CN105085603A - Reusable load type platinum complex oxidizing agents, and preparation method and application thereof - Google Patents
Reusable load type platinum complex oxidizing agents, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses reusable load type platinum complex oxidizing agents. The reusable load type platinum complex oxidizing agents are silicon dioxide pellets of load platonic complex, and have a structure shown in a formula (I). In the structure shown in the formula (I), n=3, M is Pt4+, Y is -1 valence halide ions, and grain sizes of the silicon dioxide pellets are 100nanometers to 2,000 nanometers. The invention also provides a preparation method of the oxidizing agents. The preparation method comprises the following steps of (a) using toluene as a solvent and heating the silicon dioxide pellets and a siloxane reagent to perform reflex reaction so as to obtain white solid; (b) performing stirring reaction on the obtained white solid and platinous complex to obtain offwhite solid; and (c) fully reacting the offwhite solid, H2O2/hydrochloric acid, chlorine or liquid bromine to obtain the load type platinum complex oxidizing agents. The load type platinum complex oxidizing agents are easy to prepare and can be reused after being subjected to regeneration treatment, the yield of synthesized oxidation type polypeptide is not affected by reusing frequency of the oxidizing agents, and the oxidizing agents are recycled and subjected to regeneration treatment simply.
Description
Technical field
The present invention relates to loading type oxygenant, specifically a kind of load type platinum title complex oxygenant that can be recycled and its preparation method and application.
Background technology
Polypeptide drug containing intramolecular disulfide bond for the treatment of various disease, such as: the polypeptide drug such as thyrocalcitonin, uterine tonic pitocin, antiplatelet drug eptifibatide, Remedies for diabetes tripro-amylin of the Somatostatin of Therapeutic cancer, treatment Paget ' s disease.At present, a large amount of polypeptide containing intramolecular disulfide bond is developed, facilitate polypeptide drug development (
natureChem., 2014,
6, 1009 – 1016;
eur.J.Med.Chem., 2014,
77, 248 – 257;
futureMed.Chem., 2009,
1, 361 – 377.).The generation of polypeptide drug intramolecular disulfide bond is an important reaction in meticulous organic chemical industry and pharmaceutical chemistry.
In the building-up process of the polypeptide drug containing intramolecular disulfide bond, in peptide molecule, the synthesis of disulfide linkage is its committed step, general employing method for oxidation homogeneous oxidizing synthesis in the solution at present.
At present, the oxygenant be bonded to for polypeptide drug intramolecular disulfide comprises: iodine, thallium trifluoroacetate (III), oxygen, DMSO, Sleep-promoting factor B and Ellman ' s reagent etc.But, these oxygenants are for the synthesis of in peptide molecule during disulfide linkage, some meetings and the residue generation side reactions such as the methionine(Met) in polypeptide chain, tyrosine, tryptophane, some meetings make polypeptide generate dimer or polymeric by product, productive rate is caused to reduce, and these oxygenants all can not regenerate and recycle, some oxygenants even can produce the larger by product of toxicity (
eur.J.Org.Chem., 2014,3519 – 3530;
rSCAdv.2014,
4, 13854 – 13881;
synthesis, 2008,
16, 2491 – 2509.).
Except above-mentioned conventional oxygenant, the application widely that tetravalence platinum complex oxygenant obtains when synthetic drugs intramolecular disulfide bond, and oxidation effectiveness be all better than other oxygenant used at present (
j.Am.Chem.Soc.2000,
122, 6809 – 6815;
j.Org.Chem.1999,
64, 4590 – 4595;
bioorg.Med.Chem.Lett.2002,
12, 2237 – 2240.).But, platinum complex is due to expensive, the not easily reason such as preparation and limit its application, therefore, if a kind of returnable platinum complex oxygenant can be prepared, then cost payout when using such oxygenant to carry out synthetic drugs intramolecular disulfide bond greatly can be reduced.
Summary of the invention
An object of the present invention is to provide a kind of load type platinum title complex oxygenant that can be recycled and application, solves existing platinum complex oxygenant for the synthesis of cannot the problem of recycling during disulfide linkage in peptide molecule.
