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MD4505C1 - Process for the synthesis of 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one - Google Patents

Process for the synthesis of 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one Download PDF

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MD4505C1
MD4505C1 MDA20160146A MD20160146A MD4505C1 MD 4505 C1 MD4505 C1 MD 4505C1 MD A20160146 A MDA20160146 A MD A20160146A MD 20160146 A MD20160146 A MD 20160146A MD 4505 C1 MD4505 C1 MD 4505C1
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acetone
dimethyl
butan
triazol
solution
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MDA20160146A
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Romanian (ro)
Russian (ru)
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MD4505B1 (en
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Флюр МАКАЕВ
Марина ЗВЯГИНЦЕВА
Еуджения СТЫНГАЧ
Сергей ПОГРЕБНОЙ
Георге ДУКА
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Институт Химии Академии Наук Молдовы
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Abstract

The invention relates to organic chemistry, namely to a process for preparation of 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one - an intermediate for the synthesis of biologically active substances with antituberculous or fungicidal activity.Summary of the invention consists in that 1,2,4-triazole is alkylated with 1-chloro-3,3-dimethyl-2-butan-2-one in the acetone/K2CO3 system, according to the scheme:The reaction mixture is boiled for 5…7 hours, the acetone solution is separated from the formed precipitate, the acetone is distilled off, the residue is extracted with boiling hexane, from which pure product (1) is precipitated upon cooling.The reaction runs in one step, in a shorter time and with a high yield (99%) compared to analogue processes.

Description

Invenţia se referă la chimia organică, şi anume la prepararea 3,3-dimetil-1-(1H-1,2,4-triazol-1-il)butan-onei 1, care poate fi aplicată ca un intermediar la sinteza unor compuşi cunoscuţi sau noi cu activitate fungicidă sau antituberculoasă. The invention relates to organic chemistry, namely to the preparation of 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-one 1, which can be applied as an intermediate in the synthesis of some compounds known or new with fungicidal or antituberculosis activity.

C8H13N3O C8H13N3O

În literatura de specialitate sunt cunoscute substanţe cu activitate antituberculoasă şi fungicidă, care în molecula lor conţin inelul triazolic [1, 2]. Triazolilcetona 1 a fost utilizată ca precursor în sinteza unui şir de compuşi cu activitate fungicidă şi de reglare a creşterii plantelor [3]. După mai multe studii de cercetare efectuate de solicitant au fost descoperite proprietăţi noi, şi anume antituberculoase, la unii compuşi obţinuţi pornind de la triazolilcetona 1. Substances with antituberculosis and fungicidal activity are known in the specialized literature, which contain the triazole ring in their molecule [1, 2]. Triazolyl ketone 1 was used as a precursor in the synthesis of a series of compounds with fungicidal activity and plant growth regulation [3]. After several research studies carried out by the applicant, new properties, namely anti-tuberculosis, were discovered in some compounds obtained starting from triazolyl ketone 1.

Este cunoscut procedeul de obţinere a cetonei 1, care se foloseşte la producerea fungicidelor şi include alchilarea 1,2,4-triazolului cu bromură de pinacolină în mediu etanolic în prezenţa etoxidului de sodiu [4]. The procedure for obtaining ketone 1 is known, which is used in the production of fungicides and includes the alkylation of 1,2,4-triazole with pinacoline bromide in an ethanol medium in the presence of sodium ethoxide [4].

Alt procedeu de obţinere a triazolilcetonei 1 constă în alchilarea triazolului cu clorură de pinacolină şi necesită preventiv pregătirea soluţiei de metoxid de sodiu [5]. Another process for obtaining the triazolyl ketone 1 consists in the alkylation of the triazole with pinacoline chloride and requires the preventive preparation of the sodium methoxide solution [5].

Ambele procedee necesită preventiv pregătirea soluţiei de metoxid ori etoxid de sodiu, totodată în ambele procedee se foloseşte sodiu metalic. Reacţia decurge în mediu metanolic, care reprezintă un reagent foarte toxic. Both processes require the preventive preparation of sodium methoxide or ethoxide solution, at the same time in both processes metallic sodium is used. The reaction takes place in a methanol medium, which is a very toxic reagent.

