CN103980277B - The preparation method of a kind of folic acid thiolated derivative - Google Patents
The preparation method of a kind of folic acid thiolated derivative Download PDFInfo
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Abstract
The present invention discloses the preparation method of a kind of folic acid thiolated derivative.-SH protection in mercaptan is obtained its derivative by the present invention, thus realizes the protection to the sulfydryl with high reaction activity; Then, under the existence of catalyzer and dewatering agent, the protected hydroxyl on thiol derivative and folic acid generation esterification, obtain modified folic acid derivatives; Carbon-sulfur bond in this folic acid derivatives is ruptured by reduction reaction, again forms sulfydryl in product, thus obtains target product sulfhydrylation folic acid. The present invention adopts triphenylcarbinol to carry out substituting trityl chloride, overcome product separation difficulty and the lower drawback of product yield, it is to increase product yield. In the esterification reaction, the present invention adopts solid catalyst (large hole cation exchanger resin), and product separation efficiency is improved greatly, and adopts the small molecules such as DMAP (DMAP) in common biology preparation, it is soluble in solvent, it is very difficult to separation.
Description
Technical field
The present invention relates to the preparation method of a kind of folic acid thiolated derivative, belong to technical field of organic synthesis.
Background technology
The medication efficiency improving disease treatment is the ultimate target of medical circle. After common drug oral administration or injection, the real part arriving targeted site tissue is extremely low, and most of drug accumulation, in HUMAN HEALTH tissue, does not reach result for the treatment of. Meanwhile, medicine all has certain toxic side effect, and healthy cell is had negative impact. In recent years, the nano load of medicine and targeted obtain to be studied widely, substantially increases utilization ratio and the disease therapeuticing effect of medicine. The targeting of medicine by targeting agent as biological antigens, antibody, DNA, RNA and bio-ligand etc. provide, they with specific to tumor focus and the antibody expressed of transition, antigen and biological acceptor there is special affinity and combination of matching, thus realize the target administration of focus. The targeting agent adopted at present mostly is biomacromolecule, and they only have targeting for certain specific tumor tissues, and storage, preparation condition harshness, limit the range of application of material. Folic acid is a kind of small molecules bio-ligand, and its biological acceptor (FR) presents process LAN in kinds of tumors tissue. Research in recent years finds, folic acid has the biological target tropism of good biological activity and wide spectrum, has good bio-medical prospect, and multiple targeted drug and drug delivery system based on folic acid arise at the historic moment, and are widely used.
Golden nanometer particle mixture based on folacin receptor targeting type is the typically used research field of folic acid as targeting agent. Metal nanoparticle (especially gold and silver etc.) has a wide range of applications at the biomedical sector such as diagnosis and photo-thermal therapy of the identification of immunoassay, biosensor, DNA and detection, tumour. Another big feature of metallic element is exactly very easily form the golden key (S-Me) of firmly mercapto with the compound containing sulfydryl and be combined in together, the surface biological utilizing this principle can realize metal nanoparticle is modified, thus gives metal nanoparticle biologic applications potential.Foreign scholar Pan Di (Pandey) etc. realize the coupling of folic acid and nanometer gold by 11-Mercaptoundecanoic acid. Chinese patent 201010566939.6 realizes folic acid to the modification of golden nanometer particle using gsh (GSH) as coupling agent, thus prepares the golden nanometer particle of a kind of folacin receptor targeting type. The complex body of the modified with folic acid nanometer gold that this kind of method obtains, all preparation processes are all carry out in aqueous, the concentration of the initial period golden nanometer particle of first whole preparation process is just very low, and coupling agent and folic acid are generally organism, lower in the solubleness of the aqueous solution, various intermediate product and final product all can not the preparations of high density; Moreover, the preparation condition of nanometer gold itself and storage requirement require strict, the all solvents mixed with it and medicine all need highly purified, otherwise very easily cause the reunion of nano metal particles, adding operation easier, therefore, product preparation efficiency is low, separation and purification difficulty, target product can not be prepared in a large number. The method also having in addition first adopts coated with polyethylene glycol nanometer gold, then by physical adsorption, folic acid is adsorbed on nano particle skin, and this kind of method is difficult to realize folic acid and the unimolecular layer of nanometer gold is modified, and modifies fastness and also is difficult to ensure lastingly. The concentration of above method goods is very low, it is difficult to accomplish scale production, and large scale storage, the transport of product also will be the difficult problems being difficult to overcome.
