CN106748971B - A kind of 1- methyl -3-(piperidin-4-yl) urea hydrochloride synthetic method - Google Patents

A kind of 1- methyl -3-(piperidin-4-yl) urea hydrochloride synthetic method Download PDF

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CN106748971B
CN106748971B CN201611140228.6A CN201611140228A CN106748971B CN 106748971 B CN106748971 B CN 106748971B CN 201611140228 A CN201611140228 A CN 201611140228A CN 106748971 B CN106748971 B CN 106748971B
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boc
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piperidin
urea
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CN106748971A (en
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王治国
李涛
李超
田贝贝
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SHANGHAI ZAIQI BIO-TECHNOLOGY CO LTD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/58—Nitrogen atoms attached in position 4

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Abstract

The present invention relates to a kind of synthetic methods of 1- methyl -3- (piperidin-4-yl) urea hydrochloride, and wherein the synthetic method generates N-Boc-4- [(methoxy acyl group) amino] piperidines comprising steps of (1) reacts N-Boc-4- amino piperidine with methylchloroformate in a solvent in the presence of an organic base；(2) N-Boc-4- made from step (1) [(methoxy acyl group) amino] piperidines is reacted in a solvent in the presence of an organic base with methylamine and generates 1- methyl -3- (N-Boc- piperidin-4-yl) urea；(3) it reacts 1- methyl -3- (N-Boc- piperidin-4-yl) urea made from step (2) to obtain final products 1- methyl -3- (piperidin-4-yl) urea hydrochloride in a solvent with chloroacetic chloride.Method raw material of the invention is easy to get, reaction condition is mild, and easily operated, total recovery is higher, and three-step reaction mole total recovery can reach 87% or more (in terms of raw material N-Boc-4- amino piperidine), is suitable for industrialized production.

