CN101812158B - Acyclovir molecularly imprinted polymer, preparation method and application thereof - Google Patents
Acyclovir molecularly imprinted polymer, preparation method and application thereof Download PDFInfo
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- CN101812158B CN101812158B CN2010101189510A CN201010118951A CN101812158B CN 101812158 B CN101812158 B CN 101812158B CN 2010101189510 A CN2010101189510 A CN 2010101189510A CN 201010118951 A CN201010118951 A CN 201010118951A CN 101812158 B CN101812158 B CN 101812158B
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- acyclovir
- molecularly imprinted
- imprinted polymer
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- acyclovirs
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Abstract
The invention discloses an acyclovir molecularly imprinted polymer, a preparation method and application thereof. The polymer is prepared through the following steps of: (1) dissolving bi-methyl acryloyl acyclovir into an acetonitrile and dimethylsulfoxide solution containing a cross-linking agent and an initiating agent, sealing an obtained mixed solution and then carrying out a polymerization reaction to generate a white powdered polymer, wherein the temperature of the polymerization reaction is 50-70 DEG C, and the reaction time is 12-24h; and (2) heating and extracting the white powdered polymer to remove the template molecule acyclovir, and then extracting by using pure methanol to remove water to obtain the acyclovir molecularly imprinted polymer. The acyclovir molecularly imprinted polymer can be applied to efficiently purifying valcyte intermediates.
Description
Technical field
The present invention relates to a kind of Acyclovir molecularly imprinted polymer and preparation method thereof, this molecularly imprinted polymer can be used for the valganciclovir intermediate of efficiently purifying.
Background technology
Ganciclovir (ganciclovir) be at present clinically anti-cytomegalovirus (CMV) infect one of the most effective medicine because oral administration biaavailability is poor, can only drug administration by injection.Valganciclovir (valganciclovir) is the L-valine ester prodrug of ganciclovir, and oral administration biaavailability improves greatly.After entering human body, in enteron aisle and liver cell by the rapid hydrolysis of esterase dissociate Xie Ansuan and ganciclovir.The former participates in the normal physiological biochemical metabolism in vivo, and the latter then will effectively bring into play its antiviral effect with enough concentration.
With the ganciclovir is that starting raw material can synthesize valganciclovir: ganciclovir is at N; in dinethylformamide (DMF) solution with the Xie Ansuan (Cbz-Va) of amido protecting dehydrating condensation under dicyclohexylcarbodiimide (DCC) effect; owing to there are two hydroxyls that activity is identical in the ganciclovir molecule; obtain the mixture of mono-esterification thing precursor and double esterification thing precursor; obtain mono-esterification thing precursor after the separation and purification; it is obtained target compound Xie Ansuan ganciclovir by hydrogenation deprotection base; because the mixture separation difficulty of mono-esterification thing precursor and double esterification thing precursor, total recovery has only about 20%.
Summary of the invention
The object of the invention is to provide a kind of Acyclovir molecularly imprinted polymer, solved in the prior art valganciclovir when synthetic its intermediate mono-esterification thing precursor be difficult to separate problem such as purify, yield is not high.
In order to solve these problems of the prior art, technical scheme provided by the invention is:
A kind of Acyclovir molecularly imprinted polymer is characterized in that described polymkeric substance prepares by following steps:
(1) two methacryloyl acyclovirs is dissolved in the acetonitrile that contains linking agent, initiator, the dimethyl sulfoxide solution, generate the white powder shaped polymer with carrying out polyreaction after the mixing solutions sealing, polymeric reaction temperature is 50-70 ℃, and the reaction times is 12-24h;
(2) the white powder polymkeric substance is extracted removal template molecule acyclovir with the aqueous hydrochloric acid heating, remove water with pure methanol extraction then, obtain Acyclovir molecularly imprinted polymer.
Preferably, linking agent is selected from trimethylolpropane trimethacrylate among the described preparation method, and initiator is selected from Diisopropyl azodicarboxylate.
Another object of the present invention is to provide a kind of preparation method of molecularly imprinted polymer, it is characterized in that said method comprising the steps of:
(1) two methacryloyl acyclovirs is dissolved in the acetonitrile that contains linking agent, initiator, the dimethyl sulfoxide solution, generate the white powder shaped polymer with carrying out polyreaction after the mixing solutions sealing, polymeric reaction temperature is 50-70 ℃, and the reaction times is 12-24h;
(2) the white powder polymkeric substance is extracted removal template molecule acyclovir with the aqueous hydrochloric acid heating, remove water with pure methanol extraction then, obtain Acyclovir molecularly imprinted polymer.
Preferably, linking agent is selected from trimethylolpropane trimethacrylate in the described method, and initiator is selected from Diisopropyl azodicarboxylate.
Preferably, two methacryloyl acyclovirs can obtain by acyclovir and methacrylic chloride condensation reaction in the described method.
Preferably, described method also comprises and places vacuum drying oven to be dried to the step of constant weight Acyclovir molecularly imprinted polymer.
Highly preferred, the step of described method is:
(1) be raw material with acyclovir and methacrylic chloride, synthetic two methacryloyl acyclovirs.
