CN104387385B - 6-carboxylate methyl ester-2-oxygen-7-azaindole and preparation method thereof and application - Google Patents
6-carboxylate methyl ester-2-oxygen-7-azaindole and preparation method thereof and application Download PDFInfo
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- CN104387385B CN104387385B CN201410647370.4A CN201410647370A CN104387385B CN 104387385 B CN104387385 B CN 104387385B CN 201410647370 A CN201410647370 A CN 201410647370A CN 104387385 B CN104387385 B CN 104387385B
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- azaindole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to as shown in the formula the 6-carboxylate methyl ester-2-oxygen-7-azaindole shown in (I), also relate to its preparation method and application, its preparation method is with 6-itrile group-7-azaindole for raw material, obtains through itrile group hydrolysis, carboxylate methyl ester, bromine oxidation and reduction four-step reaction.The method raw material is easy to get, easy and simple to handle, productive rate is high.As key intermediate, for the multiple preparation with bioactive final product opens the approach of new uniqueness.Especially, preparation method of the present invention can obtain the product of purity more than 98%, thus makes the synthesis mass-producing continuous seepage of final product.
Description
Technical field
The present invention relates to 6-carboxylate methyl ester-2-oxygen-7-azaindole and preparation method thereof and application.
Background technology
The compound that it is parent nucleus that 6-carboxylate methyl ester-2-oxygen-7-azaindole belongs to 2-oxygen-7-azaindole, (7-aza-2-oxindoleor2-oxo-1,3-dihydropyrrolo [2,3-b] pyridines), due to chemical structure and the physico-chemical property of its uniqueness of 2-oxygen-7-azaindole, be widely used in field of medicaments.At present, 2-oxygen-7-azaindoles has been found to have many pharmacologically actives: have anti-internal organs Fibrosis parameters, is applied to the diseases such as tumour, liver cirrhosis, treatment pulmonary fibrosis, osteoporosis and cerebral apoplexy.
Compound containing 6-carboxylate methyl ester-2-oxygen-7-azaindole structure, tool report has antitumor, anti-liver cirrhosis, suppress the Fibrotic effect (Preparationofpyrrolopyridinesasanti-fibroticcompounds of pathology, PCTInt.Appl. (2013), 61pp.WO2013112959); 2-oxygen-7-azaindole the protein kinase that Selective depression is relevant with cells multiply in model in vivo, can Therapeutic cancer.(Azaindolederivativesaskinaseinhibitors, US2011294806); Simultaneously, 2-oxygen-7-7-azaindole derivatives shows antiallergic activity (1 in some animal excessive immune reaction disease model, 3-dihydro-2H-pyrrolo [2,3-b] pyridin-2-oneandoxazolo [4,5-b] pyridin-2-(3H)-onecompounds, US5618819); 2-oxygen-7-the azaindole replaced has the effect suppressing TYR protein kinase and serineprotein kinase, therefore the growth of anticancer, there is the effect (Substitutedaza-oxindolederivatives, WO0055159) of the alopecia preventing chemotherapeutics from causing simultaneously; Further data presentation, this compounds can suppress the receptor tyrosine protein kinase family member of vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR), therefore obvious restraining effect (Azaindolederivatives, WO9921859) is had to tumour cell.
In sum, with the compound that 2-oxygen-7-azaindole is parent nucleus, there is multiple biological activity, or further structure of modification is carried out to it, can synthesize and multiple there is bioactive final product.
6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention to be the present inventor successfully synthesize through experimental study for many years a new compound.It is as intermediate, has important value, manyly has bioactive final product because only have just can be synthesized by it.
Such as; for the synthesis of having bioactive final product; 1-ethanoyl-3 vinylbenzene replace-6-carboxylate methyl ester-2-oxygen-7-azaindoles; (Preparationofpyrrolopyridinesasanti-fibroticcompounds; PCTInt.Appl. (2013); 61pp.WO2013112959); this patent applies 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention; as the intermediate of its key; just successfully synthesize these final products; in other words, for the preparation of these final products opens the approach of new uniqueness.Especially there is no this high quality intermediate, scale continuous seepage can not be embodied as, because method of the present invention can also prepare the 6-carboxylate methyl ester-2-oxygen-7-azaindole that purity is 99%, thus, this kind of final product continuous seepage on a large scale can be realized.
