CN115160167A - In accordance with GMP standard 18 Novel preparation method of F-FDOPA - Google Patents
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- 238000000034 method Methods 0.000 claims abstract description 50
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 11
- 229940125904 compound 1 Drugs 0.000 claims abstract description 9
- 229940125782 compound 2 Drugs 0.000 claims abstract description 8
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
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- XLYOFNOQVPJJNP-NJFSPNSNSA-N ((18)O)water Chemical compound [18OH2] XLYOFNOQVPJJNP-NJFSPNSNSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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- LYRCQNDYYRPFMF-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C LYRCQNDYYRPFMF-UHFFFAOYSA-N 0.000 description 2
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- 210000000936 intestine Anatomy 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
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- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
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- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for meeting GMP (good manufacturing practice) standard 18 A novel process for the preparation of F-FDOPA, comprising the steps of, S1: compound 1 and suitable forms 18 F-ion reaction to produce compound 2, the radionuclide used in the nucleophilic substitution reaction being 18 F-ion form; s2: compound 2 is obtained by deprotection 18 F-FDOPA; the precursor (starting material) used in the present invention is similar to that used in conventional electrophilic reactions, except that step 1 of the present invention is a nucleophilic substitution reaction, and the radionuclide used is 18 F-ion form, by affinityThe nuclear substitution reaction is completed in a simpler step 18 The preparation of F-FDOPA can obtain higher synthesis yield and optical purity, meet the requirement of GMP standardized production and meet the requirement of GMP standardized production 18 The increasing clinical use of F-FDOPA is in demand.
Description
Technical Field
The invention relates to the field of medicine preparation, in particular to a medicine meeting GMP (good manufacturing practice) standard 18 A novel process for the preparation of F-FDOPA.
Background
Parkinson's Disease (PD) is a chronic degenerative disease of the nervous system of the elderly. The disease belongs to primary central nervous system degenerative diseases.
Neuroendocrine tumors are tumors that originate from neuroendocrine cells. Neuroendocrine cells are a large class of cells that have a neuroendocrine phenotype in the body and can produce a variety of hormones. Neuroendocrine cells are distributed throughout the body, so neuroendocrine tumors can occur anywhere in the body, but most commonly neuroendocrine tumors of the digestive system, such as the stomach, intestine, pancreas, etc., account for about 2/3 of all neuroendocrine tumors. The incidence of neuroendocrine tumor of European and American people is 2.5-5/10 ten thousand, the incidence of neuroendocrine tumor is increased by 5 times in the last 30 years, and the incidence of neuroendocrine tumor is increased more rapidly compared with other tumors.
6-[ 18 F]fluorine-L-dopa (hereinafter abbreviated: 18 F-FDOPA or FDOPA) is an analogue of levodopa, useful for assessing the activity of dopamine metabolic pathways in vivo, 18 the PET/CT imaging of the F-FDOPA has unique application value in diseases such as neuroendocrine tumors (including pheochromocytoma/paraganglioma, medullary thyroid carcinoma, gastrointestinal carcinoid and neuroblastoma), congenital hyperinsulinemia, brain tumors, parkinson's disease and the like. Thus efficiently producing 18 F-FDOPA has great clinical significance.
At present, in China and internationally, the methods for synthesizing 18F-FDOPA are various and are divided into nucleophilic reaction and electrophilic reaction, and the respective characteristics of other methods are briefly described as follows:
the method is the earliest synthesis used 18 Process for the preparation of F-FDOPA by the use of radioactive fluorine gas (F-FDOPA) 18 F-F 2 ) As electrophiles, trimethyltin or similar substituent groups are attacked, and the introduction of fluorine atoms is achieved by electrophilic reactions. Radioactive fluorine gas ( 18 F-F 2 ) Generally by cyclotron production, the typical nuclear reaction of which is 20 Ne(d,α) 18 F, the ion source is deuterium gas, the target material is neon gas mixed with 0.2% fluorine gas, and the target type is a gas target.
The greatest disadvantage of this process is that the species used is in the form of a gas (fluorine, 18 F-F 2 ) Fluorine gas (f) 18 F-F 2 ) The corrosion is extremely strong, the requirements on the sealing performance and the corrosion resistance of equipment and pipelines are extremely high, and once leakage occurs, the influence on the environment is also extremely large; and domestic units, scientific research institutions or hospitals with gas target production conditions are few, so that the application of the method is severely restricted.
