CN1948311A - 2-iodine substituted phenyl-6-trifluoro methyl imidazole [1,2-a]-pyridine-3-acetamide compounds and its preparation method - Google Patents
2-iodine substituted phenyl-6-trifluoro methyl imidazole [1,2-a]-pyridine-3-acetamide compounds and its preparation method Download PDFInfo
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Abstract
The present invention relates to a 2-iodophenyl-6-trifluoromethylimidazo[1,2-a] pyridine-3-acetamide compound, belonging to the field of medicine engineering technology. Said invention also provides its chemical structure formula. Said compound is obtained by using p-bromophenyl-3-bromo-4-ketoamide and 5-trifluoromethyl-2-aminopyridine and making them produce condensation reaction, separation and purification. Its product purity is high. Besides, said invention also discloses the application of said compound which can be used as GABAA-BZR receptor subtype (BZ1,BZ2 and BZ3) developing agent.
Description
Technical field
The present invention relates to compound of a kind of technical field of pharmaceuticals and preparation method thereof, specifically is a kind of 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] pyridine-3-acetamides and preparation method.
Background technology
In central nervous system, GABA
AIt (is BZ that-BZR acceptor has three kinds of hypotypes
1, BZ
2And BZ
3).At two the export structure pallidum veutros and the black substance reticulated structure part of basal ganglion, BZ
1The density of acceptor is the highest; Caudatum and lenticular nucleus BZ
2The acceptor advantage.E Ding district cortex and thalamus BZ
1And BZ
2All exist.At ependyma, choroid, olfactory bulb, spongiocyte BZ
3Acceptor has lower concentration to distribute.Normally used benzodiazepine (as stable) is to GABA
A-BZR receptor subtype (is BZ
1, BZ
2And BZ
3) selectivity is relatively poor.Two radioligands that always are used for brain biochemistry, physiology and drug efficacy study during the last ten years (
11C) flumazenil and (
123I) iomazenil but can not distinguish GABA
A-BZ
1And BZ
2Receptor subtype.Many imidazos [1,2-] pyridine-3-ethanamide medicine (comprising zolpidem and alpidem) pharmacological Mechanism is that specificity acts on BZ
1Acceptor, and external (
14C) Zolpidem and (
3H) Zolpidem all shows BZ
1Acceptor highly selective and affinity.Surprisingly (
11C) Zolpidem is produced and when rodents and primates interior evaluating, demonstrates low blood-brain barrier permeability and can not be used for BZ
1Hypotype detects.Therefore suddenly wait to seek to GABA
A-BZR receptor subtype (is BZ
1, BZ
2And BZ
3) highly selective and affinity ligands.
Through the literature search of prior art is found, A.Katsifis etc. are at " Life Sciences " 2006,79 (3): the article of delivering on the 287-294 " Pharmacological evaluation of an[
123I] labeled imidazopyridine-3-acetamide for the study of benzodiazepinereceptors " (life science, 2006,79 (3): 287-294, [
123I] research estimated as the benzodiazepine receptors pharmacology of the imidazopyridine-3-ethanamide of mark), this article proposes to use the iodine substituent methyl, make (
123I) Zolpidem (molecular structural formula is as follows), and be used for BZ in the body
1Hypotype detects.The result still shows low brain capture.Spike GABA in vivo
A-BZR receptor subtype (is BZ
1, BZ
2And BZ
3) distribution in brain.
Also find in the retrieval, F.Mattner etc. are at " Eur J Nucl Med Mol I " 2005,32 (5): the article of delivering on the 557-563 " Evaluation of a radiolabelled peripheralbenzodiazepine receptor ligand in the central nervous systeminflammation of experimental autoimmune encephalomyelitis:a possibleprobe for imaging multiple sclerosis " (European nuclear medicine molecular image magazine, 2005,32 (5): 557-563, radio-labeling peripheral benzodiazepine receptor part is the experimental evaluation of encephalomyelitis autoimmunity due to inflammation of the central nervous system: a kind of potential probe of polytypism sclerosis video picture).The radioligand that this article adopts for replaced with chlorine (
123I) another methyl of Zolpidem has prepared
123I-CLINDE (molecular structural formula is as follows):
Comparison shows that by external beam radiotherapy autography and immunohistochemical methods
123I-CLINDE can be used as potential SPECT tracer agent and is used for central nervous system inflammation and multirow hardened video picture research in the body, and under inflammatory conditions,
123I-CLINDE has certain brain penetrating power, and brain is right certainly
123The intake of I-CLINDE still is not enough to spike GABA
A-BZR receptor subtype (is BZ
1, BZ
2And BZ
3) distribution in brain.
