WO2011092618A1 - Procédé de préparation de fluazinam - Google Patents

Procédé de préparation de fluazinam Download PDF

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Publication number
WO2011092618A1
WO2011092618A1 PCT/IB2011/050286 IB2011050286W WO2011092618A1 WO 2011092618 A1 WO2011092618 A1 WO 2011092618A1 IB 2011050286 W IB2011050286 W IB 2011050286W WO 2011092618 A1 WO2011092618 A1 WO 2011092618A1
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WO
WIPO (PCT)
Prior art keywords
chloro
reaction
amino
trifluoromethylpyridine
pyridine
Prior art date
Application number
PCT/IB2011/050286
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English (en)
Inventor
Andrea Pastorio
Claudia Mora
Original Assignee
Finchimica S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Finchimica S.P.A. filed Critical Finchimica S.P.A.
Publication of WO2011092618A1 publication Critical patent/WO2011092618A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms

Definitions

  • the present invention relates to a method for preparing 3-chloro, N- (3-chloro-5-trifluoromethyl-2- pyridyl) , a, a, a-trifluoro, 2, 6-dinitro-p-toluidine (Fluazinam; CAS registry no. 79622-59-6) .
  • the reaction is conducted in an aqueous ammonia solution, having a concentration ranging from 28-40%, which is prepared before the reaction by dissolution of the gas in water.
  • the ammonia acts as a nucleophile towards the Pyridine 1, causing selective substitution of the halogen in position 2 with an amine group.
  • the ammonia performs therefore a dual role as nucleophile and as counter-ion for the halogen released from the pyridine ring, to obtain the corresponding ammonium salt.
  • the temperature must be between 100°C and 150°C, with a consequent increase in pressure inside the reactor up to a maximum of 30 atmospheres, and such conditions must be maintained for 3 to 12 hours.
  • the Pyridine 2 obtained in the first step is coupled with 2 , 4-dichloro, 3,5-dinitro, benzotrifluoride (2, 4DC-3, 5DN-BTF) to obtain the fungicide Fluazinam.
  • the prime necessity is to treat it appropriately at the end of the reaction: the precipitated product must be filtered and dried, or extracted using a volatile organic solvent insoluble in water, purified and made anhydrous for use in the subsequent coupling stage.
  • the present invention relates to a method making it possible to produce Pyridine 2, more economically and efficiently than the currently known methods and which, furthermore, permits simplification of the final synthesis steps of Fluazinam.
  • Such objective is achieved by a method for the synthesis of 3-chloro, N- (3-chloro-5-trifluoromethyl-2- pyridyl) , a, a, a-trifluoro, 2, 6-dinitro-p-toluidine or Fluazinam comprising steps of:
  • R is a halogen and, preferably, chlorine or fluorine, to obtain 2-amino, 3-chloro, 5- trifluoromethylpyridine;
  • the present invention refers therefore to a method of obtaining Fluazinam by means of a first step to produce 2-amino, 3-chloro, 5-trifluoromethylpyridine which no longer uses ammonia in aqueous solution, but which utilises anhydrous ammonia in an organic solvent suitable to be used in the subsequent formation step of the product .
  • the aforesaid final product is efficiently obtained by the mere addition of a strong base to the mixture resulting from the amination reaction and of a suitable dose of the reagent 2, DC-3, 5DN-BTF.
  • the strong base comprises an alkaline hydroxide and, even more preferably, potassium hydroxide.
  • the organic solvents suitable to conduct the reaction steps described are the solvents usually used in nucleophilic substitutions, which must at the same time have ' an elevated dissolving effect on the ammonia and which must furthermore be also good solvent mediums for the Fluazinam formation reaction.
  • the aforesaid formation reaction is in fact also conducted in the same organic solvent in which the amination reaction takes place.
  • the final mixture obtained by the amination reaction can be used directly in the subsequent formation reaction of the product, without the need for further treatment of such mixture, by the mere addition of the strong base and of the 2,4DC-3, 5DN-BTF.
  • the organic solvent used in such reactions is a polar aprotic solvent.
  • the organic solvent is chosen from the group consisting in dimethylformamide (DMF) , tetrahydrofuran (THF) , dimethylsulfoxide (D SO) and N-methyl-2- pyrrolidone (NMP) .
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • D SO dimethylsulfoxide
  • NMP N-methyl-2- pyrrolidone
  • THF although not having the highest dissolvent effect on ammonia, is a good medium for both steps and generally allows the best results to be achieved.
  • the amination reaction is followed by a filtering step of the insoluble salts formed during the reaction of the mixture, especially NH 4 R.
  • a filtering step of the insoluble salts formed during the reaction of the mixture especially NH 4 R.
