CN207243786U - A kind of synthesis module for the coumarin kind compound for targeting amyloid beta - Google Patents
A kind of synthesis module for the coumarin kind compound for targeting amyloid beta Download PDFInfo
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- CN207243786U CN207243786U CN201721069500.6U CN201721069500U CN207243786U CN 207243786 U CN207243786 U CN 207243786U CN 201721069500 U CN201721069500 U CN 201721069500U CN 207243786 U CN207243786 U CN 207243786U
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Abstract
A kind of synthesis module for the coumarin kind compound for targeting amyloid beta, including reactor (1) are the utility model is related to, [18F‑]H2 18O solution bottles (2), gas sample injection device (17), heating unit (18), solution containment,18F adsorbent equipments (4), heavy oxygen water recovery device (3) and pure preparations device, the reactor (1) are placed on heating unit (18), described [18F‑]H2 18O solution bottles (2) pass through connection18Coupled reaction device (1) and heavy oxygen water recovery device (3), the gas sample injection device (17), solution containment and pure preparations device are all connected with reactor (1) to F adsorbent equipments (4) respectively.Compared with prior art, the utility model has the advantages that automated production, safe and reliable.
Description
Technical field
Coumarin kind compound is the utility model is related to, more particularly, to a kind of Coumarins for targeting amyloid-beta
The system module of compound synthesis.
Background technology
Intracerebral amyloid-beta ((β-amyloid protein, A β)) derives from its precursor substance beta-amyloyd precursor egg
(amyloid precursor protein, APP) in vain.Have been acknowledged that A β derive from the APP of gene code, molecular weight is about
4kD, is transmembrane glycoprotein, and is in β-pleated sheet in a three-dimensional structure, therefore claims " amyloid beta ".A β by APP cell membranes outside
12 amino acid of 28 amino acid and transmembrane segment form, positioned at the hydrophobic part of APP.With very strong aggregation, easy shape
Into extremely poorly soluble precipitation.A β are the main components of senile plaque expelling, are neuropathologic hallmark (Glenner G G.Wong C
W.Alzheimer's disease:initial report of the purification and characterization
of a novel cerebrovascular amyloid protein[J].Biochem Biophys Res Commun,
1984,120(3):855-900.Toreilles F,Touchon J.Pathogenic theories and intrathecal
analysis of the sporadic form of Alzheimer's disease[J].Prog Neurobiol,2002,
66(3):191-203.Lambert M P,Barlow A K,Chromy B A,etal.Diffusible,non fibrillar
ligands derived from Abeta1-42are potent central nervous system neurotoxins
[J].Pro Natl Acad Sci USA,1998,95(11):6448-6453.).Alzheimer's disease (Alzheimer's
Disease, AD) pathogenesis have a variety of theories, wherein Hardy etc. propose AD A β cascade hypothesis it is of greatest concern,
Say that the AD that is gathered in for thinking A β occurs, plays the role of a nucleus in evolution, A β result in nerve cell dysfunction and death, most
Cause dementia (HARDY J, SELKOE DJ.The amyloid hypo thesis of Alzheimer's disease eventually:
progress and problems on the road to therapeutics[J].Science,2002,297(5580):
353-356.)。
Positron emission tomography (PET) (Positron Emission are carried out using the specific molecular probes for targeting A β
Tomograph, PET) it is optimum AD early stages to make a definite diagnosis means.The major drugmaker in the whole world is all selectively targeted in research and development always
The PET developers of A β, until 2012, gift carried out the product of (Eli Lilly) company,18F-Florbetapir(US7687052/
US8506929 U.S. FDA approval) is obtained；Afterwards, U.S. FDA have approved two marketing drugs in succession again, and General Electric's medical treatment is public
Take charge of (GE HEALTHCARE)18F-Flutemetamol(US7270800/US7351401/US8236282/US8691185/
) and PIRAMAL IMAGING companies US891613118F-Florbetaben(US7807135).The country there is no targeting A β at present
PET developers get the Green Light listing, it is domestic AD early stages to be made a definite diagnosis and curative effect evaluation is the available situation of no medicine, research and develop new
The PET imaging medicaments of targeting A β can fill up blank of China's Bio-pharmaceutical Industry in the field.
