CN102936215A - 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 speaking, 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 are in running balance, and are jointly regulated and control 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; combine closely with electronegative DNA, 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 the 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) then can be by improving chromatin specific region acetylation of histone; thereby the relevant protein expression of regulating cell apoptosis and differentiation and stability; cell death inducing and differentiation become the new antitumor drug of a class.The design of such drug molecule, synthetic reaching in the bioactive research, about the existing relevant report of synthetic and bioactivity research of 2-Mercaptoamides and N-oxyamide compounds.Wherein, 2-Mercaptoamides compounds is widely studied take 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide as representative again.
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 after deliberation 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide has good restraining effect to Laryngeal Cancer cell (SQ-20B), its IC
50Value is 50uM(WO 2005/007091).In the same year, these compounds of usefulness 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﹠amp; 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 the 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, (WO 2005/007091 for the identical synthetic methods of successively having reported for work such as Kozikowski, Chen, Tang, Rivieccio; US 20050032831; 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 ﹠amp; Medicinal Chemistry Letters.2005,15,1389-1392).Namely take Methyl Thioglycolate as raw material, take chloroform as solvent, under the trifluoroacetic acid katalysis, make triphenyl methylthio group acetic acid methyl esters with the triphenylcarbinol effect; Triphenyl methylthio group acetic acid methyl esters and 1,6-hexanediamine are carried out acylation reaction get 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 N-(6-(3-phenylurea) hexyl)-2-triphenyl methylmercaptan ethyl acid amides with the effect of benzene isocyanide ester in methylene dichloride; At last in dichloromethane solvent, N-(6-(3-phenylurea) hexyl)-2-triphenyl methylmercaptan ethyl acid amides and trifluoroacetic acid and triethyl silicane reaction deprotection are obtained 2-sulfydryl-N-(6-(3-phenylurea) hexyl) ethanamide.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 ° of C, simultaneously aftertreatment difficulty; Secondly, raw materials cost is high, and expensive raw material price such as triphenylcarbinol, triethyl silicane, and the protecting group trityl group will slough are at last failed fine embodiment Atom economy; At last, 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, only is 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 the 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, may further comprise the steps:
1) 1,6-hexanediamine and tert-Butyl dicarbonate are dissolved in the 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 the 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 the 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 carry out acylation reaction in the inert solvent and obtain 2-chloro-N-(6-(3-aryl ureas) hexyl) acid amides;
5) 2-chloro-N-(6-(3-aryl ureas) hexyl) acid amides and sulfuration reagent are dissolved in the polar solvent, carry out mercaptolation and obtain 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) acid amides.
Further, in the step 1) 1,6-hexanediamine and tert-Butyl dicarbonate molar mass are than being 5:1, and the amido protecting temperature of reaction is 0～35 ℃.
Further, step 2) 6-amino cyclohexyl amino t-butyl formate and the molar mass of aryl isonitrile acid esters are than being 1:1 ~ 1.2 in, and the temperature of condensation reaction is 0～35 ° of C.
Further; acylation reaction is that 1-(6-amino hexyl)-3-aryl ureas hydrochloride, acid binding agent, acyl chlorides are dissolved in the inert solvent than for 1:2～4:1～1.2 according to molar mass in the step 4), reacts 2～4h and obtain 2-chloro-N-(6-(3-aryl ureas) hexyl) acid amides under 0～35 ° of C.
Further, the mol ratio of 2-chloro-N-in the 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 ° of C.
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, the thioacetic acid.
Further, inert solvent selects a kind of in chloroform, methylene dichloride, tetrahydrofuran (THF) or the toluene; Polar solvent selects a kind of in methyl alcohol, ethanol, the water or their mixing solutions.
Further; in NSC 630176 derivative synthetic; the aryl isonitrile acid esters is phenyl isocyanate among the present invention; 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; 2-chloro-3-fluorophenyl 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; 2-chloro-5-nitrophenyl isocyanide ester; 2-methyl-5-nitrophenyl isocyanide ester; 2-chloro-4-trifluoromethyl isocyanide ester; 4-N; N-3,5-dimethylphenyl isocyanide ester; 2; 3; a kind of in 5, the 6-tetrachloro phenyl isocyanide ester.
