CN102432529B - Preparation method of styryl pyridine disulfide dinitrogen derivative - Google Patents
Preparation method of styryl pyridine disulfide dinitrogen derivative Download PDFInfo
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- CN102432529B CN102432529B CN201110359296.2A CN201110359296A CN102432529B CN 102432529 B CN102432529 B CN 102432529B CN 201110359296 A CN201110359296 A CN 201110359296A CN 102432529 B CN102432529 B CN 102432529B
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Abstract
The invention relates to a styryl pyridine disulfide dinitrogen derivative and a preparation method thereof and belongs to the field of a synthesis technology of a radiopharmaceutical labelled precursor compound. (E)-2-(2-(2-(2-(N-thiolethyl)-(N-(N-thiolethyl aminoethyl))aminoethoxy)ethoxy)ethoxy)-5-(4-methylaminostyryl) pyridine provided in the preparation method disclosed by the invention is called as BAT-AV-45 for short and is used for preparing a technetium-labelled radiopharmaceutical 99mTc-BAT-AV-45. The BAT-AV-45 has no a registration mark on the CA (Chemil Abstracts) and related reports of the BAT-AV-45 also do not exist at home and abroad. A medicine box can be conveniently prepared by mixing the BAT-AV-45 and other auxiliary materials and freezing and drying the mixture. The medicine box has high stability and over 95 percent of labelling yield and is convenient to be used for further researching biological characteristics. The technetium-labelled radiopharmaceutical 99mTc-BAT-AV-45 of the BAT-AV-45 is used for research work of SPECT (single photon emission computed tomography) development of an A alpha plaque.
Description
Technical field
The preparation method who the present invention relates to a kind of (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine, belongs to radiopharmaceuticals labelled precursor compou nd synthesis technical field.
Background technology
(E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine (being called for short BAT-AV-45), its structural formula is as shown in compound 7, and molecular formula is C
26h
40n
4o
3s
2, can easily form stable complex compound with isotropic substance technetium
99mtc-(E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine (is called for short
99mtc-BAT-AV-45).
Along with society progressively enters aging, alzheimer's disease (Alzheimer disease, AD) patient increases gradually, causes great burden to patient family and society, more and more receives the concern of various circles of society.AD is a kind of nerve degenerative diseases that carries out sexual development, and clinical manifestation is cognition dysfunction and is losing one's memory, judgement decline, and human communication disorders, self care ability is lost.The foundation of making a definite diagnosis that AD generally acknowledges is that the pathological changes such as neurofibrillary tangle (neurofibril-lary tangles, NFTs) and A β (β-amyloid, A β) patch are found in pathology postmortem at positions such as pallium, hippocampus and amygdala.Although the pathogenesis for AD also exists dispute at present, it is the major cause that causes senile dementia that most of scholar tends to A beta plaque deposition, prior to the generation of NFTs.AD does not still have the confirmation means outside postmortem at present, therefore, develops quick, noninvasive AD detection means and is significant clinically.
Along with molecular imaging development and single photon emission computerized tomography technology (Single photon emission computed tomography, SPECT) and positron emission computerized tomography (Positron emission tomography, PET), in neural application, make the SPECT/PET molecular imaging of non-invasive check that AD patient becomes possibility.Utilize the A beta plaque specific binding in developer and cerebral tissue, just can see intuitively A beta plaque distribution situation in brain, can help clinician's early diagnosis AD and anti-A beta plaque curative effect monitoring.
At present, the domestic and international research about A beta plaque PET/SPECT developer has small molecules developer: mainly around Congo red class, chrysamine-G, distyryl benzene type, thioflavine-T series, diphenylethylene, biphenyl class, acridine orange class, flavonoid, stibazole etc., carry out relevant research work.PET medicine mainly contain [
18f] FDDNP, [
11c] PIB, [
11c] SB-13, [
11c] BF-227, [
18f] BAY94-9172, [
18f] AV-45 and [
123i] IMPY etc., part PET medicine has started clinical experiment, demonstrates potential clinical value.Although PET clinical drug is obtained inspirer result,
11c and
18the F transformation period is short, and the cost that magnetic resonance acceleator is produced nucleic is high, and restriction PET medicine is in clinical being widely used.