Sunt cunoscute procedee de obţinere a triazolilcetonei 1, care constă în alchilarea 1,2,4-triazolului cu halogen-cetone la fierbere, într-un şir de diferiţi solvenţi, în prezenţa substanţelor neutralizatoare de acizi, inclusiv cu utilizarea sistemului acetonă/carbonat de potasiu [6,7]. Randamentul procedeelor descrise, de exemplu, pornind de la bromcetone nu este mai mare de 80…88%, iar reacţia de alchilare decurge 15 ore în sistemul acetonă/carbonat de potasiu. Totodată în aceste procedee pentru izolarea compusului 1 se foloseşte metoda de cromatografiere pe coloană sau cristalizarea, fapt ce contribuie la o complicare a procedeelor propuse şi la o reducere a randamentului final. There are known processes for obtaining triazolyl ketone 1, which consists in the alkylation of 1,2,4-triazole with halogen-ketones at boiling, in a series of different solvents, in the presence of acid neutralizing substances, including the use of the acetone/carbonate system potassium [6,7]. The yield of the processes described, for example, starting from bromoketones is not higher than 80...88%, and the alkylation reaction takes 15 hours in the acetone/potassium carbonate system. At the same time, in these procedures for the isolation of compound 1, the column chromatography or crystallization method is used, a fact that contributes to a complication of the proposed procedures and to a reduction of the final yield.

Problema pe care o rezolvă invenţia dată constă în elaborarea unui procedeu de sinteză a triazolilcetonei 1 prin alchilare în sistemul acetonă/carbonat de potasiu cu un randament mărit şi cu o durată mai mică de realizare a reacţiei. The problem that the given invention solves consists in the development of a process for the synthesis of triazolyl ketone 1 by alkylation in the acetone/potassium carbonate system with an increased yield and with a shorter duration of the reaction.

Esenţa invenţiei revendicate constă în elaborarea unui procedeu de sinteză a 3,3-dimetil-1-(1H-1,2,4-triazol-1-il)butan-2-onei din 1-clor-3,3-dimetil-2-butan, conform schemei: The essence of the claimed invention consists in the development of a process for the synthesis of 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one from 1-chloro-3,3-dimethyl- 2-butane, according to the scheme:

Procedeul de obţinere a 3,3-dimetil-1-(1H-1,2,4-triazol-1-il)butan-2-onei include fierberea timp de 8…15 min a unei soluţii de 1H-1,2,4-triazol (1 parte) în acetonă, care conţine K2CO3 (1,09 părţi), după care se adaugă treptat o soluţie de 1-clor-3,3-dimetil-2-butan (1 parte) în acetonă, părţile fiind luate în raportul molar respectiv, amestecul reactant se fierbe timp de 5…7 ore, precipitatul rezidual se separă de soluţia acetonică a produsului final obţinut, acetona se distilează, produsul final se extrage cu hexan, din care la răcire se sedimentează produsul pur (1), cu un randament de 99%. The process for obtaining 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one includes boiling for 8...15 min a solution of 1H-1,2, 4-triazole (1 part) in acetone, containing K2CO3 (1.09 parts), after which a solution of 1-chloro-3,3-dimethyl-2-butane (1 part) in acetone is gradually added, the parts being taken in the respective molar ratio, the reactant mixture is boiled for 5...7 hours, the residual precipitate is separated from the acetone solution of the final product obtained, the acetone is distilled, the final product is extracted with hexane, from which the pure product (1 ), with a yield of 99%.

Reacţia decurge într-o singură etapă cu un randament foarte bun (99%), aproape cantitativ. Triazolilcetona 1 este o substanţă care se dizolvă uşor în solvenţi organici şi în apă. S-a depistat că izolarea ei efectivă din amestecul reactant se poate face cu hexan la fierbere, acest factor a contribuit la obţinerea compusului 1 cu un randament foarte înalt şi cu o puritate suficientă. Ca rezultat compusul 1 nu necesită o purificare suplimentară. The reaction proceeds in a single step with a very good yield (99%), almost quantitative. Triazolylketone 1 is a substance that dissolves easily in organic solvents and water. It was found that its effective isolation from the reactant mixture can be done with boiling hexane, this factor contributed to obtaining compound 1 with a very high yield and sufficient purity. As a result compound 1 does not require further purification.

Utilizarea anume a clorpinacolinei în calitate de halogencetonă iniţială, efectuarea reacţiei de alchilare în sistemul acetonă/carbonat de potasiu şi utilizarea hexanului la izolarea produsului final sunt factori esenţiali pentru a atinge randamentul de 99%, totodată durata reacţiei fiind de două ori mai scurtă, comparativ cu procedeul din stadiul tehnicii. The particular use of chlorpinacoline as the starting haloketone, the performance of the alkylation reaction in the acetone/potassium carbonate system and the use of hexane to isolate the final product are essential factors to reach the 99% yield, while the reaction time is twice as short, compared with the procedure from the state of the art.

