CN102399235A - Synthesis method of 2-amino-5-pyrimidine pinacol borate - Google Patents
Synthesis method of 2-amino-5-pyrimidine pinacol borate Download PDFInfo
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- CN102399235A CN102399235A CN201110326855XA CN201110326855A CN102399235A CN 102399235 A CN102399235 A CN 102399235A CN 201110326855X A CN201110326855X A CN 201110326855XA CN 201110326855 A CN201110326855 A CN 201110326855A CN 102399235 A CN102399235 A CN 102399235A
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Abstract
The invention relates to a synthesis method of 2-amino-5-pyrimidine pinacol borate. The preparation method is characterized by comprising the following steps of: reacting 2-amino-5-bromo pyrimidine with ditertbutyl dicarbonate under the catalysis action of 4-dimethylaminopyridine to obtain a product in which an amino group at the second position in pyrimidine is protected by two tertiarybutoxy carbonyl groups; carrying out lithiation on the obtained product under the action of nbutyl lithium, reacting with the lithiated product with triisopropyl borate under the protection of nitrogen at a temperature between 70 DEG C below zero and 80 DEG C below zero so that bromine at the fifth position is converted into boric acid, wherein a tertiarybutoxy carbonyl group possibly falls off from a part of the product on a quenching condition so as to finally obtain a product which is a compound; removing the tertiarybutoxy carbonyl group serving as a protection group from the obtained product under the action of acid so as to obtain 2-amino pyrimidine-5-boric acid; carrying out reflux and water distillation on the obtained 2-amino pyrimidine-5-boric acid and pinacol in an organic solvent to obtain 2-amino-5-pyrimidine pinacol borate. The preparation method has the advantages of simple process and high production efficiency and can be applied to mass production.
Description
Technical field
The present invention relates to the amplification production technique of a kind of compound 2-aminopyrimidine-5-boric acid pinacol ester, belong to biomedicine field.
Background technology
2-aminopyrimidine fragment is all having appearance in a lot of marketed drug, Novartis's tyrosine kinase inhibitor imatinib (2003) of producing for example, the angiogenesis inhibitor handkerchief azoles handkerchief Buddhist nun (2009) that nilotinib (2007) and GlaxoSmithKline PLC are produced.2-aminopyrimidine-5-boric acid pinacol ester is to make up the segmental important midbody of 2-aminopyrimidine; But the method for bibliographical information mainly is to be obtained by 2-amino-5-bromo pyrimi piperidine and the coupling under the catalytic effect of palladium of duplex tetramethyl ethylene ketone boric acid ester at present, though this method has only single step reaction, the reagent that relates to costs an arm and a leg; Catalyzer is to air-sensitive; Severe reaction conditions, and the product heavy metal content is higher, is not easy to suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention provides the amplification production technique of a kind of 2-aminopyrimidine-5-boric acid pinacol ester; With 2-amino-5-bromo pyrimi piperidine as raw material; At first amino is protected, then through carrying out lithiumation, production boric acid 5; Pass through deprotection again, generate target compound 2-aminopyrimidine-5-boric acid pinacol ester with the tetramethyl ethylene ketone reaction.
For solving the problems of the technologies described above, the present invention is achieved in that
The amplification production technique of a kind of 2-aminopyrimidine-5-boric acid pinacol ester is characterized in that according to following reaction formula reaction:
(1), amino-5 bromo pyrimi piperidines of 2-react under the katalysis of catalyzer 4-Dimethylamino pyridine with tert-Butyl dicarbonate, obtain the product that pyrimidine 2 bit aminos are protected by two tertbutyloxycarbonyls; Temperature of reaction is 15-30 ℃, and reaction times 5-8h, solvent for use are N (DMF); The mol ratio of amino-5 bromo pyrimi piperidines of tert-Butyl dicarbonate and 2-is 2-3; Preferred 2.5, the mol ratio of amino-5 bromo pyrimi piperidines of catalyzer 4-Dimethylamino pyridine and 2-is 0.1-0.2, preferred 0.15.
