CN1324002C - Dipropyl phthalic ester hapten derivant and its preparation method - Google Patents
Dipropyl phthalic ester hapten derivant and its preparation method Download PDFInfo
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- CN1324002C CN1324002C CNB2005100300191A CN200510030019A CN1324002C CN 1324002 C CN1324002 C CN 1324002C CN B2005100300191 A CNB2005100300191 A CN B2005100300191A CN 200510030019 A CN200510030019 A CN 200510030019A CN 1324002 C CN1324002 C CN 1324002C
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Abstract
The present invention discloses a dipropyl phthalate semiantigen derivative, and the structure of the dipropyl phthalate semiantigen derivative is represented by the formula (1) or the formula (2). The present invention also discloses a preparation method of the derivative, which comprises the following steps: (A) an esterification reaction between 4-nitro phthalic acid represented by the formula (3) and n propanol happens under an acid condition to obtain a dipropyl phthalate semiantigen derivative represented by the formula (1); (B) the dipropyl phthalate semiantigen derivative represented by the formula (1) reacts with a reducing agent under the acid condition to obtain an other dipropyl phthalate semiantigen derivative represented by the formula (2). The present invention has the advantages of simple and convenient preparation method, no need of special devices, high purity and ability of being used to prepare a complete antigen which can be applied to animal immunization.
Description
Technical field
The present invention relates to hapten derivant of dipropyl phthalate in and preparation method thereof, particularly relate to a kind ofly by obtaining 4-nitrophthalic acid dipropyl with 4-nitrophthalic acid and n-propyl alcohol generation esterification, 4-nitrophthalic acid dipropyl obtains the method for 4-aminophthalic acid dipropyl again by reduction reaction.
Background technology
Contribute a foreword by U.S. vice president Ai Geer since in March, 1996, at first proposed since environmental hormone (Environmental endocrine disruptors) and the influence thereof in " Our Stolen Future " book of works such as American scholar Theo Colborn (TheoColborn) doctor environment, cause the academia and the public's very big concern about environment incretion interferent matter kind and to problems such as the harm of human health and mechanism of action, also caused the great attention of mechanisms such as government of developed country, WHO.Environmental hormone, the foreign matter that promptly refers to make the mankind and biological endocrine system to get muddled, it has similar estrogenic effect, mainly is discharged in the environment with human being's production and life.Field study and experimental study show, sickness rate increases such as environmental hormone class material can cause the sex hormone secretion amount of biological and human body and activity to descend, sperm quantity reduces, reproductive organ is unusual, cancer, and make reproductive performance reduce degradation under offspring's health and the surviving rate.Environmental Hormone Pollution makes biological with human persistent existence and procreation is on the hazard and seriously threatening global environment.At (the World Wild Animal Foundation of World Wildlife Fund, WWF) in 68 kinds of environmental hormones listing in 1997, phthalate (Phthalic Acid Esters, PAEs, also be phthalate) environmental hormone is occupied 8 kinds, is a wherein main big class.Dipropyl phthalate also is put into wherein.
Dipropyl phthalate is used for industries such as plastics, rubber and makeup, spices, printing and dyeing, coating in a large number mainly as softening agent.China is production, the consumption big country of plastics, and " white pollution " is also very general.But the harm of plastic pollution is not paid attention to by people in the past for a long time.Recently discover that such environmental hormone material can be absorbed by the body by approach such as diet, breathing and skin see through, the target organ of main harm human body is a male reproductive system.Along with the use scale of plastics constantly enlarges, the phthalate environmental hormone causes environmental influence and to the chronic and long-time effect of human health, is subjected to people's attention and worry day by day.
The Environmental Hormone material often exists with ppt concentration even ppq concentration, and this has higher requirement to environmental monitoring and analysis, and Japan, the U.S. implement China's stage at the startup.The R and D of ultramicron environmental monitoring technology are one of pendulum vital tasks in face of China environmental science worker.The present main gas-chromatography of monitoring, liquid chromatography and gas-liquid coupling isochromatic spectrum technology to O-phthalic acids environmental hormone, but because the restriction of chromatographic technique itself, must carry out derivatize before measuring, make that the pre-treatment of sample is very complicated, complex operation, used instrument costliness requires to have skilled operator and long analytical cycle, the sensitivity of method also is restricted, and is difficult to adapt to detection and monitoring requirement to environmental hormone.Therefore people urgently wishes to have a kind of simple, fast, sensitivity and inexpensive detection technique can carry out large batch of screening experiment in the open air with in the laboratory to phthalate Environmental Hormone Pollution thing, on-site investigation of polluting and analysis and toxicity Journal of Sex Research, the prediction development trend, check Pollution abatement effect etc.
