CN1255400C - Improvement for 18F-FMISO mark forebody synthetic method - Google Patents
Improvement for 18F-FMISO mark forebody synthetic method Download PDFInfo
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- CN1255400C CN1255400C CN 200410044899 CN200410044899A CN1255400C CN 1255400 C CN1255400 C CN 1255400C CN 200410044899 CN200410044899 CN 200410044899 CN 200410044899 A CN200410044899 A CN 200410044899A CN 1255400 C CN1255400 C CN 1255400C
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- glycerol
- tosic acid
- tetrahydropyrans
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- acid base
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Abstract
The present invention discloses an improvement of the method for synthesizing 18F-FMISO marked precursors, particularly the synthesis of fluorine marked precursor compounds. The present invention improves the method for synthesizing 18F-FMISO marked precursors, which is reported in literature, the purification, the purification conditions and the adopted reagents of intermediate products in the reaction of each step are improved more beneficial, and the technique is made to be more reasonable and perfect.
Description
Technical field
18The synthetic of fluorine labelled precursor compound addressed in the improvement of F-FMISO labelled precursor synthetic method.
Background technology
18The chemical name of F-FMISO is 1-(2 '-nitro-1 '-imidazolyl)-2-O-THP trtrahydropyranyl-3-O-tosic acid base propylene glycol.
18The F-FMISO labelled precursor is used
18Be used for positron imaging behind the F mark,
18F-FMISO often is used to the level diagnosis of tumor hypoxia tissue in the PET video picture.Simultaneously,
18F-FMISO also can be used for the diagnosis of heart perfusion, myocardial ischemia etc.
Document Appl.Radiat.Isot.Vol.44, No.8, pp.1085-1091,1993 reports,
18F-FMISO labelled precursor synthetic route:
R is a p-toluenesulfonyl
Summary of the invention
The objective of the invention is the synthetic technological condition of bibliographical information is improved.
Technical scheme of the present invention: on the synthesis technique basis of bibliographical information, carry out following improvement.
1, is that raw material synthesizes 1 with glycerine, phenyl aldehyde, in the technology of 3-O-Ben Yajiaji glycerol, adopts ether extraction during aftertreatment, effectively remove excessive glycerine; Recrystallization solvent is selected the petroleum ether solution with 15~40% ethyl acetate.
2,, in 3-O-Ben Yajiaji-2-O-tetrahydropyrans glycerol synthetic, only use ethyl alcohol recrystallization 1.
3, at 2-O-tetrahydropyrans-1, in 3-O-two tosic acid base glycerol synthetic, employings methylene dichloride is a solvent, adds the hydrogenchloride of triethylamine neutralization reaction generation.
4, in 1-(2 '-nitro-1 '-imidazolyl)-2-O-THP trtrahydropyranyl-3-O-tosic acid base propylene glycol synthetic, adopted silicagel column during purifying products, eluent is an ethyl acetate: sherwood oil/7: 3 purifying.
Beneficial effect of the present invention
1, in the synthetic aftertreatment of 3-O-Ben Yajiaji glycerol (I), (mp:60~65 ℃) of product in the document (I) are molten apart from longer, present method adopts ether extraction, effectively removed excessive glycerine, prevent that glycerine from bringing in the product, make (mp:79~82 ℃) of product (I) molten apart from shortening, purity improves.In the selection of recrystallization solvent,, avoided the use of a large amount of noxious solvent benzene with the solvent of " benzene: sherwood oil/1: 1 " that uses on " petroleum ether solutions of 15~40% ethyl acetate " replacement document.
1, in 3-O-Ben Yajiaji-2-O-tetrahydropyrans glycerol (II) synthetic, document uses the method for silica gel column chromatography, and present method is only used ethyl alcohol recrystallization, pure product.Productive rate (76%) is consistent with document (75%).
