CN110452146A - Trifluoromethyl seleno-amino acids derivative and preparation method thereof - Google Patents

Trifluoromethyl seleno-amino acids derivative and preparation method thereof Download PDF

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CN110452146A
CN110452146A CN201910806750.0A CN201910806750A CN110452146A CN 110452146 A CN110452146 A CN 110452146A CN 201910806750 A CN201910806750 A CN 201910806750A CN 110452146 A CN110452146 A CN 110452146A
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seleno
boc
amino
trifluoromethyl
amino acids
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张成潘
明小霞
韩周洲
施进
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Wuhan University of Technology WUT
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Wuhan University of Technology WUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C391/00—Compounds containing selenium
    • C07C391/02—Compounds containing selenium having selenium atoms bound to carbon atoms of six-membered aromatic rings

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Abstract

The present invention discloses a kind of trifluoromethyl seleno-amino acids derivative and preparation method thereof, which reacts the following steps are included: protecting reagent to carry out N-Boc protection with N-Boc as starting material using amino acid, obtain the boc-protected amino acid of amino N-；The boc-protected amino acid of amino N-and esterifying reagent are subjected to esterification, obtain esterification products；Esterification products and sulfonylation agent are subjected to sulfonylation, obtain sulfonylated product；Sulfonylated product and fluoroform seleno salt are subjected to fluoroform selenium glycosylation reaction, obtain the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-.The reaction is not only easy to operate, mild condition, yield is higher, functional group tolerance is fine, but also raw material is cheap and easy to get, provides a kind of very useful method for synthesis trifluoromethyl seleno-amino acids derivative.

Description

Trifluoromethyl seleno-amino acids derivative and preparation method thereof
Technical field
The present invention relates to organic synthesis, in particular to a kind of trifluoromethyl seleno-amino acids derivative and preparation method thereof.
Background technique
Basic composition unit of the amino acid as protein is the most basic object for participating in organic intracorporal various vital movements One of matter.Cysteine and methionine are the special sulfur-containing amino acid of two of them, are promoting human body and animal growth side Face plays an important role.As cysteine, selenocysteine can be synthesized by human body itself, be that selenium element is present in Principal mode in human body, the two also have similar property.Selenocysteine is for As3+、Hg2+Etc. heavy metal ion tool There is very strong affinity, the heavy metal toxicity that can be effectively reduced in human body；It can also by enhance selenoenzyme activity, And then excessive in vivo peroxide and free radical are removed, to achieve the purpose that anti-aging.Selenium-methyl selenium substituted aminothiopropionic It is only two kinds of nature with selenomethionine and contains selenoaminoacid, is primarily present in plant and yeast in natural environment.Phase For inorganic selenium, organic selenium has low toxicity, is easy to be absorbed by organisms, and is not easy largely to accumulate in vivo and cause to be poisoned The advantages that.And selenocysteine is found to have the effect for preventing and treating cancer.It has been reported that selenium-methyl selenium selenium Breast cancer MCF-7, oophoroma SKOV-3 cell, prostatic cell DU145, osteosarcoma MG63 can be promoted thin for cysteine Born of the same parents, the isocellular apoptosis of preceding marrow cell leukemia HL-6 (A.Bhattacharya, Expert Opin.Drug Del.2011,8,749-763.)。
In past tens of years, fluorine atom or fluoro-containing group are introduced into amino acid be proved to be improve polypeptide and A kind of effective means of protein biology characteristic.Trifluoromethyl selenocysteine is a kind of novel seleno containing fluoroform Amino acid, compared with selenocysteine, the former has obtained a degree of promotion in lipophilicity.In recent years, to amino acid It is middle introduce fluoroform seleno method only have an example report, this method using N-Boc-L- acid tert-butyl as starting material, It is respectively trifluoromethyl source by selenium source, trimethyl trifluoromethyl silane of Potassium Selenocyanate, just obtains target product through the reaction of seven steps Trifluoro selenomethionine, synthesis step relatively complicated (E.Block, S.J.Booker, S.Roovsky, et al.ChemBioChem,2016,17,1738-1751.)。
Summary of the invention
It is an object of the invention to overcome above-mentioned technical deficiency, propose a kind of trifluoromethyl seleno-amino acids derivative and its Preparation method, the preparation method raw material is cheap and easily-available, mild condition, synthesis step is simple, instrument and equipment requirement is low and operates It is easy.
To reach above-mentioned technical purpose, the present invention provides the first solutions: a kind of trifluoromethyl seleno-amino acids spread out Biology preparation method, the preparation method the following steps are included:
It protects reagent to carry out N-Boc protection with N-Boc as starting material using amino acid to react, obtain amino N-Boc protection Amino acid；
The boc-protected amino acid of amino N-and esterifying reagent are subjected to esterification, obtain esterification products；
Esterification products and sulfonylation agent are subjected to sulfonylation, obtain sulfonylated product；
Sulfonylated product and fluoroform seleno salt are subjected to fluoroform selenium glycosylation reaction, obtain amino N-boc-protected three Methyl fluoride seleno-amino acids derivative.
The present invention provides the second solutions: a kind of boc-protected trifluoromethyl seleno-amino acids derivative of amino N-, The boc-protected trifluoromethyl seleno-amino acids derivative of the amino N-is by trifluoromethyl seleno in aforementioned first solution Obtained by the preparation method of amino acid derivativges.
The boc-protected trifluoromethyl seleno-amino acids derivant structure formula of amino N-is as follows:
Wherein, n is any one of 1 or 2, R1For C1-12Saturated alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, benzyl Base, allyl, any one in 3- oxocyclopentyl.
