CN205223067U - Automatic preparation facilities of 18F - (2S, 4R) 4 - fluorine - L - millet amine acid amides - Google Patents

Automatic preparation facilities of 18F - (2S, 4R) 4 - fluorine - L - millet amine acid amides Download PDF

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CN205223067U
CN205223067U CN201520784779.0U CN201520784779U CN205223067U CN 205223067 U CN205223067 U CN 205223067U CN 201520784779 U CN201520784779 U CN 201520784779U CN 205223067 U CN205223067 U CN 205223067U
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magnetic valve
bottle
valve
cillin bottle
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朱霖
孔繁渊
张岩
乔洪文
查智豪
吴泽辉
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BEIJING INSTITUTE FOR BRAIN DISORDERS
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BEIJING INSTITUTE FOR BRAIN DISORDERS
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Abstract

The utility model relates to an automatic preparation facilities of 18F - (2S, 4R) 4 - fluorine - L - millet amine acid amides, include: the stock solution unit, with the pipeline valve unit that the stock solution unit is connected, with pipeline valve unit is connected fluoridizes react unit and deprotection react unit, it passes through to fluoridize react unit the unit is retrieved with low temperature tail gas respectively to pipeline valve unit, and ion exchange unit and solid -phase extraction unit are connected, the deprotection unit pass through pipeline valve unit respectively with the solid -phase extraction unit, purification preparation unit and low temperature tail gas are retrieved the unit and are connected, low temperature tail gas is retrieved the unit and is connected with the negative pressure unit through pipeline valve unit. The utility model discloses an automatic preparation facilities of 18F - (2S, 4R) 4 - fluorine - L - millet amine acid amides for automatic preparation 18F - (2S, 4R) 4 - fluorine - L - millet amine acid amides can be realized, is favorable to improving the efficiency and the stability of preparation, can protect operating personnel to avoid radiation damage simultaneously, lays a good foundation for the clinical practice of novel metabolism developer 18F - (2S, 4R) 4 - fluorine - L - millet amine acid amides.

Description

A kind of 18the automatization preparation facilities of the fluoro-L-glutamine of F-(2S, 4R)-4-
Technical field
The utility model relates to the preparation of automatization mark and the purification devices of a kind of positron emission tomography (PET) medicine, is specifically related to one 18the automatization preparation facilities of F-(2S, 4R)-4-fluoro-L-glutamine [the fluoro-5-oxopentanoic acid of (2S, 4R)-2,5-diamino-4-].
Background technology
Positron emission tomography (positronemissiontomography, PET) be a kind ofly be widely used in clinical video picture means, its principle be by detect the distribution of positron medicine in human body reflect particular target to physiology and pathological change, thus carry out medical diagnosis on disease and research.Positron medicine is the key of PET practical function, and such medicine is marked by medical positron radionuclide, particular physiological process can be participated in after entering human body or be incorporated into particular target to.
Current clinical application the most widely radiopharmaceuticals is 2- 18f-2-DDG ([ 18f] FDG), be mainly used in the diagnosis of tumour, somatotype and curative effect criticism.Find in clinical application, some tumours [ 18f] FDG-PET video picture is negative result, and this shows that the metabolism of these tumours and energy derive may be other materials beyond glucose.Recent research shows, [ 18f] the tumor metabolic substrate of FDG scan negative may be glutamine.Glutamine is amino acid that in blood of human body, concentration is the highest (the highest be about 1mM), can at plastosome internal reference and tricarboxylic acid cycle generate energy, or synthetic cell constitute, for propagation and the survival of tumour cell.Glucose and glutamine two kinds of pathways metabolisms may be there are simultaneously in tumour cell, make tumour cell to select energy derive, therefore with glutamine metabolism be target PET video picture positron medicine may can detect [ 18f] tumour of FDG scan negative, make up [ 18f] deficiency of FDG, thus improve the accuracy in detection to tumour.In the radiopharmaceuticals of reflection glutamine metabolism, preliminary assessment research shows 18f-(2S, 4R)-4-fluoro-L-glutamine [the fluoro-5-oxopentanoic acid of (2S, 4R)-2,5-diamino-4-, 18f-(2S, 4R)-4-FGln] there is good biological activity, may make up [ 18f] deficiency of FDG on diagnosing tumor, there is great using value.
The energy metabolism participated in the glutamine PET video picture positron medicine that is target mainly with glutamine for architecture basics, introduce different radionuclides in the molecule, wherein radionuclide F-18 has longer physical half life (109.8 minutes), and can be obtained easily by medical cyclotron, be conducive to applying clinically.
Chinese invention patent CN102083772A (publication number), US Patent No. 2010/0290991A1 (publication number), US Patent No. 2014/0301948A1 (publication number) report the glutamine analogues of F-18 mark for tumor imaging, Problems existing does not all split the chirality position on glutamine analogues No. 2 position of mark in these patents, and its structure is as follows:
Configuration on known amino acid compounds 2 has important impact to its metabolic condition in vivo, only have the amino acid of this position L configuration to participate in body metabolism, therefore the biological property of the mark glutamine analogues that 2 configurations are different may have larger difference; Above-mentioned patent does not clearly report the preparation method of the glutamine analogues of F-18 mark simultaneously.
It should be noted that above-mentioned patent key point report F-18 marks the preparation method of L-glutamic acid analogue, L-glutamic acid is different with the structure of glutamine, and the group on L-glutamic acid end is carboxylic acid, and the group on glutamine end is acid amides, and concrete structure is as follows:
Left side (A) is L-glutamic acid, and right side (B) is glutamine; Both passway of metabolisms are different with mechanism: L-glutamic acid mainly participates in the amino acid metabolisms such as Amino acid synthesis, directly can not enter tricarboxylic acid cycle and generate energy, and glutamine can participate in tricarboxylic acid cycle and provide energy, therefore energy metabolism is the PET video picture positron medicine of target need take glutamine as architecture basics.
Chinese invention patent CN102595888A (publication number) and US Patent No. 8747809B2 (grant number) reports the preparation method that F-18 marks glutamine analogues 4-fluorine glutamine (4-FGln), specifically on 4 of glutamine, introduce radionuclide F-18, this causes there are two chiral centres in molecule, thus there are 4 optical isomers, concrete structure is as follows:
Above patent reports the preparation method of 4 optical isomers respectively.The article [QuWenchao, ZhaZhihao, PloesslKarl, LiebermanBrianP., ZhuLin, WiseDavidR., B.ThompsonCraig, the KungHankF. that deliver; SynthesisofOpticallyPure4-Fluoro-GlutaminesasPotentialMe tabolicImagingAgentsforTumors; JournaloftheAmericanChemicalSociety, 2011,133 (4), 1122-1133] show, be configured as 18f-(2S, 4R)-4-FGln and 18the isomer of F-(2S, 4S)-4-FGln has higher cellular uptake, and two other isomer 18f-(2R, 4R)-4-FGln and 18the uptake values of F-(2R, 4S)-4-FGln is lower, and this and the amino acid whose expection of organism selective absorbing L-type coincide.
Further report [LiebermanBrianP., PloesslKarl, WangLimin, QuWenchao, ZhaZhihao, WiseDavidR., ChodoshLewisA., BelkaGeorge, ThompsonCraigB., KungHankF.; JournalofNuclearMedicine, 2011,52 (14), 1947-1955] show, 18f-(2S, 4R)-4-FGln has and absorbs kinetic property fast in tumour cell, cell is entered mainly through ASC amino acid transporter system, the synthesis of protein and biomacromolecule can be participated in after entering cell, this shows that this compound take part in Tricarboxylic Acid Metabolism process in cell, in conjunction with transgenic mice PET video picture research, show that the picked-up of this compound may can reflect the situation of cellular energy metabolism, therefore, it is possible to for the PET video picture of tumor metabolic.