(2) two methacryloyl acyclovirs are dissolved in the acetonitrile that contains linking agent, initiator, the dimethyl sulfoxide solution, are prepared into mixed solution, and wherein, linking agent is a trimethylolpropane trimethacrylate, and initiator is a Diisopropyl azodicarboxylate;
(3) with after the mixed solution sealing, adopt the mode polyreaction of heated and stirred to generate the white powder shaped polymer, polymeric reaction temperature is 50-70 ℃, the reaction times is 12-24h;
(4) extract synthetic good white powder shaped polymer with the aqueous hydrochloric acid heating, remove template molecule, continue then to remove water with pure methanol extraction;
(5) after extraction finishes, place vacuum drying oven to be dried to weight in polymkeric substance, obtain molecularly imprinted polymer at last.
Another object of the present invention is to provide the application of a kind of Acyclovir molecularly imprinted polymer aspect separation purification valganciclovir intermediate ganciclovir mono-esterification thing precursor.
With respect to scheme of the prior art, advantage of the present invention is:
The Acyclovir molecularly imprinted polymer that technical solution of the present invention obtains can have high selectivity to ganciclovir mono-esterification thing precursor, can be used to separate the mixture of mono-esterification thing precursor and double esterification thing precursor, obtain target compound mono-esterification thing valganciclovir, can be used for the efficient preparation valganciclovir of purifying.
Description of drawings
Below in conjunction with drawings and Examples the present invention is further described:
Fig. 1 is the preparation were established figure of valganciclovir in the prior art;
Fig. 2 is the preparation of embodiment of the invention molecularly imprinted polymer and the process schematic representation that separates ganciclovir mono-esterification thing precursor, double esterification thing precursor thereof;
Fig. 3 is the adsorption curve of embodiment of the invention ganciclovir mono-esterification thing precursor, double esterification thing.
Embodiment
Below in conjunction with specific embodiment such scheme is described further.Should be understood that these embodiment are used to the present invention is described and are not limited to limit the scope of the invention.The implementation condition that adopts among the embodiment can be done further adjustment according to the condition of concrete producer, and not marked implementation condition is generally the condition in the normal experiment.
The preparation of embodiment Acyclovir molecularly imprinted polymer and absorption property test
1) preparation of two methacryloyl acyclovirs
The methacrylic chloride of the acyclovir of 0.1mol and 0.4mol is dissolved in the mixing solutions of acetonitrile, 20mL methyl-sulphoxide of 100mL, backflow 2-4 hour, the acetonitrile of about 50mL is removed in distillation, cooling, in the aqueous sodium carbonate of the 0.1mol/L of adding 100mL, stirred 0.5 hour, and got the two methacryloyl acyclovirs of white solid, yield 86%.
HMNR(DMSOD6)：8.16(s，1H)，5.52(s，2H)，5.25(s，2H)5.14(s，2H)，3.96(s，5H)，2.92(s，4H)，1.82(s，6H)。
2) preparation of Acyclovir molecularly imprinted polymer
The two methacryloyl acyclovirs of 2mmol, the 4mmol trimethylolpropane trimethacrylate, the initiator Diisopropyl azodicarboxylate of 80mg is added in the mixing solutions of 100mL acetonitrile, 20mL methyl-sulphoxide, with mixed solution sealing back ultrasonic degas 6min, logical nitrogen 10min removes oxygen molecule, then with after the mixed solution sealing, adopts the mode polyreaction of heated and stirred to generate from toner powder polymkeric substance, polymerization temperature is 55-70 ℃, and the reaction times is 24h.After polymerization is finished,, synthetic good polymkeric substance is extracted with the aqueous solution of hydrochloric acid of 100mL, removing template molecule, and then with pure methanol extraction removal water molecules.After extracting end, place vacuum drying oven to be dried to weight in polymkeric substance, obtain Acyclovir molecularly imprinted polymer (MIPs) at last.
The absorption property test
1) preparation of blank imprinted polymer
The 4mmol trimethylolpropane trimethacrylate, the initiator Diisopropyl azodicarboxylate of 80mg is added in the mixing solutions of 100mL acetonitrile, 20mL methyl-sulphoxide, with mixed solution sealing back ultrasonic degas 6min, logical nitrogen 10min removes oxygen molecule, then with after the mixed solution sealing, adopt the mode polyreaction of heated and stirred to generate from toner powder polymkeric substance, polymerization temperature is 55-70 ℃, and the reaction times is 24h.After polymerization is finished,, synthetic good polymkeric substance is extracted with the aqueous solution of hydrochloric acid of 100mL, removing template molecule, and then with pure methanol extraction removal water molecules.After extracting end, place vacuum drying oven to be dried to weight in polymkeric substance, obtain blank imprinted polymer (NIPs) at last.
2) Acyclovir molecularly imprinted polymer adopts the molecularly imprinted polymer (MIP) of embodiment 1 preparation.
