CN1775795A - Improved method for synthesizing PET developer labeled precursor thymidine derivative - Google Patents
Improved method for synthesizing PET developer labeled precursor thymidine derivative Download PDFInfo
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- CN1775795A CN1775795A CN 200510123046 CN200510123046A CN1775795A CN 1775795 A CN1775795 A CN 1775795A CN 200510123046 CN200510123046 CN 200510123046 CN 200510123046 A CN200510123046 A CN 200510123046A CN 1775795 A CN1775795 A CN 1775795A
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- dimethoxytrityl
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- thymine deoxyriboside
- flt
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Abstract
The invention relates to the improvement of synthetic method for a PET developer labeled precursor thymine deoxyriboside derivant. It concretely relates the improvement for compounding 3'-noso-FLT that belongs to the compounding field of FI labeled precursor. 3'-noso-FLT is the labeled precursor of 18F-FLT, which is the thymine imaging agent for showing the state of cell multiplication. 18F-FLT could be used for tumor imaging and could take discriminate for tumor and inflammation. The invention supplies a feasible compounding method for 3'-noso-FLT.
Description
Technical field
A kind of improvement of PET developer labeled precursor thymidine derivative synthetic method; be specifically related to that [5 '-O-(4; 4 '-dimethoxytrityl)-2 '-and deoxidation-3 '-O-(4-oil of mirbane alkylsulfonyl-β-1)-Su penta furanose] improvement of Thymine deoxyriboside synthetic method, belong to the synthetic field of fluorine labelled precursor.
Background technology
Positron emission tomography (positron emission tomography, PET) value in the tumour diagnosis and treatment has aspect following five, 1. the early diagnosis of tumour and by stages, 2. differentiate remaining focus, scar, necrotic tissue after the oncotherapy or have or not recurrence, 3. curative effect is followed up a case by regular visits to and is monitored, 4. seek primary tumo(u)r, 5. prognosis information is provided.
Clinical tumour PET medicine commonly used is deoxyglucose (FDG) at present, its mechanism is to mainly contain glycoprotein translocator (Glu) 2,4,5 on the human cell membrane, but lack Glu1,3, and has Glu1,3 on the after birth of tumour, so picked-up sugar is than normal cell height, aerobic oxidation and the anaerobic glycolysis of glucose in tumour cell is also fast than normal cell.Picked-up by both sugar,, is trapped in the cell under the effect of 6-diphosphate glucose isomerase because of taking in intracellular FDG in hexokinase and 1 with metabolic different, organizes video picture thereby make, so carry out tumour differential diagnosis with PET.But FDG also has stronger gathering at the inflammation kitchen range, and non-special aggregation is also arranged beyond the tumor tissues, and tumour cell that simultaneously neither be all has high picked-up to FDG, thus false positive and non-specific be the subject matter of FDG tumour PET.Thereby to develop the new PET medicine at other biochemical metabolisms of tumour be the research emphasis of positron medicine always.
[5 '-O-(4; 4 '-dimethoxytrityl)-2 '-and deoxidation-3 '-O-(4-oil of mirbane alkylsulfonyl-β-1)-Su penta furanose] Thymine deoxyriboside; English is by name, and [5 '-O-(4; 4 '-Dimethoxytriphenylmethyl)-2 '-deoxy-3 '-O-(4-nitrobenzesulfonyl)-β-D-threopentofuranosyl] thymine; be abbreviated as 3 '-Noso-FLT; be 3 ' deoxidation-3 '-fluorine Thymine deoxyriboside (18F-FLT; the labelled precursor of 3 '-deoxy-3 '-fluorothymidine); 18F-FLT is a kind of thymus pyrimidine class developer of showed cell vegetative state; it under the effect of thymidine kinase by phosphorylation; it is synthetic that its product does not participate in DNA, can only accumulate in the cell.When the rapid hyperplasia of tumor tissues, a large amount of DNA is synthetic, needs the mediation activity that goes up of thymidine kinase to increase, thereby has lot of F LT to assemble in the tumour cell, therefore
18F-FLT can make the tumor tissues imaging.And for inflammation focus and tuberculose focus, although carbohydrate metabolism strengthens, uptake ratio all shows as higher level, and hyperplasia is also inactive, therefore
18The F-FLT video picture can be carried out differential diagnosis at an easy rate.
Existing relevant synthetic route is seen document [1] S.J.Martin, et al, Nuclear Medicine andBiology, Vol.29, pp.263～273. reports, and document [2] Mikyung Yun, et al, Nuclear Medicineand Biology, Vol.30, pp151～157. reports
But, can't repeat the reaction result of document according to the product (1) of bibliographical information and the synthesis condition of product (3).
Summary of the invention
The purpose of this invention is to provide that a kind of [5 '-O-(4; 4 '-dimethoxytrityl)-2 '-and deoxidation-3 '-O-(4-oil of mirbane alkylsulfonyl-β-1)-Su penta furanose] Thymine deoxyriboside (3 '-Noso-FLT) synthetic method; synthesis condition to existing bibliographical information improves, and makes it more practical.
