CN105646601A - Hydrolyzation purification method for preparing 18F-FDG - Google Patents
Hydrolyzation purification method for preparing 18F-FDG Download PDFInfo
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- CN105646601A CN105646601A CN201610039226.1A CN201610039226A CN105646601A CN 105646601 A CN105646601 A CN 105646601A CN 201610039226 A CN201610039226 A CN 201610039226A CN 105646601 A CN105646601 A CN 105646601A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/08—Deoxysugars; Unsaturated sugars; Osones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C07B2200/05—Isotopically modified compounds, e.g. labelled
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Abstract
The invention relates to the technical field of preparation of positive electron radioactive drugs, in particular to a hydrolyzation purification method for preparing 18F-FDG. 18F-FDG prepared through the method contains no trimethyl silanol solvent impurity and conforms to pharmacopeia residual solvent regulations, and no unknown residual solvent is detected through a pharmacopeia residual solvent detection method. The method comprises the steps that firstly, 18F-FTAG is diluted with water and then passes through a polymer filler SPE column (a polymer filler solid phase extraction column), and 18F-FTAG is reserved on the SPE column; secondly, the SPE column obtained in the first step is washed with 5-60 mL of injection water, and blown to be dry with nitrogen or helium; thirdly, 1-3 mL of a NaOH solution with the concentration ranging from 0.5 M to 2 M is introduced into the SPE column obtained in the second step for 30-180 s; fourthly, the SPE column obtained in the third step is washed with 5-30 mL of injection water with the flowing speed ranging from 0.5 mL/min to 5 mL/min, obtained liquid passes through a Grace IC-H SPE column, a Waters alkaline Al2O3 SPE column and a Waters C18SPE column in sequence, and all liquid is collected and is purified 18F-PDG.
Description
One, technical field:
The present invention relates to positron emitting tracer preparing technical field, be specifically related to one and prepare18The hydrolysising purification method of F-FDG.
Two, background technology:
Positron Emission Computed Tomography (PositronEmissionTomography, PET) is a kind of technology utilizing positron-emitting radionuclides spike to carry out live body functional imaging. PET imaging medicament the most frequently used clinically at present is18F(T1/2=110 minutes) 2-of labelling18F-��-D-deoxyglucose (18F-FDG), it can accurately reflect the glucose metabolism level of intracorporeal organ/tissue, has opened new era of functional image, is described as " century molecule ".18The current most common method of synthesis of F-FDG be by Germany scientist Hamacher etc. (HamacherK, CoenenHH, StocklinG.Efficientstereospecificsynthesisofno-carrier-a dded2-[18F] fluoro-2-deoxy-D-glucoseusingaminopolyethersupportednucl eophilicsubstitution.J.Nucl.Med., 1986,27 (2): 235-238.) 1986 set up classical nucleophilic synthetic route.
Produce in cyclotron target18F, uses anion-exchange resin column to catch18F, with containing amino-polyether K2.2.2(4,7,13,16,21,24-six oxa--1,10-diazabicyclo (8.8.8)-hexacosane, is also called cave ether 2.2.2 or hidden part 2.2.2) and what anion-exchange resin column was caught by the acetonitrile solution of potassium carbonate18F is eluted into reaction tube, is evaporated at 105 DEG C of azeotropic, adds precursor 1,3,4,6-tetra--O-acetyl group-2-O-trifyl-��-D-mannopyranose (abbreviation mannose triflate) necleophilic reaction occurs after cooling, the trifyl quilt of C-2 position18F replaces, and obtains after spatial rearrangement18The tetra-acetylated glucose ester of F labelling (18F-FTAG).Will18F-FTAG obtains after using acid or basic hydrolysis18The thick product of F-FDG, crosses sterilised membrane filter and is after purification18F-FDG injection.