Exemplu de realizare a invenţiei Example of realization of the invention

La soluţia constituită din 6,9 g (0,1 mol) 1H-1,2,4-triazol şi 50 mL acetonă se adaugă 15,1 g (0,109 mol) K2CO3, amestecul se fierbe timp de 10 min, ulterior se adaugă cu picătura soluţia alcătuită din 13,4 g (0,1 mol) 1-clor-3,3-dimetil-2-butan în 20 mL acetonă. Amestecul reactant se fierbe timp de 5…7 ore (control CSS). Precipitatul format se filtrează, spălându-se minuţios, pe filtru, cu acetonă. Soluţia acetonică se distilează, reziduul obţinut se extrage cu hexan la fierbere, după răcirea hexanului se izolează un precipitat alb 16,5 g (99%) de 3,3-dimetil-1-(1H-1,2,4-triazol-1-il)butan-2-onă 1. To the solution consisting of 6.9 g (0.1 mol) 1H-1,2,4-triazole and 50 mL acetone, add 15.1 g (0.109 mol) K2CO3, boil the mixture for 10 min, then add dropwise the solution consisting of 13.4 g (0.1 mol) 1-chloro-3,3-dimethyl-2-butane in 20 mL acetone. The reaction mixture is boiled for 5...7 hours (CSS control). The formed precipitate is filtered, thoroughly washing the filter with acetone. The acetone solution is distilled, the residue obtained is extracted with boiling hexane, after cooling the hexane a white precipitate is isolated 16.5 g (99%) of 3,3-dimethyl-1-(1H-1,2,4-triazol- 1-yl)butan-2-one 1.

Randamentul reacţiei este de 99% (16,5 g), p.t.=65…67°C. The yield of the reaction is 99% (16.5 g), m.p.=65...67°C.

Structura compusului a fost confirmată pe baza analizei elementelor şi datelor spectrale: C8H13N3O, M=167,21. The structure of the compound was confirmed based on element analysis and spectral data: C8H13N3O, M=167.21.

Calculat,(%): C, 57,46; H, 7,84; N, 25,13. Calculated, (%): C, 57.46; H, 7.84; N, 25,13.

Găsit,(%): C, 57,49; H, 7,68; N, 24.99. IR (ν, cm-1): 680,3; 742,2; 883,4; 1020,3; 1034,7; 1135,9; 1210,2; 1275,3; 1363,8; 1470,7; 1508,4; 1595,2; 1719,9; 2948,7; 2977,5; 3114,9. Found, (%): C, 57.49; H, 7.68; N, 24.99. IR (ν, cm-1): 680.3; 742.2; 883.4; 1020.3; 1034.7; 1135.9; 1210.2; 1275.3; 1363.8; 1470.7; 1508.4; 1595.2; 1719.9; 2948.7; 2977.5; 3114.9.

Spectrul RMN 1H (400 MHz, CDCl3, δ, ppm, J/Hz ): 1,24 (s, 9H, Bu), 5,16 (s, 2H, N-CH2), 7,91 (s, 1H, triazol), 8,1(s, 1H, triazol). 1H NMR spectrum (400 MHz, CDCl3, δ, ppm, J/Hz ): 1.24 (s, 9H, Bu), 5.16 (s, 2H, N-CH2), 7.91 (s, 1H, triazole), 8.1(s, 1H, triazole).

Spectrul RMN 13C (100 MHz, CDCl3, δ, ppm): 206,25, 151,69, 144,74, 53,17, 43,49, 26,05. 13 C NMR spectrum (100 MHz, CDCl 3 , δ, ppm): 206.25, 151.69, 144.74, 53.17, 43.49, 26.05.

Exemplu de aplicare a compusului sintetizat Example of application of the synthesized compound

Cetona 1 - 3,3-dimetil-1-(1H-1,2,4-triazol-1-il)butan-2-onă poate fi aplicată în calitate de compus iniţial la obţinerea compuşilor cu activitate biologică antituberculoasă sau fungicidă. The 1-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one ketone can be applied as a starting compound to obtain compounds with antitubercular or fungicidal biological activity.

Drept exemplu serveşte procedeul de sinteză stereospecifică a (Z)-4,4-dimetil-1-(4-nitrofenil)-2-(1H-1,2,4-triazol-1-il)pent-1-en-3-onei - compus cu acţiune antituberculoasă. An example is the stereospecific synthesis process of (Z)-4,4-dimethyl-1-(4-nitrophenyl)-2-(1H-1,2,4-triazol-1-yl)pent-1-en-3 -onei - compound with antituberculosis action.

