CN101481399A - Method for synthesizing positive electron radioactive imaging agent labeled precursor thymidine derivative - Google Patents
Method for synthesizing positive electron radioactive imaging agent labeled precursor thymidine derivative Download PDFInfo
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- CN101481399A CN101481399A CNA2009100367734A CN200910036773A CN101481399A CN 101481399 A CN101481399 A CN 101481399A CN A2009100367734 A CNA2009100367734 A CN A2009100367734A CN 200910036773 A CN200910036773 A CN 200910036773A CN 101481399 A CN101481399 A CN 101481399A
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- thymidine
- dimethoxytrityl
- aqueous solution
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Abstract
The invention discloses a synthetic method of a labelled precursor of a positron emission developer (a thymidine derivative), in particular relates to a synthetic method of 5'-O-(4,4'-dimethoxytriphenylmethyl)-2,3'-anhydro-thymidine. The synthetic method comprises the following steps: thymidine is taken as a raw material for reacting with 4,4'-dimethoxytriphenylmethyl and methylsulfonyl chloride, an intermediate product is subject to a cyclization reaction in alkaline aqueous solution, and finally separated and purified to obtain a final product. The synthetic method has the advantages of low-cost raw materials, simple operation, few process steps, short reaction time and high product yield.
Description
Technical field
The invention belongs to the field of chemical synthesis, the synthetic method of particularly a kind of positive electron radioactive imaging agent labeled precursor thymidine derivative 5 '-O-(4,4 '-dimethoxytrityl)-2,3 '-dehydration thymidine.
Technical background
3 '-deoxidation-3 '-[
18F] the fluoro thymidine (3 '-Deoxy-3 '-[
18F] fluorothymidine, [
18F] FLT) be positron emission tomography (position emission tomography, a kind of radiological imaging agent PET).[
18F] FLT can detect proliferative activity at external non-invasive, and diagnosis, discriminating and the curative effect monitoring of tumour had important value.According to the difference of labelled precursor kind, [
18F] preparation method of FLT mainly is divided into two kinds; the labelled precursor that uses is respectively that the 3-N-tertbutyloxycarbonyl-[5 '-O-(4; 4 '-dimethoxytrityl)-and 2-deoxidation-3 '-O-(4-oil of mirbane alkylsulfonyl)-β-five yuan of glycosyls of D-furans threo form] (3-N-Boc-1-[5-O-(4 for thymus pyrimidine; 4 '-dimethoxytrityl)-3-O-nitrophenylsulfonyl-2-deoxy-β-D-lyxofuranosyl] thymidine) and 5 '-O-(4; 4 '-dimethoxytrityl)-2; (5 '-O-(4 for 3 '-dehydration thymidine; 4 '-dimethoxytrityl)-2,3 '-anhydrothymidine).People such as S.J.Matin (document [1] Martin SJ, et al.Nucl Med Biol 2002; 29:263-73.) and people (document [2] Yun MY, et al.Nucl Med Biol2003 such as M.Y.Yun; 30:151-7.) used first kind of preparation method respectively, [
18F] the radiological chemistry productive rate of FLT is respectively 19.8% and 42%, but the labelled precursor that this method is used costs an arm and a leg, productive rate only is 30% when with the thymidine being the synthetic precursor of raw material.People such as C.Wodarski (document [3] Wodarski C, et al.J Labelled Compd Radiopharm 2000; 43:1211-8.), people (document [4] Machulla HJ, et al.J Radioanal Nucl Chem 2000 such as H.J.Machulla; 243:843-6.) and people (document [5] Blocher A, et al.J Radioanal Nucl Chem 2002 such as A.Blocher; 251 (1): 55-58.) used second kind of preparation method respectively, [
18F] the radiological chemistry productive rate of FLT is respectively 5.6%, 14.3% and 20%, though with first method relatively this method [
18F] the radiological chemistry productive rate of FLT is lower, but the labelled precursor price of using is low, productive rate is more than 60% when with the thymidine being the synthetic precursor of raw material.Therefore with second method use 5 '-O-(4,4 '-dimethoxytrityl)-2,3 '-dehydration thymidine be the labelled precursor preparation [
18F] FLT still adopts by many research institutions.