The method 2 comprises the following steps: the nucleophilic reaction method comprises the following steps:
nucleophilic reactions are precursors (starting reaction materials) and 18 F - the reaction of the ions takes place. 18 F - The ions are generated by a cyclotron, the typical nuclear reaction of which is 18 O(p,n) 18 F, the ion source is hydrogen, the target material is oxygen 18 water, and the target type is a liquid target. Because of convenient operation, low requirements on equipment and personnel, stable process, good repeatability, no volatility and 18 F - the ion yield is large, the commercial production is easy, and the preparation method is the preparation which is most widely applied at present 18 Method of F-FDOPA. According to the difference of the precursors and routes, the method is divided into the following parts:
the method is reported at present 18 The highest synthesis yield of F-FDOPA, about 35% (uncorrected synthesis yield), is obtained by fluorination, reduction, iodination, alkylation, hydrolysis of nitro (or quaternary ammonium) precursorFive-step reactions such as reaction to obtain the final product, wherein the form of the used radionuclide is 18 F - Ions. 18 F - The ions are generated by a cyclotron, the typical nuclear reaction of which is 18 O(p,n) 18 F, the ion source is hydrogen, the target material is oxygen 18 water, and the target type is a liquid target.
The main advantage of this method is the high synthesis yield, but the greatest disadvantage is that 18 The quality standard of F-FDOPA has a very important check item of optical purity, because the precursor of the method has no chirality, the optical purity of the precursor is mainly determined by the alkylation reaction step of the 4 th step, and the optical purity of the final product obtained by chiral resolution of the method is lower, generally lower than 97 percent. The synthesis steps are five steps, the synthesis process is too complicated, so that the requirements on synthesis modules are high, the synthesis modules of general units, scientific research institutions or hospitals cannot meet the test requirements, and expensive special synthesis modules need to be purchased independently; the method has complicated steps, so that the requirement on the professional skills of operators is high, the experimental result can be greatly influenced by careless operation, and the method cannot be popularized and used in a large range.
The method 3 comprises the following steps:
the method is that 18 The most widely used method for synthesizing F-FDOPA is to obtain the final product by three reactions of fluoro reaction, mCPBA oxidation reaction, hydrolysis reaction and the like through a nitro (or quaternary ammonium salt) precursor. The method also belongs to a nucleophilic reaction method, and the form of the used radionuclide is the same as that of the method 2 18 F - Ions.
The method has the greatest advantage that the optical purity of the product is determined by a precursor, so that the optical purity can reach more than 99 percent, but has the greatest defect that the synthesis yield is too low and is only about 10 percent, and the self-synthesis use in hospitals can not be acceptable, but cannot meet the requirement 18 GMP-normalized production, commercial production and shipping requirements for F-FDOPA.And the step is three steps, so that the operation requirements on synthesis equipment and personnel are higher, and the clinical application of the step is restricted.
Other methods are as follows:
in addition, there are other nucleophilic synthetic methods, such as a nickel salt method, a higher iodine salt method, a borate method, a fluorine exchange method, and the like. However, these methods have their own disadvantages (the nickel salt method has the disadvantages of difficult and expensive precursor synthesis technology, the high-price iodine and borate methods have the disadvantages of low precursor stability and difficult storage, the fluorine exchange method has the disadvantages of low specific activity of the product, affecting the diagnostic effect), and the method has the common disadvantage of low synthesis yield, generally about 15%, which cannot meet the requirements 18 The increasing clinical use of F-FDOPA is in demand.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a novel preparation method of 18F-FDOPA which conforms to GMP (good manufacturing practice) specifications.
In order to achieve the purpose, the invention adopts the technical scheme that: a novel preparation method of 18F-FDOPA conforming to GMP (good manufacturing practice) specifications is characterized in that as shown in the formula I,
wherein R1, R2 are each independently a hydroxy protecting group; r3 is a hydrocarbyl group; r4, R5 are each independently H or an amino protecting group; r6 is a carboxyl protecting group;
the method comprises the following steps: s1: compound 1 with appropriate form 18 F-ion reaction to produce compound 2, the radionuclide used in the nucleophilic substitution reaction being 18 F-ion form; s2: compound 2 is obtained by deprotection 18 F-FDOPA。
In a preferred embodiment of the invention, compound 1 and the appropriate form in step S1 are 18 F-ion is sealed in organic solvent to react at 80-140 deg.C for 3-30min.
