CN102432529A - Styryl pyridine disulfide dinitrogen derivative and preparation method thereof - Google Patents
Styryl pyridine disulfide dinitrogen derivative and preparation method thereof Download PDFInfo
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- CN102432529A CN102432529A CN2011103592962A CN201110359296A CN102432529A CN 102432529 A CN102432529 A CN 102432529A CN 2011103592962 A CN2011103592962 A CN 2011103592962A CN 201110359296 A CN201110359296 A CN 201110359296A CN 102432529 A CN102432529 A CN 102432529A
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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 present invention relates to the preparation method of 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, belong to the synthetic technical field of radiopharmaceuticals labelled precursor compound.
Background technology
(E)-and 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 shown in compound 7, and molecular formula is C
26H
40N
4O
3S
2, can form stable complex compound easily with the 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 gets into aging, (Alzheimer disease, AD) patient increases alzheimer's disease gradually, causes great burden for 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 that judgment descends, human communication disorders, self care ability forfeiture.AD generally acknowledges make a definite diagnosis according to be the pathology postmortem find at positions such as pallium, hippocampus and amygdala NFT (neurofibril-lary tangles, NFTs) and pathological change such as A β (β-amyloid, A β) patch.Though also there is dispute in the pathogenesis for AD 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 outer conclusive evidence means of 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), make the SPECT/PET molecular imaging inspection AD patient of non-invasive become possibility in neural application.Utilize developer to combine, just can see A beta plaque distribution situation in the brain intuitively, can help clinician's early diagnosis AD and anti-A beta plaque curative effect monitoring with the interior A beta plaque specificity of cerebral tissue.
At present, domestic and international research about A beta plaque PET/SPECT developer has the small molecules developer: mainly carry out relevant research work around Congo red class, chrysamine-G, diphenylethyllene benzene class, thioflavine-T series, diphenylethylene, biphenyl class, SP 15 Lemon Yellow class, flavonoid, stibazole etc.The PET medicine mainly contain [
18F] FDDNP, [
11C] PIB, [
11C] SB-13, [
11C] BF-227, [
18F] BAY94-9172, [
18F] AV-45 with [
123I] IMPY etc., part PET medicine has begun clinical experiment, demonstrates the potential clinical value.Though the PET clinical drug is obtained inspirer result,
11C with
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 ideal nuclear physics character (pure γ photon emitter, energy 140kev, T
1/2Be 6.02h) and conveniently be easy to get, the medicine of its mark can medicine box production, in clinical, is widely used.Therefore, carry out
99mThe research of Tc mark A beta plaque developer has very big 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, do not have registration number, do not have 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%, conveniently is further used for biological Characteristics Study.
Summary of the invention
The purpose 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, be used to prepare 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), be used 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 is used for the research work of A beta plaque SPECT video picture.
The preparation method of said (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, and leaches solid; Use acetic acid ethyl dissolution, water is used ethyl acetate extraction, merges organic phase; The saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying is after solvent is removed in decompression; Get faint yellow solid compound 1, promptly 4-vinyl phenyl t-butyl carbamate directly is used for next step reaction.
(2) N-methyl-4-vinyl phenyl t-butyl carbamate is synthetic:
N
2Protection is dissolved in an amount of dry DMF with compound 1, and ice bath is cooled to about 0 ℃, slowly drips the anhydrous DMF solution of 60% sodium hydride that contains 1.5 times of compound 1 molar weights while stirring; Drip and finish, rise to room temperature, slowly be added drop-wise to 2 times of methyl iodide in the reaction mixture to compound 1 molar weight; Continue to stir 2 hours, reaction solution is carefully joined in an amount of frozen water, add ethyl acetate extraction; The ester layer washs through saturated sodium-chloride water solution, anhydrous sodium sulfate drying, and solvent is removed in decompression; Get red oil 2, promptly N-methyl-4-vinyl phenyl t-butyl carbamate directly is used for next step reaction.
(3) 2-(2-(2-(5-iodine pyridine-2-oxygen base) oxyethyl group) oxyethyl group) alcoholic acid is synthetic:
The triglycol of 2-bromo-5-iodine pyridine and 4 times of compound 2-bromo-5-iodine pyridine molar weights is dissolved in an amount of THF, under the stirring at room, the potassium tert.-butoxide of 1.1 times of 2-bromo-5-iodine pyridine molar weights is added in the reaction solution back flow reaction 24 hours in batches; THF is removed in decompression, adds ETHYLE ACETATE and water, separatory, and water is used ethyl acetate extraction; Merge organic phase, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying; Solvent is removed in decompression, gets faint yellow oily thing, solidifies under the room temperature; The ETHYLE ACETATE column chromatography for separation gets product 3, i.e. 2-(2-(2-(5-iodine pyridine-2-oxygen base) oxyethyl group) oxyethyl group) ethanol.