Project team delivers the Preparation and characterization of paper sulfhydrylation folic acid at " Guangzhou chemical industry "; Yu Yanan etc.; trityl group chlorine is adopted to do protective material and mercaptoethanol reaction; achieving the protection to sulfydryl, but it adopts mercaptoethanol and triphenyl first chlorine as reactant, triphenyl first chlorine has toxicity on the one hand; use inconvenience; producing by product sodium-chlor in reaction process on the other hand, the separation of product is caused difficulty, product yield is lower.
This project team patent 2013100094201 invention in early stage preparation method of a kind of sulfhydrylation folic acid, make the modification that it can be directly used in nano metal particles, but its existing problems are product rate lower (maximum outputs 50%), and product postprocessing is comparatively complicated.
Summary of the invention
It is an object of the invention to provide a kind of mild condition, it be easy to the synthetic method preparing folic acid thiolated derivative that operates, step is simple, product rate is higher.
-SH protection in mercaptan is obtained its derivative by the present invention, thus realizes the protection to the sulfydryl with high reaction activity; Then, under the existence of catalyzer and dewatering agent, the protected hydroxyl on thiol derivative and folic acid generation esterification, obtain modified folic acid derivatives; Carbon-sulfur bond in this folic acid derivatives is ruptured by reduction reaction, again forms sulfydryl in product, thus obtains target product sulfhydrylation folic acid.
The method specifically comprises the following steps:
1) protection of sulfydryl
Mercaptoalcohol compounds is dissolved in organic solvent, under cryogenic, adds appropriate NaOH, stir 30min-2h, then add triphenylcarbinol, reaction 12-24h. Reaction terminates, by reaction solution underpressure distillation. With the product after organic solvent dissolution underpressure distillation, with water extracting 3 times, finally use desiccant dryness organic phase. Again steam except solvent, thick product Diethyl ether recrystallization. Adopt infrared spectra that mercaptoalcohol compounds and derivative thereof carry out test to characterize, the structure of research product.
Can adopt thiol compound have two sulphur tetrahydroxybutanes, 3-sulfydryl-1,2-propylene glycol, 2,3-dimercaprol dimercaptopropanol, the own alcohol of 3-sulfydryl, 2-sulfydryl-3-butanols, 3-mercaprol etc.
The organic solvent that can adopt has normal hexane, ethanol, methyl alcohol, second eyeball, ether, tetrahydrofuran (THF), chloroform etc.
In reactant, the mol ratio of thiol compound and triphenylcarbinol is 1: (0.5～2).
The reaction equation of derivative is shown in formula (1):
R in formula (1)1For-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-CH2-CH2-、-CH2-CH2-CH2-etc.
2) mercapto derivatives after protection and the reaction of folic acid
Folic acid is dissolved in solvent; add dewatering agent and catalyzer (Zeo-karb); add above-mentioned mercapto derivatives again; stirring reaction 12～24 hours under nitrogen protection; centrifugal (2000～10000rpm; 5～20min); retain supernatant liquor; joined and dehydrated alcohol is precipitated out precipitation, more centrifugal (2000～10000rpm, 5～20min); and by precipitation distilled water wash, centrifugal three times; it is dry that the precipitation obtained puts into vacuum drying oven, and temperature is set to 15～50 DEG C, finally obtains the folic acid derivatives containing sulfydryl. The folic acid derivatives of employing infrared spectra to folic acid and containing sulfydryl carries out test and characterizes, the structure of research product.
The solvent that can adopt is dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride, and temperature of reaction is 20～40 DEG C.
