroformate (8.4g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 1 hour, is reheated Stirred 1 hour to 60 DEG C, starting material left is detected by TLC.After reaction terminates, inorganic salts are removed by filtration, with dioxane (20ml*2) washs filter cake, and filtrate is washed with 10%HCl (20ml*2), and layering obtains organic layer and washed with water (20ml*2), passes through After drying, 60 DEG C are recovered under reduced pressure solvent, obtain white solid (23g) crude product, it is small that addition methanol (30ml) is heated to backflow about 0.5 All dissolved up to solid.The solution is cooled to 10 DEG C with about 1 hour and 5 hours are stood.Product is filtered, and with cold methanol (10ml*2) washs filter cake.It is dried in vacuo 2 hours in 60 DEG C, obtains 10g white solid sterlings, yield 75%, mp:99.1~ 99.4℃；ESI-MS m/z:300[M+H]+,322[M+Na]+
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (12.9g) and N- (4- luorobenzyls) -1- methyl -4- Piperidinamine (8g) is dissolved in toluene (30ml), is heated to flowing back and is stirred 12 hours, and surplus stock N- (4- fluorine is detected with TLC Benzyl) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is produced Isobutoxy benzyl) urea toluene solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Slough toluene solvant, add 30ml absolute ethyl alcohols, 40 DEG C to 45 DEG C with 30 minutes by tartaric acid solid (3.24g) It is added in ethanol solution (yield 100%, in terms of piperidinamine), is stirred 2 hours under the temperature, the solution is cooled to 30 DEG C and arrived 35 DEG C, the suspension is stirred 30 minutes in about 34 DEG C of crystallizations, was then cooled to 0 DEG C with 1 hour by product at this temperature And stand 5 hours.The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Obtain crude product, wet product absolute ethyl alcohol (150ml) is heated to flowing back and stirred 2 hours, and solution then is cooled into 25 DEG C to 30 DEG C with 1 hour, and 3 are stood in this temperature Hour.The product is filtered, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid pure Product (13.7g), yield 89.4%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450 [M+Na]+；1H NMR(400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2), 4.02 (s, 1H, CH), 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46 (m,1H,NH),2.41–2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H,CH2), 1.51 (d, J=11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)δ 174.99,162.58,160.18,157.95,137.27,133.44,128.86,128.78,128.63,115.35,115.14, 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 3, blocking group is made with tertbutyloxycarbonyl
1) N- (4- hydroxybenzyls)-t-butyl carbamate
4- hydroxy benzylamines (20g) and saleratus (22g) are added to tetrahydrofuran (60ml) and water (15ml) in room temperature Di-tert-butyl dicarbonate (46.1g), was added drop-wise in suspension by middle stirring at 0 DEG C to 20 DEG C with 1 hour., will after addition terminates The mixture is stirred 24 hours at 20 DEG C to 25 DEG C, and starting material left is detected with TLC.After the completion of reaction, solid suction filtration is used Tetrahydrofuran (30ml × 2) washs filter cake, and solid is washed with 5% watery hydrochloric acid (36ml × 2), solid is filtered, with water (50ml × 2) wash, suction filtration.Solid is dried in vacuo 5 hours at 60 DEG C, obtains pale powder 14.7g, yield:72.1%, mp:105 ~107 DEG C, ESI-MS m/z:224[M+H]+,246[M+Na]+
2) N- (4- isobutoxies benzyl) t-butyl carbamate
N- (4- hydroxybenzyls)-t-butyl carbamates (25g) are dissolved in tetrahydrofuran (75ml) in room temperature, then <30 DEG C are added portionwise Anhydrous potassium carbonate (23g), and the suspension are heated into 60 DEG C.In 60 DEG C with 2 hours by bromo isobutyl Alkane (23g) is added drop-wise in suspension.After addition terminates, the mixture is stirred 24 hours at 60 DEG C -65 DEG C, detected by TLC Surplus stock.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, suction filtration is carried out to remove excessive sylvite, uses dichloromethane Alkane (50ml × 2) washs filter cake.Solvent is recovered under reduced pressure.Residual liquid is poured into 100ml water, will separate out solid suction filtration, and filter cake is used 5%NaOH (30ml × 2) is washed, and then water (30ml × 2) is washed, and is obtained solid addition toluene (60ml) and is heated to 60 DEG C of stirrings Dissolving, is then cooled to 10 DEG C to 15 DEG C and stands 10 hours, the light yellow crystal of precipitation is filtered, cold toluene is used under agitation (15ml*2) is washed, and is dried in vacuo 5 hours at 45 DEG C, is obtained brown flat crystal (19.7g), yield：70.1%, mp:59~ 61℃,ESI-MS m/z:280[M+H]+,302[M+Na]+
3) 4- isobutoxies benzylamine
N- (4- isobutoxies benzyl) t-butyl carbamate 20g is dissolved in dichloromethane (200ml) in room temperature, so Afterwards at -25-0 DEG C, trifluoroacetic acid (160ml) is added dropwise in solution, goes to and is stirred at room temperature 3 hours after being added dropwise to complete, examined with TLC Survey starting material left.After the completion of reaction, solution PH is adjusted to alkalescence, and layering is washed with water (50ml*2), 30 DEG C are concentrated under reduced pressure, and obtain To oily amino bases 9.6g, yield 74%, ESI-MS m/z:180[M+H]+, 202 [M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (12g) oily liquids for sloughing protection group is dissolved in toluene (40ml) in room temperature, then Add triethylamine (9g), suspension be cooled to 0 DEG C to 10 DEG C, and 0 DEG C to 10 DEG C with 1 hour by phenyl chloroformate (14.6g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 3 hours, is passed through TLC detects starting material left.After reaction terminates, triethylamine hydrochloride is removed by filtration, filter cake is washed with toluene (30ml*2), filtrate is used 10%HCl (30ml*2) is washed, and layering obtains organic layer and washed with water (20ml*2), and after drying, 60 DEG C are recovered under reduced pressure solvent, White solid (18g) crude product is obtained, ethanol (30ml) is added and is heated to flowing back about 0.5 hour and all dissolved to solid.It is small with about 1 When by the solution be cooled to 10 DEG C and stand 5 hours.Product is filtered, and filter cake is washed with cold ethanol (10ml*2).In 60 DEG C Vacuum drying 2 hours, obtains 14.4g white solid sterlings, yield 78%, mp:98.6~99.1 DEG C, ESI-MS m/z:300[M +H]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (21g) and N- (4- luorobenzyls) -1- methyl -4- piperazines Pyridine amine (12g) is dissolved in isopropanol (24ml), is heated to flowing back and is stirred 8 hours, and surplus stock N- (4- fluorine is detected with TLC Benzyl) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is produced Isobutoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (5.68g) was added to the isopropanol prepared in embodiment 5 at 60 DEG C to 65 DEG C with 30 minutes molten In liquid (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, have white solid precipitation, the solution is cooled to 20 DEG C to 25 DEG C, 3 hours are stood at this temperature.The product is filtered, and filter cake is washed with cold isopropanol (20ml*2).Obtain thick Product, wet product are heated to flowing back and stirred 2 hours with absolute ethyl alcohol (80ml), and solution then is cooled into 25 DEG C with 1 hour and arrived 30 DEG C, 3 hours are stood in this temperature.The product is filtered, and filter cake is washed with cold ethanol (20ml*2).8 are dried in vacuo at 45 DEG C Hour, obtain white solid sterling (20.1g), yield 87%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+,ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR(400MHz,CDCl3)δ 7.25 (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,CH2), 4.19 (d, J=5.5Hz, 2H, CH2), 4.02 (s, 1H, CH), 3.70 (d, J= 6.5Hz,2H,CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH),2.41–2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2), 1.51 (d, J=11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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, blocking group is made with acetyl group
1) N- (4- hydroxybenzyls) acetamide
4- hydroxy benzylamines (25g) and sodium acid carbonate (31g) are added to stirring in toluene (50ml) in room temperature, arrived at 0 DEG C 20 DEG C were added drop-wise to acetic anhydride (29.1g) in suspension with 1 hour.After addition terminates, the mixture is stirred at 20 DEG C to 25 DEG C Mix 0.5 hour, starting material left is detected with TLC.After the completion of reaction, solid suction filtration is washed with dichloromethane (25ml × 2) Filter cake, solid is washed with 5% watery hydrochloric acid (45ml × 2), adjusts PH to 3-4, solid is filtered, is washed, obtained with water (40ml × 2) To white solid.60 DEG C are dried in vacuo 5 hours, obtain white solid 32.7g, yield:81.2%, mp:135~137 DEG C, ESI- MS m/z:166[M+H]+,188[M+Na]+
2) N- (4- isobutoxies benzyl) acetamide