(2), the product that obtains of step (1) after the lithiumation under the effect of n-Butyl Lithium with triisopropyl borate ester under nitrogen protection; At-70 to-80 ℃ of scope internal reactions; 5 bromines are converted into boric acid; Under quenched conditions, there is portion of product can lose a tertbutyloxycarbonyl, obtaining at last is the mixture of product (3) and product (4).In this step, the molar equivalent of n-Butyl Lithium is 1.0-1.5, preferred 1.2 equivalents, because in this ratio, the yield of product is the highest.Solvent for use is THF (THF).
(3), the mix products that obtained of step (2) under the acid effect, slough tertbutyloxycarbonyl protection base, obtain 2-aminopyrimidine-5-boric acid, the acid in the reaction can be methanol hydrochloride solution or concentrated hydrochloric acid, because the cost of concentrated hydrochloric acid is lower, so preferred concentrated hydrochloric acid.The amount of concentrated hydrochloric acid does not have particular requirement in this step, and its effect is merely creates the sour environment that product is separated out.
(4), step (3) product and the tetramethyl ethylene ketone reflux water-dividing in organic solvent that obtain, obtain 2-aminopyrimidine-5-boric acid pinacol ester, organic solvent is a toluene; YLENE; Because when toluene is made solvent, the needed temperature of reaction of system is lower, so preferred toluene.
Beneficial effect of the present invention is following:
2-aminopyrimidine-5-boric acid pinacol ester is the important intermediate of biological medicine, but does not up to the present also have sophisticated technology to produce amplification, step route of the present invention, and technology is simple, and production efficiency is high, can amplify production.
Description of drawings
Fig. 1 accompanying drawing is the HNMR collection of illustrative plates of 2-aminopyrimidine-5-boric acid pinacol ester of preparing of embodiment 1; Wherein contain three groups of Wasserstoffatomss in the product structure, and its chemical shift and product structure coincideing, the peak at 8.378 places is-peak of the H of CH-, the peak at 7.042 places is-NH
2The peak of H, the peak at 1.276 places is-CH
3The peak of H.
Embodiment
Below in conjunction with embodiment the present invention is done further detailed description.
Main raw material 2-amino-5-bromo pyrimi piperidine that following examples adopted, tert-Butyl dicarbonate, n-Butyl Lithium and other auxiliary materials are all bought in Chemical Reagent Co., Ltd., Sinopharm Group.
Embodiment one:
(1) gets raw material 2-amino-5-bromo pyrimi piperidine 7500g and mix in the 50L N, add 750g 4-Dimethylamino pyridine and 23.6kg tert-Butyl dicarbonate, be warming up to 25 ℃ of reaction 6h; Emerge to the no bubble of reaction, the solution clarification adds the 150L water filtration; Washing, oven dry.Obtain the product 2 of pyrimidine 2 bit aminos, productive rate: 94.3% by two tertbutyloxycarbonyl protections.
(2) add the product 1600g that step (1) obtains in the 20L flask; THF 8L; Triisopropyl borate ester 1050g; Stirring makes solid dissolving chuck add ethanol and cooled with liquid nitrogen to-70 to-80 ℃, and the n-Butyl Lithium temperature variation that drips 2.5mol/L is controlled in 5 ℃, adds 4L water stopped reaction behind reaction end 15 clocks.Revolve THF, filter, get filtrating and wash with MTBE, water with acetic acid transfer pH 5, have solid to separate out, continue to stir after 15 minutes, filter, solid directly gets into next step reaction.
(3) get the product that step (2) obtains, add equal-volume methyl alcohol, be warming up to 25-30 ℃, stir and slowly drip concentrated hydrochloric acid down, the complete reaction after-filtration, filter cake adds less water, the hydro-oxidation sodium water solution is transferred PH under the room temperature>7, refiltering, filter cake is 50 ℃ of ℃ of oven dry.
The overall yield about 35% of step (2) and step (3) two-step reaction.
(4) the 20L reaction flask drops into product and the 1.336kg tetramethyl ethylene ketone and the 13L toluene of 1.31kg step (3), and reflux is divided water, reacts 8 hours; Substantially anhydrous taking out of, cooling, product is separated out from solution; Cross and filter bullion, add ethanol (EtOH) stirring at room 2h, making beating; Filter, filter cake dry product, total recovery 84.4%.