Two of object of the present invention is to provide a kind of preparation method of the load type platinum title complex oxygenant that can be recycled.
An object of the present invention is achieved in that
The load type platinum title complex oxygenant that can be recycled, it is the silicon dioxide microsphere of load tetravalence platinum complex, and it has structure as shown in formula I:
（Ⅰ）
In structure shown in formula I: n=3, M are Pt
4+, Y is-1 valency halogen ion, and silicon dioxide microsphere particle diameter is 100nm ~ 2000nm.
The load type platinum title complex oxygenant that can be recycled of the present invention, described Y is Cl
-or Br
-.
The load type platinum title complex oxygenant that can be recycled of the present invention, described silicon dioxide microsphere particle diameter is 500nm.
Present invention also offers described load type platinum title complex oxygenant in preparation containing the application in the polypeptide of intramolecular disulfide bond.
Described application specifically realizes by following technical scheme:
The silicon dioxide microsphere of load tetravalence platinum complex and reduced form polypeptide solution are shaken at ambient temperature and react 0.5-6h, after reaction terminates, centrifugation, reclaims throw out and the supernatant liquor containing reaction product respectively; Utilize the reaction product in high performance liquid chromatography separation of supernatant; The silicon dioxide microsphere of load tetravalence platinum complex is regenerated, recycle after throw out manipulation of regeneration.
The silicon dioxide microsphere of described load tetravalence platinum complex and described reduced form polypeptide amount ratio are to be advisable at 1 ~ 1.5: 1 with tetravalence platinum and reduced form polypeptide mol ratio.
Described reduced form polypeptide solution be with reduced form polypeptide be solute, with the mixed solution of NaAc_HAc buffer solution or NaAc_HAc buffer solution and acetonitrile for solvent is made; In the mixed solution of described NaAc_HAc buffer solution and acetonitrile, the volume ratio of NaAc_HAc buffer solution and acetonitrile is 1: 1.
Described reduced form polypeptide be containing sulfydryl, the reduced form polypeptide that can form intramolecular disulfide bond, concrete comprises reduced form polypeptide (1), reduced form polypeptide (2), reduced form polypeptide (3), reduced form RGD peptide and reduced form pitocin.The aminoacid sequence of described reduced form polypeptide (1) is: Ac-Cys-Pro-Phe-Cys-NH
2; The aminoacid sequence of described reduced form polypeptide (2) is: Ac-Thr-Cys-Pro-Phe-Cys-Arg-NH
2; The aminoacid sequence of described reduced form polypeptide (3) is: Ac-Cys-Thr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH
2; The aminoacid sequence of described reduced form RGD peptide is: Ac-Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys-NH
2; The aminoacid sequence of described reduced form pitocin is: Ac-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH
2.
Two of object of the present invention is achieved in that
A preparation method for the load type platinum title complex oxygenant that can be recycled,
A) take toluene as solvent, by silicon dioxide microsphere and silicone agent in mass ratio 1: 2 ~ 6, heating reflux reaction 12 ~ 50h under 110 ~ 130 DEG C of conditions;
React complete, filter after reaction system being cooled to room temperature, gained solid is dry with washing with alcohol final vacuum, obtains white solid thing;
B) by gained white solid thing ultrasonic disperse in water, divalence platinum complex is then added, 40 ~ 50 DEG C of stirrings, reaction 15 ~ 20h;
React complete, filter after being cooled to room temperature, gained solid is dry with washing with alcohol final vacuum, obtains pale solid thing;
C) by pale solid thing in DMF after ultrasonic disperse, with H under 20 ~ 50 DEG C of conditions
2o
2/ hydrochloric acid mixed solution, chlorine or bromine are fully reacted;
React complete, centrifugation, gained solids wash final vacuum is dry, and the light yellow solid thing obtained is described load type platinum title complex oxygenant.
The preparation method of the load type platinum title complex oxygenant that can be recycled of the present invention, described silicone agent is N-(aminoethyl)--aminopropyl trimethoxysilane.