Technical scheme of the present invention:
3 '-Noso-FLT synthetic route:
The technology of product (1) synthetic product (2) is identical with bibliographical information.The present invention improves the synthesis condition of product (1) and product (3).Because according to the reaction conditions of document, can't repeat the reaction result of document.
Improvement of the present invention is: when synthetic mesophase product 5 '-O-(4,4 '-dimethoxytrityl) Thymine deoxyriboside (product 1), employing acetone is solvent, and Anhydrous potassium carbonate is a catalyzer;
[5 '-O-(4 at synthetic final product; 4 '-dimethoxytrityl)-2 '-deoxidation-3 '-O-(4-oil of mirbane alkylsulfonyl-β-1)-Su penta furanose] during Thymine deoxyriboside (product 3); the employing methylene dichloride is a solvent, 4-N, and N-dimethyl amine yl pyridines is a catalyzer.
Beneficial effect of the present invention: the reaction conditions of synthetic [5 '-O-(4,4 '-dimethoxytrityl)-2 '-deoxidation-3 '-O-(4-oil of mirbane alkylsulfonyl-β-the 1)-Su penta furanose] Thymine deoxyriboside of the present invention improves the reaction conditions of bibliographical information.During synthetic product (1), it is solvent that document adopts pyridine, what the present invention adopted is that acetone is solvent, we find that when adopting pyridine commercially available or that handled to make solvent, reaction is difficult to take place, when making solvent with acetone, Anhydrous potassium carbonate is a catalyzer, when 4, when 4 '-dimethoxytrityl chlorine dropwised, reaction was finished very soon.During synthetic product (3), it is solvent that document adopts pyridine, reacts 6 days, perhaps adds silver triflate and makees catalyzer, and we discover that reaction is difficult to take place under the document condition.What the present invention adopted is that methylene dichloride is a solvent, 4-N, and N-dimethyl amine yl pyridines is a catalyzer, reacts fine finishing.We have carried out with cold Potassium monofluoride mark 3 '-Noso-FLT, and result of study shows that 3 '-Noso-FLT is than being easier to fluorine atom on the mark.The invention provides the synthetic method of a kind of practicable 3 '-Noso-FLT.
Embodiment
Synthesizing of 5 '-O-(4,4 '-dimethoxytrityl) Thymine deoxyribosides (1).
Get 1.5g beta-thymidine and 10g Anhydrous potassium carbonate and join in the 250mL acetone, stir about is ten minutes under nitrogen protection.Drip 2.54g 4,4 '-dimethoxytrityl chlorine (DMTrCl) is dissolved in the acetone soln of 50mL, drip and finish, filter, filtrate concentrates the back and crosses silicagel column, is eluent with volume ratio ethyl acetate/normal hexane=3/1, get 1.3g weak yellow foam shape solid, productive rate is 38.6%, mp:110～115 ℃, m/z:567 (M+Na); IR (cm
-1): 3413,3183,2960,2835,1690,1607,1509,1466
1HNMR: δ 8.28 (s, 1H), 7.60～7.20 (m, 10H), 6.84 (m, 4H), 6.40 (m, 1H), 4.58 (s, 1H), 4.05 (s, 1H), 3.80 (s, 6H), 3.50～3.36 (m, 2H), 2.46～2.30 (m, 2H), 2.05 (s, 1H), 1.60～1.58 (d, 3H).
Synthesizing of 5 '-O-(4,4 '-dimethoxytrityl) d-Soviet Union's formula furanose Thymine deoxyriboside (2).
Get 0.5g compound (1), be dissolved in the 15mL dry tetrahydrofuran,, slowly drip the 10mL dry tetrahydrofuran solution of 0.11mL methylsulfonyl chloride (MsCl), have precipitation to generate in 0 ℃ of adding 0.4mL triethylamine.Stirring reaction 1.5h.The NaoH solution that adds 10mL ethanol and 10mL 1mol/L, reflux 4h.The NaoH solution that adds 9.25mL 10mol/L again, backflow 1.5h.After reacting completely, tetrahydrofuran (THF) and ethanol are removed in decompression, twice of dichloromethane extraction in water-soluble back of resulting product.To obtain faint yellow solid behind the organic phase evaporate to dryness, 0.45g, productive rate: 90%, mp:120～124 ℃ m/z:567 (M+Na); IR (cm
-1): 3413,3183,2960,2835,1690,1607,1509,1466;
1HNMR: δ 8.78 (s, 1H), 7.76～7.20 (m, 10H), 6.82 (d, 4H), 6.20 (m, 1H), 4.44 (s, 1H), 4.00 (m, 1H), 3.80 (s, 6H), 3.64～3.50 (m, 2H), 3.06 (s, 1H), 2..08～2.02 (m, 1H), 1.80～1.78 (m, 4H).