Description

A kind of 1- methyl -3-(piperidin-4-yl) urea hydrochloride synthetic method
Technical field
The present invention relates to a kind of synthetic methods of 1- methyl -3- (piperidin-4-yl) urea hydrochloride, belong to organic chemical synthesis Technical field.
Background technique
1- methyl -3- (piperidin-4-yl) urea hydrochloride can be used for synthesizing a kind of peptide amide ligand of K opiate receptor.Contain The prevention and treatment of the drug pair of this peptide amide ligand pain relevant to various diseases and inflammation are effective.Such drug The pain for the treatment of mainly includes splanchnodynia, neuropathic pain and hyperalgia.Aspect of inflammation includes IBD and IBS, and E & E is scorching Disease, other diseases, such as pruitus, oedema, hyponatremia, hypopotassaemia, intestinal obstruction, cough and glaucoma use this medicine Object is all effective to prevent and treat.
Currently, the report of the synthetic method about 1- methyl -3- (piperidin-4-yl) urea hydrochloride is seldom.Bioorganic& Medicinal Chemistry Letters 11 (2001) 2475-2479, which is reported, uses N-Boc-4- piperidones for raw material, Reduction amination obtains N-Boc-4- amino piperidine under the action of sodium triacetoxy borohydride, in N, N- diisopropylamine and 4- It reacts to obtain 1- methyl -3- (N-Boc- piperidin-4-yl) urea with methyl isocyanate under the action of dimethylamino naphthyridine, finally uses salt Sour methanol or trifluoracetic acid take off Boc.But the raw material methyl isocyanate used in the method is inflammability toxic articles, and market is come Source is few, and the step reaction time is longer, is not suitable for industrialized production.
The report of Bioorganic&Medicinal Chemistry Letters 21 (2011) 983-988 is also to use N- Boc-4- piperidones is raw material, reacts to obtain N-Boc-4- (oxyimino) piperidines with hydroxylamine hydrochloride, and then Raney's nickel restores N-Boc-4- amino piperidine is obtained, synthesizes 1- methyl -3- (N-Boc- piperidin-4-yl) urea followed by two kinds of approach.It is a kind of Approach is that N-Boc-4- amino piperidine and methyl isocyanate react to obtain 1- methyl -3- (N-Boc- piperidin-4-yl) urea；It is another Approach is N-Boc-4- amino piperidine first and the reaction of 4- nitro phenyl chloroformate generates ester, then reacts in tetrahydrofuran with methylamine Reflux, obtains 1- methyl -3- (N-Boc- piperidin-4-yl) urea.Finally Boc is taken off with trifluoracetic acid again.Both methods synthesizes 1- The reaction time of this step of methyl -3- (N-Boc- piperidin-4-yl) urea is all long, and the raw materials used isocyanic acid first of first method Ester is toxic articles, is difficult to obtain, and second method generates ester higher cost, therefore both with 4- nitro phenyl chloroformate Method is not suitable for industrialized production.
Poor in view of the stability of 1- methyl -3- (piperidin-4-yl) urea at room temperature, people are often acidified, 1- methyl -3- (piperidin-4-yl) urea hydrochloride is made to be saved.The compound easy to absorb moisture, needs filling with inert gas to store.
Summary of the invention
The shortcomings that the purpose of the present invention is to overcome in the prior art and provide it is a kind of under mild conditions, efficiently and mistake The method that journey controllably synthesizes 1- methyl -3- (piperidin-4-yl) urea hydrochloride.
For achieving the above object, the present invention adopts the following technical scheme:
A kind of synthetic method of 1- methyl -3- (piperidin-4-yl) urea hydrochloride, wherein the synthetic method includes following step It is rapid:
(1) N-Boc-4- amino piperidine is reacted in a solvent in the presence of an organic base with methylchloroformate and generates N- Boc-4- [(methoxy acyl group) amino] piperidines；
(2) [(methoxy acyl group) amino] piperidines of N-Boc-4- made from step (1) and methylamine are existed in the presence of an organic base Reaction generates 1- methyl -3- (N-Boc- piperidin-4-yl) urea in solvent；
(3) 1- methyl -3- (N-Boc- piperidin-4-yl) urea made from step (2) is reacted in a solvent with chloroacetic chloride To final products 1- methyl -3- (piperidin-4-yl) urea hydrochloride.
In a preferred embodiment of the invention, the organic base in step (1) is triethylamine.
In a preferred embodiment of the invention, the organic base in step (2) is triethylamine.
In a preferred embodiment of the invention, solvent described in step (1) is methylene chloride, and the reaction exists 1-4 hour is carried out at 15-35 DEG C, it is highly preferred that the reaction carries out 2 hours at 25 DEG C.
In a preferred embodiment of the invention, N-Boc-4- amino piperidine, methylchloroformate and have in step (1) The molar ratio of machine alkali is 1:1~1.5:3~3.5, it is highly preferred that N-Boc-4- amino piperidine, methylchloroformate and organic base Molar ratio is about 1:1.1:3.1.