The preparation method of the load type platinum title complex oxygenant that can be recycled of the present invention, described divalence platinum complex is cis Pt (en) Cl
2; In mole, the consumption of described divalence platinum complex is not less than the consumption of described silicone agent.
The preparation method of the load type platinum title complex oxygenant that can be recycled of the present invention, described silicon dioxide microsphere particle diameter is 100 ~ 2000nm, preferably 300 ~ 600nm.
The preparation method of the load type platinum title complex oxygenant that can be recycled of the present invention,
Step c) is specifically: pale solid thing after ultrasonic disperse, is passed into chlorine 0.5 ~ 6h under 20 ~ 50 DEG C of conditions and reacts in DMF;
React complete, centrifugation, gained solids wash final vacuum is dry, and the light yellow solid thing obtained is described load type platinum title complex oxygenant.
The preparation method of the load type platinum title complex oxygenant that can be recycled of the present invention,
Step c) is specifically: pale solid thing after ultrasonic disperse, is added bromine concussion reaction 1 ~ 3h in DMF under 20 ~ 50 DEG C of conditions; In mole, the consumption of described bromine is not less than the consumption of described divalence platinum complex;
React complete, centrifugation, gained solids wash final vacuum is dry, and the light yellow solid thing obtained is described load type platinum title complex oxygenant.
The preparation method of the load type platinum title complex oxygenant that can be recycled of the present invention,
Step c) is specifically: pale solid thing after ultrasonic disperse, is added H under 20 ~ 50 DEG C of conditions in DMF
2o
2-hydrochloric acid mixed solution concussion reaction 5 ~ 8h; Described H
2o
2h in-hydrochloric acid mixed solution
2o
2be 1 with the volume ratio of hydrochloric acid (1.0mol/L)
:1; With H
2o
2the molar amount of institute's chloride ion-containing in-hydrochloric acid mixed solution, described H
2o
2the consumption of-hydrochloric acid mixed solution is not less than 2 times of described divalence platinum complex consumption;
React complete, centrifugation, gained solids wash final vacuum is dry, and the light yellow solid thing obtained is described load type platinum title complex oxygenant.
Oxygenant of the present invention and preparation thereof have many-sided advantage:
1, the preparation of this loading type oxygenant is simple, and can be recycled after manipulation of regeneration, and the productive rate of synthesized oxidized form polypeptide is not by the impact of this Recycling of oxidize access times.
2, relative to conventional oxidation agent, use during this loading type oxidizing generation oxidized form polypeptide and there is the high advantage of productive rate.
3, after improvement on synthesis intramolecular disulfide bond, oxygenant recovery and manipulation of regeneration simple, after this loading type oxygenant and reduced form polypeptide react, by filtration or centrifugal, can arrive the object reclaiming oxygenant, the oxygenant reclaimed is reused after manipulation of regeneration.
Accompanying drawing explanation
Fig. 1 is loading type oxygenant preparation feedback schema of the present invention.
Fig. 2 is the SEM scintigram of oxygenant of the present invention.
Fig. 3 is the distribution diagram of element of oxygenant of the present invention.
Fig. 4 is the XPS detected result of oxygenant of the present invention.
Fig. 5 is that the color atlas before and after reduced form RGD peptide and oxidant reaction of the present invention contrasts.
Fig. 6 is chemical formula and the mass spectrum contrast of reduced form RGD peptide and oxidized form RGD peptide.
The productive rate of oxidized form RGD peptide of Fig. 7 prepared by embodiment 2 and the relation recycled between number of times of oxygenant of the present invention.