Immune analysis method can satisfy this requirement with technology such as its specificity and high-sensitive chemoluminescence, fluorescence in conjunction with methods such as setting up corresponding fluorescence immunoassay and chemiluminescence immunoassay.
Berson S.A in 1958 and Yellow have founded radioimmunoassay (RIA), and its labeling technique is that the highly sensitive with isotopic analysis combines with the specificity of antigen antibody reaction, with the label immunoassay method of radio isotope as tracer.The enzyme-linked immunosorbent assay (ELISA), fluoroimmunoassay, chemiluminescence immune assay of development etc. be widely used in the analysis and the quantitative assay of various trace proteins, hormone, small-molecule drug and tumor markers etc. in the research field of medical science and other biological subject and clinical experiment diagnosis gradually afterwards.But because people are later to the harm understanding of phthalate environmental hormone, immune analysis method is applied to the study on monitoring of phthalate environmental hormone and also starts late.
The report of first phthalate environmental hormone immunoassay is the anti-dimethyl phthalate antibody of people such as Ius A. preparation in 1993, has proved the possibility of dimethyl phthalate, diethyl phthalate, dibutyl phthalate, butyl benzyl phthalate and the total flow measurement of dioctyl phthalate (DOP) by antigen antibody reaction.People such as Goda Y in 2000 have proposed to measure with ELISA the method for phthalic ester total amount.U.S. Pat 6 in 2002,399,318 disclose the method for antigens such as preparing dimethyl phthalate, diethyl phthalate, dibutyl phthalate, butyl benzyl phthalate and phthalic acid hexamethylene diester, antibody and the method that ELISA measures diethyl phthalate.But document does not relate to the report of hapten derivant, holoantigen and the immunoassay of dipropyl phthalate.
Because dipropyl phthalate is a small-molecule substance, it has atopic, but does not have immunogenicity.Prepare corresponding antibody and must obtain keeping the artificial antigen (or immunogen) of its antigenic determinant earlier.Again since do not contain in the dipropyl phthalate can with corresponding proteins matter link coupled group, earlier must the corresponding hapten derivant of preparation.The present invention promptly is based on above consideration and a series of dipropyl phthalic ester hapten derivants of designing, and preparation method easily and easily is provided.
This derivative can be applicable to the antigen, Antibody Preparation of dipropyl phthalate and and then is applied to the immunoassay dipropyl phthalate.
Reference:
(1)Ius?A，Bacigalupo?MA，Meroni?G，Pistillo?A，Roda?A.Development?ofa?time-resolved?fluoroimmunoassay?for?phthalate?esters?in?water.Fresenius’J?Anal?Chem.1993，345，589-591.
(2)Goda?Y，Kobayashi?A，Fukuda?K，Fujimoto?S，Ike?M，Fujita?M.Development?of?the?ELISA?for?detection?of?hormone-disruptingchemicals.Water?Sci?Technol.2000，42(7-8)，81-88.
(3)Estevez-Alberola?M.-C.；Marco?M.-P.Immunochemical?determination?ofxenobiotics?with?endocrine?disrupting?effects.Anal?BioanalChem.2004，378：563-575
(4)Yanaihara，Noboru；Kato，Ikuo；Nagasawa，Shingo；Kodaira，Tsukasa.Immunoassay?for?phthalic?acid?esters[P].US?6399318?B1，2002-7-4
Summary of the invention
Technical problem to be solved by this invention provides a kind of dipropyl phthalic ester hapten derivant and preparation method thereof, to remedy the deficiencies in the prior art, satisfies the needs of some field development.
In order to solve the problems of the technologies described above, one of the technical solution adopted in the present invention is: a kind of dipropyl phthalic ester hapten derivant, and its structure is represented with following formula (II):
Two of the technical solution adopted in the present invention is: the preparation method of described derivative comprises the steps:
(A) esterification takes place in 4-nitrophthalic acid and the n-propyl alcohol with following formula (III) expression under acidic conditions, obtains the compound of structural formula (I) expression;
(B) compound with following formula (I) expression is dissolved in the organic solvent, with the reductive agent reaction, obtains a kind of dipropyl phthalic ester hapten derivant of following formula (II) expression under acidic conditions.