(4) (E)-2-(2-(2-(2-hydroxy ethoxy) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine synthetic:
N
2Protection is with the palladium of 3,0.05 times of compound 2 molar weights of compound of compound 2 and equimolar amount; 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 an amount of dry DMF, and 100 ℃ were reacted 24 hours, and DMF is removed in decompression; Add ETHYLE ACETATE and water, water is used ethyl acetate extraction, merges organic phase; The saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression; The gained crude product gets white solid compound 4, i.e. (E)-2-(2-(2-(2-hydroxy ethoxy) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine through the ETHYLE ACETATE column chromatography for separation;
(5) (E)-2-(2-(2-(2-tolysulfonyl oxygen base oxethyl) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine synthetic:
N
2Protection is dissolved in compound 4 in an amount of anhydrous methylene chloride, and ice bath is cooled to about 0 ℃; Slowly drip the anhydrous methylene chloride solution of the Tosyl chloride that contains 2 times of compound 4 molar weights while stirring, drip and finish, slowly be added drop-wise to the triethylamine of 3 times of compound 4 molar weights in the reaction mixture; Room temperature reaction 6 hours adds water stratification, tells organic layer; Anhydrous sodium sulfate drying, solvent is removed in decompression, and the gained crude product is through the ether column chromatography purification; Get compound 5, i.e. (E)-2-(2-(2-(2-tolysulfonyl oxygen base oxethyl) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine.
(6) (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 synthetic:
N
2Protection, with 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 an amount of dry DMF, and 60 ℃ were reacted 24 hours, and DMF is removed in decompression; Add ETHYLE ACETATE and water, water is used ethyl acetate extraction, merges organic phase; The saturated sodium-chloride water solution washing; Anhydrous sodium sulfate drying, solvent is removed in decompression, and the gained crude product separates [eluent: V (methyl alcohol): V (methylene dichloride): V (ammoniacal liquor)=1:20:0.05] through silica gel column chromatography; Get 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) (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine synthetic:
N
2Protection, about 0 ℃ of ice bath cooling temperature control is dissolved in an amount of trifluoroacetic acid with compound 6, stirs down, adds the dry-out benzene methyl ether of 2.3 times of compound 6 molar weights; Stir 30min, add the mercuric acetate of 6 times of compound 6 molar weights again, stir 30min, vacuum concentration gets thickness oily matter; Oil pump is taken out 30min, adds an amount of anhydrous diethyl ether, and ultrasonic concussion 5min has yellow solid to generate, and filters; Get yellow solid, the solid oil pump is drained, and solid is dissolved in an amount of absolute ethyl alcohol, logical dry H
2S reacts 30min, the centrifugal black powder shape zunsober of removing, and inclining supernatant liquid, and normal temperature decompression is down removed solvent, and oil pump is taken out 30min, gets yellow oil, promptly gets the trifluoroacetate of compound 7.With compound
7Trifluoroacetate be dissolved in an amount of water, about 0 ℃ of ice bath temperature control, slow dropping ammonia, adjust pH to 7, extracted with diethyl ether, layering, the organic layer anhydrous sodium sulfate drying removes ether under reduced pressure, promptly gets 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; Because compound
7Be prone to the moisture absorption oxidation, do not characterize so carry out nuclear-magnetism, inflated with nitrogen protection cryopreservation is prepared against
99mThe Tc mark is further studied its biological characteristics.
(8) froze-dried kit reaches
99mThe preparation of Tc-BAT-AV-45
Take by weighing an amount of labelled precursor BAT-AV-45, sodium glucoheptonate, YD 30; With the phosphate buffered saline buffer dissolving, add the hydrochloric acid soln of an amount of tin protochloride again, after shaking up; Adding is filled the nitrogen distilled water and is diluted to pre-determined volume; Be sub-packed in the 10mL cillin bottle by the 1.0mL/ bottle after the sterile filtration, nitrogen-filled seal after the lyophilize, subsequent use.
Get above-mentioned froze-dried kit, add proper amount of fresh
99mTcO
4 -Elutriant places boiling water to boil the regular hour, and cooling promptly gets
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 is used to prepare 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), be used 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, do not have registration number, do not have 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%, conveniently is further used for biological Characteristics Study.