Embodiment
Fig. 1 gives loading type oxygenant preparation feedback schema of the present invention.As shown in Figure 1, the present invention is by silicon dioxide microsphere and silicone agent (N-(aminoethyl)--aminopropyl trimethoxysilane) react, obtain ethylene diamine-modified silicon dioxide microsphere (for white solid thing), as shown in formula II in Fig. 1; Ethylene diamine-modified silicon dioxide microsphere and cis dichloride quadrol close platinum (cis Pt(en) Cl
2) reaction, obtain the silicon dioxide microsphere (pale solid thing) of load divalence platinum complex, as shown in formula III in Fig. 1; The silicon dioxide microsphere of load divalence platinum complex and chlorine generation oxidizing reaction, obtain the silicon dioxide microsphere (light yellow solid thing) of load tetravalence platinum complex, as shown in formula I in Fig. 1, the silicon dioxide microsphere of the load tetravalence platinum complex obtained is loading type tetravalence platinum complex oxygenant of the present invention, and its concrete preparation process is shown in embodiment 1 ~ 3:
Embodiment 1
The silicon dioxide microsphere used in the present embodiment is commercial obtaining, particle diameter 500nm.
1., in 250mL three-necked flask, add 2.0g silicon dioxide microsphere and 150mL dry toluene, then add 5gN-(aminoethyl)--aminopropyl trimethoxysilane, magnetic agitation, 120
oc back flow reaction 48h; Be cooled to room temperature after completion of the reaction, filter, gained solid washing with alcohol 3 times, then 50
oc vacuum-drying 12h, obtains the ethylene diamine-modified silicon dioxide microsphere of white;
2. silicon dioxide microsphere ethylene diamine-modified for 1.5g is joined in the three-necked bottle of 250mL, then add 100mL water, after ultrasonic disperse, add 0.3g cis Pt (en) Cl
2, stir, 50
oc reacts 20h; Be cooled to room temperature after completion of the reaction, filter, solid washing with alcohol 3 times, then vacuum-drying, obtains the silicon dioxide microsphere of canescence load divalence platinum complex;
3. the silicon dioxide microsphere taking 0.1g load divalence platinum complex, in test tube, adds 10mLDMF, ultrasonic disperse, then logical chlorine 4h under room temperature; Centrifugation after completion of the reaction, solid washed with water 3 times, then use washing with alcohol 3 times, then dried in vacuo overnight, obtain the silicon dioxide microsphere of light yellow load tetravalence platinum complex.
The SEM result of the silicon dioxide microsphere of prepared load tetravalence platinum complex as shown in Figure 2.
The silicon dioxide microsphere distribution diagram of element of prepared load tetravalence platinum complex as shown in Figure 3.Can be known by Fig. 3, tetravalence platinum complex has loaded on silicon dioxide microsphere.
ICP-MS(inductivity coupled plasma mass spectrometry) content that measures the platinum of the silicon dioxide microsphere of load tetravalence platinum complex is 3.9 × 10
-4mol/g.The XPS result of the silicon dioxide microsphere of load tetravalence platinum complex is as Fig. 4, and utilize XPS to measure divalence platinum and platinic ratio in the silicon dioxide microsphere of load tetravalence platinum complex, measuring platinic content according to the charge capacity of platinum is 2.1 × 10
-4mol/g.
Embodiment 2
The silicon dioxide microsphere used in the present embodiment is commercial obtaining, particle diameter 100nm.
1., in 250mL three-necked flask, add 2.0g silicon dioxide microsphere and 150mL dry toluene, then add 5gN-(aminoethyl)--aminopropyl trimethoxysilane, magnetic agitation, 130
oc back flow reaction 20h; Be cooled to room temperature after completion of the reaction, filter, gained solid washing with alcohol 3 times, then 50
oc vacuum-drying 12h, obtains the ethylene diamine-modified silicon dioxide microsphere of white;
2. silicon dioxide microsphere ethylene diamine-modified for 1.5g is joined in the three-necked bottle of 250mL, then add 100mL water, after ultrasonic disperse, add 0.3g cis Pt (en) Cl
2, stir, 40
oc reacts 20h; Be cooled to room temperature after completion of the reaction, filter, solid washing with alcohol 3 times, then vacuum-drying, obtains the silicon dioxide microsphere of canescence load divalence platinum complex;
3. the silicon dioxide microsphere taking 0.1g load divalence platinum complex, in test tube, adds 10mLDMF, ultrasonic disperse, then adds 10mL bromine, concussion reaction 2.5h; Centrifugation after completion of the reaction, solid washed with water 3 times, then use washing with alcohol 3 times, then dried in vacuo overnight, obtain the silicon dioxide microsphere of light yellow load tetravalence platinum complex.