Further, acyl chlorides is 2-chlorpromazine chloride, chloroacetyl chloride, 3-chlorpromazine chloride, 2,3-two chlorpromazine chlorides, 2-chlorobenzene Acetyl Chloride 98Min., 2-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 amido protecting reaction, condensation reaction, deaminizating protective reaction, acylation reaction, mercaptolation and obtains 2-sulfydryl-N-(6-(3-aryl ureas) hexyl) amide compound, synthetic method is simple, reaction conditions is gentle, can finish whole synthetic reaction process under 0～78 ℃, working method is simple; 1,6-hexanediamine and tert-Butyl dicarbonate all are raw materials cheap and easy to get, have reduced reaction cost.Relatively under the 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.The below is with reference to figure, and the present invention is further detailed explanation.
Description of drawings
The accompanying drawing that consists of the application partly is used for proving synthetic result of the present invention, and illustrative examples of the present invention and explanation thereof are used for explaining the present invention, do not consist of improper restriction of the present invention.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.May further comprise the steps:
1) 1,6-hexanediamine and tert-Butyl dicarbonate are dissolved in the 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 the 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 the 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 carry out acylation reaction in the inert solvent and obtain 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide;
5) 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide and Sodium sulfhydrate are dissolved in the 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 amido protecting reaction, condensation reaction, deaminizating protective reaction, acylation reaction, mercaptolation and obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) acid amides, synthetic method is simple, reaction conditions is gentle, in 0～78 ℃ of temperature range, can finish whole synthetic reaction process, easy to operate simple and easy; 1,6-hexanediamine and tert-Butyl dicarbonate all are 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 inventive method provides reference for the synthetic development research of novel NSC 630176.
Wherein in 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, then 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 of reaction is better to the reaction effect of 1,6-hexanediamine and tert-Butyl dicarbonate take inert solvent as amido protecting.
In condensation reaction, carry out condensation reaction with not protected amino in phenyl isocyanide ester and 1, the 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 the ethyl acetate; pass into HCl gas and carry out the deaminizating protective reaction; make the ester end in 6-(the 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 2-chloro-N-(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 with the chlorine atomic substitutions in 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide.With the solvent of polar solvent as mercaptolation, 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide and the reaction effect of sulfuration reagent in polar solvent are better.
Further, in the step 1) 1,6-hexanediamine and tert-Butyl dicarbonate molar mass are than being 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) 6-amino cyclohexyl amino t-butyl formate is 1:1 ~ 1.2 with the molar mass ratio of phenyl isocyanide ester in, the temperature of condensation reaction is 0～35 ° of C, and the speed of condensation reaction is faster, and the yield of 6-(3-phenylurea hexyl) t-butyl carbamate is higher.
Further; acylation reaction obtains 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide for 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, acid binding agent, 2-chlorpromazine chloride are dissolved in the inert solvent than for 1:2:1.2～4:1:1.2 according to molar mass at 0～35 ℃ of lower reaction 2～4h in the step 4).Under this condition, acylation reaction speed is faster, and the yield of 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide is higher.
Further, the mol ratio of 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide and sulfuration reagent is 1:1 ~ 1.5, the temperature of mercaptolation is 25～78 ° of C, 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 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide is higher.
Further, sulfuration reagent can be a kind of in Sodium sulfhydrate, thiocarbamide, thioacetic acid potassium, the thioacetic acid.Make sulfhydrylization reagent with thiocarbamide, can be converted into first isothiuronium salts, obtain the sulfhydrylation product with sodium sulfite aqueous solution reaction deaminizating again.When making sulfhydrylization reagent with thioacetic acid potassium or thioacetic acid, thioesters can be converted into first, with alkali effect deacetylation, also the sulfhydrylation product can be obtained finally by acidifying again.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 the toluene; Polar solvent is a kind of in methyl alcohol, ethanol, the water or their mixing solutions.
Further; in NSC 630176 2-chloro-N-(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 the isocyanide ester and amino generation; the phenyl isocyanide ester is replaceable to be 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; 2-chloro-3-fluorophenyl 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; 2-chloro-5-nitrophenyl isocyanide ester; 2-methyl-5-nitrophenyl isocyanide ester; 2-chloro-4-trifluoromethyl isocyanide ester; 4-N; N-3,5-dimethylphenyl isocyanide ester; 2; 3; a kind of in 5, the 6-tetrachloro phenyl isocyanide ester.In condensation reaction, reaction amino and above-mentioned each isocyanide ester all can be carried out according to amino reaction conditions with phenyl isocyanate, and above-mentioned isocyanic ester all dissolves in the inert solvent.