In a preferred embodiment of the present invention, the organic solvent is preferably DMF, DMA, tert-butanol, 2-methyl-2-butanol, acetonitrile, or a mixture thereof in different proportions.
In a preferred embodiment of the present invention, a copper salt in a suitable form is further added during the reaction of step S1.
In a preferred embodiment of the present invention, the copper salt comprises at least copper (II) trifluoromethanesulfonate or copper (II) tetrapyridine trifluoromethanesulfonate or copper (II) trifluoromethanesulfonate.
In a preferred embodiment of the present invention, the reaction conditions in step S2 are acidic hydrolysis conditions.
In a preferred embodiment of the invention, the automated synthesis is performed using disposable cartridges/kits and purification separation is performed using preparative chromatography.
The invention solves the defects in the background technology, and has the following beneficial effects:
1. by nucleophilic substitution reactions using simple steps 18 The synthesis of the F-FDOPA is only two steps, the operation is convenient, and the synthesis modules currently owned by general units, scientific research institutions or hospitals can be used in the preparation process without additionally purchasing complex synthesis modules with high price;
the precursor (starting material) used in the present invention is similar to the precursor used in the previous electrophilic reaction (method 1 described in the background above), but the step 1 of the present invention is a nucleophilic substitution reaction, and the radionuclide used is 18 F-ion form.
The key factor for realizing this is that the proper reaction conditions and reagents are selected, such as the use of proper organic solvent, proper copper salt, under the special catalysis of the above-mentioned precursor and the above-mentioned reaction reagent 18 F-ion form is subjected to nucleophilic substitution reaction, the synthesis yield is high, and the radiochemical purity and the optical purity are high.
2. Introduction of 18 The reaction of F nuclide is nucleophilic substitution reaction, and the used radionuclide is 18 The form of the F-ion is shown as, 18 f-ion is a liquid target and has an operation methodHas the advantages of low requirements on equipment and personnel, stable process, good repeatability, no volatility, high yield of 18F-ions, easy commercial production and the like, and overcomes the defects of fluorine gas (F) 18 F-F2) has strong corrosivity, high requirements on equipment, great environmental hazards, few units for domestic conditional production and the like.
3. The preparation method has high synthesis yield (about 35 percent) (uncorrected synthesis yield), and can reach the current synthesis yield 18 The highest synthesis yield level of F-FDOPA, and the key technical indexes of the product obtained by the preparation method are as follows: high optical purity and radioactive chemical purity>99% radiochemical purity>99 percent all achieve the prior 18 The highest level of F-FDOPA synthesis; the method uses the precursor (initial synthesis raw material) which is tested by the market for a long time, and the precursor has good stability and safety and low price.
4. The preparation method meets the requirements of GMP standardized production, and can perfectly meet the requirements 18 Clinical use requirements for F-FDOPA; the technical key point for realizing GMP standardized production is that based on the test steps, the disposable card sleeve/kit meeting GMP specifications can be designed, so that the repeatability of the production process is good, and pollution and cross contamination are avoided.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the description of the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments described in the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts;
FIG. 1 is a process flow diagram of a preferred embodiment of the present invention;
fig. 2 is a schematic diagram of a ferrule of a preferred embodiment of the present invention;
FIG. 3 is a radiochemical purity profile of a preferred embodiment of the invention;
FIG. 4 is an optical purity measurement profile of a preferred embodiment of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and all other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without any creative efforts belong to the protection scope of the present invention.
A GMP compliant device as shown in figure 1 18 A novel process for the preparation of F-FDOPA by nucleophilic substitution in relatively simple steps 18 The preparation of F-FDOPA, and the higher synthesis yield and optical purity are obtained, and the requirements of GMP standardized production are met 18 The increasing clinical use of F-FDOPA is in demand.
Specifically, the following formula is shown:
(1) Step 1 is the reaction of Compound 1 with an appropriate form 18 F-ion reaction to produce compound 2, and step 1 is nucleophilic substitution reaction using radionuclide 18 F-ion form.
(2) Step 2 is that compound 2 is obtained by deprotection 18 F-FDOPA。
(3) To compound 1, wherein R 1 、R 2 Each independently is a hydroxyl protecting group; r 3 Is a hydrocarbon radical, R 4 、R 5 Each independently is H or an amino protecting group, R 6 Is a carboxyl protecting group.
