CN101054379A - Pyrrole substituted pyrimidinone derivative, preparation method and use thereof in medicine - Google Patents

Pyrrole substituted pyrimidinone derivative, preparation method and use thereof in medicine Download PDF

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CN101054379A
CN101054379A CNA2006100724066A CN200610072406A CN101054379A CN 101054379 A CN101054379 A CN 101054379A CN A2006100724066 A CNA2006100724066 A CN A2006100724066A CN 200610072406 A CN200610072406 A CN 200610072406A CN 101054379 A CN101054379 A CN 101054379A
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pyrroles
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邓炳初
苏熠东
张蕾
肖璐
赵松竹
胡兵
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Shanghai Hengrui Pharmaceutical Co Ltd
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Abstract

The present invention relates to general formula (I) 2- acetamido-3- carbomethoxy -5(6,7-dihydro-6-oxo-4- arylamino [2,3-d]pyridine-5- ylidene)methyl-1H- pyrrole derivative or its salt, its preparation method and pharmaceutical composition containing same, and uses as therapeutic agent especially as protein kinase inhibitor, in which each substituted group is specified as description.

Description

The pyrimidone derivatives that the pyrroles replaces, its preparation method and in pharmaceutically purposes
Technical field
The present invention relates to a kind of new 2-acetamido-3-methoxycarbonyl-5 (6,7-dihydro-6-oxo-4-aryl amine pyrroles [2,3-d] pyrimidine-5-subunit) methyl isophthalic acid H-pyrrole derivative, its preparation method and contain they pharmaceutical composition and they as therapeutical agent particularly as the purposes of kinases inhibitor.
Background technology
(Protein kinases PKs) has important effect to protein kinase in the signal conductive process.It can be transferred to γ-phosphate of ATP on the particular amino acid residue of functional protein, causes a series of biological respinses.According in the phosphorylation process as the amino acid classification of substrate, protein kinase can be divided into serine-threonine kinase (STKs) and Tyrosylprotein kinase (PTKs).
Tyrosine phosphorylation mechanism is prevalent in the signal conductive process, regulating and control such as various kinds of cell functions such as mitotic division, cell cycle progression and differentiation (Hanks and Hunter, 1995, FASEB is J.9:576-596; Cadena and Gill, 1992, FASEB is J.6:2332-2337; Schlessinger and Ullrich, 1992, Neuron 9:383-391; Vandergeer et al., 1994, Annu.Rev.Cell Biol.10:251-337).When protein tyrosine kinase is expressed under variation, situation out of control, or when under abnormal high level, expressing, change normal cell into tumour phenotype (neoplastic phenotype) (Chiao et al., 1994, Cancer Metast.Rev.9:63-80; Hunter, 1991, Cell 64:249-270).
Be that the oncotherapy of target spot mainly contains following five kinds with VEGF and VEGFR at present: 1. (Ellis LMet al.J Biol Chem 1998,273,1052-1057): VEGF and VEGFR play positive control for neonate tumour blood vessel in gene therapy.By gene therapy, make VEGF and VEGFR expression decreased, or block its signal transduction pathway, thereby suppress the two performance biologic activity.2. anti-VEGF/VEGFR monoclonal antibody (Gordon M et al.ProcAm Soc Clin Oneol, I998, I7,2IIa): the monoclonal antibody of using VEGF and VEGFR, can seal excretory VEGF and VEGFR, the endothelium signal transduction that stops VEGF to bring out suppresses the formation of blood vessel.3. small molecules inhibition: the su series compound of developing by sugen company.4. soluble VEGFR: solvable VEGFR only has the binding ability with VEGF, but no signal transduction function.5. two of targeted therapy: VEGF principal recipient Fit-1 and Flk-1/KDR overexpression in tumor vascular endothelial cell, and VEGFR almost can not detect in adjacent healthy tissues blood vessel endothelium.Therefore, VEGF and VEGFR provide specificity higher target spot for the targeted therapy of tumour, VEGF can with couplings such as other antitumor drugs, toxin, radionuclide, be used for the targeted therapy of tumour.
Content of the present invention
The present invention relates to novel 2-acetamido-3-methoxycarbonyl-5 (6,7-dihydro-6-oxo-4-aryl amine pyrroles [2,3-d] pyrimidine-5-subunit) methyl isophthalic acid H-pyrrole derivatives, promptly have the compound or its salt of following general formula:
Figure A20061007240600071
Wherein:
X is selected from W (CH 2), (CH 2) W or W, wherein W is O, S, SO or SO 2Or X is-NR 6, R wherein 6Be hydrogen atom or alkyl;
Y is Sauerstoffatom or hydrogen atom;
When X is-NR 6, R 6Be alkyl, R then 6And R 1Form 4～8 yuan of heterocyclic radicals; Wherein, if 5～8 yuan of heterocycles, then it contains one or more N, O or S atom; If 4～8 yuan of heterocycles, then its further by one or more alkyl, halogen, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR 7R 8Replace;
R 1Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl further by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, alkoxyl group, aryloxy, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR 7R 8Replace; Wherein aryl, heteroaryl, aralkyl or heteroaralkyl and become dicyclo;
R 2Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl ,-(CH 2CH 2O) nR 6, alkenyl or alkynyl ,-COOR 7,-CONR 7R 8,-C (=S) NR 7R 8,-COR 7,-SOR 7,-SO 2R 7,-SO 2NR 7R 8Perhaps-P (=O) (OR 7) (OR 8), wherein alkyl, cycloalkyl, Heterocyclylalkyl, alkenyl or alkynyl are further replaced by one or more alkyl, hydroxyl, alkoxyl group, cyano group, amino, alkylamino, carboxylic acid or carboxylicesters;
R 3Be selected from the aryl or the trifluoromethyl of hydrogen atom, alkyl, aryl, halogen replacement;
R 4Be selected from hydroxyl, alkoxyl group, aryloxy, heterocycle alkoxyl group, aralkoxy ,-(OCH 2CH 2) nR 6,-N (R 7) (CH 2) nR 8,-NR 7[CH 2CH 2O] nR 8,-NR 7R 8Perhaps-NR 6(CH 2) n[CH (OH) CH 2] rZ (wherein Z be aryl, heteroaryl, Heterocyclylalkyl ,-NR 7R 8,-COOR 6Or CONR 7R 8);
R 5Be selected from hydroxyl, alkoxyl group, aryloxy, heterocycle alkoxyl group, aralkoxy ,-N (R 7) (CH 2) nR 8,-NR 7[CH 2CH 2O] nR 8,-NR 7R 8Perhaps-NR 6(CH 2) n[CH (OH) CH 2] rZ (wherein Z be aryl, heteroaryl, Heterocyclylalkyl ,-NR 7R 8,-COOR 6Or CONR 7R 8);
R 6Be hydrogen atom or alkyl;
R 7And R 8Be selected from respectively and be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or heteroaralkyl respectively, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or heteroaralkyl are further replaced by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid or carboxylicesters;
Simultaneously, R 7And R 8Form 4～8 yuan of heterocyclic radicals; Wherein, if 5～8 yuan of heterocycles, then it contains one or more N, O or S atom; If 4～8 yuan of heterocycles, then on it further by one or more alkyl, halogen, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, amino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR 7R 8Replace;
N is 1～6;
R is 1～2.
In the described compound or its salt of general formula of the present invention (I), preferably X is-NR 6, R wherein 6Be hydrogen atom or alkyl.
In the described compound or its salt of general formula of the present invention (I), more preferably X is-NH, R 1Be hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl are further replaced by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, alkoxyl group, aryloxy, Heterocyclylalkyl, carboxylic acid, carboxylicesters.
In the described compound or its salt of general formula of the present invention (I), preferably Y is a Sauerstoffatom.
In the described compound or its salt of general formula of the present invention (I), R preferably 2Be hydrogen atom or alkyl.
In the described compound or its salt of general formula of the present invention (I), general formula I-1c compound obtains general formula I-1d compound at ambient temperature behind the selective hydrolysis of lithium hydroxide solution.
Particularly, the described compound or its salt of general formula of the present invention (I) comprises:
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(3-morphine quinoline-4-base-third carbamyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-2-[(2-diethylin-ethylamino formyl)-methyl]-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(2-piperidines-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-2-[2-(3,5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(2-tetramethyleneimine-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(2-morpholine-4-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-2-[(2-diethylin-ethylamino formyl)-methyl]-4-phenyl-1 hydrogen-pyrroles-3-ethyl formate.
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-2-[(2-diethylin-ethylamino formyl)-methyl]-4-Trifluoromethyl-1 hydrogen-pyrroles-3-ethyl formate
Further, the invention still further relates to the preparation method of compound or its salt shown in the general formula (I), may further comprise the steps:
Figure A20061007240600091
With the raw material I-1a that is easy to get is starting raw material, obtains general formula I-1b compound with the Sodium Nitrite reaction;
Gained I-1b compound is obtained general formula I-1c compound through Knorr Pyrrole (Ke Nuoer-pyrroles) Cheng Huan;
Figure A20061007240600093
Through alkali hydroxide soln, obtain general formula I-1d compound behind the selective hydrolysis of preferred lithium hydroxide solution under the described I-1c compound room temperature;
I-1d compound and R 5NH 2Carry out amidate action and obtain general formula I-1e compound;
Figure A20061007240600101
The I-1e compound obtains general formula I-1f compound through the decarboxylation under the trifluoracetic acid effect;
The I-1f compound obtains general formula I-1g compound with phosphorus oxychloride through formylation reaction in anhydrous system;
Figure A20061007240600103
At last, general formula I-1g compound with Condensation promptly obtains the compound shown in the general formula I.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it contains The compounds of this invention or its salt and the pharmaceutical carriers for the treatment of effective dose.
Further, the present invention relates to the purposes of general formula (I) compound or its salt in preparation tyrosine kinase inhibitor medicine.
Further, the present invention relates to the purposes of composition of the present invention in preparation tyrosine kinase inhibitor medicine.
The synthetic method of The compounds of this invention
In order to finish purpose of the present invention, the present invention adopts following technical scheme:
The compounds of this invention can be synthetic by methods known in the art.The suitable synthetic method of these compounds is provided in an embodiment.Usually, these compounds can prepare according to following synthesis flow:
Figure A20061007240600111
With the raw material I-1a that is easy to get is starting raw material, obtains general formula I-1b compound with the Sodium Nitrite reaction; Gained I-1b compound obtains general formula I-1c compound through Ke Nuoer-pyrroles Cheng Huan; under the I-1c compound room temperature through alkali hydroxide soln; obtain general formula I-1d compound behind the selective hydrolysis of preferred lithium hydroxide solution; the different amine of I-1d compound carries out amidate action and obtains general formula I-1e compound; the I-1e compound obtains general formula I-1f compound through the decarboxylation under the trifluoracetic acid effect; the I-1f compound is in anhydrous system; obtain general formula I-1g compound with phosphorus oxychloride through formylation reaction; last and the different ketone condensation of general formula I-1g compound promptly obtains the target compound shown in the general formula I; wherein fairly good with the effect of lithium hydroxide selective hydrolysis substrate I-1d, and can remove the by product that produces in a small amount of Ke Nuoer-pyrroles's annulation that contains in the raw material.