Embodiment two:
(1) gets raw material 2-amino-5-bromo pyrimi piperidine 750g and mix in the 5L N, add 50g 4-Dimethylamino pyridine and 1.89kg tert-Butyl dicarbonate, be warming up to 25 ℃ of reaction 6h; Emerge to the no bubble of reaction, the solution clarification adds 15L water; Filter washing, oven dry.Obtain product 2, productive rate: 90.0%.
(2) add the product 160g of step (1) in the 2L flask; THF 800mL, triisopropyl borate ester 105g stirs and makes the solid dissolving; Chuck adds ethanol and cooled with liquid nitrogen to below-78 ℃; Drip 2.5 moles every liter n-Butyl Lithium, temperature variation is controlled in 5 ℃, and reaction finishes to add 400mL water stopped reaction behind 15 clocks.Revolve THF, filter, get filtrating and wash with MTBE, water with acetic acid transfer PH 5, have solid to separate out, continue to stir after 15 minutes, filter, solid directly gets into next step reaction.
(3) get the product of step (2), add equal-volume methyl alcohol, be warming up to 25-30 ℃, stir and slowly drip concentrated hydrochloric acid down, the complete reaction after-filtration, filter cake adds less water, the hydro-oxidation sodium water solution is transferred PH under the room temperature>7, refiltering, filter cake is 50 ℃ of oven dry.
The overall yield about 30% of step (2) and step (3) two-step reaction.
(4) 20L reaction article bottle drops into product and the 134g tetramethyl ethylene ketone and the 1.3L YLENE of 130g step (3), and reflux is divided water, reacts 3 hours; Substantially anhydrous taking out of, cooling, product is separated out from solution; Cross and filter bullion, add absolute ethyl alcohol stirring at room 2h making beating, filter; Filter cake dry product, yield 85.0%.
Embodiment three:
(1) gets raw material 2-amino-5-bromo pyrimi piperidine 750g and mix in the 5L N, add 100g 4-Dimethylamino pyridine and 2.83kg tert-Butyl dicarbonate, be warming up to 25 ℃ of reaction 6h; Emerge to the no bubble of reaction, the solution clarification adds 15L water; Filter washing, oven dry.Obtain product 2, productive rate: 92.3%.
(2) add the product 160g of step (1) in the 2L flask; THF 800mL, triisopropyl borate ester 105g stirs and makes the solid dissolving; Chuck adds ethanol and cooled with liquid nitrogen to below-78 ℃; Drip the n-Butyl Lithium of 2.5M, temperature variation is controlled in 5 ℃, and reaction finishes to add 400mL water stopped reaction behind 15 clocks.Revolve THF, filter, get filtrating and wash with MTBE, water with acetic acid transfer PH 5, have solid to separate out, continue to stir after 15 minutes, filter, solid directly gets into next step reaction.
(3) get the product of step (2), add equal-volume methyl alcohol, be warming up to 25-30 ℃, stir slow dripping hydrochloric acid methanol solution down, the complete reaction after-filtration, filter cake adds less water, the hydro-oxidation sodium water solution is transferred PH under the room temperature>7, refiltering, filter cake is 50 ℃ of oven dry.
The overall yield about 31% of step (2) and step (3) two-step reaction.
(4) 20L reaction article bottle drops into product and the 134g tetramethyl ethylene ketone and the 1.3L toluene of 130g step (3), and reflux is divided water, reacts 8 hours; Substantially anhydrous taking out of, cooling, product is separated out from solution; Cross and filter bullion, add EtOH stirring at room 2h making beating, filter; Filter cake dry product, yield 85.2%.
Above-mentioned embodiment does not limit technical scheme of the present invention in any form, and the technical scheme that mode obtained that every employing is equal to replacement or equivalent transformation all drops on protection scope of the present invention.
Claims (7)
1. the compound method of 2-amino-5-pyrimidine boric acid pinacol ester is characterized in that may further comprise the steps:
(1), amino-5 bromo pyrimi piperidines of 2-react under the katalysis of catalyzer 4-Dimethylamino pyridine with tert-Butyl dicarbonate, obtain the product that pyrimidine 2 bit aminos are protected by two tertbutyloxycarbonyls;
(2), the product of step (1) acquisition is after lithiumation under the effect of n-Butyl Lithium; Reacting 5-8h with triisopropyl borate ester at-70 to-80 ℃, 5 bromines are converted into boric acid, under quenched conditions; Have portion of product can fall next tertbutyloxycarbonyl, the product that obtains at last is a mixture;
(3), the mixture that obtains of step (2) under the acid effect, slough tertbutyloxycarbonyl protection base, obtain 2-aminopyrimidine-5-boric acid;
(4), step (3) product and the tetramethyl ethylene ketone reflux water-dividing in organic solvent that obtain, obtain 2-amino-5-pyrimidine boric acid pinacol ester.