As optimized technical scheme: 4-nitrophthalic acid (III) is 1: 3～10 with the amount of substance ratio of n-propyl alcohol in the step (A); Used acid is dense H
2SO
4Or dense HCl; 4-nitrophthalic acid (III) is 1: 0.3～1.0 with the amount of substance ratio of used acid; Heated and stirred refluxed 5～20 hours under 100-180 ℃ of temperature.
4-nitrophthalic acid (III) is 1: 6～8 with the amount of substance ratio of n-propyl alcohol in the step (A); Used acid is dense H
2SO
4, 4-nitrophthalic acid (III) is 1: 0.5～0.8 with the amount of substance ratio of used acid; Heated and stirred refluxed 5～20 hours under 110～130 ℃ of temperature.
In the step (B) 4-nitrophthalic acid dipropyl (I) is dissolved in the organic solvent, add reductive agent; 4-nitrophthalic acid dipropyl (I) is 1: 6～20 with the ratio of the amount of substance of reductive agent reaction; Gradation adds strong acid, and 4-nitrophthalic acid dipropyl (I) is 1: 15～40 with the amount of substance ratio of adding strong acid, stirring at room 10～60min; Add reductive agent once more, 4-nitrophthalic acid dipropyl (I) is 1: 6～20 with the ratio of the amount of substance of reductive agent reaction; Stirring at room 10～20 hours; In reaction system, add 0～10 ℃ of cold water, and be neutralized to alkalescence with mineral alkali; Separate the organic phase that obtains, water layer is used this organic solvent extraction again, combining extraction liquid, washing back siccative drying; Organic solvent is removed in distillation, gets solid, and carries out separation and purification.
Described organic solvent is sherwood oil, benzene, chloroform, ether, ethyl acetate or ethylene dichloride, preferred benzene; Described reductive agent is zinc powder, magnesium powder or iron powder, preferred zinc powder; 4-nitrophthalic acid dipropyl (I) is 1: 6～20 with the amount of substance ratio of reductive agent, preferred 1: 9～12; Strong acid is dense H
2SO
4Or dense HCl, preferred dense HCl, 4-nitrophthalic acid dipropyl (I) is 1: 20～25 with the amount of substance ratio of adding strong acid.
Described mineral alkali is a kind of or its mixture in saleratus, sodium bicarbonate, salt of wormwood and yellow soda ash, potassium hydroxide and the sodium hydroxide; Described siccative is an anhydrous Na
2SO
4, anhydrous CuSO
4, anhydrous CaCl
2, silica gel, molecular sieve or soda-lime, preferred anhydrous Na
2SO
4
The description of experimental program:
Hapten derivant 4-nitrophthalic acid dipropyl of the present invention (I) can pass through step (A), is raw material with 4-nitrophthalic acid (III), with n-propyl alcohol esterification takes place under acidic conditions and obtains.Hapten derivant 4-aminophthalic acid dipropyl of the present invention (II) can pass through step (B) by the 4-nitrophthalic acid dipropyl (I) that step (A) obtains, and obtains with zinc generation reduction reaction under acidic conditions.
A: esterification B: reduction
Step (A):
(1) adds n-propyl alcohol in the 4-nitrophthalic acid (III).It is excessive that described compound (III) and n-propyl alcohol can be chosen any one kind of them, so that esterification is complete.Selection depends on whether economic factors, material source is convenient, the difficulty or ease of the Separation and Recovery of product purification and excessive materials etc., and preferred n-propyl alcohol is excessive.Compound (III) is 1: 3～10 with the ratio of the amount of substance of the reaction of n-propyl alcohol, preferred 1: 6～8;
(2) agitation condition adds strong acid catalysis down.The optional dense H of strong acid
2SO
4Or dried HCl, preferred dense H
2SO
4
(3) reflux under the heated and stirred and generated 4-nitrophthalic acid dipropyl (I) in 5～20 hours.The condition of heating and the temperature of reaction can decide with different situations, and preferably temperature is at 100～180 ℃, more preferably 110～130 ℃;
(4) reaction can be for recycling and reuse the also retortable water of removing unreacted propyl alcohol and generation to unreacted propyl alcohol after finishing.Distillation can be normal pressure and decompression, preferred underpressure distillation;
(5) residuum is poured in the frozen water while hot, the oily crude product washs to neutrality with mineral alkali, uses the organic solvent recrystallization, and separation and purification is carried out in the combination of also available thin-layer chromatography and column chromatography or these methods.Mineral alkali can select carbonate to comprise alkaline carbonate for example saleratus, sodium bicarbonate, salt of wormwood and yellow soda ash; Alkali metal hydroxide is potassium hydroxide and sodium hydroxide for example.These alkali may be used singly or in combin.Preferred alkali metal carbonate.The organic solvent that recrystallization described in the present invention, thin-layer chromatography and column chromatography are used can be low carbon chain alcohol, ether, acetic acid, ethyl acetate, chlorine or methane polychlorides such as methyl alcohol, ethanol, tetrahydrofuran (THF), acetone, dioxy six alkane, hexanaphthene, normal hexane and pyridine etc.Recrystallization preferred alcohol, thin-layer chromatography and column chromatography ethyl acetate and normal hexane.