Wherein, in general formula (I) molecule two keys be configured as Z configuration (cis), this point can be inferred by nuclear magnetic data.Usually the chemical shift at NH on the pyrrole ring is about 9ppm, and in the compound that obtains the NH on the pyrrole ring about 14ppm, major cause is that the oxygen of NH and the indolone carbonyl that closes on the pyrrole ring has the intramolecular hydrogen bond effect, causes the chemical shift of NH to shift to low.This point also is described in patent WO0160814 (Su-11248).
The present invention relates to a kind of pharmaceutical composition, it contains The compounds of this invention or its salt and the pharmaceutical carriers for the treatment of effective dose.
Further, the present invention relates to the purposes of general formula (I) compound or its salt in preparation tyrosine kinase inhibitor medicine.In other words, the present invention also provides the above-claimed cpd that contains medicine effective dose composition, and described compound and/or the purposes of pharmaceutical composition in the preparation tyrosine kinase inhibitor that contain this compound.
Be used to further describe the present invention below in conjunction with embodiment, but these embodiment are not limiting scope of the present invention.
Embodiment
The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.The mensuration of NMR is that measuring solvent is deuterochloroform (CDCl with Bruker AVANCE-400 nuclear magnetic resonance spectrometer 3), deuterated dimethyl sulfoxide (DMSO-D 6), in be designated as tetramethylsilane (TMS), chemical shift is with 10 -6(ppm) provide as unit.
The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph.
The mensuration of the average inhibiting rate of kinases VEGFR is used HTScan microplate reader (Cell Signaling company).
The mensuration of the average inhibiting rate of kinases EGFR/HER-2 is with NovoStar microplate reader (German BMG company).
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate.
Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.
DMSO-D 6: deuterated dimethyl sulfoxide;
CDCl 3: deuterochloroform;
Preparation embodiment:
Embodiment 1
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(3-morphine quinoline-4-base-third carbamyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 1
Figure A20061007240600121
Figure A20061007240600131
The preparation of 2-oximido-3-carbonyl-tert-butyl acetate 1b
Under the condition of ice bath, (32g, 0.2mol), Glacial acetic acid (60ml) joins in the 250ml there-necked flask, stirs dropwise to drip sodium nitrite solution down (0.2mol), control reaction temperature is 0～5 ℃ for 20ml, 10mol/L with 3-carbonyl-tert-butyl acetate 1a.After dripping end, reaction is 1 hour in ice-water bath, thorough deicing water-bath, at room temperature continue about 3 hours of reaction, (normal hexane: ethyl acetate: acetate=15: 10: 2) the raw material primitive reaction is complete for the tracking of some plate, reaction finishes, and obtains the solution of title product 2-oximido-3-carbonyl-tert-butyl acetate 1b, directly casts single step reaction.
5-ethoxy carbonyl methyl-3-methyl isophthalic acid hydrogen-pyrroles-2, the preparation of the 4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 1c
Is furnished with thermometer to one, add 3-carbonyl-ethyl glutarate (40g in the three-necked flask of the 250ml of dropping funnel successively, 0.2mmol) and Glacial acetic acid (90ml), be warming up to 65 ℃ under stirring, the zinc powder that adds 1/8 amount (is total to 26g, 0.4mmol), drip the first step reaction solution 1b of 1/8 amount again, water-bath hierarchy of control temperature can not rise too fast, treat that temperature is lower than 65 ℃ after, add again 1/8 the amount zinc powder and 1/8 the amount the first step reaction solution.So be repeated to zinc powder and the first step reaction solution 1b all adds.Elevated temperature to 75 ℃ reacts and puts plate (normal hexane: ethyl acetate: acetate=15: 10: 2) follow the tracks of reaction and finish after about 2 hours.Under the agitation condition, reaction solution is poured in the 100ml frozen water, continue to be stirred to room temperature, cross and filter out unreacted zinc powder, with ethyl acetate (100ml * 3) abstraction reaction liquid, merge organic phase, water (100ml * 3), saturated sodium bicarbonate water (100ml * 4) solution, saturated sodium-chloride water solution (100ml * 1) washing successively, the organic layer anhydrous sodium sulfate drying, concentrate and obtain title product 5-ethoxy carbonyl methyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1c (60g, oily product), productive rate 88.5%.
MS：340.3(M+1)。
5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2, the preparation of the 4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 1d
In the single port bottle of 1000ml, add 5-ethoxy carbonyl methyl-3-methyl isophthalic acid hydrogen-pyrroles-2 successively, 4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1c (30g, 0.088mol), tetrahydrofuran (THF) (268ml) and methyl alcohol (134ml), adding lithium hydroxide aqueous solution under stirring (134ml, 2.36mol/L, 0.316mol), room temperature condition reacted 1.5 hours down, and the some plate tracks to the raw material completely dissolve.After the reaction solution concentrating under reduced pressure removed most of tetrahydrofuran (THF) and methyl alcohol, add water (200ml) to concentrated solution, use ether (100ml * 5) extraction mixed solution then, water is transferred in the single port bottle of 1000ml, ice bath stir drip down 20% hydrochloric acid to pH be 1～3, there are a large amount of faint yellow precipitations to separate out, suction filtration, solid washs with a small amount of ether, vacuum-drying obtains title title product 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2, the 4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 1d (20g, faint yellow solid), productive rate 72.3%.
3-methyl-5-[(3-morphine quinoline-4-base-third carbamyl)-and methyl]-1 hydrogen
-pyrroles-2, the preparation of the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 1e
With 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1d (2.18g, 7mmol) be dissolved in the mixed solvent of methylene dichloride (35ml) and N ' dinethylformamide (3.5ml), the ice bath cooling, stir and add 3-morphine quinoline-4-base-propylamine (1.1g down successively, 7.7mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (2.67g, 14mmol) and I-hydroxybenzotriazole (0.945g, 7mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (40ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (50ml * 1) successively, water (50ml * 1) and saturated nacl aqueous solution (50ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 3-methyl-5-[(3-morphine quinoline-4-base-third carbamyl)-methyl]-1 hydrogen-pyrroles-2, the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 1e (4.49g, brown oily matter), thick product directly drops into next step reaction.
MS?m/z(ESI)：438.5(M+1)。
4-methyl-2-[(3-morphine quinoline-4-base-third carbamyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 1f
Under the argon atmospher, in the there-necked flask of 500ml, add 3-methyl-5-[(3-morphine quinoline-4-base-third carbamyl successively)-methyl]-1 hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 1e (4.49g, 7mmol), methylene dichloride (224ml) and trifluoroacetic acid (56ml), reflux 2 hours removes oil bath, room temperature continues to stir 2 hours, and the some plate tracks to the raw material completely dissolve.The ice bath cooling, slowly drip under the vigorous stirring 30% aqueous sodium hydroxide solution to the pH of reaction solution be 9, leave standstill, separatory, water dichloromethane extraction mixed solution (100ml * 4), merge organic phase, organic phase is washed (25ml * 1) with saturated nacl aqueous solution, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 4-methyl-2-[(3-morphine quinoline-4-base-third carbamyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 1f (2.01g, brown sticky solid).Thick product directly drops into next step reaction.
MS?m/z(ESI)：338.5(M+1)。
5-formyl radical-4-methyl-2-[(3-morphine quinoline-4-base-third carbamyl)-methyl]
The preparation of-1 hydrogen-pyrroles-3-ethyl formate 1g
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (0.12ml, 1.25mmol), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (0.05ml down, 0.55mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel again and bathe cooling, in reaction flask, drip 4-methyl-2-[(3-morphine quinoline-4-base-third carbamyl)-methyl]-the anhydrous N ' dinethylformamide solution (169mg of 1 hydrogen-pyrroles-3-ethyl formate 1f, 0.5mmol, be dissolved in the 0.6ml N ' dinethylformamide), keeping temperature of reaction is 0 ℃ of reaction 2 hours, after the some plate tracks to the raw material disappearance, add frozen water (15ml) cancellation reaction in reaction solution, stirred 5 minutes, regulating pH with 30% sodium hydroxide solution again is 12.Reaction solution extracts with ethyl acetate (15ml * 6); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (10ml * 2); the ethyl acetate layer anhydrous sodium sulfate drying; filter; filtrate decompression concentrates and obtains title product 5-formyl radical-4-methyl-2-[(3-morphine quinoline-4-base-third carbamyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 1g (0.192g, reddish-brown sticky solid), thick product directly drops into next step reaction.
MS?m/z(ESI)：364.3(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[(3-morphine quinoline-4-base-third carbamyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 1
Under the argon atmospher, in the single port bottle of a 10ml, add 5-formyl radical-4-methyl-2-[(3-morphine quinoline-4-base-third carbamyl successively)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 1g (0.183g, 0.5mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone (0.139g, 0.5mmol) (Bioorganic ﹠amp; Medicinal Chemistry letters., 2002,12 (16), 2153～2157.), piperidines (0.125ml, 1.25mmol) and ethanol (1.5ml), reflux 1.5 hours, the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve, reaction solution is naturally cooled to room temperature, have a large amount of solids to produce, decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(3-morphine quinoline-4-base-third carbamyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 1 (0.129g, yellow solid), productive rate 41.3%.
MS?m/z(ESI)：626.4(M+1)。
1H?NMR(DMSO-D 6，400MHz)δ8.324(s，1H，-CH＝N)，7.704(dd，1H，-ArH)，7.389～7.337(m，3H，-ArH；-CH＝C)，4.237；4.184(q，2H，-CO 2CH 2-)，3.540(t，4H，2×-OCH 2-)，3.289(s，2H，-CH 2CON-)，3.108(t，2H，-CONCH 2-)，2.363(s，3H，-ArCH 3)，2.320～2.266(m，6H，3×-NCH 2-，)，1.628～1.560(m，2H，-CH 2-)，1.273(t，3H，-CH 3)。
Embodiment 2
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 2-[(2-diethyl
Amido-ethylamino formyl)-methyl]-preparation of 4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 2
5-[(2-diethylin-ethylamino formyl)-methyl]-3-methyl isophthalic acid hydrogen-pyrroles
-2, the preparation of the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 2a
With 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1d (125mg, 0.4ml) be dissolved in the mixed solvent of methylene dichloride (2ml) and N ' dinethylformamide (0.2ml), the ice bath cooling, stir and add N ' N-diethyl ethylenediamine (60ul down successively, 0.44mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (154mg, 0.8mmol) and I-hydroxybenzotriazole (56mg, 0.4mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (5ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (5ml * 1) successively, water (5ml * 1) and saturated nacl aqueous solution (25ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 5-[(2-diethylin-ethylamino formyl)-methyl]-3-methyl isophthalic acid hydrogen-pyrroles-2, the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 2a (136mg, light yellow mucus), productive rate 83%.