2-O-tetrahydropyrans-1, synthesizing of 3-O-two tosic acid base glycerol (IV): document adopts product III and Tosyl chloride to react (inventor adopts its method not obtain product) in the exsiccant pyridine, used pyridine needs processed, and product (III) (IV) two step productive rates is 67.5%.It is solvent that present method is used methylene dichloride instead, adds the hydrogenchloride that the triethylamine neutralization reaction produces, and reagent does not all need special processing.And last step reaction product need not purifying, and the two-step reaction yield is 71%.
Synthesizing of 1-(2 '-nitro-1 '-imidazolyl)-2-O-THP trtrahydropyranyl-3-O-tosic acid base propylene glycol (V): during purifying products, document neutral alumina column purification, product is that (this liquid of document description can slowly decompose in room temperature and solvent liquid, this liquid need can be stablized the several months except that desolvating and preserving under rare gas element.But the inventor is under actual repeated experiments situation, and stability is very poor).Present method adopts the silicagel column purifying, gets solid (mp:100-104 ℃) after the processing, and its stability was above three months.The chemical structure of this product is identified through nuclear-magnetism (1H-NMR), mass spectrum (MS), infrared (IR).
Embodiment
Embodiment:
1,3-O-Ben Yajiaji glycerol (I) synthetic
Get glycerine (22 grams, 0.24mol), phenyl aldehyde (20 grams, 0.19mol) and tosic acid (0.25 restrain) join in the 25ml benzene.Reflux (installation water trap) is when collecting 2.5ml water.Stop heating, benzene is removed in decompression.Add the 100ml ether, place, after the layering, get the upper strata.Lower floor is again with a small amount of ether washing.Merge ether, ether is removed in decompression, gets white solid.0~20 ℃ of recrystallization (petroleum ether solutions of 15~40% ethyl acetate).Product I (9.0 gram), white solid mp:79~82 ℃, productive rate is 27%.
1H-NMR (CDC13,300MHz) chemical displacement value: 7.50 (m, 2H), 7.38 (m, 3H), 5.56 (s, 1Hbenzyl), 4.14 (dd, 4H), 3.63 (s, 1H), 2.48 (s, 1H, OH).IR(KBr):3280(OH),2926,2866,1833,1752,1566,1164,1095,1023,954,750cm
-1。
1,3-O-Ben Yajiaji-2-O-tetrahydropyrans glycerol (II) synthetic
Get product I (7.2 the gram, 40mmol), 3, the 4-dihydropyrane (7.4 the gram, 88mmol) and the tosic acid pyridine (2 the gram, 8mmol) join in the 100ml exsiccant tetrahydrofuran (THF) stirred overnight at room temperature.The ethyl acetate extraction brine layer is used in the half saturated brine washing.Combined ethyl acetate and reaction solution, behind the concentrating under reduced pressure, ethyl alcohol recrystallization, product II (8.0 gram) white solid, mp:49~51 ℃.Productive rate is 76%.
1H-NMR (CDCl3,300MHz) chemical displacement value: 7.45 (m, 3H), 7.29 (m, 3H), 5.49 (s, 1H, benzyl), 4.78 (t, 1H), 4.27 (t, 2H), 4.06 (m, 1H), 3.95 (d, 1H), 3.60 (m, 1H), 3.45 (m, 1H), 1.72-1.45 (m, 6H).IR(KBr)2938,2854,1458,1395,1347,1143,1080,1029,807,753,705cm
-1。MS.ES+, C
15H
20O
4Molecular weight is 264 (M), finds 264.5 (M), 287.3 (M+Na), 304.4 (M+K).
Synthesizing of 2-O-tetrahydropyrans glycerol (III)
Get about 3.0 gram sodium, join product II (5 grams in 60ml liquefied ammonia suspension 18.9mmol), did not take off until mazarine in lasting 20 minutes in batches.Reacted again 10 minutes.Add 10 gram NH
4Cl, liquefied ammonia dries up with nitrogen.After solid residue ground with sherwood oil, solid was used dichloromethane extraction again.Methylene dichloride is removed in decompression, gets yellow oil III.IR(KBr)3355(OH),2938,2866,1455,1266,1139,816cm
-1。MS molecular formula: C
8H
16O
4Molecular weight: 176 (M) find 199.5 (M+Na).