99mtc has desirable nuclear physics character (pure γ photon emitter, energy 140kev, T
1/2for 6.02h) and be conveniently easy to get, the medicine of its mark can medicine boxization be produced, and in clinical, is widely used.Therefore, carry out
99mthe research of Tc mark A beta plaque developer has very large actual application value and social effect.
99mtc-BAT-AV-45 is a kind of novel A beta plaque SPECT developer that we design.On CA, without registration number, there is no relevant report both at home and abroad yet.BAT-AV-45 and other auxiliary materials are mixed together through lyophilize can make medicine box easily, and the stability of medicine box is better, and mark rate reaches more than 95%, is conveniently further used for the research of biological characteristics.
Summary of the invention
The object of this invention is to provide a kind of (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine preparation method, for the preparation of the radiopharmaceuticals of mtc labeled
99mtc-(E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine (is called for short
99mtc-BAT-AV-45), for the research work of A beta plaque SPECT video picture.
Technical scheme of the present invention: a kind of (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine, be called for short BAT-AV-45, its structural formula is:
Its mtc labeled product
99mtc-BAT-AV-45, for the research work of A beta plaque SPECT video picture.
The preparation method of described (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine, is characterized in that reaction equation is:
(1) 4-vinyl phenyl t-butyl carbamate is synthetic:
Two dimethyl dicarbonate butyl methyl esters of 4-amino-benzene ethene and 1.1 times of 4-amino-benzene ethene molar weights are dissolved in suitable quantity of water, and stirring at room reaction 3 hours has solid to generate, leach solid, with acetic acid ethyl dissolution, water is extracted with ethyl acetate, and merges organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, decompression is removed after solvent, obtains faint yellow solid compound 1, be 4-vinyl phenyl t-butyl carbamate, be directly used in next step reaction.
(2) N-methyl-4-vinyl phenyl t-butyl carbamate is synthetic:
N
2protection, compound 1 is dissolved in to appropriate dry DMF, ice bath is cooled to 0 ℃ of left and right, slowly drip while stirring the anhydrous DMF solution containing 60% sodium hydride of 1.5 times of compound 1 molar weights, drip and finish, rise to room temperature, 2 times of methyl iodide to compound 1 molar weight are slowly added drop-wise in reaction mixture, continue to stir 2 hours, reaction solution is carefully joined in appropriate frozen water, add ethyl acetate extraction, ester layer washs through saturated sodium-chloride water solution, anhydrous sodium sulfate drying, solvent is removed in decompression, obtain red oil 2, it is N-methyl-4-vinyl phenyl t-butyl carbamate, be directly used in next step reaction.
(3) 2-(2-(2-(5-iodine pyridine-2-oxygen base) oxyethyl group) oxyethyl group) ethanol is synthetic:
The triglycol of the bromo-5-iodine pyridine of 2-and the 4 times of bromo-5-iodine pyridine of compound 2-molar weights is dissolved in to appropriate tetrahydrofuran (THF), under stirring at room, the potassium tert.-butoxide of the 1.1 times of bromo-5-iodine pyridine of 2-molar weights is added in reaction solution in batches, back flow reaction 24 hours, tetrahydrofuran (THF) is removed in decompression, add ethyl acetate and water, separatory, water is extracted with ethyl acetate, merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression, obtain faint yellow oily matter, under room temperature, solidify, ethyl acetate column chromatography for separation, obtain product 3, be 2-(2-(2-(5-iodine pyridine-2-oxygen base) oxyethyl group) oxyethyl group) ethanol.