The synthetic method of existing 5 '-O-(4,4 '-dimethoxytrityl)-2,3 '-dehydration thymidine is seen document [3], [4] and [5], and its operational path is as follows respectively:
Document [3]:
Document [4] and [5]:
Document [4] and [5] be with 5 '-O-(4,4 '-dimethoxytrityl)-thymidine be raw material through the two-step reaction synthetic product, but that the raw material that this method is used and thymidine are compared cost is higher, and ring-closure reaction was for up to three days; Document [3] has improved synthetic method but operation is still complicated and need reflux, and same higher 5 '-O-(4,4 '-dimethoxytrityl)-thymidine of use cost is a raw material.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of 5 '-O-that a kind of raw materials cost is low, simple to operate, processing step is few, the reaction times is short, product yield is high (4,4 '-dimethoxytrityl)-2,3 '-dehydration thymidine.
The object of the present invention is achieved like this: a kind of 5 '-O-(4,4 '-dimethoxytrityl)-2, the synthetic method of 3 '-dehydration thymidine, be to be raw material with the thymidine, with 4,4 '-dimethoxytrityl chlorine and methylsulfonyl chloride react, and intermediate product carries out ring-closure reaction under alkaline aqueous solution, obtain final product through separation and purification at last.
The synthesis route of 5 '-O-among the present invention (4,4 '-dimethoxytrityl)-2,3 '-dehydration thymidine is as follows:
The synthetic of 5 '-O-among the present invention (4,4 '-dimethoxytrityl)-2,3 '-dehydration thymidine carries out according to the following steps:
Synthesizing of (1) 5 '-O-(4,4 '-dimethoxytrityl)-thymidine: with the thymidine is raw material, and with 4,4 '-dimethoxytrityl chlorine reacts in pyridine.
(2) 3 '-methylsulfonyls-5 '-O-(4,4 '-dimethoxytrityl)-thymidine synthetic: add methylsulfonyl chloride in minute product of descriscent step (1) and react.
Synthesizing of (3) 5 '-O-(4,4 '-dimethoxytrityl)-2,3 '-dehydration thymidine: be concentrated into the product of step (2) dried, residue is dissolved in the water-fast organic solvent, add alkaline aqueous solution, fully stir, carry out ring-closure reaction.
(4) separation and purification of final product: get the organic phase of step (3), through washing, dry, carry out silica gel column chromatography after concentrating and separate.
Synthetic method of the present invention, thymidine and 4 in step (1), the mol ratio of 4 '-dimethoxytrityl chlorine are 1:1～4, and the pyridine consumption is 3～10 liters of pyridines of every mole of thymidine, temperature of reaction is 10～35 ℃, and the reaction times is 1～4 hour.
Synthetic method of the present invention, the methylsulfonyl chloride consumption is 1～4 mole of a methylsulfonyl chloride of every mole of thymidine raw material in step (2), and temperature of reaction is 0～35 ℃, and the reaction times is 1～4 hour.
Synthetic method of the present invention, at the water-fast organic solvent described in the step (3) can be ether, ethyl acetate, methylene dichloride, in trichloromethane and the normal hexane one or more, consumption of organic solvent is 5～15 liters of organic solvents of every mole of thymidine raw material, alkaline aqueous solution can be a sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, in the aqueous solution of sodium bicarbonate and saleratus one or more, alkaline aqueous solution concentration is 1%～20% (w/v), the consumption of alkaline aqueous solution is 0.2～1 times of consumption of organic solvent, and churning time is 10～60 minutes.
Advantage of the present invention is:
1. raw materials cost is low: compare with the raw materials used 5 '-O-of prior art (4,4 '-dimethoxytrityl)-thymidine, raw material of the present invention is a thymidine, and the source is wide and cost is low.
2. processing step is few, and is simple to operate: the present invention obtains product through three step building-up reactionss and separation and purification, and synthetic reaction process does not need to separate, and the ring-closure reaction time is short, and is simple to operate.
3. product yield height: the inventive method is synthetic to obtain product, and yield is more than 60%.
Embodiment
Below in conjunction with embodiment the present invention is done to describe further, but do not constitute any limitation of the invention.
