The summary of the invention the technical problem to be solved in the present invention is to avoid above-mentioned the deficiencies in the prior art part and the preparation method that proposes a kind of solid phase organo-tin compound; do not need in the preparation process protective group and deprotection; reduce production stage, increase the charge capacity of solid-phase compound.Utilize prepared solid phase organo-tin compound of the present invention and the formed radioactive compound of radiohalogen reagent react to can be used for medical diagnosis on disease or the treatment of mammal (comprising the mankind); As mammary cancer, neuroma, brain tumor, Sigma acceptor, MAO acceptor and renal imaging.
The present invention solve the technical problem can be by realizing by the following technical solutions:
Propose a kind of preparation method of solid phase organo-tin compound, utilize the reaction of halogenide and zinc to obtain organic zinc reagent earlier, utilize the resin 1 of organic zinc reagent and load trialkyl tin chloride group again, reaction prepares solid phase organo-tin compound 2, and reaction formula is as follows:
Above-mentioned reaction is to operate under the protection of dry solvent and nitrogen or argon gas;
Resin 1 is load-SnR
2The resin of Cl group or silica gel; R group representative-(CH
2)
nCH
3, n=0-6;
[cat.] representative can make R
1The reagent that ZnX forms easily or stablizes and adds comprises Me
3SiCl, BrCH
2CH
2Br, CoBr
2, and/or LiCl;
The employed solvent of solvent representative reaction comprises THF, 1, and 4-dioxane, ethylene glycol dimethyl ether, ether, N, N-diformamide (DMF) and/or N,N-dimethylacetamide;
T
1℃ representing temperature of reaction is 0 ℃-80 ℃;
T
2℃ represent temperature of reaction to be-78 ℃-100 ℃;
R
1Represent aromatic base, heterocycle, thiazolinyl or alkyl;
X represents I, Br, Cl, OTf (trifluoromethanesulfonic acid root).
Compare with prior art; technique effect of the present invention is: because the organic zinc preparation reaction temperature that the inventive method is used and, some common functional group reactionses of discord under suitable temperature are as halogen; cyano group; ester group, aldehyde radical, ketone group; nitro etc.; so many halogenated aromatic compounds that have functional group are not needed functional group is carried out chemoproection, so not only reduced preparation cost, and reduced the preparation difficulty and improved production security.In addition, the price of zinc is low, utilizes organic zinc to prepare the solid phase organo-tin compound, can reduce production costs greatly.
Utilize the prepared SOLID ORGANIC tin compound that contains functional group of aforesaid method, perhaps the functional group of prepared SOLID ORGANIC tin compound like this is carried out prepared SOLID ORGANIC tin compound and radiohalogen reagent [X after the chemical conversion
*] reaction generation radioactive compound 16 in suitable oxygenant and solvent.Insoluble solid phase byproduct 15 is removed through simple filtration; Contain 16 solution and obtain purifying through simple extraction or by a little anti-phase SPE post or silicagel column.Entire reaction and purifying time can finish in 15 minutes.The radioactivity of the radioactive compound 16 that makes thus can be near used radiohalogen reagent [X
*] radioactivity.Reaction formula is as follows:
Ar represents aromatic nucleus, heterocycle or thiazolinyl;
G represents the substituted radical on the Ar;
[X
*] represent the radiohalogen compound, as Na
123I, Na
125I, Na
131I, Na
123I, Na
76Br,
18F
2,
18F-CH
3COOF,
18F-OF
2
Oxidant representative can the iodine oxide negative ion and the oxygenant of bromine negative ion, comprises chloramine-T, acetate/hydrogen peroxide mixed solution tertbutyl peroxide, Iodogen, iodine pearl (Iodobead).
Embodiment is described in further detail below in conjunction with the most preferred embodiment shown in the accompanying drawing.
The present invention has utilized the resin of organic zinc reagent and load trialkyl tin chloride group, and as Neumann resin 1a, reaction prepares a series of solid phase organo-tin compound (2) (reaction formula one).Protection and deprotection operation have successfully been avoided among the Hunter preparation method to functional group.Thereby reduced production stage, increased the charge capacity of solid-phase compound.
