CN1858050A - 8-iodo-imidazo[1,2-alpha] pyridine-3-acetamide compound and preparing method - Google Patents
8-iodo-imidazo[1,2-alpha] pyridine-3-acetamide compound and preparing method Download PDFInfo
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Abstract
The present invention relates to a kind of medicine engineering compound 8-iodo imidazo [1,2-a] pyridine -3-acetamide and its preparation process. The preparation process includes the condensation reaction between p-chlorphenyl -3-bromo-4-keto amide and 5-chloro-3-bromo-2-amino pyridine, tinning with trialkyl tin, and detinning with iodine. The present invention is simple and practical without high temperature, high pressure and expensive reagent, and has convenient product separation and purification, high product yield and high product purity.
Description
Technical field
The present invention relates to a kind of compound and preparation method of medical engineering technical field, specifically, that relate to is a kind of 8-iodo imidazo [1,2-a] pyridine-3-acetamides and preparation method.
Technical background
Peripheral benzodiazepine receptor (PBR) is the another kind of Benzodiazepine binding site that is different from maincenter benzodiazepine receptors (CBR).People such as Maaser K. were reported in different tumours (comprising solid tumor, as the tumour of colon, mammary gland, ovary, esophagus and the brain) process of growth in 2002, and PBR shows overexpression and density increases.The variation of traceable peripheral benzodiazepine receptor density of peripheral benzodiazepine receptor radioisotope labeling part or binding site provides the disease cause of disease and the course of disease on molecular level.By means of PET or SPECT and peripheral benzodiazepine receptor radioisotope labeling part the ANOMALOUS VARIATIONS video picture of peripheral benzodiazepine receptor density or binding site be can be used for the tumour of peripheral benzodiazepine receptor mediation and the diagnosis of nervous system degenerative disease.
Find the article that K.Sekimata etc. deliver " Radiosynthesis and in vivoevaluation of N-[through literature search on " J Label Compd.Radiopharm " 2005:48:S1-S341 to prior art
11C]-methylated imidazopyridine derivatives as positronemission tomography tracer for peripheral benzodiazepine receptors " (tagged compound and radiopharmaceuticals magazine; 2005:48:S1-S341, N-[
11C] mark Methylimidazole and pyridine derivate be used as the synthetic and interior evaluating of radiation of peripheral benzodiazepine receptor positron emission computerized tomography tracer agent), this article propose N-methyl aryl acid amides-2-(4-chloro-phenyl-)-6-chloro-8-chloro-imidazo [1,2a] pyridine-3-ethanamide can through radionuclide [
11C] mark, be prepared into [
11C] N-methyl aryl acid amides-2 (4-chloro-phenyl-)-6-chloro-8-chloro-imidazo [1,2a] pyridine-3-ethanamide, this compound as a kind of peripheral benzodiazepine receptor radionuclide [
11C] tagged ligand be the peripheral benzodiazepine receptor radionuclide [
11C] the positron emission computerized tomography tracer agent, video picture is used for the diagnosing tumor that peripheral benzodiazepine receptor mediates to the peripheral benzodiazepine receptor variable density by means of PET.This article result of study tentatively shown [
11C] N-methyl aryl acid amides-2-(4-chloro-phenyl-)-6-chloro-8-chloro-imidazo [1,2a] pyridine-3-ethanamide molecule as peripheral benzodiazepine receptor [
11C] the potential video picture effect of positron emission computerized tomography tracer agent.
[
11C] be the short-half-life radionuclide, the transformation period is 20.4 minutes.Therefore by short-half-life [
11C] mark N-methyl aryl acid amides-2-(4-chloro-phenyl-)-6-chloro-8-chloro-imidazo [1,2a] pyridine-this peripheral benzodiazepine receptor radionuclide of 3-ethanamide [
11C] tagged ligand, limited [
11C] mark N-methyl aryl acid amides-2-(4-chloro-phenyl-)-6-chloro-8-chloro-imidazo [1,2a] pyridine-3-ethanamide can only be applied to the PET center that magnetic resonance acceleator is arranged of limited quantity.