About basic hydrolysis18The method of F-FTAG generally has two kinds of methods, hydrolysis and post hydrolysis in reaction tube. In reaction tube, hydrolysis is in reaction tube18F-FTAG adds 0.25-0.5MNaOH solution, reacts 30-180s, then cross purification column. In reaction tube, the shortcoming of hydrolysis is that in finished product, acetonitrile residual height and amino-polyether K2.2.2 easily exceed standard. Post hydrolysis be by18Silica gel bonded phase C18 solid-phase extraction column is crossed after F-FTAG dilute with water,18F-FTAG is retained by C18 post, and acetonitrile and part ion state amino-polyether K2.2.2(include K2.2.2 and the K of protonation+-K2.2.2) enter waste liquid, after using a large amount of water to rinse C18 post, use 1-2MNaOH solution to cross C18 post, be hydrolyzed 30-120s, cross purification column purification.
The Pharmacopoeia of the People's Republic of China 2015 editions two (hereinafter referred to as " pharmacopeia ") is included18F-FDG, wherein defines the detection method of residual solvent. Post hydrolysis preparation18There is a unknown residual solvent peak when residual solvent detects in F-FDG, and identifies that this peak is that (CAS numbers trimethyl silanol: 1066-40-6) through GC-MS. Use official method detection trimethyl silanol standard solution retention time consistent with unknown residual solvent peak. So, post hydrolysis preparation18Containing trimethyl silanol in F-FDG.
18F-FDG building-up process does not use trimethyl silanol, and it is probably derived from the silica gel bonded phase C18 solid-phase extraction column of hydrolysis. Simulate post hydrolytic process by C18 post with 2MNaOH solution, collect hydrolyzed solution and test according to pharmacopeia residual solvent detection method, a chromatographic peak, retention time and post hydrolysis preparation only detected18The unknown residual solvent peak that F-FDG occurs is consistent, it is determined that this peak is trimethyl silanol, derives from C18 post hydrolytic process.
Silica gel bonded phase C18 solid-phase extraction column reacts first by the SiOH of octadecylsilylated reagent Yu Silica Surface in production process, octadecyl is bonded in Silica Surface, namely C18 is formed, then little molecule silane is used to terminate, the SiOH exposed typically by trim,ethylchlorosilane and Silica Surface reacts, it is thus achieved that bigger surface coverage and better selectivity. Use 2MNaOH solution hydrolysis C18, make the Si-O bond fission that end-blocking is formed, form trimethyl silanol entrance and produce sheet solution eventually.
Replace silica gel bonded phase C18 solid-phase extraction column that hydrolytic process can be avoided to produce trimethyl silanol with polymeric solid phase extraction column. The polymeric solid phase extraction column (hereinafter referred to as " polymer SPE post ") that can select as, divinylbenzene and NVP copolymer, styrene-divinylbenzene polymer, NVP etc. are the polymer SPE post of filler.
Three, summary of the invention
Prepared by the offer one of the present invention18The hydrolysising purification method of F-FDG, does not contain trimethyl silanol solvent impurity in its product produced.
For achieving the above object, the technical solution used in the present invention is: prepared by one18The hydrolysising purification method of F-FDG, it is characterised in that:
1) will18By the SPE post (solid-phase extraction column of polymer filler) of polymer filler after F-FTAG dilute with water,18F-FTAG is retained on SPE post;
2) with 5-60mL water for injection rinsing step (1) the SPE post obtained, and dry up with nitrogen or helium;
3) step 2 is passed into by the NaOH solution that 1-3mL concentration is 0.5-2M) the SPE post of gained, keep 30-180s;
4) 5-30mL water for injection rinsing step 3 is used) the SPE post of gained, flow velocity is 0.5-5mL/min, passes sequentially through GraceIC-HSPE post, Waters alkalescence Al2O3SPE post and WatersC18SPE post, collect all liq and be purification18F-FDG��
Described polymer filler is divinylbenzene and NVP copolymer or styrene-divinylbenzene polymer or the functional polymer containing NVP.
It is 1:1 that described divinylbenzene and NVP copolymer obtain mol ratio.
Compared with prior art, the invention have the advantages that and effect: without trimethyl silanol solvent impurity in the present invention, meet pharmacopeia residual solvent regulation, be not detected by unknown residual solvent according to pharmacopeia residual solvent detection method.
Four, detailed description of the invention
Embodiment one:
(1) (filler is divinylbenzene and NVP copolymer to take a WatersOasisHLBPlusSPE post, the mol ratio of described divinylbenzene and NVP copolymer is 1:1), post is crossed with 5mL dehydrated alcohol, then rinse SPE post with 10mL water for injection, use air blow drying.