The dewatering agent that can adopt is anhydrous sodium sulphate, N, N '-dicyclohexylcarbodiimide (DCC), 2,4,6-trichloro-benzoyl chloride, described catalyzer be styrene type cation exchange resin, dewatering agent and catalyzer with the use of.
The mol ratio of folic acid, dewatering agent, mercapto derivatives is 1: (0.5～10): (1～4).
The esterification equation of folic acid and mercapto derivatives is shown in formula (2):
Wherein R1Structure in same formula (1).
3) deprotection of sulfydryl in folic acid derivatives
By triethyl silicane, trifluoroacetic acid mixing, then add the above-mentioned folic acid derivatives containing sulfydryl, stir 30min, dropped in ether, precipitate out yellow mercury oxide, centrifugal be precipitated, washing of precipitate three times, vacuum-drying. Sample vacuum-drying obtained repeats above operation once again, both thick product. Adopt infrared spectra and NMR (Nuclear Magnetic Resonance) spectrum that folic acid and sulfhydrylation folic acid carry out test respectively to characterize, the structure of research product.
The centrifugal condition that separation adopts is 2000～10000rpm, 5～20min, washing composition be ether, second alcohol and water optional its one or with the use of.
In folic acid derivatives, sulfydryl deprotection reaction equation is shown in formula (3):
Wherein R1Structure in same formula (1).
Compared to the prior art relatively, there is following useful effect in the present invention:
1, the application adopts triphenylcarbinol to carry out substituting trityl chloride, overcome product separation difficulty and the lower drawback of product yield, it is to increase product yield.
2, in the esterification reaction, the present invention adopts solid catalyst (large hole cation exchanger resin), and product separation efficiency is improved greatly, and adopts the small molecules such as DMAP (DMAP) in common biology preparation, it is soluble in solvent, it is very difficult to separation. The application's esterification product rate reaches more than 80%.
3, target product total recovery of the present invention reaches more than 60%.
Nano silver grain has been modified by the sulfhydrylation folic acid utilizing the present invention to prepare, and utilizes transmission electron microscope to characterize, and experimental result shows that folate molecule evenly has been modified at nano grain of silver sub-surface.
Accompanying drawing explanation
Fig. 1 is the infrared spectrum of mercaprol, and its charateristic avsorption band is: 3364cm-1(O-H)、2935cm-1, 2875cm-1(C-H)、2568cm-1(S-Hst)、1053cm-1, 1015cm-1(C-O)、908cm-1(S-Hδ)。
Fig. 2 is the infrared spectrum of pure folic acid, 3545cm-1(O-H)、3416cm-1, 3333cm-1(N-H)、2924cm-1, 2856cm-1(-CH2-)、1692cm-1(C=O), 1113cm-1(C-O)。
Fig. 3 is the infrared spectrum of sulfhydrylation folic acid, 3460cm-1(O-H)、3330cm-1(N-H)、2930cm-1, 2850cm-1(-CH2-)、2530cm-1(S-H)、1720cm-1(C=O).
Fig. 4 is the transmission scan Electronic Speculum of sulfhydrylation modified with folic acid nano metal
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.
Embodiment 1
The protection of 3-mercaprol (MP) sulfydryl
In the 100mL Erlenmeyer flask that magneton, constant pressure funnel are housed, add the tetrahydrofuran solution 25mL being dissolved with 0.9216g (0.0100mol) 3-mercaprol (MP), then the tetrahydrofuran solution that 25mL is dissolved with 5mmol sodium hydroxide is added, stir and after 30 minutes, add the tetrahydrofuran (THF) 25mL being dissolved with 2.6033g triphenylcarbinol, stir 6 hours. Whole process temperature controls at 45 DEG C. The flask filling mixing solutions is put into Rotary Evaporators after terminating by reaction, temperature is set to 45 DEG C, until stopping when solution no longer produces bubble revolving steaming, then product 20mL chloroform is dissolved, then with 20mL distilled water extracting three times, get organic phase, with anhydrous sodium sulfate drying, again steam except solvent, thick product acetone recrystallization, obtaining product is trityl sulphur propyl alcohol, product rate 90%.