Summary of the invention
The objective of the invention is to overcome the deficiency of above-mentioned iodine labeling imidazopyridine part in the prior art, a kind of 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] pyridine-3-acetamides and preparation method is provided,
123Replace chlorine with trifluoromethyl in the I-CLINDE molecule, further improve
123I-CLINDE hydrophobicity and stability etc. improve the ability and the brain capture amount of its saturating hemato encephalic barrier, and the introducing of trifluoromethyl that product is prepared is simple and easy to do.But the novel 2-iodophenyl of the present invention's high yield synthesizing series-6-trifluoromethyl-imidazo [1,2-a] pyridine-3-acetamides, this compound useful as gaba
A-BZR receptor subtype (is GABA
A-BZ
3) developer.In addition, because GABA
A-BZ
3It expresses and the density increase acceptor when nervous system degenerative disease such as Parkinson's disease (PD), alzheimer's disease (AD), Huntington Chorea (HD) and multiple sclerosis neurologic disorder such as (MS), and also show overexpression and density in different tumours (comprising solid tumor) and increase as the tumour of colon, mammary gland, ovary, esophagus and brain.Therefore, high-affinity provided by the invention and selectivity GABA
A-BZ
3Receptors ligand can be used for GABA
A-BZ
3The diagnosis (video picture) of receptor-mediated relative disease (as tumour and nerve degenerative diseases) and treatment (comprising radiotherapy).
The present invention is achieved by the following technical solutions:
The invention provides class 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1, a 2-a] pyridine-3-acetamides.2-iodine substituted phenyl-6-trifluoro methyl imidazo of the present invention [1,2-a] pyridine-3-acetamides, its molecular structural formula is as follows:
I wherein
*Be respectively
123I,
124I,
125I,
127I,
130I,
131I or
132I.
R
1And R
2Be independently or simultaneously:
1)H；
2) C
1-C
6Alkyl, one or dihydroxy C
1-C
6Alkyl, C
1-C
6Alkoxyl group replaces C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl group, halo C
1-C
6Alkyl, C
1-C
6Alkyl-NH-, (C
1-C
6Alkyl)
2-N-, C
3-C
4Cycloalkyl, cycloalkyl substituted C
1-C
6Alkyl, nitrogen heterocyclic replaces C
1-C
6Alkyl;
3) aryl, wherein aryl is represented phenyl, and pyridyl is by one or more halogens that are selected from, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, CF
3, OH, nitro, amino, C
1-C
6Alkyl-NH-, (C
1-C
6Alkyl)
2-N-, the substituting group of carbonyl acyl group or CN replaces arbitrarily;
4) C of aryl replacement
1-C
6Alkyl, aryl is represented phenyl in the base, and pyridyl is by one or more halogens that are selected from, C
1-C
6Alkane, C
1-C
6Alkoxyl group, CF
3, OH, nitro, amino, C
1-C
6Alkane-NH-, (C
1-C
6Alkyl)
2-N-, the substituting group of carbonyl acyl group or CN replaces arbitrarily;
The present invention also provides a kind of 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] preparation method of pyridine-3-acetamides, through bromophenyl-3-bromo-4-keto-amide and 5-trifluoromethyl-2-aminopyridine condensation, trialkyltinization, iodine detinization are got.Concrete steps are as follows:
The first step: to be raw material, in inert solvent, react, add or not doping, make also [1,2-a] pyridine-3-ethanamide of 2-bromo phenyl-6-trifluoromethyl imidazoles with 5-trifluoromethyl-2-aminopyridine to bromophenyl-3-bromo-4-keto-amide.
Second step: 2-bromo phenyl-6-trifluoromethyl imidazoles is [1,2-a] pyridine-3-ethanamide and tin alkyl also, makes also [1,2-a] pyridine-3-ethanamide of 2-tri-n-butyl tin phenyl-6-trifluoromethyl imidazoles under metal palladium catalyst catalysis.
The 3rd step: 2-tri-n-butyl tin phenyl-6-trifluoromethyl imidazoles also [1,2-a] pyridine-3-ethanamide and iodide reacts and makes 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] pyridine-3-ethanamide.
The 4th step: 2-tri-n-butyl tin phenyl-6-trifluoromethyl imidazoles also [1,2-a] pyridine-3-ethanamide and radionuclide [
123/124/125/130/131/132I] iodide obtain having in the presence of the oxygenant [
123/124/125/130/131/132I] 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] pyridine-3-ethanamide.
In the first step reaction, described inert solvent is N-Methyl pyrrolidone, glycol dimethyl ether, propyl carbinol, pimelinketone, tetramethylene sulfone, methyl-sulphoxide, N, dinethylformamide, N,N-dimethylacetamide, methyl iso-butyl ketone (MIBK) or its miscible agent.Described additive is tosic acid, sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sal epsom, sodium-acetate, triethylamine or Tetrabutyl amonium bromide.The first step temperature of reaction is the 90-180 degree, reaction times 2-24 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 metal palladium catalyst is four (triphenyl phosphorus) palladium, dichloro two (triphenylphosphine) palladium/triphenyl phosphorus or three pairs of benzyl acetone two palladiums/tri-tert phosphorus.
