CN102936215B - Synthesizing method for 2-sulfydryl-N-(6-(3-arylurea) hexyl) amide - Google Patents
Synthesizing method for 2-sulfydryl-N-(6-(3-arylurea) hexyl) amide Download PDFInfo
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Abstract
The invention provides a synthesizing method for 2-sulfydryl-N-(6-(3-arylurea) hexyl) amide. The method includes: dissolving 1,6-hexamethylenediamine and di-tert-butyl dicarbonate in an inert solvent to conduct an amino protection reaction to obtain 6-amino hexyl carbamic acid tert-butyl ester; then conducting a condensation reaction with aromatic isocyanate in a dry inert solvent to obtain 6-(3-arylurea hexyl) carbamic acidtert-butyl ester; then leading HCI gas into ethyl acetate to conduct a deamination protective reaction to obtain 1-(6-amino hexyl)-3-arylurea hydrochloride; dissolving 1-(6-amino hexyl)-3-arylurea hydrochloride, an acid-binding agent and acyl chloride in an inert solvent to conduct an acylation reaction to obtain 2-chlorine-N-(6-(3-acrylurea) hexyl) amide; and then dissolving 2-chlorine-N-(6-(3-acrylurea) hexyl) amide and a vulcanizing reagent in a polar solvent, and conducting a sulfhydrylation reaction to obtain the 2-sulfydryl-N-(6-(3-arylurea) hexyl) amide. The synthesizing method solves the problems in the prior art that synthesizing conditions of the existing histone deacetylase inhibitor 2-sulfydryl-N-(6-(3-phenylurea) hexyl) acetamide are harsh, raw material cost is high, and yield is low.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, particularly the synthetic method of a kind of 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) acid amides.
Background technology
Histon deacetylase (HDAC) (histone deacetylase, HDAC) is a proteinoid enzyme, and chromosomal structural modification and gene expression regulation are played an important role.Generally, the acetylize of histone is conducive to dissociating of DNA and octameric histone, and nucleosomal structure is lax, thus make various transcription factors and collaborative transcription factor can with DNA binding site specific binding, the transcribing of activated gene.In nucleus, acetylation of histone and DNA methylase inhibitor process be in running balance, and jointly regulated and controled by acetylation of histone transferring enzyme (histone acetyltransferase, HAT) and histon deacetylase (HDAC).The acetylation of histone transferring enzyme is transferred to the ethanoyl of acetyl-CoA on the specific lysine residue of histone N-terminal; histon deacetylase (HDAC) makes DNA methylase inhibitor; with electronegative DNA, combine closely, the chromatin densification is curling, and transcribing of gene is suppressed.In cancer cells, the overexpression of histon deacetylase (HDAC) causes the enhancing of acetylizing, by recovering the histone positive charge; thereby increase the gravitation between DNA and histone; make lax nucleosome become very tight, be unfavorable for the expression of specific gene, comprise some tumor suppressor genes.NSC 630176 (histone deacetylase inhibitors; HDACi) can be by improving chromatin specific region acetylation of histone; thereby expression and the stability of regulating cell apoptosis and differentiation associated protein; cell death inducing and differentiation, become the antitumor drug that a class is new.In the design of such drug molecule, synthetic and bioactive research, about the existing relevant report of synthetic and bioactivity research of 2-Mercaptoamides and N-oxyamide compounds.Wherein, 2-Mercaptoamides compounds be take again 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide and is widely studied as representative.
2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide, English 2-mercapto-N-(6-(3-phenylureido) hexyl) acetamide by name, its structural formula is as follows:
About the existing relevant report of the biological activity of 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide, Kozikowski in 2005 etc. confirm that 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide has good restraining effect to Laryngeal Cancer cell (SQ-20B), its IC after deliberation
50value is 50uM(WO2005/007091).In the same year, these compounds of use such as Chen B have carried out the in vitro tests that fluorine Methionin is made matrix, and its 50%HDAC inhibition concentration is 0.63uM(Chen B., Petukhov P.A., Jung M.et al.Bioorganic& Medicinal Chemistry Letters.2005,15,1389-1392).These compounds of utilization such as Kozikowski in 2007 have carried out the protection test research of crust neurocyte, and result shows that the Determination of oil-water partition coefficient of this compound is 2.04, suppresses the IC of HDAC1, HDAC2, HDAC6, HDAC8 and HDAC10
50value be respectively 10800 ± 1800nM,>30000nM, 2010 ± 60nM, 13900 ± 600nM,>30000nM(Kozikowski A.P.; Chen Y.F.; Gaysin A.et al.J.Med.Chem.2007; 50; 3054-3061), illustrate that 2-sulfydryl-N-(6-(3-phenylurea) hexyl) external cutaneous nerve cell of ethanamide has good provide protection.
About synthesizing of 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide, the identical synthetic method of the successively having reported for work (WO2005/007091 such as Kozikowski, Chen, Tang, Rivieccio; US20050032831; Proceedings of the National Academy of Sciences of the United States of America, 2009,106 (46), 19599-19604; CHEMMEDCHEM.2009,4,842-852; Journal of Chemical Information and Modeling.2009,49 (2), 461-476; J.Med.Chem.2007,50,3054-3061; Bioorganic& Medicinal Chemistry Letters.2005,15,1389-1392).Take Methyl Thioglycolate as raw material, take chloroform as solvent, under the trifluoroacetic acid katalysis, with the triphenylcarbinol effect, make triphenyl methylthio group acetic acid methyl esters; Triphenyl methylthio group acetic acid methyl esters and 1,6-hexanediamine are carried out to acylation reaction and obtain N-(the amino hexyl of 6-)-2-triphenyl methylmercaptan ethyl acid amides; N-(the amino hexyl of 6-)-2-triphenyl methylmercaptan ethyl acid amides is obtained to N-(6-(3-phenylurea) hexyl)-2-triphenyl methylmercaptan ethyl acid amides with the effect of benzene isocyanide ester in methylene dichloride; Finally, in dichloromethane solvent, N-(6-(3-phenylurea) hexyl)-2-triphenyl methylmercaptan ethyl acid amides is reacted to deprotection obtain 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide with trifluoroacetic acid and triethyl silicane.Synthetic route is as follows:
In the synthetic method of above-mentioned bibliographical information, there are several point defects, severe reaction conditions at first, the second step acylation reaction need be heated to 100 ℃, the difficulty of aftertreatment simultaneously; Secondly, raw materials cost is high, and expensive raw material price such as triphenylcarbinol, triethyl silicane, and the protecting group trityl group finally will slough are failed fine embodiment Atom economy; Finally, second step acylation reaction yield is lower, only has 29%.The synthetic total recovery of 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide is low, is only 16%.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of NSC 630176 derivative 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) acid amides; to solve 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide synthesis condition harshness in prior art; raw materials cost is high, the technical problem that yield is lower.