2-[(2-diethylin-ethylamino formyl)-methyl]-preparation of 4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 2b
Under the argon atmospher, in the there-necked flask of 500ml, add 5-[(2-diethylin-ethylamino formyl successively)-methyl]-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 2a (420mg, 1mmol), methylene dichloride (40ml) and trifluoroacetic acid (10ml), reflux 2 hours removes oil bath, room temperature continues to stir 2 hours, and the some plate tracks to the raw material completely dissolve.The ice bath cooling, slowly drip under the vigorous stirring 30% aqueous sodium hydroxide solution to the pH of reaction solution be 12, with frozen water (30ml), leave standstill separatory, water dichloromethane extraction mixed solution (30ml * 4), merge organic phase, organic phase is washed (25ml * 1) with saturated nacl aqueous solution, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 2-[(2-diethylin-ethylamino formyl)-methyl]-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 2b (300mg, grey mucus).Productive rate 95%.
MS?m/z(ESI)：310.5(M+1)。
2-[(2-diethylin-ethylamino formyl)-methyl]-the 5-formyl radical
The preparation of-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 2c
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (0.3ml), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (112ul down, 1.1mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel and bathe cooling, in reaction flask, drip 2-[(2-diethylin-ethylamino formyl)-methyl]-the anhydrous N ' dinethylformamide solution (309mg of 4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 2b, 1mmol, be dissolved in the 0.6ml N ' dinethylformamide), keeping temperature of reaction is 0 ℃ of reaction 2 hours, and the some plate tracks to raw material and disappears, and adds frozen water (4ml) cancellation reaction in reaction solution, stirred 5 minutes, regulating pH with 30% sodium hydroxide solution again is 12.Reaction solution extracts with ethyl acetate (15ml * 4); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (10ml * 1); the ethyl acetate layer anhydrous sodium sulfate drying; filter; filtrate decompression concentrates and obtains title product 2-[(2-diethylin-ethylamino formyl)-methyl]-5-formyl radical-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 2c (283mg, pale solid), productive rate 84%.
MS?m/z(ESI)：338.7(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 2-[(2-diethyl
Amido-ethylamino formyl)-methyl]-preparation of 4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 2
Under the argon atmospher; in the single port bottle of a 10ml; add 2-[(2-diethylin-ethylamino formyl successively)-methyl]-5-formyl radical-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 2c (0.077g; 0.23mmol); 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2; 3-d] pyrimidine-6-ketone (0.056g; 0.2mmol), piperidines (0.05ml, 0.5mmol) and ethanol (0.5ml); reflux 1.5 hours; the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve; reaction solution is naturally cooled to room temperature; have a large amount of solids to produce, decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6; 7-dihydro-pyrroles [2; 3-d] pyrimidine-5-methylene radical-methyl]-2-[(2-diethylin-ethylamino formyl)-methyl]-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 2 (0.049g, yellow solid), productive rate 41%.
MS?m/z(ESI)：598.3(M+1)。
1H?NMR(DMSO-D 6，400MHz)δ8.323(s，1H，-CH＝N)，7.686(dd，1H，-ArH)，7.394～7.360(m，3H，-ArH；-CH＝C)，4.187(q，2H，-CO 2CH 2-)，3.474(s，2H，-CH 2CON-)，3.188(t，2H，-CONCH 2-)，2.351～2.329(m，9H，3×-NCH 2-；-ArCH 3)，1.486～1.358(m，6H，2×-CH 3)，1.275(t，3H，-CH 3)。
Embodiment 3
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[(2-piperidines-1-base-ethylamino formyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 3
3-methyl-5-[(2-piperidines-1-base-ethylamino formyl)-and methyl]-1 hydrogen
-pyrroles-2, the preparation of the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 3a
With 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1d (4.351g, 14mmol) be dissolved in the mixed solvent of methylene dichloride (70ml) and N ' dinethylformamide (7ml), the ice bath cooling, stir and add 2-piperidines-1-base-ethamine (1.971g down successively, 154mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (5.351g, 28mmol) and I-hydroxybenzotriazole (1.891g, 14mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (40ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (50ml * 1) successively, water (50ml * 1) and saturated nacl aqueous solution (50ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 3-methyl-5-[(2-piperidines-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-2, the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 3a (4.818g, the brown thick liquid), thick product directly drops into next step reaction.
MS?m/z(ESI)：422.3(M+1)。
4-methyl-2-[(2-piperidines-1-base-ethylamino formyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 3b
Under the argon atmospher, in the there-necked flask of 500ml, add 3-methyl-5-[(2-piperidines-1-base-ethylamino formyl successively)-methyl]-1 hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 3a (4.81g, 11.4mmol), methylene dichloride (365ml) and trifluoroacetic acid (68ml), reflux 2 hours removes oil bath, room temperature continues to stir 2 hours, and the some plate tracks to the raw material completely dissolve.The ice bath cooling, slowly drip under the vigorous stirring 30% aqueous sodium hydroxide solution to the pH of reaction solution be 9, leave standstill, separatory, water dichloromethane extraction mixed solution (100ml * 4), merge organic phase, organic phase is washed (25ml * 1) with saturated nacl aqueous solution, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 4-methyl-2-[(2-piperidines-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 3b (2.39g, the brown thick liquid), thick product directly drops into next step reaction.
MS?m/z(ESI)：322.5(M+1)。
5-formyl radical-4-methyl-2-[(2-piperidines-1-base-ethylamino formyl)-methyl]
The preparation of-1 hydrogen-pyrroles-3-ethyl formate 3c
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (0.58ml, 7.5mmol), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (0.307ml down, 3.3mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel again and bathe cooling, in reaction flask, drip 4-methyl-2-[(2-piperidines-1-base-ethylamino formyl)-methyl]-the anhydrous N ' dinethylformamide solution (0.963mg of 1 hydrogen-pyrroles-3-ethyl formate 3b, 3mmol is dissolved in the 3.6ml N ' dinethylformamide), keeping temperature of reaction is 0 ℃ of reaction 2 hours, after the some plate tracks to the raw material disappearance, add frozen water (15ml) cancellation reaction in reaction solution, stirred 5 minutes, regulating pH with 30% sodium hydroxide solution again is 12.Reaction solution extracts with ethyl acetate (15ml * 6); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (10ml * 2); the ethyl acetate layer anhydrous sodium sulfate drying; filter; filtrate decompression concentrates and obtains title product 5-formyl radical-4-methyl-2-[(2-piperidines-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 3c (0.952g, orange/yellow solid), thick product directly drops into next step reaction.
MS?m/z(ESI)：350.4(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[(2-piperidines-1-base-ethylamino formyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 3
Under the argon atmospher; in the single port bottle of a 10ml; add 5-formyl radical-4-methyl-2-[(2-piperidines-1-base-ethylamino formyl successively)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 3c (0.233g; 0.66mmol); 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2; 3-d] pyrimidine-6-ketone (0.169g; 0.6mmol), piperidines (0.15ml, 1.5mmol) and ethanol (1.5ml); reflux 1.5 hours; the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve; reaction solution is naturally cooled to room temperature; have a large amount of solids to produce, decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6; 7-dihydro-pyrroles [2; 3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(2-piperidines-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 3 (0.289g, yellow solid), productive rate 79%.
MS?m/z(ESI)：610.6(M+1)。
1H?NMR(DMSO-D 6，400MHz)δ8.318(s，1H，-CH＝N)，7.687(dd，1H，-ArH)，7.405～7.333(m，3H，-ArH；-CH＝C)，4.183(q，2H，-CO 2CH 2-)，3.482(s，2H，-CH 2CON-)，3.139(t，2H，-CONCH 2-)，2.491～2.438(m，6H，3×-NCH 2-)，2.348(s，3H，-ArCH 3)，1.273(t，3H，-CH 3)，0.915(t，6H，3×-CH 2-)。
Embodiment 4
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-(3,5-two for 2-[2-
Methyl-piperazine-1-yl)-2-oxo-ethyl]-preparation of 4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 4
Figure A20061007240600201
5-[2-(3,5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-3-methyl isophthalic acid hydrogen
-pyrroles-2, the preparation of the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 4a
With 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1d (0.933g, 3mmol) be dissolved in the mixed solvent of methylene dichloride (15ml) and N ' dinethylformamide (1.5ml), the ice bath cooling, stir and add (2S down successively, 6R)-2,6-dimethyl-piperazine (0.377g, 3.3mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (1.146g, 6mmol) and I-hydroxybenzotriazole (0.405g, 3mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (40ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (50ml * 1) successively, water (50ml * 1) and saturated nacl aqueous solution (50ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and obtains title product 5-[2-(3,5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 4a (0.710g, brown thick liquid), thick product directly drops into next step reaction.
MS?m/z(ESI)：408.4(M+1)。
2-[2-(3,5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-the 4-methyl
The preparation of-1 hydrogen-pyrroles-3-ethyl formate 4b
Under the argon atmospher, in the there-necked flask of 500ml, add 5-[2-(3 successively, 5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 4a (0.710g, 1.7mmol), methylene dichloride (55.8ml) and trifluoroacetic acid (7ml), reflux 2 hours, remove oil bath, room temperature continues to stir 2 hours, and the some plate tracks to the raw material completely dissolve.The ice bath cooling, slowly drip under the vigorous stirring 30% aqueous sodium hydroxide solution to the pH of reaction solution be 9, leave standstill, separatory, water dichloromethane extraction mixed solution (100ml * 4), merge organic phase, organic phase is washed (25ml * 1) with saturated nacl aqueous solution, the dichloromethane layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, obtain title product 2-[2-(3,5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 4b (0.309g, brown thick liquid), thick product directly drops into next step reaction.