Cumarin (Coumarin), also known as bifuran and cumarin, are the black tonka-bean of south China endemic plant, perfume (or spice)
The active ingredient of prairie pine etc..We are innovative to carry out F-18 marks to coumarin derivative, develops a species specific PET
Imaging probe, makes a definite diagnosis and curative effect evaluation for the early stage of AD, has highly important application prospect, but party's law limitation is a kind of
Effective synthesizer.
The content of the invention
The purpose of this utility model is exactly to provide a kind of targeting β-shallow lake to overcome the problems of the above-mentioned prior art
The synthesis module of the coumarin kind compound of powder sample albumen.
The purpose of this utility model can be achieved through the following technical solutions：A kind of tonka-bean for targeting amyloid-beta
The synthesis module of chlorins compound, it is characterised in that including reactor, [18F-]H2 18O solution bottles, gas sample injection device, heating
Device, solution containment,18F adsorbent equipments, heavy oxygen water recovery device and pure preparations device, the reactor are placed in heating dress
Put, described [18F-]H2 18O solution bottles pass through connection18F adsorbent equipments distinguish coupled reaction device and heavy oxygen water recovery device, institute
Gas sample injection device, solution containment and the pure preparations device stated are all connected with reactor.
Described [18F-]H2 18Be equipped with O solution bottles containing [18F-] H2 18O solution, and [18F-]H2 18O solution bottles connect gas
Body sampling device, by gas sample injection device input gas will [18F-]H2 18Liquid in O solution bottles extrudes, input18F absorption dresses
Put absorption18After F, into heavy oxygen water recovery device.
The solution containment includes phase transfer catalyst bottle, acetonitrile solution bottle, wherein precursor bottle, phase transfer catalyst bottle
One end connects gas sample injection device, other end connection18F adsorbent equipments, the acetonitrile solution bottle, precursor bottle are connected in gas in parallel
Between body sampling device and reactor.
Solution is K in the phase transfer catalyst bottle222With the acetonitrile solution of potassium carbonate.
The DMF solution that solution in the precursor bottle is precursor compound B.
The pure preparations device include half preparation systems of HPLC, waste collection bottle, crude product receiving flask, dilution bottle,
Elute bottle, enriching column, waste liquid bottle, office preparation bottle, finished product bottle and sterilised membrane filter；The half preparation system injection ports of HPLC and reaction
Bottle connection, outlet are connected with waste collection bottle and crude product receiving flask respectively, the crude product receiving flask and dilution bottle, enrichment
Column and gas sample injection device connection, wherein dilution bottle is also sequentially connected with gas sample injection device, enriching column one end by pipeline
Bottle and gas sample injection device are eluted, the other end connects the waste liquid bottle and office preparation bottle of parallel connection respectively, and the office preparation bottle is also connected with gas
Body sampling device, and finished product bottle, and sterilised membrane filter is equipped with the pipeline between office preparation bottle and finished product bottle.Gas sampling
Solution in reaction bulb is depressed into half preparation systems of HPLC by device by positive pressure, and solution is collected in waste collection bottle or crude product
In receiving flask, the crude product receiving flask is connected with dilution bottle, enriching column, and the solution of dilution bottle is depressed into crude product by positive pressure
Receiving flask, then by the solution after dilution by enriching column enriched products, waste collection is to waste liquid bottle, then the solution that will elute bottle
By enriching column eluted products, product is collected to office preparation bottle, and finished product in office preparation bottle finally is collected in end by sterilised membrane filter
Product bottle, obtains final products.
Solution in the elution bottle is the normal saline solution containing 45% ethanol.
Described18F adsorbent equipments are QMA columns.