For achieving the above object, the invention provides the synthetic method of a kind of 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) acid amides, comprise the following steps:
1) 1,6-hexanediamine and tert-Butyl dicarbonate are dissolved in inert solvent, carry out the amido protecting reaction and obtain 6-amino cyclohexyl amino t-butyl formate;
2) 6-amino cyclohexyl amino t-butyl formate and aryl isonitrile acid esters are dissolved in dry inert solvent, carry out condensation reaction and obtain 6-(3-aryl ureas hexyl) t-butyl carbamate;
3) 6-(3-aryl ureas hexyl) t-butyl carbamate is dissolved in ethyl acetate, passes into HCl gas and carry out the deaminizating protective reaction and obtain 1-(6-amino hexyl)-3-aryl ureas hydrochloride;
4) 1-(6-amino hexyl)-3-aryl ureas hydrochloride, acid binding agent and acyl chlorides are dissolved in inert solvent and carry out acylation reaction and obtain the chloro-N-of 2-(6-(3-aryl ureas) hexyl) acid amides;
5) the chloro-N-of 2-(6-(3-aryl ureas) hexyl) acid amides and sulfuration reagent are dissolved in polar solvent, carry out mercaptolation and obtain 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) acid amides.
Further, in step 1) 1,6-hexanediamine and tert-Butyl dicarbonate mol ratio are 5:1, and the amido protecting temperature of reaction is 0～35 ℃.
Further, step 2) in, the mol ratio of 6-amino cyclohexyl amino t-butyl formate and aryl isonitrile acid esters is 1:1～1.2, and the temperature of condensation reaction is 0～35 ℃.
Further; in step 4), acylation reaction is that 1-(6-amino hexyl)-3-aryl ureas hydrochloride, acid binding agent, acyl chlorides are that 1:2～4:1～1.2 are dissolved in inert solvent according to mol ratio, reacts 2～4h and obtain the chloro-N-of 2-(6-(3-aryl ureas) hexyl) acid amides under 0～35 ℃.
Further, the mol ratio of the chloro-N-of 2-in step 5) (6-(3-aryl ureas) hexyl) acid amides and sulfuration reagent is 1:1～1.5, and the temperature of mercaptolation is 25～78 ℃.
Further, acid binding agent selects salt of wormwood, triethylamine, pyridine, 4-picoline, 4-N, N-Dimethylamino pyridine, 1, a kind of in 8-diazacyclo [5,4,0] 11 carbon-7-alkene.
Further, sulfuration reagent is a kind of in Sodium sulfhydrate, thiocarbamide, thioacetic acid potassium, thioacetic acid.
Further, inert solvent selects a kind of in chloroform, methylene dichloride, tetrahydrofuran (THF) or toluene; Polar solvent selects a kind of in methyl alcohol, ethanol, water or their mixing solutions.
Further, in NSC 630176 derivative synthetic, in the present invention, the aryl isonitrile acid esters is phenyl isocyanate, the naphthyl alcohol isocyanide ester, the 2-Naphthol isocyanide ester, 2-chloro-phenyl-isocyanide ester, 3,4-dichlorophenyl isocyanide ester, 4-methylthio group phenyl isocyanide ester, 4-iodophenyl isocyanide ester, 4-trifluoromethyl isocyanide ester, 4-benzyl phenyl isocyanide ester, 3,5-Dimethoxyphenyl isocyanide ester, 3-Phenoxyphenyl isocyanide ester, 3,5-dinitrophenyl isocyanide ester, 2,6-Dimethoxyphenyl isocyanide ester, 3-methoxyl group-4-ethoxyl phenenyl isocyanide ester, the chloro-3-fluorophenyl of 2-isocyanide ester, 2-methyl-4-butyl phenyl isocyanide ester, 2,3-Dimethoxyphenyl isocyanide ester, 4-xenyl isocyanide ester, 4-fluoroform thio-phenyl isocyanide ester, 2-itrile group-4-ethylphenyl isocyanide ester, 4-difluoro-methoxy phenyl isocyanide ester, 3-fluoro-2-methylbenzene base isocyanide ester, the chloro-5-nitrophenyl of 2-isocyanide ester, 2-methyl-5-nitrophenyl isocyanide ester, the chloro-4-trifluoromethyl of 2-isocyanide ester, 4-N, N-3,5-dimethylphenyl isocyanide ester, a kind of in 2,3,5,6-tetrachloro phenyl isocyanide ester.
Further, acyl chlorides is that 2-chlorpromazine chloride, chloroacetyl chloride, 2-chlorobenzene Acetyl Chloride 98Min., 2-are chloro-2, a kind of in the 2-diphenyl-acetyl chloride.
The present invention has following beneficial effect:
The synthetic method of 2-sulfydryl-N-provided by the invention (6-(3-aryl ureas) hexyl) acid amides, with 1,6-hexanediamine and tert-Butyl dicarbonate are that raw material carries out that amido protecting reacts, condensation reaction, deaminizating protective reaction, acylation reaction, mercaptolation obtain 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) amide compound, synthetic method is simple, the reaction conditions gentleness, can complete whole synthetic reaction process under 0～78 ℃, working method is simple; 1,6-hexanediamine and tert-Butyl dicarbonate are all raw materials cheap and easy to get, have reduced reaction cost.Relatively, under prior art, both known that the synthetic total recovery of thing 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide was 16%.The invention provides the synthetic method of both knowing thing 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide congener, the synthetic total recovery of congener 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide brings up to 43%, improve largely the yield of product, reduced raw materials cost.