The present invention provides third solutions: a kind of amino N atom takes off boc-protected trifluoromethyl seleno-amino acids and spreads out Biology, it is by by aforementioned second solution that the amino N atom, which takes off boc-protected trifluoromethyl seleno-amino acids derivative, The middle boc-protected trifluoromethyl seleno-amino acids derivative of amino N-and de- Boc protection reagent carry out obtained by de- Boc protection.
It is as follows that amino N atom takes off boc-protected trifluoromethyl seleno-amino acids derivant structure formula:
The boc-protected trifluoromethyl seleno-amino acids derivative of amino N-take off with de- Boc protection reagent boc-protected Reaction equation is as follows:
Wherein, n is any one of 1 or 2, R1For C1-12Saturated alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, benzyl Base, allyl, any one in 3- oxocyclopentyl.
Compared with prior art, the beneficial effect comprise that the present invention passes through from cheap and easily-available amino acid Simple amino N atom Boc protection, carboxyl esterification and hydroxysulfonamide step prepare corresponding sulfonylated product, then exist No metal and any additive participate in lower and fluoroform seleno reactant salt, obtain the boc-protected trifluoromethyl seleno ammonia of amino N- Base acid derivative finally takes off Boc protection to product amino N atom, obtains amino N atom and take off boc-protected trifluoromethyl seleno Amino acid derivativges.The reaction is not only easy to operate, mild condition, yield is higher, functional group tolerance is fine, but also raw material is honest and clean Valence is easy to get, and provides a kind of very useful method for synthesis trifluoromethyl seleno-amino acids derivative.
Detailed description of the invention
Fig. 1 is the process flow chart of one embodiment of preparation method of trifluoromethyl seleno-amino acids derivative of the present invention.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to Limit the present invention.
For the first solution of the invention, the present invention provides a kind of systems of trifluoromethyl seleno-amino acids derivative Preparation Method, such as Fig. 1, the preparation method comprises the following steps:
S1: it protects reagent to carry out N-Boc protection with N-Boc as starting material using amino acid and reacts, obtain amino N-Boc guarantor The amino acid of shield；
S2: the boc-protected amino acid of amino N-and esterifying reagent are subjected to esterification, obtain esterification products；
S3: esterification products and sulfonylation agent are subjected to sulfonylation, obtain sulfonylated product；
S4: sulfonylated product and fluoroform seleno salt are subjected to fluoroform selenium glycosylation reaction, it is boc-protected to obtain amino N- Trifluoromethyl seleno-amino acids derivative.
In the present invention, amino acid is any one in serine or homoserine.
In the present invention, carried out under the conditions of N-Boc protection reaction is existing for the first alkali, amino acid, the first alkali and N-Boc are protected The molar ratio for protecting reagent is 1:(1~2): (1.2~1.5).
In the present invention, the first alkali is potassium carbonate, sodium carbonate, sodium bicarbonate, saleratus, potassium phosphate, potassium hydrogen phosphate, hydrogen-oxygen The mixture of any one or more in change potassium, sodium hydroxide.
In the present invention, N-Boc protects reagent for di-tert-butyl dicarbonate, Isosorbide-5-Nitrae-diphenyl di-tert-butyl dicarbonic acid ester, 1, 2,2,2- tetrachloro ethyl tert-butyl carbonic ester, 2- pyridyl group tert-butyl carbonate, the tertiary fourth of norbornene -2,3- dicarboxyl imido grpup It is any one in base carbonic ester, 2- amino -2- [2- (3- chlorine) pyrazinyl] vinyl tert-butyl carbonate or isobutylchloroformate Kind.
In the present invention, carried out under the conditions of esterification is existing for the second alkali, the boc-protected amino acid of amino N-, second The molar ratio of alkali and esterifying reagent is 1:(1~1.5): (2~2.5), it is therefore preferable to 1:(1~1.1): (2~2.2).Compare herein In example range, esterification can be made sufficiently to carry out, and avoid raw material excessive, cause to waste.
In the present invention, the second alkali is potassium carbonate, cesium carbonate, sodium hydride, sodium bicarbonate, saleratus, potassium phosphate, phosphoric acid hydrogen Potassium, lithium hydroxide, the mixture of any one or more in sodium hydroxide.
In the present invention, esterifying reagent C1-12It is saturated idoalkane, C3-6Iodo cycloalkane, benzyl bromine, benzyl chloride, allyl bromide, bromoallylene, 3- Any one of (4- methoxyphenoxy) -1- iodopropane, 3- iodine tetrahydrofuran, 4- iodomethyl tetrahydrofuran, it is preferred that esterification Reagent is iodomethane.
In the present invention, the molar ratio of esterification products and sulfonylation agent is 1:(0.5~3).In this proportional region, it can make Sulfonylation sufficiently carries out, and avoids raw material excessive, causes to waste.
In the present invention, sulfonylation agent is paratoluensulfonyl chloride, 3,5- Dimethylbenzenesulfonyl chloride, toluene sulfochloride, neighbour Toluene sulfochloride, 4- ethyl benzene sulfonyl chloride, 4- trifluoromethoxy benzene sulfonyl chloride, 3- cyano -4- fluorophenylsulfonyl chloride, 2- nitrobenzene sulphur The chloro- 3- nitrobenzene sulfonyl chloride of acyl chlorides, 4-, 4- biphenylsulfonyl chloride, 4- methyl-1-naphthalene sulfonyl chloride, 8- quinoline sulfuryl chloride, C1-6It is full With alkyl sulfonyl chloride, C3-6Naphthene sulfamide chlorine, 3- cyanobenzyls sulfonic acid chloride, 4- fluorobenzylsulfonyl chloride, 4- trifluoromethyl benzyl sulphur Acyl chlorides, 3- chlorobenzyl sulfonic acid chloride, 2- phenethyl sulfonic acid chloride, any one in 4- nitrobenzylsulfonyl chloride；Preferably, sulfonylation Reagent is 4- toluene sulfochloride.