Embodiment 2
The protection of 2-sulfydryl-3-butanols (MB) sulfydryl
In the 100mL Erlenmeyer flask that magneton, constant pressure funnel are housed, add the tetrahydrofuran solution 25mL being dissolved with 1.062g (0.0100mol) 2-sulfydryl-3-butanols (MB), then the tetrahydrofuran solution that 25mL is dissolved with 5mmol sodium hydroxide is added, stir and after 30 minutes, add the tetrahydrofuran (THF) 25mL being dissolved with 2.6033g triphenylcarbinol, stir 9 hours. Whole process temperature controls at 45 DEG C. The flask filling mixing solutions is put into Rotary Evaporators after terminating by reaction, temperature is set to 45 DEG C, until stopping when solution no longer produces bubble revolving steaming, then dissolve with 20mL chloroform, then with 20mL distilled water extracting three times, get organic phase, with anhydrous sodium sulfate drying, again steam except solvent, thick product acetone recrystallization, obtaining product is 2-trityl sulphur-3-butanols, product rate 91%.
Embodiment 3
The own alcohol of 3-sulfydryl (MH) sulfhydryl protected
The 100mL Erlenmeyer flask that magneton, constant pressure funnel are housed adds the tetrahydrofuran solution 25mL being dissolved with the own alcohol of 1.3424g (0.010mol) 3-sulfydryl (MH), then the tetrahydrofuran solution that 25mL is dissolved with 5mmol sodium hydroxide is added, stir and after 30 minutes, add the tetrahydrofuran (THF) 25mL being dissolved with 2.6033g triphenylcarbinol, stir 12 hours. Whole process temperature controls at 45 DEG C. The flask filling mixing solutions is put into Rotary Evaporators after terminating by reaction, temperature is set to 45 DEG C, until stopping when solution no longer produces bubble revolving steaming, then dissolve with 20mL chloroform, then with 20mL distilled water extracting three times, get organic phase, with anhydrous sodium sulfate drying, again steam except solvent, thick product acetone recrystallization, obtaining product is the 3-own alcohol of trityl sulphur, product rate 93%.
Embodiment 4
The esterification of folic acid and trityl sulphur propyl alcohol
0.221g (0.5mmol) folic acid, 60mL dimethyl sulfoxide (DMSO) (DMSO), 0.5g (3.5mmol) anhydrous sodium sulphate, 1.0g Zeo-karb, magneton are joined in the single necked round bottom flask of 100mL; flask is put into the water-bath that temperature is 37 DEG C; after folic acid is dissolved in DMSO completely; add the trityl sulphur propyl alcohol of 0.344g (1mmol) embodiment 1 preparation again, stirring heating reaction 8h under the protection of nitrogen. React by centrifugal for product (8500r/min, 15min) after terminating, remove lower floor not tolerant, get the clear liquid of upper strata yellow and add in 50mL dehydrated alcohol, precipitate out yellow mercury oxide.Successively with 30mL distilled water and 30mL dehydrated alcohol constantly disperse, centrifugal, last vacuum-drying obtains the folic acid derivatives of 3-mercaprol modification, product rate 80.1%.
Embodiment 5
The esterification of folic acid and 2-trityl sulphur-3-butanols
By 0.221g (0.5mmol) folic acid, 60mL dimethyl sulfoxide (DMSO) (DMSO), 1.0g Zeo-karb, 0.206g (1mmol) N; N '-dicyclohexylcarbodiimide (DCC), magneton join in the single necked round bottom flask of 100mL; flask is put into the water-bath that temperature is 37 DEG C; after folic acid, DCC are dissolved in DMSO completely; add the 2-trityl sulphur-3-butanols of 0.348g (1mmol) embodiment 2 preparation again, stirring heating reaction 12h under the protection of nitrogen. React by centrifugal for product (8500r/min, 15min) after terminating, remove lower floor not tolerant, get the clear liquid of upper strata yellow and add in 50mL dehydrated alcohol, precipitate out yellow mercury oxide. Successively with 30mL distilled water and 30mL dehydrated alcohol constantly disperse, centrifugal, last vacuum-drying obtains the folic acid derivatives of 2-trityl sulphur-3-butanols modification, product rate 83.5%.