MS?m/z(ESI)：308.4(M+1)。
2-[2-(3,5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-5-formyl radical-4-methyl isophthalic acid hydrogen
The preparation of-pyrroles-3-ethyl formate 4c
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (0.2ml, 2.5mmol), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (0.1ml down, 1.1mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel again and bathe cooling, in reaction flask, drip 2-[2-(3,5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-anhydrous N ' dinethylformamide solution (0.309g, the 1mmol of 4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 4b, be dissolved in the 1.2ml N ' dinethylformamide), keeping temperature of reaction is 0 ℃ of reaction 2 hours, after the some plate tracks to the raw material disappearance, adds frozen water (15ml) cancellation reaction in reaction solution, stirred 5 minutes, regulating pH with 30% sodium hydroxide solution again is 12.Reaction solution extracts with ethyl acetate (15ml * 6); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (10ml * 2); the ethyl acetate layer anhydrous sodium sulfate drying; filter, filtrate decompression concentrates and obtains title product 2-[2-(3,5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-5-formyl radical-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 4c (0.329g; burgundy look thick liquid), thick product directly drops into next step reaction.
MS?m/z(ESI)：336.4(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-(3,5-two for 2-[2-
Methyl-piperazine-1-yl)-2-oxo-ethyl]-preparation of 4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 4
Under the argon atmospher; in the single port bottle of a 10ml; add 2-[2-(3 successively; 5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-5-formyl radical-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 4c (0.114g; 0.34mmol); 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone (0.086g; 0.3mmol); piperidines (0.08ml, 0.8mmol) and ethanol (0.8ml), reflux 1.5 hours; the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve naturally cools to room temperature with reaction solution; there are a large amount of solids to produce; decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2; 3-d] pyrimidine-5-methylene radical-methyl]-2-[2-(3; 5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 4 (0.049g, yellow solid), productive rate 27.4%.
MS?m/z(ESI)：596.6(M+1)。
1H?NMR(DMSO-D 6，400MHz)δ8.324(s，1H，-CH＝N)，7.713(dd，1H，-ArH)，7.409～7.341(m，3H，-ArH；-CH＝C)，4.166(q，2H，-CO 2CH 2-)，3.434～3.377(m，6H，-CH 2CON-；2×-CONCH 2-)，2.668～2.563(m，2H，2×-NCHR-)，2.378(s，3H，-ArCH 3)，1.255(t，3H，-CH 3)，0.964(d，6H，2×-CH 3)。
Embodiment 5
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[(2-tetramethyleneimine-1-base-ethylamino formyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 5
Figure A20061007240600221
Figure A20061007240600231
3-methyl-5-[(2-tetramethyleneimine-1-base-ethylamino formyl)-and methyl]-1 hydrogen
-pyrroles-2, the preparation of the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 5a
With 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1d (2.8g, 9mmol) be dissolved in the mixed solvent of methylene dichloride (45ml) and N ' dinethylformamide (4.5ml), the ice bath cooling adds 2-tetramethyleneimine-1-base-ethamine (1.13g under stirring successively, 909mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (3.44g, 18mmol) and I-hydroxybenzotriazole (1.22g, 9mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (40ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (50ml * 1) successively, water (50ml * 1) and saturated nacl aqueous solution (50ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 3-methyl-5-[(2-tetramethyleneimine-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-2, the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 5a (4.48g, the brown thick liquid), thick product directly drops into next step reaction.
MS?m/z(ESI)：408.3(M+1)。
4-methyl-2-[(2-tetramethyleneimine-1-base-ethylamino formyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 5b
Under the argon atmospher, in the there-necked flask of 500ml, add 3-methyl-5-[(2-tetramethyleneimine-1-base-ethylamino formyl successively)-methyl]-1 hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 5a (4.48g, 9mmol), methylene dichloride (288ml) and trifluoroacetic acid (54ml), reflux 2 hours removes oil bath, room temperature continues to stir 2 hours, and the some plate tracks to the raw material completely dissolve.The ice bath cooling, slowly drip under the vigorous stirring 30% aqueous sodium hydroxide solution to the pH of reaction solution be 9, leave standstill, separatory, water dichloromethane extraction mixed solution (100ml * 4), merge organic phase, organic phase is washed (25ml * 1) with saturated nacl aqueous solution, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 4-methyl-2-[(2-tetramethyleneimine-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 5b (1.68g, the brown thick liquid), thick product directly drops into next step reaction.
MS?m/z(ESI)：308.4(M+1)。
5-formyl radical-4-methyl-2-[(2-tetramethyleneimine-1-base-ethylamino formyl)-and methyl]-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 5c
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (0.4ml, 5.0mmol), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (0.2ml down, 2.2mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel again and bathe cooling, in reaction flask, drip 4-methyl-2-[(2-tetramethyleneimine-1-base-ethylamino formyl)-methyl]-the anhydrous N ' dinethylformamide solution (0.614g of 1 hydrogen-pyrroles-3-ethyl formate 5b, 2mmol is dissolved in the 2.4ml N ' dinethylformamide), keeping temperature of reaction is 0 ℃ of reaction 2 hours, after the some plate tracks to the raw material disappearance, add frozen water (15ml) cancellation reaction in reaction solution, stirred 5 minutes, regulating pH with 30% sodium hydroxide solution again is 12.Reaction solution extracts with ethyl acetate (15ml * 6); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (10ml * 2); the ethyl acetate layer anhydrous sodium sulfate drying; filter; filtrate decompression concentrates and obtains title product 5-formyl radical-4-methyl-2-[(2-tetramethyleneimine-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 5c (0.517g, brown solid), productive rate 77%.
MS?m/z(ESI)：336.6(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2
The preparation of-[(2-tetramethyleneimine-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 5
Under the argon atmospher; in the single port bottle of a 10ml; add 5-formyl radical-4-methyl-2-[(2-tetramethyleneimine-1-base-ethylamino formyl successively)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 5c (0.26g; 0.782mmol); 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2; 3-d] pyrimidine-6-ketone (0.112g; 0.403mmol), piperidines (0.15ml, 1.5mmol) and ethanol (1.5ml); reflux 1.5 hours; the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve; reaction solution is naturally cooled to room temperature; have a large amount of solids to produce, decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6; 7-dihydro-pyrroles [2; 3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(2-tetramethyleneimine-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 5 (39mg, tawny solid), productive rate 16.3%.
MS?m/z(ESI)：596.4(M+1)。
1H?NMR(DMSO-D 6，400MHz)δ8.320(s，1H，-CH＝N)，7.684(dd，1H，-ArH)，7.392～7.356(m，3H，-ArH；-CH＝C)，4.185(q，2H，-CO 2CH 2-)，3.478(s，2H，-CH 2CON-)，3.200(t，2H，-CONCH 2-)，2.567(t，2H，-NCH 2-)，2.475～2.408(m，4H，2×-NCH 2-)，2.350(s，3H，-ArCH 3)，1.660(q，4H，2×-CH 2-)，1.274(t，3H，-CH 3)。
Embodiment 6
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[(2-morpholine-4-base-ethylamino formyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 6
3-methyl-5-[(2-morpholine-4-base-ethylamino formyl)-and methyl]-1 hydrogen
-pyrroles-2, the preparation of the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 6a
With 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1d (10.9g, 35mmol) be dissolved in the mixed solvent of methylene dichloride (175ml) and N ' dinethylformamide (17.5ml), the ice bath cooling, stir and add 2-morpholine-4-base-ethamine (5.0g down successively, 38.5mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (13.37g, 70mmol) and I-hydroxybenzotriazole (4.73g, 35mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (40ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (50ml * 1) successively, water (50ml * 1) and saturated nacl aqueous solution (50ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 3-methyl-5-[(2-morpholine-4-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-2, the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 6a (12.88g, the brown thick liquid), thick product directly drops into next step reaction.
MS?m/z(ESI)：424.4(M+1)。
4-methyl-2-[(2-morpholine-4-base-ethylamino formyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 6b
Under the argon atmospher, in the there-necked flask of 500ml, add 3-methyl-5-[(2-morpholine-4-base-ethylamino formyl successively)-methyl]-1 hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 6a (4.23g, 10mmol), methylene dichloride (320ml) and trifluoroacetic acid (60ml), reflux 2 hours removes oil bath, room temperature continues to stir 2 hours, and the some plate tracks to the raw material completely dissolve.The ice bath cooling, slowly drip under the vigorous stirring 30% aqueous sodium hydroxide solution to the pH of reaction solution be 9, leave standstill, separatory, water dichloromethane extraction mixed solution (100ml * 4), merge organic phase, organic phase is washed (25ml * 1) with saturated nacl aqueous solution, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 4-methyl-2-[(2-morpholine-4-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 6b (2.35g, the brown thick liquid), thick product directly drops into next step reaction.
MS?m/z(ESI)：324.3(M+1)。
5-formyl radical-4-methyl-2-[(2-morpholine-4-base-ethylamino formyl)-and methyl]-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 6c
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (1.6ml, 20mmol), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (0.75ml down, 8.0mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel and bathe cooling, in reaction flask, drip 4-methyl-2-[(2-morpholine-4-base-ethylamino formyl)-methyl]-the anhydrous N ' dinethylformamide solution (2.346mg of 1 hydrogen-pyrroles-3-ethyl formate 6b, 7.26mmol, be dissolved in the 8.7ml N ' dinethylformamide), keeping temperature of reaction is 0 ℃ of C reaction 2 hours, after the some plate tracks to the raw material disappearance, add frozen water (15ml) cancellation reaction in reaction solution, stirring and regulating pH with 30% sodium hydroxide solution after 5 minutes is 12.Reaction solution extracts with ethyl acetate (15ml * 6); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (10ml * 2); the ethyl acetate layer anhydrous sodium sulfate drying; filter; filtrate decompression concentrates and obtains title product 5-formyl radical-4-methyl-2-[(2-morpholine-4-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 6c (1.105g, brown thick liquid), productive rate 43.3%.
MS?m/z(ESI)：352.5(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[(2-morpholine-4-base-ethylamino formyl)-methyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 6
Under the argon atmospher; in the single port bottle of a 10ml; add 5-formyl radical-4-methyl-2-[(2-morpholine-4-base-ethylamino formyl successively)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 6c (0.253g; 0.72mmol); 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2; 3-d] pyrimidine-6-ketone (0.169g; 0.6mmol), piperidines (0.15ml, 1.5mmol) and ethanol (3ml); reflux 1.5 hours; the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve; reaction solution is naturally cooled to room temperature; have a large amount of solids to produce, decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6; 7-dihydro-pyrroles [2; 3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(2-morpholine-4-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate 6 (0.204g, yellow solid), productive rate 54.8%.