Summary of the invention
The objective of the invention is at deficiency of the prior art, a kind of 8-iodo imidazo [1,2-a] pyridine-3-acetamides and preparation method is provided.The long transformation period of 8-iodo imidazo [1,2-a] pyridine-3-acetamides both can be applicable to PET with different ray energies and also can be applicable in the clinical diagnosis research of SPECT.Greatly expand short-half-life [
11C] mark N-methyl aryl acid amides-2-(4-chloro-phenyl-)-6-chloro-8-chloro-imidazo [1,2a] pyridine-this peripheral benzodiazepine receptor radionuclide of 3-ethanamide [
11C] the clinical application space of tagged ligand.
The present invention is achieved by the following technical solutions:
The invention provides a class N-methyl aryl acid amides-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide and be called for short 8-iodo imidazo [1,2-a] pyridine-3-acetamides.8-iodo imidazo of the present invention [1,2-a] pyridine-3-acetamides, its molecular structural formula is as follows:
Wherein
I
*Be respectively
123I,
124I,
125I,
127I,
130I or
131I.
Ar is respectively the substituting group of following 1-6:
In the following formula, R is respectively hydrogen, nitro, halogen, trifluoromethyl, C
1-C
10Alkyl, alkoxyl group, phenyl.
Radioactive nuclide iodine the long half-lift of the present invention promptly [
123/124/125/130/131I], refer to respectively
123I,
124I,
125I,
130I or
131I.Transformation period is respectively
123I:13.0 hour;
124I:4.2 days:
125I:60 days;
130I:12.3 hour;
131I:8.04 days.
The present invention also provides the preparation method of a kind of 8-iodo imidazo [1,2-a] pyridine-3-acetamides, through rubigan-3-bromo-4-keto-amide and the condensation of 5-chloro-3-bromo-2-aminopyridine, trialkyltinization, iodine detinization and get.Concrete steps are as follows:
The first step: with rubigan-3-bromo-4-keto-amide is raw material, reacts in inert solvent with 5-chloro-3-bromo-2-aminopyridine, adds or not doping, makes 8-bromo imidazo [1,2-a] pyridine-3-ethanamide.
Second step: 8-bromo imidazo [1,2-a] pyridine-3-ethanamide and tin alkyl makes 8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide under catalyzing by metal palladium.
The 3rd step: 8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and iodide reaction make 8-iodo imidazo [1,2-a] pyridine-3-ethanamide.
The 4th step: 8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and radionuclide [
123/124/125/130/131I] iodide obtain having in the presence of the oxygenant [
123/124/125/130/131I] 8-iodo imidazo [1,2-a] pyridine-3-ethanamide.
In the first step reaction, described reaction-inert solvent is acetonitrile, toluene, N-Methyl pyrrolidone, tetrahydrofuran (THF), glycol dimethyl ether, dioxane, isopropyl ether, Virahol, propyl carbinol, acetone, pimelinketone, tetramethylene sulfone, methyl-sulphoxide, N, dinethylformamide, N,N-dimethylacetamide, methyl iso-butyl ketone (MIBK) or its miscible agent.Described additive is tosic acid, methylsulfonic acid, sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sal epsom, sodium-acetate, N, N-lutidine, N, N-diethylbenzene, triethylamine or Tetrabutyl amonium bromide.The first step is reflected at 20-180 degree reaction 2-48 hour.
In the reaction of second step, described tin alkyl is chloro tin trimethyl, chloro tributyl tin, two tin trimethyl or two tributyl tin.Described reacting metal palladium catalyst is Pd (PPh
3)
4, Pd (PPh
3)
2Cl
2Or Pd
2(dba)
3/ P (t-Bu)
3
In the three-step reaction, described iodide are sodium iodide, potassiumiodide, elemental iodine, sodium iodate or Potassium Iodate and composition thereof.