Step (B):
(1) 4-nitrophthalic acid dipropyl (I) is dissolved in the organic solvent.Described organic solvent is lipophilic organic solvent, as sherwood oil, benzene, chloroform, ether, ethyl acetate, ethylene dichloride etc., and preferred benzene;
(2) add reductive agent.Reductive agent can be zinc powder, magnesium powder or iron powder, preferred zinc powder; 4-nitrophthalic acid dipropyl (I) is 1: 6～20 with the amount of substance ratio of reductive agent reaction, preferred 1: 9～12;
(3) gradation adds strong acid, stirring at room 10～60 minutes.Described strong acid is dense H
2SO
4Or dense HCl, preferred dense HCl; The temperature of reaction has no particular limits, preferred room temperature; The time of stirring at room is 10-60 minute behind the adding strong acid, preferred 15 minutes;
(4) add reductive agent once more, 4-nitrophthalic acid dipropyl (I) is 1: 6～20 with the amount of substance ratio of reductive agent reaction, preferred 1: 9～12; Stirring at room 10～20 hours.Reaction times is 10～20 hours, preferred 12 hours;
(5) in reaction system, add cold water, and be neutralized to alkalescence with mineral alkali.The temperature that adds cold water in reaction system is 0～10 ℃, preferred 0 ℃.Described mineral alkali is that carbonate comprises alkaline carbonate for example saleratus, sodium bicarbonate, salt of wormwood and yellow soda ash; Alkali metal hydroxide is potassium hydroxide and sodium hydroxide for example.These alkali may be used singly or in combin, preferred alkali metal hydroxide.
(6) separate the organic phase that obtains, water layer is used this organic solvent extraction again, combining extraction liquid, washing back siccative drying.Described siccative is an anhydrous Na
2SO
4, anhydrous CuSO
4, anhydrous CaCl
2, silica gel, molecular sieve or soda-lime, preferred anhydrous Na
2SO
4
(7) organic solvent is removed in distillation, gets solid, uses the organic solvent recrystallization, and separation and purification is carried out in the combination of also available thin-layer chromatography and column chromatography or these methods.Distillation can be normal pressure and decompression, preferred underpressure distillation.The organic solvent that recrystallization described in the present invention, thin-layer chromatography and column chromatography are used can be low carbon chain alcohol, ether, acetic acid, ethyl acetate, chlorine or methane polychloride, tetrahydrofuran (THF), acetone, dioxy six alkane, hexanaphthene, normal hexane or pyridines such as methyl alcohol, ethanol.The organic solvent preferred alcohol that recrystallization is used, organic solvent ethyl acetate and normal hexane that thin-layer chromatography is used, organic solvent ethyl acetate and normal hexane that column chromatography is used.
The invention has the beneficial effects as follows: hapten derivant 4-aminophthalic acid dipropyl (II) can be used as raw material, is used to prepare the holoantigen that is applicable to that animal immune is used, as can with carrier protein couplet, obtain being suitable for the holoantigen of animal immune.Hapten derivant of the present invention, not only simple synthetic method need not special equipment, and purity is higher, and can be applied to prepare the holoantigen that is applicable to animal immune.
The invention provides a kind of new dipropyl phthalic ester hapten derivant-4-nitrophthalic acid dipropyl and 4-aminophthalic acid dipropyl, it can be used for preparing the dipropyl phthalate holoantigen, and and then is used to prepare dipropyl phthalate antibody and immunoassay dipropyl phthalate.