(4) As described above 18 In the method for synthesizing F-FDOPA, the reaction conditions in the step 1 are preferably as follows: compound 1 and suitable forms 18 F - Ion is put into organic solvent for closed reaction; the reaction temperature is 80-140 ℃; the reaction time is 3-30min; the organic solvent is preferably an organic solvent such as DMF (N, N-dimethylformamide), DMA (N, N-dimethylacetamide), t-butanol, 2-methyl-2-butanol, acetonitrile, or the like; or the mixed solvent of the organic solvents according to different proportions.
(5) As described above 18 In the process for the synthesis of F-FDOPA, the material used in step 1, in addition to compound 1, needs to contain a copper salt in a suitable form, preferably copper (II) trifluoromethanesulfonate (molecular weight C) 2 CuF 6 O 6 S 2 Structural formula is Cu (OTf) 2 ). Including but not limited to direct addition of copper (ii) trifluoromethanesulfonate; or a copper tetrapyridyl trifluoromethanesulfonate derived therefrom; or the copper (II) trifluoromethanesulfonate produced by pretreatment with other materials.
(6) As described above 18 In the synthesis method of F-FDOPA, the reaction conditions of the step 2 are the conventional deprotection operation conditions in organic experiments or the existing reaction conditions 18 F-FDOPA hydrolysis conditions. Acidic hydrolysis conditions (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like) are preferred.
It should be noted that the present invention is described 18 The synthesis method of F-FDOPA is suitable for automatic synthesis and manual synthesis. As shown in FIG. 2, it is preferred that the automated synthesis be performed using a synthesis module, that the purification be performed using a disposable cartridge/kit, and that preparative chromatography be used to perform the purification 18 GMP-normalized production of F-FDOPA.
Example one
Automated synthesis 18 A process for F-FDOPA comprising the steps of:
(1) Passing through an anion exchange column to capture accelerator 18 F - Ion 1000mci;
(2) 0.8ml KOTf/K was used 2 CO 3 The eluent liquid is 18 F - Eluting ions into a reaction bottle;
(3) The reaction flask was heated to evaporate the solvent.
(4) 10mg of trimethyltin dopa precursor (chemical name: N-formyl-3, 4-di-tert-butoxycarbonyl-6-trimethyltin-L-phenylalanine ethyl ester), 10mg of copper (II) trifluoromethanesulfonate, 0.2ml of pyridine and 2ml of DMA (N, N-dimethylacetamide) solution were added to carry out nucleophilic substitution reaction under 110 ℃ for 15min.
(5) And cooling the obtained intermediate, adding a 57% hydriodic acid solution, and reacting for 15min at 120 ℃.
(6) Cooling, performing preparative chromatography purification by automatic sample introduction, and collecting the desired product peak to obtain 8 F-FDOPA pure product. The preparative chromatographic conditions were as follows:
the type of the chromatographic column: xbridge BEH C18 OBD Pre Column
Flow rate: 5 ml/min
Mobile phase: 500mL of sterile water for injection contains 1mL of acetic acid, 68mg of sodium acetate, 250mg of ascorbic acid, and 930mg of EDTA.
(7) The final product was 365mCi with a synthetic yield of about 36.5% (uncorrected synthetic yield), with >99% radiochemical purity and >99% optical purity of the product as shown in fig. 3 and 4.
In light of the foregoing description of the preferred embodiment of the present invention, it is to be understood that various changes and modifications may be made by one skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (7)
1. In accordance with GMP standard 18 The novel preparation method of F-FDOPA is characterized in that as shown in the formula I,
wherein R1, R2 are each independently a hydroxy protecting group;
r3 is a hydrocarbyl group;
r4, R5 are each independently H or an amino protecting group;
r6 is a carboxyl protecting group;
the method comprises the following steps:
s1: compound 1 and suitable forms 18 F-ion reaction to produce compound 2, the radionuclide used in the nucleophilic substitution reaction being 18 F-ion form;
s2: compound 2 is obtained by deprotection 18 F-FDOPA。
2. GMP compliant garment according to claim 1 18 The novel preparation method of F-FDOPA is characterized by comprising the following steps: compound 1 and the appropriate forms in step S1 18 F-ion is sealed in organic solvent to react at 80-140 deg.C for 3-30min.