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 [
123/124/125/130/131/132I] iodide are sodium iodide, potassiumiodide, elemental iodine, sodium iodate or Potassium Iodate and composition thereof.Described oxygenant is Peracetic Acid, chloramine-T, chlorine glycoluril, peroxide uncle butyric acid, metachloroperbenzoic acid, hydrogen peroxide or clorox.
Pyridine-preparation technology is simple for the 3-acetamides for 2-iodophenyl of the present invention-6-trifluoromethyl-imidazo [1,2-a], and the product separation and purification is convenient, and putting yield is good, the product purity height.Be easy to see through hemato encephalic barrier.2-iodophenyl-6-trifluoromethyl-imidazo [1, the 2-a] pyridine-3-acetamides of the present invention's preparation can be used as GABA
A-BZ
3The application of receptor developer, and can be used for GABA
A-BZ
3The diagnosis (video picture) of receptor-mediated relative disease (as tumour and nerve degenerative diseases) and treatment (comprising radiotherapy).
Description of drawings
Fig. 1 is preparation method's synthetic route chart of the present invention
Embodiment
Below in conjunction with accompanying drawing embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.As shown in Figure 1, the present embodiment method steps is as follows:
1. to be raw material, to react in inert solvent with 5-trifluoromethyl-2-aminopyridine and to make also [1,2-a] pyridine-3-ethanamide of product a:2-bromo phenyl-6-trifluoromethyl imidazoles bromophenyl-3-bromo-4-keto-amide.
2.2-bromo phenyl-6-trifluoromethyl imidazoles is [1,2-a] pyridine-3-ethanamide and tin alkyl also, makes also [1,2-a] pyridine-3-ethanamide of product b:2-tri-n-butyl tin phenyl-6-trifluoromethyl imidazoles under metal palladium catalyst catalysis.
3.2-tri-n-butyl tin phenyl-6-trifluoromethyl imidazoles also the iodine detinization of the electrophilic substitution of [1,2-a] pyridine-3-ethanamide and iodide react product c:2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] pyridine-3-ethanamide.
4.2-tri-n-butyl tin phenyl-6-trifluoromethyl imidazoles also [1,2-a] pyridine-3-ethanamide and radionuclide [
123/124/125/130/131/132I] the iodine detinization of electrophilic substitution of iodide react radionuclide iodine label d:[
123/124/125/130/131/132I] 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] pyridine-3-ethanamide.
Embodiment one
Embodiment 1a.N, N-diethyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide.
With 4 gram N; N-diethyl-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 1.6 gram 5-trifluoromethyl-2-aminopyridine are dissolved in 200 milliliters of methyl iso-butyl ketone (MIBK), in 80-90 degree reaction 2 hours, are cooled to 25 degree under the nitrogen protection; add 0.8 gram sodium bicarbonate, refluxed 4 hours.Decompression is desolvated.Residuum is with 200 milliliters of chloroforms, water washing, organic phase drying.Desolvate.Residuum gets product 2.8 gram white needle-like crystals with ethanol and water crystallization.Fusing point: 199-200 degree.
1H?NMR(DMSO-d
6)δ1.04(3H，t，J＝6.9Hz，-CH
2CH
3)；1.17(3H，t，J＝6.9Hz，-CH
2CH
3)；3.30(2H，q，J＝6.9Hz，-CH
2CH
3)；3.45(2H，q，J＝6.9Hz，-CH
2CH
3)；4.34(2H，s，-CH
2CO)；7.53(1H，d，J＝9.3Hz，arom)；7.60(2H，d，J＝8.4Hz，arom)；7.68(2H，d，J＝8.4Hz，arom)；7.78(1H，d，J＝9.3Hz，arom)；8.82(1H，s，arom)。MS(ESI)m/z：456，454，455，457。
Embodiment 1b.6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N, N-diethyl) imidazo [1,2-a] pyridine-3-ethanamide
With N; N-diethyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1; 2-a] pyridine-3-ethanamide 0.45 gram is dissolved in 15 milliliters of dioxane; after adding 50 milligrams of six normal-butyls, two tin 1.16 gram and dichloro two (triphenylphosphine) palladiums and 100 milligrams of triphenyl phosphorus; nitrogen protection refluxed 10 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; get 6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N, N-diethyl) imidazo [1,2-a] pyridine-3-ethanamide product.Fusing point: 60-64 degree.