MS?m/z(ESI)：612.2(M+1)。
1H?NMR(DMSO-D 6，400MHz)：δ8.325(s，1H，-CH＝N)，7.685(dd，1H，-ArH)，7.394～7.359(m，3H，-ArH；-CH＝C)，4.190(q，2H，-CO 2CH 2-)，3.541(t，4H，2×-OCH 2-)，3.476(s，2H，-CH 2CON-)，3.213(t，2H，-CONCH 2-)，2.404～2.334(m，9H，3×-NCH 2-，-ArCH 3)，1.276(t，3H，-CH 3)。
Embodiment 7
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-preparation of 1 hydrogen-pyrroles-3-ethyl formate 7
Figure A20061007240600271
3-methyl-5-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-1 hydrogen-pyrroles-2,4-dioctyl phthalate-2-
The preparation of the tert-butyl ester-4-ethyl ester 7a
With 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1d (4.35g, 14mmol) be dissolved in the mixed solvent of methylene dichloride (70ml) and N ' dinethylformamide (7ml), the ice bath cooling, stir and add (2R)-3-(2-methyl-piperidines-1-yl)-propylamine (2.41g down successively, 15.4mmol), the N-ethyl n '-(dimethylamino-propyl)-carbodiimide (5.35g, 28mmol) and I-hydroxybenzotriazole (1.89g, 14mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (40ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (50ml * 1) successively, water (50ml * 1) and saturated nacl aqueous solution (50ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 3-methyl-5-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-1 hydrogen-pyrroles-2, the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 7a (6.617g, brown oily matter), thick product directly drops into next step reaction.
MS?m/z(ESI)：450.3(M+1)。
4-methyl-2-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 7b
Under the argon atmospher, in the there-necked flask of 500ml, add 3-methyl-5-{[3-(2-methyl-piperidines-1-yl)-third carbamyl successively]-methyl }-1 hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 7a (6.3g, 14mmol), methylene dichloride (450ml) and trifluoroacetic acid (84ml), reflux 2 hours removes oil bath, room temperature continues to stir 2 hours, and the some plate tracks to the raw material completely dissolve.The ice bath cooling, slowly drip under the vigorous stirring 30% aqueous sodium hydroxide solution to the pH of reaction solution be 9, leave standstill, separatory, water dichloromethane extraction mixed solution (100ml * 4), merge organic phase, organic phase is washed (25ml * 1) with saturated nacl aqueous solution, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 4-methyl-2-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-1 hydrogen-pyrroles-3-ethyl formate 7b (3.348g, white solid), thick product directly drops into next step reaction.
MS?m/z(ESI)：350.4(M+1)。
5-formyl radical-4-methyl-2-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 7c
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (0.66ml, 8.25mmol), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (0.3ml down, 3.3mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel again and bathe cooling, in reaction flask, drip 4-methyl-2-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-the anhydrous N ' dinethylformamide solution (1.048mg of 1 hydrogen-pyrroles-3-ethyl formate 7b, 3mmol is dissolved in the 3.6mlN ' dinethylformamide), keeping temperature of reaction is 0 ℃ of reaction 2 hours, after the some plate tracks to the raw material disappearance, add frozen water (15ml) cancellation reaction in reaction solution, stirred 5 minutes, regulating pH with 30% sodium hydroxide solution again is 12.Reaction solution extracts with ethyl acetate (15ml * 6); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (10ml * 2); the ethyl acetate layer anhydrous sodium sulfate drying; filter; filtrate decompression concentrates and obtains title product 5-formyl radical-4-methyl-2-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-1 hydrogen-pyrroles-3-ethyl formate 7c (1.422g, brown solid), thick product directly drops into next step reaction.
MS?m/z(ESI)：378.5(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2
The preparation of-{ [3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-1 hydrogen-pyrroles-3-ethyl formate 7
Under the argon atmospher; in the single port bottle of a 10ml; add 5-formyl radical-4-methyl-2-{[3-(2-methyl-piperidines-1-yl)-third carbamyl successively]-methyl }-1 hydrogen-pyrroles-3-ethyl formate 7c (0.226g; 0.6mmol); 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2; 3-d] pyrimidine-6-ketone (0.167g; 0.6mmol), piperidines (0.15ml, 1.5mmol) and ethanol (1.5ml); reflux 1.5 hours; the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve; reaction solution is naturally cooled to room temperature; have a large amount of solids to produce, decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6; 7-dihydro-pyrroles [2; 3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-1 hydrogen-pyrroles-3-ethyl formate 7 (102mg, yellow solid), productive rate 26.6%.
MS?m/z(ESI)：639.3(M+1)。
1H?NMR(DMSO-D 6，400MHz)：δ8.324(s，1H，-CH＝N)，7.684(dd，1H，-ArH)，7.393～7.359(m，3H，-ArH；-CH＝C)，4.187(q，2H，-CO 2CH 2-)，3.454(s，2H，-CH 2CON-)，3.081(t，2H，-CONCH 2-)，2.350～2.334(m，6H，-NCH 2-，-NCHR-，-ArCH 3)，2.233(t，2H，-NCH 2-)，1.579～1.526(m，6H，3×-CH 2-)，1.273(t，3H，-CH 3)，1.204～1.156(m，2H，-CH 2-)，0.952(d，3H，-CH 3)。
Embodiment 8
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 8
Figure A20061007240600291
3-methyl-5-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-1 hydrogen
-pyrroles-2, the preparation of the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 8a
With 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1d (933mg, 3mmol) be dissolved in the mixed solvent of methylene dichloride (15ml) and N ' dinethylformamide (1.5ml), ice bath cooling is stirred and is added 1-methyl-Pai piperazine (331mg down successively, 3.3mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (1.146g, 6mmol) and I-hydroxybenzotriazole (405mg, 3mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (40ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (50ml * 1) successively, water (50ml * 1) and saturated nacl aqueous solution (50ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 3-methyl-5-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-2, the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 8a (676mg, brown oil), slightly product directly drops into next step reaction.
MS?m/z(ESI)：394.4(M+1)。
4-methyl-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 8b
Under the argon atmospher, in the there-necked flask of 500ml, add 3-methyl-5-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl successively]-1 hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 8a (676mg, 1.7mmol), methylene dichloride (180ml) and trifluoroacetic acid (30ml), reflux 2 hours removes oil bath, room temperature continues to stir 2 hours, and the some plate tracks to the raw material completely dissolve.The ice bath cooling, slowly drip under the vigorous stirring 30% aqueous sodium hydroxide solution to the pH of reaction solution be 9, leave standstill, separatory, water dichloromethane extraction mixed solution (100ml * 4), merge organic phase, organic phase is washed (25ml * 1) with saturated nacl aqueous solution, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 4-methyl-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-3-ethyl formate 8b (504mg, brown oil), slightly product directly drops into next step reaction.
MS?m/z(ESI)：294.3(M+1)。
5-formyl radical-4-methyl-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 8c
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (0.37ml, 4.625mmol), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (0.17ml down, 1.87mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel again and bathe cooling, in reaction flask, drip 4-methyl-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-the anhydrous N ' dinethylformamide solution (501mg of 1 hydrogen-pyrroles-3-ethyl formate 8b, 1.7mmol, be dissolved in the 2ml N ' dinethylformamide), keeping temperature of reaction is 0 ℃ of reaction 2 hours, after the some plate tracks to the raw material disappearance, add frozen water (15ml) cancellation reaction in reaction solution, stirred 5 minutes, regulating pH with 30% sodium hydroxide solution again is 12.Reaction solution extracts with ethyl acetate (15ml * 6); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (10ml * 2); the ethyl acetate layer anhydrous sodium sulfate drying; filter; filtrate decompression concentrates and to obtain title product 5-formyl radical-4-methyl-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-3-ethyl formate 8c (404mg, brown oil), thick product directly drops into next step reaction.
MS?m/z(ESI)：324.3(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 8
Under the argon atmospher; in the single port bottle of a 10ml; add 5-formyl radical-4-methyl-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl successively]-1 hydrogen-pyrroles-3-ethyl formate 8c (192mg; 0.6mmol); 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2; 3-d] pyrimidine-6-ketone (167mg; 0.6mmol), piperidines (0.15ml, 1.5mmol) and ethanol (1.5ml); reflux 1.5 hours; the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve; reaction solution is naturally cooled to room temperature; have a large amount of solids to produce, decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6; 7-dihydro-pyrroles [2; 3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-3-ethyl formate 8 (168mg, yellow solid), productive rate 48.1%.
MS?m/z(ESI)：582.5(M+1)。
1H?NMR(DMSO-D 6，400MHz)：δ8.324(s，1H，-CH＝N)，7.694(dd，1H，-ArH)，7.403～7.340(m，3H，-ArH；-CH＝C)，4.167(q，2H，-CO 2CH 2-)，3.534～3.477(m，6H，-CH 2CON-；2×-CONCH 2-)，2.366(s，3H，-ArCH 3)，2.344～2.290(m，4H，2×-NCH 2-)，2.190(s，3H，-NCH 3)，1.257(t，3H，-CH 3)。
Embodiment 9
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 9
Figure A20061007240600311
3-methyl-5-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-1 hydrogen
-pyrroles-2, the preparation of the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 9a
With 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1d (1.236g, 3.97mmol) be dissolved in the mixed solvent of methylene dichloride (20ml) and N ' dinethylformamide (2ml), the ice bath cooling, stir and add 4-piperidin-4-yl-morpholine (0.75g down successively, 4.4mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (2g, 7.94mmol) and I-hydroxybenzotriazole (0.6g, 3.97mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (40ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (50ml * 1) successively, water (50ml * 1) and saturated nacl aqueous solution (50ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 3-methyl-5-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-2, the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 9a (1.673g, the brown thick liquid), productive rate 90.33%.
MS?m/z(ESI)：464.7(M+1)。
4-methyl-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 9b
Under the argon atmospher, in the there-necked flask of 500ml, add 3-methyl-5-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl successively]-1 hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 9a (1.673g, 3.6mmol), methylene dichloride (113ml) and trifluoroacetic acid (20ml), reflux 2 hours removes oil bath, room temperature continues to stir 2 hours, and the some plate tracks to the raw material completely dissolve.The ice bath cooling, slowly drip under the vigorous stirring 30% aqueous sodium hydroxide solution to the pH of reaction solution be 9, leave standstill, separatory, water dichloromethane extraction mixed solution (100ml * 4), merge organic phase, organic phase is washed (25ml * 1) with saturated nacl aqueous solution, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 4-methyl-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-3-ethyl formate 9b (1.141g, brown oily liquids).Productive rate 86.99%.
MS?m/z(ESI)：364.5(M+1)。
5-formyl radical-4-methyl-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 9c
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (0.3ml, 3.9mmol), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (112ul down, 1.1mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel again and bathe cooling, in reaction flask, drip 4-methyl-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-the anhydrous N ' dinethylformamide solution (363mg of 1 hydrogen-pyrroles-3-ethyl formate 9b, 1mmol is dissolved in the 0.6ml N ' dinethylformamide), keeping temperature of reaction is 0 ℃ of reaction 2 hours, after the some plate tracks to the raw material disappearance, add frozen water (15ml) cancellation reaction in reaction solution, stirred 5 minutes, regulating pH with 30% sodium hydroxide solution again is 12.Reaction solution extracts with ethyl acetate (15ml * 6); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (10ml * 1); the ethyl acetate layer anhydrous sodium sulfate drying; filter; filtrate decompression concentrates and obtains title product 5-formyl radical-4-methyl-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-3-ethyl formate 9c (0.292g, reddish-brown solid), productive rate 74.68%.