Except purpose described above, feature and advantage, the present invention also has other purpose, feature and advantage.Below, with reference to figure, the present invention is further detailed explanation.
The accompanying drawing explanation
Form the application's accompanying drawing partly for proving synthetic result of the present invention, schematic description and description of the present invention the present invention does not form inappropriate limitation of the present invention for explaining.In the accompanying drawings:
Fig. 1 is the LC-MS collection of illustrative plates of preferred embodiment of the present invention target compound;
Fig. 2 is preferred embodiment of the present invention target compound
1h NMR collection of illustrative plates;
Fig. 3 is preferred embodiment of the present invention target compound
13c NMR collection of illustrative plates.
Embodiment
Below in conjunction with accompanying drawing, embodiments of the invention are elaborated, but the multitude of different ways that the present invention can be defined by the claims and cover is implemented.
The invention provides the synthetic method of a kind of NSC 630176 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide congener 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) acid amides.Comprise the following steps:
1) 1,6-hexanediamine and tert-Butyl dicarbonate are dissolved in inert solvent, carry out the amido protecting reaction and obtain 6-amino cyclohexyl amino t-butyl formate;
2) 6-amino cyclohexyl amino t-butyl formate and phenyl isocyanide ester are dissolved in dry inert solvent, carry out condensation reaction and obtain 6-(3-phenylurea hexyl) t-butyl carbamate;
3) 6-(3-phenylurea hexyl) t-butyl carbamate is dissolved in ethyl acetate, passes into HCl gas and carry out the deaminizating protective reaction and obtain 1-(6-amino hexyl)-3-phenylurea hydrochloride;
4) 1-(6-amino hexyl)-3-phenylurea hydrochloride, acid binding agent and 2-chlorpromazine chloride are dissolved in inert solvent and carry out acylation reaction and obtain the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide;
5) the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide and Sodium sulfhydrate are dissolved in polar solvent, carry out mercaptolation and obtain 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide.
Wherein, 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide is a kind of in 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) acid amides, and its structural formula is:
Synthetic route is as follows:
2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide is the congener of 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide and has no bibliographical information.The present invention has synthesized new compound 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide with brand-new method first.This synthetic method has that cost is low, yield is high, mild condition, characteristics simple to operate.According to composition principle of the present invention; the analogue that can synthesize equally other 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide is 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) amides, for NSC 630176 derivative synthetic provides new, better synthetic method.
The synthetic method of 2-sulfydryl-N-provided by the invention (6-(3-phenylurea) hexyl) ethanamide congener, with 1,6-hexanediamine and tert-Butyl dicarbonate are that raw material carries out that amido protecting reacts, condensation reaction, deaminizating protective reaction, acylation reaction, mercaptolation obtain 2-sulfydryl-N-(6-(3-phenylurea) hexyl) acid amides, synthetic method is simple, the reaction conditions gentleness, can complete whole synthetic reaction process in 0～78 ℃ of temperature range, easy to operate simple and easy; 1,6-hexanediamine and tert-Butyl dicarbonate are all raw materials cheap and easy to get, have reduced reaction cost.With respect to prior art, both known the synthetic total recovery 16% of thing 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide.Synthetic method provided by the invention, the total recovery of congener 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide brings up to 43%, has improved largely the yield of target product, has reduced raw materials cost.The synthetic development research that the inventive method is novel NSC 630176 provides reference.
Wherein, in the amido protecting reaction, an end amino of 1,6-hexanediamine is protected with tert-Butyl dicarbonate; if do not carry out the amido protecting reaction,, in next step reaction, the phenyl isocyanide ester will be with 1; two aminoterminals of 6-hexanediamine all carry out condensation reaction, can't obtain expecting product.The 6-amino cyclohexyl amino t-butyl formate that the amido protecting reaction obtains is colourless oil liquid, does not need further separation directly to carry out next step reaction, simplifies lock out operation.The solvent that the inert solvent of take is the amido protecting reaction, better to the reaction effect of 1,6-hexanediamine and tert-Butyl dicarbonate.
In condensation reaction, carry out condensation reaction with not protected amino in phenyl isocyanide ester and 1,6-hexanediamine and obtain 6-(3-phenylurea hexyl) t-butyl carbamate.
In the deaminizating protective reaction; 6-(3-phenylurea hexyl) t-butyl carbamate is dissolved in ethyl acetate; pass into HCl gas and carry out the deaminizating protective reaction; make the ester end in 6-(3-phenylurea hexyl) t-butyl carbamate slough protection, and obtain 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride.
In acylation reaction, amino and the effect of 2-chlorpromazine chloride in 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, form the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide; In order to guarantee the carrying out of acylation reaction, the present invention has added acid binding agent in the acylation reaction process, guarantees carrying out smoothly of acylation reaction.
In mercaptolation, sulfuration reagent is that sulfydryl obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide by the chlorine atomic substitutions in the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide.Using polar solvent as the solvent of mercaptolation, and the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide and the reaction effect of sulfuration reagent in polar solvent are better.
Further, in step 1) 1,6-hexanediamine and tert-Butyl dicarbonate mol ratio are 5:1, and the amido protecting temperature of reaction is 0～35 ℃, and the yield of 6-amino cyclohexyl amino t-butyl formate is higher.
Further, step 2) in, the mol ratio of 6-amino cyclohexyl amino t-butyl formate and phenyl isocyanide ester is 1:1～1.2, the temperature of condensation reaction is 0～35 ℃, and the speed of condensation reaction is faster, and the yield of 6-(3-phenylurea hexyl) t-butyl carbamate is higher.
Further; in step 4), acylation reaction, for being that 1:2:1.2～4:1:1.2 is dissolved in inert solvent by 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, acid binding agent, 2-chlorpromazine chloride according to mol ratio, is reacted 2～4h and is obtained the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide under 0～35 ℃.Under this condition, acylation reaction speed is faster, and the yield of the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide is higher.
Further, the mol ratio of the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide and sulfuration reagent is 1:1～1.5, the temperature of mercaptolation is 25～78 ℃, mercaptolation speed is faster, and the yield of 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide is higher.