Reaction formula one is as follows:
R represents saturated alkyl, comprises methyl, ethyl, normal-butyl;
[cat.] representative can make R
1The reagent that ZnCl forms easily or stablizes and adds comprises Me
3SiCl, BrCH
2CH
2Br, CoBr
2, LiCl;
The employed solvent of solvent representative reaction, comprise tetrahydrofuran THF,, 1, the 4-dioxane, ethylene glycol dimethyl ether, ether, N, N-diformamide (DMF) and or N,N-dimethylacetamide;
The temperature of T ℃ of representative reaction;
R
1Represent aromatic base, heterocycle, thiazolinyl, alkyl;
X represents I, Br, Cl, OTf.
The preparation of organic zinc reagent utilize bromide or iodide and zinc powder or the reaction of Rieke zinc powder usually and obtain [
a.Knochel, P.*; Leuser, H.; Gong, L.-Z.; Perrone, S.; Kneisel, F.F. " Polyfunctional ZincOrganometalics for Organic Synthesis " in Handbook of Functionalized Organometallics, Knochel, P. (Ed.), Wiley-VCH 2005, chapter 7.;
b.Oranozinc Reagents (Eds.:Knochel, P.; Jones, P.), Oxford University Press, New York, 1999;
c.Krasovskiy, A.; Malakhov, V; Gavryushin, A.; Knochel, P.Angew.Chem.Int.Ed.2006, the 45th volume, 6040-6044 page or leaf].To some inactive halogenide (as muriate) and triflate (Triflates), the preparation of its zincon need add catalyzer and activate zinc, as adding CoBr
2Deng [Kazmierski, I.; Gosmini, C.; Paris, J.-M.; P é richon, J.Synlett, 2006, the 6 volumes, 881.].Some are more sensitive to have the preparation of the zincon of the aromatic compound of reactive hydrogen and heterocycle compound, can insert by direct metal and make (Mosrin, M.; Knochel, P.Org.Lett.2009, the 11st volume, 1837-1840 page or leaf) (reaction formula two).The used reagent of these class methods is R
2NZnClLiCl.Wherein commonly used is 2,2,6,6-tetramethylpiperidide zinc chloride lithium chloride (TMP-ZnCl.LiCl).The organic zinc solution that the above method obtained after removing insoluble solid, can be directly and resin 1a reaction form resin 3.
Reaction formula two is as follows:
In reaction formula three, organic zinc reagent 4-ethoxy carbonyl phenyl zinc iodide and Neumann resin (1a) reaction obtain resin 4.Through alkaline hydrolysis, obtain resin 5 after the acidifying.Resin 5 can be further and amine HNR
1R
2Under the effect of suitable coupling reagent, form corresponding amide resin 11; Perhaps under the effect of suitable coupling reagent, form corresponding carboxylic acid ester resin 12 with oxy-compound HOR.
Reaction formula three is as follows:
Solvent represents reaction solvent, comprises THF, and 1,4-dioxane, ethylene glycol dimethyl ether, ether, DMF and N,N-dimethylacetamide;
MOH represents the oxyhydroxide of main group element metal, comprises LiOH, NaOH, KOH;
H
+Represent protonic acid.
The compound of the active ester of HOR representative can formation with phenylformic acid comprises N-maloyl imines (NHS), Pentafluorophenol, polytetrafluoroethylene phenol;
Coupling reagent representative can impel carboxylic acid and amine HNR
1R
2Form the coupling reagent of acid amides, comprise dicyclohexyl carbodiimide/1-hydroxyl-benzo-triazole, DCC-HOBt; Or represent the coupling reagent that can impel carboxylic acid and HOR to form ester group, comprise 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC).
In reaction formula four, 4-cyano-phenyl zinc iodide and Neumann resin (1a) reaction obtain resin 6.Cyano group forms resin 7 through being reduced into aldehyde radical.In liquid phase reaction, become aldehyde radical that many methods are arranged cyano reduction.The present invention has adopted by reported method such as Cha and has utilized three (dihexyl amido) lithium aluminium hydride, and transformation efficiency is almost 100%[Cha, J.S.; Lee, S.E.; Lee, H.S.Organic Preparations and Procedures International 1992, the 24 (3) volumes, 331].The resin 7 that makes can be proceeded the conversion of functional group and make other solid phase organo-tin compound.For example and R
1NH
2, R
2CO
2H, and R
3The mixture of NC carries out the Ugi reaction and generates the resin 13 that contains two amido linkages; With amine HNR
1R
2Reaction generates resin 17 after reducing; Reaction formula four is as follows:
Solvent represents reaction solvent, comprises THF, and 1,4-dioxane, ethylene glycol dimethyl ether, ether, DMF and N,N-dimethylacetamide;
R represents N, N-dialkyl amino, alkyl, alkoxyl group;
HNR
1R
2Represent aliphatic amide or aromatic amine;
[H] representative can be gone back the reagent of the imines of institute's load on the unmodified resin, comprises sodium triacetoxy borohydride, sodium cyanoborohydride;
R
1NH
2Represent aminated compounds;
R
2CO
2H represents carboxylic acid;
R
3NC represents isocyanic ester;
In reaction formula five, 4-iodobenzene methane amide 8 and ZnLiCl reaction form corresponding organic zinc 9.9 and Neumann resin (1a) reaction obtains resin 10.10 through LiAlH
4Be reduced into aldehyde and form resin 7.