The gas of the gas sample injection device output is N2。
In use, positive pressure is provided by gas sample injection device, will [18F-]H2 18In O solution bottles [18F-]H2 18O is pressed
To QMA columns (18F adsorbent equipments), will [18F-] after absorption, remaining liq is collected into heavy oxygen water recovery device, then passes through gas
Sampling device is by the K in transfer catalyst bottle222The acetonitrile solution and absorption of (10-12mg) and potassium carbonate (1-2mg)
[18F-] QMA columns are depressed into, then it is collected in reactor, reactor is heated to 90 DEG C by heating unit, is passed through nitrogen
(1mL/min) is dried up, and 0.5mL acetonitriles in acetonitrile solution bottle are depressed into reactor in next step, at 90 DEG C, are passed through nitrogen
(1mL/min) is dried up, then the anhydrous DMF solution of 1mL precursor compounds containing 2mg B in precursor bottle is depressed into reaction bulb in next step,
30min is reacted at 120 DEG C.Crude product in reaction bulb is collected into 25-27min crude products extremely by half preparation systems of HPLC afterwards
In crude product receiving flask and 100mL pure water dilution in dilution bottle is added, remaining liquid is collected into waste collection bottle, by crude product
All crude products are enriched with by silicagel column (enriching column) in receiving flask, waste collection to waste liquid bottle, and the 2mL for eluting bottle is contained 45%
The normal saline solution of ethanol by enriching column eluted products, collect to office preparation bottle, finally leads to finished product in office preparation bottle by product
Cross sterilised membrane filter and be collected in finished product bottle, obtain final products.
Above device is that the synthetic method for the coumarin kind compound for being directed to targeting amyloid-beta is specially designed
Device, the coumarin kind compound of the targeting amyloid-beta, its structural formula is as follows：
Wherein, R1For CH3Or CF3；R2For C2H4Or C3H6Straight chained alkyl.
The preparation method of the coumarin kind compound of above-mentioned targeting amyloid-beta, is labelled precursor by compound B,
With18F-Carry out nucleophilic substitution, you can, the structural formula of the compound B is as follows：
Wherein, R1For CH3Or CF3；R2For C2H4Or C3H6Straight chained alkyl, TsO is octadecyl trichlorosilane alkane base.
The method specifically includes following steps：In organic solvent, under inert gas shielding, containing phase transfer catalysis (PTC)
Agent, sylvite and18F-Mixture under the action of with compound B carry out nucleophilic substitution, 40 DEG C~120 DEG C of reaction temperature, instead
5-30min between seasonable, up to the coumarin kind compound of amyloid-beta is targeted.
The coumarin kind compound of gained targeting amyloid-beta is post-processed, and post-processing approach is：Select radiation
Property HPLC by target amyloid-beta coumarin kind compound isolate and purify, then diluted with pure water, cross silicagel column enrichment,
Eluted with the normal saline solution containing 45% ethanol, be collected in physiological saline cillin bottle, be finally prepared into containing 10% ethanol
Normal saline solution, is filtered through sterilised membrane filter, is obtained18F marks coumarin compound preparation.It is isolated and purified with radioactivity HPLC
Before, also can first it be purified with Sep-Pak C18 columns to product.
The organic solvent includes anhydrous acetonitrile, anhydrous tetrahydro furan, anhydrous DMF (N,N-dimethylformamide), nothing
One or more in water DMSO (dimethyl sulfoxide (DMSO)), preferably anhydrous DMF.
The sylvite is potassium carbonate or saleratus；
The phase transfer catalyst is cyclic crown ether class catalyst, and the cyclic crown ether class catalyst is selected from 4,7,
Six oxygen -1,10- diaza-bicyclo [8.8.8] hexacosanes (K of 13,16,21,24-222)。
The inert gas is nitrogen and/or argon gas and/or helium.
It is described containing K222, potassium carbonate and18F-Mixture can be made by following methods：Eluted with K222 solution rich
Collection18F-QMA columns, solvent evaporated, you can.
Used labelled precursor compound B such as wads a quilt with cotton bio tech ltd purchased from Shanghai in the utility model, remaining
Used reagent is commercial reagents.
Compared with prior art, the synthesis of the coumarin kind compound of the targeting amyloid-beta of the utility model design
Module is employed nitrogen as power source, is connected respectively with participating in each reaction vessel of reaction, and set on each connecting line
Respective valves, the switch of each valve is controlled by control device, realizes automated production, avoids radioactive element from producing human body
Raw injury.
Brief description of the drawings
Fig. 1 is the structure diagram of the utility model.
Embodiment
The utility model is described in detail with specific embodiment below in conjunction with the accompanying drawings.