(4) synthesizing of (E)-2-(2-(2-(2-hydroxy ethoxy) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine:
N
2protection, by the compound of compound 2 and equimolar amount 3, the palladium of 0.05 times of compound 2 molar weight, the salt of wormwood of the Tetrabutyl amonium bromide of 3 times of compound 2 molar weights and 5 times of compound 2 molar weights is dissolved in appropriate dry DMF, 100 ℃ are reacted 24 hours, DMF is removed in decompression, add ethyl acetate and water, water is extracted with ethyl acetate, merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression, gained crude product is through ethyl acetate column chromatography for separation, obtain white solid compound 4, i.e. (E)-2-(2-(2-(2-hydroxy ethoxy) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine,
(5) synthesizing of (E)-2-(2-(2-(2-tolysulfonyl oxygen base oxethyl) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine:
N
2protection, compound 4 is dissolved in appropriate anhydrous methylene chloride, ice bath is cooled to 0 ℃ of left and right, slowly drip while stirring the anhydrous methylene chloride solution containing the Tosyl chloride of 2 times of compound 4 molar weights, drip and finish, the triethylamine of 3 times of compound 4 molar weights is slowly added drop-wise in reaction mixture, room temperature reaction 6 hours, add water stratification, separate organic layer, anhydrous sodium sulfate drying, solvent is removed in decompression, gained crude product is through ether column chromatography purification, obtain compound 5, i.e. (E)-2-(2-(2-(2-tolysulfonyl oxygen base oxethyl) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine.
(6) synthesizing of (E)-2-(2-(2-(2-(N-(4-methoxybenzyl mercaptoethyl)-N-(N-(4-methoxybenzyl mercaptoethyl) aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine:
N
2protection, by the N1 of compound 4 and 1.1 times of compound 4 molar weights, two (the 4-methoxybenzyl mercapto ethyl) quadrols of N2-, the potassiumiodide of the salt of wormwood of 2 times of compound 4 molar weights and 0.23 times of compound 4 molar weight is dissolved in appropriate dry DMF, 60 ℃ are reacted 24 hours, DMF is removed in decompression, add ethyl acetate and water, water is extracted with ethyl acetate, merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression, gained crude product is through silica gel column chromatography separated [eluent: V (methyl alcohol): V (methylene dichloride): V (ammoniacal liquor)=1:20:0.05], obtain compound 6, i.e. (E)-2-(2-(2-(2-(N-(4-methoxybenzyl mercaptoethyl)-N-(N-(4-methoxybenzyl mercaptoethyl) aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine.
(7) synthesizing of (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine:
N
2protection, 0 ℃ of left and right of the cooling temperature control of ice bath, is dissolved in appropriate trifluoroacetic acid by compound 6, under stirring; the dry-out benzene methyl ether that adds 2.3 times of compound 6 molar weights, stirs 30min, then adds the mercuric acetate of 6 times of compound 6 molar weights; stir 30min, vacuum concentration, obtains thickness oily matter; oil pump is taken out 30min, adds appropriate anhydrous diethyl ether, ultrasonic concussion 5min; there is yellow solid to generate, filter, obtain yellow solid; solid oil pump is drained, and dissolution of solid, in appropriate dehydrated alcohol, is led to dry H
2s reacts 30min, and the centrifugal black powder shape zunsober of removing, inclines and supernatant liquid, and under normal temperature, solvent is removed in decompression, and oil pump is taken out 30min, obtains yellow oil, obtains the trifluoroacetate of compound 7.By compound
7trifluoroacetate be dissolved in appropriate water, 0 ℃ of left and right of ice bath temperature control, slowly drips ammoniacal liquor, adjust pH to 7, extracted with diethyl ether, layering, organic layer anhydrous sodium sulfate drying, removes ether under reduced pressure, obtains compound
7, i.e. (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine; Due to compound
7easily moisture absorption oxidation, therefore do not carry out nuclear-magnetism sign, inflated with nitrogen protection cryopreservation, prepares against
99mtc mark, further studies its biological characteristics.
(8) froze-dried kit and
99mthe preparation of Tc-BAT-AV-45
Take appropriate labelled precursor BAT-AV-45, sodium glucoheptonate, ethylenediamine tetraacetic acid (EDTA), with phosphate buffered saline buffer, dissolve, then add the hydrochloric acid soln of appropriate tin protochloride, after shaking up, add and fill nitrogen distilled water and be diluted to pre-determined volume, after sterile filtration, by 1.0mL/ bottle, be sub-packed in 10mL cillin bottle, nitrogen-filled seal after lyophilize, standby.
Get above-mentioned froze-dried kit, add proper amount of fresh
99mtcO
4 -elutriant, is placed in boiling water and boils the regular hour, cooling, obtains
99mtc-BAT-AV-45.