N- (4- hydroxybenzyls) acetamides (10g) are dissolved in acetonitrile (30ml) in room temperature, Ran Hou<30 DEG C add in batches Enter natrium carbonicum calcinatum (11g), and the suspension is heated to 78 DEG C to 82 DEG C.In 78 DEG C to 82 DEG C with 2 hours by bromo isobutyl Alkane (12g) is added drop-wise in suspension.After addition terminates, the mixture is stirred 24 hours at 78 DEG C -82 DEG C, detected by TLC Surplus stock.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, suction filtration is carried out to remove excessive sodium salt, uses dichloromethane Alkane (50ml × 2) washs filter cake.Solvent is recovered under reduced pressure.Residual liquid is poured into 100ml water, will separate out solid suction filtration, and filter cake is used 5%NaOH (30ml × 2) is washed, and then water (30ml × 2) is washed, and is obtained solid addition toluene (60ml) and is heated to 60 DEG C of stirrings 30 minutes, filtrate was cooled to 15 DEG C to 20 DEG C and stands 5 hours under agitation, and the light yellow crystal of precipitation is filtered, cold first is used Benzene (15ml*2), washing is dried in vacuo 5 hours at 45 DEG C, obtains faint yellow solid (7.75g), yield：50.3%, mp:53~ 55℃,ESI-MS m/z:222[M+H]+,244[M+Na]+
3) 4- isobutoxies benzylamine
Hydrazine hydrate (80ml) is dissolved in methanol (100ml) in room temperature, N- (4- isobutoxies benzyl) second is then added Acid amides (10g) solid, is heated to reflux temperature by solution and stirs 8 hours, starting material left is detected with TLC.After the completion of reaction, 80 DEG C Solvent is recovered under reduced pressure, dichloromethane (80ml) is added in residue, water (30ml*2) is washed, and is then concentrated under reduced pressure in 30 DEG C, Obtain oily amino bases 5.3g, yield 65%, ESI-MS m/z:180[M+H]+, 202 [M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (15g) oily liquids for sloughing protection group is dissolved in tetrahydrofuran (75ml) in room temperature, Then addition sodium acid carbonate (15g), 0 DEG C to 10 DEG C is cooled to by suspension, and 0 DEG C to 10 DEG C with 1 hour by chloro-carbonic acid benzene Ester (19.6g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 1 hour, then is added Hot to 60 DEG C are stirred 10 hours, and starting material left is detected by TLC.After reaction terminates, inorganic salts are removed by filtration, with tetrahydrofuran (30ml*2) washs filter cake, and filtrate is washed with 10%HCl (50ml*2), and layering obtains organic layer and washed with water (20ml*2), passes through After drying, 60 DEG C are recovered under reduced pressure solvent, obtain white solid (25g) crude product, it is small that addition methanol (50ml) is heated to backflow about 0.5 All dissolved up to solid.The solution is cooled to 10 DEG C with about 1 hour and 5 hours are stood.Product is filtered, and with cold methanol (20ml*2) washs filter cake.It is dried in vacuo 2 hours in 60 DEG C, obtains 15.8g white solid sterlings, yield 62%, mp:97.8~ 98.5℃,ESI-MS m/z:300[M+H]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (37.7g) and N- (4- luorobenzyls) -1- methyl -4- Piperidinamine (20g) is dissolved in methanol (60ml), is heated to flowing back and is stirred 6 hours, and surplus stock N- (4- fluorine is detected with TLC Benzyl) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is produced Isobutoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (4.5g) was added to the methanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled down 0 DEG C and 5 hours are stood.By product Filtering, and filter cake is washed with cold methanol (20ml*2).Obtain crude product, wet product and backflow is heated to absolute methanol (150ml) simultaneously Stirring 2 hours, was then cooled to 25 DEG C to 30 DEG C with 1 hour by solution, and 24 hours are stood in this temperature.The product is filtered, and Filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (28.2g), yield 62%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR (400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2),4.02(s,1H, ), CH 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH),2.41– 2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2),1.51(d,J =11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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 5, blocking group is made with formoxyl
1) N- (4- hydroxybenzyls) formamide
4- hydroxy benzylamines (20g) and sodium acid carbonate (27g) are added to stirring in toluene (60ml) in room temperature, arrived at 0 DEG C 20 DEG C were added drop-wise to brand-new acetic formic anhydride (21.5g) in suspension with 1 hour.After addition terminates, by the mixture at 20 DEG C to 25 DEG C stirring 2 hours, be then heated to 60 DEG C stir 1 hour, with TLC detect starting material left.After the completion of reaction, suction filtration is carried out To remove excessive sodium salt.Filter cake is washed with toluene (30ml × 2).Filtrate is washed with 5% watery hydrochloric acid (35ml × 2), then uses water (45ml × 2) washing layering, organic layer is dried.30 DEG C to 40 DEG C are recovered under reduced pressure solvent, obtain red oil, 20 DEG C to 25 DEG C Placement obtains yellow solid for 3 hours, and solid is filtered and washed with dichloromethane (30ml), during 60 DEG C of vacuum drying 3, obtains yellowish Color solid 20.6g, yield:60.0%, mp:122~124 DEG C, ESI-MS m/z:152[M+H]+,174[M+Na]+
2) N- (4- isobutoxies benzyl) formamide
N- (4- hydroxybenzyls) formamides (12g) are dissolved in dimethylformamide (50ml) in room temperature, Ran Hou<30 DEG C Anhydrous potassium carbonate (15g) is added portionwise, and the suspension is heated to 78 DEG C to 82 DEG C.Will with 2 hours in 78 DEG C to 82 DEG C Isobutane bromide (17g) is added drop-wise in suspension.After addition terminates, the mixture is stirred 24 hours at 78 DEG C -82 DEG C, passed through TLC detects surplus stock.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, carries out suction filtration to remove excessive sylvite, is used Dichloromethane (20ml × 2) washs filter cake.Dimethylformamide is recovered under reduced pressure.Residual liquid is poured into 100ml water, solid by separating out Body suction filtration, filter cake is washed with 5%NaOH (30ml × 2), and then water (30ml × 2) is washed, and is obtained solid and is added acetonitrile (50ml) It is heated to 80 DEG C to dissolve and stir 30 minutes, solution is cooled to 15 DEG C to 20 DEG C and stands 5 hours under agitation, by the white of precipitation Color crystal is filtered, and with cold toluene (15ml*2), washing is dried in vacuo 5 hours at 45 DEG C, obtains white powder solid (13.9g), receives Rate：70.0%, mp:78~81 DEG C, ESI-MS m/z:208[M+H]+,230[M+Na]+
3) 4- isobutoxies benzylamine
Sodium hydroxide (20g) is dissolved in ethanol (40ml) in 40 DEG C to 45 DEG C, N- (4- isobutoxy benzyls are then added Base) formamide (19g) solid, solution is stirred at room temperature 5 hours, starting material left is detected with TLC.After the completion of reaction, 50 DEG C Ethanol is recovered under reduced pressure, dichloromethane (75ml) is added in residue, is stirred at room temperature 10 minutes, insoluble matter, Ran Houyu is filtered 30 DEG C are concentrated under reduced pressure, and obtain oily amino bases 12.3g, yield 75%, ESI-MS m/z:180[M+H]+, 202 [M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (13g) oily liquids for sloughing protection group is dissolved in dichloromethane (65ml) in room temperature, Then addition Anhydrous potassium carbonate (15g), -25 DEG C to 0 DEG C are cooled to by suspension, and 0 DEG C to 10 DEG C with 1 hour by chloro-carbonic acid Phenyl ester (18.1g) is added drop-wise in the suspension.After addition terminates, the mixture is cooled at -25 DEG C and stirred 2.5 hours, is passed through TLC detects starting material left.After reaction terminates, inorganic salts are removed by filtration, filter cake is washed with DCM (25ml*2), filtrate uses 10%HCl (20ml*2) is washed, and layering obtains organic layer and washed with water (20ml*2), and after drying, 30 DEG C are recovered under reduced pressure solvent, obtain white Color solid (23g) crude product, adds methanol (50ml) and is heated to flowing back about 0.5 hour and all dissolved to solid.Should with about 1 hour Solution is cooled to 10 DEG C and stands 5 hours.Product is filtered, and filter cake is washed with cold methanol (20ml*2).It is dry in 60 DEG C of vacuum Dry 2 hours, obtain 18g white solid sterlings, yield 83%, mp:98.2~99.5 DEG C, ESI-MS m/z:300[M+H]+,322 [M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (30.3g) and N- (4- luorobenzyls) -1- methyl -4- Piperidinamine (15g) is dissolved in ethanol (60ml), is heated to flowing back and is stirred 3 hours, and surplus stock N- (4- fluorine is detected with TLC Benzyl) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is produced Isobutoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (9.12g) was added to the ethanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled to 30 DEG C to 35 DEG C, product is about 34 DEG C of crystallizations, the suspension is stirred 30 minutes, be then cooled to 0 DEG C with 1 hour and stand 5 hours at this temperature. The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Obtain crude product, wet product absolute ethyl alcohol (150ml) heating To flowing back and stirring 2 hours, solution is then cooled to 25 DEG C to 30 DEG C with 1 hour, 3 hours are stood in this temperature.Filtering should Product, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (26g), is received Rate 90%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR (400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2),4.02(s,1H, ), CH 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH),2.41– 2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2),1.51(d,J =11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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 6, blocking group is made with benzyloxycarbonyl group
1) N- (4- hydroxybenzyls) benzyq carbamate