Further; in NSC 630176 2-chloro-N-(6-(3-phenylurea) hexyl) ethanamide congener synthetic; all generate the same reaction principle of acid amides according to the amino nucleophilic substitution reaction that occurs with acyl chlorides; the 2-chlorpromazine chloride is replaceable to be chloroacetyl chloride, 3-chlorpromazine chloride, 2; 3-two chlorpromazine chlorides, 2-chlorobenzene Acetyl Chloride 98Min., 2-chloro-2, a kind of in the 2-diphenyl-acetyl chloride.In acylation reaction, reactions amino and above-mentioned various acyl chlorides all can be carried out according to amino reaction conditions with the 2-chlorpromazine chloride, and above-mentioned each acyl chlorides all dissolves in the 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 ° of C, the tert-Butyl dicarbonate that slowly drips 22.5g (0.103mol) obtains the first solution; The first solution behind normal-temperature reaction 5h, is used respectively the dichloromethane extraction three times of 150mL, merge the organic phase that three extractions obtain.With 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, obtain the second solution at 0 ℃ of lower isonitrile acid phenenyl ester that slowly drips 0.33g (2.77mmol).Behind stirring at normal temperature 4h, the dichloromethane extraction of usefulness 50mL 3 times merges the organic phase that three extractions obtain with the second solution.With the organic phase anhydrous magnesium sulfate drying, then carry out suction filtration, removal of solvent under reduced pressure gets crude product.Mixing solutions take sherwood oil and ethyl acetate volume ratio as 15:1 through silica gel column chromatography, obtains 6-(the 3-phenylurea hexyl) t-butyl carbamate of 0.73g as eluent, is white solid, fusing point: 97～99 ℃.
6-(3-phenylurea hexyl) t-butyl carbamate is carried out 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 the 1-that ethyl acetate obtains 4.35g (the amino hexyl of 6-)-3-phenylurea hydrochloride through reduction vaporization, be white solid, fusing point: 154～156 ° of C.
(the amino hexyl of 6-)-3-phenylurea hydrochloride carries out nucleus magnetic resonance and MS detects with 1-, 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, the 1-of adding 1.5g (5.5mmol) (the amino hexyl of 6-)-3-phenylurea hydrochloride, the methylene dichloride of 50mL, the heavily steaming triethylamine of 1.68g (17mmol) stir 1h under the normal temperature; Then obtain the 4th solution at 0 ℃ of lower 2-chlorpromazine chloride that slowly drips 0.84g (6.6mmol).The 4th solution is reacted 4h at normal temperatures, then use the 60mL dichloromethane extraction 3 times, merge the organic phase that three extractions obtain.Organic phase is obtained 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide crude product through removal of solvent under reduced pressure.In crude product, add ethyl acetate and fully stir, then after filtration, drying step obtains 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide of 1.27g, is white solid, fusing point: 142～144 ℃.
2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide is carried out 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, 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide, the methyl alcohol of 15mL, 59mg (0.74mmol) mass concentration that add 0.16g (0.49mmol) are 70% Sodium sulfhydrate, and the 3h that refluxes under 64 ℃ obtains the 5th solution.With the 5th solution by the underpressure distillation desolventizing after, 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 that extracts for three times, anhydrous magnesium sulfate drying, suction filtration, removal of solvent under reduced pressure gets crude product.Mixing solutions take methylene dichloride and methyl alcohol volume ratio as 30:1 through silica gel column chromatography, obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide of 0.11g as eluent, is white solid, fusing point: 128～130 ℃.