In the four-step reaction, described radionuclide [
123/124/125/130/131I] iodide are sodium iodide, potassiumiodide, elemental iodine, sodium iodate or Potassium Iodate and composition thereof.Described reaction oxygenant is Peracetic Acid, chloramine-T, chlorine glycoluril, peroxide uncle butyric acid, metachloroperbenzoic acid, hydrogen peroxide or clorox.
The invention discloses class 8-iodo imidazo [1, a 2-a] pyridine-3-acetamides and an its preparation method.This method need not high temperature, high pressure, and responsive expensive reagent, simple and easy to do.The product separation and purification is convenient, and putting yield is good, product purity (comprising radiochemical purity) height.The compounds of this invention has good selectivity and affinity to PBR, and transformation period that it is long and different-energy ray are than its short-half-life positron
11The C marker is more suitable for clinical diagnosis (video picture) and treatment (comprising radiotherapy) to the receptor-mediated relative disease of PBR (as tumour and nerve degenerative diseases).
Description of drawings
Fig. 1 is preparation method's synthetic route chart of the present invention
Embodiment
As shown in Figure 1, the reflection step is as follows:
1. be raw material with rubigan-3-bromo-4-keto-amide, react in inert solvent with 5-chloro-3-bromo-2-aminopyridine and make product a:8-bromo imidazo [1,2-a] pyridine-3-acetamides.
2.8-bromo imidazo [1,2-a] pyridine-3-ethanamide and tin alkyl makes product b:8-tributyl tinbase imidazo [1,2-a] pyridine-3-ethanamide product under metal palladium catalyst catalysis.
3.8-the iodine detinization of the electrophilic substitution of tributyl tinbase imidazo [1,2-a] pyridine-3-ethanamide and iodide react product c:8-iodo imidazo [1,2-a] pyridine-3-acetamides.
4.8-tributyl tinbase imidazo [1,2-a] pyridine-3-ethanamide and radionuclide [
123/124/125/130/131I] the iodine detinization of electrophilic substitution of iodide react radionuclide iodine label d:[
123/124/125/130/131I] N-methyl aryl acid amides-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide.
Following examples help to understand the present invention, but are not limited to content of the present invention.
Embodiment one
Embodiment 1a.N-methyl, N-phenyl-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide
With 4 gram (10.5 mmole) N-methyl; N-phenyl-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 2.2 gram (10.5 mmole) 5-chloro-3-bromo-2-aminopyridine are dissolved in 200 milliliters of N; dinethylformamide, and 100 milligrams of N, N-lutidine and 50 milligrams of Tetrabutyl amonium bromides.Nitrogen protection refluxed 12 hours down.Decompression is desolvated.Residuum is with 150 milliliters of dilutions of chloroform, water washing, organic phase drying.Desolvate.Residuum gets product 2.3 gram light yellow crystal with methylene dichloride and normal hexane crystallization.MS(ESI)m/e：489。C
22H
16BrCl2N
3O＝489.19。
1H?NMR(DMSO-d
6)δ3.22(3H，s，-NCH
3)；3.88(2H，s，-CH
2CO-)；7.36-7.57(9H，m，arom)；7.79(1H，s，arom)；8.77(1H，s，arom)。
Embodiment 1b.N-methyl, N-phenyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide
With the N-methyl; N-phenyl-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1; 2a] pyridine-3 ethanamide 0.49 gram is dissolved in 15 milliliters of toluene; behind 100 milligrams of two tributyl tins 1.16 grams of adding and four (triphenyl phosphorus) palladiums; nitrogen protection refluxed 6 hours down; the decompression of cooling back is desolvated; residuum is through silica gel column chromatography; with ethyl acetate/normal hexane (6: 4, V/V) wash-out, the N-methyl; N-phenyl-6-chloro-8 tributyl tinbase 2-(4 chloro-phenyl-)-imidazos [1; 2-a] pyridine-3-ethanamide product, be white low melting point solid 0.38 gram, fusing point 48-52 degree.MS(ESI)m/e：699?C
34H
43Cl
2N
3OSn＝699.34.