1H?NMR(CDCl
3))δ0.75-1.02(9H，m，-(CH
2)
3CH
3)；1.04(3H，t，J＝7.1Hz，-NCH
2CH
3)；1.17(3H，t，J＝7.1Hz，-NCH
2CH
3)；1.24(18H，s，-CH
2)；3.24(2H，q，J＝7.1Hz，-N(CH
2CH
3)
2；3.30(2H，q，J＝7.1Hz，-N(CH
2CH
3)
2)；4.10(2H，s，-CH
2)；7.24(1H，dd，J
1＝1.7Hz，J
2＝7.6Hz，arom)；7.50-7.60(5H，m，arom)；8.30(1H，d，J＝1.7Hz，arom).MS(ESI)m/z：664，666，662，665。
Embodiment 1c.N, N-diethyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N, the N-diethyl) imidazo [1,2-a] pyridine-3-ethanamide (0.32 gram) is dissolved in 1 milliliter of acetic acid, add sodium iodide (0.20 gram) and peroxide uncle butyric acid (1.5 gram) .25 degree reaction 5 minutes. add 1 milliliter of 0.1M sodium pyrosulfate to reaction system, add 1 milliliter of 1M sodium bicarbonate.With 5 milliliters of chloroform methane extractions three times.Merge organic phase with anhydrous sodium sulfate drying after, revolve and boil off solvent, off-white powder.Fusing point: 198-199 degree.
1H?NMR(DMSO-d
6)δ1.07(3H，t，J＝6.9Hz，-CH
2CH
3)；1.17(3H，t，J＝6.9Hz，-CH
2CH
3)；3.32(2H，q，J＝6.9Hz，-CH
2CH
3)；3.40(2H，q，J＝6.9Hz，-CH
2CH
3)；4.35(2H，s，-CH
2CO)；7.57(1H，d，J＝9.3Hz，arom)；7.60(2H，d，J＝8.4Hz，arom)；7.70(2H，d，J＝8.4Hz，arom)；7.78(1H，d，J＝9.3Hz，arom)；8.83(1H，s，arom)。MS(ESI)m/z：503，501，502。
Embodiment 1d.[
123/124/125/130/131/132I]-N, N-diethyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N, N-diethyl) imidazo [1,2-a] pyridine-3-ethanamide is dissolved in acetic acid (10 microlitres, 1 mg/ml), adds Na[
123/124/125/130/131/132I] and peroxide uncle butyric acid .25 degree reaction 5 minutes. add 0.1M sodium pyrosulfate 20 microlitres to reaction system, add 1 milliliter of 1M sodium bicarbonate.Reaction mixture is through the separation and purification of HPLC semipreparative column, and mobile phase methanol: (76: 24, V/V) wash-out got product to water.
Embodiment two
Embodiment 2a.N, N-dimethyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide.
With 3.51 gram N, N-dimethyl-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 1.62 gram 5-trifluoromethyl-2-aminopyridine are dissolved in 200 milliliters of pimelinketone, 0.6 gram sodium-acetate, and 120 degree reactions are 15 hours under the nitrogen protection.Decompression is desolvated.Residuum is with 200 milliliters of chloroforms, water washing, organic phase drying.Desolvate.Residuum gets product 2.6 gram white crystals with second alcohol and water recrystallization.Fusing point: 216-218 degree.
1H?NMR(CDCl
3)δ3.00(3H，s，-NCH
3)；3.03(3H，s，-NCH
3)；4.10(2H，s，-CH
2CO)；7.34(1H，d，J＝9.3Hz，arom)；7.54(2H，d，J＝8.4Hz，arom)；7.60(2H，d，J＝8.4Hz，arom)；7.70(1H，d，J＝9.3Hz，arom)；8.53(1H，s，arom)。MS(ESI)m/z：426，428，429，427，430。
Embodiment 2b.6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N, N-dimethyl) imidazo [1,2-a] pyridine-3-ethanamide
With N, N-dimethyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide.0.43 gram is dissolved in 15 milliliters of glycol dimethyl ethers; after adding 200 milligrams in 100 milligrams of six normal-butyls, two tin 1.16 gram and three pairs of benzyl acetone two palladiums and tri-tert phosphorus; nitrogen protection refluxed 14 hours down, and the decompression of cooling back is desolvated, and residuum is through silica gel column chromatography; with ethyl acetate/normal hexane (8: 2; V/V) wash-out gets 6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N, N-dimethyl) imidazo [1; 2-a] pyridine-3-ethanamide product, be off-white color solid 0.32 gram.
Fusing point: 103-105 degree.
1H?NMR(CDCl
3))δ0.85-1.12(9H，m，-(CH
2)
3CH
3)；1.04-1.24(18H，m，-CH
2)；3.04(3H，s，-NCH
3)；3.30(3H，s，-NCH
3)；4.12(2H，s，-CH
2)；7.36(1H，d，J＝9.3Hz，arom)；7.45(2H，d，J＝8.4Hz，arom)；7.62(2H，d，J＝8.4Hz，arom)；7.66(1H，d，J＝9.3Hz，arom)；8.34(1H，d，J＝1.7Hz，arom).MS(ESI)m/z：636，638，633，635，939。
Embodiment 2c.N, N-dimethyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide.
Get 1M 6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N, N-dimethyl) 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 5 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, brown solid.Fusing point: 215-217 degree.