La soluţia alcătuită din 1,67 g (0,01 mol) de triazolil-cetona - 3,3-dimetil-1-(1H-1,2,4-triazol-1-il)butan-2-onă (1) şi 1,66 g (0,011mol) para-nitro-benzaldehidă în 300 mL benzen se adaugă piperidină/acid acetic în cantităţi catalitice. Amestecul se fierbe timp de 5…7 ore (controlat periodic cu ajutorul CSS) cu distilarea azeotropă a apei formate, folosind aparatul Dean-Stark, apoi soluţia de benzen se răceşte până la temperatura camerei, rămăşiţele de catalizator se extrag cu apă, apoi soluţia benzenică a produsului final se usucă cu Na2SO4. Solventul se distilează, iar reziduul se recristalizează din etanol. To the solution consisting of 1.67 g (0.01 mol) of triazolyl ketone - 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one (1) and 1.66 g (0.011 mol) of para-nitro-benzaldehyde in 300 mL of benzene is added catalytic amounts of piperidine/acetic acid. The mixture is boiled for 5...7 hours (controlled periodically with CSS) with the azeotropic distillation of the formed water, using the Dean-Stark apparatus, then the benzene solution is cooled to room temperature, the catalyst remains are extracted with water, then the solution benzene of the final product is dried with Na2SO4. The solvent is distilled off and the residue is recrystallized from ethanol.

Randamentul reacţiei este de 70% (2,1 g), p.t.= 114…116°С. The yield of the reaction is 70% (2.1 g), m.t.= 114...116°С.

Structura compusului este confirmată pe baza analizei elementelor şi datelor spectrale : C15H16N4O3, M=300,31. The structure of the compound is confirmed based on elemental analysis and spectral data: C15H16N4O3, M=300.31.

Compusul posedă activitate antituberculoasă la nivelul remediului cunoscut Rifampicina. The compound possesses antituberculosis activity at the level of the well-known remedy Rifampicin.

1. Rangappa S. Keri, Siddappa A. Patil, Srinivasa, Budagumpi, Bhari Mallanna Nagaraja. Triazole: A Promising Antitubercular Agent. Chem Biol Drug Des 2015, 86, 410-423 1. Rangappa S. Keri, Siddappa A. Patil, Srinivasa, Budagumpi, Bhari Mallanna Nagaraja. Triazoles: A Promising Antitubercular Agent. Chem Biol Drug Des 2015, 86, 410-423

2. Pawan Kumar Mishra, Jaya Dwivedi, Rajani Chauhan. Triazoles as potential antitubercular agent: a review. Journal of Advanced Scientific Research, 2016, 7(1), 9-13. 2. Pawan Kumar Mishra, Jaya Dwivedi, Rajani Chauhan. Triazoles as potential antitubercular agents: a review. Journal of Advanced Scientific Research, 2016, 7(1), 9-13.

3. Funaki Y. et al. Structure-activity relationships of vinyl triazole fungicides. J. Pesticide Sci., 1984, 9, 229-236 3. Funaki Y. et al. Structure-activity relationships of vinyl triazole fungicides. J. Pesticide Sci., 1984, 9, 229-236

4. US 4243405 A 1981.01.06 4. US 4243405 A 1981.01.06

Description: column 6 Description: column 6

5. CN 102351803 A 2012.02.15 (SUZHOU CHENGHE PHARMACEUTICAL & CHEMICAL CO LTD) 5. CN 102351803 A 2012.02.15 (SUZHOU CHENGHE PHARMACEUTICAL & CHEMICAL CO LTD)

Description (Espacenet translation in english) Description (Espacenet translation in English)

6. CA 1168248 A1984-05-29 (Bayer AG) 6. CA 1168248 A1984-05-29 (Bayer AG)

Description: pag. 14-15; pag. 30 lines 14-22; pag. 33 lines 23-26; pag. 34 lines 1-7; pag. 36 lines 1-10; Description: pages 14-15; page 30 lines 14-22; page 33 lines 23-26; page 34 lines 1-7; page 36 lines 1-10;

7. GB 1464224 A 1977-02-09 (BAYER AG) 7. GB 1464224 A 1977-02-09 (BAYER AG)

Description: pag. 2, lines 18-26; pag. 4, lines 60-65 and pag. 5, lines 1-15; pag. 13, example 2; pag. 16, Example No.19; Claims 6 Description: page 2, lines 18-26; page 4, lines 60-65 and page 5, lines 1-15; page 13, example 2; page 16, Example No. 19; Claims 6