2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide is carried out nucleus magnetic resonance, LC-MS and ultimate analysis 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; The first solution is used respectively the dichloromethane extraction three times of 60mL behind reaction 5h under 0 ° of C, merge organic phase.With 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 ° of C obtains the second solution.With the second solution 0 ℃ lower stir 4h after, use respectively the dichloromethane extraction 3 times of 50mL, merges three times and extracts the organic phase that obtains.With the organic phase anhydrous magnesium sulfate drying, then carry out suction filtration, removal of solvent under reduced pressure gets crude product.Mixing solutions take sherwood oil and ethyl acetate volume ratio as 15:1 through silica gel column chromatography, obtains 6-(3-phenylurea hexyl) t-butyl carbamate as eluent, 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.Ethyl acetate is removed in the evaporation of the 3rd solution decompression obtain 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, be white solid, fusing point: 154 ℃.
4) in the single port reaction flask of 100mL, the 1-of adding 5mmol (the amino hexyl of 6-)-3-phenylurea hydrochloride, the methylene dichloride of 50mL, the salt of wormwood of 10mmol stir 1h under the normal temperature; Then obtain the 4th solution at 0 ℃ of lower 2-chlorpromazine chloride that slowly drips 5mmol.The 4th solution is continued at 0 ℃ of lower reaction 2h, then use respectively the dichloromethane extraction 3 times of 60mL, merges three times and extract the organic phase that obtains.Organic phase is got crude product through removal of solvent under reduced pressure.In crude product, add an amount of ethyl acetate and fully stir, then after filtration, drying obtains 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 142 ℃.
5) in the single port reaction flask of 25mL, 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide of adding 0.5mmol, the methyl alcohol of 15mL and mass concentration are 70% Sodium sulfhydrate 0.5mmol, are obtaining the 5th solution behind the reaction 6h under 25 ° of C.The 5th solution after the underpressure distillation desolventizing, is added 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 gets crude product.Mixing solutions take methylene dichloride and methyl alcohol volume ratio as 30:1 through silica gel column chromatography, obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide as eluent, is white solid, fusing point: 128 ° of C.
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; The first solution behind 35 ℃ of lower reaction 5h, is used respectively the chloroform extraction three times of 60mL, merges three times and extract the organic phase that obtains.With 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, obtain the second solution at 35 ℃ of lower phenyl isocyanide esters that slowly drip 2.4mmol.With the second solution 35 ℃ lower stir 4h after, use respectively the chloroform extraction 3 times of 50mL, merges three times and extracts the organic phase that obtains.With 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.Mixing solutions take sherwood oil and ethyl acetate volume ratio as 15:1 through silica gel column chromatography, obtains 6-(3-phenylurea hexyl) t-butyl carbamate as eluent, 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.Ethyl acetate is removed in the evaporation of the 3rd solution decompression obtain 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, be white solid, fusing point: 156 ℃.
4) in the single port reaction flask of 100mL, add the 1-(the amino hexyl of 6-) of 10mmol-3-phenylurea hydrochloride, the chloroform of 50mL, the pyridine of 40mmol, stir the 2-chlorpromazine chloride that slowly drips 12mmol behind the 0.5h under 35 ° of C and obtain the 4th solution.The 4th solution is reacted 4h under 35 ° of C, then use respectively the 60mL chloroform extraction 3 times, merge the organic phase that three extractions obtain.Organic phase is got crude product through removal of solvent under reduced pressure.In crude product, add ethyl acetate and fully stir, then after filtration, drying obtains 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 144 ℃.
5) in the single port reaction flask of 25mL, 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide, 15mL ethanol and the mass concentration that add 0.5mmol are 70% Sodium sulfhydrate 0.75mmol, are obtaining the 5th solution behind the reaction 3h under 78 ° of C.The 5th solution after the underpressure distillation desolventizing, is added 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 gets crude product.Mixing solutions take methylene dichloride and methyl alcohol volume ratio as 30:1 obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide as eluent through silica gel column chromatography, is white solid, fusing point: 130 ℃.
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; Behind 20 ℃ of reaction 5h, the toluene with 100mL extracts three times respectively with the first solution, merges the organic phase that three extractions obtain.Organic phase is obtained 6-amino cyclohexyl amino t-butyl formate with anhydrous magnesium sulfate drying, suction filtration, removal of solvent under reduced pressure, be 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 ° of C obtains the second solution.Behind 20 ℃ of stirring 6h, the toluene with 50mL extracts 3 times respectively with the second solution, merges the organic phase that three extractions obtain.Organic phase is got crude product with anhydrous magnesium sulfate drying, suction filtration, removal of solvent under reduced pressure.Mixing solutions take sherwood oil and ethyl acetate volume ratio as 15:1 through silica gel column chromatography, gets 6-(3-phenylurea hexyl) t-butyl carbamate as eluent, 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, obtain the 3rd solution at 20 ℃ of lower reaction 5h.Ethyl acetate is removed in the evaporation of the 3rd solution decompression obtain 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, be white solid, fusing point: 155 ℃.