In the present invention, the molar ratio of sulfonylated product and fluoroform seleno salt is 1:(1.2~10).In this proportional region It is interior, fluoroform selenium glycosylation reaction can be made sufficiently to carry out, and avoid raw material excessive, cause to waste.
In the present invention, fluoroform seleno salt is any one in fluoroform seleno ammonium salt or fluoroform seleno metal salt.
In the present invention, fluoroform seleno salt is [Me4N][SeCF3]、[Et4N][SeCF3]、[Pr4N][SeCF3]、[Bu4N] [SeCF3]、AgSeCF3、CuSeCF3、Hg(SeCF3)2、NaSeCF3、KSeCF3、CsSeCF3In any one.
In the present invention, the temperature of fluoroform selenium glycosylation reaction is 25 DEG C~80 DEG C, and the time is 5min~72h.In this temperature In time range, can react fully progress.Specifically, at identical conditions, extending the reaction time, products collection efficiency is had It is improved；Thermotonus is increased, reaction time when reaching same effect can shorten, and improve reaction rate.
As preferred embodiment, step of the invention includes:
S1: amino acid and the first alkali is soluble in water, after being cooled to 0 DEG C, N-Boc protection reagent solution is slowly added dropwise, stirs Reaction is mixed, the boc-protected amino acid of amino N-is obtained；
S2: it by the boc-protected amino acid of amino N-and the second alkali soluble in the first solvent, after being cooled to 0 DEG C, is slowly added to Esterifying reagent solution reacts 30min, then rises again to 25 DEG C, be stirred to react 4h, obtain esterification products；
S3: esterification products are dissolved in the second solvent, are cooled to 0 DEG C, and sulfonylation agent is added, is added after being stirred to react 8h Third solvent rises again to 25 DEG C, continues to be stirred to react 14h, obtain sulfonylated product；
S4: sulfonylated product and fluoroform seleno salt are added in the 4th solvent, is stirred to react, is obtained after isolating and purifying The boc-protected trifluoromethyl seleno-amino acids derivative of amino N-.
In the present invention, the first solvent is any one or more in DMF, methylene chloride, tetrahydrofuran, acetonitrile and NMP Mixture；
In the present invention, the second solvent is pyridine.
In the present invention, third solvent is ether.
In the present invention, the 4th solvent is acetonitrile, methylene chloride, 1,2- dichloroethanes, chloroform, tetrahydrofuran, Isosorbide-5-Nitrae- The mixture of any one or more in dioxane, ether, toluene, benzene and sulfone class solvent.
In the present invention, the reaction equation of the preparation method is as follows:
S1:
S2:
S3
S4
Wherein, n is any one of 1 or 2, R1For C1-12Saturated alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, benzyl Base, allyl, any one in 3- oxocyclopentyl；R2For p-methylphenyl, 3,5- 3,5-dimethylphenyl, tolyl, adjacent first Phenyl, 4- ethylphenyl, 4- Trifluoromethoxyphen-l, 3- cyano -4- fluorophenyl, 2- nitrobenzophenone, chloro- 3 nitrobenzophenone of 4-, connection Phenyl, 4- methyl naphthalene, 8- quinolyl, C1-6Saturated alkyl, C3-6Naphthenic base, 3- cyanobenzyls, 4- luorobenzyl, 4- trifluoromethyl Benzyl, 3- chlorobenzyl, 2- phenethyl, any one in 4- nitrobenzyl.
For the second solution of the invention, the present invention provides a kind of boc-protected trifluoromethyl selenos of amino N- Amino acid derivativges, the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-is by aforementioned first solution party In case obtained by the preparation method of trifluoromethyl seleno-amino acids derivative, therefore trifluoromethyl selenium in two solutions of the invention It should be structurally and functionally consistent for amino acid derivativges.
The boc-protected trifluoromethyl seleno-amino acids derivant structure formula of amino N-is as follows:
Wherein, n is any one of 1 or 2, R1For C1-12Saturated alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, benzyl Base, allyl, any one in 3- oxocyclopentyl.
For third solution of the invention, the present invention provides a kind of amino N atoms to take off boc-protected trifluoromethyl Seleno-amino acids derivative, it is by will be aforementioned that the amino N atom, which takes off boc-protected trifluoromethyl seleno-amino acids derivative, The boc-protected trifluoromethyl seleno-amino acids derivative of amino N-and de- Boc protection reagent carry out de- Boc in second solution Obtained by protection.
It is as follows that the amino N atom takes off boc-protected trifluoromethyl seleno-amino acids derivant structure formula:
The boc-protected trifluoromethyl seleno-amino acids derivative of amino N-and de- Boc protection reagent carry out de- Boc and protect The reaction equation of shield is as follows:
Wherein, n is any one of 1 or 2, R1For C1-12Saturated alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, benzyl Base, allyl, any one in 3- oxocyclopentyl.
In the present invention, the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-and de- Boc protect reagent into It includes: by the dioxane solution of trifluoromethyl seleno-amino acids derivative, methanol and hydrogen chloride that row, which takes off boc-protected step, It is stirred 3 hours at 25 DEG C, obtains amino N atom and take off boc-protected trifluoromethyl seleno-amino acids derivative.
Based on trifluoromethyl seleno-amino acids derivative is prepared by starting material of serine, successively constitution and implementation example 1~ 7, wherein product obtained in Examples 1 to 6 is the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-, embodiment Product obtained in 7 is that amino N atom takes off boc-protected trifluoromethyl seleno-amino acids derivative.