Further, salt of wormwood, triethylamine, pyridine, 4-picoline, 4-N, N-Dimethylamino pyridine, 1; 8-diazacyclo [5,4,0] 11 carbon-7-alkene is as acid binding agent; acylation reaction speed is faster, and the yield of the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide is higher.
Further, sulfuration reagent can be a kind of in Sodium sulfhydrate, thiocarbamide, thioacetic acid potassium, thioacetic acid.Make sulfhydrylization reagent with thiocarbamide, can first be converted into isothiuronium salts, then react deaminizating with sodium sulfite aqueous solution and obtain the sulfhydrylation product.While with thioacetic acid potassium or thioacetic acid, making sulfhydrylization reagent, can first be converted into thioesters, then with alkali effect deacetylation, also can obtain the sulfhydrylation product finally by acidifying.Make sulfuration reagent with Sodium sulfhydrate, can directly carry out mercaptolation and obtain the sulfhydrylation product.The route of several mercaptolations is as follows:
Further, inert solvent is a kind of in chloroform, methylene dichloride, tetrahydrofuran (THF) or toluene; Polar solvent is a kind of in methyl alcohol, ethanol, water or their mixing solutions.
Further, in the chloro-N-of NSC 630176 2-(6-(3-phenylurea) hexyl) ethanamide congener synthetic, all generate the same reaction principle of urea according to the nucleophilic addition of the group of the isonitrile acid functional group in isocyanide ester and amino generation, the phenyl isocyanide ester is replaceable is the naphthyl alcohol isocyanide ester, the 2-Naphthol isocyanide ester, 2-chloro-phenyl-isocyanide ester, 3,4-dichlorophenyl isocyanide ester, 4-methylthio group phenyl isocyanide ester, 4-iodophenyl isocyanide ester, 4-trifluoromethyl isocyanide ester, 4-benzyl phenyl isocyanide ester, 3,5-Dimethoxyphenyl isocyanide ester, 3-Phenoxyphenyl isocyanide ester, 3,5-dinitrophenyl isocyanide ester, 2,6-Dimethoxyphenyl isocyanide ester, 3-methoxyl group-4-ethoxyl phenenyl isocyanide ester, the chloro-3-fluorophenyl of 2-isocyanide ester, 2-methyl-4-butyl phenyl isocyanide ester, 2,3-Dimethoxyphenyl isocyanide ester, 4-xenyl isocyanide ester, 4-fluoroform thio-phenyl isocyanide ester, 2-itrile group-4-ethylphenyl isocyanide ester, 4-difluoro-methoxy phenyl isocyanide ester, 3-fluoro-2-methylbenzene base isocyanide ester, the chloro-5-nitrophenyl of 2-isocyanide ester, 2-methyl-5-nitrophenyl isocyanide ester, the chloro-4-trifluoromethyl of 2-isocyanide ester, 4-N, N-3,5-dimethylphenyl isocyanide ester, a kind of in 2,3,5,6-tetrachloro phenyl isocyanide ester.In condensation reaction, reacting all of amino and above-mentioned each isocyanide ester can be carried out according to the amino reaction conditions with phenyl isocyanate, and above-mentioned isocyanic ester all dissolves in inert solvent.
Further; in the chloro-N-of NSC 630176 2-(6-(3-phenylurea) hexyl) ethanamide congener synthetic; all generate the same reaction principle of acid amides according to the amino nucleophilic substitution reaction occurred with acyl chlorides; the 2-chlorpromazine chloride is replaceable is that chloroacetyl chloride, 2-chlorobenzene Acetyl Chloride 98Min., 2-are chloro-2, a kind of in the 2-diphenyl-acetyl chloride.In acylation reaction, reacting all of amino and above-mentioned various acyl chlorides can be carried out according to the amino reaction conditions with the 2-chlorpromazine chloride, and above-mentioned each acyl chlorides all dissolves in inert solvent.
The preparation method of HCl gas is for slowly dripping the vitriol oil preparation HCl gas in salt.
Embodiment
Material and instrument used in following examples are commercially available.
1) in the single port reaction flask of 500mL, add 1 of 60.0g (0.516mol), 6-hexanediamine, 200mL methylene dichloride, under 0 ℃, the tert-Butyl dicarbonate that slowly drips 22.5g (0.103mol) obtains the first solution; The first solution, after normal-temperature reaction 5h, is used respectively to the dichloromethane extraction three times of 150mL, merge the organic phase that three extractions obtain.By the organic phase anhydrous magnesium sulfate drying, then carry out the 6-amino cyclohexyl amino t-butyl formate that suction filtration, removal of solvent under reduced pressure obtain 21.5g, be colorless oil.
2) in the single port reaction flask of 25mL, add the 6-amino cyclohexyl amino t-butyl formate of 0.5g (2.31mmol), the methylene dichloride of 6mL, the isonitrile acid phenenyl ester that slowly drips 0.33g (2.77mmol) under 0 ℃ obtains the second solution.By the second solution, after stirring at normal temperature 4h, the dichloromethane extraction of use 50mL 3 times, merge the organic phase that three extractions obtain.By the organic phase anhydrous magnesium sulfate drying, then carry out suction filtration, removal of solvent under reduced pressure obtains crude product.The mixing solutions that sherwood oil and ethyl acetate volume ratio be 15:1 of take is eluent, through silica gel column chromatography, obtains 6-(the 3-phenylurea hexyl) t-butyl carbamate of 0.73g, is white solid, fusing point: 97～99 ℃.