In a preferred embodiment of the invention, solvent described in step (2) is methylene chloride, and the organic base exists After being added in the solution of N-Boc-4- [(methoxy acyl group) amino] piperidines and methylamine at 0~5 DEG C, reaction is at 0-10 DEG C in nitrogen Atmosphere encloses 3-6 hour of middle progress, it is highly preferred that the reaction carries out 4 hours in nitrogen atmosphere at 5 DEG C.
In a preferred embodiment of the invention, N-Boc-4- [(methoxy acyl group) amino] piperidines, first in step (2) The molar ratio of amine and organic base is 1:1.1~1.5:2.3~2.6, it is highly preferred that N-Boc-4- [(methoxy acyl group) amino] piperazine The molar ratio of pyridine, methylamine and organic base is 1:1.2:2.4.
In a preferred embodiment of the invention, step (2) further comprises with ethyl alcohol and petroleum ether mixtures pair It reacts obtained 1- methyl -3- (N-Boc- piperidin-4-yl) urea to be recrystallized, filters out product, and with petroleum ether, 1- methyl -3- (N-Boc- piperidin-4-yl) urea of middle 1kg uses ethyl alcohol and petroleum ether mixtures (ethyl alcohol and petroleum of 2-3L The volume ratio of ether is 1:6~8) it is recrystallized.
In a preferred embodiment of the invention, solvent described in step (3) is methanol or ethyl alcohol, and chloroacetic chloride is molten It stirs 1-3 hour in agent at 10-25 DEG C in nitrogen atmosphere, adds 1- methyl -3- (N-Boc- piperidin-4-yl) urea, Reaction carries out 1-3 hour at 35-50 DEG C again, it is highly preferred that chloroacetic chloride stirs at 25 DEG C in nitrogen atmosphere in a solvent 1 hour is mixed, 1- methyl -3- (N-Boc- piperidin-4-yl) urea is added, reaction carries out 2 hours at 37-41 DEG C again.
In a preferred embodiment of the invention, in step (3) 1- methyl -3- (N-Boc- piperidin-4-yl) urea and The molar ratio of chloroacetic chloride is 1:4~4.5, it is highly preferred that mole of 1- methyl -3- (N-Boc- piperidin-4-yl) urea and chloroacetic chloride Than for 1:4.
In a preferred embodiment of the invention, step (3) further comprises by product 1- methyl -3- (piperidines -4- Base) urea hydrochloride recrystallized with ethyl acetate.In another more preferred of the invention, ethyl acetate is used The detailed process recrystallized are as follows: 1- methyl -3- (piperidin-4-yl) urea hydrochloride is added in ethyl acetate, is heated to 50- 70 DEG C stirring 20-40 minutes, be cooled to 20-30 DEG C, there is sticky solid precipitation, continue stirring 1 hour, be filtered to remove acetic acid second Ester is to get 1- methyl -3- (N-Boc- piperidin-4-yl) urea urea hydrochloric acid, wherein 1- methyl -3- (piperidin-4-yl) urea hydrochloric acid of 1kg Salt is recrystallized using the ethyl acetate of 2.5-3.5L.
Advantage of the invention is as follows:
(1) raw material is easy to get, and N-Boc-4- amino piperidine Commercial sources are wide, and the raw materials such as methylchloroformate and methylamine are also cheap easy ?.
(2) reaction condition is mild, and substantially reduces compared to the existing raw materials used toxicity of other synthetic methods.
(3) post-processing is simple, easily operated.
(4) total recovery is higher, and three-step reaction total moles yield can reach 87% or more (with raw material N-Boc-4- amino piperidine Molar amount), be suitable for industrialized production.
Specific embodiment
Below by embodiment, the present invention is described in further detail.
Specific synthetic route of the invention is as follows:
Embodiment 1
(1) by the N-Boc-4- amino piperidine of 2.0kg (about 10mol), 1.0kg (about 11mol) in suitable reaction kettle Methylchloroformate and the triethylamine of 3.1kg (about 31mol) be dissolved into 20L methylene chloride (N-Boc-4- amino piperidine, chloromethane The molar ratio of sour methyl esters and triethylamine is about 1:1.1:3.1), 25 DEG C are stirred 2 hours, and TLC tracking display raw material disappears.To reaction The water of 10L is added in liquid, separates organic layer, and water phase is extracted with methylene chloride (2 × 5L).Merge organic phase, successively with water (4L) and Saturated salt solution (4L) washing, then dried, filtered with the anhydrous sodium sulfate of 2kg, and concentration, obtain the N-Boc-4- of 2.64kg [(methoxy acyl group) amino] piperidines (LCMS [M+Na]+281.1), purity about 95%, about 9.7mol.The product is directly used in next Step reaction.
(2) by the N-Boc-4- of 2.64kg obtained above (about 9.7mol) [(methoxy acyl group) in suitable reaction kettle Amino] piperidines and 5.8L (about 11.6mol) methylamine (2M methanol solution) be dissolved into 8L methylene chloride (N-Boc-4- [(methoxy acyl Base) amino] molar ratio of piperidines and methylamine is about 1:1.2), which is cooled to 0 DEG C, 2.4 kg are added dropwise thereto (about Triethylamine (about 2.4eq) 23.3mol), maintenance system temperature is not higher than 5 DEG C during dropwise addition, and rear nitrogen displacement is added dropwise Twice, then at 0~5 DEG C it is stirred to react 4 hours, the reaction of thin-layer chromatography (method) (TLC) tracking display is completed.It is added into reaction solution 8L water stirs 10 minutes, separates organic layer, and water phase is extracted with methylene chloride (2X4L).Merge organic phase, successively with water (3L) and Saturated salt solution (3L) washing, is dried, filtered with 1.8kg anhydrous sodium sulfate, is evaporated methylene chloride and obtains white solid, is added 0.7L ethyl alcohol and the crystallization of 5L petroleum ether and stirring, filter out product, and with 12.5L petroleum ether, obtain the 1- first of 2.52kg Base -3- (N-Boc- piperidin-4-yl) urea (white solid), purity about 96%, about 9.4mol.