For another example,-6-carboxylate methyl ester-2-oxygen-7-azaindoles (3-(2-pyrroles's methylene radical) azaindole quinoline-2-ketone derivatives and preparation method thereof and application is replaced as intermediate synthesis final product 3-pyrroles alkene, ZL201010010039.3), also for the preparation of this kind of final product opens the approach of new uniqueness.In its building-up reactions step as intermediate, when the aldehyde substituting group of pyrroles is connected with the indole ring of 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention, the purity requirement of 6-carboxylate methyl ester-2-oxygen-7-azaindole is in purity more than 90%, and what guarantee reacted effectively carries out.Preparation method of the present invention, through lot of experiments for many years, can obtain the product of purity more than 98%, thus make final product be easy to continuous seepage on a large scale.
Summary of the invention
The object of the present invention is to provide 6-carboxylate methyl ester-2-oxygen-7-azaindole.
Another object of the present invention is to provide the method preparing 6-carboxylate methyl ester-2-oxygen-7-azaindole.
Another object of the present invention is to provide the 6-carboxylate methyl ester-2-oxygen-7-purposes of azaindole, and it is as intermediate, has bioactive compound for the synthesis of multiple.
According to 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention, its structure is for as shown in the formula shown in (I):
According to the preparation method of 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention, be step as follows:
Step one itrile group hydrolysis reaction: first dissolved by 6-itrile group-7-azaindole with alcoholic solvent, then add dense mineral alkali, generates 6-carboxylic acid-7-azaindole;
Step 2 carboxylic esterification reacts: with dense mineral acid for catalyzer, by 6-carboxylic acid-7-azaindole methanol esterification, generates 7-azaindole-6-carboxylate methyl ester;
Step tribromo oxidizing reaction: 7-azaindole-6-carboxylate methyl ester is dissolved in alcoholic solvent, temperature controls 40 DEG C, added pyridinium bromide hydrobromide, react, maintain the temperature at 3 ~ 7 DEG C again, carry out aftertreatment with vinyl acetic monomer, use methanol/water recrystallization, the obtained bromo-2-oxygen of 3,3-bis--7-azaindole-6-carboxylate methyl ester;
Step 4 reduction reaction: bromo-for 3,3-bis-2-oxygen-7-azaindole-6-carboxylate methyl ester is dissolved in tetrahydrofuran solvent, reacts with reductive agent, then through aftertreatment and activated carbon decolorizing, obtained 6-carboxylate methyl ester-2-oxygen-7-azaindole;
Wherein, in step one, alcoholic solvent is methyl alcohol, ethanol or propyl alcohol, and mineral alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide;
In step 2, mineral acid is sulfuric acid, hydrochloric acid, hydroiodic acid HI or Phenylsulfonic acid;
In step 3, alcoholic solvent is the trimethyl carbinol or propyl carbinol, maintains the temperature at 3 ~ 6 DEG C with in vinyl acetic monomer last handling process;
In step 4, reductive agent is the hydrogenation reaction of zinc powder and ammonium chloride, Pd/C or Raney-Ni catalysis.
According to the preparation method of 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention, it is characterized in that, in step 3, alcoholic solvent used is the trimethyl carbinol, maintains the temperature at 4 ~ 5 DEG C with in vinyl acetic monomer last handling process.
According to the preparation method of 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention, it is characterized in that, reacting reductive agent in step 4 is zinc powder, and auxiliary reagent is saturated aqueous ammonium chloride.
According to the preparation method of 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention, it is characterized in that, when being reaction reductive agent with zinc powder in step 4, reaction solvent tetrahydrofuran (THF) and auxiliary reagent saturated aqueous ammonium chloride usage ratio are 1:1 ~ 1.2.