Embodiment 3
The silicon dioxide microsphere used in the present embodiment is commercial obtaining, particle diameter 2000nm.
1., in 250mL three-necked flask, add 2.0g silicon dioxide microsphere and 150mL dry toluene, then add 5gN-(aminoethyl)--aminopropyl trimethoxysilane, magnetic agitation, 110
oc back flow reaction 30h; Be cooled to room temperature after completion of the reaction, filter, gained solid washing with alcohol 3 times, then 50
oc vacuum-drying 12h, obtains the ethylene diamine-modified silicon dioxide microsphere of white;
2. silicon dioxide microsphere ethylene diamine-modified for 1.5g is joined in the three-necked bottle of 250mL, then add 100mL water, after ultrasonic disperse, add 0.3g cis Pt (en) Cl
2, stir, 40
oc reacts 15h; Be cooled to room temperature after completion of the reaction, filter, solid washing with alcohol 3 times, then vacuum-drying, obtains the silicon dioxide microsphere of canescence load divalence platinum complex;
3. the silicon dioxide microsphere taking 0.1g load divalence platinum complex, in test tube, adds 10mLDMF, ultrasonic disperse, then adds 20mLH
2o
2-hydrochloric acid mixed solution is (with hydrochloric acid and the H of 1.0mol/L
2o
21: 1 mixing by volume), concussion reaction 5h; Centrifugation after completion of the reaction, solid washed with water 3 times, then use washing with alcohol 3 times, then dried in vacuo overnight, obtain the silicon dioxide microsphere of light yellow load tetravalence platinum complex.
Embodiment 4
Oxygenant of the present invention (i.e. the silicon dioxide microsphere of load tetravalence platinum complex) can with multiple containing disulfide linkage in the reduced form polypeptide Reactive Synthesis peptide molecule of sulfydryl.
The silicon dioxide microsphere of load tetravalence platinum complex and the reduced form polypeptide containing sulfydryl are by following scheme improvement on synthesis intramolecular disulfide bond: the silicon dioxide microsphere of load tetravalence platinum complex and reduced form polypeptide solution are shaken at ambient temperature and react 0.5-6h, after reaction terminates, centrifugation, reclaims throw out and the supernatant liquor containing reaction product respectively; Utilize the reaction product in high performance liquid chromatography separation of supernatant, and by mass spectrum, reaction product is identified; The silicon dioxide microsphere of load tetravalence platinum complex is regenerated, recycle after throw out manipulation of regeneration.
Oxygenant of the present invention is the oxidable multiple reduced form polypeptide containing sulfydryl also, as reduced form polypeptide (1), reduced form polypeptide (2), reduced form polypeptide (3), reduced form RGD peptide and reduced form pitocin etc., reduced form and the oxidized form aminoacid sequence of these polypeptide are as follows:
Concrete, utilize the oxidizing above-mentioned reduced form polypeptide of the loading type prepared by embodiment 1, concrete reaction process is as follows:
Silicon dioxide microsphere and the reduced form polypeptide (1) of one, load tetravalence platinum complex react
The NaAc_HAc buffer solution of the pH=4.65 by volume ratio of 1:1 adds acetonitrile and obtains mixing solutions, and it is for subsequent use that mixing solutions leads to nitrogen 1h; In the reaction flask of 20mL, be 5.3 × 10 by the mixing solutions preparation 8mL concentration of preparation
-4reduced form polypeptide (1) solution of mol/L, then adds the silicon dioxide microsphere of 0.1g load tetravalence platinum complex in reaction flask, room temperature concussion reaction 1h.
Reaction terminates, and reaction system is centrifugal, and centrifugal rear gained liquid phase liquid chromatography separated product, with the molecular weight of mass spectroscopy product is: 508.1681, and this result meets the fignal center of the oxidized form polypeptide (1) forming intramolecular disulfide bond; Productive rate is 75%; Centrifugal rear gained solid phase carries out manipulation of regeneration, and concrete grammar is by solid phase dispersion in DMF, completes regeneration (concrete non-regenerative operating procedure is identical with step 3) condition in embodiment 1) with chlorine oxidation 4h.