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, and leaches solid; Acetic acid ethyl dissolution, water is used ethyl acetate extraction, merges organic phase; The saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying is after solvent is removed in decompression; Get faint yellow solid compound 1, promptly 4-vinyl phenyl t-butyl carbamate directly is used for next step reaction.
Embodiment 2
Synthesizing of N-methyl-4-vinyl phenyl t-butyl carbamate (compound 2)
N
2Protection is dissolved in the 30mL dry DMF with 6.7g (30mmol) compound 1, and ice bath is cooled to about 0 ℃, slowly drips the 100mL anhydrous DMF solution that contains 1.8g (45mmol) 60% sodium hydride while stirring; Drip and finish, rise to room temperature, slowly be added drop-wise to 8.5g (60mmol) methyl iodide in the reaction mixture; Continue to stir 2 hours, reaction solution is carefully joined in the 200mL frozen water, add ethyl acetate extraction (70mL * 3 time); The ester layer washs through saturated sodium-chloride water solution, anhydrous sodium sulfate drying, and solvent is removed in decompression; Get red oil 2 (6.5g, 89%), directly be used for next step reaction.
Embodiment 3
Synthesizing of 2-(2-(2-(5-iodine pyridine-2-oxygen base) oxyethyl group) oxyethyl group) ethanol (compound 3)
With 5g (17.6mmol) 2-bromo-5-iodine pyridine, 5.3g (70mmol) triglycol is dissolved in the 50mL THF, under the stirring at room; 2.35g (19mmol) potassium tert.-butoxide is added in the reaction solution in batches, back flow reaction 24 hours, THF is removed in decompression, adds ETHYLE ACETATE and water; Separatory, water is used ethyl acetate extraction, merges organic phase, the saturated sodium-chloride water solution washing; Anhydrous sodium sulfate drying, solvent is removed in decompression, gets faint yellow oily thing, solidifies under the room temperature; The ETHYLE ACETATE column chromatography for separation gets 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)-2-(2-(2-(2-hydroxy ethoxy) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine (compound 4) synthetic
N
2Protection, with 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 the 10mL dry DMF, 100 ℃ were reacted 24 hours, and DMF is removed in decompression; Add ETHYLE ACETATE and water, water is used ethyl acetate extraction, merges organic phase; The saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression; The gained crude product gets white solid 4 (0.24g, 77%) through the ETHYLE ACETATE column chromatography for separation.[
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)-2-(2-(2-(2-tolysulfonyl oxygen base oxethyl) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine (compound 5) synthetic
N
2Protection is dissolved in 0.18g (0.39mmol) compound 4 in the 5mL anhydrous methylene chloride, and ice bath is cooled to about 0 ℃; Slowly drip the 5mL anhydrous methylene chloride solution that contains 0.15g (0.79mmol) Tosyl chloride while stirring, drip and finish, slowly be added drop-wise to 0.17mL (1.2mmol) triethylamine in the reaction mixture; Room temperature reaction 6 hours adds water stratification, tells organic layer; Anhydrous sodium sulfate drying, solvent is removed in decompression, and the gained crude product is through the ether column chromatography purification; Get 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)-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) synthetic
N
2Protection, with 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 the 10mL dry DMF, 60 ℃ were reacted 24 hours, and DMF is removed in decompression; Add ETHYLE ACETATE and water, water is used ethyl acetate extraction, merges organic phase; The saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression; The gained crude product separates [eluent is V (methyl alcohol): V (methylene dichloride): V (ammoniacal liquor)=1:20:0.05] through silica gel column chromatography, gets 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)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine (compound 7) synthetic
N
2Protection, about 0 ℃ of ice bath cooling temperature control is dissolved in the 10mL trifluoroacetic acid with 0.18g (0.2mmol) compound 6, stirs down, adds 0.05mL (0.46mmol) dry-out benzene methyl ether; Stir 30min, add (0.39g, 1.22mmol) mercuric acetate, stirring 30min, vacuum concentration again; Get thickness oily matter, oil pump is taken out 30min, adds 10 mL anhydrous diethyl ethers, and ultrasonic concussion 5min has yellow solid to generate; Filter, get yellow solid, the solid oil pump is drained, and solid is dissolved in the 10 mL absolute ethyl alcohols, logical dry H
2S reacts 30min, the centrifugal black powder shape zunsober of removing, and inclining supernatant liquid, and normal temperature decompression is down removed solvent, and oil pump is taken out 30min, gets yellow oil, promptly gets the trifluoroacetate (0.12g, 29%) of compound 7.With compound
7Trifluoroacetate be dissolved in an amount of water, 0 ℃ of ice bath temperature control, slow dropping ammonia, adjust pH to 7, extracted with diethyl ether, layering, the organic layer anhydrous sodium sulfate drying removes ether under reduced pressure, 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)
+, because compound 7 is prone to the moisture absorption oxidation, not characterizing so carry out nuclear-magnetism, inflated with nitrogen protection cryopreservation is prepared against
99mThe Tc mark is further studied its biological characteristics.