3. GMP compliant according to claim 2 18 The novel preparation method of F-FDOPA is characterized by comprising the following steps: the organic solvent is preferably DMF or DMA or tert-butyl alcohol or 2-methyl-2 butanol or acetonitrile, or a mixed solvent of the above organic solvents in different proportions.
4. GMP compliant garment according to claim 1 18 The novel preparation method of F-FDOPA is characterized by comprising the following steps: in the step S1, a copper salt with a proper form is added in the reaction process.
5. GMP compliant according to claim 4 18 The novel preparation method of F-FDOPA is characterized by comprising the following steps: the copper salt at least comprises copper (II) trifluoromethanesulfonate or copper (II) tetrapyridine trifluoromethanesulfonate or copper (II) trifluoromethanesulfonate.
6. GMP compliant according to claim 1 18 The novel preparation method of F-FDOPA is characterized by comprising the following steps: the reaction conditions in step S2 are acidic hydrolysis conditions.
7. GMP compliant according to claim 1 18 The novel preparation method of F-FDOPA is characterized by comprising the following steps: automated synthesis was performed using disposable cartridges/kits and purification separation was performed using preparative chromatography.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5393908A (en) * | 1992-06-25 | 1995-02-28 | Satyamurthy; Nagichettiar | Synthesis of N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester and its regioselective radiofluorodestannylation to 6-[18 F]fluoro-L-dopa |
TWI232109B (en) * | 2002-05-24 | 2005-05-11 | Inst Nuclear Energy Res | An automatic synthesis apparatus for production of L-6-[18F] Fluorodopa |
US20120123120A1 (en) * | 2009-04-08 | 2012-05-17 | The Regents Of The University Of California | No-Carrier-Added Nucleophilic [F-18] Fluorination of Aromatic Compounds |
US20150175553A1 (en) * | 2011-11-30 | 2015-06-25 | Ge Healthcare Limited | Production of 18f-labelled compounds comprising hydrolytic deprotection step and solid phase extraction |
CN114736112A (en) * | 2022-06-14 | 2022-07-12 | 北京先通国际医药科技股份有限公司 | Preparation method and application of PET imaging agent for myocardial metabolism |
-
2022
- 2022-08-08 CN CN202210942376.9A patent/CN115160167A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5393908A (en) * | 1992-06-25 | 1995-02-28 | Satyamurthy; Nagichettiar | Synthesis of N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester and its regioselective radiofluorodestannylation to 6-[18 F]fluoro-L-dopa |
TWI232109B (en) * | 2002-05-24 | 2005-05-11 | Inst Nuclear Energy Res | An automatic synthesis apparatus for production of L-6-[18F] Fluorodopa |
US20120123120A1 (en) * | 2009-04-08 | 2012-05-17 | The Regents Of The University Of California | No-Carrier-Added Nucleophilic [F-18] Fluorination of Aromatic Compounds |
US20150175553A1 (en) * | 2011-11-30 | 2015-06-25 | Ge Healthcare Limited | Production of 18f-labelled compounds comprising hydrolytic deprotection step and solid phase extraction |
CN114736112A (en) * | 2022-06-14 | 2022-07-12 | 北京先通国际医药科技股份有限公司 | Preparation method and application of PET imaging agent for myocardial metabolism |
Non-Patent Citations (4)
Title |
---|
AURÉLIE MAISONIAL-BESSET,等: "Base/Cryptand/Metal-Free Automated Nucleophilic Radiofluorination of [18F]FDOPA from Iodonium Salts: Importance of Hydrogen Carbonate Counterion", EUR. J. ORG. CHEM., vol. 2018, no. 48, pages 7058 - 7065 * |
DE VRIES,等: "Fully automated synthesis module for the high yield one-pot preparation of 6-[18F]fluoro-L-DOPA", APPLIED RADIATION AND ISOTOPES, vol. 51, no. 04, pages 1 * |
KATARINA J.,等: "Copper-Mediated Radiofluorination of Arylstannanes with [18F]KF", ORG. LETT., vol. 18, no. 20, pages 5440, XP093024285, DOI: 10.1021/acs.orglett.6b02911 * |
成伟华,等: "[18F]F-DOPA合成方法的研究进展", 中国药科大学学报, vol. 50, no. 03, pages 357 - 363 * |
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