According to the preparation method of 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention, it is characterized in that, in step 4, the ratio of last handling process tetrahydrofuran (THF) and vinyl acetic monomer 1:1 ~ 1.2 extracts.
According to the purposes of 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention, it is characterized in that, with its preparation, there is bioactive compound.
According to the purposes of 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention, it is characterized in that with its preparation, there is bioactive 3-pyrroles's alkene and replace-6-carboxylate methyl ester-2-oxygen-7-azaindoles.
According to the purposes of 6-carboxylate methyl ester-2-oxygen-7-azaindole of the present invention, it is characterized in that with its preparation, there are bioactive 1-ethanoyl-3 vinylbenzene and replace-6-carboxylate methyl ester-2-oxygen-7-azaindoles.
Described 6-carboxylate methyl ester-2-oxygen-7-azaindole is as intermediate; the compound with anti-histoorgan Fibrosis parameters can be synthesized;-3 vinylbenzene of 1-ethanoyl shown in following formula II replace-6-carboxylate methyl ester-2-oxygen-7-azaindoles, and it can be prepared by following synthetic route:
6-carboxylate methyl ester-2-oxygen-7-azaindole, as intermediate, necessarily requires high purity, to ensure the validity of reacting, if purity is less than 90%, can not realize final product synthesis mass-producing continuous seepage.Preparation method of the present invention, can reach purity be 99% 6-carboxylate methyl ester-2-oxygen-7-azaindole, final product synthesis mass-producing continuous seepage can be realized.
6-carboxylate methyl ester-2-oxygen-7-azaindole is as intermediate, the TYR kinases inhibitor with antitumous effect can be synthesized, 3-pyrroles's alkene shown in following formula III replaces-6-carboxylate methyl ester-2-oxygen-7-azaindoles, and it can be prepared by following synthetic route:
When the aldehyde substituting group of the pyrroles in above-mentioned reaction is connected with the indole ring of 6-carboxylate methyl ester-2-oxygen-7-azaindole, 6-carboxylate methyl ester-2-oxygen-7-azaindole purity necessarily requires in purity more than 90%, effectively carrying out of guarantee reaction.Preparation method of the present invention can obtain the product of purity more than 98%, thus makes the synthesis mass-producing continuous seepage of final product.
6-carboxylate methyl ester-2-oxygen-7-azaindole synthetic method of the present invention, has the advantages that cheaper starting materials is easy to get, easy and simple to handle, productive rate is high.
Embodiment
Following embodiment, only for explaining the present invention, does not form the restriction to right, other alternative means that those skilled in the art can expect according to description, all should within the protection domain of the claims in the present invention.
Embodiment: the preparation of 6-carboxylate methyl ester-2-oxygen-7-azaindole:
Step as follows:
1, the preparation of 7-azaindole-6-carboxylate methyl ester:
Itrile group hydrolysis reaction:
With 5 liters of there-necked flasks, under mechanical stirring, 6-itrile group-7-azaindole 123 grams is added in ethanol 1.7 liters, under room temperature, adding concentration is 5N caustic lye of soda 1.2 liters, keeps temperature 80 DEG C of backflows to spend the night, detect with thin-layer chromatography TLC, complete to raw material reaction, stopped reaction.
Aftertreatment:
Naturally after being down to room temperature, by reaction solution impouring 5 liters of frozen water, adjust pH to 3 ~ 4 with hydrochloric acid, separate out solid product, suction filtration, dry, obtained 7-azaindole 6-carboxylic acid 176 grams.Sampling detects, and high-pressure liquid phase HPLC shows purity 97%.
Carboxylic esterification reacts:
With 5 liters of there-necked flasks, under mechanical stirring, 7-azaindole 6-carboxylic acid 176 grams is added in methyl alcohol 1.9 liters, then, slowly add the vitriol oil 80 milliliters, heating, flows through night next time 70 DEG C of temperature, and HPLC detects, complete to raw material reaction, stopped reaction, is down to room temperature naturally.