Dipropyl phthalic ester hapten derivant of the present invention also can be used as the precursor of each hapten derivant that comprises dipropyl phthalate on phenyl ring preparation.Such hapten derivant can be used as the intermediate of hapten derivant preparation of the dipropyl phthalate of new type.
Embodiment
Below in conjunction with specific embodiment the present invention is done further to elaborate, the product among the embodiment characterizes through ultraviolet, infrared and nuclear magnetic resonance spectrum.
Embodiment 1:
Synthetic (steps A) of 4-nitrophthalic acid dipropyl
To add n-propyl alcohol in the 4-nitrophthalic acid, the amount of substance ratio of the two is 1: 6, and agitation condition adds dense H down
2SO
4Catalysis, 4-nitrophthalic acid and dense H
2SO
4The ratio of amount of substance be 1: 0.6,110 ℃ of stirring and refluxing are after 7 hours, the water of unreacted propyl alcohol and generation is removed in distillation.Pour in the frozen water oily crude product 10%Na while hot into
2CO
3Wash be colourless (pH=7～8) to water layer after, get yellow oily liquid with the dehydrated alcohol recrystallization, productive rate Y=88%.
UV：λ
1＝214nm，λ
2＝258nm。
IR(KBr，υ)：1529，1357(-NO
2)，1735(C＝O)，1281，1128(C-O-C)，2968(-CH
3)，2875(-CH
3)，1430(δ-OCH
2-)，1611(C＝C)cm
-1。
1H?NMR(300MHz，CDCl
3)：δ8.56(d，1H，ArH)，8.35(dd，1H，ArH)7.82(d，1H，ArH)，4.30(t，2H，OCH
2CH
2CH
3)，4.26(t，2H，OCH
2CH
2CH
3)，1.82-1.77(m，2H，2H，OCH
2CH
2CH
3)，1.75-1.69(m，2H，2H，OCH
2CH
2CH
3)，100-0.98(t，3H，OCH
2CH
2CH
3)，0.97-0.94(t，3H，OCH
2CH
2CH
3)ppm。
Synthetic (the step B) of 4-aminophthalic acid dipropyl
4-nitrophthalic acid dipropyl is dissolved in the benzene, add pure zinc powder, 4-nitrophthalic acid dipropyl (I) is 1: 6 with the amount of substance ratio of pure zinc powder.Gradation adds dense HCl, 4-nitrophthalic acid dipropyl (I) is 1: 20 with the amount of substance ratio of the enriching HCl of institute, and stirring at room adds pure zinc powder after 15 minutes once more, 4-nitrophthalic acid dipropyl (I) is 1: 6 with the amount of substance ratio of pure zinc powder, stirring at room 12 hours.In reaction system, add cold water, and use 1molL
-1NaOH solution is neutralized to alkalescence, isolates the benzene layer, and water layer extracts with benzene again.Combining extraction liquid is used anhydrous Na after the washing
2SO
4Dry.Benzene is removed in distillation, gets light yellow solid, and the dehydrated alcohol recrystallization gets light yellow crystal, productive rate 80%.Fusing point: 87-88 ℃.
UV：λ
1＝226nm，λ
2＝288nm；
IR(KBr，υ)：3462，3371(-NH
2)，1698(C＝O)，1275，1139(C-O-C)，2973，2884(-CH
3)，1446(δ-OCH
2-)，1626(C＝C，Ar)cm
-1；
1H?NMR(300MHz，CDCl
3)：δ7.60(d，1H，ArH)，6.59(dd，1H，ArH)，6.54(d，1H，ArH)，4.13(q，2H，OCH
2CH
2CH
3)，4.07(q，2H，OCH
2CH
2CH
3)，3.99(b，2H，NH
2)，1.69-1.62(m，2H，2H，OCH
2CH
2CH
3)，1.60-1.55(m，2H，2H，OCH
2CH
2CH
3)，0.87(t，6H，OCH
2CH
2CH
3)ppm.