Embodiment 6
The esterification of folic acid and the own alcohol of 3-trityl sulphur
0.221g (0.5mmol) folic acid, 50mL dimethyl sulfoxide (DMSO) (DMSO), 1.0g Zeo-karb, 0.710g (5mol) anhydrous sodium sulphate, magneton are joined in the single necked round bottom flask of 100mL; flask is put into the water-bath that temperature is 37 DEG C; after folic acid is dissolved in DMSO completely; add the 3-own alcohol of trityl sulphur of 0.752g (2mmol) embodiment 3 preparation again, stirring heating reaction 10h under the protection of nitrogen. React by centrifugal for product (8500r/min, 15min) after terminating, remove lower floor not tolerant, get the clear liquid of upper strata yellow and add in 50mL dehydrated alcohol, precipitate out yellow mercury oxide. Successively with 40mL distilled water and 40mL dehydrated alcohol constantly disperse, centrifugal, last vacuum-drying obtains the folic acid derivatives of the own alcohol modification of 2-trityl sulphur, product rate 81%.
Embodiment 7
The preparation of 3-mercaprol modification folic acid
25mL triethyl silicane and 25mL trifluoroacetic acid are mixed, add the folic acid of the trityl sulphur propyl alcohol modification of 0.383g (0.5mmol) embodiment 4 preparation, stir after 30 minutes, dropped in 50mL ice ether, forming yellow mercury oxide, centrifugal (5000rpm, 5min) is precipitated, precipitation ice washed with diethylether three times, vacuum-drying. The sample that vacuum-drying is obtained, then repeat above operation once, both the folic acid of thick product 3-mercaprol modification, product rate 75%.
Adopting infrared spectra that folic acid and product carry out test to characterize, the infrared spectrum of product sulfhydrylation folic acid is shown in accompanying drawing 3, has occurred the charateristic avsorption band 2368cm of sulfydryl in the infrared spectrum of product sulfhydrylation folic acid-1(S-H), show that product is the folic acid derivatives of 3-mercaprol modification.
Embodiment 8
The preparation of 2-sulfydryl-3-butanols modification folic acid
5mL triethyl silicane and 5mL trifluoroacetic acid are mixed, add the folic acid derivatives of the 2-trityl sulphur-3-butanols modification of 0.0787g (0.1mmol) embodiment 5 preparation, stir after 30 minutes, dropped in 20mL ice ether, forming yellow mercury oxide, centrifugal (7000rpm, 5min) is precipitated, precipitation ice washed with diethylether three times, vacuum-drying. Sample vacuum-drying obtained repeats above operation once again, both the folic acid of thick product 2-sulfydryl-3-butanols modification, product rate 77%.
Embodiment 9
The preparation of the own alcohol modification folic acid of 3-sulfydryl
25mL triethyl silicane and 25mL trifluoroacetic acid are mixed, add the folic acid derivatives that 0.399g (0.5mmol) embodiment 6 prepares the own alcohol modification of 2-trityl sulphur, stir after 30 minutes, dropped in 50mL ice ether, forming yellow mercury oxide, centrifugal (10000rpm, 10min) is precipitated, precipitation ice washed with diethylether three times, vacuum-drying.Sample vacuum-drying obtained repeats above operation once again, both the folic acid of the thick own alcohol modification of product 3-sulfydryl, product rate 79%.