Embodiment 1
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps:
Serine (3.15g, 30mmol) and NaOH (1.28g, 32mmol) are dissolved in 32mL water, after being cooled to 0 DEG C, delayed The slow dioxane solution that 30mL di-tert-butyl dicarbonate is added dropwise, wherein the concentration of di-tert-butyl dicarbonate is 1.2M；Stirring is anti- After answering 30min, rise again to 25 DEG C the reaction was continued for 24 hours；After reaction, reaction solution decompression is boiled off into most of solvent, then 0 The pH to 2 of reaction solution is adjusted at DEG C with the sodium bisulfate of 1mol/L；After ethyl acetate extracts 3 times, by the organic of merging Mutually dry with anhydrous sodium sulfate, evaporated under reduced pressure obtains N-Boc serine (weak yellow liquid 6.09g, yield 99%).
N-Boc serine (1.23g, 6mmol) and potassium carbonate (0.90g, 6.5mmol) are dissolved in 12mLDMF, are cooled to The DMF solution of 6mL iodomethane is slowly added dropwise after 0 DEG C, wherein the concentration of iodomethane is 2.1M, and is stirred to react 30min, then It rises again to 25 DEG C of the reaction was continued 4h；Gained reaction solution is filtered, and collects filtrate；Excessive water is added into filtrate, and uses second Acetoacetic ester extracts 3 times；Combined organic phase is washed, then dry with anhydrous sodium sulfate with saturated sodium chloride solution, is then depressurized It is evaporated；Gained residue uses the n-hexane that volume ratio is 1:1 and ethyl acetate as eluant, eluent, after column chromatographic isolation and purification, The eluent evaporated under reduced pressure that will be collected into obtains product N-Boc serine methylester (colourless oil liquid 1.17g, yield 89%).
N-Boc serine methylester (0.44g, 2mmol) is dissolved in 7mL pyridine, is cooled to 0 DEG C, adds 4- toluene sulphur Acyl chlorides (0.76g, 4mmol), continues to be stirred to react 8h；Then 6.5mL ether is added, rises again and is stirred to react 14h to 25 DEG C；Terminate Afterwards, reaction solution is poured into ice water, aqueous potassium hydrogen sulfate is added to neutralize；Then it is extracted with ethyl acetate 3 times, merges organic layer, It is washed with saturated sodium chloride solution, and dry with anhydrous sodium sulfate；By organic layer evaporated under reduced pressure, obtained solid volume ratio is 2: 1 petroleum ether and ethyl acetate is as eluant, eluent, and after column chromatographic isolation and purification, the eluent evaporated under reduced pressure that will be collected into is obtained To sulfonylated product (white solid 0.58g, yield 78%).
Under conditions of 25 DEG C and nitrogen protection, 2mL acetonitrile, sulfonylated product are sequentially added into the reaction tube of 20mL (74.6mg, 0.2mmol) and [Me4N][SeCF3] (67mg, 0.3mmol), reaction solution is spin-dried for after being stirred to react 24 hours, it is residual Object petroleum ether in a volume ratio of 10:1 and ethyl acetate is stayed to obtain amino N-Boc protection through column chromatographic purifying as eluant, eluent Trifluoromethyl seleno-amino acids derivative (62.5mg, yield 89%).1H NMR(500MHz,CDCl3)δ5.39(brs,1H), 4.72 (s, 1H), 3.79 (s, 3H), 3.44 (ddd, J=79.2,12.7,3.4Hz, 2H), 1.45 (s, 9H)；19F NMR (471MHz,CDCl3)δ-34.2(s,3F)；13C NMR(126MHz,CDCl3) δ 170.5,154.9,122.2 (q, J= 330.5Hz), 80.6,53.1,52.9 (q, J=1.4Hz), 28.2,27.8.IR (KBr): 3363,3003,2974,2955, 2930,2801,1730,1676,1522,1439,1412,1395,1372,1342,1322,1290,1257,1237,1163, 1117,1049,1034,1012,949,914,877,834,798,780,739,656,621cm-1.HRMS-ESI(m/z) calcd.for[C10H17F3NO4Se]+([M+H]+):352.0269；found:352.0261.
Embodiment 2:
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps:
Serine (1.58g, 15mmol) and NaOH (1.20g, 30mmol) are dissolved in 30mL water, after being cooled to 0 DEG C, delayed The slow dioxane solution that 18mL isobutylchloroformate is added dropwise, wherein the concentration of isobutylchloroformate is 1.25M；Then at 0 DEG C Under be stirred to react for 24 hours；After reaction, reaction solution is boiled off to most of solvent under reduced pressure, then with 1mol/L's at 0 DEG C The pH to 2 of sodium bisulfate adjusting reaction solution；It is extracted with ethyl acetate 3 times, combined organic phase is dry with anhydrous sodium sulfate again Dry, organic layer evaporated under reduced pressure, obtained solid uses the petroleum ether that volume ratio is 2:3 and ethyl acetate as eluant, eluent, chromatographs through column After isolating and purifying, the eluent evaporated under reduced pressure that will be collected into obtains N-Boc serine (weak yellow liquid 1.5g, yield 49%).