Embodiment 2:
Synthetic (steps A) of 4-nitrophthalic acid dipropyl
To add n-propyl alcohol in the 4-nitrophthalic acid, the amount of substance ratio of the two is 1: 3, and agitation condition adds down does HCl catalysis, and the 4-nitrophthalic acid is 1: 0.3 with the ratio of the amount of substance of dried HCl, 100 ℃ of stirring and refluxing are after 20 hours, and the water of unreacted propyl alcohol and generation is removed in distillation.Pour in 5 ℃ of cold water oily crude product 10%Na while hot into
2CO
3Wash be colourless (pH=7～8) to water layer after, get yellow oily liquid with the dehydrated alcohol recrystallization, productive rate Y=83%.UV：λ
1＝214nm，λ
2＝258nm。IR(KBr，υ)：1528，1356(-NO
2)，1735(C＝O)，1281，1128(C-O-C)，2968(-CH
3)，2875(-CH
3)，1430(δ-OCH
2-)，1612(C＝C)cm
-1；
Synthetic (the step B) of 4-aminophthalic acid dipropyl
4-nitrophthalic acid dipropyl is dissolved in the benzene, add straight iron powder, 4-nitrophthalic acid dipropyl (I) is 1: 20 with the amount of substance ratio of straight iron powder.Gradation adds dense HCl, 4-nitrophthalic acid dipropyl (I) is 1: 15 with the amount of substance ratio of the enriching HCl of institute, and stirring at room adds straight iron powder after 15 minutes once more, 4-nitrophthalic acid dipropyl (I) is 1: 20 with the amount of substance ratio of straight iron powder, stirring at room 12 hours.In reaction system, add 4 ℃ of cold water, and use 1molL
-1NaOH solution is neutralized to alkalescence, isolates the benzene layer, and water layer extracts with benzene again.Combining extraction liquid is used anhydrous Na after the washing
2SO
4Dry.Benzene is removed in distillation, gets light yellow solid, and the dehydrated alcohol recrystallization gets light yellow crystal, productive rate Y=78%.Fusing point: 86-88 ℃.UV：λ
1＝226nm，λ
2＝288nm；IR(KBr，υ)：3463，3373(-NH
2)，1698(C＝O)，1275，1139(C-O-C)，2973，2884(-CH
3)，1447(δ-OCH
2-)，1626(C＝C，Ar)cm
-1；
Embodiment 3:
Synthetic (steps A) of 4-nitrophthalic acid dipropyl
To add n-propyl alcohol in the 4-nitrophthalic acid, the amount of substance ratio of the two is 1: 10, and agitation condition adds dense H down
2SO
4Catalysis, 4-nitrophthalic acid and dense H
2SO
4The ratio of amount of substance be 1: 0.9,180 ℃ of stirring and refluxing are after 5 hours, the water of unreacted propyl alcohol and generation is removed in distillation.Pour in 0 ℃ of cold water oily crude product 10%Na while hot into
2CO
3Wash be colourless (pH=7～8) to water layer after, get yellow oily liquid with the dehydrated alcohol recrystallization, productive rate Y=85%.UV：λ
1＝214nm，λ
2＝258nm。IR(KBr，υ)：1531，1358(-NO
2)，1735(C＝O)，1280，1129(C-O-C)，2968(-CH
3)，2875(-CH
3)，1430(δ-OCH
2-)，1610(C＝C)cm
-1。
Synthetic (the step B) of 4-aminophthalic acid dipropyl
4-nitrophthalic acid dipropyl is dissolved in the sherwood oil, add pure magnesium powder, 4-nitrophthalic acid dipropyl (I) is 1: 10 with the amount of substance ratio of pure magnesium powder.Gradation adds dense H
2SO
4, 4-nitrophthalic acid dipropyl (I) and the enriching H of institute
2SO
4The amount of substance ratio be 1: 40, stirring at room adds pure magnesium powder after 20 minutes once more, 4-nitrophthalic acid dipropyl (I) is 1: 10 with the amount of substance ratio of pure magnesium powder, stirring at room 10 hours.In reaction system, add 0 ℃ of cold water, and use 1molL
-1NaOH solution is neutralized to alkalescence, isolates petroleum ether layer, and water layer extracts with sherwood oil again.Combining extraction liquid is used anhydrous Na after the washing
2SO
4Dry.Benzene is removed in distillation, gets light yellow solid, and the dehydrated alcohol recrystallization gets light yellow crystal, productive rate Y=77%.Fusing point: 87-88 ℃.UV：λ
1＝226nm，λ
2＝288nm；IR(KBr，υ)：3461，3372(-NH
2)，1698(C＝O)，1275，1138(C-O-C)，2973，2883(-CH
3)，1446(δ-OCH
2-)，1625(C＝C，Ar)cm
-1。
Claims (10)
1. dipropyl phthalic ester hapten derivant is characterized in that: its structure is with following formula (II) expression:
2. the preparation method of a derivative as claimed in claim 1 is characterized in that, comprises the steps:
(A) esterification takes place in 4-nitrophthalic acid and the n-propyl alcohol with following formula (III) expression under acidic conditions, obtains the compound of structural formula (I) expression;
(B) compound with following formula (I) expression is dissolved in the organic solvent, with the reductive agent reaction, obtains a kind of dipropyl phthalic ester hapten derivant of following formula (II) expression under acidic conditions.