Beneficial effect of the present invention: (E)-2-provided by the invention (2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine preparation method, for the preparation of the radiopharmaceuticals of mtc labeled
99mtc-(E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine (is called for short
99mtc-BAT-AV-45), for the research work of A beta plaque SPECT video picture.
99mtc-BAT-AV-45 is a kind of novel A beta plaque SPECT developer that we design.On CA, without registration number, there is no relevant report both at home and abroad yet.BAT-AV-45 and other auxiliary materials are mixed together through lyophilize can make medicine box easily, and the stability of medicine box is better, and mark rate reaches more than 95%, is conveniently further used for the research of biological characteristics.
Embodiment
Embodiment 1
Synthesizing of 4-vinyl phenyl t-butyl carbamate (compound 1)
Two dimethyl dicarbonate butyl methyl esters of 4-amino-benzene ethene and 1.1 times of 4-amino-benzene ethene molar weights are dissolved in suitable quantity of water, and stirring at room reaction 3 hours has solid to generate, leach solid, acetic acid ethyl dissolution, water is extracted with ethyl acetate, and merges organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, decompression is removed after solvent, obtains faint yellow solid compound 1, be 4-vinyl phenyl t-butyl carbamate, be directly used in next step reaction.
Embodiment 2
Synthesizing of N-methyl-4-vinyl phenyl t-butyl carbamate (compound 2)
N
2protection, 6.7g (30mmol) compound 1 is dissolved in to 30mL dry DMF, ice bath is cooled to 0 ℃ of left and right, slowly drip containing 1.8g(45mmol while stirring) the 100mL anhydrous DMF solution of 60% sodium hydride, drip and finish, rise to room temperature, 8.5g (60mmol) methyl iodide is slowly added drop-wise in reaction mixture, continue to stir 2 hours, reaction solution is carefully joined in 200mL frozen water, add ethyl acetate extraction (70mL * 3 time), ester layer washs through saturated sodium-chloride water solution, anhydrous sodium sulfate drying, solvent is removed in decompression, obtain red oil 2(6.5g, 89%), be directly used in next step reaction.
Embodiment 3
Synthesizing of 2-(2-(2-(5-iodine pyridine-2-oxygen base) oxyethyl group) oxyethyl group) ethanol (compound 3)
By 5g(17.6mmol) the bromo-5-iodine pyridine of 2-, 5.3g(70mmol) triglycol, being dissolved in 50mL tetrahydrofuran (THF), under stirring at room, by 2.35g(19mmol) potassium tert.-butoxide adds in reaction solution in batches, back flow reaction 24 hours, tetrahydrofuran (THF) is removed in decompression, adds ethyl acetate and water, separatory, water is extracted with ethyl acetate, merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression, obtain faint yellow oily matter, under room temperature, solidify ethyl acetate column chromatography for separation, obtain product 3(2.34g, 75%).[
1H]NMR（500MHz，CDCl
3）δ：8.30（1H，d），7.76（1H，d，d），6.63（1H，d），4.44（2H，t），3.84（2H，t），3.73-3.60（6H，m），3.61（2H，t）。
Embodiment 4
(E) synthesizing of-2-(2-(2-(2-hydroxy ethoxy) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine (compound 4)
N
2protection; by 0.16g(0.68mmol) compound 2; 0.24g(0.68mmol) compound 3; 0.8mg(0.034mmol) palladium; 0.66g(2mmol) Tetrabutyl amonium bromide and 0.48g(3.4mmol) salt of wormwood is dissolved in 10mL dry DMF; 100 ℃ are reacted 24 hours, and DMF is removed in decompression, adds ethyl acetate and water; water is extracted with ethyl acetate; merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying; solvent is removed in decompression; gained crude product, through ethyl acetate column chromatography for separation, obtains white solid 4 (0.24g, 77%).[
1h] NMR(400MHz, CDCl
3) δ: 8.18 (1H, s), 7.80(1H, d, d), 7.44(2H, d), 7.24 (3H, t), 6.96 (1H, s), 6.81 (1H, d), 4.51 (2H, t), 3.88 (2H, t), 3.75-3.70 (6H, m), 3.62(2H, t), 3.27 (3H, s), 1.46 (9H, s); Mass spectrum: MS m/z 459(M+1).