Physical half life due to radionuclide F-18 is only 109 minutes, prepares tagged compound 18the difficult point of F-(2S, 4R)-4-FGln is to need to obtain target compound by limited chemical step within the as far as possible short time (being less than a transformation period), also needs the optical activity keeping compound simultaneously.Chinese invention patent CN102595888A (publication number) and US Patent No. 8747809B2 and the article [QuWenchao, ZhaZhihao, the PloesslKarl that deliver, LiebermanBrianP., ZhuLin, WiseDavidR., B.ThompsonCraig, KungHankF.; SynthesisofOpticallyPure4-Fluoro-GlutaminesasPotentialMe tabolicImagingAgentsforTumors; JournaloftheAmericanChemicalSociety, 2011,133 (4), 1122-1133] report in 18chemical reaction method prepared by F-(2S, 4R)-4-FGln: precursor compound is same in the presence of a phase transfer catalyst 18there is nucleophilic substitution fluoridation in F-, obtained mark intermediate, deprotection in acid condition after mark intermediate is purified, then through purifying and formulation obtained 18f-(2S, 4R)-4-FGln product.In order to ensure the optical purity of product, need alkalescence and the temperature of the reaction of accurate control mark and deprotection reaction.Above chemical preparation process has all manually operated.But when radiopharmaceuticals is used for clinical video picture; the initial F-18 radioactive activity dropped into can reach several Curie; in order to protect operator from radiation injury; preparation process needs to have been implemented by radiopharmaceuticals Fully automated synthesis device; in addition; the automatization mark preparation of developer is conducive to the stdn of medicine preparation process, ensures security and the validity of obtained radiopharmaceuticals preparation, therefore realizes 18radiopharmaceutic efficient, the automatization mark preparation of F-(2S, 4R)-4-FGln is that it realizes the prerequisite of clinical application.
18the automatization preparation of F-(2S, 4R)-4-FGln is faced with some significant challenge: first, and often walking reaction conditions needs accurately to control, and ensures the optical purity of product; The second, the deprotection reaction in preparation process needs to use organic acid, is generally trifluoroacetic acid, can ensure that end product racemization does not occur, but trifluoroacetic acid has stronger volatility and corrodibility; 3rd, need after deprotection reaction completes to remove the impurity such as the organic acid in product as far as possible, ensure that product formulation meets the requirement of body internal jugular vein injection.Particular requirement more than in preparation, causes 18the preparation of F-(2S, 4R)-4-FGln imaging medicament cannot have been implemented on existing commercialization radiopharmaceuticals Fully automated synthesis device.
According to the difference of project organization, current business-like F-18 positron medicine Fully automated synthesis device is divided into two classes substantially: the first kind is the synthesizer adopting fixing circuit design; Equations of The Second Kind is the synthesizer adopting removable disposable piping system.The TracerLabFXN type Fully automated synthesis device (introducing in detail with reference to network address http://www.gehealthcare.com) that the former representative is produced as GE company of the U.S., this device adopts the flowing of solenoid control fluid, if for 18prepared by F-(2S, 4R)-4-FGln automatization, the corrosive reagents such as trifluoroacetic acid need flow through electromagnetic valve body inside and cause valve body to be corroded, and it is not easy to operate to change magnetic valve and piping system and costliness; Another one problem is that synthetic chemistry reagent may remain in electromagnetic valve body inside, causes synthesizing the crossed contamination between different batches medicine, and therefore, prepared by this type device 18f-(2S, 4R)-4-FGln is absolutely not feasible.Equations of The Second Kind synthesizer is as the FASTlab of GE company of the U.S. tMtype (introducing in detail with reference to network address http://www.gehealthcare.com), the SynthERA type (http://www.iba-radiopharmasolutions.com/) of Belgian IBA company, the NeptisPerform type (http://www.neptis-vsa.com/) of Belgian ORA company and the ALLINONE type synthesizer of Belgian TRASIS company, the advantage of these devices adopts conveniently replaced disposable pipeline (cutting ferrule), but for different types of radiopharmaceuticals, special disposable pipeline and cutting ferrule need be developed.The advantage of such device prepares pipeline and the cutting ferrule single use of medicine, avoids the cleaning process of device and the problem of radiopharmaceutic crossed contamination.If but for 18the preparation of F-(2S, 4R)-4-FGln remains in following problem: first, not yet develop for 18the disposable pipeline of tailored version prepared by F-(2S, 4R)-4-FGln and cutting ferrule; The second, the material erosion resistance that disposable pipeline uses is poor, not easily contacts the organic acids such as trifluoroacetic acid; 3rd, be not provided with the emission-control equipment for VFA, use the organic acids such as trifluoroacetic acid that device can be caused to be corroded.In sum, be not yet applicable at present 18commercialization Fully automated synthesis module prepared by F-(2S, 4R)-4-FGln.
The people such as Qiao Hongwen, Zhu Lin be published in article on Beijing Normal University's natural science journal (2011-0247 (1)) " 18the development of F positron medicine Fully automated synthesis device BNUF-A2 and application " disclose a kind of BNUF-A2 type for laboratory 18f positron medicine Fully automated synthesis device.The advantage of this device is to adopt clamping tube type magnetic valve, makes to prepare reagent and all flows in pipeline, avoids residual in valve body and the corrosion to valve body; Shortcoming does not arrange exhaust treatment system, and use VFA can cause the corrosion of device, therefore BNUF-A2 type can not be applicable to 18the preparation of F-(2S, 4R)-4-FGln.
Therefore, provide a kind of efficient, stable, safe 18the automatization preparation facilities of F-(2S, 4R)-4-fluoro-L-glutamine (the fluoro-5-oxopentanoic acid of (2S)-2,5-diamino-4-) just becomes the technical barrier that this technical field is badly in need of solution.
Utility model content
One of the purpose of this utility model is to provide a kind of efficient, stable, safe 18the automatization preparation method of the fluoro-L-glutamine of F-(2S, 4R)-4-.
Above-mentioned purpose of the present utility model reaches by the following technical programs:
A kind of 18the automatization preparation method of the fluoro-L-glutamine of F-(2S, 4R)-4-, comprises the following steps:
(1) fluorination reagent 18f -catch
Make to contain 18f -the aqueous solution of (hydrofluoric acid), will by ion-exchange unit 18f -be adsorbed on ion-exchange unit;
(2) nucleophilic reaction is active 18f -preparation
Will with the solution containing phase-transfer catalyst 18f -wash-out from the ion-exchange unit step (1), joins in fluoridation unit, by dry for the solution evaporation in fluoridation unit under inert gas purge and heating condition, obtains having nucleophilic reaction activity 18f -;
(3) fluoridation
The acetonitrile solution of precursor compound is joined and there is nucleophilic reaction activity obtained by step (2) 18f -in, also there is fluoridation in a heated condition in sealing fluoridation unit, then cools, obtain the reaction mixture solution containing intermediate;
(4) purification of intermediate
Contain in the reaction mixture solution of intermediate to step (3) gained and add suitable quantity of water, make gained solution by Solid-Phase Extraction unit, then rinse this Solid-Phase Extraction unit with 5 to 30 ml waters to be further purified, after completing with elutriant by intermediate from wash-out Solid-Phase Extraction unit, obtain midbody solution to deprotection reaction unit;
(5) intermediate deprotection reaction
By purified for step (4) midbody solution obtained evaporate to dryness under inert gas purge and heating condition, trifluoroacetic acid or the trifluoroacetic acid solution containing methyl-phenoxide is added in resistates, sealing deprotection reaction unit, react in a heated condition, heating is stopped after completing, at reduced pressure conditions trifluoroacetic acid evaporate to dryness is also collected by cooling the trifluoroacetic acid steamed simultaneously, evaporated in backward deprotection reaction device and added suitable quantity of water, obtained thick product solution;
(6) purifying products and formulation
The thick product solution making step (5) obtained is by pure preparations unit, obtained 18f-(2S, 4R)-4-fluoro-L-glutamine solution.
Preferably, described in described step (1), anion exchange unit is QMA post, ChromafixPS-HCO 3post or other anion-exchange column.
Preferably, described in described step (2), fluoridation unit is reaction flask; Described rare gas element is N 2, the gas such as He or Ar.
Preferably, phase-transfer catalyst described in described step (2) is 18-hat-6/KHCO 3solution, amino-polyether K 222/ K 2cO 3solution or TBAHCO 3solution.
Preferably, in described step (2), after evaporation drying, in evaporation residue, 0.2 to 2 milliliter of anhydrous acetonitrile is added, further evaporation drying.
Preferably, the number of times adding acetonitrile repeated evaporation in described step (2) in evaporation residue is 2 to 5 times, preferably 2 times, adds no more than 2 milliliters of acetonitrile amount at every turn.
Preferably, precursor compound described in described step (3) is conventional compound, and its structure is as follows:
Wherein R 1for leavings group, be preferably tosic acid ester group, methylsulphonic acid ester group, halogen etc.; R 2, R 3, R 4for blocking group, wherein R 2for C 1-6alkyl or C 1-6cycloalkyl; R 3for the nitrogen-protecting group group that acid is unstable, be preferably tertbutyloxycarbonyl; Each R 4be independently-OC 1-6alkyl or C 1-6cycloalkyl; And n is 0,1,2,3,4.
The temperature of described step (3) described heating is 80-120 DEG C, preferably 100 DEG C.