Synthesizing of [5 '-O-(4,4 '-dimethoxytrityl)-2 '-deoxidation-3 '-O-(4-oil of mirbane alkylsulfonyl-β-1)-Su penta furanose] Thymine deoxyriboside (3).
Get 0.9g compound (2), be dissolved in 20mL CH
2Cl
2, adding 0.25g 4-N, N-dimethyl amine yl pyridines (DMAP) is in 0 ℃ of 10mL CH that drips 0.74g 4-nitrobenzene sulfonyl chloride
2Cl
2, adding the 1mL triethylamine, the adularescent precipitation generates, continue reaction, precipitation disappears, behind the reaction 5h, pour in the frozen water, tell organic layer, washing, dry, cross silicagel column (volume ratio ethyl acetate/normal hexane=3/1 is developping agent), get yellow spumescence solid 0.7g, productive rate 58.3%, mp:110～115 ℃, m/z:752 (M+Na); IR (cm
-1): 3458,3184,3046,2963,2837,1692,1608,1534,1509,1466,1350;
1HNMR δ 8.25～7.85 (m, 4H), 7.40～7.18 (m, 11H), 6.89～6.80 (m, 4H), 6.21 (m, 1H), 5.22 (m, 1H), 4.20～4.10 (m, 1H), 3.80 (s, 6H), 3.60～3.52 (m, 1H), 3.28～3.22 (m, 1H), 2.82～2.72 (m, 1H), 2.52～2.48 (m, 1H), 1.80～1.78 (s, 3H).
Claims (1)
1. the improvement of one kind [5 '-O-(4,4 '-dimethoxytrityl)-2 '-deoxidation-3 '-O-(4-oil of mirbane alkylsulfonyl-β-1)-Su penta furanose] Thymine deoxyriboside synthetic method is characterized in that:
When synthetic mesophase product 5 '-O-(4,4 '-dimethoxytrityl) Thymine deoxyriboside, employing acetone is solvent, and Anhydrous potassium carbonate is a catalyzer;
[5 '-O-(4 at synthetic final product, 4 '-dimethoxytrityl)-2 '-deoxidation-3 '-O-(4-oil of mirbane alkylsulfonyl-β-1)-Su penta furanose] during Thymine deoxyriboside, the employing methylene dichloride is a solvent, 4-N, and N-dimethyl amine yl pyridines is a catalyzer; Described improved synthesis technique is:
(1) .5 '-O-(4,4 '-dimethoxytrityl) Thymine deoxyriboside is synthetic: get 1.5g beta-thymidine and 10g Anhydrous potassium carbonate and join in the 250mL acetone, under nitrogen protection, stirred 10 minutes, drip 2.54g 4,4 '-dimethoxytrityl chlorine is dissolved in the acetone soln of 50mL, drips to finish, filter, filtrate concentrates the back and crosses silicagel column, is eluent with volume ratio ethyl acetate/normal hexane=3/1, gets 1.3g weak yellow foam shape solid;
(2) .[5 '-O-(4; 4 '-dimethoxytrityl)-2 '-and deoxidation-3 '-O-(4-oil of mirbane alkylsulfonyl-β-1)-Su penta furanose] Thymine deoxyriboside synthetic: get 5 ' of 0.9g-O-(4; 4 '-dimethoxytrityl) d-Soviet Union formula furanose Thymine deoxyriboside is dissolved in 20mL CH
2Cl
2, adding 0.25g 4-N, N-dimethyl amine yl pyridines is in 0 ℃ of 10mL CH that drips 0.74g 4-nitrobenzene sulfonyl chloride
2Cl
2, adding 1mL triethylamine, the adularescent precipitation generates, and continues reaction, precipitates to disappear, and behind the reaction 5h, pours in the frozen water, tells organic layer, washing, drying is crossed silicagel column, and volume ratio ethyl acetate/normal hexane=3/1 is a developping agent, gets yellow spumescence solid 0.7g.
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| CNB2005101230463A CN100344644C (en) | 2005-12-08 | 2005-12-08 | Improved method for synthesizing PET developer labeled precursor thymidine derivative |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101168554B (en) * | 2007-11-28 | 2011-03-02 | 中国人民解放军总医院 | Method for preparing 18F-FLT |
| US9669118B2 (en) | 2011-06-17 | 2017-06-06 | University Court Of The University Of St. Andrews | Method of labelling a biologically active molecule with 5-fluoro-5-deoxypentose or a 3-fluoro-3-deoxypentose |
-
2005
- 2005-12-08 CN CNB2005101230463A patent/CN100344644C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101168554B (en) * | 2007-11-28 | 2011-03-02 | 中国人民解放军总医院 | Method for preparing 18F-FLT |
| US9669118B2 (en) | 2011-06-17 | 2017-06-06 | University Court Of The University Of St. Andrews | Method of labelling a biologically active molecule with 5-fluoro-5-deoxypentose or a 3-fluoro-3-deoxypentose |
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| Publication number | Publication date |
|---|---|
| CN100344644C (en) | 2007-10-24 |
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