Aftertreatment:
By in reaction solution impouring 5 liters of frozen water, suction filtration, filter cake, with after 500 milliliters of washings, adds in 2 premium on currency, adjust pH to 7 ~ 8 with saturated sodium bicarbonate solution, stir 30 minutes, suction filtration, filter cake is with after 500 milliliters of washings, and decompression drying, obtains 7-azaindole-6-carboxylate methyl ester (2) 127 grams.Sampling detects, and HPLC shows purity 96.7%.Mass spectrum LRMS (M+1)=176.9.
2, the preparation of 3,3-bis-bromo-2-oxygen-7-azaindole-6-carboxylate methyl esters:
Bromine oxidizing reaction:
With 5 liters of there-necked flasks, under mechanical stirring, by 7-azaindole 6-carboxylate methyl ester 60 grams, add in the trimethyl carbinol 3.7 liters, when being warming up to 40 DEG C, adding pyridinium bromide hydrobromide (PBPB) 545 grams in batches, and added in 1 hour.Be incubated again to 40 DEG C of reactions 1 hour.Sampling monitoring, HPLC shows feed/product ratio and is not more than 1%.
Aftertreatment and recrystallization:
Poured into by reaction solution in 5 liters of frozen water, with vinyl acetic monomer 5 liters, at 5 DEG C of temperature, gradation extraction, collects organic layer, after being evaporated to 1/3 quantity of solvent, pours in 3 liters of frozen water, separates out solid, suction filtration, and filter cake is with after 500 milliliters of washings, dry.Carry out recrystallization by ethyl acetate and methanol weight than 1:5, suction filtration, after drying under reduced pressure, the obtained bromo-2-oxygen of 3,3-bis--7-azaindole-6-carboxylate methyl ester (3) 85 grams, sampling detects, and HPLC shows purity 90%.Fusing point MP:157 ~ 159 DEG C, mass spectroscopy LRMS:(M+1)=350.9; Nucleus magnetic resonance 1H-NMR (DMSO-d6), (ppm), 12.3 (1H, br), 8.19 (1H, d, J=7.8Hz), 7.85 (1H, d, J=7.8Hz), 3.89 (3H, s).
3, the preparation of 6-carboxylate methyl ester-2-oxygen-7-azaindole (I)
Reduction reaction:
With 5 liters of there-necked flasks, under mechanical stirring, bromo-for 3,3-bis-2-oxygen-7-azaindole-6-carboxylate methyl ester 64 grams is added in tetrahydrofuran (THF) 0.75 liter, after all dissolving, add saturated aqueous ammonium chloride 0.75 liter.When being warming up to 40 DEG C, within half an hour, add zinc powder 117 grams, gradation adds, and reacts half an hour under room temperature.