MS?m/z(ESI)：392.6(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-preparation of 1 hydrogen-pyrroles-3-ethyl formate 9
Under the argon atmospher; in the single port bottle of a 10ml; add 5-formyl radical-4-methyl-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl successively]-1 hydrogen-pyrroles-3-ethyl formate 9c (0.292g; 0.75mmol); 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2; 3-d] pyrimidine-6-ketone (0.115g; 0.75mmol), piperidines (0.15ml, 1.5mmol) and ethanol (1.2ml); reflux 1.5 hours; the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve; reaction solution is naturally cooled to room temperature; have a large amount of solids to produce, decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6; 7-dihydro-pyrroles [2; 3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-3-ethyl formate 9 (40mg, pale brown look solid), productive rate 16.43%.
MS?m/z(ESI)：652.5(M+1)。
1H?NMR(DMSO-D 6，400MHz)：δ8.321(s，1H，-CH＝N)，7.692(dd，1H，-ArH)，7.425～7.337(m，3H，-ArH；-CH＝C)，4.165(q，2H，-CO 2CH 2-)，3.529(t，4H，2×-OCH 2-)，3.474(s，2H，-CH 2CON-)，3.049(t，4H，2×-CONCH 2-)，2.441～2.435(m，5H，2×-NCH 2-，-NCHR-)，2.346(s，3H，-ArCH 3)，1.798～1.768(m，4H，2×-CH 2-)，1.273(t，3H，-CH 3)。
Embodiment 10
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl]-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 10
Figure A20061007240600331
Figure A20061007240600341
3-methyl-5-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl]-1 hydrogen-pyrroles-2, the 4-dioctyl phthalate
The preparation of-2-the tert-butyl ester-4-ethyl ester 10a
With 5-carboxymethyl-3-methyl isophthalic acid hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 1d (1.244g, 4mmol) be dissolved in the mixed solvent of methylene dichloride (20ml) and N ' dinethylformamide (2ml), the ice bath cooling, stir and add (s)-2-(tetramethyleneimine-1-ylmethyl)-tetramethyleneimine (0.72ml down successively, 4.4mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (2g, 8mmol) and I-hydroxybenzotriazole (0.6g, 4mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (40ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (50ml * 1) successively, water (50ml * 1) and saturated nacl aqueous solution (50ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 3-methyl-5-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl]-1 hydrogen-pyrroles-2, the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 10a (1.755g, pale brown look oily matter), productive rate 98.15%.
MS?m/z(ESI)：448.3(M+1)。
4-methyl-2-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl]
The preparation of-1 hydrogen-pyrroles-3-ethyl formate 10b
Under the argon atmospher, in the there-necked flask of 500ml, add 3-methyl-5-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl successively]-1 hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 10a (1.255g, 3.93mmol), methylene dichloride (124ml) and trifluoroacetic acid (22ml), reflux 2 hours removes oil bath, room temperature continues to stir 2 hours, and the some plate tracks to the raw material completely dissolve.The ice bath cooling, slowly drip under the vigorous stirring 30% aqueous sodium hydroxide solution to the pH of reaction solution be 9, leave standstill, separatory, water dichloromethane extraction mixed solution (100ml * 4), merge organic phase, organic phase is washed (25ml * 1) with saturated nacl aqueous solution, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 4-methyl-2-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl]-1 hydrogen-pyrroles-3-ethyl formate 10b (0.566g, pale brown look oily matter).Productive rate 41.63%.
MS?m/z(ESI)：348.3(M+1)。
5-formyl radical-4-methyl-2-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl]
The preparation of-1 hydrogen-pyrroles-3-ethyl formate 10c
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (ml, mmol), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (183ul down, 1.8mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel again and bathe cooling, in reaction flask, drip 4-methyl-2-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl]-the anhydrous N ' dinethylformamide solution (566mg of 1 hydrogen-pyrroles-3-ethyl formate 10b, 1.63mmol, be dissolved in the 2ml N ' dinethylformamide), keeping temperature of reaction is 0 ℃ of reaction 2 hours, after the some plate tracks to the raw material disappearance, add frozen water (15ml) cancellation reaction in reaction solution, stirred 5 minutes, regulating pH with 30% sodium hydroxide solution again is 12.Reaction solution extracts with ethyl acetate (15ml * 6); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (10ml * 1); the ethyl acetate layer anhydrous sodium sulfate drying; filter; filtrate decompression concentrates and obtains title product 5-formyl radical-4-methyl-2-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl]-1 hydrogen-pyrroles-3-ethyl formate 10c (0.536g, reddish-brown solid), productive rate 87.72%.
MS?m/z(ESI)：376.4(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 4-methyl
-2-[2-oxo-2-(2-tetramethyleneimine-1 ylmethyl-tetramethyleneimine-1-yl)-ethyl]
The preparation of-1 hydrogen-pyrroles-3-ethyl formate 10
Under the argon atmospher; in the single port bottle of a 10ml; add 5-formyl radical-4-methyl-2-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl successively]-1 hydrogen-pyrroles-3-ethyl formate 10c (0.2g; 0.5mmol); 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2; 3-d] pyrimidine-6-ketone (0.14g; 2.5mmol), piperidines (0.1ml, 1mmol) and ethanol (1.2ml); reflux 1.5 hours; the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve; reaction solution is naturally cooled to room temperature; have a large amount of solids to produce, decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6; 7-dihydro-pyrroles [2; 3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[2-oxo-2-(2-tetramethyleneimine-1 ylmethyl-tetramethyleneimine-1-yl)-ethyl]-1 hydrogen-pyrroles-3-ethyl formate 10 (0.103g, yellow solid), productive rate 37.44%.
MS?m/z(ESI)：636.5(M+1)。
1H?NMR(DMSO-D 6，400MHz)：δ8.323(s，1H，-CH＝N)，7.710(dd，1H，-ArH)，7.398～7.339(m，3H，-ArH；-CH＝C)，4.209～4.063(m，3H，-CO 2CH 2-，-CONCHR-)，3.522(t，2H，-CONCH 2-)，3.291(s，2H，-CH 2CON-)，2.465～2.433(m，6H，3×-NCH 2-)，2.371(s，3H，-ArCH 3)，1.944～1.837(m，4H，2×-CH 2-)，1.666～1.653(m，4H，2×-CH 2-)，1.251(t，3H，-CH 3)。
Embodiment 11
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 2-[(2-diethyl
Amido-ethylamino formyl)-methyl]-preparation of 4-phenyl-1 hydrogen-pyrroles-3-ethyl formate 11
Figure A20061007240600361
The preparation of 2-ethoxy carbonyl methyl-4-phenyl-1 hydrogen-pyrroles-3-carboxylic acid, ethyl ester 11b
In the there-necked flask of a 250ml who is furnished with reflux condensing tube, add 2-amino-1-phenyl-ethyl ketone 11a (10.3g, 0.06mol) and sodium-acetate (9.86g, 0.12mol), oil pump is evacuated to vacuum, stir add down 3-carbonyl-ethyl glutarate (10.9ml, 0.06mol) and water (60ml) stir, reflux stops heating, stirred overnight at room temperature after 5 hours.Next day, the some plate tracks to raw material and disappears substantially, finishes reaction.Reaction solution extracts with ethyl acetate (50ml * 7), merge organic phase, water (50ml * 1) is washed, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrate the dry organic phase of title product, concentrate and obtain product 2-ethoxy carbonyl methyl-4-phenyl-1 hydrogen-pyrroles-3-carboxylic acid, ethyl ester 11b (16.802g, light yellow solid), productive rate 93.03%.
MS?m/z(ESI)：302.2(M+1)。
The preparation of 4-phenyl-1 hydrogen-pyrroles-3-carboxylic acid, ethyl ester-2-carboxylic acid 11c
Under the argon atmospher, with 2-ethoxy carbonyl methyl-4-phenyl-1 hydrogen-pyrroles-3-carboxylic acid, ethyl ester 11b (20.387g, 0.068mmol) stir and descend to be dissolved in the mixing solutions of methyl alcohol (101.6ml) and tetrahydrofuran (THF) (101.6ml), add lithium hydroxide aqueous solution (11.38g, 0.27mol be dissolved in the water of 154ml), behind the room temperature reaction 0.5 hour, reflux 2 hours, the point plate tracks to raw material and disappears, finish reaction, vacuum rotary steam is removed methyl alcohol and tetrahydrofuran (THF), adds water (50ml) dilution, drip in the condition of ice bath downhill reaction liquid 20% hydrochloric acid to pH be 4, there are this moment a large amount of white solids to generate, suction filtration obtains title product 4-phenyl-1 hydrogen-pyrroles-3-carboxylic acid, ethyl ester-2-carboxylic acid 11c (18.48g, white solid), productive rate 100%.
MS?m/z(ESI)：274(M+1)。
2-[(2-diethylin-ethylamino formyl)-methyl]-preparation of 4-phenyl-1 hydrogen-pyrroles-3-ethyl formate 11d
With 5-methyl-4-phenyl-1 hydrogen-pyrroles-3-carboxylic acid, ethyl ester-2-carboxylic acid 11c (18.48g, 0.068mol) be dissolved in the mixed solvent of methylene dichloride (33.8.5ml) and N ' dinethylformamide (33.85ml), the ice bath cooling, stir and add N ' N-diethyl ethylenediamine (10.155ml down successively, 0.074mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (33.85g, 0.135mmol) and I-hydroxybenzotriazole (10.188g, 0.068mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 11c completely dissolve, add cold water (50ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (100ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (50ml * 1) successively, water (50ml * 1) and saturated nacl aqueous solution (50ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 2-[(2-diethylin-ethylamino formyl)-methyl]-4-phenyl-1 hydrogen-pyrroles-3-ethyl formate 11d (22.94g, brown oil), productive rate 91.33%.