Described step (4) also can be as follows:
Contain in the reaction mixture solution of intermediate to step (3) gained the water adding appropriate (1 to 10 milliliter) to dilute; then gained solution is injected Semi-preparative high pressure liquid chromatographic system (HPLC); collect the moving phase containing intermediate; the moving phase of the collecting water of 10 to 30 milliliters dilutes; then make it by Solid-Phase Extraction unit; intermediate is made to be adsorbed on Solid-Phase Extraction unit; then with elutriant by intermediate from wash-out Solid-Phase Extraction unit; to deprotection reaction unit, obtain midbody solution.
Described in described step (4), Solid-Phase Extraction unit is the reverse phase solid phase extraction pillars such as C-18 or OasisHLB; Described deprotection reaction unit is deprotection reaction bottle.
The Specific amounts adding suitable quantity of water described in described step (4) is the reaction mixture solution volume 5 to 50 times containing intermediate.
Described in described step (4), elutriant is the low boiling point organic solvents such as acetonitrile, ethanol or ether.Described in described step (4), the stationary phase of semi-preparative HPLC is the reverse-phase chromatographic columns such as C-18; Moving phase is the mixing solutions of aqueous solution composition of the organic solvent such as ethanol, acetonitrile and water, buffering salt.
The Specific amounts adding suitable quantity of water described in described step (5) is 1 to 10 milliliter.
Described in described step (5), the temperature of heating is 50-70 DEG C, preferably 60 DEG C.
Pure preparations unit described in described step (6) is anion-exchange column, ionic adsorption alumina column and the coupling of C-18 post, or again with the coupling of OasisHLC solid-phase extraction column, or be used alone wherein a kind of.
Another object of the present utility model is to provide one 18the automatization preparation facilities of the fluoro-L-glutamine of F-(2S, 4R)-4-.
Above-mentioned purpose of the present utility model reaches by the following technical programs:
A kind of 18the automatization preparation facilities of the fluoro-L-glutamine of F-(2S, 4R)-4-, comprising: liquid storage unit; The pipe valve unit be connected with described liquid storage unit; The fluoridation unit be connected with described pipe valve unit and deprotection reaction unit; Described fluoridation unit by described pipe valve unit respectively with low temperature exhaust gas recovery unit, ion-exchange unit and Solid-Phase Extraction unit are connected; Described deprotection reaction unit by pipe valve unit respectively with Solid-Phase Extraction unit, pure preparations unit and low temperature exhaust gas recovery unit are connected; Described low temperature exhaust gas recovery unit is connected with negative pressure unit by pipe valve unit.
Described liquid storage unit comprises the cillin bottle (1 to 13) of 13 glands, for storing 18f-(2S, reagent 4R) required for the fluoro-L-glutamine preparation of-4-, which is provided with a gas feed and a taphole, described cillin bottle 2-10, the gas feed of 12-13 is connected with rare gas element feeding mechanism with pipeline by valve, and air is connected in the gas feed of described cillin bottle 1 and cillin bottle 11.
Described pipe valve unit comprises pipe clamping electromagnetic valve (19 to 44) and pipeline, and wherein 22 is two-way electromagnetic valve, and 4 is three-way solenoid valve; For the flowing of control device inner fluid, be characterized in adopting clamping tube type magnetic valve, make solution flow in pipeline and avoid same valve body contact, thus avoid the corrosion to electromagnetic valve body, make pipeline be easy to change simultaneously.
Described negative pressure unit is vacuum pump 46, for providing negative pressure for system.
Described low temperature exhaust gas recovery unit is cold well 45, for collecting the waste gas produced in preparation process.
Described fluoridation unit 17 is connected with cillin bottle 4 with cillin bottle 2, XiLin 3 respectively by magnetic valve 23, magnetic valve 24 and magnetic valve 25, be connected with waste liquid bottle 14 with ion-exchange unit (anion-exchange column) 47 respectively by three-way solenoid valve 38, be connected with the cold well 45 in low temperature exhaust gas recovery unit by magnetic valve 42, be connected with rare gas element feeding mechanism by magnetic valve 29;
Described deprotection reaction unit (deprotection reaction bottle) 18 is connected with cillin bottle 13 with cillin bottle 11, XiLin 12 respectively by magnetic valve 33, magnetic valve 34 and magnetic valve 35, be connected with waste liquid bottle 15 with Solid-Phase Extraction unit 48 respectively by three-way solenoid valve 40, be connected with the cold well 45 in low temperature exhaust gas recovery unit by magnetic valve 43, be connected with rare gas element feeding mechanism by magnetic valve 36, be connected with pure preparations unit (post 49-post 51) by magnetic valve 41;
Described pure preparations unit is connected with product bottle 16 by sterilised membrane filter 52;
Described Solid-Phase Extraction unit (solid-phase extraction column) 48 is connected with fluoridation unit (reaction flask) 17 by magnetic valve 39, be connected with rare gas element feeding mechanism by magnetic valve 29, be connected with cillin bottle 10 with cillin bottle 8, XiLin 9 respectively by magnetic valve 30, magnetic valve 31 and magnetic valve 32;
Described tail gas recycle unit (cold well) 45 is connected with negative pressure unit 46 by three-way solenoid valve 44;
Described ion-exchange unit is connected with waste liquid bottle 14 by three-way solenoid valve 38, by three-way solenoid valve 37 respectively with cillin bottle 1 He 18f -aqueous solution feeding mechanism is connected;
Described waste liquid bottle 14 and waste liquid bottle 15 are equipped with gas feed and connect air.
The outlet end (right-hand member of schematic diagram) of described magnetic valve 39 is connected with the injection annulus of Semi-preparative high pressure liquid chromatographic system (HPLC), by the outlet of Semi-preparative high pressure liquid chromatographic system (HPLC) access cillin bottle 8.
Cillin bottle 1 is for loading phase-transfer catalysis agent solution, and air is connected in the gas feed of cillin bottle 1, and the taphole of cillin bottle 1 is connected to the normal-closed end of three-way solenoid valve 37, is connected, fluorination reagent after anion-exchange column 47 with the normal-closed end of three-way solenoid valve 38 18f -enter fluoridation unit 17 with containing after the eluant solution of phase-transfer catalyst, the Chang Kaiduan of three-way solenoid valve 37 respectively with 18f -aqueous solution feeding mechanism is connected with anion exchange unit (ion exchange column) 47, and the waste liquid after ion-exchange enters waste liquid bottle 14 through three-way solenoid valve 38 Chang Kaiduan.
Cillin bottle 2 is for loading acetonitrile, and its gas feed connects rare gas element feeding mechanism by magnetic valve 19, and rare gas element provides liquid in pressure-driven cillin bottle 2 to flow in piping system; Its liquid exit connected electromagnetic valve 23, then accesses fluoridation unit 17.
Cillin bottle 3 is for loading acetonitrile, and gas feed connects rare gas element by magnetic valve 19, liquid exit connected electromagnetic valve 24, then accesses fluoridation unit 17.
Cillin bottle 4 is for loading 18precursor compound solution prepared by the fluoro-L-glutamine of F-(2S, 4R)-4-, gas feed connects rare gas element by magnetic valve 19, liquid exit connected electromagnetic valve 25, then accesses fluoridation unit 17.
Cillin bottle 5,6,7 is for loading water, and gas feed all connects rare gas element by magnetic valve 20, and liquid exit is connected electromagnetic valve 26,27,28 successively, then merges access fluoridation unit 17.
The pipeline connected electromagnetic valve 39 of tapping in fluoridation unit 17; then enter Solid-Phase Extraction unit (solid phase extraction column) 48 and carry out extracting and separating; waste liquid passes in waste liquid bottle 15 through the Chang Kaiduan of magnetic valve 40, and gained midbody solution enters deprotection reaction unit (deprotection reaction bottle) 18 by the normal-closed end of magnetic valve 40.
Cillin bottle 8,9 loads water, and gas feed connects rare gas element feeding mechanism by magnetic valve 21, and liquid exit is connected electromagnetic valve 30,31 respectively, then accesses Solid-Phase Extraction unit (solid phase extraction column) 48.Load the organic solvent being used for wash-out intermediate in cillin bottle 10, access Solid-Phase Extraction unit (solid phase extraction column) 48 by magnetic valve 32.
Cillin bottle 11 is for loading acid deprotecting regent, and air is connected in gas feed, and liquid exit is connected to deprotection reaction unit (deprotection reaction bottle) 18 by magnetic valve 33; Cillin bottle 12,13 is for loading water, and gas feed connects rare gas element feeding mechanism by magnetic valve 22, and liquid exit is connected electromagnetic valve 34,35 respectively, then merges access deprotection reaction unit (deprotection reaction bottle) 18; The pipeline of deprotection reaction unit (deprotection reaction bottle) 18 tappings is connected to the purifying pillar 49,50 and 51 of series connection by magnetic valve 41, be then linked in product bottle 16 through sterilised membrane filter 52.Fluoridation unit 17 and deprotection reaction unit 18 are connected to low temperature exhaust gas recovery unit (cold well) 45 through magnetic valve 42,43 respectively, and cold well 45 is for collecting the waste gas produced in preparation process.Cold well 45 is connected to vacuum pump 46 through magnetic valve 44, vacuum pump 46 in preparation process for device provides negative pressure.