2-O-tetrahydropyrans-1,3-O-two tosic acid base glycerol (IV) synthetic
Get step product III and be dissolved in the 50ml methylene dichloride, add the 9ml triethylamine again, under the ice-water bath condition, drip the dichloromethane solution 40ml of 7.5 gram Tosyl chlorides, rise to room temperature, stirring is spent the night.With the 0.25mol/mlNaOH solution washing for several times, anhydrous Na
2SO
4Methylene dichloride is removed in decompression, crude product, re-crystallizing in ethyl acetate gets product IV (6.5 gram) white solid, mp:109~111 ℃, two step yields are 71%.
1H-NMR (CDCl3,300MHz) chemical displacement value: 7.76 (m, 4H, H
2H
6), 7.34 (d, 4H, H
3H
5), 4.60 (m, 1H), 4.16-3.98 (m, 6H), 3.69 (m, 1H), 3.40 (m, 1H), 2.46 (s, 6H, CH
3), 1.59 (m, 1H), 1.46 (m, 4H).IR(KBr)2949,1596,1359,1176,1119,1096,1024,1002,978,835,667cm
-1。MS molecular formula: C
22H
28O
8S
2Molecular weight: 484 molecular ion peaks 484 (M), 507 (M+Na), 523 (M+K).
Synthesizing of 1-(2 '-nitro-1 '-imidazolyl)-2-O-THP trtrahydropyranyl-3-O-tosic acid base propylene glycol (V)
First logical nitrogen 10 minutes in 10ml exsiccant DMF, add product IV (0.47 gram, 1mmol), the 2-nitroimidazole (0.1 gram, 0.9mmol) and cesium carbonate (0.29 restrains, and 0.9mmol), is heated to 110 ℃, stirs 1 hour.Cooling, DMF is removed in decompression, and residue washs with ethyl acetate, filters.Ethyl acetate is removed in decompression, gets yellow liquid.(eluent: ethyl acetate: sherwood oil/7: 3), get light yellow liquid V, drain, inflated with nitrogen is kept at 0~4 ℃ and spends the night, and becomes little yellow solid 0.12 gram, and yield is 30% to cross silicagel column.
1H-NMR (CDCl3,300MHz) chemical displacement value: 7.80 (t, 2H, H
2H
6), 7.38 (d, 2H, H
3H
5), 7.10 (s, 2H, imidazolyl), 4.78 (dd, 1H), 4.37 (dd, 1H), 4.27-4.20 (m, 2H), 4.09-4.02 (m, 2H), 3.65 (m, 1H), 3.32 (m, 1H), 2.46 (s, 3H, CH
3), 1.68-1.57 (m, 2H), 1.46-1.30 (m, 4H).IR(KBr)2950,2870,1534,1483,1361,1170,1020,981,669cm
-1。MS molecular weight: 425 molecular formula: C
18H
23N
3O
7S molecular ion peak 425 (M), base peak 448 (M+Na), 463 (M+K), 873 (2M+Na).
Reference examples: the bibliographical information method is
1,3-O-Ben Yajiaji glycerol (I) synthetic
Get glycerine (22 grams, 0.24mol), phenyl aldehyde (20 grams, 0.19mol) and tosic acid (0.25 restrain) join in the 25ml benzene.Reflux (installation water trap) is when collecting 2.5ml water.Stop heating, benzene is removed in decompression.Reaction mixture spends the night-5 ℃ of preservations, has solid to form, and filters recrystallization (benzene: sherwood oil/1: 1).Product I (8.5 gram), white solid, mp:60~65 ℃, productive rate is 25%.