N-Boc serine (1.23g, 6mmol) and sodium bicarbonate (0.55g, 6.5mmol) are dissolved in 12mLDMF, cooled down The DMF solution of 6mL iodomethane is slowly added dropwise after to 0 DEG C, wherein the concentration of iodomethane is 2.1M, and is stirred to react 30min, with After rise again to 25 DEG C of the reaction was continued 4h；Gained reaction solution is filtered, and collects filtrate；Excessive water is added into filtrate, is used in combination Ethyl acetate extracts 3 times；Combined organic phase is washed, then dry with anhydrous sodium sulfate with saturated sodium chloride solution, is then subtracted Pressure is evaporated；Gained residue uses the n-hexane that volume ratio is 1:1 and ethyl acetate as eluant, eluent after column chromatographic isolation and purification, The eluent evaporated under reduced pressure that will be collected into obtains product N-Boc serine methylester (colourless oil liquid 0.80g, yield 61%).
N-Boc serine methylester (0.66g, 3mmol) is dissolved in 10mL pyridine, is cooled to 0 DEG C, adds 4- toluene sulphur Acyl chlorides (1.14g, 6mmol), continues to be stirred to react 8h；Then 10mL ether is added, rises again and is stirred to react 14h to 25 DEG C；Terminate Afterwards, reaction solution is poured into ice water, aqueous potassium hydrogen sulfate is added to neutralize；Then it is extracted with ethyl acetate 3 times, merges organic layer, It is washed with saturated sodium chloride solution, and dry with anhydrous sodium sulfate；Organic layer evaporated under reduced pressure, obtained solid are 2:1 with volume ratio Petroleum ether and ethyl acetate as eluant, eluent, after column chromatographic isolation and purification, the eluent evaporated under reduced pressure that will be collected into Obtain sulfonylated product (white solid 0.90g, yield 80%).
Under conditions of 25 DEG C and nitrogen protection, 2mL methylene chloride, sulfonylated product are sequentially added into 20mL reaction tube (74.6mg, 0.2mmol) and KSeCF3Reaction solution is spin-dried for by (188mg, 1mmol) after being stirred to react 72 hours, residue body Petroleum ether and ethyl acetate of the product than being 10:1 are purified by silica gel column chromatography as eluant, eluent, obtain amino N-boc-protected three Methyl fluoride seleno-amino acids derivative (64.4mg, yield 92%).
Embodiment 3
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps: remove Outside the preparation process of N-Boc serine methylester, remaining condition is consistent with embodiment 1.
The preparation process of N-Boc serine methylester is as follows: by N-Boc serine (1.23g, 6mmol) and potassium hydrogen phosphate (0.77g, 6.5mmol) is dissolved in 12mLDMF, and the DMF solution of 6mL iodomethane is slowly added dropwise after being cooled to 0 DEG C, wherein iodine first The concentration of alkane is 2.1M, and is stirred to react 30min, is then risen again to 25 DEG C of the reaction was continued 4h.Gained reaction solution is filtered, and is received Collect filtrate；Excessive water is added into filtrate, and is extracted with ethyl acetate 3 times；Combined organic phase saturated sodium-chloride is molten Liquid washs, then dry with anhydrous sodium sulfate, then evaporated under reduced pressure；The n-hexane and acetic acid that gained residue is 1:1 with volume ratio Ethyl ester is as eluant, eluent, and after column chromatographic isolation and purification, the eluent evaporated under reduced pressure that will be collected into obtains N-Boc ammonia of product Sour methyl esters (colourless oil liquid 0.60g, yield 46%).
Finally, the boc-protected trifluoromethyl seleno-amino acids of amino N-are obtained after fluoroform seleno reaction process to spread out Biological (63.0mg, yield 90%),
Embodiment 4
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps: remove Outside the preparation process of the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-, remaining condition is consistent with embodiment 1.
The preparation process of the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-is as follows: protecting in 25 DEG C and nitrogen Under conditions of shield, 2mL acetonitrile, sulfonylated product (746mg, 2mmol) and [Me are sequentially added into 20mL reaction tube4N] [SeCF3] (667mg, 3mmol), it is stirred to react at 30 DEG C after 36 hours and is spin-dried for reaction solution, residue volume ratio is 10: 1 petroleum ether and ethyl acetate is as eluant, eluent, after being purified by silica gel column chromatography, obtains the boc-protected trifluoromethyl of amino N- Seleno-amino acids derivative (573.4mg, yield 82%).
Embodiment 5
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps: remove Outside the preparation process of the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-, remaining condition is consistent with embodiment 1.
The preparation process of the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-is as follows: protecting in 25 DEG C and nitrogen Under conditions of shield, 2mL acetonitrile, sulfonylated product (74.6mg, 0.2mmol) and [Me are sequentially added into 20mL reaction tube4N] [SeCF3] (53.6mg, 0.24mmol), it is stirred to react at 40 DEG C after 48 hours and is spin-dried for reaction solution, residue volume ratio For 10:1 petroleum ether and ethyl acetate as eluant, eluent, after being purified by silica gel column chromatography, obtain the boc-protected trifluoro of amino N- Methyl seleno-amino acids derivative (49.3mg, yield 70%).
Embodiment 6
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps: remove Outside the preparation process of the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-, remaining condition is consistent with embodiment 1.
The preparation process of the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-is as follows: protecting in 25 DEG C and nitrogen Under conditions of shield, sequentially add 2mL methylene chloride into 20mL reaction tube, sulfonylated product (74.6mg, 0.2mmol) and KSeCF3(188mg, 1mmol) is stirred to react after 72 hours at 25 DEG C and is spin-dried for reaction solution, and residue is 10:1 with volume ratio Petroleum ether and ethyl acetate as eluant, eluent, after being purified by silica gel column chromatography, obtain the boc-protected trifluoromethyl selenium of amino N- For amino acid derivativges (64.4mg, yield 92%).