MS?m/z(ESI)：372(M+1)。
2-[(2-diethylin-ethylamino formyl)-methyl]-5-formyl radical-4-phenyl-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 11e
Under the argon atmospher, in the single port bottle of a 25ml, add anhydrous N ' dinethylformamide (0.58ml, 7.5mmol), ice bath is cooled to 0 ℃, stir and slowly drip phosphorus oxychloride (0.42ml down, 4.5mmol), dropwising the back stirred 15 minutes under room temperature, continue cryosel again and bathe cooling, in reaction flask, drip 2-[(2-diethylin-ethylamino formyl)-methyl]-the anhydrous N ' dinethylformamide solution (1.113g of 4-phenyl-1 hydrogen-pyrroles-3-ethyl formate 11d, 3mmol is dissolved in the 3.6ml N ' dinethylformamide), keeping temperature of reaction is 0 ℃ of reaction 2 hours, after the some plate tracks to the raw material disappearance, add frozen water (25ml) cancellation reaction in reaction solution, stirred 5 minutes, regulating pH with 30% sodium hydroxide solution again is 12.Reaction solution extracts with ethyl acetate (25ml * 6); merge organic phase; organic phase is washed with saturated sodium-chloride water solution (15ml * 2); the ethyl acetate layer anhydrous sodium sulfate drying; filter, filtrate decompression concentrates and obtains title product 2-[(2-diethylin-ethylamino formyl)-methyl]-5-formyl radical-4-phenyl-1 hydrogen-pyrroles-3-ethyl formate 11e (1.19g, brown oil); productive rate 99.33%, thick product directly drops into next step reaction.
MS?m/z(ESI)：400.1(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 2-[(2-diethyl
Amido-ethylamino formyl)-methyl]-preparation of 4-phenyl-1 hydrogen-pyrroles-3-ethyl formate 11
Under the argon atmospher; in the single port bottle of a 10ml; add 2-[(2-diethylin-ethylamino formyl successively)-methyl]-5-formyl radical-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate 2c (0.14g; 0.35mmol); 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2; 3-d] pyrimidine-6-ketone (0.097g; 0.35mmol), piperidines (0.07ml, 0.7mmol) and ethanol (0.84ml); reflux 1.5 hours; the point plate tracks to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrroles [2,3-d] pyrimidine-6-ketone completely dissolve; reaction solution is naturally cooled to room temperature; have a large amount of solids to produce, decompress filter obtains title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6; 7-dihydro-pyrroles [2; 3-d] pyrimidine-5-methylene radical-methyl]-2-[(2-diethylin-ethylamino formyl)-methyl]-4-phenyl-1 hydrogen-pyrroles-3-ethyl formate 11 (0.041g, yellow solid), productive rate 17%.
MS?m/z(ESI)：660.8(M+1)。
1H?NMR(DMSO-D 6，400MHz)δ13.70(s，1H，NH)，8.84(s，1H，-NH)，7.36(s，1H，-CH＝C)，7.43(dd，1H，-ArH)，7.29-7.35(m，5H，-ArH)，7.22-7.27(m，2H，-ArH)，7.16(s，1H，-ArH)，4.02(t，2H，-CO 2CH 2-)，3.99(s，2H，-CH 2CON-)，3.19(t，2H，-CONCH 2-)，2.50(t，2H，-NCH 2-)，2.49(q，4H，2×-NCH 2-)，1.00(t，3H，CH 3)，0.95(t，3H，2×-CH 3)。
Embodiment 12
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 2-[(2-diethyl
Amido-ethylamino formyl)-methyl]-preparation of 4-Trifluoromethyl-1 hydrogen-pyrroles-3-ethyl formate 12
Figure A20061007240600381
Figure A20061007240600391
4,4, the preparation of 4-three fluoro-2-oximidos-3-carbonyl-tert-butyl acetate 12b
Under the condition of ice bath, with 4,4,4-three fluoro-3-carbonyl-tert-butyl acetate 12a (42.4g, 0.2mol), Glacial acetic acid (60ml) joins in the 250ml there-necked flask, stir the aqueous solution (20ml that dropwise drips Sodium Nitrite down, 10mol/L, 0.2mol), control reaction temperature is 0～5 ℃ in whole process.After dripping end, reaction is 1 hour in ice-water bath, removes ice-water bath, at room temperature continues about 3 hours of reaction, the point plate tracks to raw material and disappears, and reaction finishes, and obtains title product 4,4, the solution of 4-three fluoro-2-oximidos-3-carbonyl-tert-butyl acetate 12b is directly cast single step reaction.
5-ethoxy carbonyl methyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2, the preparation of the 4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 12c
Is furnished with thermometer to one, add 3-carbonyl-ethyl glutarate (48.2g in the three-necked flask of the 250ml of dropping funnel successively, 0.2mmol) and Glacial acetic acid (90ml), be warming up to 65 ℃ under stirring, the weighing zinc powder (is total to 26g, 0.4mol), zinc powder (the 3.25g that adds 1/8 amount, 0.05mmol), drip the first step reaction solution 12b of 1/8 amount with dropping funnel, water-bath hierarchy of control temperature can not rise too fast, treat that temperature is lower than 65 ℃ after, add again 1/8 the amount zinc powder and 1/8 the amount the first step reaction solution.So be repeated to zinc powder and the first step reaction solution 12b all adds.Elevated temperature to 75 ℃ reacted about 2 hours, and the some plate is followed the tracks of reaction and finished.Under the agitation condition, reaction solution is poured in the 100ml frozen water, continue to be stirred to room temperature, cross and filter out unreacted zinc powder, with ethyl acetate (100ml * 3) abstraction reaction liquid, merge organic phase, water (100ml * 3), saturated sodium bicarbonate water (100ml * 4) solution, saturated sodium-chloride water solution (100ml * 1) washing successively, the organic layer anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains title product 5-ethoxy carbonyl methyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2, the 4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 12c (67.6g, white waxy solid), productive rate 86%.
MS?m/z(ESI)：394(M+1)。
5-carboxymethyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2, the preparation of the 4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 12d
In the single port bottle of 1000ml, add 5-ethoxy carbonyl methyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2 successively, 4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 12c (34.6g, 0.088mol), tetrahydrofuran (THF) (268ml) and methyl alcohol (134ml), adding lithium hydroxide aqueous solution under stirring (134ml, 2.36mol/L, 0.316mol), room temperature condition reacted 1.5 hours down, and the some plate tracks to the raw material completely dissolve.After the reaction solution concentrating under reduced pressure removed most of tetrahydrofuran (THF) and methyl alcohol, add water (200ml) to concentrated solution, use ether (100ml * 5) extraction mixed solution then, water is transferred in the single port bottle of 1000ml, ice bath stir drip down 20% hydrochloric acid to pH be 1～3, there are a large amount of faint yellow precipitations to separate out, suction filtration, solid washs with a small amount of ether, vacuum-drying obtains title title product 5-carboxymethyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2, the 4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 12d (24g, white solid), productive rate 74.7%.
MS?m/z(ESI)：364(M-1)。
5-[(2-diethylin-ethylamino formyl)-methyl]-3-Trifluoromethyl-1 hydrogen
-pyrroles-2, the preparation of the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 12e
With 5-carboxymethyl-3-Trifluoromethyl-1 hydrogen-pyrroles-2,4-dicarboxylic acid-2-the tert-butyl ester-4-ethyl ester 12d (146mg, 0.4mmol) be dissolved in the mixed solvent of methylene dichloride (2ml) and N ' dinethylformamide (0.2ml), the ice bath cooling, stir and add N ' N-diethyl ethylenediamine (60ul down successively, 0.44mmol), N-ethyl-N '-(dimethylamino-propyl)-carbodiimide (154mg, 0.8mmol) and I-hydroxybenzotriazole (56mg, 0.4mmol), reaction system rises to room temperature naturally, and stirring is spent the night.Put plate next day to raw material 1d completely dissolve, add cold water (5ml) in the vigorous stirring downhill reaction liquid, leave standstill separatory, dichloromethane extraction reaction solution (50ml * 3), merge organic phase, organic phase is used unsaturated carbonate potassium solution (5ml * 1) successively, water (5ml * 1) and saturated nacl aqueous solution (25ml * 1) washing, the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 5-[(2-diethylin-ethylamino formyl)-methyl]-3-Trifluoromethyl-1 hydrogen-pyrroles-2, the 4-dioctyl phthalate-2-tert-butyl ester-4-ethyl ester 12e (154mg, light yellow mucus), productive rate 83%.
MS?m/z(ESI)：464(M+1)。
5-[(2-diethylin-ethylamino formyl)-methyl]-3-Trifluoromethyl-1 hydrogen
-pyrroles-2, the preparation of 4-dioctyl phthalate 4-ethyl ester 12f
In the there-necked flask of 100ml, with 5-[(2-diethylin-ethylamino formyl)-methyl]-3-Trifluoromethyl-1 hydrogen-pyrroles-2,4-dioctyl phthalate-2-the tert-butyl ester-4-ethyl ester 12e (5.87g, 12.67mmol) be dissolved in the methylene dichloride (35ml), stir and add trifluoracetic acid (5ml down, 67.4mmol), room temperature reaction 1.5 hours, the point plate is followed the tracks of raw material and is disappeared substantially, the reaction solution concentrating under reduced pressure is spin-dried for solvent, obtains title product 5-[(2-diethylin-ethylamino formyl)-methyl]-3-Trifluoromethyl-1 hydrogen-pyrroles-2,4-dioctyl phthalate 4-ethyl ester 12f (5.17g, light yellow solid), productive rate 100%.Be directly used in next step reaction.
2-[(2-diethylin-ethylamino formyl)-methyl]-5-hydroxymethyl-4-Trifluoromethyl-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 12g
Under the nitrogen atmosphere, in the 250ml round-bottomed flask, with 5-[(2-diethylin-ethylamino formyl)-methyl]-3-Trifluoromethyl-1 hydrogen-pyrroles-2,4-dioctyl phthalate 4-ethyl ester 12f (13.594g, 33.4mmol) stir down and be dissolved in the anhydrous tetrahydro furan (20ml) tetrahydrofuran solution (100ml, the 1mol/L of dropping borine in reaction solution, 100mmol), room temperature reaction spends the night.The point plate tracks to raw material and disappears, and is chilled to 0 ℃, and (50ml 1mol/L) with the cancellation reaction, stirs after 15 minutes, is neutralized to pH12 with 10% sodium hydroxide, uses ethyl acetate extraction reaction solution (50ml * 3) more slowly to drip dilute hydrochloric acid in reaction solution.Merge organic phase, the ethyl acetate layer anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates, obtain title product 2-[(2-diethylin-ethylamino formyl)-methyl]-5-hydroxymethyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-ethyl formate 12g (2.94g, white solid), productive rate 55%.