6-(3-phenylurea hexyl) t-butyl carbamate is carried out to nucleus magnetic resonance and MS detection, and detected result is as follows:
1H?NMR(400MHz,CDCl
3)δ(ppm)：1.26(s,4H,NCCCH
2CH
2CCN)，1.36(s,9H,3×CH
3)，1.41(s,4H,NCCH
2CCCH
2CN)，2.88(dd,J
1=6.4Hz,J
2=10.6Hz,2H,N(C=O)NCH
2)，3.04(dd,J
1=6.4Hz,J
2=10.6Hz,2H,O(C=O)NCH
2)，6.08(t,J=5.6Hz,1H,PhN(C=O)NH)，6.76(t,J=5.6Hz,1H,O(C=O)NH),6.85～7.37(m,5H,ArH)，8.35(s,1H,PhNH)。EI?MS：m/z(%)336([M+1]
+,1)，335(M
+,4)，279(10)，206(3)，143(12)，119(2)，93(100)。
3) in three mouthfuls of reaction flasks of 250mL, add 6-(3-phenylurea hexyl) t-butyl carbamate and the 150mL ethyl acetate of 5.5g (0.016mmol), pass into HCl gas under stirring, react at normal temperatures 5h and obtain the 3rd solution.The 3rd solution is removed to the 1-that ethyl acetate obtains 4.35g (the amino hexyl of 6-)-3-phenylurea hydrochloride through reduction vaporization, is white solid, fusing point: 154～156 ℃.
By 1-, (the amino hexyl of 6-)-3-phenylurea hydrochloride carries out nucleus magnetic resonance and MS detects, and detected result is as follows:
1H?NMR(400MHz,CDCl
3)δ(ppm)：1.32(s,4H,(CO)NCCCH
2CH
2-CCN)，1.41(s,2H,NCCH
2)，1.55(s,2H,(CO)NCCH
2)，2.77(dd,J
1=13.2Hz,J
2=6.8Hz,2H,NCH
2)，3.06(dd,J
1=13.2Hz,J
2=6.8Hz,2H,(CO)NCH
2)，6.41(t,J=5.2Hz,1H,PhN(C=O)NH)，6.84～7.39(m,5H,ArH)，7.87(s,2H,NH
2)，8.76(s,1H,PhNH)。EI?MS：m/z(%)236([M+1]
+,1)，235(M
+,3)，219(1)，183(10)，149(4)，143(12)，126(6)，93(100)。
4) in the single port reaction flask of 100mL, add the 1-(6-amino hexyl) of 1.5g (5.5mmol)-3-phenylurea hydrochloride, the methylene dichloride of 50mL, the heavily steaming triethylamine of 1.68g (17mmol), stir 1h under normal temperature; Then the 2-chlorpromazine chloride that slowly drips 0.84g (6.6mmol) under 0 ℃ obtains the 4th solution.The 4th solution is reacted to 4h at normal temperatures, then use the 60mL dichloromethane extraction 3 times, merge the organic phase that three extractions obtain.Organic phase is obtained to the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide crude product through removal of solvent under reduced pressure.In crude product, add ethyl acetate fully to stir, then after filtration, drying step obtains the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide of 1.27g, is white solid, fusing point: 142～144 ℃.
The chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide is carried out to nucleus magnetic resonance and MS detection, and detected result is as follows:
1H?NMR(400MHz,CDCl
3)δ(ppm)：1.29(s,4H,NCCCH
2CH
2CCN)，1.43(s,4H,NCCH
2CCCH
2CN)，1.51(d,J=6.8Hz,3H,ClCCH
3)，3.99(dd,J
1=11.6Hz,J
2=5.6Hz,4H,N(CO)NCH
2CCCCCH
2N(CO)，4.43(dd,J
1=12.6Hz,J
2=6.8Hz,1H,ClCH)，6.08(t,J=5.6Hz,1H,PhN(C=O)NH-)，6.84～7.37(m,5H,ArH)，8.18(s,1H,NH(CO)CCl)，8.35(s,1H,PhNH(CO)。EI?MS：m/z(%)313([M+2]
+,1)，311(M
+,3)，219(6)，174(12)，162(13)，128(21)，119(25)，106(22)，98(16)，93(100)。
5) in the single port reaction flask of 25mL, add the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide of 0.16g (0.49mmol), the methyl alcohol of 15mL, the Sodium sulfhydrate that 59mg (0.74mmol) mass concentration is 70%, the 3h that refluxed under 64 ℃ obtains the 5th solution.After the 5th solution is removed to desolventizing by underpressure distillation, add 50mL water, the dilute hydrochloric acid with 5% is reconciled PH to 3, then uses respectively 50mL chloroform extraction 3 times, merges the organic phase of three extractions, anhydrous magnesium sulfate drying, and suction filtration, removal of solvent under reduced pressure obtains crude product.The mixing solutions that methylene dichloride and methyl alcohol volume ratio be 30:1 of take is eluent, through silica gel column chromatography, obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide of 0.11g, is white solid, fusing point: 128～130 ℃.
2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide is carried out to nucleus magnetic resonance, LC-MS and ultimate analysis and detect, detected result is as follows:
1H?NMR(400MHz,DMSO-d
6)δ(ppm)：1.28(m,4H,NCCCH
2CH
2CCN)，1.32(d,J=6.8Hz,3H,(CO)CCH
3)，1.41(m,4H,NCCH
2CCCH
2CN)，2.79(d,J=8.5Hz,1H,SH)，3.02(m,4H,N(CO)NCH
2CCCCCH
2N(CO)，3.41(dd,J
1=7.0Hz,J
2=8.5Hz,1H,SCH-)，6.09(t,J=4.0Hz,1H,PhN(C=O)NH-)，6.85～7.38(m,5H,ArH)，7.91(t,J=5.1Hz,1H,NH(CO)CS)，8.35(s,1H,PhNH(CO)。
13C?NMR(100MHz,DMSO-d
6)δ(ppm)：172.98，155.74，141.13，129.13，121.42，118.11，40.08，39.17，36.83，30.26，29.45，26.60，22.69。LC-MS?calcd?for[C
16H
25N
3O
2S+1]
+,324,found,324.1.[2×C
16H
25N
3O
2S+Na]
+,669,found,669.3.Anal.Calcd?for?C
16H
25N
3O
2S：C,59.41；H,7.79；N,12.99.Found：C,59.37；H,7.72；N,13.07。
1) in the single port reaction flask of 100mL, add 1 of 0.1mol, 6-hexanediamine, 60mL methylene dichloride, under 0 ℃, the tert-Butyl dicarbonate that slowly drips 0.02mol obtains the first solution; After the first solution reacts 5h under 0 ℃, use respectively the dichloromethane extraction three times of 60mL, merge organic phase.By the organic phase anhydrous magnesium sulfate drying, then carry out suction filtration, removal of solvent under reduced pressure obtains 6-amino cyclohexyl amino t-butyl formate, is colorless oil.