Embodiment 1
As shown in Figure 1, a kind of synthesis module for the coumarin kind compound for targeting amyloid-beta, including reactor 1,
[18F-]H2 18O solution bottles 2, gas sample injection device 17, heating unit 18, solution containment,18F adsorbent equipments 4, heavy oxygen Water Sproading dress
3 and pure preparations device are put, the reactor 1 is placed on heating unit 18, described [18F-]H2 18O solution bottles 2 pass through company
Connect18F adsorbent equipments 4 distinguish coupled reaction device 1 and heavy oxygen water recovery device 3, the gas sample injection device 17, solution containment and
Pure preparations device is all connected with reactor 1.
Described [18F-]H2 18Be equipped with O solution bottles 2 containing [18F-] H2 18O solution, and [18F-]H2 18O solution bottles 2 connect
Gas sample injection device 17, by gas sample injection device 17 input gas will [18F-]H2 18Liquid in O solution bottles 2 extrudes, input18F adsorbent equipments 4 adsorb18After F, into heavy oxygen water recovery device 3.
The solution containment includes phase transfer catalyst bottle 5, acetonitrile solution bottle 6, wherein precursor bottle 7, phase transfer catalysis (PTC)
5 one end of agent bottle connects gas sample injection device 17, other end connection18F adsorbent equipments 4, the acetonitrile solution bottle 6, precursor bottle 7 are simultaneously
Connection is connected between gas sample injection device 17 and reactor 1.Solution is K in the phase transfer catalyst bottle 5222And potassium carbonate
The acetonitrile solution of 1-2mg.The DMF solution that solution in the precursor bottle 7 is precursor compound B.
The pure preparations device includes half preparation systems 8 of HPLC, waste collection bottle 9, crude product receiving flask 10, dilution
Bottle 11, elution bottle 15, enriching column 14, waste liquid bottle 12, office preparation bottle 13, finished product bottle 16 and sterilised membrane filter 19；The HPLC half makes
Standby 8 injection port of system is connected with reaction bulb 1, and outlet is connected with waste collection bottle 9 and crude product receiving flask 10 respectively, described thick
Product receiving flask 10 is connected with dilution bottle 11, enriching column 14 and gas sample injection device 17, wherein dilution bottle 11 also with gas into
Sampling device 17,14 one end of enriching column are sequentially connected elution bottle 15 and gas sample injection device 17 by pipeline, and the other end connects respectively
Waste liquid bottle 12 and office preparation bottle 13 in parallel, the office preparation bottle 13 are also connected with gas sample injection device 17, and finished product bottle 16, and
Sterilised membrane filter 19 is equipped with pipeline between office preparation bottle 13 and finished product bottle 16.Solution in described elution bottle 15 be containing
The normal saline solution of 45% ethanol.
Described18F adsorbent equipments 4 are QMA columns.
The gas that the gas sample injection device 17 exports is N2。
In use, positive pressure is provided by gas sample injection device 17, will [18F-]H2 18In O solution bottles 2 [18F-]H2 18O
Be depressed into QMA columns (18F adsorbent equipments 4), will [18F-] after absorption, remaining liq is collected into heavy oxygen water recovery device 3, is then passed through
Gas sample injection device 17 is by the K in transfer catalyst bottle 5222The acetonitrile solution and suction of (10-12mg) and potassium carbonate (1-2mg)
Attached [18F-] QMA columns are depressed into, then it is collected in reactor 1, reactor 1 is heated to 90 DEG C by heating unit 18, is passed through
Nitrogen (1mL/min) dries up, and 0.5mL acetonitriles in acetonitrile solution bottle 6 are depressed into reactor 1 in next step, at 90 DEG C, are passed through nitrogen
Gas (1mL/min) dries up, then the anhydrous DMF solution of 1mL precursor compounds containing 2mg B in precursor bottle 7 is depressed into reaction bulb in next step
In, react 30min at 120 DEG C.Crude product in reaction bulb 1 is collected 25-27min and slightly produced by half preparation systems 8 of HPLC afterwards
Product are into crude product receiving flask 10 and add in dilution bottle 11 100mL pure water and dilute, remaining liquid is collected to waste collection bottle 9
In, all crude products in crude product receiving flask 10 are enriched with by silicagel column (enriching column 14), waste collection to waste liquid bottle 12 will
Normal saline solutions of the 2mL containing 45% ethanol of bottle 15 is eluted by 14 eluted products of enriching column, product is collected to office preparation bottle 13,
Finished product in office preparation bottle 13 is finally collected in finished product bottle 16 by sterilised membrane filter 19, obtains final products.