With described 18the automatization preparation facilities preparation of the fluoro-L-glutamine of F-(2S, 4R)-4- 18the process of F-(2S, 4R)-4-fluoro-L-glutamine is as follows:
Containing H 18the aqueous solution of F enters anion-exchange column 47 by the Chang Kaiduan of magnetic valve 37, 18f -be attracted on anion-exchange column, contain 18f -solvent in the aqueous solution enters waste liquid bottle 14 through magnetic valve 38 Chang Kaiduan.Open vacuum pump 46, magnetic valve 42 and 44, for providing negative pressure in reaction flask 17.Phase-transfer catalysis agent solution in cillin bottle 1 enters anion-exchange column 47 by magnetic valve 37 normal-closed end under suction function in reaction flask 17, will 18f -wash-out also enters reaction flask 17 through magnetic valve 38 normal-closed end.17 to 80-120 DEG C, reacting by heating bottle, by solution evaporate to dryness wherein, steam enters cold well 45 under suction function after magnetic valve 42, and the solvent steamed condenses at cold Jing45Chu.After having evaporated by the acetonitrile in cillin bottle 2 under the promotion of the rare gas element through magnetic valve 19, join in reaction flask 17 through magnetic valve 23.17 to 80-120 DEG C, reacting by heating bottle, by the evaporate to dryness again of the solution in reaction flask 17 under inert gas purge and suction function, steam enters cold well 45 under suction function after magnetic valve 42, the solvent steamed condenses at cold Jing45Chu, after completing, the acetonitrile in cillin bottle 3 joined reaction flask 17 and repeat evaporative process, obtained dry have nucleophilic reaction activity 18f -.Precursor solution in cillin bottle 4 joins in reaction flask 17 through 25 magnetic valves under rare gas element effect, then sealed reaction bottle 17 carry out fluoridation under heating condition (80-120 DEG C).After fluoridation completes, water in cillin bottle 5 is under the promotion of the rare gas element through magnetic valve 20, join in reaction flask 17 through magnetic valve 26 and dilute fluoridation solution, fluoridation solution after dilution enters solid phase extraction column 48 through magnetic valve 39 under rare gas element promotes, intermediate is adsorbed on solid phase extraction column 48, and waste liquid enters waste liquid bottle 15 through magnetic valve 40 Chang Kaiduan.Then joined in reaction flask 17 by the water in cillin bottle 6,7 successively, and make it by solid phase extraction column 48, object rinses reaction flask 17 and solid phase extraction column 48, and waste liquid enters waste liquid bottle 15 through magnetic valve 40 Chang Kaiduan.Under the promotion of the rare gas element through magnetic valve 21, make water in cillin bottle 8,9 by solid phase extraction column 48, then enter waste liquid bottle 15 through the Chang Kaiduan of magnetic valve 40.Then, the organic solvent in cillin bottle 10 enters solid phase extraction column 48 by magnetic valve 32 under the promotion of rare gas element, and the normal-closed end through magnetic valve 40 enters deprotection reaction bottle 18, by the intermediate of preparation from solid phase extraction column 48 wash-out.Open magnetic valve 43; by vacuum pump 46 for providing negative pressure in deprotection reaction bottle 18; reacting by heating bottle 18; at reduced pressure conditions by midbody solution evaporate to dryness; steam enters cold well 45 under suction function after magnetic valve 43; the solvent steamed condenses at cold Jing45Chu, then opens solenoid valve 33, and the acid deprotecting regent in cillin bottle 11 is added deprotection reaction bottle 18.Seal deprotection reaction bottle 18 and be heated to 50-70 DEG C and carry out deprotection reaction.After deprotection reaction completes, by the acid deprotecting regent evaporate to dryness in deprotection reaction bottle 18 under the suction function that vacuum pump 46 provides, acid vapors is by collecting by condensation during cold well 45.Opening magnetic valve 34, the water in cillin bottle 12 is joined in deprotection reaction bottle 18, then in deprotection reaction bottle 18, passing into rare gas element for fully mixing thick product solution by magnetic valve 36.Thick product solution in deprotection reaction bottle 18 by magnetic valve 41, enters the serial purification pillar 49,50 and 51 of series connection, then enters product bottle 16 by sterilised membrane filter 52 under inert gas pressure promotes.Open magnetic valve 35, the water in cillin bottle 13 is joined in deprotection reaction bottle 18, then make it enter product bottle 16 by serial purification pillar 49,50 and 51 and sterilised membrane filter 52 successively, obtained 18f-(2S, 4R)-4-fluoro-L-glutamine product solution.
Described automatization preparation facilities can also access Semi-preparative high pressure liquid chromatographic system (HPLC), for purification intermediate.The injection annulus of the outlet end of magnetic valve 39 with Semi-preparative high pressure liquid chromatographic system (HPLC) is connected, Semi-preparative high pressure liquid chromatographic system (HPLC) is collected the outlet access cillin bottle 8 of moving phase.The flow process of the intermediate of employing Semi-preparative high pressure liquid chromatographic system (HPLC) purification is: the water dilution in the fluoridation solution cillin bottle 5 in reaction flask 17, then enter in the injection annulus of Semi-preparative high pressure liquid chromatographic system (HPLC) through magnetic valve 39 under the promotion of rare gas element, then be loaded in semi-preparative chromatographic column, also collecting by semi-preparative chromatographic column (HPLC) system acquisition chromatographic data the moving phase containing intermediate enters in cillin bottle 8, then be loaded on solid phase extraction column 48 by cillin bottle 8 through magnetic valve 30 under the promotion of rare gas element, then pillar 48 is rinsed with the water in cillin bottle 9, with the organic solvent in cillin bottle 10, intermediate is added in deprotection reaction bottle 18 from wash-out solid phase extraction column and through the normal-closed end of magnetic valve 40 again.
Beneficial effect:
Of the present utility model 18f-(2S, 4R) advantage of the automatization preparation facilities of the fluoro-L-glutamine of-4-is: first, adopt clamping tube type solenoid control liquid-flow, make liquid directly not contact electromagnetic valve body, avoid reagent to the corrosion of magnetic valve and remaining in valve body; The second, device is equipped with two reaction flasks, has been respectively used to preparation 18two step chemical reactions needed for the fluoro-L-glutamine of F-(2S, 4R)-4-; 3rd, be provided with negative pressure unit, can fully remove VFA for deprotection reaction in reaction system by reduction vaporization; 4th, be provided with low temperature exhaust gas recovery system, avoid the leakage of VFA, prevent from causing corrosion to device.
Of the present utility model 18the automatization preparation facilities of the fluoro-L-glutamine of F-(2S, 4R)-4-, makes automatization prepare 18the fluoro-L-glutamine of F-(2S, 4R)-4-is achieved, and be conducive to the efficiency and the stability that improve preparation, operator can be protected to avoid radiation injury, be novel metabolize imaging agent simultaneously 18the clinical application of the fluoro-L-glutamine of F-(2S, 4R)-4-is laid a good foundation.
Below by the drawings and specific embodiments, the utility model is described further, but and does not mean that the restriction to the utility model protection domain.
Accompanying drawing explanation
Fig. 1 is the utility model 18the structural representation of F-(2S, 4R)-4-fluoro-L-glutamine preparation facilities.
Fig. 2 is prepared by the utility model 18the efficient liquid phase chromatographic analysis result of F-(2S, 4R)-4-fluoro-L-glutamine product solution.
Fig. 3 is the control compound containing stable nuclide 19f-(2S, 4R)-4-fluoro-L-glutamine solution efficient liquid phase chromatographic analysis result.