2) in the single port reaction flask of 25mL, add the 6-amino cyclohexyl amino t-butyl formate of 2.3mmol, the methylene dichloride of 7mL, the phenyl isocyanide ester that slowly drips 2.3mmol under 0 ℃ obtains the second solution.After the second solution is stirred to 4h under 0 ℃, use respectively the dichloromethane extraction 3 times of 50mL, merge the organic phase that three extractions obtain.By the organic phase anhydrous magnesium sulfate drying, then carry out suction filtration, removal of solvent under reduced pressure obtains crude product.The mixing solutions that sherwood oil and ethyl acetate volume ratio be 15:1 of take is eluent, through silica gel column chromatography, obtains 6-(3-phenylurea hexyl) t-butyl carbamate, is white solid, fusing point: 97 ℃.
3) in three mouthfuls of reaction flasks of 250mL, add 6-(3-phenylurea hexyl) t-butyl carbamate and the 150mL ethyl acetate of 0.016mmol, pass into HCl gas under stirring, react at normal temperatures 5h and obtain the 3rd solution.The 3rd solution decompression evaporation being removed to ethyl acetate and obtain 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, is white solid, fusing point: 154 ℃.
4) in the single port reaction flask of 100mL, add the 1-(6-amino hexyl) of 5mmol-3-phenylurea hydrochloride, the methylene dichloride of 50mL, the salt of wormwood of 10mmol, stir 1h under normal temperature; Then the 2-chlorpromazine chloride that slowly drips 5mmol under 0 ℃ obtains the 4th solution.The 4th solution is continued to react 2h under 0 ℃, then use respectively the dichloromethane extraction 3 times of 60mL, merge the organic phase that three extractions obtain.Organic phase is obtained to crude product through removal of solvent under reduced pressure.In crude product, add appropriate ethyl acetate fully to stir, then after filtration, drying obtains the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 142 ℃.
5) in the single port reaction flask of 25mL, add the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide of 0.5mmol, the methyl alcohol of 15mL and the Sodium sulfhydrate 0.5mmol that mass concentration is 70%, obtain the 5th solution after reaction 6h under 25 ℃.The 5th solution, after underpressure distillation removes desolventizing, is added to 50mL water, and the dilute hydrochloric acid with 5% is reconciled PH to 3, then uses respectively 50mL chloroform extraction 3 times, merges the organic phase of three extractions, anhydrous magnesium sulfate drying, and suction filtration, removal of solvent under reduced pressure obtains crude product.The mixing solutions that methylene dichloride and methyl alcohol volume ratio be 30:1 of take is eluent, through silica gel column chromatography, obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 128 ℃.
Embodiment 3
1) in the single port reaction flask of 100mL, add 1 of 0.1mol, 6-hexanediamine, 60mL chloroform, under 35 ℃, the tert-Butyl dicarbonate that slowly drips 0.02mol obtains the first solution; After the first solution is reacted to 5h under 35 ℃, use respectively the chloroform extraction three times of 60mL, merge the organic phase that three extractions obtain.By the organic phase anhydrous magnesium sulfate drying, then carry out suction filtration, removal of solvent under reduced pressure obtains 6-amino cyclohexyl amino t-butyl formate, is colorless oil.
2) in the single port reaction flask of 25mL, add the 6-amino cyclohexyl amino t-butyl formate of 2mmol, the chloroform of 6mL, the phenyl isocyanide ester that slowly drips 2.4mmol under 35 ℃ obtains the second solution.After the second solution is stirred to 4h under 35 ℃, use respectively the chloroform extraction 3 times of 50mL, merge the organic phase that three extractions obtain.By the organic phase anhydrous magnesium sulfate drying, then carry out suction filtration, removal of solvent under reduced pressure obtains 6-(3-phenylurea hexyl) t-butyl carbamate crude product.The mixing solutions that sherwood oil and ethyl acetate volume ratio be 15:1 of take is eluent, through silica gel column chromatography, obtains 6-(3-phenylurea hexyl) t-butyl carbamate, is white solid, fusing point: 99 ℃.
3) in three mouthfuls of reaction flasks of 250mL, add 6-(3-phenylurea hexyl) t-butyl carbamate and the 150mL ethyl acetate of 0.02mmol, pass into HCl gas under stirring, react at normal temperatures 5h and obtain the 3rd solution.The 3rd solution decompression evaporation being removed to ethyl acetate and obtain 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, is white solid, fusing point: 156 ℃.
4) in the single port reaction flask of 100mL, add the 1-(6-amino hexyl) of 10mmol-3-phenylurea hydrochloride, the chloroform of 50mL, the pyridine of 40mmol, stir after 0.5h the 2-chlorpromazine chloride that slowly drips 12mmol under 35 ℃ and obtain the 4th solution.The 4th solution is reacted to 4h under 35 ℃, then use respectively the 60mL chloroform extraction 3 times, merge the organic phase that three extractions obtain.Organic phase is obtained to crude product through removal of solvent under reduced pressure.In crude product, add ethyl acetate fully to stir, then after filtration, drying obtains the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 144 ℃.
5), in the single port reaction flask of 25mL, the Sodium sulfhydrate 0.75mmol that the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide, 15mL ethanol and the mass concentration that adds 0.5mmol is 70% obtains the 5th solution after reaction 3h under 78 ℃.The 5th solution, after underpressure distillation removes desolventizing, is added to 60mL water, and the dilute hydrochloric acid with 5% is reconciled PH to 3, then uses respectively 50mL chloroform extraction 3 times, merges the organic phase of three extractions, anhydrous magnesium sulfate drying, and suction filtration, removal of solvent under reduced pressure obtains crude product.The mixing solutions that methylene dichloride and methyl alcohol volume ratio be 30:1 of take is eluent, through silica gel column chromatography, obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 130 ℃.