Reacted with the reduced form polypeptide (1) of identical amount by oxygenant after regeneration, so, repeat experiment 5 times, the productive rate scope of oxidized form polypeptide (1) is 69-75% again.
Silicon dioxide microsphere and the reduced form polypeptide (2) of two, load tetravalence platinum complex react
The NaAc_HAc buffer solution of the pH=5.5 by volume ratio of 1:1 adds acetonitrile and obtains mixing solutions, and it is for subsequent use that mixing solutions leads to nitrogen 1h; Take 3.1mg reduced form polypeptide (2) to join in the reaction flask of 20mL, then add 10mL mixing solutions dissolving polypeptide, obtaining concentration is 4.0 × 10
-4reduced form polypeptide (2) solution of mol/L, then adds the silicon dioxide microsphere of 0.1g load tetravalence platinum complex in reaction flask, room temperature concussion reaction 1.5h.
Reaction terminates, and reaction system is centrifugal, and centrifugal rear gained liquid phase liquid chromatography separated product, with the molecular weight of mass spectroscopy product is: 765.3161, and what this result met oxidized form polypeptide (2) adds hydrionic mass signal peak; Centrifugal rear gained solid phase carries out manipulation of regeneration, and concrete grammar is by solid phase dispersion in DMF, completes regeneration with chlorine oxidation 4h.
Reacted with the reduced form polypeptide (2) of identical amount by oxygenant after regeneration, so, repeat experiment 5 times, the productive rate scope of oxidized form polypeptide (2) is 73-80% again.
Silicon dioxide microsphere and the reduced form polypeptide (3) of three, load tetravalence platinum complex react
The NaAc_HAc buffer solution of the pH=6 by volume ratio of 1:1 adds acetonitrile and obtains mixing solutions, and it is for subsequent use that mixing solutions leads to nitrogen 1h; Take 4.8mg reduced form polypeptide (3) to join in the reaction flask of 20mL, then add 10mL mixing solutions dissolving polypeptide, obtaining concentration is 5.0 × 10
-4reduced form polypeptide (3) solution of mol/L, then adds the silicon dioxide microsphere of 0.1g load tetravalence platinum complex in reaction flask, room temperature concussion reaction 1.5h.
Reaction terminates, and reaction system is centrifugal, and centrifugal rear gained liquid phase liquid chromatography separated product, with the molecular weight of mass spectroscopy product is: 945.4262, and what this result met oxidized form polypeptide (3) adds hydrionic mass signal peak; Centrifugal rear gained solid phase carries out manipulation of regeneration, and concrete grammar is by solid phase dispersion in DMF, completes regeneration with chlorine oxidation 4h.
Reacted with the reduced form polypeptide (3) of identical amount by oxygenant after regeneration, so, repeat experiment 5 times, the productive rate scope of oxidized form polypeptide (3) is 76-85% again.
The silicon dioxide microsphere of four, load tetravalence platinum complex and reduced form RGD reactive polypeptide
It is for subsequent use that the NaAc_HAc buffer solution of pH=5.5 leads to nitrogen 1h, and take 5.0mg reduced form RGD peptide and join in the reaction flask of 20mL, then add the buffered soln of 10mL, obtaining concentration is 5.2 × 10
-4the reduced form RGD peptide solution of mol/L, then adds the silicon dioxide microsphere of 0.1g load tetravalence platinum complex in reaction flask, room temperature concussion reaction 0.5h.
Reaction terminates, and reaction system is centrifugal, and centrifugal rear gained liquid phase liquid chromatography separated product is: 474.1944 that this result meets the mass signal peak of oxidized form RGD peptide with the molecular weight of mass spectroscopy product; Centrifugal rear gained solid phase carries out manipulation of regeneration, and concrete grammar is by solid phase dispersion in DMF, completes regeneration with chlorine oxidation 4h.