MS?m/z(ESI)：394(M+1)。
2-[(2-diethylin-ethylamino formyl)-methyl]-5-formyl radical-4-Trifluoromethyl-1 hydrogen
The preparation of-pyrroles-3-ethyl formate 12h
With pyridine chromium trioxide hydrochloride (4.3g, 20mmol), sodium-acetate (1.0g, 12.19mmol) and methylene dichloride (50ml) add in the 250ml round-bottomed flask, stir and slowly to drip 2-[(2-diethylin-ethylamino formyl down)-methyl]-the methylene dichloride suspension solution (7.14g of 5-hydroxymethyl-4-Trifluoromethyl-1 hydrogen-pyrroles-3-ethyl formate 12g, 18.7mmol, be dissolved in the 80ml methylene dichloride), room temperature reaction 5 hours, some plate are followed the tracks of raw material and are disappeared substantially.Reaction solution is through diatomite filtration; concentrating under reduced pressure with silica gel column chromatography purifying gained resistates, obtains title product 2-[(2-diethylin-ethylamino formyl)-methyl]-5-formyl radical-4-Trifluoromethyl-1 hydrogen-pyrroles-3-ethyl formate 12h (4.985g; white solid), productive rate 70%.
MS?m/z(ESI)：392(M+1)。
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-the 2-[(2-diethyl
Amido-ethylamino formyl)-methyl]-preparation of 4-Trifluoromethyl-1 hydrogen-pyrroles-3-ethyl formate 12
Under the argon atmospher; in the single port bottle of a 10ml; add 2-[(2-diethylin-ethylamino formyl successively)-methyl]-5-formyl radical-4-Trifluoromethyl-1 hydrogen-pyrroles-3-ethyl formate 12h (90mg; 0.23mmol); 4-(3-chloro-4-fluoro-aniline)-5; 7-dihydro-pyrroles [2; 3-d] and pyrimidine-6-ketone (56mg, 0.2mmol), piperidines (0.05ml; 0.5mmol) and ethanol (0.5ml); reflux 1.5 hours, the some plate tracks to 4-(3-chloro-4-fluoro-aniline)-5, and 7-dihydro-pyrroles [2; 3-d] pyrimidine-6-ketone completely dissolve; reaction solution is naturally cooled to room temperature, have a large amount of solids to produce decompress filter; repeatedly wash yellow solid with small amount of ethanol; obtain title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-2-[(2-diethylin-ethylamino formyl)-methyl]-4-Trifluoromethyl-1 hydrogen-pyrroles-3-ethyl formate 12 (61mg; yellow solid), productive rate 41%.
MS?m/z(ESI)：652(M+1)。
Test case:
The mensuration of kinase inhibiting activity
At target spot VEGFR, detection mode is that (Time-resolved Fluorescence TRF), uses the HTScan of Cell Signaling company to time-resolved fluoroimmunoassay TMVEGF-R2 Kinase Assay Kit (Cat.No.7788) tests highly sensitive.Through groping of experiment condition repeatedly, determine that in 30 μ l reaction systems use reorganization VEGFR2 albumen 6U, concentration of substrate is 1.5 μ M, suppressing compound concentration is the basic parameters of 10 μ M as screening model, and testing compound is screened;
At target spot EGFR/HER-2, use the K-LISA of CALBIOCHEM company TM96 hole elisa plates of PTK ScreeningKit (Cat.No.539701) and EGFR/HER-2 effect E4Y substrate bag quilt, kinases (rat spleen extract) 0.25-1 μ g is used in the reaction of every hole, using the inhibition compound concentration simultaneously is the basic parameter of the experiment condition of 50 μ M as the screening platform, and testing compound is screened.
With A431 epidermoid carcinoma and different concns compound (being respectively 100～0.001 μ g/ml) incubation 72 hours, estimate the inhibition degree of embodiment 2 compound on cell proliferation, calculate inhibiting rate, adopt the Logit method to calculate IC according to inhibiting rate 50, the IC of 2 couples of EGFR of discovery embodiment 50Be 0.28 μ M.
The present invention records the EGFR/HER-2 of compound and the average kinase inhibition rate of VEGFR sees Table 1
The average kinase inhibition rate of table 1EGFR/HER-2 and VEGFR
Figure A20061007240600421
Figure A20061007240600431

Claims (11)

1. compound or its salt by general formula (I) expression:
Figure A2006100724060002C1
Wherein:
X is selected from W (CH 2), (CH 2) W or W, wherein W is O, S, SO, SO 2Or X is-NR 6, R wherein 6Be hydrogen atom or alkyl;
Y is Sauerstoffatom or hydrogen atom;
When X is-NR 6, R 6When being alkyl, R 6And R 1Form 4～8 yuan of heterocyclic radicals; Wherein, if 5～8 yuan of heterocycles, then it contains one or more N, O, S atom; If on 4～8 yuan of heterocycles, then its further by one or more alkyl, halogen, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR 7R 8Replace;
R 1Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl further by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, alkoxyl group, aryloxy, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR 7R 8Replace; Wherein aryl, heteroaryl, aralkyl or heteroaralkyl and become dicyclo;
R 2Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl ,-(CH 2CH 2O) nR 6, alkenyl or alkynyl ,-COOR 7,-CONR 7R 8,-C (=S) NR 7R 8,-COR 7,-SOR 7,-SO 2R 7,-SO 2NR 7R 8Perhaps-P (=O) (OR 7) (OR 8), wherein alkyl, cycloalkyl, Heterocyclylalkyl, alkenyl or alkynyl are further replaced by one or more alkyl, hydroxyl, alkoxyl group, cyano group, amino, alkylamino, carboxylic acid or carboxylicesters;
R 3Be selected from the aryl or the trifluoromethyl of hydrogen atom, alkyl, aryl, halogen replacement;
R 4Be selected from hydroxyl, alkoxyl group, aryloxy, heterocycle alkoxyl group, aralkoxy ,-(OCH 2CH 2) nR 6,-N (R 7) (CH 2) nR 8,-NR 7[CH 2CH 2O] nR 8,-NR 7R 8Perhaps-NR 6(CH 2) n[CH (OH) CH 2] rZ; Wherein Z be aryl, heteroaryl, Heterocyclylalkyl ,-NR 7R 8,-COOR 6Or CONR 7R 8
R 5Be selected from hydroxyl, alkoxyl group, aryloxy, heterocycle alkoxyl group, aralkoxy ,-N (R 7) (CH 2) nR 8,-NR 7[CH 2CH 2O] nR 8,-NR 7R 8Perhaps-NR 6(CH 2) n[CH (OH) CH 2] rZ; Wherein Z be aryl, heteroaryl, Heterocyclylalkyl ,-NR 7R 8,-COOR 6Or CONR 7R 8
R 6Be hydrogen atom or alkyl;
R 7And R 8Be selected from hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or heteroaralkyl respectively, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or heteroaralkyl are further replaced by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid or carboxylicesters;
Simultaneously, R 7And R 8Form 4～8 yuan of heterocyclic radicals; Wherein, if 5～8 yuan of heterocycles, then it contains one or more N, O, S atom; If on 4～8 yuan of heterocycles, then its further by one or more alkyl, halogen, aryl, heteroaryl, haloalkyl, halogenated alkoxy, hydroxyl, amino, amide group, amine acyl group, cyano group, alkoxyl group, aryloxy, amine alkyl, hydroxyalkyl, Heterocyclylalkyl, carboxylic acid, carboxylicesters or-NR 7R 8Replace;
N is 1～6;
R is 1～2.
2. compound or its salt according to claim 1, wherein X is-NR 6, R wherein 6Be hydrogen atom or alkyl.
3. compound or its salt according to claim 1, wherein X is-NH, R 1Be hydrogen atom, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl are further replaced by one or more alkyl, halogen, aryl, hydroxyl, amino, alkylamino, amide group, amine acyl group, alkoxyl group, aryloxy, Heterocyclylalkyl, carboxylic acid, carboxylicesters.
4. compound or its salt according to claim 1, wherein Y is a Sauerstoffatom.
5. compound or its salt according to claim 1, wherein R 2Be hydrogen atom or alkyl.
6. according to the described compound or its salt of claim 1～4, comprising:
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(3-morphine quinoline-4-base-third carbamyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-2-[(2-diethylin-ethylamino formyl)-methyl]-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(2-piperidines-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-2-[2-(3,5-dimethyl-piperazine-1-yl)-2-oxo-ethyl]-4-methyl isophthalic acid hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(2-tetramethyleneimine-1-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[(2-morpholine-4-base-ethylamino formyl)-methyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-{[3-(2-methyl-piperidines-1-yl)-third carbamyl]-methyl }-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[2-(4-methyl-Pai piperazine-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[2-(4-morpholine-4-base-piperidines-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-4-methyl-2-[2-oxo-2-(2-tetramethyleneimine-1-ylmethyl-tetramethyleneimine-1-yl)-ethyl]-1 hydrogen-pyrroles-3-ethyl formate
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-2-[(2-diethylin-ethylamino formyl)-methyl]-4-phenyl-1 hydrogen-pyrroles-3-ethyl formate.
5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrroles [2,3-d] pyrimidine-5-methylene radical-methyl]-2-[(2-diethylin-ethylamino formyl)-methyl]-4-Trifluoromethyl-1 hydrogen-pyrroles-3-ethyl formate.
7. the preparation method of general formula according to claim 1 (I) compound or its salt may further comprise the steps:
Figure A2006100724060004C1
With the raw material I-1a that is easy to get is starting raw material, obtains general formula I-1b compound with the Sodium Nitrite reaction;
Figure A2006100724060004C2
Gained I-1b compound is obtained general formula I-1c compound through Ke Nuoer-pyrroles Cheng Huan;
Figure A2006100724060004C3
Behind the selective hydrolysis of alkali hydroxide soln, obtain general formula I-1d compound under the described I-1c compound room temperature;
Figure A2006100724060004C4
I-1d compound and R 5NH 2Carry out amidate action and obtain general formula I-1e compound;
The I-1e compound obtains general formula I-1f compound through the decarboxylation under the trifluoracetic acid effect;
Figure A2006100724060005C2
The I-1f compound obtains general formula I-1g compound with phosphorus oxychloride through formylation reaction in anhydrous system;
Figure A2006100724060005C3
General formula I-1g compound with
Figure A2006100724060005C4
Condensation promptly obtains compound shown in the general formula I.
8. according to the preparation method of claims 6 described general formula (I) compounds, wherein said alkali hydroxide soln is a lithium hydroxide solution.
9. pharmaceutical composition, its contain the treatment effective dose according to compound or its salt and pharmaceutical carriers shown in any one described general formula (I) in the claim 1～4.
10. according to the purposes of any one described compound or its salt in the claim 1～4 in preparation tyrosine kinase inhibitor medicine.
11. the purposes of composition according to claim 8 in preparation tyrosine kinase inhibitor medicine.
CNA2006100724066A 2006-04-11 2006-04-11 Pyrrole substituted pyrimidinone derivative, preparation method and use thereof in medicine Pending CN101054379A (en)

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