1H?NMR(CDCl
3)δ2.90(3H，s，-NCH
3)；3.13(3H，s，-NCH
3)；4.23(2H，s，-CH
2CO)；7.34(1H，d，J＝9.3Hz，arom)；7.45(2H，d，J＝8.4Hz，arom)；7.60(2H，d，J＝8.4Hz，arom)；7.68(1H，d，J＝9.3Hz，arom)；8.51(1H，s，arom)。MS(ESI)m/z：473，475，474。
Embodiment 2d.[
123/124/125/130/131/132I] N, N-dimethyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide.
Get 1M6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N, N-dimethyl) imidazo [1,2-a] pyridine-3-ethanamide 10 microlitres, 0.2M hydrochloric acid 10 microlitres, 0.1M chloramine-T 10 microlitres, Na[
123/124/125/130/131/132I] an amount of.25 degree reactions 5 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.
Embodiment three
Embodiment 3a.N-methyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 1a similar approach, make title compound by N-methyl-3-bromo-3-(4-iodobenzene formyl radical) propionic acid amide and 5-trifluoromethyl-2-aminopyridine.Fusing point: 306-308 degree.
1H?NMR(CDCl
3)δ2.90(3H，s，-NCH
3)；4.03(2H，s，-CH
2CO)；7.34(1H，d，J＝9.3Hz，arom)；7.54(2H，d，J＝8.4Hz，arom)；7.68(2H，d，J＝8.4Hz，arom)；7.80(1H，d，J＝9.3Hz，arom)；8.64(1H，d，J＝1.8Hz，arom)。MS(ESI)m/z：412，414，413。
Embodiment 3b.6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N-methyl) imidazo [1,2-a] pyridine-3-ethanamide
According to embodiment 1b similar approach, make title compound by N-methyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide and six normal-butyls, two tin and four (triphenyl phosphorus) palladium.Fusing point: 176-178 degree.
1H?NMR(CDCl
3)δ0.85-1.12(9H，m，-(CH
2)
3CH
3)；1.04-1.24(18H，m，-CH
2)；3.02(3H，s，-NCH
3)；4.12(2H，s，-CH
2)；7.34(1H，d，J＝9.3Hz，arom)；7.54(2H，d，J＝8.4Hz，arom)；7.68(2H，d，J＝8.4Hz，arom)；7.80(1H，d，J＝9.3Hz，arom)；8.64(1H，d，J＝1.81Hz，arom)。MS(ESI)m/z：622，620，624。
Embodiment 3c.N-methyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 1c similar approach, make title compound by 6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N-methyl) imidazo [1,2-a] pyridine-3-ethanamide and sodium iodide.Fusing point: 230-232 degree.Fusing point: 302-303 degree.
1H?NMR(CDCl
3)δ2.90(3H，s，-NCH
3)；4.03(2H，s，-CH
2CO)；7.30(1H，d，J＝9.3Hz，arom)；7.54(2H，d，J＝8.4Hz，arom)；7.60(2H，d，J＝8.4Hz，arom)；7.68(1H，d，J＝9.3Hz，arom)；8.54(1H，d，J＝1.8Hz，arom)。MS(ESI)m/z：459，461，460。
Embodiment 3d.[
123/124/125/130/131/132I] N-methyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 1d similar approach, by 6-trifluoromethyl-2-(4-tri-n-butyl tin base phenyl)-3-(N-methyl) imidazo [1,2-a] pyridine-3-ethanamide and Na[
123/124/125/130/131/132I] make title compound.
Embodiment four
Embodiment 4a.N-methyl, N-is to fluorophenyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
With 4 gram (10.5 mmole) N-methyl, N-is dissolved in 200 milliliters of N, dinethylformamide, and 50 milligrams of Tetrabutyl amonium bromides to fluorophenyl-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 2.2 gram (10.5 mmole) 5-trifluoromethyl-2-aminopyridine.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 with methylene dichloride and normal hexane crystallization.Fusing point: 182-184 degree.
Embodiment 4b.N-methyl, N-is to fluorophenyl-6-trifluoromethyl-(4-tri-n-butyl tin base phenyl)-imidazo [1,2-a] pyridine-3-ethanamide
With the N-methyl; N-is to fluorophenyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1; 2a] pyridine-3-ethanamide 0.49 gram is dissolved in 15 milliliters of toluene; behind 100 milligrams of two positive 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; get the N-methyl, N-is to fluorophenyl-6-chloro-8-tri-n-butyl tin base-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide product.Fusing point: 72-74 degree.
Embodiment 4c.N-methyl, N-is to fluorophenyl-6-trifluoromethyl-(4-tri-n-butyl tin base phenyl)-imidazo [1,2-a] pyridine-3-ethanamide
Get the N-methyl, N-is to fluorophenyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] 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: 179-181 degree.