Embodiment 1
(1) get thymidine 1.5g (6mmol) and be dissolved in the 25mL anhydrous pyridine, magnetic agitation adds 4 under nitrogen protection, 4 '-dimethoxytrityl chlorine 2.54g (7.5mmol), room temperature (20～25 ℃) reaction 2 hours.
(2) mixture is cooled to 0 ℃, adds methylsulfonyl chloride 1.16ml (15mmol), then mixture temperature is increased to room temperature (20～25 ℃), magnetic agitation 2 hours.
(3) the mixture rotary evaporation is concentrated into dried, residue is dissolved in the 60mL methylene dichloride, adds 1% aqueous sodium hydroxide solution (w/v) 20mL, fully stirs, and reacts 30 minutes.
(4) get dichloromethane layer, collect organic phase after washing 3 times with water.Organic addition anhydrous sodium sulfate drying concentrates, through silica gel column chromatography separate (elutriant is an ethyl acetate: normal hexane=3:1), white solid 2.36g, productive rate 75%, purity is greater than 98% (high performance liquid chromatography).mp：119～125℃；TLC：Rf＝0.60(silica?gel；Hexane:ethylacetate＝1:3，v/v)；LCMS?m/z(ESI
+)：303.1[C
21H
19O
2]
+，549.2[M+Na]
+，565.2[M+K]
+；
1H-NMR(CDCl
3，300MHz)：δ＝7.39-6.81(m，14H，Ar-H?&?H-6)，4.33-4.01(m，1H，H-4’)，3.79(s，6H，OCH
3)，3.09(m，2H，H-5’)，2.61-2.35(m，2H，H-2’)，1.92(s，3H，5-CH
3)。
Embodiment 2
(1) get thymidine 1.5g (6mmol) and be dissolved in the 30mL anhydrous pyridine, magnetic agitation adds 4 under nitrogen protection, 4 '-dimethoxytrityl chlorine 2.54g (7.5mmol), and 30 ℃ were reacted 3 hours.
(2) mixture is cooled to 0 ℃, adds methylsulfonyl chloride 1.16ml (15mmol), mixture temperature is increased to 30 ℃ then, magnetic agitation 3 hours.
(3) the mixture rotary evaporation is concentrated into dried, residue is dissolved in the 60mL methylene dichloride, adds 10% sodium bicarbonate aqueous solution 30mL, fully stirs, and reacts 30 minutes.
(4) get dichloromethane layer, collect organic phase after washing 3 times with water.Organic addition anhydrous sodium sulfate drying concentrates, through silica gel column chromatography separate (elutriant is an ethyl acetate: normal hexane=3:1), white solid 2.81g, productive rate 89%, purity is greater than 98% (high performance liquid chromatography).
Embodiment 3
(1) get thymidine 1.5g (6mmol) and be dissolved in the 30mL anhydrous pyridine, magnetic agitation adds 4 under nitrogen protection, 4 '-dimethoxytrityl chlorine 3.05g (9mmol), room temperature (20～25 ℃) reaction 3 hours.
(2) mixture is cooled to 0 ℃, adds methylsulfonyl chloride 1.55ml (20mmol), then mixture temperature is increased to room temperature (20～25 ℃), magnetic agitation 3 hours.
(3) the mixture rotary evaporation is concentrated into dried, residue is dissolved in the 50mL ethyl acetate, adds 20% aqueous sodium carbonate 25mL, fully stirs, and reacts 45 minutes.
(4) get ethyl acetate layer, collect organic phase after washing 3 times with water.Organic addition anhydrous sodium sulfate drying concentrates, through silica gel column chromatography separate (elutriant is an ethyl acetate: normal hexane=3:1), white solid 1.93g, productive rate 61%, purity is greater than 98% (high performance liquid chromatography).
Embodiment 4
(1) get thymidine 1.5g (6mmol) and be dissolved in the 25mL anhydrous pyridine, magnetic agitation adds 4 under nitrogen protection, 4 '-dimethoxytrityl chlorine 2.54g (7.5mmol), room temperature (20～25 ℃) reaction 2 hours.
(2) mixture is cooled to 0 ℃, adds methylsulfonyl chloride 1.16ml (15mmol), then mixture temperature is increased to room temperature (20～25 ℃), magnetic agitation 2 hours.