Embodiment 4
1) in the single port reaction flask of 100mL, add 1 of 0.1mol, 6-hexanediamine, 60mL toluene, under 20 ℃, the tert-Butyl dicarbonate that slowly drips 0.02mol obtains the first solution; The first solution, after 20 ℃ of reaction 5h, is extracted three times with the toluene of 100mL respectively, merge the organic phase that three extractions obtain.Anhydrous magnesium sulfate drying, suction filtration, removal of solvent under reduced pressure for organic phase are obtained to 6-amino cyclohexyl amino t-butyl formate, are colorless oil.
2) in the single port reaction flask of 25mL, add the 6-amino cyclohexyl amino t-butyl formate of 2mmol, the toluene of 7mL, the phenyl isocyanide ester that slowly drips 2.2mmol under 20 ℃ obtains the second solution.The second solution, after 20 ℃ of stirring 6h, is extracted 3 times with the toluene of 50mL respectively, merge the organic phase that three extractions obtain.Anhydrous magnesium sulfate drying, suction filtration, removal of solvent under reduced pressure for organic phase are obtained to crude product.The mixing solutions that sherwood oil and ethyl acetate volume ratio be 15:1 of take is eluent, through silica gel column chromatography, obtains 6-(3-phenylurea hexyl) t-butyl carbamate, is white solid, fusing point: 98 ℃.
3) in three mouthfuls of reaction flasks of 250mL, add 6-(3-phenylurea hexyl) t-butyl carbamate and the 180mL ethyl acetate of 0.076mmol, pass into HCl gas under stirring, under 20 ℃, reaction 5h obtains the 3rd solution.The 3rd solution decompression evaporation being removed to ethyl acetate and obtain 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, is white solid, fusing point: 155 ℃.
4) in the single port reaction flask of 100mL, add the 1-(6-amino hexyl) of 5mmol-3-phenylurea hydrochloride, the toluene of 50mL, the 4-picoline of 15mmol, stir 1h under normal temperature; Then the 2-chlorpromazine chloride that slowly drips 5.5mmol under 20 ℃ obtains the 4th solution.The 4th solution is reacted to 6h under 20 ℃, then, respectively with 100mL toluene extraction 3 times, merge the organic phase that three extractions obtain.Organic phase is obtained to crude product in removal of solvent under reduced pressure.In crude product, add ethyl acetate fully to stir, then after filtration, drying step obtains the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 143 ℃.
5) in the single port reaction flask of 25mL, add the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide of 0.5mmol, 80% methanol solution of 15mL and the Sodium sulfhydrate 0.6mmol that mass concentration is 70%, under 50 ℃, after reaction 4h, obtain the 5th solution.The 5th solution, after underpressure distillation removes desolventizing, is added to 60mL water, and the dilute hydrochloric acid with 5% is reconciled PH to 3, then uses respectively 50mL chloroform extraction 3 times, merges the organic phase of three extractions, anhydrous magnesium sulfate drying, and suction filtration, removal of solvent under reduced pressure obtains crude product.The mixing solutions that methylene dichloride and methyl alcohol volume ratio be 30:1 of take is eluent, through silica gel column chromatography, obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 129 ℃.
Embodiment 5
1) in the single port reaction flask of 100mL, add 1 of 0.1mol, 6-hexanediamine, 60mL tetrahydrofuran (THF), under 20 ℃, the tert-Butyl dicarbonate that slowly drips 0.02mol obtains the first solution; By the first solution, after 20 ℃ of reaction 5h, removal of solvent under reduced pressure, use respectively the chloroform extraction three times of 100mL, merges the organic phase that three extractions obtain.Anhydrous magnesium sulfate drying, suction filtration, removal of solvent under reduced pressure for organic phase are obtained to 6-amino cyclohexyl amino t-butyl formate, are colorless oil.
2) in the single port reaction flask of 25mL, add the 6-amino cyclohexyl amino t-butyl formate of 2mmol, the tetrahydrofuran (THF) of 8mL, the phenyl isocyanide ester that slowly drips 2.4mmol under 20 ℃ obtains the second solution.By the second solution 20 ℃ stir 6h after, removal of solvent under reduced pressure, use respectively the chloroform extraction 3 times of 50mL, merges the organic phase that three extractions obtain.Anhydrous magnesium sulfate drying, suction filtration, removal of solvent under reduced pressure for organic phase are obtained to crude product.The mixing solutions that sherwood oil and ethyl acetate volume ratio be 15:1 of take is eluent, through silica gel column chromatography, obtains 6-(3-phenylurea hexyl) t-butyl carbamate, is white solid, fusing point: 98 ℃.
3) in three mouthfuls of reaction flasks of 250mL, add 6-(3-phenylurea hexyl) t-butyl carbamate and the 180mL ethyl acetate of 0.076mmol, pass into HCl gas under stirring, under 20 ℃, reaction 5h obtains the 3rd solution.The 3rd solution decompression evaporation being removed to ethyl acetate and obtain 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, is white solid, fusing point: 155 ℃.
4) in the single port reaction flask of 100mL, add the 1-(6-amino hexyl) of 6mmol-3-phenylurea hydrochloride, the tetrahydrofuran (THF) of 50mL, the 4-N of 24mmol, the N-Dimethylamino pyridine, stir after 1h the 2-chlorpromazine chloride that slowly drips 7.2mmol under 20 ℃ and obtain the 4th solution.The 4th solution is reacted to 6h under 20 ℃, after removal of solvent under reduced pressure, use respectively the 60mL chloroform extraction 3 times, merge the organic phase that three extractions obtain.Organic phase is obtained to crude product in removal of solvent under reduced pressure.In crude product, add ethyl acetate fully to stir, then after filtration, drying step obtains the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 143 ℃.
5), in the single port reaction flask of 25mL, the Sodium sulfhydrate 0.75mmol that the chloro-N-of 2-(6-(3-phenylurea) hexyl) propionic acid amide, 95% ethanolic soln 15mL and the mass concentration that adds 0.5mmol is 70% obtains the 5th solution after reaction 3h under 78 ℃.The 5th solution, after underpressure distillation removes desolventizing, is added to 50mL water, and the dilute hydrochloric acid with 5% is reconciled PH to 3, then uses respectively 50mL chloroform extraction 3 times, merges the organic phase of three extractions, anhydrous magnesium sulfate drying, and suction filtration, removal of solvent under reduced pressure obtains crude product.The mixing solutions that methylene dichloride and methyl alcohol volume ratio be 30:1 of take is eluent, through silica gel column chromatography, obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 129 ℃.