1,3-O-Ben Yajiaji-2-O-tetrahydropyrans glycerol (II) synthetic
Get product I (7.2 the gram, 40mmol), 3, the 4-dihydropyrane (7.4 the gram, 88mmol) and the tosic acid pyridine (2 the gram, 8mmol) join in the 100ml exsiccant tetrahydrofuran (THF) stirred overnight at room temperature.Catalyzer is removed in the half saturated brine washing, uses ethyl acetate extraction.Behind the concentrating under reduced pressure, liquid (11 gram), cross silicagel column, eluent is 40% ethyl acetate/petroleum ether, product II (8.0 gram) white solid, mp:46~48 ℃.Productive rate is 75%.
Synthesizing of 2-O-tetrahydropyrans glycerol (III)
Under argon shield, get about 0.45 gram sodium, join product II (1 gram in 60ml liquefied ammonia suspension 3.8mmol), did not take off until mazarine in lasting 20 minutes in batches.Reacted again 10 minutes.Add NH
4Cl, blueness is taken off, and liquefied ammonia dries up with argon gas.After solid residue ground with the 40ml sherwood oil, solid was used the 40ml dichloromethane extraction again.Methylene dichloride is removed in decompression, gets yellow oil III (0.5 gram), yield 75%.
2-O-tetrahydropyrans-1,3-O-two tosic acid base glycerol (IV) synthetic
(0.4 gram 2.3mmol) is dissolved in the 10ml anhydrous pyridine, under the ice-water bath, drips Tosyl chloride (1.0 grams, anhydrous pyridine solution 5.75mmol) to get product III.After dripping off, stirred overnight at room temperature.Reactant is poured in the frozen water, sedimentation and filtration, product IV (1.0 gram), mp:108~110 ℃, yield is 90%.
Synthesizing of 1-(2 '-nitro-1 '-imidazolyl)-2-O-THP trtrahydropyranyl-3-O-tosic acid base propylene glycol (V)
First logical argon gas 10 minutes in 10ml exsiccant DMF, add product IV (0.47 gram, 1mmol), the 2-nitroimidazole (0.1 gram, 0.9mmol) and cesium carbonate (0.29 restrains, and 0.9mmol), is heated to 110 ℃, stirs 1 hour.Cooling, DMF is removed in decompression, and residue washs with ethyl acetate, filters.Ethyl acetate is removed in decompression, gets yellow liquid.Cross the neutral alumina post, (ethyl acetate: sherwood oil/7: 3), get light yellow liquid V (0.16 gram), yield is 41% to eluent.Drain applying argon gas, 0 ℃ of storage temperature.
Claims (1)
1. the improvement of a 1-(2 '-nitro-1 '-imidazolyl)-2-O-THP trtrahydropyranyl-3-O-tosic acid base propylene glycol labelled precursor synthetic method is characterized in that
(1) is that raw material synthesizes 1 with glycerine, phenyl aldehyde, in the technology of 3-O-Ben Yajiaji glycerol, adopts ether extraction during aftertreatment, effectively remove excessive glycerine; Recrystallization solvent is selected the petroleum ether solution with 15~40% ethyl acetate;
(2) with 1,3-O-Ben Yajiaji glycerol, 3,4-dihydropyrane and tosic acid pyridine are 1 of raw material, in 3-O-Ben Yajiaji-2-O-tetrahydropyrans glycerol synthetic, only use ethyl alcohol recrystallization;
(3) with 2-O-tetrahydropyrans glycerol and Tosyl chloride be the 2-O-tetrahydropyrans-1 of raw material, in 3-O-two tosic acid base glycerol synthetic, employings methylene dichloride is a solvent, adds the hydrogenchloride of triethylamine neutralization reaction generation;
(4) with 2-O-tetrahydropyrans-1,3-O-two tosic acid base glycerol, 2-nitroimidazole and cesium carbonate are in 1-(2 '-nitro-1 '-imidazolyl)-2-O-THP trtrahydropyranyl-3-O-tosic acid base propylene glycol synthetic of raw material, adopted silicagel column during purifying products, eluent is an ethyl acetate: sherwood oil/7: 3 purifying.
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