Reaction formula five is as follows:
Following table has been enumerated some SOLID ORGANIC tin compounds that prepared by the above method:
ArI represents iodo aromatic compound and iodo heterogeneous ring compound;
T[℃] centigradetemperature of representative reaction;
The time that t (min) representative reaction is carried out (with a minute note);
The product of products representative reaction.
Embodiment one: the preparation of 4-ethylamino benzonitrile acid esters resin (4)
In the round-bottomed flask of a 25mL, put into 4.0 gram resin 1a (6.8mmol Sn-Cl).Opening clogs with a rubber plug.By the vacuum pump that connects syringe needle the air in the flask is taken out, fed dried nitrogen then.So repeat twice.Add 20 milliliters of exsiccant tetrahydrofuran (THF)s by syringe then.Under protection of nitrogen gas, reaction flask is put into ice-water bath.Under magnetic agitation slowly, and injection ethyl 4-ethoxycarbonylzinc iodide tetrahydrofuran solution in reaction flask (0.5M, 16.0mL, 8.0mmol).In ice-water bath, stir after 5 hours, in reaction flask, add 4mL 95% methanol aqueous solution.Stir under the room temperature after 30 minutes, filter with the sand core funnel and collect resin.The resin that obtains is further used distilled water again, and methyl alcohol, acetone and methylene dichloride wash respectively for several times.Obtain a white solid (4.8 gram) after the dry air.
React with trifluoroacetic acid: in the round-bottomed flask of a 15mL, put into 0.30 gram resin 4,5mL methylene dichloride and 0.5mL trifluoroacetic acid, at room temperature slowly stir 30 minutes after, solid resin filtered out and wash twice with the 3mL methylene dichloride, 3mL methyl alcohol is washed twice.Obtain the 63.1mg ethyl benzoate after rotary evaporation falls volatile solvent after all filtrate merging, being equivalent to every gram resin 4 loads has 1.40 ± 0.10mmol ethyl benzoate.
Iodine is separated reaction: put into 0.20 gram resin 4 in the round-bottomed flask of a 15mL, the second cyanogen solution of 5mL methyl alcohol and 2mL 0.2M iodine. after at room temperature slowly stirring 5 hours, in reaction flask, add 0.5mL10%Na
2S
2O
3The aqueous solution is to remove unnecessary iodine. and filter out insoluble solid and use methylene dichloride (2mL) and each wash-out of methyl alcohol (2mL) according to this twice. merging all filtrate afterwards, rotary evaporation falls volatile solvent. and resistates is quenched with ether (15mL) and water (5mL) and is got. and organic layer water (5mL) and saturated brine (5mL) is respectively quenched and is got once.With rotary evaporation behind the anhydrous sodium sulfate drying fall volatile solvent and obtain 69.1mg right-the iodo ethyl benzoate; Be equivalent to every gram resin 4 loads 1.39 ± 0.10mmol ethyl benzoate is arranged.
The preparation of 4 benzoic acid resin (5)
In the round-bottomed flask of a 25mL, put into 1.0 gram resin 4,5mL tetrahydrofuran (THF) and 0.5mL 1N lithium hydroxide aqueous solutions.Slowly stirred 5 hours down at 40 ℃.Filter with the sand core funnel and to collect resin.The resin that obtains is further used distilled water again, methyl alcohol, and acetone, the mixed solvent of 2N aqueous citric acid solution and methyl alcohol (1: 5), distilled water, methyl alcohol, acetone and washed with dichloromethane are for several times.Obtain a white solid (0.92 gram) after the dry air.