4- hydroxy benzylamines (10g) and triethylamine (14g) are added to stirring in acetonitrile (40ml) in room temperature, at 0 DEG C to 20 DEG C benzyl chloroformate (22.2g) is added drop-wise in suspension with 1 hour.After addition terminates, by the mixture at 35 DEG C to 40 DEG C Stirring 2 hours, starting material left is detected with TLC.After the completion of reaction, carry out suction filtration to remove excess of triethylamine hydrochloride.Subtract Pressure removes solvent, and residual solid is diluted with dichloromethane (20ml × 2).Filtrate washs acid adjustment with 5% watery hydrochloric acid (25ml × 2), Washed again with water (30ml × 2), water layer is discarded after layering, organic layer is dried.30 DEG C to 40 DEG C are recovered under reduced pressure solvent, obtain red Solid, solid suction filtration is washed with toluene, and 40 DEG C are dried in vacuo 5 hours, obtain white solid 11.7g.Yield:77.8%.mp:50 ~51 DEG C of ESI-MS m/z:258[M+H]+,280[M+Na]+
2) N- (4- isobutoxies benzyl) benzyq carbamate
N- (4- hydroxybenzyls) benzyq carbamates (18g) are dissolved in dimethylformamide (90ml) in room temperature, so Exist afterwards<30 DEG C are added portionwise Anhydrous potassium carbonate (19g), and the suspension are heated into 78 DEG C to 82 DEG C.In 78 DEG C to 82 DEG C with 2 Isobutane bromide (14g) is added drop-wise in suspension by hour.It is after addition terminates, the mixture is small in 78 DEG C of -82 DEG C of stirrings 24 When, surplus stock is detected by TLC.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, carries out suction filtration to remove excess Sylvite, filter cake is washed with dichloromethane (50ml × 2).Dimethylformamide is recovered under reduced pressure.Residue is with dichloromethane (150ml) Dilution, dichloromethane solution is washed with 5%NaOH (30ml × 2), and then water (50ml × 2) is washed, water layer discarded, dichloromethane Solution is recovered under reduced pressure at 50 DEG C, and residual solid adds after methanol (60ml) is heated to 60 DEG C of stirrings, solid dissolving and is cooled to 50 DEG C, 8g active carbon powders are added, 60 DEG C is reheated to and stirs 30 minutes, insoluble matter is filtered while hot, filtrate cools down under agitation To 15 DEG C to 20 DEG C (about 25 DEG C when crystallization) and 5 hours are stood, product is filtered and filter is washed with cold methanol (25ml × 2) Cake, 30 DEG C are dried in vacuo 5 hours, obtain yellow solid (14.7g), yield：83.4%, mp:38~39 DEG C, ESI-MS m/z: 314[M+H]+,336[M+Na]+
3) 4- isobutoxies benzylamine
N- (4- isobutoxies benzyl) benzyq carbamates (5g) and 5%Pd-C (0.3g) are added in (30ml) ethanol simultaneously Hydrogen is passed through, is stirred 5 hours at room temperature, starting material left is detected with TLC.Reaction, which is finished, filters palladium carbon, then in 50 DEG C of decompressions Concentration, obtains oily amino bases 2.3g, yield 63%, ESI-MS m/z:180[M+H]+, 202 [M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (11g) oily liquids for sloughing protection group is dissolved in dichloromethane (65ml) in room temperature, Then addition Anhydrous potassium carbonate (13g), 0 DEG C to 10 DEG C is cooled to by suspension, and 0 DEG C to 10 DEG C with 1 hour by chloro-carbonic acid Phenyl ester (13.4g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 1 hour, is led to Cross TLC detection starting material lefts.After reaction terminates, inorganic salts are removed by filtration, filter cake is washed with DCM (30ml*2), filtrate uses 10% HCl (40ml*2) is washed, and layering obtains organic layer and washed with water (30ml*2), and after drying, 30 DEG C are recovered under reduced pressure solvent, obtain White solid (19g) crude product, adds methanol (30ml) and is heated to flowing back about 0.5 hour and all dissolved to solid.Will with about 1 hour The solution is cooled to 10 DEG C and stands 5 hours.Product is filtered, and filter cake is washed with cold methanol (20ml*2).In 60 DEG C of vacuum Dry 2 hours, obtain 15.4g white solid sterlings, yield 84%, mp:98.2~99.5 DEG C, ESI-MS m/z:300[M+H ]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (16.3g) and N- (4- luorobenzyls) -1- methyl -4- Piperidinamine (11g) is dissolved in ethanol (55ml), is heated to flowing back and is stirred 3 hours, and surplus stock N- (4- fluorine is detected with TLC Benzyl) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is produced Isobutoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (7.43g) was added to the ethanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled to 30 DEG C to 35 DEG C, product is about 34 DEG C of crystallizations, the suspension is stirred 30 minutes, be then cooled to 0 DEG C with 1 hour and stand 5 hours at this temperature. The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Obtain crude product, wet product absolute ethyl alcohol (100ml) heating To flowing back and stirring 2 hours, solution is then cooled to 25 DEG C to 30 DEG C with 1 hour, 3 hours are stood in this temperature.Filtering should Product, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (19.3g), Yield 91%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR(400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2),4.02(s, 1H, CH), 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH), 2.41–2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2), 1.51 (d, J=11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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 7, Ehud methoxycarbonyl group makees blocking group
1) N- (4- hydroxybenzyls) carbamic acid tablet held before the breast by officials methyl esters
4- hydroxy benzylamines (15g) and sodium acid carbonate (23g) are added to stirring in dioxane (75ml) in room temperature, 0 DEG C fluorenes methoxy dicarbonyl chloride (53.6g) is added drop-wise in suspension with 1 hour to 20 DEG C.After addition terminates, by the mixture 20 DEG C to 25 DEG C stir 2 hours, then be warming up to 50 DEG C stir 1 hour, with TLC detect starting material left.After the completion of reaction, carry out Suction filtration is to remove excessive sodium salt.Filter cake is washed with dioxane (30ml × 2).Filtrate is washed with 5% watery hydrochloric acid (30ml × 2), Layering is washed with water (50ml × 2) again, organic layer is dried.60 DEG C to 80 DEG C are recovered under reduced pressure solvent, residual solid ethanol (30ml) is diluted and is poured into 300ml water, and the solid of precipitation is carried out into suction filtration and spent glycol (50ml*2) washs filter cake, 60 DEG C 3h is dried in vacuo, white solid 17.1g, yield is obtained:85.7%, mp:144~146 DEG C, ESI-MS m/z:346[M+H]+, 368[M+Na]+
2) N- (4- isobutoxies benzyl) carbamic acid tablet held before the breast by officials methyl esters
N- (4- hydroxybenzyls) benzyq carbamates (12g) are dissolved in dimethylformamide (70ml) in room temperature, so Exist afterwards<30 DEG C are added portionwise Anhydrous potassium carbonate (19g), and the suspension are heated into 78 DEG C to 82 DEG C.In 78 DEG C to 82 DEG C with 2 Isobutane bromide (14g) is added drop-wise in suspension by hour.It is after addition terminates, the mixture is small in 78 DEG C of -82 DEG C of stirrings 24 When, surplus stock is detected by TLC.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, carries out suction filtration to remove excess Sylvite, filter cake is washed with dichloromethane (30ml × 2).Dimethylformamide is recovered under reduced pressure.Residue is with dichloromethane (300ml) Dilution, dichloromethane solution is washed with 5%NaOH (25ml × 2), then wash layering, water layer discarded, solvent with water (50ml × 2) It is recovered under reduced pressure at 50-60 DEG C, residual solid adds after isopropyl ether (20ml) is heated to 60 DEG C of stirrings, solid dissolving and is cooled to 50 DEG C, 1g active carbon powders are added, 60 DEG C is reheated to and stirs 30 minutes, insoluble matter is filtered while hot, filtrate cools down under agitation To 15 DEG C to 20 DEG C and stand 10 hours, product filter and filter cake is washed with cold isopropyl ether (5ml × 2), 60 DEG C be dried in vacuo 5 Hour, obtain faint yellow solid (7.4g), yield：84.7%, mp:138~139 DEG C, ESI-MSm/z:402[M+H]+,424[M +Na]+
3) 4- isobutoxies benzylamine
By N- (4- isobutoxies benzyl) carbamic acid tablet held before the breast by officials methyl esters (3g) and 20% piperidinamine (15ml) in dimethyl formyl (10ml) is dissolved in amine, is stirred at room temperature 3 hours, and starting material left is detected with TLC.Desolvation after after the completion of reaction, adds two Chloromethanes (10ml*2), water (5ml*2) is washed, and is sloughed solvent and is obtained oily amino bases 0.82g, yield 52%, ESI-MS m/z: 180[M+H]+, 202 [M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (10g) oily liquids for sloughing protection group is dissolved in dichloromethane (60ml) in room temperature, Then addition Anhydrous potassium carbonate (12g), 0 DEG C to 10 DEG C is cooled to by suspension, and 0 DEG C to 10 DEG C with 1 hour by chloro-carbonic acid Phenyl ester (15.7g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 1 hour, is led to Cross TLC detection starting material lefts.After reaction terminates, inorganic salts are removed by filtration, filter cake is washed with DCM (30ml*2), filtrate uses 10% HCl (25ml*2) is washed, and layering obtains organic layer and washed with water (20ml*2), and after drying, 30 DEG C are recovered under reduced pressure solvent, obtain White solid (20g) crude product, adds methanol (30ml) and is heated to flowing back about 0.5 hour and all dissolved to solid.Will with about 1 hour The solution is cooled to 10 DEG C and stands 5 hours.Product is filtered, and filter cake is washed with cold methanol (10ml*2).In 60 DEG C of vacuum Dry 2 hours, obtain 13.4g white solid sterlings, yield 80%, mp:98.2~99.5 DEG C, ESI-MS m/z:300[M+H ]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (21g) and N- (4- luorobenzyls) -1- methyl -4- piperazines Pyridine amine (13g) is dissolved in ethanol (80ml), is heated to flowing back and is stirred 3 hours, and surplus stock N- (4- fluorine benzyls are detected with TLC Base) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is different is produced Butoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (4.39g) was added to the ethanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled to 30 DEG C to 35 DEG C, product is about 34 DEG C of crystallizations, the suspension is stirred 30 minutes, be then cooled to 0 DEG C with 1 hour and stand 5 hours at this temperature. The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Obtain crude product, wet product absolute ethyl alcohol (120ml) heating To flowing back and stirring 2 hours, solution is then cooled to 25 DEG C to 30 DEG C with 1 hour, 3 hours are stood in this temperature.Filtering should Product, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (22g), is received Rate 88%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR (400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2),4.02(s,1H, ), CH 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH),2.41– 2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2),1.51(d,J =11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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 8, blocking group is made with trimethylsilyl ethoxycarbonyl
1) N- (4- hydroxybenzyls) carbamic acid-(2,2,2- trimethylsilyls) ethyl ester
4- hydroxy benzylamines (15g) and sodium acid carbonate (25g) are added to stirring in dichloromethane (90ml) in room temperature, 0 DEG C 2,2,2- trimethyl silicane methylamino ethoxy acyl chlorides (38.6g) is added drop-wise in suspension with 1 hour to 20 DEG C., will after addition terminates The mixture is stirred 12 hours at 20 DEG C to 25 DEG C, and starting material left is detected with TLC.After the completion of reaction, carry out suction filtration with except Remove excessive sodium salt.Filter cake is washed with dichloromethane (45ml × 2).Filtrate is washed with 5% watery hydrochloric acid (15ml × 2), then uses water (70ml × 2) are washed, and water layer is discarded after layering, and organic layer is dried.30 DEG C to 40 DEG C are recovered under reduced pressure solvent, and vacuum is done at 40 DEG C Dry 5 hours, obtain red liquid 14.8g, yield:61.5%, ESI-MS m/z:268[M+H]+,290[M+Na]+
2) N- (4- isobutoxies benzyl) carbamic acid-(2,2,2- trimethylsilyls) ethyl ester
N- (4- hydroxybenzyls) carbamic acid-(2,2,2- trimethylsilyls) ethyl ester (11g) is dissolved in two in room temperature In NMF (66ml), Ran Hou<30 DEG C are added portionwise Anhydrous potassium carbonate (13g), and the suspension are heated into 78 DEG C To 82 DEG C.Isobutane bromide (11g) is added drop-wise in suspension with 2 hours in 78 DEG C to 82 DEG C.After addition terminates, this is mixed Thing is stirred 24 hours at 78 DEG C -82 DEG C, and surplus stock is detected by TLC.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, suction filtration is carried out to remove excessive sylvite, and filter cake is washed with dichloromethane (50ml × 2).Dimethylformamide is recovered under reduced pressure.It is residual Excess is diluted with dichloromethane (150ml), washs dichloromethane solution with 5%NaOH (30ml × 2), then water (50ml × 2) Washing, water layer discarded, dichloromethane solution is recovered under reduced pressure at 50 DEG C, is dried in vacuo 5 hours at 40 DEG C, obtains brown oil liquid Body (7.1g), yield：83.3%, ESI-MS m/z:324[M+H]+,346[M+Na]+
3) 4- isobutoxies benzylamine
N- (4- isobutoxies benzyl) carbamic acid-(2,2,2- trimethylsilyls) ethyl ester (5g) and the tetrabutyl are fluorinated Ammonium (7.3g) is dissolved in tetrahydrofuran (50ml), and the solution is stirred at room temperature 12 hours, is remained with TLC detection reaction raw materials It is remaining.After the completion of reaction, solvent is recovered under reduced pressure, residual liquid is extracted with dichloromethane (15ml*2), water (50ml*2) is washed layering, abandoned Water layer is removed, solvent is sloughed, oily amino bases 2.1g, yield 68%, ESI-MS m/z is obtained:180[M+H]+,202[M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (25g) oily liquids for sloughing protection group is dissolved in dichloromethane (150ml) in room temperature, Then addition Anhydrous potassium carbonate (33g), 0 DEG C to 10 DEG C is cooled to by suspension, and 0 DEG C to 10 DEG C with 1 hour by chloro-carbonic acid Phenyl ester (41.4g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 1 hour, is led to Cross TLC detection starting material lefts.After reaction terminates, inorganic salts are removed by filtration, filter cake is washed with DCM (30ml*2), filtrate uses 10% HCl (100ml*2) is washed, and layering obtains organic layer and washed with water (100ml*2), and after drying, 30 DEG C are recovered under reduced pressure solvent, obtain To white solid (45g) crude product, add methanol (60ml) and be heated to flowing back about 0.5 hour and all dissolved to solid.With about 1 hour The solution is cooled to 10 DEG C and 5 hours are stood.Product is filtered, and filter cake is washed with cold methanol (20ml*2).It is true in 60 DEG C Sky is dried 2 hours, obtains 33g white solid sterlings, yield 79%, mp:98.2~99.5 DEG C, ESI-MS m/z:300[M+H ]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (22.6g) and N- (4- luorobenzyls) -1- methyl -4- Piperidinamine (14g) is dissolved in ethanol (100ml), is heated to flowing back and is stirred 3 hours, and surplus stock N- (4- fluorine is detected with TLC Benzyl) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is produced Isobutoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (5.2g) was added to the ethanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled to 30 DEG C to 35 DEG C, product is about 34 DEG C of crystallizations, the suspension is stirred 30 minutes, be then cooled to 0 DEG C with 1 hour and stand 5 hours at this temperature. The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Obtain crude product, wet product absolute ethyl alcohol (120ml) heating To flowing back and stirring 2 hours, solution is then cooled to 25 DEG C to 30 DEG C with 1 hour, 3 hours are stood in this temperature.Filtering should Product, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (24.8g), Yield 92%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR(400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2),4.02(s, 1H, CH), 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH), 2.41–2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2), 1.51 (d, J=11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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 9, blocking group is made with p-toluenesulfonyl
1) N- (4- hydroxybenzyls)-N- (4- aminomethyl phenyls) sulfonamide
4- hydroxy benzylamines (10g) and sodium acid carbonate (25g) are added to stirring in tetrahydrofuran (90ml) in room temperature, 0 DEG C paratoluensulfonyl chloride (38.6g) is added drop-wise in suspension with 1 hour to 20 DEG C.After addition terminates, by the mixture 20 DEG C to 25 DEG C stir 10 hours, then be warming up to 50 DEG C stir 2 hours, with TLC detect starting material left.After the completion of reaction, enter Row suction filtration is to remove excessive sodium salt.Filter cake is washed with tetrahydrofuran (40ml × 2).Filtrate is washed with 5% watery hydrochloric acid (10ml × 2) Wash, then wash with water (40ml × 2) layering, organic layer is dried.60 DEG C to 80 DEG C are recovered under reduced pressure solvent, are dried in vacuo at 60 DEG C 3h, obtains yellow oily liquid 10g, yield:68.9%, ESI-MS m/z:278[M+H]+,300[M+Na]+
2) N- (4- isobutoxies benzyl)-N- (4- aminomethyl phenyls) sulfonamide
N- (4- hydroxybenzyls)-N- (4- aminomethyl phenyls) sulfonamide liquid (13g) is dissolved in dimethyl formyl in room temperature In amine (65ml), Ran Hou<30 DEG C are added portionwise Anhydrous potassium carbonate (16g), and the suspension are heated into 78 DEG C to 82 DEG C.In 78 DEG C to 82 DEG C were added drop-wise to isobutane bromide (14g) in suspension with 2 hours.Addition terminate after, by the mixture 78 DEG C- 82 DEG C are stirred 24 hours, and surplus stock is detected by TLC.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, taken out Filter washs filter cake to remove excessive sylvite with dichloromethane (50ml × 2).Dimethylformamide is recovered under reduced pressure.Residue uses two Chloromethanes (100ml) dilutes, and adds 5%NaOH (50ml × 2) washings, then washs with water (100ml × 2) layering, water layer discarded, Solvent is recovered under reduced pressure at 50-60 DEG C, is dried in vacuo 5 hours at 60 DEG C, obtains pale brown oil liquid (9.4g), yield： 80.1%, ESI-MS m/z:334[M+H]+,356[M+Na]+
3) 4- isobutoxies benzylamine