By the oxygenant after regeneration again with the reduced form RGD reactive polypeptide of identical amount, so, repeat experiment 5 times, as shown in Figure 7, the productive rate scope of oxidized form RGD peptide is 75-83% to result.
Contrasted by the chromatographic results that the silicon dioxide microsphere of reduced form RGD peptide solution in the present embodiment and load tetravalence platinum complex reacts forward and backward, result as shown in Figure 5.As seen from Figure 5, reduced form RGD peptide is all oxidized to oxidized form RG peptide.
Contrasted by the mass spectral results that the silicon dioxide microsphere of reduced form RGD peptide solution in the present embodiment and load tetravalence platinum complex reacts forward and backward, result as shown in Figure 6.As seen from Figure 6, the molecular weight of mass spectroscopy reduced form RGD peptide is 475.20201, and the molecular weight of mass spectroscopy reaction products therefrom is: 474.1944, and this result meets the mass signal peak of oxidized form RGD peptide.
Silicon dioxide microsphere and the reduced form pitocin of five, load tetravalence platinum complex react
It is for subsequent use that the NaAc_HAc buffer solution of pH=4 leads to nitrogen 1h, and take 5.0mg reduced form pitocin and join in the reaction flask of 20mL, then add the buffered soln of 10mL, obtaining concentration is 5.4 × 10
-4the reduced form pitocin solution of mol/L, then adds the silicon dioxide microsphere of 0.1g load tetravalence platinum complex in reaction flask, room temperature concussion reaction 0.5h.
Reaction terminates, and reaction system is centrifugal, and centrifugal rear gained liquid phase liquid chromatography separated product is: 1007.4412 that this result meets the mass signal peak of oxidized form pitocin with the molecular weight of mass spectroscopy product; Centrifugal rear gained solid phase carries out manipulation of regeneration, and concrete grammar is by solid phase dispersion in DMF, completes regeneration with chlorine oxidation 4h.
Reacted with the reduced form pitocin of identical amount by oxygenant after regeneration, so, repeat experiment 5 times, the productive rate scope of oxidized form pitocin is 73-81% again.
Comparative example 1
The NaAc_HAc buffer solution of the pH=4.65 by volume ratio of 1:1 adds acetonitrile and obtains mixing solutions, and it is for subsequent use that mixing solutions leads to nitrogen 1h; In the reaction flask of 20mL, be 5.3 × 10 by the mixing solutions preparation 8mL concentration of preparation
-4reduced form polypeptide (1) solution of mol/L, the oxygen reaction in this solution and air, magnetic agitation reaction 22h, reaction terminates.Productive rate is 45%.
Comparative example 2
It is for subsequent use that acetonitrile leads to nitrogen 1h; In the reaction flask of 20mL, preparation 8mL concentration is 5.3 × 10
-4reduced form polypeptide (1) solution of mol/L, adds 50 μ L triethylamines, then adds the acetonitrile solution that 5mL contains 10mg iodine, and reaction 16h, reaction terminates, and remove excessive elemental iodine, separation of oxygenated type polypeptide (1), productive rate is 60%.
Above embodiment and experimental data show, the synthesis of disulfide linkage in the peptide molecule that loading type oxygenant of the present invention can be used in different structure.Oxygenant of the present invention is compared with existing loading type Ellman ' s oxidising agent, and the preparation of this loading type oxygenant is simple, and can be recycled, and productive rate is not by the impact recycling number of times; With traditional oxygenant as iodine, oxygen, DMSO compares, and this loading type oxygenant also has the high advantage of productive rate, and as when synthesizing oxidized form polypeptide (1), utilize oxygen as oxygenant, productive rate only has 45%; And utilize elemental iodine to be 60% as productive rate during oxygenant.After improvement on synthesis intramolecular disulfide bond, the purification processes of polypeptide is simple, and it is as well known to those skilled in the art when using DMSO as oxygenant, after reaction, the purification of polypeptide needs to carry out repeatedly lyophilize process, and DMSO is reduced to the very large dimethyl thioether of toxicity, and this loading type oxygenant with the mixed solution of NaAc_HAc buffer solution or NaAc_HAc buffer solution and acetonitrile for reaction solvent, by filter or centrifugal after reaction, the object of separated product can be arrived.