(3) the mixture rotary evaporation is concentrated into dried, residue is dissolved in the 50mL ethyl acetate, adds 10% sodium bicarbonate aqueous solution 25mL, fully stirs, and reacts 45 minutes.
(4) get ethyl acetate layer, collect organic phase after washing 3 times with water.Organic addition anhydrous sodium sulfate drying concentrates, through silica gel column chromatography separate (elutriant is an ethyl acetate: normal hexane=3:1), white solid 2.21g, productive rate 70%, purity is greater than 98% (high performance liquid chromatography).
Claims (4)
1. positive electron radioactive imaging agent labeled precursor thymidine derivative 5 '-O-(4,4 '-dimethoxytrityl)-2, the synthetic method of 3 '-dehydration thymidine, be to be raw material with the thymidine, with 4,4 '-dimethoxytrityl chlorine and methylsulfonyl chloride react, and intermediate product carries out ring-closure reaction under alkaline aqueous solution, obtain final product through separation and purification at last, it is characterized in that carrying out according to the following steps:
Synthesizing of (1) 5 '-O-(4,4 '-dimethoxytrityl)-thymidine: with the thymidine is raw material, and with 4,4 '-dimethoxytrityl chlorine reacts in pyridine;
(2) 3 '-methylsulfonyls-5 '-O-(4,4 '-dimethoxytrityl)-thymidine synthetic: add methylsulfonyl chloride in minute product of descriscent step (1) and react;
Synthesizing of (3) 5 '-O-(4,4 '-dimethoxytrityl)-2,3 '-dehydration thymidine: be concentrated into the product of step (2) dried, residue is dissolved in the water-fast organic solvent, add alkaline aqueous solution, fully stir, carry out ring-closure reaction;
(4) separation and purification of final product: get the organic phase of step (3), through washing, dry, carry out silica gel column chromatography after concentrating and separate.
2. synthetic method according to claim 1, it is characterized in that thymidine and 4 in the step (1), the mol ratio of 4 '-dimethoxytrityl chlorine is 1:1～4, the pyridine consumption is 3～10 liters of pyridines of every mole of thymidine, temperature of reaction is 10～35 ℃, and the reaction times is 1～4 hour.
3. synthetic method according to claim 1 is characterized in that the methylsulfonyl chloride consumption is 1～4 mole of a methylsulfonyl chloride of every mole of thymidine raw material in the step (2), and temperature of reaction is 0～35 ℃, and the reaction times is 1～4 hour.
4. synthetic method according to claim 1, it is characterized in that the water-fast organic solvent described in the step (3) can be an ether, ethyl acetate, methylene dichloride, in trichloromethane and the normal hexane one or more, consumption of organic solvent is 5～15 liters of organic solvents of every mole of thymidine raw material, alkaline aqueous solution can be a sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, in the aqueous solution of sodium bicarbonate and saleratus one or more, alkaline aqueous solution concentration is 1%～20% (w/v), the consumption of alkaline aqueous solution is 0.2～1 times of consumption of organic solvent, and churning time is 10～60 minutes.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119289A (en) * | 2014-07-16 | 2014-10-29 | 成都丽凯手性技术有限公司 | Novel synthesis method of furoxan |
| CN107473972A (en) * | 2016-06-07 | 2017-12-15 | 上海兆维科技发展有限公司 | Novel nucleoside protection group and its preparation |
-
2009
- 2009-01-19 CN CNA2009100367734A patent/CN101481399A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119289A (en) * | 2014-07-16 | 2014-10-29 | 成都丽凯手性技术有限公司 | Novel synthesis method of furoxan |
| CN104119289B (en) * | 2014-07-16 | 2016-08-17 | 成都丽凯手性技术有限公司 | A kind of method synthesizing furoxan compound |
| CN107473972A (en) * | 2016-06-07 | 2017-12-15 | 上海兆维科技发展有限公司 | Novel nucleoside protection group and its preparation |
| CN107473972B (en) * | 2016-06-07 | 2021-01-08 | 上海兆维科技发展有限公司 | Nucleoside protective group and preparation thereof |
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Open date: 20090715 |