In N- (4- isobutoxies benzyl)-N- (4- aminomethyl phenyls) sulfonamide (0.25g) is added into sodium naphtholate at -78 DEG C In tetrahydrofuran (20ml) solution of (15ml, how phenol 2g, sodium 1g), and in the temperature stirred under nitrogen atmosphere 10 hours.Reaction After the completion of, water (5ml) terminating reaction is added, removal of solvent under reduced pressure adds water (5ml), and is extracted with ethyl acetate (10ml*2), Then washed with saturated aqueous common salt (10ml*2), solvent is recovered under reduced pressure after drying, oily amino bases 0.09g, yield is obtained：59%, ESI-MS m/z:180[M+H]+, 202 [M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (21g) oily liquids for sloughing protection group is dissolved in dichloromethane (120ml) in room temperature, Then addition Anhydrous potassium carbonate (29g), 0 DEG C to 10 DEG C is cooled to by suspension, and 0 DEG C to 10 DEG C with 1 hour by chloro-carbonic acid Phenyl ester (36.6g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 1 hour, is led to Cross TLC detection starting material lefts.After reaction terminates, inorganic salts are removed by filtration, filter cake is washed with DCM (30ml*2), filtrate uses 10% HCl (100ml*2) is washed, and layering obtains organic layer and washed with water (100ml*2), and after drying, 30 DEG C are recovered under reduced pressure solvent, obtain To white solid (45g) crude product, add methanol (75ml) and be heated to flowing back about 0.5 hour and all dissolved to solid.With about 1 hour The solution is cooled to 10 DEG C and 5 hours are stood.Product is filtered, and filter cake is washed with cold methanol (20ml*2).It is true in 60 DEG C Sky is dried 2 hours, obtains 28.4g white solid sterlings, yield 81%, mp:98.2~99.5 DEG C, ESI-MS m/z:300[M+ H]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (25.9g) and N- (4- luorobenzyls) -1- methyl -4- Piperidinamine (16g) is dissolved in ethanol (120ml), is heated to flowing back and is stirred 3 hours, and surplus stock N- (4- fluorine is detected with TLC Benzyl) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is produced Isobutoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (6.49g) was added to the ethanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled to 30 DEG C to 35 DEG C, product is about 34 DEG C of crystallizations, the suspension is stirred 30 minutes, be then cooled to 0 DEG C with 1 hour and stand 5 hours at this temperature. The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Obtain crude product, wet product absolute ethyl alcohol (130ml) heating To flowing back and stirring 2 hours, solution is then cooled to 25 DEG C to 30 DEG C with 1 hour, 3 hours are stood in this temperature.Filtering should Product, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (26.2g), Yield 85%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR(400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2),4.02(s, 1H, CH), 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH), 2.41–2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2), 1.51 (d, J=11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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 10, blocking group is made with trityl
1) N- (4- hydroxybenzyls)-trityl amine
4- hydroxy benzylamines (12g) and triethylamine (22g) are added to stirring in chloroform (60ml) in room temperature, at 0 DEG C to 20 DEG C it is added drop-wise to 1 hour chloroformic solution by triphenylchloromethane (57.1g) in suspension.After addition terminates, by the mixture Stirred 10 hours at 20 DEG C to 25 DEG C, then be warming up to 40 DEG C and stirred 2 hours, starting material left is detected with TLC.Reaction is completed Afterwards, suction filtration is carried out to remove triethylamine salt.Filter cake is washed with chloroform (30ml × 2).Layering is washed with water (50ml × 2), it is organic Layer is dried.60 DEG C to 80 DEG C are recovered under reduced pressure solvent, and solid is washed with n-hexane (50ml*2), pale yellow powder are filtered, at 60 DEG C Lower vacuum drying 3h, obtains 10.5g.Yield：66.8%, mp:182~184 DEG C, ESI-MS m/z:366[M+H]+,388[M+ Na]+
2) N- (4- isobutoxies benzyl)-trityl amine
N- (4- hydroxybenzyls)-trityl amine (15g) is dissolved in dimethylformamide (120ml) in room temperature, so Exist afterwards<30 DEG C are added portionwise Anhydrous potassium carbonate (14g), and the suspension are heated into 78 DEG C to 82 DEG C.In 78 DEG C to 82 DEG C with 2 Isobutane bromide (14g) is added drop-wise in suspension by hour.It is after addition terminates, the mixture is small in 78 DEG C of -82 DEG C of stirrings 24 When, surplus stock is detected by TLC.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, carries out suction filtration to remove excess Sylvite, filter cake is washed with dichloromethane (50ml × 2).Dimethylformamide is recovered under reduced pressure.Residue is diluted with ethanol (50ml), It is then poured into water (200ml), filters the solid separated out, adds 5%NaOH (50ml × 2) washings, then washed with water (80ml × 2) Wash, solid is dried in vacuo 5 hours at 60 DEG C, obtains white powder (8.1g), yield：78.3%, mp:141~143 DEG C, ESI- MS m/z:422[M+H]+,444[M+Na]+
3) 4- isobutoxies benzylamine
N- (4- isobutoxies benzyl)-trityl amine 8g is dissolved in tetrahydrofuran (50ml) in room temperature, Ran Hou 0-20 DEG C, glacial acetic acid (40ml) is added dropwise in solution, 40 DEG C are heated to after being added dropwise to complete and is stirred 4 hours, raw material is detected with TLC It is remaining.After the completion of reaction, solution PH is adjusted to alkalescence at 0-25 DEG C, and layering is washed with water (25ml*2), 30 DEG C are concentrated under reduced pressure Solvent, obtains oily amino bases 3.1g, yield 79%, ESI-MS m/z:180[M+H]+, 202 [M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (14g) oily liquids for sloughing protection group is dissolved in dichloromethane (120ml) in room temperature, Then addition Anhydrous potassium carbonate (22g), 0 DEG C to 10 DEG C is cooled to by suspension, and 0 DEG C to 10 DEG C with 1 hour by chloro-carbonic acid Phenyl ester (14.6g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 1 hour, is led to Cross TLC detection starting material lefts.After reaction terminates, inorganic salts are removed by filtration, filter cake is washed with DCM (30ml*2), filtrate uses 10% HCl (100ml*2) is washed, and layering obtains organic layer and washed with water (100ml*2), and after drying, 30 DEG C are recovered under reduced pressure solvent, obtain To white solid (25g) crude product, add methanol (40ml) and be heated to flowing back about 0.5 hour and all dissolved to solid.With about 1 hour The solution is cooled to 10 DEG C and 5 hours are stood.Product is filtered, and filter cake is washed with cold methanol (20ml*2).It is true in 60 DEG C Sky is dried 2 hours, obtains 19.4g white solid sterlings, yield 83%, mp:98.2~99.5 DEG C, ESI-MS m/z:300[M+ H]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (15.8g) and N- (4- luorobenzyls) -1- methyl -4- Piperidinamine (9g) is dissolved in ethanol (70ml), is heated to flowing back and is stirred 3 hours, and surplus stock N- (4- fluorine benzyls are detected with TLC Base) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is different is produced Butoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (3.95g) was added to the ethanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled to 30 DEG C to 35 DEG C, product is about 34 DEG C of crystallizations, the suspension is stirred 30 minutes, be then cooled to 0 DEG C with 1 hour and stand 5 hours at this temperature. The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Obtain crude product, wet product absolute ethyl alcohol (150ml) heating To flowing back and stirring 2 hours, solution is then cooled to 25 DEG C to 30 DEG C with 1 hour, 3 hours are stood in this temperature.Filtering should Product, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (14.5g), Yield 84.2%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR(400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2),4.02(s, 1H, CH), 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH), 2.41–2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2), 1.51 (d, J=11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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 11, blocking group is made with 2,4- dimethoxy-benzyls
1) N- (4- hydroxybenzyls)-N- (2,4- dimethoxys) benzylamine
4- hydroxy benzylamines (15g) and 2,4- dimethoxy benzaldehydes (10g) are dissolved in dichloromethane (50ml) at room temperature In, the suspension is added portionwise in Sodium triacetoxyborohydride (17g) in 0-15 DEG C.After addition terminates, stirred at 20-25 DEG C 12 hours, surplus stock is detected with TLC.After reaction terminates, insoluble matter is filtered and filter cake is washed with dichloromethane (20ml*2), Sodium hydroxide (3g-5g) is added at 0-20 DEG C and adjusts PH10 to 12, then water (100ml*2) washes layering, 40 after organic layer drying DEG C removal of solvent under reduced pressure, 60 DEG C are dried in vacuo 2 hours, obtain brown oil 17g, yield：77.5%, ESI-MS m/z:244[M +H]+,266[M+Na]+
2) N- (4- isobutoxies benzyl)-N- (2,4- dimethoxys) benzylamine
N- (4- hydroxybenzyls)-N- (2,4- dimethoxys) benzylamines (12g) are dissolved in dimethylformamide at room temperature In (90ml), Ran Hou<30 DEG C are added portionwise Anhydrous potassium carbonate (18g), and the suspension are heated into 78 DEG C to 82 DEG C.In 78 DEG C isobutane bromide (17g) is added drop-wise in suspension with 2 hours to 82 DEG C.After addition terminates, by the mixture at 78 DEG C -82 DEG C stirring 24 hours, surplus stock is detected by TLC.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, suction filtration is carried out To remove excessive sylvite, filter cake is washed with dichloromethane (30ml × 2).Dimethylformamide is recovered under reduced pressure.Residue dichloro Methane (100ml) dilutes, and adds 5%NaOH (50ml × 2) washings, then is washed with water (50ml × 2), removes solvent and at 60 DEG C Vacuum drying 5 hours, obtains dark oil liquid (9.3g), yield:75.1%, ESI-MS m/z:300[M+H]+,322[M+ Na]+.