  • the salts which are formed during the amination reaction are insoluble in the aprotic organic solvent, so that they can be removed in a highly pure grade from the reaction mixture by mere filtration.
  • the filtration step is followed by a recovery step of the 2-amino, 3-chloro, 5- trifluoromethylpyridine from the filtered salt.
  • such recovery step of the 2-amino, 3- chloro, 5-trifluoromethylpyridine comprises a step of washing, advantageously with the reaction solvent.
  • the method further comprises a recovery step of the excess gaseous ammonia.
  • the recovery step of the ammonia is followed by a step of reutilisation of the latter in the amination reaction or in a different industrial process.
  • the formation reaction takes place at a temperature between 0°C and 150°C,' advantageously between 30°C and 100°C, and even more preferably between 30°C and 70°C.
  • the formation reaction is conducted for a time ranging from a few minutes to 35 hours; such time depends, among other things, on the ammonia pressure which can be exerted.
  • the present invention relates to a method for the amination of a pyridine having the following general formula (I) :
  • R is a halogen
  • Such amination is conducted with anhydrous ammonia in an aprotic polar organic solvent, where such solvent is preferably of the type illustrated in the above description.
  • R is fluorine or chlorine and, even more preferably, is fluorine.
  • reaction progresses, there is a drop in pressure due to the consumption of ammonia by the pyridine reagent; the reaction may be considered complete when the pressure drops no further and the datum can be confirmed analytically.
  • This addition consisting in washing solvent combined with the mixture produced in the reaction, also has the function of diluting the mixture to the necessary degree for the subsequent reaction.
  • a solution containing 34,1 grams (0,173 moles) of 2-Amino-3Chloro-5- Trifluoromethylpyridine is thereby obtained.
  • reaction progresses, there is a drop in pressure due to the ammonia consumption by the pyridine reagent; the reaction may be considered complete when the pressure drops no further and the datum can be confirmed analytically.
  • the suspension is stirred vigorously for 30 minutes at 20°C and, for further 30 minutes, at 0°C.
  • the discharged mixture is concentrated by partial evaporation of the solvent, to a weight of 163 grams.
  • the method of the present invention makes it possible to improve the yield and obtain an extremely pure aminate product: in fact working under much milder temperature conditions, the parallel reactions, leading to the formation of by-products are made much less competitive or are even prevented; this makes for a considerable economic advantage given that the expensive general formula (I) compound is . thus used in stoichiometric quantities.
  • Such advantages consist mainly in an evident process simplification, both as regards equipment and as regards the reaction times required, and in a drastic reduction of any loss of 2-amine, 3-chloro, 5- trifluoromethylpyridine caused by work-up.
  • the excess ammonia gas loaded can be recovered and used either in a subsequent and similar amination reaction, or be absorbed in water to produce solutions for commercial use.
  • the NH 4 R may be separated by filtration from the mixture and any 2-amino, 3-chloro, 5- trifluoromethylpyridine present in the salt may be recovered by washing the same with the reaction solvent.
  • the method of the present invention makes it possible to synthesise extremely pure 2-amino, 3- chloro, 5-trifluoromethylpyridine, with consequent high yield and thereby stoichiometric consumption of the expensive general formula (I) compound.
  • reaction conditions illustrated make it possible to obtain yields of over 98% and selectivity of over 99%.
  • the milder working temperatures mentioned above can be reached by virtue of the possibility of acting on two reaction parameters, i.e. pressure and temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne un procédé de synthèse du 3-chloro, N- (3-chloro-5- trifluorométhyl-2-pyridyl), α, α, α-trifluoro, 2,6-dinitro- p-toluidine (Fluazinam) comprenant une réaction d'amination d'une pyridine, pour obtenir de la 2-amino, 3-chloro, 5- trifluorométhylpyridine, l'adjonction d'une base forte à la 2-amino, 3-chloro, 5-trifluorométhylpyridine, et une réaction de formation de fluazinam par couplage de la 2- amino-3-chloro-5-trifluorométhylpyridine avec le trifluorure 2,4- dichloro, 3,5-dinitro, de benzényle. La réaction d'amination est conduite avec de l'ammoniac anhydre dans un solvant organique. En outre, la réaction de couplage ci-dessus a lieu directement dans la solution de Pyridine 2 provenant de l'étape d'amination.
PCT/IB2011/050286 2010-01-28 2011-01-21 Procédé de préparation de fluazinam WO2011092618A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000012A ITBS20100012A1 (it) 2010-01-28 2010-01-28 Procedimento per la preparazione di fluazinam
ITBS2010A000012 2010-01-28