Embodiment 7
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps:
It is former using the boc-protected trifluoromethyl seleno-amino acids derivative preparation amino N of amino N-obtained in embodiment 1 The specific steps that son takes off boc-protected trifluoromethyl seleno-amino acids derivative include:
It is derivative that the boc-protected trifluoromethyl seleno-amino acids of 5mL methanol, amino N-are sequentially added into 50mL round-bottomed flask The dioxane solution (5mL) of object (175.1mg, 0.5mmol) and hydrogen chloride, wherein the concentration of hydrogen chloride is 4M；At 25 DEG C Reaction solution is spin-dried for by stirring after 3 hours, using ether wash residual object, is obtained amino N atom after dry and is taken off boc-protected trifluoro Methyl seleno-amino acids derivative (130.4mg, yield 91%).1H NMR(500MHz,DMSO-d6)δ9.05(s,3H),4.47 (t, J=6.0Hz, 1H), 3.76 (s, 3H), 3.60-3.49 (m, 2H)；19F NMR(471MHz,DMSO-d6)δ-35.1(s, 3F)；13C NMR(126MHz,DMSO-d6) δ 168.6,123.2 (q, J=332.1Hz), 53.5,52.6.IR (KBr): 3355, 3028,3002,2979,2957,2915,1728,1677,1525,1463,1440,1395,1370,1345,1306,1283, 1258,1231,1205,1153,1052,1035,1012,985,928,879,863,814,790,737,729,677,601cm-1.HRMS-ESI(m/z)calcd.for[C5H9F3NO2Se]+([M+H]+):251.9745；found:251.9754.
Based on trifluoromethyl seleno-amino acids derivative is prepared by starting material of homoserine, successively constitution and implementation example 8 ~12, wherein product obtained in embodiment 8~11 is the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-, real Applying product obtained in example 12 is that amino N atom takes off boc-protected trifluoromethyl seleno-amino acids derivative.
Embodiment 8
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps:
Homoserine (2.38g, 20mmol) and NaOH (0.80g, 20mmol) are dissolved in water (20mL), are cooled to 0 DEG C The dioxane solution of 20mL di-tert-butyl dicarbonate is slowly added dropwise afterwards, wherein the concentration of di-tert-butyl dicarbonate is 1.2M；It stirs Mix reaction 30min after, rise again to 25 DEG C the reaction was continued for 24 hours；After reaction, reaction solution is boiled off under reduced pressure most of molten Agent, the sodium bisulfate that 1mol/L is then added at 0 DEG C adjust the pH to 2 of reaction solution；With n-hexane extraction 3 times, merge Organic phase it is dry with anhydrous sodium sulfate again, obtained after evaporated under reduced pressure N-Boc protection homoserine (viscous liquid 4.08g, 93%) yield is.
The homoserine (1.31g, 6mmol) of N-Boc protection and potassium carbonate (0.90g, 6.5mmol) are dissolved in 12mLDMF In, the DMF solution of 6mL iodomethane is slowly added dropwise after being cooled to 0 DEG C, wherein the concentration of iodomethane is 2.1M, is stirred to react 30min, then rise again and be stirred to react 4h to 25 DEG C；Gained reaction solution is filtered, and collects filtrate；It is added into filtrate excessive Water, and be extracted with ethyl acetate 3 times.Combined organic phase is washed with saturated sodium chloride solution, then dry with anhydrous sodium sulfate, Then evaporated under reduced pressure directly carries out the mixture being collected into feed intake in next step.
Mixture obtained in the previous step is dissolved in 30mL pyridine, after being cooled to 0 DEG C be added 4- toluene sulfochloride (3.7g, 17.2mmol), continue to be stirred to react 8h；Then 50mL ether is added, rises again and is stirred to react 14h to 25 DEG C；After, it will react Liquid pours into ice water, and aqueous potassium hydrogen sulfate is added to neutralize, and is then extracted with ethyl acetate 3 times, merges organic layer, with saturation chlorination Sodium solution washing, and it is dry with anhydrous sodium sulfate；Organic layer evaporated under reduced pressure, obtained solid with volume ratio be 2:1 petroleum ether and Ethyl acetate is as eluant, eluent, and through column chromatographic isolation and purification, the eluent evaporated under reduced pressure that will be collected into obtains sulfonylated product (white solid 1.32g), the merging yield of two steps are 57%.
Under conditions of 25 DEG C and nitrogen protection, 2mL acetonitrile, sulfonylated product are sequentially added into 20mL reaction tube (77.4mg, 0.2mmol) and [Me4N][SeCF3] (67mg, 0.3mmol), reaction solution is spin-dried for after being stirred to react 24 hours, it is residual It stays object petroleum ether in a volume ratio of 10:1 and ethyl acetate as eluant, eluent, is purified by silica gel column chromatography, obtain amino N-Boc The trifluoromethyl seleno-amino acids derivative (70.6mg, yield 97%) of protection.1H NMR(500MHz,CDCl3)δ5.16(brs, 1H),4.43(s,1H),3.76(s,3H),2.98(m,2H),2.34(m,1H),2.11(m,1H),1.43(s,9H)；19F NMR (471MHz,CDCl3)δ-34.6(s,3F)；13C NMR(126MHz,CDCl3) δ 172.3,155.4,122.6 (q, J= 330.1Hz), 80.3,53.1,52.6 (q, J=1.5Hz), 34.2,28.2,21.2.IR (KBr): 3419,2931,2896, 2831,2746,2673,2635,2594,1754,1636,1601,1568,1493,1444,1390,1371,1346,1271, 1236,1169,1103,1061,994,938,904,939,754,739,692,647cm-1.HRMS-ESI(m/z)calcd.for [C11H18F3NO4Se]+([M+H]+):366.0426；found:366.0420.