3) 4- isobutoxies benzylamine
N- (4- isobutoxies benzyl)-N- (2,4- dimethoxys) benzylamine 3g is dissolved in tetrahydrofuran (30ml) in room temperature In, then at 0-20 DEG C, hydrochloric acid (6ml) is added dropwise in solution, reflux temperature is heated to after being added dropwise to complete and is stirred 8 hours, is used TLC detects starting material left.After the completion of reaction, solvent is sloughed in decompression, dichloromethane (10ml) is added, by solution PH at 0-25 DEG C Alkalescence is adjusted to, and washes with water (20ml*2) layering, 30 DEG C of solvents that are concentrated under reduced pressure obtain oily amino bases 1.4g, yield 68%, ESI-MS m/z:180[M+H]+, 202 [M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (18g) oily liquids for sloughing protection group is dissolved in dichloromethane (140ml) in room temperature, Then addition Anhydrous potassium carbonate (35g), 0 DEG C to 10 DEG C is cooled to by suspension, and 0 DEG C to 10 DEG C with 1 hour by chloro-carbonic acid Phenyl ester (23.5g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 1 hour, is led to Cross TLC detection starting material lefts.After reaction terminates, inorganic salts are removed by filtration, filter cake is washed with DCM (30ml*2), filtrate uses 10% HCl (100ml*2) is washed, and layering obtains organic layer and washed with water (100ml*2), and after drying, 30 DEG C are recovered under reduced pressure solvent, obtain To white solid (30g) crude product, add methanol (50ml) and be heated to flowing back about 0.5 hour and all dissolved to solid.With about 1 hour The solution is cooled to 10 DEG C and 5 hours are stood.Product is filtered, and filter cake is washed with cold methanol (20ml*2).It is true in 60 DEG C Sky is dried 2 hours, obtains 25.6g white solid sterlings, yield 85%, mp:98.2~99.5 DEG C, ESI-MS m/z:300[M+ H]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (17.5g) and N- (4- luorobenzyls) -1- methyl -4- Piperidinamine (10g) is dissolved in ethanol (80ml), is heated to flowing back and is stirred 3 hours, and surplus stock N- (4- fluorine is detected with TLC Benzyl) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is produced Isobutoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (4.05g) was added to the ethanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled to 30 DEG C to 35 DEG C, product is about 34 DEG C of crystallizations, the suspension is stirred 30 minutes, be then cooled to 0 DEG C with 1 hour and stand 5 hours at this temperature. The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Obtain crude product, wet product absolute ethyl alcohol (150ml) heating To flowing back and stirring 2 hours, solution is then cooled to 25 DEG C to 30 DEG C with 1 hour, 3 hours are stood in this temperature.Filtering should Product, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (15.6g), Yield 84%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR(400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2),4.02(s, 1H, CH), 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH), 2.41–2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2), 1.51 (d, J=11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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 12, blocking group is made with 4- methoxy-benzyls
1) N- (4- hydroxybenzyls)-N- (4- methoxyl groups) benzylamine
4- hydroxy benzylamines (18g) and 4-methoxybenzaldehyde (20.5g) are dissolved in dichloromethane under room temperature (25 DEG C, similarly hereinafter) In alkane (50ml), the suspension is added portionwise in Sodium triacetoxyborohydride (31g) in 0-15 DEG C.After addition terminates, in 20-25 Stirred 12 hours at DEG C, surplus stock is detected with TLC.After reaction terminates, insoluble matter is filtered and dichloromethane (20ml*2) is used Filter cake is washed, filtrate adjusts PH to 2 to 3 with the 20%HCl aqueous solution (50ml*2), and sodium hydroxide (3g-5g) is added at 0-20 DEG C PH10 to 12 is adjusted, then water (100ml*2) washes layering, 40 DEG C of removal of solvent under reduced pressure after organic layer is dried, 60 DEG C of vacuum drying 2 are small When, obtain bright yellow solid 27.4g, yield：75.7%, mp:179~179.5 DEG C, ESI-MS m/z:274[M+H]+,296[M +Na]+
2) N- (4- isobutoxies benzyl)-N- (4- methoxyl groups) benzylamine
N- (4- hydroxybenzyls)-N- (4- dimethoxys) benzylamines (15g) are dissolved in absolute ethyl alcohol (135ml) at room temperature In, Ran Hou<30 DEG C are added portionwise Anhydrous potassium carbonate (21g), and the suspension are heated into 78 DEG C to 82 DEG C.In 78 DEG C to 82 DEG C isobutane bromide (21g) is added drop-wise in suspension with 2 hours.After addition terminates, the mixture is stirred at 78 DEG C -82 DEG C Mix 24 hours, surplus stock is detected by TLC.After the completion of reaction, suspension is cooled to 20 DEG C to 30 DEG C, carry out suction filtration with except Excessive sylvite is removed, filter cake is washed with dichloromethane (30ml × 2).Dimethylformamide is recovered under reduced pressure.Residue ethanol (30ml) dilutes, and is then poured into water (150ml), filters the solid separated out, and solid adds 5%NaOH (50ml × 2) washings, then Washed with water (50ml × 2), be dried in vacuo 5 hours by solid suction filtration and at 60 DEG C, obtain buff powder (6.9g), yield： 50.1%, mp:122~124 DEG C, ESI-MS m/z:330[M+H]+,352[M+Na]+
3) 4- isobutoxies benzylamine
N- (4- isobutoxies benzyl)-N- (4- methoxyl groups) benzylamine 6g is dissolved in dichloromethane (60ml) in room temperature, Then at -25-0 DEG C, trifluoroacetic acid (48ml) is added dropwise in solution, goes to and is stirred at room temperature 5 hours after being added dropwise to complete, use TLC Detect starting material left.After the completion of reaction, solution PH is adjusted to alkalescence at 0-25 DEG C, and layering, 30 DEG C are washed with water (20ml*2) It is concentrated under reduced pressure, obtains oily amino bases 3.4g, yield 77%, ESI-MS m/z:180[M+H]+, 202 [M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (15g) oily liquids for sloughing protection group is dissolved in dichloromethane (120ml) in room temperature, Then addition Anhydrous potassium carbonate (34g), 0 DEG C to 10 DEG C is cooled to by suspension, and 0 DEG C to 10 DEG C with 1 hour by chloro-carbonic acid Phenyl ester (23.5g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 1 hour, is led to Cross TLC detection starting material lefts.After reaction terminates, inorganic salts are removed by filtration, filter cake is washed with DCM (30ml*2), filtrate uses 10% HCl (100ml*2) is washed, and layering obtains organic layer and washed with water (100ml*2), and after drying, 30 DEG C are recovered under reduced pressure solvent, obtain To white solid (30g) crude product, add methanol (50ml) and be heated to flowing back about 0.5 hour and all dissolved to solid.With about 1 hour The solution is cooled to 10 DEG C and 5 hours are stood.Product is filtered, and filter cake is washed with cold methanol (20ml*2).It is true in 60 DEG C Sky is dried 2 hours, obtains 21.3g white solid sterlings, yield 85%, mp:98.2~99.5 DEG C, ESI-MS m/z:300[M+ H]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (10g) and N- (4- luorobenzyls) -1- methyl -4- piperazines Pyridine amine (7g) is dissolved in ethanol (50ml), is heated to flowing back and is stirred 8 hours, and surplus stock N- (4- fluorine benzyls are detected with TLC Base) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is different is produced Butoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (2.25g) was added to the ethanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled to 30 DEG C to 35 DEG C, product is about 34 DEG C of crystallizations, the suspension is stirred 30 minutes, be then cooled to 0 DEG C with 1 hour and stand 5 hours at this temperature. The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Crude product, wet product is obtained to be heated to absolute ethyl alcohol (80ml) Flow back and stir 2 hours, solution is then cooled to 25 DEG C to 30 DEG C with 1 hour, 3 hours are stood in this temperature.Filter the production Thing, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (13g), yield 82.8%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR (400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5Hz, 2H, CH2),4.02(s,1H, ), CH 3.70 (d, J=6.5Hz, 2H, CH2), 2.98 (d, J=11.1Hz, 2H, CH2),2.56–2.46(m,1H,NH),2.41– 2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6Hz, 2H, CH2), 1.73 (q, J=12.3Hz, 2H, CH2),1.51(d,J =11.4Hz, 2H, CH2), 0.97 (d, J=6.7Hz, 6H, CH3)；13C NMR(400MHz,CDCl3)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 13, blocking group is made with benzyl