4) in the single port reaction flask of 100mL, the 1-of adding 5mmol (the amino hexyl of 6-)-3-phenylurea hydrochloride, the toluene of 50mL, the 4-picoline of 15mmol stir 1h under the normal temperature; Then obtain the 4th solution at 20 ℃ of lower 2-chlorpromazine chlorides that slowly drip 5.5mmol.The 4th solution at 20 ℃ of lower reaction 6h, then respectively with 100mL toluene extraction 3 times, is merged the organic phase that three extractions obtain.Organic phase is got crude product in removal of solvent under reduced pressure.In crude product, add ethyl acetate and fully stir, then after filtration, drying step obtains 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 143 ° of C.
5) in the single port reaction flask of 25mL, 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide of adding 0.5mmol, 80% methanol solution of 15mL and mass concentration are 70% Sodium sulfhydrate 0.6mmol, are obtaining the 5th solution behind 50 ℃ of lower reaction 4h.The 5th solution after the underpressure distillation desolventizing, is added 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 gets crude product.Mixing solutions take methylene dichloride and methyl alcohol volume ratio as 30:1 through silica gel column chromatography, obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide as eluent, is white solid, fusing point: 129 ° of C.
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; Behind 20 ℃ of reaction 5h, removal of solvent under reduced pressure is used respectively the chloroform extraction three times of 100mL, merges three times and extracts the organic phase that obtains with the first solution.Organic phase is obtained 6-amino cyclohexyl amino t-butyl formate with anhydrous magnesium sulfate drying, suction filtration, removal of solvent under reduced pressure, be 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 ° of C obtains the second solution.With the second solution 20 ℃ stir 6h after, removal of solvent under reduced pressure is used respectively the chloroform extraction 3 times of 50mL, merges three times and extracts the organic phase that obtains.Organic phase is got crude product with anhydrous magnesium sulfate drying, suction filtration, removal of solvent under reduced pressure.Mixing solutions take sherwood oil and ethyl acetate volume ratio as 15:1 through silica gel column chromatography, gets 6-(3-phenylurea hexyl) t-butyl carbamate as eluent, 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, obtain the 3rd solution at 20 ℃ of lower reaction 5h.Ethyl acetate is removed in the evaporation of the 3rd solution decompression obtain 1-(the amino hexyl of 6-)-3-phenylurea hydrochloride, be white solid, fusing point: 155 ° of C.
4) in the single port reaction flask of 100mL, the 1-of adding 6mmol (the amino hexyl of 6-)-3-phenylurea hydrochloride, the tetrahydrofuran (THF) of 50mL, the 4-N of 24mmol, the N-Dimethylamino pyridine, the slow 2-chlorpromazine chloride that drips 7.2mmol obtains the 4th solution behind 20 ℃ of lower 1h of stirring.The 4th solution at 20 ℃ of lower reaction 6h, after the removal of solvent under reduced pressure, is used respectively the 60mL chloroform extraction 3 times, merge the organic phase that three extractions obtain.Organic phase is got crude product in removal of solvent under reduced pressure.In crude product, add ethyl acetate and fully stir, then after filtration, drying step obtains 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide, is white solid, fusing point: 143 ° of C.
5) in the single port reaction flask of 25mL, 2-chloro-N-(6-(3-phenylurea) hexyl) propionic acid amide, 95% ethanolic soln 15mL and the mass concentration that add 0.5mmol are 70% Sodium sulfhydrate 0.75mmol, obtain the 5th solution behind 78 ℃ of lower reaction 3h.The 5th solution after the underpressure distillation desolventizing, is added 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 gets crude product.Mixing solutions take methylene dichloride and methyl alcohol volume ratio as 30:1 through silica gel column chromatography, obtains 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide as eluent, is white solid, fusing point: 129 ° of C.