1H?NMR(DMSO-d
6)：δ0.76-0.92(9H，m，-(CH
2)
3CH
3)；1.24(18H，s，-CH
2)；3.26(3H，s，-NCH
3)；4.05(2H，s，-CH
2CO-)；7.50-7.61(9H，m，arom)；7.76(1H，s，arom)：8.79(1H，s，arom).
Embodiment 1c.N-methyl, N-phenyl-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
Get 1M N-methyl, N-phenyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine 3-ethanamide 500 microlitres, 0.2M hydrochloric acid 500 microlitres, 0.1M chloramine-T 500 microlitres, 5 milligrams of sodium iodides.25 degree reactions 15 minutes add 0.1M sodium pyrosulfate 500 microlitres, add in 1M ammoniacal liquor 100 microlitres and after, with 5 milliliters of dichloromethane extractions three times.Merge organic phase with anhydrous magnesium sulfate drying after, revolve and boil off solvent, solid, fusing point 196 degree (decomposition).MS(ESI)m/e：534。C
22H
16Cl
2IN
3O＝536.19。
1H?NMR(DMSO-d
6)：δ3.26(3H，s，-NCH
3)；4.04(2H，s，-CH
2CO)；7.50-7.61(9H，m，arom)；7.74(1H，s，arom)：8.79(1H，s，arom).
Embodiment 1d.[
123/124/125/130/131I]-the N-methyl, N-phenyl-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
Get 1M N-methyl, N-phenyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide 10 microlitres, 0.2M hydrochloric acid 10 microlitres, 0.1M chloramine-T 10 microlitres, [
123/124/125/130/131I] sodium iodide is an amount of.25 degree reactions 15 minutes add 0.1M sodium pyrosulfate 10 microlitres, add 1M ammoniacal liquor 5 microlitres.Sampling is through the separation and purification of HPLC semipreparative column, and mobile phase methanol: (76: 24, V/V) wash-out got product to water.Putting yield 72%, radiochemicsl purity is greater than 98%.
Embodiment two
Embodiment 2a.N-methyl, N-phenyl-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide
With 4 gram (10.5 mmole) N-methyl, N-phenyl-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 2.2 gram (10.5 mmole) 5-chloro-3-bromo-2-aminopyridine are dissolved in 150 milliliters of propyl carbinols, and nitrogen protection refluxed 16 hours down.Aftertreatment makes title compound with embodiment 1a..
Embodiment 2b.N-methyl, N-phenyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide
With the N-methyl, N-phenyl-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide 0.49 gram is dissolved in 15 milliliters of toluene, adds two tin trimethyl 1.16 gram and Pd
2(dba)
3/ P (t-Bu)
3After 150 milligrams, nitrogen protection refluxed 12 hours down.Aftertreatment makes title compound with embodiment 1b..
Embodiment 2c.N-methyl, N-phenyl-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
Get 1M N-methyl, N-phenyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide 500 microlitres, acetic acid 500 microlitres, 5% Peracetic Acid, 500 microlitres, 5 milligrams of sodium iodides.25 degree reactions 30 minutes.Aftertreatment makes title compound with embodiment 1c..
Embodiment 2d.[
123/124/125/130/131I]-the N-methyl, N-phenyl-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
Get 1M N-methyl, N-phenyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide 10 microlitres, acetic acid 10 microlitres, 5% Peracetic Acid, 10 microlitres, [
123/124/125/130/131I] sodium iodide is an amount of.25 degree reactions 30 minutes.Aftertreatment makes title compound with embodiment 1d..