Claims (7)
1. the load type platinum title complex oxygenant that can be recycled, it is characterized in that, it is the silicon dioxide microsphere of load tetravalence platinum complex, and it has structure as shown in formula I:
（Ⅰ）
In structure shown in formula I: n=3, M are Pt
4+, Y is-1 valency halogen ion, and silicon dioxide microsphere particle diameter is 100nm ~ 2000nm.
2. the load type platinum title complex oxygenant that can be recycled according to claim 1, is characterized in that, described Y is Cl
-or Br
-.
3. the load type platinum title complex oxygenant that can be recycled according to claim 1, is characterized in that, described silicon dioxide microsphere particle diameter is 500nm.
4. load type platinum title complex oxygenant described in claim 1 contains the application in the polypeptide of intramolecular disulfide bond in preparation.
5. a preparation method for the load type platinum title complex oxygenant that can be recycled, is characterized in that,
A) take toluene as solvent, by silicon dioxide microsphere and silicone agent in mass ratio 1: 2 ~ 6, heating reflux reaction 12 ~ 50h under 110 ~ 130 DEG C of conditions;
React complete, filter after being cooled to room temperature, gained solid is dry with washing with alcohol final vacuum, obtains white solid thing;
B) by gained white solid thing ultrasonic disperse in water, divalence platinum complex is then added, 40 ~ 50 DEG C of stirrings, reaction 15 ~ 20h;
React complete, filter after being cooled to room temperature, gained solid is dry with washing with alcohol final vacuum, obtains pale solid thing;
C) by pale solid thing in DMF after ultrasonic disperse, with H under 20 ~ 50 DEG C of conditions
2o
2/ hydrochloric acid mixed solution, chlorine or bromine are fully reacted;
React complete, centrifugation, gained solids washing final vacuum is dry, and the light yellow solid thing obtained is loading type tetravalence platinum complex oxygenant.
6. the preparation method of the load type platinum title complex oxygenant that can be recycled according to claim 5, is characterized in that, described silicone agent is N-(aminoethyl)--aminopropyl trimethoxysilane.
7. the preparation method of the load type platinum title complex oxygenant that can be recycled according to claim 5, is characterized in that, described divalence platinum complex is cis Pt (en) Cl
2.
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| CN108948745A (en) * | 2018-06-04 | 2018-12-07 | 榛硕（武汉）智能科技有限公司 | A kind of high-performance conductive silicon rubber and preparation method thereof |
| CN109912477A (en) * | 2019-03-07 | 2019-06-21 | 河北大学 | A kind of selenomethionine oxide and preparation method thereof and the application in synthesis polypeptide intramolecular disulfide bond |
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| CN107892710A (en) * | 2017-10-10 | 2018-04-10 | 河北大学 | A kind of load type platinum complex oxidant for being easily recycled recycling and its preparation method and application |
| CN107892710B (en) * | 2017-10-10 | 2021-04-13 | 河北大学 | Supported platinum complex oxidant easy to recycle and use and preparation method and application thereof |
| CN108892778A (en) * | 2018-06-04 | 2018-11-27 | 榛硕（武汉）智能科技有限公司 | A kind of novel high-performance catalyst and preparation method thereof |
| CN108948745A (en) * | 2018-06-04 | 2018-12-07 | 榛硕（武汉）智能科技有限公司 | A kind of high-performance conductive silicon rubber and preparation method thereof |
| CN109912477A (en) * | 2019-03-07 | 2019-06-21 | 河北大学 | A kind of selenomethionine oxide and preparation method thereof and the application in synthesis polypeptide intramolecular disulfide bond |
| CN109912477B (en) * | 2019-03-07 | 2020-12-29 | 河北大学 | Selenomethionine oxide, preparation method thereof and application thereof in synthesis of polypeptide intramolecular disulfide bond |
| WO2023190768A1 (en) * | 2022-03-30 | 2023-10-05 | 日本ゼオン株式会社 | Method for recovering platinum group element |
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