Embodiment 5
(E) synthesizing of-2-(2-(2-(2-tolysulfonyl oxygen base oxethyl) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine (compound 5)
N
2protection; 0.18g (0.39mmol) compound 4 is dissolved in 5mL anhydrous methylene chloride; ice bath is cooled to 0 ℃ of left and right; slowly drip containing 0.15g(0.79mmol while stirring) the 5mL anhydrous methylene chloride solution of Tosyl chloride; drip and finish; 0.17mL (1.2mmol) triethylamine is slowly added drop-wise in reaction mixture; room temperature reaction 6 hours; add water stratification, separate organic layer, anhydrous sodium sulfate drying; solvent is removed in decompression; gained crude product, through ether column chromatography purification, obtains compound 5(0.22g, 91%).[
1h] NMR(400MHz, CDCl
3) δ: 8.18 (1H, s), 7.79(3H, m), 7.44 (2H, d), 7.33 (2H, d), 7.24 (2H, t), 6.97 (2H, s), 6.79(1H, d), 4.48 (2H, t), 4.16 (2H, t), 3.82 (2H, t), 3.81-3.61 (6H, m), 3.27 (3H, s), 2.43 (3H, s), 1.46 (9H, s); Mass spectrum: MS m/z 613(M+1).
Embodiment 6
(E) synthesizing of-2-(2-(2-(2-(N-(4-methoxybenzyl mercaptoethyl)-N-(N-(4-methoxybenzyl mercaptoethyl) aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine (compound 6)
N
2protection, by 0.21g (0.4mmol) compound 4, 0.19g(0.45mmol) N1, two (the 4-methoxybenzyl mercapto ethyl) quadrols of N2-, 0.12g(0.81mmol) salt of wormwood and 0.07g(0.09mmol) potassiumiodide is dissolved in 10mL dry DMF, 60 ℃ are reacted 24 hours, DMF is removed in decompression, add ethyl acetate and water, water is extracted with ethyl acetate, merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression, gained crude product is through silica gel column chromatography separated [eluent is V (methyl alcohol): V (methylene dichloride): V (ammoniacal liquor)=1:20:0.05], obtain compound 6(0.18g, 62%).[
1h] NMR(400MHz, CDCl
3) δ: 8.16 (1H, s), 7.76(1H, d, d),, 7.42 (2H, d), 7.22 (6H, m), 6.95 (2H, s), 6.81 (4H, m), 6.79(1H, d), 4.46 (2H, m), 3.81 (2H, m), 3.77 (1H, m), 3.75-3.60 (13H, m), 3.49 (2H, t), 2.99 (3H, s), 2.95 (1H, br), 2.79 (6H, br), 2.69 (2H, t), 2.63 (2H, t), 2.57 (2H, t), 1.47 (9H, s); Mass spectrum: MS m/z 862(M+1).
Embodiment 7
(E) synthesizing of-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine (compound 7)
N
2protection; 0 ℃ of left and right of the cooling temperature control of ice bath, is dissolved in 10mL trifluoroacetic acid by 0.18g (0.2mmol) compound 6, under stirring; add 0.05mL(0.46mmol) dry-out benzene methyl ether; stir 30min, then add (0.39g, 1.22mmol) mercuric acetate; stir 30min; vacuum concentration, obtains thickness oily matter, and oil pump is taken out 30min; add 10 mL anhydrous diethyl ethers; ultrasonic concussion 5min, has yellow solid to generate, and filters; obtain yellow solid; solid oil pump is drained, and dissolution of solid, in 10 mL dehydrated alcohols, is led to dry H
2s reacts 30min, and the centrifugal black powder shape zunsober of removing, inclines and supernatant liquid, and under normal temperature, solvent is removed in decompression, and oil pump is taken out 30min, obtains yellow oil, obtains the trifluoroacetate (0.12g, 29%) of compound 7.By compound
7trifluoroacetate be dissolved in appropriate water, 0 ℃ of ice bath temperature control, slowly drips ammoniacal liquor, adjust pH to 7, extracted with diethyl ether, layering, organic layer anhydrous sodium sulfate drying, removes ether under reduced pressure, obtains compound
7, i.e. (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine.MS (m/z) 521 (m+1)
+, due to the easy moisture absorption oxidation of compound 7, therefore do not carry out nuclear-magnetism sign, inflated with nitrogen protection cryopreservation, prepares against
99mtc mark, further studies its biological characteristics.