Major parts title in accompanying drawing is as follows:
1-loads 18-hat-6/KHCO 3the cillin bottle 2-of broad liquid loads the cillin bottle of acetonitrile
3-loads the cillin bottle of the cillin bottle 4-loading precursor compound solution of acetonitrile
5-loads the cillin bottle of the cillin bottle 6-loading 5mL water of 10mL water
7-loads the cillin bottle of the cillin bottle 8-loading 5mL water of 5mL water
9-loads the cillin bottle of the cillin bottle 10-loading 1mL ethanol of 5mL water
11-loads the cillin bottle of the cillin bottle 12-loading 10mL water of 1mL trifluoroacetic acid
13-loads the cillin bottle 14-waste liquid bottle of 10mL water
15-waste liquid bottle 16-product bottle
17-reaction flask 18-deprotection reaction bottle
19-magnetic valve 20-magnetic valve
21-magnetic valve 22-magnetic valve
23-magnetic valve 24-magnetic valve
25-magnetic valve 26-magnetic valve
27-magnetic valve 28-magnetic valve
29-magnetic valve 30-magnetic valve
31-magnetic valve 32-magnetic valve
33-magnetic valve 34-magnetic valve
35-magnetic valve 36-magnetic valve
37-three-way solenoid valve 38-three-way solenoid valve
39-magnetic valve 40-three-way solenoid valve
41-magnetic valve 42-magnetic valve
43-magnetic valve 44-three-way solenoid valve
45-cold well 46-vacuum pump
47-SpePakQMA post 48-OasisHLB post
49-SAX strong anion exchange column 50-ionic adsorption alumina column
51-SpePakC-18 post 52-sterilised membrane filter
Embodiment
Embodiment 1 (carrying out purification of intermediate by anti-phase purifying pillar):
18the preparation of the fluoro-L-glutamine of F-(2S, 4R)-4-.
Article and material:
Containing H 18the aqueous solution of F is prepared by IBA company Cyclone-10 type medical cyclotron accelerator, and radioactive activity is 29.6GBq; 18-hat-6, KHCO 3, acetonitrile, ethanol, trifluoroacetic acid, methyl-phenoxide (it is for preparing the trifluoroacetic acid solution containing 0.5% methyl-phenoxide), the chemical reagent such as Salzburg vitriol are purchased from Sigma-Aldrich company and Beijing Chemical Plant respectively, purity is SILVER REAGENT, and unexplained reference then directly uses; Anionresin SpePakQMA post, Solid-Phase Extraction SpePakC-18 post, OasisHLB post, ionic adsorption alumina column are purchased from Waters company; SAX strong anion exchange column is purchased from Alltech company; Sterilised membrane filter is purchased from MerckMillipore company.
Precursor compound is synthesized by laboratory, and synthetic method is with reference to Chinese invention patent CN102595888A (publication number) and US Patent No. 8747809B2 (grant number), and purity is greater than 95%.Chemical structure is as follows.
As shown in Figure 1, be the utility model 18the structural representation of F-(2S, 4R)-4-fluoro-L-glutamine preparation facilities, wherein, 1 for loading 18-hat-6/KHCO 3the cillin bottle of solution, 2 for loading the cillin bottle of acetonitrile, 3 for loading the cillin bottle of acetonitrile, 4 for loading the cillin bottle of the acetonitrile solution of precursor compound, 5 for loading the cillin bottle of 10mL water, 6 for loading the cillin bottle of 5mL water, 7 for loading the cillin bottle of 5mL water, 8 for loading the cillin bottle of 5mL water, 9 for loading the cillin bottle of 5mL water, 10 for loading the cillin bottle of 1mL ethanol, 11 for loading the cillin bottle of 1mL trifluoroacetic acid, 12 for loading the cillin bottle of 10mL water, 13 for loading the cillin bottle of 10mL water, 14 is waste liquid bottle, 15 is waste liquid bottle, 16 is product bottle, 17 is reaction flask, 18 is deprotection reaction bottle, 19 is magnetic valve, 20 magnetic valves, 21 is magnetic valve, 22 is magnetic valve, 23 is magnetic valve, 24 is magnetic valve, 25 is magnetic valve, 26 is magnetic valve, 27 is magnetic valve, 28 is magnetic valve, 29-magnetic valve, 30 is magnetic valve, 31 is magnetic valve, 32 is magnetic valve, 33 is magnetic valve, 34 is magnetic valve, 35 is magnetic valve, 36 is magnetic valve, 37 is three-way solenoid valve, 38 is three-way solenoid valve, 39 is magnetic valve, 40 is three-way solenoid valve, 41 is magnetic valve, 42 is magnetic valve, 43 is magnetic valve, 44 is three-way solenoid valve, 45 is cold well, 46 is vacuum pump, 47 is SpePakQMA post, 48 is OasisHLB post, 49 is SAX strong anion exchange column, 50 is ionic adsorption alumina column, 51 is SpePakC-18 post, 52 is sterilised membrane filter.
18f-(2S, 4R)-4-fluoro-L-glutamine preparation facilities comprises liquid storage unit, pipe valve unit, fluoridation unit, deprotection reaction unit, low temperature exhaust gas recovery unit, ion-exchange unit, Solid-Phase Extraction unit, pure preparations unit and negative pressure unit.Liquid storage unit is used for storing 18reagent required for the fluoro-L-glutamine preparation of F-(2S, 4R)-4-, comprises the gland cillin bottle (in Fig. 1 label 1 to 13) that 13 volumes are 10mL, connection gas feed and a taphole on it; Pipe valve unit is made up of pipe clamping electromagnetic valve and pipeline, for the flowing of control device inner fluid, comprises 26 magnetic valves (in Fig. 1 label 19 to 44); Fluoridation unit is reaction flask 17 and deprotection reaction unit is deprotection reaction bottle 18, is respectively used to 18the fluoridation of the fluoro-L-glutamine of F-(2S, 4R)-4-and deprotection reaction; Negative pressure unit is vacuum pump 46, for providing negative pressure for device; Low temperature exhaust gas recovery unit is cold well 45, for collecting the waste gas produced in preparation process; Ion-exchange unit is the anionresin SpePakQMA post 47 being purchased from Waters company; Solid-Phase Extraction unit is the OasisHLB post 48 being purchased from Waters company; Pure preparations unit is followed successively by the SAX strong anion exchange column 49 being purchased from Alltech company, ionic adsorption alumina column 50, the Solid-Phase Extraction SpePakC-18 post 51 being purchased from Waters company, is purchased from the sterilised membrane filter 52 of MerckMillipore company, product bottle 16.
Described device is used to prepare 18the preparation work of F-(2S, 4R)-4-fluoro-L-glutamine is as follows: by the H of the Chang Kaiduan fluid inlet of three-way solenoid valve 37 with Cyclone-10 type medical cyclotron 18f aqueous solution outgoing line connects; The gas inlet that magnetic valve 22 and 36 shares is connected to nitrogen cylinder; A SpePakQMA post is loaded at anion-exchange column 47 place, an OasisHLB post is loaded at solid phase extraction column 48 place, load SAX strong anion exchange column 49, ionic adsorption alumina column 50 and SpePakC-18 post 51 successively at purifying pillar place, load sterilised membrane filter at sterilised membrane filter 52 place; Appropriate liquid nitrogen is loaded at cold Jing45Chu.1mL phase-transfer catalyst 18-hat-6/KHCO is loaded in cillin bottle 1 3solution, loads 1mL anhydrous acetonitrile in cillin bottle 2,3 respectively; The acetonitrile solution of 1mL containing 5mg precursor compound is loaded in cillin bottle 4; Cillin bottle 5,6,7 loads 10mL, 5mL, 5mL water respectively; Cillin bottle 8,9 loads 5mL water respectively, and cillin bottle 10 loads 1mL ethanol; Cillin bottle 11 loads 1mL trifluoroacetic acid; Cillin bottle 12,13 loads 10mL water respectively.Open vacuum-pump power supply after reaction reagent has loaded, open the reducing valve of rare gas element feeding mechanism-nitrogen cylinder.