(3) 6L anhydrous methanol is added into reaction kettle, nitrogen is replaced twice, controls temperature less than 25 DEG C, chloroacetic chloride is added dropwise 3.0kg (about 37.6mol) (about 4eq) continues to be stirred liquid reaction 1 hour after being added dropwise to complete, then at room temperature at room temperature 1- methyl -3- (N-Boc- piperidin-4-yl) urea of 2.52kg obtained above (about 9.4mol) is added.Mixed liquor is warming up to 37 It~41 DEG C, reacts 2 hours, the reaction of TLC tracking display is completed.Reaction solution is down to room temperature, methanol is evaporated and obtains faint yellow oily Object will be added the ethyl acetate of 6L, be heated to 60 DEG C and stir 30 minutes, be cooled to room temperature, have faint yellow in light yellow oil Sticky solid be precipitated, continue cooling stirring 1 hour, be filtered to remove ethyl acetate to get to 1.80 kg (about 9.24mol) most Finished product 1- methyl -3- (piperidin-4-yl) urea hydrochloride (faint yellow solid).In terms of N-Boc-4- amino piperidine, the final production The molar yield of product is 92.4%, purity 99.6%.
Obtained final products 1- methyl -3- (piperidin-4-yl) urea hydrochloride is characterized as below:
1H NMR(400MHz,DMSO-d6) 1.52 (m, J=12.8,2H), 1.86 (m, J=4.53,2H), 2.52 (d, J =5.2,3H), 2.88 (m, J=11.2,2H), 3.18 (m, J=5.33,2H), 3.62 (m, J=4.64,1H), 9.06 (d, J= 5.2, 2H)。
Embodiment 2
(1) by the N-Boc-4- amino piperidine of 20.0kg (about 100mol), 12.3kg (about 130 in suitable reaction kettle Mol (about 330mol) triethylamine of methylchloroformate and 33.4kg) is dissolved into the methylene chloride of 100L (N-Boc-4- ammonia The molar ratio of phenylpiperidines, methylchloroformate and triethylamine is about 1:1.3:3.3), mixed liquor is stirred 3 hours at 20 DEG C, TLC Tracking display raw material disappears.100L water is added into reaction solution, separates organic layer, water phase is extracted with methylene chloride (2X50L). Merge organic phase, successively washed with water (40L) and saturated salt solution (40L), then dried, filtered with the anhydrous sodium sulfate of 20kg, It is concentrated to get N-Boc-4- [(methoxy acyl group) amino] piperidines (LCMS [M+Na] of 25.83kg+281.1), purity about 94%, About 94mol.The product is directly used in react in next step.
(2) by the N-Boc-4- of obtained 25.83kg (about 94mol) [(methoxy acyl group) amino] in suitable reaction kettle Piperidines and 61.1L (about 122.2mol) methylamine (2M methanol solution) are dissolved into 80L methylene chloride (N-Boc-4- [(methoxy acyl Base) amino] piperidines and methylamine molar ratio about 1:1.3), mixed liquor is cooled to 0 DEG C, then thereto be added dropwise 23.8kg (about Triethylamine (about 2.5eq) 235mol), maintenance system temperature is not higher than 5 DEG C during dropwise addition, and rear nitrogen displacement two is added dropwise It is secondary, it is stirred to react at 0~5 DEG C 5 hours, the reaction of thin-layer chromatography (method) (TLC) tracking display is completed.Then it is added into reaction solution 80L water stirs 10 minutes, separates organic layer, and water phase is extracted with methylene chloride (2 × 40L).Merge organic phase, successively uses water The washing of (35L) and saturated salt solution (35L), then dried, filtered with 15kg anhydrous sodium sulfate, it is evaporated methylene chloride and obtains white admittedly Body is added 7L ethyl alcohol and the crystallization of 50L petroleum ether and stirring, filters out product, and with 125L petroleum ether, obtains 24.38kg's 1- methyl -3- (N-Boc- piperidin-4-yl) urea (white solid), purity about 95%, about 90mol.
(3) 70L dehydrated alcohol is added into reaction flask, nitrogen is replaced twice, and control temperature is dripped less than 25 DEG C, then thereto Add the chloroacetic chloride (4.2eq) of 28.3kg (about 360mol), the reaction was continued at room temperature after being added dropwise to complete 2 hours.At room temperature to this 1- methyl -3- (N-Boc- piperidin-4-yl) urea of 24.38kg obtained above (about 90mol) is added in mixed liquor, by reaction solution 30~35 DEG C are warming up to, is stirred to react 2 hours, the reaction of thin-layer chromatography (method) (TLC) tracking display is completed.Reaction solution is down to room Temperature is evaporated methanol and obtains light yellow oil.The ethyl acetate of 60L will be added in light yellow oil, is heated to 60 DEG C of stirrings 30 minutes, it is cooled to room temperature, has faint yellow sticky solid to be precipitated, continues cooling stirring 1 hour, is filtered to remove ethyl acetate, obtains To 1- methyl -3- (piperidin-4-yl) the urea hydrochloride (faint yellow solid) of 17.13 (about 88.1mol) kg.With N-Boc-4- amino Piperidines meter, the molar yield of the final products are 88.1%, purity 99.6%.