(2) fluorination reaction is generated18F-FTAG, except, after acetonitrile, diluting with water for injection, crosses the SPE post that (1) obtains,18F-FTAG is retained on SPE post.
(3) rinse, with 5mL water for injection, the SPE post that (2) obtain, and dry up with nitrogen.
(4) pass through the SPE post of (3) by the NaOH solution that 2mL concentration is 2M, soak and keep 30s.
(5) using 10mL water for injection to rinse the SPE post of (4), flow velocity is 1mL/min, and passes sequentially through GraceIC-HSPE post, alkalescence WatersAl2O3BSPE post, WatersC18SPE post, collect all liq and be purification18F-FDG��
Embodiment two:
(1) take a PhenomenexStrata-XSPE post (filler is the functional polymer containing NVP), cross post with 10mL dehydrated alcohol, then rinse SPE post with 10mL water for injection, use air blow drying.
(2) fluorination reaction is generated18F-FTAG, except, after acetonitrile, diluting with water for injection, crosses the SPE post that (1) obtains,18F-FTAG is retained on SPE post.
(3) rinse, with 30mL water for injection, the SPE post that (2) obtain, and dry up with helium.
(4) pass through the SPE post of (3) by the NaOH solution that 1.5mL concentration is 1.5M, soak and keep 120s.
(5) using 20mL water for injection to rinse the SPE post of (4), flow velocity is 1.5mL/min, and passes sequentially through GraceIC-HSPE post, WatersAl2O3BSPE post, WatersC18SPE post, collect all liq and be purification18F-FDG��
Embodiment three:
(1) take an AgilentBondElutPlexaSPE post (filler is styrene-divinylbenzene polymer), cross post with 2mL dehydrated alcohol, then accord with water for injection with 5mL and rinse SPE post, use air blow drying.
(2) fluorination reaction is generated18F-FTAG, except, after acetonitrile, diluting with water for injection, crosses the SPE post that (1) obtains,18F-FTAG is retained on SPE post.
(3) rinse, with 30mL water for injection, the SPE post that (2) obtain, and dry up with nitrogen.
(4) pass through the SPE post of (3) by the NaOH solution that 2.5mL concentration is 2M, soak and keep 150s.
(5) using 25mL water for injection to rinse the SPE post of (4), flow velocity is 3mL/min, and passes sequentially through GraceIC-HSPE post, WatersAl2O3BSPE post, WatersC18SPE post, collect all liq and be purification18F-FDG��
Embodiment four:
(1) take an AgilentBondElutPPLSPE post (filler is styrene-divinylbenzene polymer), cross post with 5mL dehydrated alcohol, then rinse SPE post with 10mL water for injection, use air blow drying.
(2) fluorination reaction is generated18F-FTAG, except, after acetonitrile, diluting with water for injection, crosses the SPE post that (1) obtains,18F-FTAG is retained on SPE post.
(3) rinse, with 60mL water for injection, the SPE post that (2) obtain, and do with helium air-blowing.
(4) pass through the SPE post of (3) by the NaOH solution that 3mL concentration is 2M, soak and keep 180s.
(5) using 30mL water for injection to rinse the SPE post of (4), flow velocity is 5mL/min, and passes sequentially through GraceIC-HSPE post, WatersAl2O3BSPE post, WatersC18SPE post, collect all liq and be purification18F-FDG��
Claims (3)
1. prepare for one kind18The hydrolysising purification method of F-FDG, it is characterised in that:
1) will18By the SPE post (solid-phase extraction column of polymer filler) of polymer filler after F-FTAG dilute with water,18F-FTAG is retained on SPE post;
2) with 5-60mL water for injection rinsing step (1) the SPE post obtained, and dry up with nitrogen or helium;
3) step 2 is passed into by the NaOH solution that 1-3mL concentration is 0.5-2M) the SPE post of gained, keep 30-180s;
4) 5-30mL water for injection rinsing step 3 is used) the SPE post of gained, flow velocity is 0.5-5mL/min, passes sequentially through GraceIC-HSPE post, Waters alkalescence Al2O3SPE post and WatersC18SPE post, collect all liq and be purification18F-FDG��
2. a kind of hydrolysising purification method preparing 18F-FDG according to claim 1, it is characterised in that: described polymer filler is divinylbenzene and NVP copolymer or styrene-divinylbenzene polymer or the functional polymer containing NVP.