Preparation 18the process of F-(2S, 4R)-4-fluoro-L-glutamine is as follows:
1) under the promotion of Cyclone-10 type medical cyclotron, containing H 18the target aqueous solution of F successively through Chang Kaiduan, SpePakQMA post 47 of three-way solenoid valve 37 and the Chang Kaiduan of three-way solenoid valve 38, 18f -be trapped on SpePakQMA post, waste liquid enters cillin bottle 14;
2) open magnetic valve 42, vacuum pump 46 provides negative pressure for reaction flask 17, then opens the normal-closed end of three-way solenoid valve 37 and three-way solenoid valve 38, the 18-hat-6/KHCO in cillin bottle 1 3solution will 18f-enters reaction flask 17 by wash-out on SpePakQMA post, then 17 to 100 DEG C, reacting by heating bottle, by elutriant evaporate to dryness, then closes the normal-closed end of three-way solenoid valve 37 and 38;
3) open magnetic valve 19 and 23, the 1mL anhydrous acetonitrile in cillin bottle 2 is joined in the reaction flask 17 containing evaporation residue, evaporate to dryness, then shut electromagnetic valve 23 again at 100 DEG C;
4) make magnetic valve 24, the 1mL anhydrous acetonitrile in cillin bottle 3 joined in reaction flask 17, at 100 DEG C third time evaporate to dryness, then shut electromagnetic valve 24;
5) magnetic valve 25 is made, the acetonitrile solution containing precursor compound in cillin bottle 4 is joined in reaction flask 17, then shut electromagnetic valve 42,25 and 19 successively, confined reaction bottle 17, reacting by heating 10 minutes at 100 DEG C, carry out fluoridation, stop heating after completing, obtain fluoridation solution;
6) open magnetic valve 42,20 and 26 successively, the water in cillin bottle 5 is joined in fluoridation solution, shut electromagnetic valve 42 after completing;
7) open magnetic valve 39, under nitrogen pressure, make the fluoridation solution after the dilute with water in reaction flask 17 enter in waste liquid bottle 15 by the Chang Kaiduan of OasisHLB post 48 and three-way solenoid valve 40, shut electromagnetic valve 39 and 26 successively after completing;
8) magnetic valve 42 and magnetic valve 27 is opened, joined by water in cillin bottle 6 in reaction flask 17, then shut electromagnetic valve 42, opens 39, the solution in reaction flask 17 is made to enter in waste liquid bottle 15 by OasisHLB post 48 and magnetic valve 40 Chang Kaiduan, shut electromagnetic valve 39 and 27 successively after completing;
9) magnetic valve 42 and magnetic valve 28 is opened, water in cillin bottle 7 is joined in reaction flask 17, then shut electromagnetic valve 42, open 39, the solution in reaction flask 17 is made to enter in waste liquid bottle 15 by OasisHLB post 48 and magnetic valve 40 Chang Kaiduan, shut electromagnetic valve 39,28 and 20 successively after completing;
10) open magnetic valve 21 and 30, rinse OasisHLB post 48 with water in cillin bottle 8, waste liquid enters waste liquid bottle 15 through magnetic valve 40 Chang Kaiduan, shut electromagnetic valve 30 after completing;
11) open magnetic valve 31, rinse OasisHLB post 48 with water in cillin bottle 9, waste liquid enters waste liquid bottle 15 through magnetic valve 40 Chang Kaiduan, shut electromagnetic valve 31 after completing;
12) normal-closed end of magnetic valve 43 and three-way solenoid valve 40 is opened, then magnetic valve 32 is opened, with the alcohol flushing OasisHLB post 48 in cillin bottle 10, elutriant is through the normal-closed end of three-way solenoid valve 40, enter deprotection reaction bottle 18, after completing, close three-way solenoid valve 40, magnetic valve 32 and magnetic valve 21 successively;
13) heat 18 to 60 DEG C, deprotection reaction bottle, incite somebody to action wherein solution evaporate to dryness at reduced pressure conditions;
14) open magnetic valve 33, the trifluoroacetic acid in cillin bottle 11 is joined in deprotection reaction bottle 18, shut electromagnetic valve 43 after completing, and then shut electromagnetic valve 33, airtight deprotection reaction bottle 18;
15) to heat in deprotection reaction bottle 18 solution to 60 DEG C and keep 5 minutes, intermediate deprotection reaction occurs;
16) deprotection reaction opens magnetic valve 43 after completing, and by the evaporate to dryness at reduced pressure conditions of the trifluoroacetic acid in deprotection reaction bottle 18, stops heating;
17) open magnetic valve 22 and 34, the water in cillin bottle 12 is joined in deprotection reaction bottle 18, shut electromagnetic valve 34 after completing;
18) open magnetic valve 36, in the solution in deprotection reaction bottle 18, blast nitrogen, solution is mixed, then shut electromagnetic valve 36;
19) shut electromagnetic valve 43, open magnetic valve 34 and magnetic valve 41, the liquid in deprotection reaction bottle 18 is made to enter product bottle 16 by SAX strong anion exchange column 49, ionic adsorption alumina column 50, SpePakC-18 post 51 and sterilised membrane filter 52 successively, shut electromagnetic valve 41 and magnetic valve 34 after completing under nitrogen promotes;
20) open magnetic valve 43 and magnetic valve 35, the water in cillin bottle 13 is joined in deprotection reaction bottle 18, shut electromagnetic valve 35 after completing;
21) open magnetic valve 36, in the solution in deprotection reaction bottle 18, blast nitrogen, solution is mixed, then shut electromagnetic valve 36;
22) shut electromagnetic valve 43; open magnetic valve 35 and magnetic valve 41; the liquid in deprotection reaction bottle 18 is made to enter product bottle 16 by SAX strong anion exchange column 49, ionic adsorption alumina column 50, SpePakC-18 post 51 and sterilised membrane filter 52 successively under nitrogen promotes; shut electromagnetic valve 41,35 and 22 after completing, obtained 18f-(2S, 4R)-4-fluoro-L-glutamine product solution.
By above automatization preparation technology preparation 18f-(2S, 4R)-4-fluoro-L-glutamine always about 60 minutes consuming time, the Radiochemical yield without time calibration is about 20%.
Product is differentiated: adopt high performance liquid chromatography to differentiate 18f-(2S, 4R)-4-fluoro-L-glutamine product solution, chromatographic condition is: stationary phase adopts ChiralChirex3126 (150 × 4.6mm) chromatographic column; Moving phase adopts 1mMCuSO 4, flow velocity is 1mL/min; Analytical results as shown in Figure 2, in product solution, the retention time of major radiation composition is 12.5 minutes, control compound containing stable nuclide F-19 [is prepared by laboratory, preparation method is with reference to Chinese invention patent CN102595888A (publication number) and US Patent No. 8747809B2 (grant number), and being mixed with concentration is that the aqueous solution of 0.1mg/mL is analyzed for HPLC] 19f-(2S, 4R) analytical results of the fluoro-L-glutamine of-4-under identical chromatographic conditions as shown in Figure 3, the analytical results of comparative product analytical results and control compound is known, both retention time under identical chromatographic conditions are consistent, illustrate obtained by above automatization preparation technology be really 18the fluoro-L-glutamine of F-(2S, 4R)-4-.
Embodiment 2 ( 18f-(2S, 4R)-4-fluoro-L-glutamine automatization optimum preparation condition)
Use 18f-(2S, 4R)-4-fluoro-L-glutamine automatization preparation facilities is optimized 18f-(2S, 4R)-4-fluoro-L-glutamine preparation technology.
Optimize 18phase-transfer catalyst 18-hat-6/KHCO in F-(2S, 4R)-4-fluoro-L-glutamine preparation technology 3solution drying process, precursor compound consumption and the finished product purification process are optimized.
Phase-transfer catalyst 18-hat-6/KHCO 3the drying of solution is implemented by the azeotropic vaporization of acetonitrile and water, repeat the effect of the times influence drying adding acetonitrile and evaporation, and drying process being consuming time longer, having considerable influence for preparing productive rate.
Optimization method is:
1) evaporation drying once: with the 18-hat-6/KHCO in device cillin bottle 1 3(also can be amino-polyether K 222/ K 2cO 3solution or TBAHCO 3) solution flushing absorption 18the QMA post of F-, wash-out enters reaction flask 17, then 17 to 100 DEG C, reacting by heating bottle, by elutriant evaporate to dryness, completes the 1mL directly added in cillin bottle 4 loads precursor compound acetonitrile solution containing 5mg, then performs according to the step in embodiment 1 18the preparation of the fluoro-L-glutamine of F-(2S, 4R)-4-, the Radiochemical yield of counting yield;
2) evaporation drying twice: with the 18-hat-6/KHCO in device cillin bottle 1 3solution rinses absorption 18the QMA post of F-, wash-out enters reaction flask 17, then 17 to 100 DEG C, reacting by heating bottle, by elutriant evaporate to dryness, complete in backward reaction flask 17 the 1mL acetonitrile added in cillin bottle 2, and then by solution evaporate to dryness, the 1mL added afterwards in cillin bottle 4 loads the acetonitrile solution of precursor compound containing 5mg and completes according to embodiment 1 18the preparation of the fluoro-L-glutamine of F-(2S, 4R)-4-, counting yield Radiochemical yield;
3) evaporation drying three times: be preced with-6/KHCO3 solution with the 18-in device cillin bottle 1 and rinse absorption 18the QMA post of F-also joins reaction flask 17, then 100 DEG C are heated by elutriant evaporate to dryness, complete in backward reaction flask 17 the 1mL acetonitrile added in cillin bottle 2, and then by solution evaporate to dryness, add 1mL acetonitrile in cillin bottle 3 afterwards and third time evaporate to dryness, after completing, add 1mL in cillin bottle 4 and load the acetonitrile solution of precursor compound containing 5mg and complete preparation process, investigate the Radiochemical yield of product.