Embodiment 4d.[
123/124/125/130/131/132I] the N-methyl, N-is to fluorophenyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
Get 1M N-methyl, N-is to fluorophenyl-6-trifluoromethyl-(4-tri-n-butyl tin base phenyl)-imidazo [1,2-a] pyridine-3-ethanamide 10 microlitres, 0.2M hydrochloric acid 10 microlitres, and 0.1M chloramine-T 10 microlitres, [
123/124/125/130/131/132I] 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 68%, radiochemicsl purity is greater than 98%.
Embodiment five
Embodiment 5a.N-methyl, N-phenyl-2-(4-bromophenyl)-6-trifluoromethyl-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..Fusing point: 196-198 degree.
1H?NMR(CDCl
3)δ2.90(3H，s，-NCH
3)；4.23(2H，s，-CH
2CO)；7.30(1H，d，J＝9.3Hz，arom)；7.58(2H，d，J＝8.4Hz，arom)；7.60-7.64(5H，m，arom)；7.70(2H，d，J＝8.4Hz，arom)；7.81(1H，d，J＝9.3Hz，arom)；8.34(1H，s，arom)。MS(ESI)m/z：488，490，489，487。
Embodiment 5b.N-methyl, N-phenyl-6-chloro-8-tri-n-butyl tin base-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, add 200 milligrams in 100 milligrams of two tri-n-butyl tins 1.16 grams and three pairs of benzyl acetone two palladiums and tri-tert phosphorus after, nitrogen protection backflow 12 hours down.Aftertreatment makes title compound with embodiment 1b..Fusing point: 82-86 degree.
1H?NMR(CDCl
3)δ0.85-1.12(9H，m，-(CH
2)
3CH
3)；1.04-1.24(18H，m，-CH
2)；2.90(3H，s，-NCH
3)；4.23(2H，s，-CH
2CO)；7.30(1H，d，J＝9.3Hz，arom)；7.58(2H，d，J＝8.4Hz，arom)；7.60-7.64(5H，m，arom)；7.70(2H，d，J＝8.4Hz，arom)；7.81(1H，d，J＝9.3Hz，arom)；8.34(1H，s，arom)。MS(ESI)m/z：684，686，682，683。
Embodiment 5c.N-methyl, N-phenyl-6-trifluoromethyl-2-(4-iodophenyl)-imidazo [1,2-a] pyridine-3-ethanamide
Get 1M N-methyl, N-phenyl-6-chloro-8-tri-n-butyl tin base-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..Fusing point: 189-192 degree.
1H?NMR(CDCl
3)δ2.90(3H，s，-NCH
3)；4.23(2H，s，-CH
2CO)；7.30(1H，d，J＝9.3Hz，arom)；7.58(2H，d，J＝8.4Hz，arom)；7.60-7.64(5H，m，arom)；7.70(2H，d，J＝8.4Hz，arom)；7.81(1H，d，J＝9.3Hz，arom)；8.34(1H，s，arom)。MS(ESI)m/z：436，435，437。
Embodiment 5d.[
123/124/125/130/131/132I] the N-methyl, N-phenyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
Get 1M N-methyl, N-phenyl-6-chloro-8-tri-n-butyl tin base-2-(4-chloro-phenyl-)-imidazo [1,2-a] pyridine-3-ethanamide 10 microlitres, acetic acid 10 microlitres, 5% Peracetic Acid, 10 microlitres, [
123/124/125/130/131/132I] sodium iodide is an amount of.25 degree reactions 30 minutes.Aftertreatment makes title compound with embodiment 1d..
Embodiment six
Embodiment 6a.N-methyl, N-cyclohexyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2a similar approach, by the N-methyl, N-cyclohexyl-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 5-trifluoromethyl-2-aminopyridine back flow reaction 24 hours in methyl iso-butyl ketone (MIBK) makes title compound.Fusing point: 226-229 degree.
1H?NMR(CDCl
3)δ1.02-1.24(m，2H，CH
2)，1.26-1.48(m，2H，CH
2)，1.58-1.98(m，6H，CH
2)，2.90(3H，s，-NCH
3)，3.68-3.84(m，1H，CH)，3.93(s，2H，CH
2CO)，7.33(d，J＝1.6Hz，1H，Ar)，7.43(d，J＝8.5Hz，2H，Ar)，7.65(d，J＝8.5Hz，2H，Ar)，8.13(d，J＝1.6Hz，1H，Ar).MS(ESI)m/z：496，494，495，497。
Embodiment 6b.N-methyl, N-cyclohexyl-6-trifluoromethyl-(4-tri-n-butyl tin base phenyl)-imidazo [1,2-a] pyridine-3-ethanamide
According to embodiment 2b similar approach, by the N-methyl, N-cyclohexyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide and two tri-n-butyl tin and four (triphenyl phosphorus) palladium reaction make title compound.Fusing point: 90-92 degree.