2. the compound method of 2-amino according to claim 1-5-pyrimidine boric acid pinacol ester; It is characterized in that the solvent that step (1) adopts is a N; The molar equivalent of tert-Butyl dicarbonate is at 2-3, and the molar equivalent of catalyzer 4-Dimethylamino pyridine is at 0.1-0.2;
In the step (2), the molar equivalent of n-Butyl Lithium is 1.0-1.5.
3. the compound method of 2-amino according to claim 1-5-pyrimidine boric acid pinacol ester is characterized in that the molar equivalent of tert-Butyl dicarbonate in the step (1) is 2.5, and the molar equivalent of catalyzer 4-Dimethylamino pyridine is 0.15; In the step (2), the molar equivalent of n-Butyl Lithium is 1.2.
4. the compound method of 2-amino according to claim 1-5-pyrimidine boric acid pinacol ester is characterized in that hydrochloric acid is methanol hydrochloride solution and concentrated hydrochloric acid described in the step (3); Organic solvent is toluene or YLENE in the step (4).
5. the compound method of 2-amino according to claim 1-5-pyrimidine boric acid pinacol ester is characterized in that hydrochloric acid is concentrated hydrochloric acid described in the step (3); Organic solvent is a toluene in the step (4).
6. the compound method of 2-amino according to claim 1-5-pyrimidine boric acid pinacol ester is characterized in that under the described quenched conditions of step (1) it being that employing water is quencher, and volume is 1/3rd of a reaction solution.
7. the compound method of 2-amino according to claim 1-5-pyrimidine boric acid pinacol ester is characterized in that heat-eliminating medium is ethanol and liquid nitrogen in the step (2).
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014180752A1 (en) | 2013-05-06 | 2014-11-13 | F. Hoffmann-La Roche Ag | Process for the preparation of boronic acid intermediates |
| JP2015534572A (en) * | 2012-10-10 | 2015-12-03 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Process for producing thienopyrimidine compounds |
| CN109053788A (en) * | 2018-09-20 | 2018-12-21 | 山东谛爱生物技术有限公司 | A kind of preparation method of pyrazole compound |
Citations (2)
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| US20080269523A1 (en) * | 2007-04-27 | 2008-10-30 | Kressierer Christoph J | Preparation of Aminoaryl and Aminoheteroaryl Boronic Acids and Derivatives Thereof |
| WO2010121164A2 (en) * | 2009-04-17 | 2010-10-21 | The Regents Of The University Of Michigan | 1,4-benzodiazepinone compounds and their use in treating cancer |
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Patent Citations (2)
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| US20080269523A1 (en) * | 2007-04-27 | 2008-10-30 | Kressierer Christoph J | Preparation of Aminoaryl and Aminoheteroaryl Boronic Acids and Derivatives Thereof |
| WO2010121164A2 (en) * | 2009-04-17 | 2010-10-21 | The Regents Of The University Of Michigan | 1,4-benzodiazepinone compounds and their use in treating cancer |
Non-Patent Citations (1)
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015534572A (en) * | 2012-10-10 | 2015-12-03 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Process for producing thienopyrimidine compounds |
| WO2014180752A1 (en) | 2013-05-06 | 2014-11-13 | F. Hoffmann-La Roche Ag | Process for the preparation of boronic acid intermediates |
| CN105189519A (en) * | 2013-05-06 | 2015-12-23 | 豪夫迈·罗氏有限公司 | Process for the preparation of boronic acid intermediates |
| CN105189519B (en) * | 2013-05-06 | 2018-01-30 | 豪夫迈·罗氏有限公司 | Method for preparing boronic acid intermediate |
| CN109053788A (en) * | 2018-09-20 | 2018-12-21 | 山东谛爱生物技术有限公司 | A kind of preparation method of pyrazole compound |
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Application publication date: 20120404 |