3. a kind of hydrolysising purification method preparing 18F-FDG according to claim 2, it is characterised in that: it is 1:1 that described divinylbenzene and NVP copolymer obtain mol ratio.
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| CN201610039226.1A CN105646601A (en) | 2016-01-21 | 2016-01-21 | Hydrolyzation purification method for preparing 18F-FDG |
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| CN201610039226.1A CN105646601A (en) | 2016-01-21 | 2016-01-21 | Hydrolyzation purification method for preparing 18F-FDG |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864213A (en) * | 2018-07-16 | 2018-11-23 | 陕西正泽生物技术有限公司 | A kind of column hydrolysis18F-FDG is prepared with C18/tC18 SPE post separation18The method of F-FDG |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0798307A1 (en) * | 1996-03-29 | 1997-10-01 | NKK Plant Engineering Corporation | Fluoro-deoxyglucose synthesizer using columns |
| CN1544443A (en) * | 2003-11-24 | 2004-11-10 | 梁万胜 | Preparation process of 2-fluo-18 substituted-2 deoxidized-beta-D-glucose |
| CN1765911A (en) * | 2005-11-18 | 2006-05-03 | 南方医科大学南方医院 | 2- 18The synthesis technique of F-2-DDG |
-
2016
- 2016-01-21 CN CN201610039226.1A patent/CN105646601A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0798307A1 (en) * | 1996-03-29 | 1997-10-01 | NKK Plant Engineering Corporation | Fluoro-deoxyglucose synthesizer using columns |
| CN1544443A (en) * | 2003-11-24 | 2004-11-10 | 梁万胜 | Preparation process of 2-fluo-18 substituted-2 deoxidized-beta-D-glucose |
| CN1765911A (en) * | 2005-11-18 | 2006-05-03 | 南方医科大学南方医院 | 2- 18The synthesis technique of F-2-DDG |
Non-Patent Citations (1)
| Title |
|---|
| C. LEMAIRE，等: ""Fast [18F]FDG synthesis by alkaline hydrolysis on a low polarity solid phase support"", 《J LABEL COMPD RADIOPHARM》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864213A (en) * | 2018-07-16 | 2018-11-23 | 陕西正泽生物技术有限公司 | A kind of column hydrolysis18F-FDG is prepared with C18/tC18 SPE post separation18The method of F-FDG |
| CN108864213B (en) * | 2018-07-16 | 2021-06-11 | 陕西正泽生物技术有限公司 | Column hydrolysis18F-FDG was prepared by separation on a C18/tC18SPE cartridge18Process for F-FDG |
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Inventor after: Liang Wansheng Inventor after: Lv Jiagen Inventor after: Pang Yan Inventor after: Liu Jing Inventor after: Liu Dazhi Inventor after: Wang Bo Inventor after: Shao Yahui Inventor before: Lv Jiagen Inventor before: Yan Dengfei Inventor before: Wang Yanjun Inventor before: Dong Kaidong Inventor before: Yu Shengmin Inventor before: Liang Wansheng Inventor before: Pang Yan Inventor before: Liu Jing Inventor before: Hu Xiaoping Inventor before: Wang Bo Inventor before: Hu Shengyan Inventor before: Shao Yahui Inventor before: Wang Xiaowei |
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Effective date of registration: 20170829 Address after: 710200 No. 2 workshop No. 101 and 103 of Jingwei Industrial Park, Jing Jing new town, Xi'an economic and Technological Development Zone, Shaanxi Applicant after: Shaanxi Ze Biotechnology Co., Ltd. Address before: Chengguan District Public Lane No. 1402, room 36 Applicant before: GANSU SHENGPUNUO BIOTECHNOLOGY CO., LTD. Applicant before: Beijing PET Co., Ltd. |
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Application publication date: 20160608 |