1) N- (4- hydroxybenzyls) benzylamine
4- hydroxy benzylamines (10g) and sodium acid carbonate (20g) are added to stirring in dichloromethane (100ml) in room temperature, 0 DEG C to 20 DEG C was added drop-wise to cylite (34.8g) in suspension with 1 hour.After addition terminates, by the mixture at 20 DEG C to 25 DEG C stirring 5 hours, with TLC detect starting material left.After the completion of reaction, carry out suction filtration to remove excessive sodium salt.Use chloromethanes (50ml × 2) wash filter cake.Filtrate is washed with 5% watery hydrochloric acid (20ml × 2), then washs layering, organic layer with water (70ml × 2) Dry.60 DEG C are recovered under reduced pressure solvent, and residue adds toluene (100ml) and is heated to 80 DEG C of stirring and dissolvings, is cooled to 20 DEG C and puts Put 5 hours, 3h is dried in vacuo at 60 DEG C, obtain white solid 9.1g.Yield:73.3%, mp:99~100 DEG C, ESI-MS m/z:214[M+H]+,236[M+Na]+
2) N- (4- isobutoxies benzyl) benzylamine
N- (4- hydroxybenzyls) benzylamines (15g) are dissolved in dimethylformamide (150ml) in room temperature, Ran Hou<30 DEG C diazabicylo (DBU, 29g) is added portionwise, and the suspension is heated to 78 DEG C to 82 DEG C.It is small with 2 in 78 DEG C to 82 DEG C When isobutane bromide (29g) is added drop-wise in suspension.After addition terminates, the mixture is stirred 36 hours at 78 DEG C -82 DEG C, Surplus stock is detected by TLC.After the completion of reaction, dimethylformamide is recovered under reduced pressure.Residue is dilute with dichloromethane (30ml) Release, washed respectively with 5% watery hydrochloric acid (100ml × 2), water (30ml × 2) washing, 5%NaOH (50ml × 2) washing dichloromethane Solution, then layering is washed with water (30ml × 2), water layer discarded, solvent is recovered under reduced pressure at 50-60 DEG C, and residual solid adds second Alcohol (40ml) is heated to being cooled to room temperature after 60 DEG C of stirrings, solid dissolving and stands 10 hours, and crystal is filtered and cold isopropyl is used Ether (10ml × 2) washs filter cake, and 60 DEG C are dried in vacuo 5 hours, obtain buff powder (12.5g), yield：70.8%, mp:71 ~73 DEG C, ESI-MS m/z:280[M+H]+,302[M+Na]+
3) 4- isobutoxies benzylamine
N- (4- isobutoxies benzyl) benzylamine 8g and 5%Pd-C (0.5g) are added in ethanol (60ml) with room temperature and stirred, Hydrogen is passed through at room temperature and is stirred 5 hours, and starting material left is detected with TLC.Palladium carbon is recovered by filtration after the completion of reaction, solvent is subtracted Receipts are pushed back, free alkali 5.1g, yield 78%, ESI-MS m/z is obtained:180[M+H]+,202[M+Na]+
4) N- (4- isobutoxies benzyl) phenyl carbamate
4- isobutoxies benzylamine (30g) oily liquids for sloughing protection group is dissolved in dichloromethane (120ml) in room temperature, Then addition Anhydrous potassium carbonate (34g), 0 DEG C to 10 DEG C is cooled to by suspension, and 0 DEG C to 10 DEG C with 1 hour by chloro-carbonic acid Phenyl ester (31g) is added drop-wise in the suspension.After addition terminates, the mixture is moved at 20 DEG C to 25 DEG C and stirred 1 hour, is passed through TLC detects starting material left.After reaction terminates, inorganic salts are removed by filtration, filter cake is washed with DCM (30ml*2), filtrate uses 10%HCl (100ml*2) is washed, and layering obtains organic layer and washed with water (100ml*2), and after drying, 30 DEG C are recovered under reduced pressure solvent, obtain White solid (45g) crude product, adds methanol (180ml) and is heated to flowing back about 0.5 hour and all dissolved to solid.With about 1 hour The solution is cooled to 10 DEG C and 5 hours are stood.Product is filtered, and filter cake is washed with cold methanol (20ml*2).It is true in 60 DEG C Sky is dried 2 hours, obtains 38g white solid sterlings, yield 76%, mp:98.5~99.2 DEG C, ESI-MS m/z:300[M+H ]+,322[M+Na]+.
5) N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea
In room temperature by N- (4- isobutoxies benzyl) phenyl carbamates (20g) and N- (4- luorobenzyls) -1- methyl -4- piperazines Pyridine amine (13.5g) is dissolved in ethanol (100ml), is heated to flowing back and is stirred 3 hours, and surplus stock N- (4- fluorine is detected with TLC Benzyl) -1- methyl -4- piperidinamines.After reaction terminates, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- is produced Isobutoxy benzyl) urea alcoholic solution.
6) tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Prepare
Tartaric acid solid (4.5g) was added to the ethanol solution prepared in embodiment 5 at 40 DEG C to 45 DEG C with 30 minutes In (yield 100%, in terms of piperidinamine), stirred 2 hours under the temperature, the solution is cooled to 30 DEG C to 35 DEG C, product is about 34 DEG C of crystallizations, the suspension is stirred 30 minutes, be then cooled to 0 DEG C with 1 hour and stand 5 hours at this temperature. The product is filtered, and filter cake is washed with cold ethanol (20ml*2).Obtain crude product, wet product absolute ethyl alcohol (150ml) heating To flowing back and stirring 2 hours, solution is then cooled to 25 DEG C to 30 DEG C with 1 hour, 3 hours are stood in this temperature.Filtering should Product, and filter cake is washed with cold ethanol (20ml*2).It is dried in vacuo 8 hours at 45 DEG C, obtains white solid sterling (27.8g), Yield 84.8%, mp:135.5-137.5 DEG C (133-135 DEG C of document), ESI-MS m/z:428[M+H]+,450[M+Na]+；1H NMR(400MHz,CDCl3) δ 7.25 (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, CH2), 4.19 (d, J=5.5 Hz, 2H, CH2),4.02 (s, 1H, CH), 3.70 (d, J=6.5 Hz, 2H, CH2), 2.98 (d, J=11.1 Hz, 2H, CH2),2.56–2.46(m,1H, NH),2.41–2.29(m,4H,CH2), 1.99 (dp, J=13.3,6.6 Hz, 2H, CH2), 1.73 (q, J=12.3 Hz, 2H, CH2), 1.51 (d, J=11.4 Hz, 2H, CH2), 0.97 (d, J=6.7 Hz, 6H, CH3)；13C NMR(400 MHz,CDCl3)δ 174.99,162.58,160.18,157.95,137.27,133.44,128.86,128.78,128.63,115.35,115.14, 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。

Claims (14)

1. a kind of tartrate of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Synthetic method, it is characterised in that：Using 4- hydroxy benzylamines as raw material, obtain N-protected base -4- hydroxy benzylamines by amido protecting, pass through again Alkylation reaction obtains N-protected base -4- isobutoxy benzylamines, then by the obtained 4- isobutoxy benzylamines of deprotection reaction, then with Phenyl chloroformate reaction be made N- (4- isobutoxies benzyl) phenyl carbamate, finally by with N- (4- luorobenzyls) -1- first N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) is made in the ammonolysis reaction of base -4- piperidinamines Urea, with tartaric acid, obtains N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Tartrate, described protection group is benzyloxycarbonyl group, tablet held before the breast by officials methoxycarbonyl group, tertbutyloxycarbonyl, trimethylsilyl ethoxycarbonyl, methoxy carbonyl Base, carbethoxyl group, formoxyl, acetyl group, p-toluenesulfonyl, trityl, 2,4- dimethoxy-benzyls, 4- methoxy-benzyls Or benzyl.