Connected by pipeline between each containers such as above-mentioned each raw material container containing, waste liquid bottle, and be provided with each pipeline
Valve, as shown in Figure 1, controlling the switch of each valve by automatic controller, so that reaction is promoted by above-mentioned steps, realizes
Automated production controls, and avoids injury of the radioactive element to human body.
Claims (9)
1. a kind of synthesis module for the coumarin kind compound for targeting amyloid-beta, it is characterised in that including reactor
(1), [18F-]H2 18O solution bottles (2), gas sample injection device (17), heating unit (18), solution containment,18F adsorbent equipments (4),
Heavy oxygen water recovery device (3) and pure preparations device, the reactor (1) are placed on heating unit (18), described [18F-]
H2 18O solution bottles (2) pass through connection18F adsorbent equipments (4) difference coupled reaction device (1) and heavy oxygen water recovery device (3), it is described
Gas sample injection device (17), solution containment and pure preparations device are all connected with reactor (1).
2. a kind of synthesis module of coumarin kind compound for targeting amyloid-beta according to claim 1, it is special
Sign is, described [18F-]H2 18Be equipped with O solution bottles (2) containing [18F-] H2 18O solution, and [18F-]H2 18O solution bottles (2) are even
Connect gas sample injection device (17), by gas sample injection device (17) input gas will [18F-]H2 18Liquid pressure in O solution bottles (2)
Go out, input18F adsorbent equipments (4) adsorb18After F, into heavy oxygen water recovery device (3).
3. a kind of synthesis module of coumarin kind compound for targeting amyloid-beta according to claim 1, it is special
Sign is that the solution containment includes phase transfer catalyst bottle (5), acetonitrile solution bottle (6), precursor bottle (7), wherein phase transfer
Catalyst bottle (5) one end connection gas sample injection device (17), other end connection18F adsorbent equipments (4), the acetonitrile solution bottle
(6), precursor bottle (7) is connected in parallel between gas sample injection device (17) and reactor (1).
4. a kind of synthesis module of coumarin kind compound for targeting amyloid-beta according to claim 3, it is special
Sign is that solution is K in the phase transfer catalyst bottle (5)222With the acetonitrile solution of potassium carbonate (1-2mg).
5. a kind of synthesis module of coumarin kind compound for targeting amyloid-beta according to claim 3, it is special
Sign is that the solution in the precursor bottle (7) is the DMF solution of precursor compound B.
6. a kind of synthesis module of coumarin kind compound for targeting amyloid-beta according to claim 1, it is special
Sign is that the pure preparations device includes half preparation systems of HPLC (8), waste collection bottle (9), crude product receiving flask
(10), dilution bottle (11), elution bottle (15), enriching column (14), waste liquid bottle (12), office preparation bottle (13), finished product bottle (16) and nothing
Bacterium filter membrane (19)；Half preparation systems of HPLC (8) injection port is connected with reactor (1), outlet respectively with waste collection bottle
(9) connected with crude product receiving flask (10), the crude product receiving flask (10) and dilution bottle (11), enriching column (14) and gas
Sampling device (17) connect, wherein dilution bottle (11) also with gas sample injection device (17), enriching column (14) one end by pipeline according to
Secondary connection elution bottle (15) and gas sample injection device (17), the other end connect the waste liquid bottle (12) and office preparation bottle of parallel connection respectively
(13), the office preparation bottle (13) is also connected with gas sample injection device (17), and finished product bottle (16), and office preparation bottle (13) with
Pipeline between finished product bottle (16) is equipped with sterilised membrane filter (19).
7. a kind of synthesis module of coumarin kind compound for targeting amyloid-beta according to claim 6, it is special
Sign is that the solution in the elution bottle (15) is the normal saline solution containing 45% ethanol.
8. a kind of synthesis module of coumarin kind compound for targeting amyloid-beta according to claim 1, it is special
Sign is, described18F adsorbent equipments (4) are QMA columns.
9. a kind of synthesis module of coumarin kind compound for targeting amyloid-beta according to claim 1, it is special
Sign is that the gas of the gas sample injection device (17) output is N2。
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| CN201721069500.6U CN207243786U (en) | 2017-08-24 | 2017-08-24 | A kind of synthesis module for the coumarin kind compound for targeting amyloid beta |
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