Embodiment 8
Froze-dried kit and
99mthe preparation of Tc-BAT-AV-45
Take 5 ~ 10mg labelled precursor BAT-AV-45,0.5 ~ 1g sodium glucoheptonate, 0.05 ~ 0.1g ethylenediamine tetraacetic acid (EDTA), the phosphate buffered saline buffer that is 6-7 by 10mL pH value dissolves, add again the hydrochloric acid soln that contains 3 ~ 10mg tin protochloride (with 0.01 ~ 0.05N dissolving with hydrochloric acid, concentration is 1mg/mL) shake up after, add and fill nitrogen distilled water and be diluted to pre-determined volume 100mL.After sterile filtration, by 1.0mL/ bottle, be sub-packed in 10mL cillin bottle, nitrogen-filled seal after lyophilize, standby.
Get above-mentioned froze-dried kit, add fresh
99mtcO
4 -elutriant 0.1 ~ 0.3mL (about 37MBq), is placed in boiling water and boils 30min, cooling, obtains
99mtc-BAT-AV-45.Research work for A beta plaque SPECT video picture.
Claims (1)
1. a preparation method for (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine, is characterized in that reaction equation is:
(1) 4-vinyl phenyl t-butyl carbamate is synthetic:
Two dimethyl dicarbonate butyl methyl esters of 4-amino-benzene ethene and its 1.1 times of molar weights are dissolved in suitable quantity of water, and stirring at room reaction 3 hours has solid to generate, leach solid, with acetic acid ethyl dissolution, water is extracted with ethyl acetate, and merges organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, decompression is removed after solvent, obtains faint yellow solid compound 1, be 4-vinyl phenyl t-butyl carbamate, be directly used in next step reaction;
(2) N-methyl-4-vinyl phenyl t-butyl carbamate is synthetic:
N
2protection, compound 1 is dissolved in to appropriate dry DMF, ice bath is cooled to 0 ℃, slowly drip while stirring the anhydrous DMF solution containing 60% sodium hydride of 1.5 times of compound 1 molar weights, drip and finish, rise to room temperature, 2 times of methyl iodide to compound 1 molar weight are slowly added drop-wise in reaction mixture, continue to stir 2 hours, reaction solution is carefully joined in appropriate frozen water, add ethyl acetate extraction, ester layer washs through saturated sodium-chloride water solution, anhydrous sodium sulfate drying, solvent is removed in decompression, obtain red oily compound 2, it is N-methyl-4-vinyl phenyl t-butyl carbamate, be directly used in next step reaction,
(3) 2-(2-(2-(5-iodine pyridine-2-oxygen base) oxyethyl group) oxyethyl group) ethanol is synthetic:
The triglycol of the bromo-5-iodine pyridine of 2-and 4 times of its molar weights is dissolved in appropriate tetrahydrofuran (THF), under stirring at room, the potassium tert.-butoxide of the 1.1 times of bromo-5-iodine pyridine of 2-molar weights is added in reaction solution in batches, back flow reaction 24 hours, tetrahydrofuran (THF) is removed in decompression, add ethyl acetate and water, separatory, water is extracted with ethyl acetate, merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression, obtain faint yellow oily matter, under room temperature, solidify, ethyl acetate column chromatography for separation, obtain compound 3, be 2-(2-(2-(5-iodine pyridine-2-oxygen base) oxyethyl group) oxyethyl group) ethanol,
(4) synthesizing of (E)-2-(2-(2-(2-hydroxy ethoxy) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine:
N
2protection, by the compound of compound 2 and equimolar amount 3, the palladium of 0.05 times of compound 2 molar weight, the salt of wormwood of the Tetrabutyl amonium bromide of 3 times of compound 2 molar weights and 5 times of compound 2 molar weights is dissolved in appropriate dry DMF, 100 ℃ are reacted 24 hours, DMF is removed in decompression, add ethyl acetate and water, water is extracted with ethyl acetate, merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression, gained crude product is through ethyl acetate column chromatography for separation, obtain white solid compound 4, i.e. (E)-2-(2-(2-(2-hydroxy ethoxy) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine,