React with trifluoroacetic acid: every gram resin 5 loads have 1.48 ± 0.10mmol phenylformic acid.
Infrared spectra (DRIFT, solid-state): 1695cm
-1C=O.
Embodiment two: the preparation of 4-cyano group benzene resin (6)
According to the reaction conditions among the embodiment one, 4-cyano-phenyl zinc iodide and resin 1a are reacted the solid that obtains a white.
Iodine is separated reaction: every gram resin 6 loads have 1.52 ± 0.10mmol 4-cyano group benzene.
Infrared spectra (DRIFT, solid-state): 2240cm
-1C ≡ N.
Embodiment three: the preparation of 4-(N-methoxyl group-N-methyl-benzamide) resin (10)
The tetrahydrofuran solution (0.5M) of 4-(N-methoxy-N-methylcarbamoyl) phenylzinc Iodide (9) is preparation method (Krasovskiy, the A. according to Knochel; Malakhov, V; Gavryushin, A.; Knochel, P.Angew.Chem.Int.Ed.2006, the 45th volume 6040-6044 page or leaf) be prepared from from 4-iodo-(N-methoxyl group-N-methyl) benzamide (8).
According to the reaction conditions among the embodiment one, 9 and resin 1a of above-mentioned preparation reaction is obtained 4-(N-methoxyl group-N-methyl-benzamide) resin (10).
Iodine is separated reaction: every gram resin 10 loads have 1.39 ± 0.10mmol N-methoxyl group-N-methyl-benzamide.
Embodiment four: preparation (the benzaldehyde)-co-divinylbenzene of 4-phenyl aldehyde resin 7 (Poly-(4-{dibutyl[2-(3-and 4-vinylphenyl) ethyl] stannyl).
Method A: according to preparation method (Krasovskiy, the A. of Knochel; Malakhov, V; Gavryushin, A.; Knochel, P.Angew.Chem.Int.Ed.2006, the 45th volume 6040-6044 page or leaf), make the tetrahydrofuran solution (0.5M) of corresponding zn cpds by 4-iodo phenyl aldehyde.
According to the reaction conditions among the embodiment one, it is resin 7 that the tetrahydrofuran solution (0.5M) of the zincon of the 4-benzaldehyde iodine of above-mentioned preparation and resin 1a reaction are obtained a white solid.
Iodine is separated reaction: every gram resin 7 loads have 1.32 ± 0.10mmol phenyl aldehyde.
Infrared spectra (DRIFT, solid-state): 1707cm
-1C=O.
Method B puts into 1.0g (1.2mmol) resin 9 and 10mL anhydrous tetrahydro furan in the round-bottomed flask of a 50mL.Under-78 ℃, in bottle, slowly drip 2.5mL 1M LiAlH by syringe
4Tetrahydrofuran solution.Continue to stir after 1 hour, in bottle, drip the 1mL cold distilled water with termination reaction.Continue to stir after 15 minutes, filter and collect resin.Use distilled water, methyl alcohol, methylene dichloride, acetone, methyl alcohol are respectively with resin elution for several times.Getting a white solid after the drying is resin 7.
Iodine is separated reaction: every gram resin 7 loads have 1.49 ± 0.10mmol phenyl aldehyde.
Infrared spectra (DRIFT, solid-state): 1707cm
-1C=O.
Method C is according to preparation method [Cha, the J.S. of Cha; Lee, S.E.; Lee, H.S.Organic Preparationsand Procedures International, 1992, the 24 volumes, 331-334], by 1.5mL 1M LiAlH
4Tetrahydrofuran solution and the reaction of dihexyl amine make 1.5mmol three dihexyl amido lithium aluminium hydride (Lithiumtris (dihexylamino) aluminum hydride). under stirring at room, above-mentioned solution added in the 25mL round-bottomed flask that fills 1 gram (1.2mmol) resin 6 and 10mL anhydrous tetrahydro furan at leisure.After continuing at room temperature to stir 8 hours, under zero degree, add the 1mL cold distilled water at leisure.Continue to stir after 15 minutes, filter and collect resin.Use distilled water, methyl alcohol, methylene dichloride, acetone, methyl alcohol are respectively with resin elution for several times.Getting a white solid after the drying is resin 7.
Iodine is separated reaction: every gram resin 7 has carried 1.51 ± 0.10mmol phenyl aldehyde.
Infrared spectra (DRIFT, solid-state): 1707cm
-1C=O.