Embodiment three
Embodiment 3a.N-methyl, N-(4-methylcyclohexyl)-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2a similar approach, by the N-methyl, N-(4-methylcyclohexyl)-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 5-chloro-3-bromo-2-aminopyridine back flow reaction 24 hours in methyl iso-butyl ketone (MIBK) makes title compound.The grey powder, fusing point 172-175 degree .C
23H
24BrCl
2N
3O=509.27.
Embodiment 3b.N-methyl, N-(4-methylcyclohexyl)-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide
According to embodiment 2b similar approach, by the N-methyl, N-(4-methylcyclohexyl)-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide and two tin trimethyl and four (triphenyl phosphorus) palladium reaction make title compound.The low melting point solid, fusing point 36 degree .C
35H
51Cl
2N
3OSn=719.41.
Embodiment 3c.N-methyl, N-(4-methylcyclohexyl)-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2c similar approach, by the N-methyl, N-(4-methylcyclohexyl)-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and sodium iodide makes title compound through acetic acid and hydrogen peroxide method.Brown ceramic powder, fusing point 187-189 degree .C
23H
24Cl
2IN
3O=556.27.
Embodiment 3d.[
123/124/125/130/131I]-the N-methyl, N-(4-methylcyclohexyl)-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2d similar approach, by the N-methyl, N-(4-methylcyclohexyl)-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and [
123/124/125/130/131I] sodium iodide, make title compound through acetic acid and hydrogen peroxide method.
Embodiment four
Embodiment 4a.N-methyl, N-naphthyl-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2a similar approach, by the N-methyl, N-naphthyl-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 5-chloro-3-bromo-2-aminopyridine 20 degree in acetonitrile reacted 48 hours, made title compound.Powder, fusing point 223-226 degree .C
26H
18BrCl
2N
3O=539.25.
Embodiment 4b.N-methyl, N-naphthyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide
According to embodiment 2b similar approach, by the N-methyl, N-naphthyl-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide and two tributyl tin and four (triphenyl phosphorus) palladium reaction make title compound.Faint yellow oily thing .C
38H
45Cl
2N
3OSn=749.4.
Embodiment 4c.N-methyl, N-naphthyl-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2c similar approach, by the N-methyl, N-naphthyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-) imidazo [1,2-a] pyridine-3-ethanamide and sodium iodide and iodine mixture makes title compound through chloramine-t method.Pressed powder, fusing point 232 degree (decomposition) .C
26H
18Cl
2IN
3O=586.25.
Embodiment 4d.[
123/124/125/130/131I]-the N-methyl, N-naphthyl-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2d similar approach, by the N-methyl, N-naphthyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and [
123/124/125/130/131I] sodium iodide and iodine mixture, make title compound through chloramine-t method.
Embodiment five
Embodiment 5a.N-methyl, N-menaphthyl-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2a similar approach, by the N-methyl, N-menaphthyl-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 5-chloro-3-bromo-2-aminopyridine back flow reaction 20 hours in N-Methyl pyrrolidone makes title compound.Solid, fusing point 233-235 degree .C
27H
20BrCl
2N
3O=553.25.
Embodiment 5b.N-methyl, N-menaphthyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide
According to embodiment 2b similar approach, by the N-methyl, N-menaphthyl-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide and two tributyl tin and four (triphenyl phosphorus) palladium reaction make title compound.Oily matter .C
39H
47Cl
2N
3OSn=753.4.
Embodiment 5c.N-methyl, N-menaphthyl-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2c similar approach, by the N-methyl, N-menaphthyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and sodium iodide makes title compound through chloramine-t method.Solid, fusing point 240 degree (decomposition) .C
27H
20Cl
2IN
3O=600.25.
Embodiment 5d.[
123/124/125/130/131I]-the N-methyl, N-menaphthyl-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2d similar approach, by the N-methyl, N-menaphthyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and [
123/124/125/130/131I] sodium iodide is through chloramine-t method, makes title compound.