2. a kind of N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 Base) urea tartrate synthetic method, it is characterised in that comprise the following steps：
(1) the N-protected base -4- hydroxy benzylamines described in formula II：
Using 4- hydroxy benzylamine as raw material, protection processing is carried out to amino through overprotection reagent and is made,
Described protection reagent is benzyl chloroformate, fluorenes methoxycarbonyl chlorine, di-tert-butyl dicarbonate, 2,2,2- trimethyl silicane ethoxies Formyl chloride, ethyl chloroformate, methylchloroformate, acetic formic anhydride, acetic anhydride, paratoluensulfonyl chloride, triphenylchloromethane, 2,4- diformazans Epoxide benzaldehyde, 2,4- dimethoxy-benzyls chlorine, 4-methoxybenzaldehyde, 4- methoxy-benzyls chlorine, benzyl chloride or bromobenzyl；
(2) the N-protected base -4- isobutoxy benzylamines shown in formula III：
N-protected base -4- hydroxy benzylamines carry out alkylation reaction with isobutane bromide and are made；
(3) the 4- isobutoxy benzylamines described in formula IV：
N-protected base -4- isobutoxy benzylamines, slough amino protecting group and are made；
(4) N- (4- isobutoxies benzyl) phenyl carbamate described in formula V：
N-protected base -4- isobutoxy benzylamines, are made after amino Deprotection, with phenyl chloroformate reaction；
(5) N- described in formula VII (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea Tartrate：
N- (4- isobutoxies benzyl) phenyl carbamate is logical with another intermediate N (4- luorobenzyls) -1- methyl -4- piperidinamines Ammonolysis reaction is crossed, is made with tartaric acid；
Wherein, in step (1) and (2), X is benzyloxycarbonyl group, tablet held before the breast by officials methoxycarbonyl group, tertbutyloxycarbonyl, trimethylsilyl ethoxycarbonyl, first Oxygen carbonyl, carbethoxyl group, formoxyl, acetyl group, p-toluenesulfonyl, trityl, 2,4- dimethoxy-benzyls, 4- methoxyl groups Benzyl or benzyl.
The synthetic method of 3.N- (4- isobutoxies benzyl) phenyl carbamate, it is characterised in that using 4- hydroxy benzylamines as raw material, By amido protecting handle N-protected base -4- hydroxy benzylamines, carry out again with isobutane bromide alkylation reaction be made N-protected base - 4- isobutoxy benzylamines, then through amino be deprotected 4- isobutoxies benzylamine, again with phenyl chloroformate react be made.
4. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method or claim 3 described in N- (4- isobutoxies benzyl) phenyl carbamate conjunction Into method, it is characterised in that protection reagent is ethyl chloroformate.
5. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method or claim 3 described in N- (4- isobutoxies benzyl) phenyl carbamate conjunction Into method, it is characterised in that described N-protected base -4- hydroxy benzylamines are prepared via a method which：By 4- hydroxy benzylamines, protection Reagent, acid binding agent, according to mol ratio 1:(1.1-2.5):(1.2-3) is added in solvent, -25~60 DEG C of reaction 0.5-24h, is obtained Obtain N-protected base -1- (4- hydroxybenzyls) amine；Described solvent be dichloromethane, dioxane, tetrahydrofuran, toluene, acetonitrile, The mixed solvent of chloroform or each solvent and water, acid binding agent is sodium acid carbonate, saleratus, triethylamine.
6. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method or claim 3 described in N- (4- isobutoxies benzyl) phenyl carbamate conjunction Into method, it is characterised in that described N-protected base -4- hydroxy benzylamines are prepared via a method which：By 4- hydroxy benzylamines, protection Reagent, acid binding agent：Mol ratio is 1:(1.1-1.2):1.5 are added in solvent, 0~25 DEG C of reaction 0.5-24h, obtain N-protected Base -1- (4- hydroxybenzyls) amine；Described solvent is dichloromethane；Acid binding agent is sodium acid carbonate.
7. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method or claim 3 described in N- (4- isobutoxies benzyl) phenyl carbamate conjunction Into method, it is characterised in that N-protected base -4- isobutoxy benzylamines are prepared via a method which：
By N-protected base -4- hydroxy benzylamines, isobutane bromide and acid binding agent according to mol ratio 1:(1.2-3):(1.2-3), is added In solvent, 12-36h is reacted at 50~82 DEG C, after reaction terminates, solvent is washed with buck, discards water layer, sloughs solvent, N- is made Protection group -4- isobutoxy benzylamines；Described solvent is：DMF, DMA, ethanol, acetonitrile, tetrahydrofuran；Acid binding agent is anhydrous carbon Sour sodium, Anhydrous potassium carbonate, DBU.
8. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method or claim 3 described in N- (4- isobutoxies benzyl) phenyl carbamate conjunction Into method, it is characterised in that by N-protected base -4- hydroxy benzylamines, isobutane bromide and acid binding agent according to mol ratio 1:(1.2- 1.5):(1.5-2), is added in solvent, 12-36h is reacted at 55~82 DEG C, after reaction terminates, solvent is washed with buck, discards water Layer, sloughs solvent, and N-protected base -4- isobutoxy benzylamines are made；Described solvent is DMF；Acid binding agent is Anhydrous potassium carbonate.
9. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method or claim 3 described in N- (4- isobutoxies benzyl) phenyl carbamate conjunction Into method, it is characterised in that 4- isobutoxy benzylamines are prepared via a method which：
By N- amino protecting groups -1- (4- isobutoxies benzyl) amine and deprotecting regent according to mol ratio 1:(3-10), is added molten In agent, 3-8h is reacted at -25~80 DEG C, 4- isobutoxy benzylamines are made, described solvent is methanol, ethanol, isopropanol, DMF, Dichloromethane；Deprotecting regent is sodium hydroxide, potassium hydroxide, sodium methoxide, caustic alcohol, hydrazine hydrate, trifluoroacetic acid, hydrochloric acid.
10. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method or claim 3 described in N- (4- isobutoxies benzyl) phenyl carbamate conjunction Into method, it is characterised in that N- amino protecting groups -1- (4- isobutoxies benzyl) amine is with deprotecting regent according to mol ratio 1: (3-4), adds in solvent, 3-8h is reacted at 50~80 DEG C, and 4- isobutoxy benzylamines are made, and described solvent is ethanol；It is described Deprotecting regent is potassium hydroxide or trifluoroacetic acid.
11. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method or claim 3 described in N- (4- isobutoxies benzyl) phenyl carbamate conjunction Into method, it is characterised in that N- (4- isobutoxies benzyl) phenyl carbamate is prepared via a method which：
By 4- isobutoxies benzylamine, phenyl chloroformate and acid binding agent according to mol ratio 1:(1.1-2):(1.2-3) adds solvent In, 0.5-3h is reacted at -25~60 DEG C, after reaction terminates, solvent is sloughed, residue is washed, solid suction filtration, N- is made, and (4- is different Butoxy benzyl) phenyl carbamate, described solvent is dichloromethane, dioxane, tetrahydrofuran, toluene, methanol, second Alcohol, isopropanol, acetonitrile；Acid binding agent is triethylamine, sodium acid carbonate, saleratus, natrium carbonicum calcinatum, Anhydrous potassium carbonate, hydroxide Sodium, potassium hydroxide.
12. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method or claim 3 described in N- (4- isobutoxies benzyl) phenyl carbamate conjunction Into method, it is characterised in that by 4- isobutoxies benzylamine, phenyl chloroformate and acid binding agent according to mol ratio 1:(1.1-2): (1.2-3) is added in solvent, and 0.5-3h is reacted at -25~60 DEG C, after reaction terminates, and sloughs solvent, and residue washing, solid is taken out Filter, is made N- (4- isobutoxies benzyl) phenyl carbamate, and the solvent is dichloromethane, and acid binding agent is Anhydrous potassium carbonate.
13. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method, it is characterised in that N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- Isobutoxy benzyl) tartrate of urea is prepared via a method which：
By N- (4- luorobenzyls) -1- methyl -4- piperidinamines, N- (4- isobutoxies benzyl) phenyl carbamates and tartaric acid according to Mol ratio 1:(1.1-1.5):(0.5-1), above-mentioned piperidinamine and phenyl carbamate are added in solvent, 25~100 DEG C of reactions 3-12h, after reaction terminates, temperature is down to 40 DEG C, and tartaric acid solid is added at this temperature and is stirred 2 hours, reaction stops and is down to Described N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxies benzyl) urea is made in room temperature crystallization, suction filtration Tartrate；
The solvent is absolute methanol, absolute ethyl alcohol, isopropanol, toluene or acetonitrile.
14. N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- isobutoxy benzyls as claimed in claim 1 or 2 Base) urea tartrate synthetic method, it is characterised in that N- (4- luorobenzyls)-N- (1- methyl piperidine -4- bases)-N '-(4- Isobutoxy benzyl) tartrate of urea is prepared via a method which：
By N- (4- luorobenzyls) -1- methyl -4- piperidinamines, N- (4- isobutoxies benzyl) phenyl carbamates and tartaric acid according to Mol ratio 1:(1.2-1.3):(0.5-0.52), above-mentioned piperidinamine and phenyl carbamate are added in solvent, and temperature is 65~ 78 DEG C of reaction 3-12h, after reaction terminates, temperature is down to 40 DEG C, and tartaric acid solid is added at this temperature and is stirred 2 hours, reaction stops Only and it is down to room temperature crystallization, N- (4- luorobenzyls)-N- (1- methyl piperidine -4- the bases)-N '-(4- isobutoxies is made in suction filtration Benzyl) urea tartrate；The solvent is absolute ethyl alcohol.
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