Obtained final products 1- methyl -3- (piperidin-4-yl) urea hydrochloride is characterized as below:
1H NMR(400MHz,DMSO-d6) 1.54 (m, J=12.8,2H), 1.88 (m, J=4.53,2H), 2.55 (d, J= 5.2,3H), 2.90 (m, J=11.2,2H), 3.24 (m, J=5.33,2H), 3.65 (m, J=4.64,1H), 9.10 (d, J= 5.2,2H)。
Embodiment 3
(1) by N-Boc-4- amino piperidine, the 141.8kg of 200.0kg (1000mol) in suitable reaction kettle The triethylamine of the methylchloroformate and 303.6kg (3000mol) of (1500mol) is dissolved into (N-Boc- in 1200L methylene chloride The molar ratio of 4- amino piperidine, methylchloroformate and triethylamine is about 1:1.5:3.5), it stirs 3 hours at 25 DEG C, TLC tracking is aobvious Show that raw material disappears, 1000L water is added into reaction solution after the reaction was completed, separates organic layer, water phase methylene chloride (2X500L) extraction.Merge organic phase, successively washed with water (500L) and saturated salt solution (400L), then is with 250kg anhydrous Sodium sulphate dries, filters, and concentration obtains N-Boc-4- [(methoxy acyl group) amino] piperidines (LCMS [M+Na] of 250.23kg+ 281.1), purity about 96%, about 930mol.The product is directly used in react in next step.
(2) by N-Boc-4- [(the methoxy acyl of about 250.23kg (about 930mol) obtained above in suitable reaction kettle Base) amino] methylamine (2M methanol solution) of piperidines and 697.5L (about 1395mol) is dissolved to (N- in 1100L methylene chloride The molar ratio of Boc-4- [(methoxy acyl group) amino] piperidines and methylamine is 1:1.5), mixed liquor is cooled to 0 DEG C, then drip thereto Add 244.7kg (about 2418mol) triethylamine (2.6eq), maintenance system temperature is not higher than 5 DEG C, after being added dropwise during dropwise addition Nitrogen is replaced twice, is stirred to react at 5~10 DEG C 5 hours, and the reaction of thin-layer chromatography (method) (TLC) tracking display is completed.Then to 800L water is added in reaction solution, stirs 10 minutes, separates organic layer, water phase is extracted with methylene chloride (2X400L).Merge organic Phase is successively washed with water (400L) and saturated salt solution (300L), then is dried, filtered with 200kg anhydrous sodium sulfate, and dichloro is evaporated Methane obtains white solid, and 70L ethyl alcohol and the crystallization of 500L petroleum ether and stirring is added, filters out product, and washed with 1250L petroleum ether It washs, obtains 238.54kg1- methyl -3- (N-Boc- piperidin-4-yl) urea, purity about 96%, about 890mol.
(3) 600L anhydrous methanol is added into reaction flask, nitrogen is replaced twice, is controlled temperature less than 25 DEG C, is dripped thereto Add the chloroacetic chloride (4.5eq) of 314.4kg (about 4005mol), the reaction was continued at room temperature after being added dropwise to complete 3 hours, then in room temperature Lower 1- methyl -3- (N-Boc- piperidin-4-yl) urea that 238.54kg obtained above (about 890mol) is added into mixed liquor, Reaction solution is warming up to 42~46 DEG C, reacts 2 hours, is reacted and is completed using thin-layer chromatography (method) (TLC) tracking display.By reaction solution It is down to room temperature, methanol is evaporated and obtains light yellow oil.The ethyl acetate of 600L will be added in light yellow oil, is heated to 60 DEG C stirring 30 minutes, it is cooled to room temperature, has faint yellow sticky solid to be precipitated, continues cooling stirring 1 hour, is filtered to remove acetic acid second Ester obtains 1- methyl -3- (piperidin-4-yl) the urea hydrochloride (faint yellow solid) of 170.17kg (about 876mol).With N-Boc- 4- amino piperidine meter, the molar yield of the final products are 87.6%, purity 99.7%.
Obtained final products 1- methyl -3- (piperidin-4-yl) urea hydrochloride is characterized as below:
1H NMR (400MHz, DMSO-d6) 1.49 (m, J=12.8,2H), 1.82 (m, J=4.53,2H), 2.48 (d, J= 5.2,3H), 2.83 (m, J=11.2,2H), 3.15 (m, J=5.33,2H), 3.58 (m, J=4.64,1H), 8.99 (d, J= 5.2,2H)。
For those skilled in the art, on the basis of the above description of the embodiment, the general technology people of this field Member can make following modification or adjustment, equally be able to achieve the purpose of the present invention.It is only a preferred and feasible embodiment of the present invention, It cannot therefore be that limiting the scope of the invention uses skill of the invention for those skilled in the art such as Art scheme and technical principle make other corresponding changes and modifications, and these change and modification used should all belong in present invention power Within the protection scope that benefit requires.