Aftertreatment and activated carbon decolorizing:
By reaction solution suction filtration, filter cake tetrahydrofuran (THF), each 200 milliliters, wash 4 times, collect filtrate, filtrate tetrahydrofuran (THF) and vinyl acetic monomer part by weight 1:1 extract, each 2 liters, extract 6 times, collect organic phase, with anhydrous sodium sulfate drying, activated carbon decolorizing, after suction filtration, filtrate reduced in volume is to half volume, and crystallization after frozen water cooling, after decompress filter, with vinyl acetic monomer, each 50 milliliters, wash 3 times, obtained 6-carboxylate methyl ester-2-oxygen-7-azaindole (I) 23 grams, sampling detects, and HPLC shows purity 99%.MP：231～233℃，LRMS，(M+1)＝193.1and(M+Na)＝215.1；1H-NMR(DMSO-d6),(ppm),11.2(1H,br),7.71(1H,d,J＝7.6Hz),6.98(1H,d,J＝7.6Hz),3.86(3H,s),3.64(2H,s)。
Claims (1)
1. a preparation method for 6-carboxylate methyl ester-2-oxygen-7-azaindole is step as follows:
The preparation of 7-azaindole-6-carboxylate methyl ester:
Itrile group hydrolysis reaction:
With 5 liters of there-necked flasks, under mechanical stirring, 6-itrile group-7-azaindole 123 grams is added in ethanol 1.7 liters, under room temperature, adding concentration is 5N caustic lye of soda 1.2 liters, keeps temperature 80 DEG C of backflows to spend the night, detect with thin-layer chromatography TLC, complete to raw material reaction, stopped reaction;
Aftertreatment:
Naturally after being down to room temperature, by reaction solution impouring 5 liters of frozen water, adjust pH to 3 ~ 4 with hydrochloric acid, separate out solid product, suction filtration, dry, obtained 7-azaindole 6-carboxylic acid;
Carboxylic esterification reacts:
With 5 liters of there-necked flasks, under mechanical stirring, 7-azaindole 6-carboxylic acid 176 grams is added in methyl alcohol 1.9 liters, then, slowly add the vitriol oil 80 milliliters, heating, flows through night next time 70 DEG C of temperature, and HPLC detects, complete to raw material reaction, stopped reaction, is down to room temperature naturally;
Aftertreatment:
By in reaction solution impouring 5 liters of frozen water, suction filtration, filter cake, with after 500 milliliters of washings, adds in 2 premium on currency, adjusts pH to 7 ~ 8, stir 30 minutes, suction filtration with saturated sodium bicarbonate solution, and filter cake is with after 500 milliliters of washings, and decompression drying, obtains 7-azaindole-6-carboxylate methyl ester;
The preparation of the bromo-2-oxygen of 3,3-bis--7-azaindole-6-carboxylate methyl ester:
Bromine oxidizing reaction:
With 5 liters of there-necked flasks, under mechanical stirring, by 7-azaindole 6-carboxylate methyl ester 60 grams, add in the trimethyl carbinol 3.7 liters, when being warming up to 40 DEG C, adding pyridinium bromide hydrobromide 545 grams in batches, and added in 1 hour, then be incubated to 40 DEG C of reactions 1 hour;
Aftertreatment and recrystallization:
Poured into by reaction solution in 5 liters of frozen water, with vinyl acetic monomer 5 liters, at 5 DEG C of temperature, gradation extraction, collects organic layer, after being evaporated to 1/3 quantity of solvent, pours in 3 liters of frozen water, separates out solid, suction filtration, and filter cake is with after 500 milliliters of washings, dry;
Recrystallization is carried out than 1:5, suction filtration by ethyl acetate and methanol weight, after drying under reduced pressure, the obtained bromo-2-oxygen of 3,3-bis--7-azaindole-6-carboxylate methyl ester;
The preparation of 6-carboxylate methyl ester-2-oxygen-7-azaindole
Reduction reaction:
With 5 liters of there-necked flasks, under mechanical stirring, bromo-for 3,3-bis-2-oxygen-7-azaindole-6-carboxylate methyl ester 64 grams is added in tetrahydrofuran (THF) 0.75 liter, after all dissolving, add saturated aqueous ammonium chloride 0.75 liter, when being warming up to 40 DEG C, within half an hour, add zinc powder 117 grams, gradation adds, and reacts half an hour under room temperature;
Aftertreatment and activated carbon decolorizing:
By reaction solution suction filtration, filter cake tetrahydrofuran (THF), washs 4 times by each 200 milliliters, collect filtrate, filtrate tetrahydrofuran (THF) and vinyl acetic monomer part by weight 1:1 extract, each 2 liters, extract 6 times, collect organic phase, with anhydrous sodium sulfate drying, activated carbon decolorizing, after suction filtration, filtrate reduced in volume is to half volume, crystallization after frozen water cooling, after decompress filter, with vinyl acetic monomer, each 50 milliliters, wash 3 times, obtained 6-carboxylate methyl ester-2-oxygen-7-azaindole.
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