Embodiment 10
Sulfhydrylation folic acid is to the finishing of nano silver particles
Take sulfhydrylation folic acid prepared by 0.1g embodiment 7, join in the weak ammonia of 5mLpH=7.5, then sulfhydrylation folic acid solution is joined in the Nano silver solution of 60mL0.4mM, ultrasonic disperse 1h at normal temperatures, then 24 hours are left standstill under normal temperature, make its abundant self-assembly, obtain the Nano silver solution of sulfhydrylation modified with folic acid. Get this solution 10mL, centrifugal 10min under 8000rpm, remove supernatant liquid, retain the black violet solid of lower floor, washing three times with the weak ammonia of 10mLpH=7.5 again, remove free sulfhydrylation folic acid, the black violet solid finally obtained is the nanometer silver of sulfhydrylation modified with folic acid. By the black violet solid ultrasonic disperse that obtains in the weak ammonia of 10mLpH=7.5, preserve at 4 DEG C. Adopting transmission electron microscope that the product obtained carries out test to characterize, see accompanying drawing 4, result shows, sulfhydrylation folic acid is attached to the surface of nano silver particles, it is achieved that to the finishing of nano silver particles.
Should be understood that, for those of ordinary skills, it is possible to improved according to the above description or convert, and all these improve and convert the protection domain that all should belong to claims of the present invention.
Claims (6)
1. the preparation method of a folic acid thiolated derivative, it is characterised in that, comprise the following steps:
1) protection of sulfydryl
Being dissolved in organic solvent by mercaptoalcohol compounds, control temperature 20～40 DEG C, adds appropriate NaOH, stirs 30min, then adds triphenylcarbinol, reaction 6-12h; Reaction terminates, by reaction solution underpressure distillation; With the product after organic solvent dissolution underpressure distillation, with water extracting 3 times, finally use desiccant dryness organic phase; Again steam except solvent, the thick product acetone recrystallization of the mercapto derivatives after protection;
2) mercapto derivatives after protection and the reaction of folic acid
Folic acid is dissolved in solvent, add dewatering agent and cation exchange resin catalyst, add the mercapto derivatives after described protection again, stirring reaction 8～12 hours under nitrogen protection, centrifugal, retain supernatant liquor, joined and dehydrated alcohol is precipitated out precipitation, centrifugal again, centrifugal condition 2000～10000rpm, time 5～20min, and by precipitation distilled water wash, centrifugal three times, it is dry that the precipitation obtained puts into vacuum drying oven, and temperature is set to 15～50 DEG C, finally obtains the folic acid derivatives containing sulfydryl; The dewatering agent adopted is anhydrous sodium sulphate or N, N '-dicyclohexylcarbodiimide; Described catalyzer be styrene type cation exchange resin, dewatering agent and catalyzer with the use of; The mol ratio of folic acid, dewatering agent, mercapto derivatives is 1: (0.5～10): (1～4);
3) deprotection of sulfydryl in folic acid derivatives
By triethyl silicane, trifluoroacetic acid mixing, then add the described folic acid derivatives containing sulfydryl, stir 30min, dropped in ether, fully stir, precipitate out yellow mercury oxide, centrifugal be precipitated, washing of precipitate three times, vacuum-drying; The sample that vacuum-drying is obtained, then repeat above operation once, obtain product.
2. preparation method according to claim 1, it is characterized in that, described step 1) in, can adopt mercaptoalcohol compounds be two sulphur tetrahydroxybutanes, 3-sulfydryl-1,2-propylene glycol, 2,3-dimercaprol dimercaptopropanol, the own alcohol of 3-sulfydryl, 2-sulfydryl-3-butanols, 3-mercaprol.
3. preparation method according to claim 1, it is characterised in that, described step 1) in, the organic solvent of employing is normal hexane, ethanol, methyl alcohol, second eyeball, ether, tetrahydrofuran (THF), chloroform.
4. preparation method according to claim 1, it is characterised in that, described step 1) in, in reactant, the mol ratio of mercaptoalcohol compounds and triphenylcarbinol is 1: (0.5～2).
5. preparation method according to claim 1, it is characterised in that, described step 2) in, the solvent of employing is dimethyl sulfoxide (DMSO) (DMSO), methylene dichloride, and temperature of reaction is 20～40 DEG C.
6. preparation method according to claim 1, it is characterised in that, described step 3) in, the centrifugal condition that separation adopts is 5000～10000rpm, 5～20min, washing composition be ether, second alcohol and water optional its one or with the use of.
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