Claims (1)

Procedeu de obţinere a 3,3-dimetil-1-(1H-1,2,4-triazol-1-il)butan-2-onei (1), care include fierberea timp de 8…15 min a unei soluţii de 1H-1,2,4-triazol (1 parte) în acetonă, care conţine K2CO3 (1,09 părţi), după care se adaugă treptat o soluţie de 1-clor-3,3-dimetil-2-butan-2-onă (1 parte) în acetonă, părţile fiind molare, amestecul reactant se fierbe timp de 5...7 ore, se separă soluţia acetonică de precipitatul format, se distilează acetona, reziduul obţinut se extrage cu hexan la fierbere, din care la răcire se sedimentează produsul pur 1.Process for obtaining 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one (1), which includes boiling for 8...15 min a solution of 1H -1,2,4-triazole (1 part) in acetone, containing K2CO3 (1.09 parts), after which a solution of 1-chloro-3,3-dimethyl-2-butan-2-one is gradually added (1 part) in acetone, the parts being molar, the reactant mixture is boiled for 5...7 hours, the acetone solution is separated from the precipitate formed, the acetone is distilled, the residue obtained is extracted with boiling hexane, from which upon cooling sediment the pure product 1.
MDA20160146A 2016-12-21 2016-12-21 Process for the synthesis of 3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one MD4505C1 (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1464224A (en) * 1974-06-29 1977-02-09 Bayer Ag Triazolyl-alkanones and triazolylalkanols processes for their preparation and their use as fungicides
US4079143A (en) * 1975-08-26 1978-03-14 Imperial Chemical Industries Limited Fungicidal 1H-1,2,4-triazoles
US4243405A (en) * 1976-08-19 1981-01-06 Imperial Chemical Industries Limited Fungicidal compounds
CA1168248A (en) * 1980-07-25 1984-05-29 Erik Regel Triazolylpropenol derivatives, a process for their preparation and their use as plant growth regulators and fungicides
CA1179352A (en) * 1980-07-25 1984-12-11 Erik Regel Triazolylpropenone derivatives, a process for their preparation and their use as intermediates
US4554007A (en) * 1979-03-20 1985-11-19 Sumitomo Chemical Company, Limited Geometrical isomer of 1-substituted-1-triazolylstyrenes, and their production and use as fungicide, herbicide and/or plant growth regulant
CN102351803A (en) * 2011-11-18 2012-02-15 苏州诚和医药化学有限公司 Method for synthesizing 3,3-dimethyl-1-(1H-1,2,4-triazole-1-yl)-2-butanone

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1464224A (en) * 1974-06-29 1977-02-09 Bayer Ag Triazolyl-alkanones and triazolylalkanols processes for their preparation and their use as fungicides
US4079143A (en) * 1975-08-26 1978-03-14 Imperial Chemical Industries Limited Fungicidal 1H-1,2,4-triazoles
US4243405A (en) * 1976-08-19 1981-01-06 Imperial Chemical Industries Limited Fungicidal compounds
US4554007A (en) * 1979-03-20 1985-11-19 Sumitomo Chemical Company, Limited Geometrical isomer of 1-substituted-1-triazolylstyrenes, and their production and use as fungicide, herbicide and/or plant growth regulant
US4749716A (en) * 1979-03-20 1988-06-07 Sumitomo Chemical Company, Limited Geometrical isomer of 1-substituted-1-triazolystyrenes
CA1168248A (en) * 1980-07-25 1984-05-29 Erik Regel Triazolylpropenol derivatives, a process for their preparation and their use as plant growth regulators and fungicides
CA1179352A (en) * 1980-07-25 1984-12-11 Erik Regel Triazolylpropenone derivatives, a process for their preparation and their use as intermediates
CN102351803A (en) * 2011-11-18 2012-02-15 苏州诚和医药化学有限公司 Method for synthesizing 3,3-dimethyl-1-(1H-1,2,4-triazole-1-yl)-2-butanone

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Funaki Y. et al. Structure-activity relationships of vinyl triazole fungicides. J. Pesticide Sci., 1984, 9, 229-236 *
Pawan Kumar Mishra, Jaya Dwivedi, Rajani Chauhan. Triazoles as potential antitubercular agent: a review. Journal of Advanced Scientific Research, 2016, 7(1), 9-13. *
Rangappa S. Keri, Siddappa A. Patil, Srinivasa, Budagumpi, Bhari Mallanna Nagaraja. Triazole: A Promising Antitubercular Agent. Chem Biol Drug Des 2015, 86, 410-423 *

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