Result shows: adopt evaporation drying once, the Radiochemical yield of product is less than 5%, prepared by automatization 18f-(2S, 4R)-4-fluoro-L-glutamine always about 50 minutes consuming time; Evaporation drying twice, product average radiation chemical yield about 15%, and variation range comparatively large (8% to 20%), prepare always about 54 minutes consuming time; Evaporation drying three times, product Radiochemical yield about 20%, prepares always about 60 minutes consuming time.Through comparing to keep the success ratio of synthesizing, the preparation technology through optimizing adopts evaporation drying phase-transfer catalyst three times.
By changing in cillin bottle 4 concentration loading the fine solution of second of precursor compound, can the consumption of precursor compound in optimized fabrication.In cillin bottle 4, load the acetonitrile solution of 1mL containing precursor compound 2mg, 5mg, 10mg and 20mg respectively, then perform according to embodiment 1 18the preparation of the fluoro-L-glutamine of F-(2S, 4R)-4-, investigate product Radiochemical yield, result is as shown in table 1.Product Radiochemical yield increases along with precursor compound input amount and raises, and when input amount is 5mg, product radiochemical product is about 20%, improves the consumption of precursor compound afterwards again, and Radiochemical yield raises further, but elevation amplitude is less.Due to precursor compound price costly, preparation 18input need to be considered during the fluoro-L-glutamine of F-(2S, 4R)-4- 18the total activity of F-and economic factors, determine the consumption of precursor compound, and the scheme of optimization is for adopting 5mg and more precursor compound.
Table 1 precursor compound input amount pair 18the impact of F-(2S, 4R)-4-fluoro-L-glutamine Radiochemical yield
Purifying products method is optimized: prepared by automatization 18the fluoro-L-glutamine of F-(2S, 4R)-4-adopts the method for purifying pillar coupling to implement.As described in Example 1, by reduction vaporization removing deprotecting regent trifluoroacetic acid, then in evaporation residue, add water, obtain thick product solution.Containing remaining trifluoroacetic acid in thick product solution, in purifying products process, therefore first to remove trifluoroacetic acid wherein, and then removing organic impurity wherein, be mainly the by product of precursor compound fluoridation.Concrete grammar is employing three pillar couplings: first by first pillar: Anion-adsorption pillar or exchange resin remove the trifluoroacetic acid in thick product, then by second pillar: alumina column removes the impurity in ionized state in thick product, the 3rd pillar is finally used: reverse phase solid phase extraction pillar removing organic impurity wherein.The SAX strong anion exchange column that first pillar can select Alltech company to produce, or AG11A8 resin pillar; 3rd reverse phase solid phase extraction pillar can select C-18 pillar or OasisHLB pillar.Thick product, after the pillar of coupling, has part radioactive activity and remains on purifying pillar, therefore rinse the purifying pillar of above-mentioned coupling with water, preparation high pressure liquid chromatographic analysis foreign matter content.Result shows, first purifying pillar selects SAX strong anion exchange column or AG11A8 resin pillar, and the 3rd pillar selects the purification effect of C-18 pillar or OasisHLB pillar suitable, all can reach good purification effect; Adopt more than 20mL water to rinse the anti-solid phase extraction column of coupling, the radioactive activity remained on pillar can be made to be less than 5% of product activity; High pressure liquid chromatographic analysis shows, in product formulation, foreign matter content meets 18f-(2S, 4R)-4-fluoro-L-glutamine injection liquid quality criteria requirements.
Embodiment 3
Preparation 18purification of intermediate in F-(2S, 4R)-4-fluoro-L-glutamine process can be implemented by high performance liquid chromatography, the SyntheraHPLC system that the Semi-preparative high pressure liquid chromatographic system (HPLC) adopted is Belgian IBA company.SyntheraHPLC system can load two kinds of moving phases, containing online UV-detector and online radioactive detector.Its cut-in method is: connected by the injection annulus of the outlet end of synthesizer magnetic valve 39 with HPLC system, HPLC is collected the outlet access cillin bottle 8 of moving phase.
Preparation 18the preparation work of F-(2S, 4R)-4-fluoro-L-glutamine is as follows: by the Chang Kaiduan fluid inlet of magnetic valve 37 with Cyclone-10 type medical cyclotron 18f -solution outgoing line connects; The gas inlet that device magnetic valve 22 and 36 shares is connected to nitrogen cylinder; A QMA post is loaded at anion-exchange column 47 place, an OasisHLB post is loaded at solid phase extraction column 48 place, at purifying pillar 49,50,51, place loads SAX strong anion exchange column, aluminum oxide pillar and SpePakC-18 post successively, loads sterilised membrane filter at sterilised membrane filter 52 place; Appropriate liquid nitrogen is loaded at cold Jing45Chu.1mL phase-transfer catalyst 18-hat-6/KHCO is loaded in cillin bottle 1 3solution; 1mL anhydrous acetonitrile is loaded respectively in cillin bottle 2,3; The acetonitrile solution of 1mL containing 5mg precursor compound is loaded in cillin bottle 4; Cillin bottle 5 loads 3mL water; Cillin bottle 8 adopts volume to be the cillin bottle of 30mL, and load 20mL water in it, cillin bottle 9 loads 10mL water, and cillin bottle 10 loads 1mL ethanol; Cillin bottle 11 loads the trifluoroacetic acid solution that 1mL contains 0.5% methyl-phenoxide; Cillin bottle 12,13 loads 10mL water respectively.In the A moving phase of SyntheraHPLC system, load 1000mL chromatographic grade acetonitrile, B bottle loads the ammonium formiate buffered soln that 1000mL concentration is 10mmol/L, and arranging mobile phase ratio is A:B=60:40, and flow velocity is 3mL/min.Arranging ultraviolet absorption detector determined wavelength is 254nm, loads Gemini250 × 10mmC18 reverse-phase chromatographic column that Féraud door company of the U.S. produces.Open vacuum-pump power supply after reaction reagent has loaded, open nitrogen cylinder reducing valve.
Synthesizer is started, preparation after completing above preparation work 18the step of F-(2S, 4R)-4-fluoro-L-glutamine is as follows:
1) under the promotion of Cyclone-10 type medical cyclotron, contain 18f -the target aqueous solution successively through Chang Kaiduan, QMA post 47 of three-way solenoid valve 37 and the Chang Kaiduan of three-way solenoid valve 38, 18f -be trapped on QMA post, waste liquid enters bottle 14;
2) open magnetic valve 42, vacuum pump 46 provides negative pressure for reaction flask 17, then opens the normal-closed end of three-way solenoid valve 37 and 38, the 18-hat-6/KHCO in cillin bottle 1 3solution will 18f -enter reaction flask 17 by wash-out on QMA post, then 17 to 100 DEG C, reacting by heating bottle, by elutriant evaporate to dryness, then close the normal-closed end of three-way solenoid valve 37 and 38;
3) open magnetic valve 19 and 23, the 1mL anhydrous acetonitrile in cillin bottle 2 is joined in the reaction flask 17 containing evaporation residue, evaporate to dryness, then shut electromagnetic valve 23 again at 100 DEG C;
4) make magnetic valve 24, the 1mL anhydrous acetonitrile in cillin bottle 3 joined in reaction flask 17, at 100 DEG C third time evaporate to dryness, then shut electromagnetic valve 24;
5) make magnetic valve 25, join in reaction flask 17 by the fine solution of the second being loaded with precursor compound in cillin bottle 4, then shut electromagnetic valve 42,25 and 19 successively, confined reaction bottle 17, at 100 DEG C, reacting by heating 10 minutes, carries out fluoridation;
6) open magnetic valve 42,20 and 26 successively, the 3mL water in cillin bottle 5 is joined in fluoridation solution, shut electromagnetic valve 42 after completing;
7) magnetic valve 39 is opened, under nitrogen pressure, the solution in reaction flask 17 is made to enter in the injection annulus of SyntheraHPLC system, all solution in question response bottle 17 all enter after in injection annulus, operation SyntheraHPLC rotates injection annulus, make solution wherein be loaded in chromatographic column, gather uv-absorbing and online radioactivity chromatographic data simultaneously;
8) observing online radiochromatogram, collecting the moving phase containing preparing intermediate, and join in cillin bottle 8, collected rear stopping SyntheraHPLC system;
9) magnetic valve 21 and 30 is opened, make in cillin bottle 8 that (HPLC of collection obtains moving phase and contains intermediate containing the solution of intermediate, moving phase is added in cillin bottle 8, so be exactly midbody solution in cillin bottle 8) by OasisHLB post 48, waste liquid enters waste liquid bottle 15 through magnetic valve 40 Chang Kaiduan, shut electromagnetic valve 30 after completing;
10) open magnetic valve 31, rinse in OasisHLB post 48 with 10mL water in cillin bottle 9, waste liquid enters waste liquid bottle 15 through magnetic valve 40 Chang Kaiduan, shut electromagnetic valve 31 after completing;
11) normal-closed end of magnetic valve 43 and three-way solenoid valve 40 is opened, then magnetic valve 32 is opened, with the alcohol flushing OasisHLB post 48 in cillin bottle 10, elutriant enters deprotection reaction bottle 18 through the normal-closed end of three-way solenoid valve 40, shut electromagnetic valve 40,32 and 21 successively after completing;
12) heat 18 to 60 DEG C, deprotection reaction bottle, incite somebody to action wherein solution evaporate to dryness at reduced pressure conditions;
13) open magnetic valve 33, the trifluoroacetic acid solution containing 0.5% methyl-phenoxide in cillin bottle 11 is joined in deprotection reaction bottle 18, shut electromagnetic valve 43 after completing, and then shut electromagnetic valve 33, airtight deprotection reaction bottle 18;
14) heat solution in deprotection reaction bottle 18 be heated to 60 DEG C and keep 5 minutes, intermediate deprotection reaction occurs;
15) deprotection reaction opens magnetic valve 43 after completing, and is steamed at reduced pressure conditions by the trifluoroacetic acid in deprotection reaction bottle 18, stops heating after completing;
16) open magnetic valve 22 and 34, the water in cillin bottle 12 is joined in deprotection reaction bottle 18, shut electromagnetic valve 34 after completing;
17) open magnetic valve 36, in the solution in deprotection reaction bottle 18, blast nitrogen, solution is mixed, then shut electromagnetic valve 36;
18) shut electromagnetic valve 43, open 34 and three-way solenoid valve 41, the liquid in deprotection reaction bottle 18 is made to enter product bottle 16 by SAX strong anion exchange column 49, alumina column 50, SpePakC-18 post 51 and sterilised membrane filter 52 successively, shut electromagnetic valve 41 and 34 after completing under nitrogen promotes;
19) open magnetic valve 43 and 35, the water in cillin bottle 13 is joined in deprotection reaction bottle 18, shut electromagnetic valve 35 after completing;
20) open magnetic valve 36, in the solution in deprotection reaction bottle 18, blast nitrogen, solution is mixed, then shut electromagnetic valve 36;
21) shut electromagnetic valve 43; open 35 and 41; the liquid in deprotection reaction bottle 18 is made to enter product bottle 16 by SAX strong anion exchange column 49, alumina column 50, SpePakC-18 post 51 and sterilised membrane filter 52 successively, shut electromagnetic valve 41,35 and 22 after completing under nitrogen promotes, obtained 18f-(2S, 4R)-4-fluoro-L-glutamine solution product.