Embodiment six
Embodiment 6a.N-methyl, N-phenmethyl-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 1a similar approach, by the N-methyl, N-phenmethyl-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 5-chloro-3-bromo-2-aminopyridine and sodium bicarbonate refluxed 2 hours in propyl carbinol, made title compound.Crystalline powder, fusing point 203-205 degree, C
23H
18BrCl
2N
3O=503.22.
Embodiment 6b.N-methyl, N-phenmethyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide
According to embodiment 2b similar approach, by the N-methyl, N-phenmethyl-2-(4-chloro-phenyl-)-6-chloro-8-bromo-imidazo [1,2a] pyridine-3-ethanamide and two tributyl tin and four (triphenyl phosphorus) palladium reaction make title compound.Pulverulent solids, fusing point 42-43 degree, C
35H
45Cl
2N
3OSn=713.27.
Embodiment 6c.N-methyl, N-phenmethyl-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 1c similar approach, by the N-methyl, N-phenmethyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and sodium iodide and Potassium Iodate mixture gets title compound through peroxide uncle butyric acid legal system.Pale yellow powder, fusing point 188 degree (decomposition), C
23H
18Cl
2IN
3O=550.22.
Embodiment 6d.[
123/124/125/130/131I]-the N-methyl, N-phenmethyl-2-(4-chloro-phenyl-)-6-chloro-8-iodo-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 1d similar approach, by the N-methyl, N-phenmethyl-6-chloro-8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and [
123/124/125/130/131I] sodium iodide and Potassium Iodate mixture, get title compound through peroxide uncle butyric acid legal system.
Claims (10)
1. a 8-iodo imidazo [1,2-a] pyridine-3-acetamides is characterized in that molecular structural formula is as follows:
Wherein
I
*Be respectively
123I,
124I,
125I,
127I,
130I or
131I,
Ar is respectively the substituting group of 1-6:
In the following formula, R is respectively hydrogen, nitro, halogen, trifluoromethyl, C
1-C
10Alkyl, alkoxyl group, phenyl.
2. the preparation method of a 8-iodo imidazo as claimed in claim 1 [1,2-a] pyridine-3-acetamides is characterized in that, comprises the steps:
The first step: with rubigan-3-bromo-4-keto-amide is raw material, reacts in inert solvent with 5-chloro-3-bromo-2-aminopyridine, makes 8-bromo imidazo [1,2-a] pyridine-3-ethanamide;
Second step: 8-bromo imidazo [1,2-a] pyridine-3-ethanamide and tin alkyl makes 8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide under catalyzing by metal palladium;
The 3rd step: 8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and iodide reaction make 8-iodo imidazo [1,2-a] pyridine-3-ethanamide;
The 4th step: 8-tributyl tinbase-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide and radionuclide [
123/124/125/130/131I] iodide obtain having in the presence of the oxygenant [
123/124/125/130/131I] 8-iodo imidazo [1,2-a] pyridine-3-ethanamide.
3. 8-iodo imidazo [1 as claimed in claim 2,2-a] preparation method of pyridine-3-acetamides, it is characterized in that, in the first step reaction, described reaction-inert solvent is acetonitrile, toluene, N-Methyl pyrrolidone, tetrahydrofuran (THF), glycol dimethyl ether, dioxane, Virahol, propyl carbinol, pimelinketone, tetramethylene sulfone, methyl-sulphoxide, N, dinethylformamide, N,N-dimethylacetamide, methyl iso-butyl ketone (MIBK) or its miscible agent.
4. 8-iodo imidazo [1 as claimed in claim 2,2-a] preparation method of pyridine-3-acetamides, it is characterized in that, in the first step reaction, add additive, described additive is tosic acid, sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sal epsom, sodium-acetate, N, N-lutidine, N, N-diethylbenzene, triethylamine or Tetrabutyl amonium bromide.
5. as the preparation method of claim 2 or 3 or 4 described 8-iodo imidazo [1,2-a] pyridine-3-acetamides, it is characterized in that the first step reaction was 20-180 degree reaction 2-48 hour.