1H?NMR(CDCl
3)δ0.95-1.08(9H，m，-(CH
2)
3CH
3)；1.24-1.34(18H，m，-CH
2)；1.38-1.48(m，6H，CH
2)，1.58-1.78(m，4H，CH
2)，2.90(3H，s，-NCH
3)，3.68-3.84(m，1H，CH)，3.93(s，2H，CH
2CO)，7.33(d，J＝1.6Hz，1H，Ar)，7.43(d，J＝8.5Hz，2H，Ar)，7.65(d，J＝8.5Hz，2H，Ar)，8.13(d，J＝1.6Hz，1H，Ar).MS(ESI)m/z：702，700，704，703。
Embodiment 6c.N-methyl, N-cyclohexyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2c similar approach, by the N-methyl, N-cyclohexyl-6-trifluoromethyl-(4-tri-n-butyl tin base phenyl)-imidazo [1,2-a] pyridine-3-ethanamide and sodium iodide makes title compound through acetic acid and hydrogen peroxide method.Fusing point: 217-230 degree.
1H?NMR(CDCl
3)δ1.13-1.26(m，2H，CH
2)，1.38-1.48(m，2H，CH
2)，1.58-1.98(m，6H，CH
2)，2.90(3H，s，-NCH
3)，3.68-3.84(m，1H，CH)，3.90(s，2H，CH
2CO)，7.32(d，J＝1.6Hz，1H，Ar)，7.58(d，J＝8.5Hz，2H，Ar)，7.65(d，J＝8.5Hz，2H，Ar)，8.24(d，J＝1.6Hz，1H，Ar).MS(ESI)m/z：542，546，541，543。
Embodiment 6d.[
123/124/125/130/131/132I] the N-methyl, N-cyclohexyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 2d similar approach, by the N-methyl, N-cyclohexyl-6-trifluoromethyl-(4-tri-n-butyl tin base phenyl)-imidazo [1,2-a] pyridine-3-ethanamide and [
123/124/125/130/131/132I] sodium iodide, make title compound through acetic acid and hydrogen peroxide method.
Embodiment seven
Embodiment 7a.N-phenmethyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 1a similar approach, by N-phenmethyl-3-bromo-3-(4-benzoyl bromide) propionic acid amide and 5-trifluoromethyl-2-aminopyridine and sodium bicarbonate, in propyl carbinol, refluxed 2 hours, make title compound.Fusing point: 178-182 degree.
1H?NMR(CDCl
3)δ4.20(2H，s，-CH
2CO)；4.32(d，J＝7.65Hz，2H，CH
2-Ar)，7.34(1H，d，J＝9.3Hz，arom)；7.58(2H，d，J＝8.4Hz，arom)；7.60-7.64(5H，m，arom)；7.76(2H，d，J＝8.4Hz，arom)；7.81(1H，d，J＝9.3Hz，arom)；8.34(1H，s，arom)。MS(ESI)m/z：474，476，475，473，477。
Embodiment 7b.N-phenmethyl-6-trifluoromethyl-(4-tri-n-butyl tin base phenyl)-imidazo [1,2-a] pyridine-3-ethanamide
According to embodiment 2b similar approach, make title compound by N-phenmethyl-2-(4-bromophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide and two tri-n-butyl tin and four (triphenyl phosphorus) palladium reaction.Fusing point: 134-138 degree.
1H?NMR(CDCl
3)δ0.88-1.14(9H，m，-(CH
2)
3CH
3)；1.24-1.28(18H，m，-CH
2)；4.23(2H，s，-CH
2CO)；4.32(d，J＝7.65Hz，2H，CH
2-Ar)，7.44(1H，d，J＝9.3Hz，arom)；7.54(2H，d，J＝8.4Hz，arom)；7.58-7.62(5H，m，arom)；7.76(2H，d，J＝8.4Hz，arom)；7.80(1H，d，J＝9.3Hz，arom)；8.33(1H，s，arom)。MS(ESI)m/z：670，668，672，679。
Embodiment 7c.N-phenmethyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 1c similar approach,, get title compound through peroxide uncle butyric acid legal system by N-phenmethyl-6-trifluoromethyl-(4-tri-n-butyl tin base phenyl)-imidazo [1,2-a] pyridine-3-ethanamide and sodium iodide and Potassium Iodate mixture.Fusing point: 156-158 degree.
1H?NMR(CDCl
3)δ4.22(2H，s，-CH
2CO)；4.42(d，J＝7.60Hz，2H，CH
2-Ar)，7.34(1H，d，J＝9.3Hz，arom)；7.56(2H，d，J＝8.4Hz，arom)；7.61-7.68(5H，m，arom)；7.78(2H，d，J＝8.4Hz，arom)；7.83(1H，d，J＝9.3Hz，arom)；8.32(1H，s，arom)。MS(ESI)m/z：522，521，524，523。
Embodiment 7d.[
123/124/125/130/131/132I]-N-phenmethyl-2-(4-iodophenyl)-6-trifluoromethyl-imidazo [1,2a] pyridine-3-ethanamide
According to embodiment 1d similar approach, by N-phenmethyl-6-trifluoromethyl-(4-tri-n-butyl tin base phenyl)-imidazo [1,2-a] pyridine-3-ethanamide and [
123/124/125/130/131/132I] sodium iodide and Potassium Iodate mixture, get title compound through peroxide uncle butyric acid legal system.