Embodiment 8
Froze-dried kit reaches
99mThe preparation of Tc-BAT-AV-45
Take by weighing 5 ~ 10mg labelled precursor BAT-AV-45; 0.5 ~ 1g sodium glucoheptonate; 0.05 ~ 0.1g YD 30 uses 10mL pH value to be the dissolving of the phosphate buffered saline buffer of 6-7, add again contain 3 ~ 10mg tin protochloride hydrochloric acid soln (with 0.01 ~ 0.05N dissolving with hydrochloric acid; Concentration is 1mg/mL) shake up after, add and to fill the nitrogen distilled water and be diluted to pre-determined volume 100mL.Be sub-packed in the 10mL cillin bottle by the 1.0mL/ bottle after the sterile filtration, nitrogen-filled seal after the lyophilize, subsequent use.
Get above-mentioned froze-dried kit, add fresh
99mTcO
4 -Elutriant 0.1 ~ 0.3mL (about 37MBq) places boiling water to boil 30min, and cooling promptly gets
99mTc-BAT-AV-45.Be used for the research work of A beta plaque SPECT video picture.
Claims (2)
1. (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 BAT-AV-45, and its structural formula is:
Its mtc labeled product
99mTc-BAT-AV-45 is used for the research work of A beta plaque SPECT video picture.
2. the preparation method of said (the E)-2-of claim 1 (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-aminobenzene ethene and its 1.1 times of moles are dissolved in suitable quantity of water, and stirring at room reaction 3 hours has solid to generate; Leach solid; Use acetic acid ethyl dissolution, the water ethyl acetate extraction merges organic facies; The saturated sodium-chloride water solution washing; Anhydrous sodium sulfate drying after solvent is removed in decompression, gets faint yellow solid compound 1; Be 4-vinyl phenyl t-butyl carbamate, directly be used for next step reaction;
(2) N-methyl-4-vinyl phenyl t-butyl carbamate is synthetic:
N
2Protection is dissolved in an amount of dry DMF with compound 1, and ice bath is cooled to 0 ℃, slowly drips the anhydrous DMF solution of 60% sodium hydride that contains 1.5 times of compound 1 molar weights while stirring; Drip and finish, rise to room temperature, slowly be added drop-wise to 2 times of methyl iodide in the reaction mixture to compound 1 molar weight; Continue to stir 2 hours, reaction solution is carefully joined in an amount of frozen water, add ethyl acetate extraction; The ester layer washs through saturated sodium-chloride water solution, anhydrous sodium sulfate drying, and solvent is removed in decompression; Get red oily compound 2, promptly N-methyl-4-vinyl phenyl t-butyl carbamate directly is used for next step reaction;
(3) 2-(2-(2-(5-iodine pyridine-2-oxygen base) oxyethyl group) oxyethyl group) alcoholic acid is synthetic:
The triethylene glycol of 2-bromo-5-iodine pyridine and 4 times of its moles is dissolved in an amount of oxolane; Under the stirring at room; Add the potassium tert-butoxide of 1.1 times of 2-bromo-5-iodine pyridine moles in the reactant liquor in batches; Back flow reaction 24 hours; Oxolane is removed in decompression, adds ethyl acetate and water, separatory; The water ethyl acetate extraction; Merge organic facies, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying; Solvent is removed in decompression; Get faint yellow oily thing, solidify the ethyl acetate column chromatography for separation under the room temperature; Get compound 3, i.e. 2-(2-(2-(5-iodine pyridine-2-oxygen base) ethyoxyl) ethyoxyl) ethanol;
(4) (E)-2-(2-(2-(2-hydroxy ethoxy) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine synthetic:
N
2Protection is with the palladium of 3,0.05 times of compound 2 molar weights of compound of compound 2 and equimolar amount; 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 an amount of dry DMF, and 100 ℃ were reacted 24 hours, and DMF is removed in decompression; Add ETHYLE ACETATE and water, water is used ethyl acetate extraction, merges organic phase; The saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression; The gained crude product gets white solid compound 4, i.e. (E)-2-(2-(2-(2-hydroxy ethoxy) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine through the ETHYLE ACETATE column chromatography for separation;
(5) (E)-2-(2-(2-(2-tolysulfonyl oxygen base oxethyl) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine synthetic:
N