Publications (1)

Publication Number Publication Date
WO2011092618A1 true WO2011092618A1 (fr) 2011-08-04

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PCT/IB2011/050286 WO2011092618A1 (fr) 2010-01-28 2011-01-21 Procédé de préparation de fluazinam

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IT (1) ITBS20100012A1 (fr)
WO (1) WO2011092618A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8648203B2 (en) 2005-11-23 2014-02-11 Makhteshim Chemical Works Ltd. Process for preparing pyridinamines and novel polymorphs thereof
CN106866518A (zh) * 2017-04-16 2017-06-20 内蒙古佳瑞米精细化工有限公司 一种2‑氨基‑3‑氯‑5三氟甲基吡啶的合成方法
CN107954924A (zh) * 2016-10-18 2018-04-24 内蒙古佳瑞米精细化工有限公司 一种2-氟-3-氯-5-三氟甲基吡啶的制备方法
CN107954925A (zh) * 2016-10-18 2018-04-24 内蒙古佳瑞米精细化工有限公司 一种2,3-二氯-5-三氟甲基吡啶前杂的去除方法
CN110143916A (zh) * 2019-05-12 2019-08-20 大连九信精细化工有限公司 一种氟啶胺的合成工艺
CN115181060A (zh) * 2022-08-19 2022-10-14 江苏禾裕泰化学有限公司 一种生产2-氨基-3-氯-5-三氟甲基吡啶的清洁生产工艺

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4331670A (en) 1979-12-25 1982-05-25 Ishihara Sangyo Kaisha, Ltd. Pyridylanilines
US4349681A (en) 1979-12-24 1982-09-14 Ishihara Sangyo Kaisha, Ltd. 2-Amino-3-chloro-5-trifluoromethylpyridine
CN101081833A (zh) 2006-05-29 2007-12-05 山东广恒化工有限公司 2－氨基－3－氯－5－三氟甲基吡啶的制备方法
WO2009017241A2 (fr) * 2007-08-02 2009-02-05 Ishihara Sangyo Kaisha, Ltd. Procédé pour produire un composé de toluidine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4349681A (en) 1979-12-24 1982-09-14 Ishihara Sangyo Kaisha, Ltd. 2-Amino-3-chloro-5-trifluoromethylpyridine
US4331670A (en) 1979-12-25 1982-05-25 Ishihara Sangyo Kaisha, Ltd. Pyridylanilines
CN101081833A (zh) 2006-05-29 2007-12-05 山东广恒化工有限公司 2－氨基－3－氯－5－三氟甲基吡啶的制备方法
WO2009017241A2 (fr) * 2007-08-02 2009-02-05 Ishihara Sangyo Kaisha, Ltd. Procédé pour produire un composé de toluidine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAKAJIMA, T; KOMYOJI, T.; AKAGI, T.; NAGATANI, K.; HAGA, T.; MATSUO, N.; SUZUKI, K.: "Synthesis and Fungicidal Activity of N-Phenylpyridinamines", vol. 38, 1995, AM.CHEM.SOC., pages: 443 - 448

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8648203B2 (en) 2005-11-23 2014-02-11 Makhteshim Chemical Works Ltd. Process for preparing pyridinamines and novel polymorphs thereof
CN107954924A (zh) * 2016-10-18 2018-04-24 内蒙古佳瑞米精细化工有限公司 一种2-氟-3-氯-5-三氟甲基吡啶的制备方法
CN107954925A (zh) * 2016-10-18 2018-04-24 内蒙古佳瑞米精细化工有限公司 一种2,3-二氯-5-三氟甲基吡啶前杂的去除方法
CN106866518A (zh) * 2017-04-16 2017-06-20 内蒙古佳瑞米精细化工有限公司 一种2‑氨基‑3‑氯‑5三氟甲基吡啶的合成方法
CN110143916A (zh) * 2019-05-12 2019-08-20 大连九信精细化工有限公司 一种氟啶胺的合成工艺
CN115181060A (zh) * 2022-08-19 2022-10-14 江苏禾裕泰化学有限公司 一种生产2-氨基-3-氯-5-三氟甲基吡啶的清洁生产工艺
CN115181060B (zh) * 2022-08-19 2024-03-19 江苏禾裕泰化学有限公司 一种生产2-氨基-3-氯-5-三氟甲基吡啶的清洁生产工艺

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