It should be noted that after esterification, it is anti-by TLC monitoring and nuclear magnetic data characterization discovery, above-mentioned esterification Two kinds of polarity analogue compounds are produced in answering, the biggish compound of polarity is esterification product, and the lesser product of polarity is point Son lactonizes the by-product of cyclization, both is not able to achieve and to be kept completely separate in treatment process after the test, but the mixture can be in sulphur Sulfonylated product is generated in acylation reaction, therefore uses " one kettle way ", and after esterification reaction of organic acid completion, reaction solution is only carried out Simple post-processing, does not attempt to separate, directly using obtained mixture as the raw material of next step sulfonylation, and previous step The molar ratio of obtained mixture and 4- toluene sulfochloride is 1:3.
Embodiment 9
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps: remove Outside the preparation process of the boc-protected homoserine of amino N-, remaining condition is consistent with embodiment 8.
The preparation process of the boc-protected homoserine of amino N-is as follows: by homoserine (2.38g, 20mmol) and NaOH (0.80g, 20mmol) is dissolved in 20mL water, and the dioxy of 30mL2- pyridyl group tert-butyl carbonate is slowly added dropwise after being cooled to 0 DEG C Six ring solution, wherein the concentration of 2- pyridyl group tert-butyl carbonate is 0.8M；After being stirred to react 30min, rises again to 25 DEG C and continue Reaction is for 24 hours.After reaction, reaction solution is boiled off to most of solvent under reduced pressure, the sulfuric acid of 1mol/L is then added at 0 DEG C The pH to 2 of hydrogen sodium solution adjusting reaction solution；With n-hexane extraction 3 times, combined organic phase is dry with anhydrous sodium sulfate again, decompression The homoserine (viscous liquid 3.85g, yield 88%) of N-Boc protection is obtained after being evaporated.
Finally, the boc-protected trifluoromethyl seleno-amino acids of amino N-are obtained after fluoroform seleno reaction process to spread out Biological (69.1mg, yield 95%).
Embodiment 10
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps: remove Outside the preparation process of the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-, remaining condition is consistent with embodiment 8.
The preparation process of the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-is as follows: protecting in 25 DEG C and nitrogen Under conditions of shield, 2mL acetonitrile, sulfonylated product (774mg, 2.0mmol) and [Me are sequentially added into 20mL reaction tube4N] [SeCF3] (667mg, 3.0mmol), reaction solution is spin-dried for after being stirred to react 36 hours, residue stone in a volume ratio of 10:1 Oily ether and ethyl acetate are purified by silica gel column chromatography as eluant, eluent, obtain the boc-protected trifluoromethyl seleno amino of amino N- Acid derivative (663.1mg, yield 91%).
Embodiment 11
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps: remove Outside the preparation process of the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-, remaining condition is consistent with embodiment 8.
The preparation process of the boc-protected trifluoromethyl seleno-amino acids derivative of amino N-is as follows: protecting in 25 DEG C and nitrogen Under conditions of shield, sequentially added into 20mL reaction tube 2mL dimethyl sulfoxide, sulfonylated product (77.4mg, 0.2mmol) and CsSeCF3(569.3mg, 2mmol) is stirred to react after 5min at 80 DEG C and is spin-dried for reaction solution, and residue volume ratio is 10: 1 petroleum ether and ethyl acetate is purified by silica gel column chromatography as eluant, eluent, obtains the boc-protected trifluoromethyl selenium of amino N- For amino acid derivativges (52.4mg, yield 72%).
Embodiment 12
Present embodiments provide a kind of preparation method of trifluoromethyl seleno-amino acids derivative, comprising the following steps:
It is former using the boc-protected trifluoromethyl seleno-amino acids derivative preparation amino N of amino N-obtained in embodiment 8 The specific steps that son takes off boc-protected trifluoromethyl seleno-amino acids derivative include:
The boc-protected trifluoromethyl seleno-amino acids of 10mL methanol, amino N-are sequentially added into 50mL round-bottomed flask to spread out The dioxane solution (10mL) of biology (364.2mg, 1mmol) and hydrogen chloride, wherein the concentration of hydrogen chloride is 4M；At 25 DEG C Reaction solution is spin-dried for by stirring after 3 hours, using ether wash residual object, is dried to obtain amino N atom and is taken off boc-protected fluoroform Base seleno-amino acids derivative (276.1mg, yield 92%).1H NMR(500MHz,D2O) δ 4.25 (t, J=6.6Hz, 1H), 3.81(s,3H),3.13(m,2H),2.52-2.33(m,2H)；19F NMR(471MHz,D2O)δ-34.6(s,3F)；13C NMR (126MHz,D2O) δ 169.9,122.6 (q, J=330.3Hz), 53.7,52.4,31.1,20.2.IR (KBr): 3428,2974, 2938,2897,2823,2729,2662,2623,1755,1606,1516,1449,1356,1287,1245,1163,1122, 1090,1029,985,959,899,838,793,734,668,633cm-1.HRMS-ESI(m/z)calcd.for [C6H11F3NO2Se]+([M+H]+):265.9902；found:265.9893.
Compared with prior art, the beneficial effect comprise that the present invention passes through from cheap and easily-available amino acid Simple amino N atom Boc protection, carboxyl esterification and hydroxysulfonamide step prepare corresponding sulfonylated product, then exist No metal and any additive participate in lower and fluoroform selenium reactant salt, obtain the boc-protected trifluoromethyl seleno amino of amino N- Acid derivative finally takes off Boc protection to product amino N atom, obtains amino N atom and take off boc-protected trifluoromethyl seleno ammonia Base acid derivative.The reaction is not only easy to operate, mild condition, yield is higher, functional group tolerance is fine, but also raw material is cheap It is easy to get, provides a kind of very useful method for synthesis trifluoromethyl seleno-amino acids derivative.