2Protection is dissolved in compound 4 in an amount of anhydrous methylene chloride, and ice bath is cooled to 0 ℃; Slowly drip the anhydrous methylene chloride solution of the Tosyl chloride that contains 2 times of compound 4 molar weights while stirring, drip and finish, slowly be added drop-wise to the triethylamine of 3 times of compound 4 molar weights in the reaction mixture; Room temperature reaction 6 hours adds water stratification, tells organic layer; Anhydrous sodium sulfate drying, solvent is removed in decompression, and the gained crude product is through the ether column chromatography purification; Get compound 5, i.e. (E)-2-(2-(2-(2-tolysulfonyl oxygen base oxethyl) oxyethyl group) oxyethyl group)-5-(4-tertbutyloxycarbonyl methylamino vinylbenzene) pyridine;
(6) (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 synthetic:
N
2Protection, with 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 an amount of dry DMF, and 60 ℃ were reacted 24 hours, and DMF is removed in decompression; Add ETHYLE ACETATE and water, water is used ethyl acetate extraction, merges organic phase; The saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, solvent is removed in decompression; The gained crude product separates through silica gel column chromatography, and eluent is a methyl alcohol: methylene dichloride: ammoniacal liquor, V:V:V=1:20:0.05; Get 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) (E)-2-(2-(2-(2-(N-mercaptoethyl)-(N-(N-mercaptoethyl aminoethyl)) ammonia oxyethyl group) oxyethyl group) oxyethyl group)-5-(4-methylamino-vinylbenzene) pyridine synthetic:
N
2Protection, 0 ℃ of ice bath cooling temperature control is dissolved in an amount of trifluoroacetic acid with compound 6, stirs down, adds the dry-out benzene methyl ether of 2.3 times of compound 6 molar weights; Stir 30min, add the mercuric acetate of 6 times of compound 6 molar weights again, stir 30min, vacuum concentration gets thickness oily matter; Oil pump is taken out 30min, adds an amount of anhydrous diethyl ether, and ultrasonic concussion 5min has yellow solid to generate, and filters; Get yellow solid, the solid oil pump is drained, and solid is dissolved in an amount of absolute ethyl alcohol, logical dry H
2S reacts 30min, the centrifugal black powder shape zunsober of removing, and inclining supernatant liquid, and normal temperature decompression is down removed solvent, and oil pump is taken out 30min, gets yellow oil, promptly gets the trifluoroacetate of compound 7; With compound
7Trifluoroacetate be dissolved in an amount of water, 0 ℃ of ice bath temperature control, slow dropping ammonia, adjust pH to 7, extracted with diethyl ether, layering, the organic layer anhydrous sodium sulfate drying removes ether under reduced pressure, 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; Because compound
7Be prone to the moisture absorption oxidation, do not characterize so carry out nuclear-magnetism, inflated with nitrogen protection cryopreservation is prepared against
99mThe Tc mark.
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| CN111499570A (en) * | 2019-01-31 | 2020-08-07 | 中国医学科学院放射医学研究所 | Synthetic method of AV-45 intermediate |
| CN111499544A (en) * | 2019-01-31 | 2020-08-07 | 中国医学科学院放射医学研究所 | Synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by one-pot method |
| CN113582885A (en) * | 2021-08-30 | 2021-11-02 | 南京克米斯璀新能源科技有限公司 | Production method of sodium alkylsulfonate |
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| CN101096358A (en) * | 2006-06-26 | 2008-01-02 | 北京师范大学 | Method for synthesizing nucleus medical imaging agent ligand |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111499570A (en) * | 2019-01-31 | 2020-08-07 | 中国医学科学院放射医学研究所 | Synthetic method of AV-45 intermediate |
| CN111499544A (en) * | 2019-01-31 | 2020-08-07 | 中国医学科学院放射医学研究所 | Synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by one-pot method |
| CN111499544B (en) * | 2019-01-31 | 2022-12-02 | 中国医学科学院放射医学研究所 | Synthetic method for preparing N-Boc-N-methyl-4-aminostyrene by one-pot method |
| CN111499570B (en) * | 2019-01-31 | 2023-05-16 | 中国医学科学院放射医学研究所 | Synthesis method of AV-45 intermediate |
| CN113582885A (en) * | 2021-08-30 | 2021-11-02 | 南京克米斯璀新能源科技有限公司 | Production method of sodium alkylsulfonate |
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