3) process of the test
50mg MIP, 50mg NIP, join respectively in the mixing solutions solution of 10mL acetonitrile, 2mL methyl-sulphoxide of the ganciclovir mono-esterification thing precursor of different concns and double esterification thing precursor, jolting is 24 hours under room temperature, and (sewing up silica gel with octadecylsilane is weighting agent to adopt high-efficient liquid phase technique; Methyl alcohol-0.02mol/L potassium dihydrogen phosphate (20: 80) is a moving phase; The detection wavelength is 251nm) measure its loading capacity, with the strength of solution X-coordinate, loading capacity is an ordinate zou, does adsorption curve.
Loading capacity (μ mol/g)=(C
0-C
1) * 200
Wherein: C
0For adsorbing preceding strength of solution (mmol/L), C
1For adsorbing back strength of solution (mmol/L)
From Fig. 3 as seen, there were significant differences to the adsorptivity of ganciclovir mono-esterification thing precursor, double esterification thing precursor for the PSD-95/nNOS uncoupling molecularly imprinted polymer of gained, can be used for the separation of ganciclovir mono-esterification thing precursor, double esterification thing precursor.
Above-mentioned example only is explanation technical conceive of the present invention and characteristics, and its purpose is to allow the people who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalent transformations that spirit is done according to the present invention or modification all should be encompassed within protection scope of the present invention.
Claims (6)
1. Acyclovir molecularly imprinted polymer is characterized in that described polymkeric substance prepares by following steps:
(1) is raw material with acyclovir and methacrylic chloride, obtains two methacryloyl acyclovirs by acyclovir and methacrylic chloride condensation reaction; Two methacryloyl acyclovirs are dissolved in the acetonitrile that contains linking agent, initiator, the dimethyl sulfoxide solution, carry out polyreaction after will the mixing solutions sealing to generate the white powder shaped polymer, polymeric reaction temperature is 50-70 ℃, and the reaction times is 12-24h;
(2) the white powder polymkeric substance is extracted removal template molecule acyclovir with the aqueous hydrochloric acid heating, remove water with pure methanol extraction then, obtain Acyclovir molecularly imprinted polymer.
2. Acyclovir molecularly imprinted polymer according to claim 1 is characterized in that linking agent is selected from trimethylolpropane trimethacrylate among the described preparation method, and initiator is selected from Diisopropyl azodicarboxylate.
3. the preparation method of the described molecularly imprinted polymer of claim 1 is characterized in that said method comprising the steps of:
(1) is raw material with acyclovir and methacrylic chloride, obtains two methacryloyl acyclovirs by acyclovir and methacrylic chloride condensation reaction; Two methacryloyl acyclovirs are dissolved in the acetonitrile that contains linking agent, initiator, the dimethyl sulfoxide solution, carry out polyreaction after will the mixing solutions sealing to generate the white powder shaped polymer, polymeric reaction temperature is 50-70 ℃, and the reaction times is 12-24h;
(2) the white powder polymkeric substance is extracted removal template molecule acyclovir with the aqueous hydrochloric acid heating, remove water with pure methanol extraction then, obtain Acyclovir molecularly imprinted polymer.
4. method according to claim 3 is characterized in that linking agent is selected from trimethylolpropane trimethacrylate in the described method, and initiator is selected from Diisopropyl azodicarboxylate.
5. method according to claim 3 is characterized in that described method also comprises to place vacuum drying oven to be dried to the step of constant weight Acyclovir molecularly imprinted polymer.
6. the application of the described Acyclovir molecularly imprinted polymer of claim 1 aspect separation purification valganciclovir intermediate ganciclovir mono-esterification thing precursor.
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| CN102850490B (en) * | 2012-08-10 | 2014-05-21 | 福州大学 | Method for preparing molecularly imprinted material by POSS compound as cross-linking agent |
| CN103285892B (en) * | 2013-06-07 | 2014-12-10 | 南昌航空大学 | Method for preparing Lewis acidic molecular imprinting type BiOI photo-catalyst with visible-light response and high selectivity by hydrothermal method |
| CN110988246B (en) * | 2019-11-29 | 2022-03-08 | 荆门医药工业技术研究院 | Method for detecting contents of Z-L-valine and intermediate (S) -4-isopropyloxazole-2, 5-diketone thereof |
| CN112362704B (en) * | 2020-10-29 | 2022-09-30 | 内蒙古科技大学 | Preparation method of molecularly imprinted composite paste electrode sensor for detecting acyclovir |
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| CN101397355A (en) * | 2008-11-13 | 2009-04-01 | 上海交通大学 | Method for preparing molecular imprinting polymer capable of identifying oxytetracycline and enrofloxacin |
| CN101507916A (en) * | 2009-02-16 | 2009-08-19 | 西北工业大学 | Preparation method of macrolide antibiotics molecular engram polymer microsphere |
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| CN101397355A (en) * | 2008-11-13 | 2009-04-01 | 上海交通大学 | Method for preparing molecular imprinting polymer capable of identifying oxytetracycline and enrofloxacin |
| CN101507916A (en) * | 2009-02-16 | 2009-08-19 | 西北工业大学 | Preparation method of macrolide antibiotics molecular engram polymer microsphere |
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