Claims (10)
1. a 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] pyridine-3-acetamides is characterized in that molecular structural formula is as follows:
I wherein
*Be respectively
123I,
124I,
125I,
127I,
130I,
131I or
132I,
R
1And R
2Be independently or simultaneously:
1)H；
2) C
1-C
6Alkyl, one or dihydroxy C
1-C
6Alkyl, C
1-C
6Alkoxyl group replaces C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl group, halo C
1-C
6Alkyl, C
1-C
6Alkyl-NH-, (C
1-C
6Alkyl)
2-N-, C
3-C
4Cycloalkyl, cycloalkyl substituted C
1-C
6Alkyl, nitrogen heterocyclic replaces C
1-C
6Alkyl;
3) aryl, wherein aryl is represented phenyl, and pyridyl is by one or more halogens that are selected from, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, CF
3, OH, nitro, amino, C
1-C
6Alkyl-NH-, (C
1-C
6Alkyl)
2-N-, the substituting group of carbonyl acyl group or CN replaces arbitrarily;
4) C of aryl replacement
1-C
6Alkyl, aryl is represented phenyl in the base, and pyridyl is by one or more halogens that are selected from, C
1-C
6Alkane, C
1-C
6Alkoxyl group, CF
3, OH, nitro, amino, C
1-C
6Alkane-NH-, (C
1-C
6Alkyl) 2-N-, the substituting group of carbonyl acyl group or CN replaces arbitrarily.
2. the preparation method of a 2-iodine substituted phenyl-6-trifluoro methyl imidazo as claimed in claim 1 [1,2-a] pyridine-3-acetamides is characterized in that, comprises the steps:
The first step: to be raw material, in inert solvent, react, make also [1,2-a] pyridine-3-acetamides of 2-bromo phenyl-6-trifluoromethyl imidazoles with 5-trifluoromethyl-2-aminopyridine to bromophenyl-3-bromo-4-keto-amide;
Second step: 2-bromo phenyl-6-trifluoromethyl imidazoles is [1,2-a] pyridine-3-ethanamide and tin alkyl also, makes also [1,2-a] pyridine-3-ethanamide of 2-tri-n-butyl tin phenyl-6-trifluoromethyl imidazoles under metal palladium catalyst catalysis;
The 3rd step: 2-tributyl tin phenyl-6-trifluoromethyl imidazoles also [1,2-a] pyridine-3-ethanamide and iodide reacts and makes 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] pyridine-3-ethanamide;
The 4th step: 2-tri-n-butyl tin phenyl-6-trifluoromethyl imidazoles also [1,2-a] pyridine-3-ethanamide and radionuclide [
123/124/125/130/131/132I] iodide obtain having in the presence of the oxygenant [
123/124/125/130/131/132I] 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] pyridine-3-ethanamide.
3. 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1 as claimed in claim 2,2-a] preparation method of pyridine-3-ethanamide, it is characterized in that, in the first step reaction, described reaction-inert solvent is N-Methyl pyrrolidone, glycol dimethyl ether, propyl carbinol, pimelinketone, tetramethylene sulfone, methyl-sulphoxide, N, dinethylformamide, N,N-dimethylacetamide, methyl iso-butyl ketone (MIBK) or its miscible agent.
4. 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1 as claimed in claim 2,2-a] preparation method of pyridine-3-ethanamide, 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, triethylamine or Tetrabutyl amonium bromide.
5. as the preparation method of claim 2 or 3 or 4 described 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1,2-a] pyridine-3-acetamides, it is characterized in that, the first step reaction, temperature of reaction is the 90-180 degree, the reaction times is 2-24 hour.
6. 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1 as claimed in claim 2,2-a] preparation method of pyridine-3-acetamides, it 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. 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1 as claimed in claim 2,2-a] preparation method of pyridine-3-acetamides, it is characterized in that, in the reaction of second step, described reacting metal palladium catalyst is four (triphenyl phosphorus) palladium, dichloro two (triphenylphosphine) palladium/triphenyl phosphorus or three pairs of benzyl acetone two palladiums/tri-tert phosphorus.
8. 2-iodine substituted phenyl-6-trifluoro methyl imidazo [1 as claimed in claim 2,2-a] preparation method of pyridine-3-acetamides, it 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 2-iodine substituted phenyl-6-trifluoro methyl imidazo as claimed in claim 2 [1,2-a] pyridine-3-acetamides is characterized in that, in the four-step reaction, described radionuclide [
123/124/125/130/131/132I] iodide are sodium iodide, potassiumiodide, elemental iodine, sodium iodate or Potassium Iodate and composition thereof.
10. 2-iodine substituted phenyl-6-trifluoro methyl 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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|---|---|---|---|
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ID=38017949
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2006
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