The target product of embodiment 1 is carried out mass spectrometric detection and magnetic resonance detection, and Fig. 1 is the mass spectrum of the embodiment of the invention 1 target compound; Fig. 2 is the hydrogen spectrogram of the embodiment of the invention 1 target compound; Fig. 3 is the carbon spectrogram of the embodiment of the invention 1 target compound, according to the detected result of Fig. 1, Fig. 2, Fig. 3, proves that the material that the method according to the embodiment of the invention 1 obtains is 2-sulfydryl-N-(6-(3-phenylurea) hexyl) propionic acid amide.
The intermediate of embodiment 1 ~ 5 and the yield of target compound are calculated, and the results are shown in Table 1 for yield.
Table 1 productive rate detected result
From the analytical results of table 1 as can be known, the total recovery of the embodiment of the invention 1 ~ 5 can reach 43.3%, the total recovery of analogue under the prior art.Wherein embodiment 1 is most preferred embodiment of the present invention.
The above is the preferred embodiments of the present invention only, is not limited to the present invention, and 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., all should be included within 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, may further comprise the steps:
1) 1,6-hexanediamine and tert-Butyl dicarbonate are dissolved in the 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 the 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 the 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 carry out acylation reaction in the inert solvent and obtain 2-chloro-N-(6-(3-aryl ureas) hexyl) acid amides;
5) described 2-chloro-N-(6-(3-aryl ureas) hexyl) acid amides and sulfuration reagent are dissolved in the 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 the step 1), and the 6-hexanediamine is 5:1 with tert-Butyl dicarbonate molar mass ratio, described amido protecting temperature of reaction is 0～35 ℃.
3. synthetic method according to claim 1 is characterized in that step 2) described in the molar mass of 6-amino cyclohexyl amino t-butyl formate and aryl isonitrile acid esters than being 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 the step 4) is that described 1-(the amino hexyl of 6-)-3-aryl ureas hydrochloride, acid binding agent are dissolved in the inert solvent than for 1:2:1.2～4:1:1.2 according to molar mass with acyl chlorides, reacts 2～4h and obtain 2-chloro-N-(6-(3-aryl ureas) hexyl) acid amides under 0～35 ° of C.
5. synthetic method according to claim 1 is characterized in that, the mol ratio of the 2-chloro-N-described in the 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 claim 1 to 5 each described synthetic methods, 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 claim 1 to 5 each described synthetic methods, it is characterized in that, described sulfuration reagent is a kind of in Sodium sulfhydrate, thiocarbamide, thioacetic acid potassium, the thioacetic acid.
8. according to claim 1 to 5 each described synthetic methods, it is characterized in that, described inert solvent is a kind of in chloroform, methylene dichloride, tetrahydrofuran (THF) or the toluene; Described polar solvent selects a kind of in methyl alcohol, ethanol, the water or their mixing solutions.
9. according to claim 1 to 5 each described synthetic methods, 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, 2-chloro-3-fluorophenyl 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, 2-chloro-5-nitrophenyl isocyanide ester, 2-methyl-5-nitrophenyl isocyanide ester, 2-chloro-4-trifluoromethyl isocyanide ester, 4-N, N-3,5-dimethylphenyl isocyanide ester, 2,3, a kind of in 5, the 6-tetrachloro phenyl isocyanide ester.
10. according to claim 1 to 5 each described synthetic methods, it is characterized in that, described acyl chlorides is 2-chlorpromazine chloride, chloroacetyl chloride, 3-chlorpromazine chloride, 2,3-two chlorpromazine chlorides, 2-chlorobenzene Acetyl Chloride 98Min., 2-chloro-2, a kind of in the 2-diphenyl-acetyl chloride.
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| CN115108953A (en) * | 2021-03-18 | 2022-09-27 | 江西师范大学 | Thiohydrogenation of alkynylamides and selective modification of polypeptide cysteines |
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| CN115108953B (en) * | 2021-03-18 | 2023-06-02 | 江西师范大学 | Sulfhydrylation of alkynylamides and selective modification of polypeptide cysteines |
| CN114807460A (en) * | 2022-04-26 | 2022-07-29 | 广河县国富皮革有限公司 | Hair-saving unhairing leather-making process method |
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