The target product of embodiment 1 is carried out to mass spectrometric detection and magnetic resonance detection, the mass spectrum that Fig. 1 is the embodiment of the present invention 1 target compound; The hydrogen spectrogram that Fig. 2 is the embodiment of the present invention 1 target compound; The carbon spectrogram that Fig. 3 is the embodiment of the present invention 1 target compound, according to the detected result of Fig. 1, Fig. 2, Fig. 3, prove that the material that the method according to the embodiment of the present invention 1 obtains is 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide.
The yield of the intermediate of embodiment 1～5 and target compound is calculated, and the results are shown in Table 1 for yield.
Table 1 productive rate detected result
From the analytical results of table 1, the total recovery of the embodiment of the present invention 1～5 can reach 43.3%, apparently higher than the total recovery of analogue under prior art.Wherein embodiment 1 is most preferred embodiment of the present invention.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (10)
1. the synthetic method of a 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) acid amides, is characterized in that, comprises the following steps:
1) 1,6-hexanediamine and tert-Butyl dicarbonate are dissolved in inert solvent, carry out the amido protecting reaction and obtain 6-amino cyclohexyl amino t-butyl formate;
2) described 6-amino cyclohexyl amino t-butyl formate and aryl isonitrile acid esters are dissolved in dry inert solvent, carry out condensation reaction and obtain 6-(3-aryl ureas hexyl) t-butyl carbamate;
3) described 6-(3-aryl ureas hexyl) t-butyl carbamate is dissolved in ethyl acetate, passes into HCl gas and carry out the deaminizating protective reaction and obtain 1-(6-amino hexyl)-3-aryl ureas hydrochloride;
4) described 1-(6-amino hexyl)-3-aryl ureas hydrochloride, acid binding agent and acyl chlorides are dissolved in inert solvent and carry out acylation reaction and obtain the chloro-N-of 2-(6-(3-aryl ureas) hexyl) acid amides;
5) the chloro-N-of described 2-(6-(3-aryl ureas) hexyl) acid amides and sulfuration reagent are dissolved in polar solvent, carry out mercaptolation and obtain 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) acid amides.
2. synthetic method according to claim 1, is characterized in that, 1 described in step 1), and 6-hexanediamine and tert-Butyl dicarbonate mol ratio are 5:1, described amido protecting temperature of reaction is 0～35 ℃.
3. synthetic method according to claim 1, is characterized in that step 2) described in 6-amino cyclohexyl amino t-butyl formate and the mol ratio of aryl isonitrile acid esters be 1:1～1.2, the temperature of described condensation reaction is 0～35 ℃.
4. synthetic method according to claim 1; it is characterized in that; acylation reaction described in step 4) is that described 1-(the amino hexyl of 6-)-3-aryl ureas hydrochloride, acid binding agent and acyl chlorides are that 1:2:1.2～4:1:1.2 is dissolved in inert solvent according to mol ratio, reacts 2～4h and obtain the chloro-N-of 2-(6-(3-aryl ureas) hexyl) acid amides under 0～35 ℃.
5. synthetic method according to claim 1, is characterized in that, the mol ratio of the chloro-N-of the 2-described in step 5) (6-(3-aryl ureas) hexyl) acid amides and sulfuration reagent is 1:1～1.5, and the temperature of described mercaptolation is 25～78 ℃.
6. according to the described synthetic method of claim 1 to 5 any one, it is characterized in that, described acid binding agent is salt of wormwood, triethylamine, pyridine, 4-picoline, 4-N, N-Dimethylamino pyridine, 1, a kind of in 8-diazacyclo [5,4,0] 11 carbon-7-alkene.
7. according to the described synthetic method of claim 1 to 5 any one, it is characterized in that, described sulfuration reagent is a kind of in Sodium sulfhydrate, thiocarbamide, thioacetic acid potassium, thioacetic acid.
8. according to the described synthetic method of claim 1 to 5 any one, it is characterized in that, described inert solvent is a kind of in chloroform, methylene dichloride, tetrahydrofuran (THF) or toluene; Described polar solvent selects a kind of in methyl alcohol, ethanol, water or their mixing solutions.
9. according to the described synthetic method of claim 1 to 5 any one, it is characterized in that, described aryl isonitrile acid esters is the phenyl isocyanide ester, the naphthyl alcohol isocyanide ester, the 2-Naphthol isocyanide ester, 2-chloro-phenyl-isocyanide ester, 3,4-dichlorophenyl isocyanide ester, 4-methylthio group phenyl isocyanide ester, 4-iodophenyl isocyanide ester, 4-trifluoromethyl isocyanide ester, 4-benzyl phenyl isocyanide ester, 3,5-Dimethoxyphenyl isocyanide ester, 3-Phenoxyphenyl isocyanide ester, 3,5-dinitrophenyl isocyanide ester, 2,6-Dimethoxyphenyl isocyanide ester, 3-methoxyl group-4-ethoxyl phenenyl isocyanide ester, the chloro-3-fluorophenyl of 2-isocyanide ester, 2-methyl-4-butyl phenyl isocyanide ester, 2,3-Dimethoxyphenyl isocyanide ester, 4-xenyl isocyanide ester, 4-fluoroform thio-phenyl isocyanide ester, 2-itrile group-4-ethylphenyl isocyanide ester, 4-difluoro-methoxy phenyl isocyanide ester, 3-fluoro-2-methylbenzene base isocyanide ester, the chloro-5-nitrophenyl of 2-isocyanide ester, 2-methyl-5-nitrophenyl isocyanide ester, the chloro-4-trifluoromethyl of 2-isocyanide ester, 4-N, N-3,5-dimethylphenyl isocyanide ester, a kind of in 2,3,5,6-tetrachloro phenyl isocyanide ester.
10. according to the described synthetic method of claim 1 to 5 any one, it is characterized in that, described acyl chlorides is that 2-chlorpromazine chloride, chloroacetyl chloride, 2-chlorobenzene Acetyl Chloride 98Min., 2-are chloro-2, a kind of in the 2-diphenyl-acetyl chloride.
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