The above described specific embodiments of the present invention are not intended to limit the scope of the present invention..Any basis Any other various changes and modifications that technical concept of the invention is made should be included in the guarantor of the claims in the present invention It protects in range.

Claims (10)

1. a kind of preparation method of trifluoromethyl seleno-amino acids derivative, which is characterized in that the preparation method includes following Step:
It protects reagent to carry out N-Boc protection with N-Boc as starting material using amino acid to react, obtain the boc-protected ammonia of amino N- Base acid；
The boc-protected amino acid of the amino N-and esterifying reagent are subjected to esterification, obtain esterification products；
The esterification products and sulfonylation agent are subjected to sulfonylation, obtain sulfonylated product；
The sulfonylated product and fluoroform seleno salt are subjected to fluoroform selenium glycosylation reaction, obtain amino N-boc-protected three Methyl fluoride seleno-amino acids derivative.
2. the preparation method of trifluoromethyl seleno-amino acids derivative according to claim 1, which is characterized in that the N- It is carried out under the conditions of Boc protection reaction is existing for the first alkali, the amino acid, first alkali and the N-Boc protect reagent Molar ratio be 1:(1~2): (1.2~1.5).
3. the preparation method of trifluoromethyl seleno-amino acids derivative according to claim 2, which is characterized in that the N- It is di-tert-butyl dicarbonate, 1,4- diphenyl di-tert-butyl dicarbonic acid ester, 1,2,2,2- tetrachloro ethyl tert-butyl that Boc, which protects reagent, Carbonic ester, 2- pyridyl group tert-butyl carbonate, norbornene -2,3- dicarboxyl imido grpup tert-butyl carbonate, 2- amino -2- Any one in [2- (3- chlorine) pyrazinyl] vinyl tert-butyl carbonate or isobutylchloroformate.
4. the preparation method of trifluoromethyl seleno-amino acids derivative according to claim 1, which is characterized in that the ester It is carried out under the conditions of changing reaction existing for the second alkali, the boc-protected amino acid of the amino N-, second alkali and the esterification The molar ratio of reagent is 1:(1~1.5): (2~2.5).
5. the preparation method of trifluoromethyl seleno-amino acids derivative according to claim 4, which is characterized in that the ester Change reagent is C1-12It is saturated idoalkane, C3-6Iodo cycloalkane, benzyl bromine, benzyl chloride, allyl bromide, bromoallylene, 3- (4- methoxyphenoxy) -1- Any one of iodopropane, 3- iodine tetrahydrofuran, 4- iodomethyl tetrahydrofuran.
6. the preparation method of trifluoromethyl seleno-amino acids derivative according to claim 1, which is characterized in that the sulphur Acylating reagent is paratoluensulfonyl chloride, 3,5- Dimethylbenzenesulfonyl chloride, toluene sulfochloride, o-toluenesulfonyl chloride, 4- ethylo benzene Sulfonic acid chloride, 4- trifluoromethoxy benzene sulfonyl chloride, 3- cyano -4- fluorophenylsulfonyl chloride, 2- nitrobenzene sulfonyl chloride, the chloro- 3- nitrobenzene of 4- Sulfonic acid chloride, 4- biphenylsulfonyl chloride, 4- methyl-1-naphthalene sulfonyl chloride, 8- quinoline sulfuryl chloride, C1-6Saturated alkyl sulfonic acid chloride, C3-6Ring Alkyl sulfonyl chloride, 3- cyanobenzyls sulfonic acid chloride, 4- fluorobenzylsulfonyl chloride, 4- trifluoromethyl benzyl sulfonic acid chloride, 3- chlorobenzyl sulphonyl Chlorine, 2- phenethyl sulfonic acid chloride, any one in 4- nitrobenzylsulfonyl chloride.
7. the preparation method of trifluoromethyl seleno-amino acids derivative according to claim 1, which is characterized in that the sulphur The molar ratio of acylate and fluoroform seleno salt is 1:(1.2~10).
8. the preparation method of trifluoromethyl seleno-amino acids derivative according to claim 7, which is characterized in that described three Fluorine first seleno salt is [Me4N][SeCF3]、[Et4N][SeCF3]、[Pr4N][SeCF3]、[Bu4N][SeCF3]、AgSeCF3、 CuSeCF3、Hg(SeCF3)2、NaSeCF3、KSeCF3、CsSeCF3In any one.
9. a kind of boc-protected trifluoromethyl seleno-amino acids derivative of amino N-, which is characterized in that the amino N-Boc is protected The trifluoromethyl seleno-amino acids derivative of shield is spread out by trifluoromethyl seleno-amino acids described in any one of claim 1~8 Obtained by the preparation method of biology.
The boc-protected trifluoromethyl seleno-amino acids derivant structure formula of amino N-is as follows:
Wherein, n is any one of 1 or 2, R1For C1-12Saturated alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, benzyl, Any one in allyl, 3- oxocyclopentyl.
10. a kind of amino N atom takes off boc-protected trifluoromethyl seleno-amino acids derivative, which is characterized in that the amino N It is by the way that amino N-described in claim 9 is boc-protected that atom, which takes off boc-protected trifluoromethyl seleno-amino acids derivative, Trifluoromethyl seleno-amino acids derivative and de- Boc protection reagent carry out obtained by de- Boc protection.
It is as follows that the amino N atom takes off boc-protected trifluoromethyl seleno-amino acids derivant structure formula:
Wherein, n is any one of 1 or 2, R1For C1-12Saturated alkyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, benzyl, Any one in allyl, 3- oxocyclopentyl.
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Application publication date: 20191115