3. method according to claim 2 is characterized in that: 4-nitrophthalic acid (III) is 1: 3～10 with the amount of substance ratio of n-propyl alcohol in the step (A); Used acid is dense H
2SO
4Or dense HCl, 4-nitrophthalic acid (III) is 1: 0.3～1.0 with the amount of substance ratio of used acid; The heated and stirred backflow is 5-20 hour under 100-180 ℃ of temperature.
4. method according to claim 3 is characterized in that: 4-nitrophthalic acid (III) is 1: 6～8 with the amount of substance ratio of n-propyl alcohol in the step (A); Used acid is dense H
2SO
4, 4-nitrophthalic acid (III) and dense H
2SO
4The amount of substance ratio be 1: 0.5～0.8; The heated and stirred backflow is 5-20 hour under 110-130 ℃ of temperature.
5. method according to claim 2 is characterized in that: in the step (B) 4-nitrophthalic acid dipropyl (I) is dissolved in the organic solvent; Add reductive agent, 4-nitrophthalic acid dipropyl (I) is 1: 6～20 with the amount of substance ratio of reductive agent; Add strong acid, 4-nitrophthalic acid dipropyl (I) is 1: 15～40 with the amount of substance ratio of adding strong acid, stirring at room 10～60 minutes; Add reductive agent once more, 4-nitrophthalic acid dipropyl (I) is 1: 6～20 with the amount of substance ratio of reductive agent; Stirring at room 10～20 hours; In reaction system, add 0-10 ℃ of cold water, and be neutralized to alkalescence with mineral alkali; Separate the organic phase that obtains, water layer is used this organic solvent extraction again, combining extraction liquid, washing back siccative drying; Organic solvent is removed in distillation, gets solid, and carries out separation and purification.
6. according to claim 2 or 5 described methods, it is characterized in that: described organic solvent is sherwood oil, benzene, chloroform, ether, ethyl acetate or ethylene dichloride; Described reductive agent is zinc powder, magnesium powder or iron powder; 4-nitrophthalic acid dipropyl (I) is 1: 9～12 with the ratio of the amount of substance of reductive agent; Described strong acid is dense H
2SO
4Or dense HCl; 4-nitrophthalic acid dipropyl (I) is 1: 20～25 with the amount of substance ratio of adding strong acid.
7. method according to claim 5 is characterized in that: described mineral alkali is a kind of or its mixture in saleratus, sodium bicarbonate, salt of wormwood, yellow soda ash, potassium hydroxide, the sodium hydroxide; Described siccative is an anhydrous Na
2SO
4, anhydrous CuSO
4, anhydrous CaCl
2, silica gel, molecular sieve or soda-lime.
8. method according to claim 5 is characterized in that: described separation purification method is the combination with organic solvent recrystallization, thin-layer chromatography or column chromatography or these methods.
9. method according to claim 8 is characterized in that: the organic solvent that recrystallization, thin-layer chromatography and column chromatography are used is methyl alcohol, ethanol, ether, acetic acid, ethyl acetate, chlorine or methane polychloride, tetrahydrofuran (THF), acetone, dioxy six alkane, hexanaphthene, normal hexane or pyridine.
10. method according to claim 9 is characterized in that: the used organic solvent of recrystallization is an ethanol; The used organic solvent of thin-layer chromatography is ethyl acetate and normal hexane, and the used organic solvent of column chromatography is ethyl acetate and normal hexane.
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| CN103204925B (en) * | 2013-03-28 | 2014-03-26 | 江南大学 | Synthetic method of general artificial antigen of phthalate plasticizers for immunodetection |
| CN104370761B (en) * | 2014-09-29 | 2016-09-14 | 安徽师范大学 | A kind of butyl benzyl phthalate hapten derivant and preparation method, the detection method of butyl benzyl phthalate |
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