Claims (10)

1. a kind of synthetic method of 1- methyl -3- (piperidin-4-yl) urea hydrochloride, wherein the synthetic method the following steps are included:
(1) N-Boc-4- amino piperidine is reacted in a solvent in the presence of an organic base with methylchloroformate and generates N-Boc-4- [(methoxy acyl group) amino] piperidines；
(2) by [(methoxy acyl group) amino] piperidines of N-Boc-4- made from step (1) and methylamine in the presence of an organic base in solvent Middle reaction generates 1- methyl -3- (N-Boc- piperidin-4-yl) urea；
(3) 1- methyl -3- (N-Boc- piperidin-4-yl) urea made from step (2) is reacted to obtain most in a solvent with chloroacetic chloride Finished product 1- methyl -3- (piperidin-4-yl) urea hydrochloride,
Wherein solvent described in step (3) is methanol or ethyl alcohol.
2. synthetic method according to claim 1, wherein the organic base in step (1) is triethylamine.
3. synthetic method according to claim 1, wherein the organic base in step (2) is triethylamine.
4. synthetic method according to claim 1, wherein solvent described in step (1) is methylene chloride, the reaction exists 1-4 hour is carried out at 15-35 DEG C.
5. synthetic method according to claim 1, wherein N-Boc-4- amino piperidine in step (1), methylchloroformate and The molar ratio of organic base is 1:1~1.5:3~3.5.
6. synthetic method according to claim 1, wherein solvent described in step (2) is methylene chloride, the organic base After being added at 0~5 DEG C in the solution of N-Boc-4- [(methoxy acyl group) amino] piperidines and methylamine, reaction at 0-10 DEG C 3-6 hour is carried out in nitrogen atmosphere.
7. synthetic method according to claim 1, wherein N-Boc-4- [(methoxy acyl group) amino] piperidines in step (2), The molar ratio of methylamine and organic base is 1:1.1~1.5:2.3~2.6.
8. synthetic method according to claim 1, wherein in step (3) chloroacetic chloride in a solvent in nitrogen atmosphere Stir 1-3 hour at 10-25 DEG C, add 1- methyl -3- (N-Boc- piperidin-4-yl) urea, react again at 35-50 DEG C into 1-3 hour of row.
9. synthetic method according to claim 1, wherein in step (3) 1- methyl -3- (N-Boc- piperidin-4-yl) urea and The molar ratio of chloroacetic chloride is 1:4~4.5.
10. synthetic method according to claim 1, wherein step (3) further comprises by product 1- methyl -3- (piperidines - 4- yl) urea hydrochloride recrystallized with ethyl acetate.
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Inventor after: Wang Zhiguo

Inventor after: Li Tao

Inventor after: Li Chao

Inventor after: Tian Beibei

Inventor after: Li Min

Inventor after: Shi Qiuyan

Inventor before: Wang Zhiguo

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