By above automatization preparation technology preparation 18about 75 minutes always consuming time of F-(2S, 4R)-4-fluoro-L-glutamine, the Radiochemical yield without time calibration is about 14%.Product is differentiated: adopt high performance liquid chromatography to differentiate 18f-(2S, 4R)-4-fluoro-L-glutamine solution product, chromatographic condition is: stationary phase adopts ChiralChirex3126 (150 × 4.6mm) chromatographic column; Moving phase adopts 1mMCuSO 4, flow velocity is 1mL/min.In product solution, the retention time of major radiation composition is for being about 12 minutes, with the control compound containing stable nuclide 19the retention time of F-(2S, 4R)-4-fluoro-L-glutamine under identical chromatographic conditions is identical, illustrate obtained by above automatization preparation technology be really 18the fluoro-L-glutamine of F-(2S, 4R)-4-.
Of the present utility model 18f-(2S, 4R) advantage of-4-fluoro-L-glutamine automatization preparation facilities is: first, adopt clamping tube type solenoid control liquid-flow, make liquid directly not contact electromagnetic valve body, avoid reagent to the corrosion of magnetic valve and remaining in valve body; The second, device is equipped with two reaction flasks, has been respectively used to preparation 18two step chemical reactions needed for the fluoro-L-glutamine of F-(2S, 4R)-4-; 3rd, be provided with negative pressure system, can fully remove VFA for deprotection reaction in reaction system by reduction vaporization; 4th, be provided with low temperature exhaust gas recovery system, avoid the leakage of VFA, prevent from causing corrosion to device.
18F-(2S of the present utility model; 4R)-4-fluoro-L-glutamine automatization preparation facilities; automatization is made to prepare 18F-(2S; 4R) the fluoro-L-glutamine of-4-is achieved; be conducive to the efficiency and the stability that improve preparation; operator can be protected to avoid radiation injury, for the clinical application of the fluoro-L-glutamine of novel metabolize imaging agent 18F-(2S, 4R)-4-is laid a good foundation simultaneously.

Claims (3)

1. one kind 18the automatization preparation facilities of the fluoro-L-glutamine of F-(2S, 4R)-4-, is characterized in that, comprising: liquid storage unit; The pipe valve unit be connected with described liquid storage unit; The fluoridation unit be connected with described pipe valve unit and deprotection reaction unit; Described fluoridation unit by described pipe valve unit respectively with low temperature exhaust gas recovery unit, ion-exchange unit and Solid-Phase Extraction unit are connected; Described deprotection unit by pipe valve unit respectively with Solid-Phase Extraction unit, pure preparations unit and low temperature exhaust gas recovery unit are connected; Described low temperature exhaust gas recovery unit is connected with negative pressure unit by pipe valve unit.
2. according to claim 1 18f-(2S, 4R) the automatization preparation facilities of the fluoro-L-glutamine of-4-, it is characterized in that: described liquid storage unit comprises the cillin bottle of 13 glands, which is provided with a gas feed and a taphole, wherein have the gas feed of 11 cillin bottles to be connected with rare gas element feeding mechanism with pipeline by valve, air is connected in the gas feed of 2 cillin bottles;
Described pipe valve unit comprises pipe clamping electromagnetic valve and pipeline, and wherein 22 is two-way electromagnetic valve, and 4 is three-way solenoid valve;
Described negative pressure unit is vacuum pump;
Described low temperature exhaust gas recovery unit is cold well;
Described fluoridation unit is connected with cillin bottle respectively by magnetic valve, be connected with waste liquid bottle with ion-exchange unit respectively by three-way solenoid valve, be connected with the cold well in tail gas recycle unit by magnetic valve, be connected with rare gas element feeding mechanism by magnetic valve;
Described deprotection reaction unit is connected with cillin bottle respectively by magnetic valve, be connected with waste liquid bottle with Solid-Phase Extraction unit respectively by three-way solenoid valve, be connected with the cold well in tail gas recycle unit by magnetic valve, be connected with rare gas element feeding mechanism by magnetic valve, be connected with pure preparations unit by magnetic valve;
Described pure preparations unit is connected with product bottle by sterilised membrane filter;
Described Solid-Phase Extraction unit is connected with fluoridation unit by magnetic valve, is connected, is connected respectively by magnetic valve with cillin bottle by magnetic valve with rare gas element feeding mechanism;
Described low temperature exhaust gas recovery unit is connected with negative pressure unit by three-way solenoid valve;
Described ion-exchange unit is connected with waste liquid bottle by three-way solenoid valve, by three-way solenoid valve respectively with cillin bottle and 18f -aqueous solution feeding mechanism is connected;
Described waste liquid bottle and waste liquid bottle are equipped with gas feed and connect air.
3. according to claim 2 18f-(2S, 4R) the automatization preparation facilities of the fluoro-L-glutamine of-4-, it is characterized in that: the outlet end of described magnetic valve is connected with the injection annulus of Semi-preparative high pressure liquid chromatographic system, and then by the outlet of the collection moving phase of Semi-preparative high pressure liquid chromatographic system access cillin bottle.
CN201520784779.0U 2015-10-11 2015-10-11 Automatic preparation facilities of 18F - (2S, 4R) 4 - fluorine - L - millet amine acid amides Active CN205223067U (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105152960A (en) * 2015-10-11 2015-12-16 北京脑重大疾病研究院 An automatic preparation method and device for 18F-(2S, 4R)-4-fluoro-L-glutamine
CN108409595A (en) * 2018-05-11 2018-08-17 北京肿瘤医院 18The automated production equipment and production method of the fluoro- L-Glutamines of F- (2S, 4R) -4-

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105152960A (en) * 2015-10-11 2015-12-16 北京脑重大疾病研究院 An automatic preparation method and device for 18F-(2S, 4R)-4-fluoro-L-glutamine
CN105152960B (en) * 2015-10-11 2017-04-19 北京脑重大疾病研究院 Automatic preparation method and device for ＜18＞F-(2S,4R)-4-fluoro-L-glutamine
CN108409595A (en) * 2018-05-11 2018-08-17 北京肿瘤医院 18The automated production equipment and production method of the fluoro- L-Glutamines of F- (2S, 4R) -4-

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