6. the preparation method of 8-iodo imidazo as claimed in claim 2 [1,2-a] pyridine-3-acetamides is characterized in that, in the reaction of second step, described tin alkyl is chloro tin trimethyl, chloro tributyl tin, two tin trimethyl or two tributyl tin.
7. the preparation method of 8-iodo imidazo as claimed in claim 2 [1,2-a] pyridine-3-acetamides is characterized in that, in the reaction of second step, described reacting metal palladium catalyst is Pd (PPh
3)
4, Pd (PPh
3)
2Cl
2Or Pd
2(dba)
3/ P (t-Bu)
3
8. the preparation method of 8-iodo imidazo as claimed in claim 2 [1,2-a] pyridine-3-acetamides is characterized in that in the three-step reaction, described iodide are sodium iodide, potassiumiodide, elemental iodine, sodium iodate or Potassium Iodate and composition thereof.
9. the preparation method of 8-iodo imidazo as claimed in claim 2 [1,2-a] pyridine-3-acetamides is characterized in that, in the four-step reaction, described radionuclide [
123/124/125/130/131I] iodide are sodium iodide, potassiumiodide, elemental iodine, sodium iodate or Potassium Iodate and composition thereof.
10. 8-iodo imidazo [1 as claimed in claim 2,2-a] preparation method of pyridine-3-acetamides, it is characterized in that, in the four-step reaction, described reaction oxygenant is Peracetic Acid, chloramine-T, chlorine glycoluril, peroxide uncle butyric acid, metachloroperbenzoic acid, hydrogen peroxide or clorox.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011160548A1 (en) * | 2010-06-25 | 2011-12-29 | 中国人民解放军军事医学科学院毒物药物研究所 | 2-aryl imidazo[1,2-a]pyridine-3-acetamide derivatives, preparation methods and use thereof |
| CN107383005A (en) * | 2017-09-11 | 2017-11-24 | 华东理工大学 | The preparation method of the acetic acid of 6 methyl 2 (4 aminomethyl phenyl) imidazo [1,2 a] pyridine 3 |
| CN108299466A (en) * | 2017-12-28 | 2018-07-20 | 辅仁药业集团熙德隆肿瘤药品有限公司 | A kind of improved Du Lutewei synthetic methods |
| CN113908162A (en) * | 2020-07-09 | 2022-01-11 | 中国人民解放军军事科学院军事医学研究院 | Application of acetamide derivative in preparation of medicine for preventing and treating Alzheimer's disease |
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2006
- 2006-06-01 CN CNB2006100271634A patent/CN100418966C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011160548A1 (en) * | 2010-06-25 | 2011-12-29 | 中国人民解放军军事医学科学院毒物药物研究所 | 2-aryl imidazo[1,2-a]pyridine-3-acetamide derivatives, preparation methods and use thereof |
| US8980887B2 (en) | 2010-06-25 | 2015-03-17 | Institute Of Pharmacology | 2-aryl imidazo[1,2-a]pyridine-3-acetamide derivatives, preparation methods and uses thereof |
| CN107383005A (en) * | 2017-09-11 | 2017-11-24 | 华东理工大学 | The preparation method of the acetic acid of 6 methyl 2 (4 aminomethyl phenyl) imidazo [1,2 a] pyridine 3 |
| CN108299466A (en) * | 2017-12-28 | 2018-07-20 | 辅仁药业集团熙德隆肿瘤药品有限公司 | A kind of improved Du Lutewei synthetic methods |
| CN108299466B (en) * | 2017-12-28 | 2023-07-25 | 辅仁药业集团熙德隆肿瘤药品有限公司 | Improved dolutegravir synthesis method |
| CN113908162A (en) * | 2020-07-09 | 2022-01-11 | 中国人民解放军军事科学院军事医学研究院 | Application of acetamide derivative in preparation of medicine for preventing and treating Alzheimer's disease |
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