(5) synthesizing of (E)-2-(2-(2-(2-tolysulfonyl oxygen base oxethyl) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine:
N
2protection, compound 4 is dissolved in appropriate anhydrous methylene chloride, ice bath is cooled to 0 ℃, slowly drip while stirring the anhydrous methylene chloride solution containing the Tosyl chloride of 2 times of compound 4 molar weights, drip and finish, the triethylamine of 3 times of compound 4 molar weights is slowly added drop-wise in reaction mixture, room temperature reaction 6 hours, add water stratification, separate organic layer, anhydrous sodium sulfate drying, solvent is removed in decompression, gained crude product is through ether column chromatography purification, obtain compound 5, i.e. (E)-2-(2-(2-(2-tolysulfonyl oxygen base oxethyl) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine,
(6) synthesizing of (E)-2-(2-(2-(2-(N-(4-methoxybenzyl mercaptoethyl)-N-(N-(4-methoxybenzyl mercaptoethyl) aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine:
N
2protection, by the N1 of compound 5 and 1.1 times of compound 5 molar weights, two (the 4-methoxybenzyl mercapto ethyl) quadrols of N2-, the potassiumiodide of the salt of wormwood of 2 times of compound 5 molar weights and 0.23 times of compound 5 molar weight is dissolved in appropriate dry DMF, 60 ℃ are reacted 24 hours, DMF is removed in decompression, add ethyl acetate and water, water is extracted with ethyl acetate, merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression, gained crude product is separated through silica gel column chromatography, eluent is methyl alcohol: methylene dichloride: ammoniacal liquor, V:V:V=1:20:0.05, obtain compound 6, i.e. (E)-2-(2-(2-(2-(N-(4-methoxybenzyl mercaptoethyl)-N-(N-(4-methoxybenzyl mercaptoethyl) aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine,
(7) synthesizing of (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine:
N
2protection, 0 ℃ of the cooling temperature control of ice bath, is dissolved in appropriate trifluoroacetic acid by compound 6, under stirring; the dry-out benzene methyl ether that adds 2.3 times of compound 6 molar weights, stirs 30min, then adds the mercuric acetate of 6 times of compound 6 molar weights; stir 30min, vacuum concentration, obtains thickness oily matter; oil pump is taken out 30min, adds appropriate anhydrous diethyl ether, ultrasonic concussion 5min; there is yellow solid to generate, filter, obtain yellow solid; solid oil pump is drained, and dissolution of solid, in appropriate dehydrated alcohol, is led to dry H
2s reacts 30min, and the centrifugal black powder shape zunsober of removing, inclines and supernatant liquid, and under normal temperature, solvent is removed in decompression, and oil pump is taken out 30min, obtains yellow oil, obtains the trifluoroacetate of compound 7; By compound
7trifluoroacetate be dissolved in appropriate water, 0 ℃ of ice bath temperature control, slowly drips ammoniacal liquor, adjust pH to 7, extracted with diethyl ether, layering, organic layer anhydrous sodium sulfate drying, removes ether under reduced pressure, obtains compound
7, i.e. (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine; Due to compound
7easily moisture absorption oxidation, therefore do not carry out nuclear-magnetism sign, inflated with nitrogen protection cryopreservation, prepares against
99mtc mark.
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| Biology》.1998,第25卷第135-140页. * |
| Shunichi Oya et al..Small and Neutral TcvO BAT, Bisaminoethanethiol (N2S2) Complexes for Developing New Brain Imaging Agents.《Nuclear Medicine & * |
| ShunichiOyaetal..SmallandNeutralTcvOBAT Bisaminoethanethiol (N2S2) Complexes for Developing New Brain Imaging Agents.《Nuclear Medicine & Biology》.1998 |
| 张建康等.放射性99mTc标记的NMDA受体配基N2S2-Memantine 的合成.《化学试剂》.2008,第30卷(第11期),第842-844页. |
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