WO2018141642A1 - Procédé de préparation de 2-chloro-4-fluoro-5-nitrobenzotrichlorure - Google Patents

Procédé de préparation de 2-chloro-4-fluoro-5-nitrobenzotrichlorure Download PDF

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Publication number
WO2018141642A1
WO2018141642A1 PCT/EP2018/051928 EP2018051928W WO2018141642A1 WO 2018141642 A1 WO2018141642 A1 WO 2018141642A1 EP 2018051928 W EP2018051928 W EP 2018051928W WO 2018141642 A1 WO2018141642 A1 WO 2018141642A1
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Prior art keywords
chloro
range
fluoro
process according
mixture
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PCT/EP2018/051928
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English (en)
Inventor
Swapnil Yerande
Prashant KAPSE
Sukunath Narayanan
Roland Goetz
Christopher Koradin
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BASF Agro B.V.
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Publication of WO2018141642A1 publication Critical patent/WO2018141642A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/07—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms
    • C07C205/11—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings
    • C07C205/12—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings the six-membered aromatic ring or a condensed ring system containing that ring being substituted by halogen atoms

Definitions

  • the present invention relates to an improved process for the preparation of 2-chloro-4-fluoro- 5-nitrobenzotrichloride.
  • the present invention further relates to a process for the purification of 2-chloro-4-fluoro-5-nitrobenzotrichloride, which reduces the isomeric impurities and acidic byproducts.
  • 2-Chloro-4-fluoro-5-nitrobenzotrichloride is reported in the literature as an intermediate in the preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid.
  • WO 2006/090210 A1 discloses the preparation of 2-chloro-4-fluoro-5-nitrobenzoic acid and derivatives thereof, by nitration of 2-chloro-4- fluorobenzo trichloride. The nitration is effected by a 'sulfonitric mixture' which is composed of concentrated nitric acid and oleum. The drawback of using oleum in the sulfonitric mixture is the generation of considerable amount of undesired, isomeric impurity.
  • the reaction is quenched in water, leading to the hydrolysis of the trichloride group, thereby increasing the amount of undesired side-product, i.e. the acid 2-chloro-4-fluoro-5-nitrobenzoic acid.
  • the yield of 2-chloro-4- fluoro-5-nitrobenzotrichloride reported in WO 2006/090210 A1 is 93% but that includes about 20% of the aforementioned acid and thus the yield of the desired product is very low.
  • the process of the prior art suffers from the drawbacks of low yield and poor quality of the prod- uct due to formation of a substantial amount of corresponding acid and isomeric nitro impurity.
  • quenching the reaction in water generates huge quantities of aqueous waste, the disposal of which is a concern when the process is applied to a large manufacturing scale.
  • the process of the present invention is a cost effective, industrially applicable and an environmentally friendly process.
  • 2-chloro-4-fluoro-5-nitrobenzotrichloride can be obtained in a high yield, i.e. > 85 %, and with high purity, i.e. > 99 %, by a process that involves nitrating 2- chloro-4-fluorobenzotrichloride with a mixture of red fuming nitric acid and concentrated sulfuric acid, adding a halogenated organic solvent, separating the organic layer comprising 2-chloro-4- fluoro-5-nitrobenzotrichloride and washing it with a basic aqueous solution and subsequent crystallization of 2-chloro-4-fluoro-5-nitrobenzotrichloride from an organic solvent and water.
  • the present invention relates to an improved process for the preparation of 2-chloro-4-fluoro-5-nitrobenzotrichloride comprising
  • step (A) adding a halogenated organic solvent to the reaction mixture of step (A) at a temperature in the range of ⁇ 0 °C to ⁇ 15 °C to obtain an organic layer and an acidic layer;
  • step (B) separating the organic layer and the acidic layer of step (B);
  • step (C) washing the organic layer of step (C) with an aqueous solution of an inorganic base at a temperature in the range of ⁇ 10 °C to ⁇ 15 °C;
  • step (E) concentrating the organic layer of step (D) to obtain a crude product
  • step (F) mixing the crude product of step (E) with at least one organic solvent and water and heating to a temperature in the range of ⁇ 60 °C to ⁇ 70 °C to obtain a crude mixture;
  • the present invention relates to an improved process for the preparation of 2-chloro-4-fluoro-5-nitrobenzotrichloride comprising
  • step (A) adding a halogenated organic solvent to the reaction mixture of step (A) at a temperature in the range of ⁇ 10 °C to ⁇ 15 °C to obtain an organic layer and an acidic layer;
  • step (B) separating the organic layer and the acidic layer of step (B);
  • step (C) washing the organic layer of step (C) with an aqueous solution of an inorganic base at a temperature in the range of ⁇ 10 °C to ⁇ 15 °C;
  • step (E) concentrating the organic layer of step (D) to obtain a crude product
  • step (F) mixing the crude product of step (E) with at least one organic solvent and water and heat- ing to a temperature in the range of ⁇ 60 °C to ⁇ 70 °C to obtain a crude mixture;
  • 'sulfonitric mixture denotes a mixture of red fuming nitric acid and concentrated sulfuric acid.
  • Halogenated organic solvent denotes class of organic solvent which contains halogens- chlorine (CI), fluorine (F), bromine (Br) or iodine (I).
  • the 'purity' is the purity of the compound as determined by High performance liquid chroma- tography (HPLC).
  • the present invention relates to an improved process for the preparation of 2- chloro-4-fluoro-5-nitrobenzotrichloride of high purity.
  • the present invention relates to a process for the preparation of 2- chloro-4-fluoro-5-nitrobenzotrichloride comprising
  • step (A) reacting 2-chloro-4-fluorobenzotrichloride with sulfonitric mixture at a temperature in the range of ⁇ 0 °C to ⁇ 15°C to obtain a reaction mixture;
  • step (B) adding a halogenated organic solvent to the reaction mixture of step (A) at a temperature in the range of ⁇ 0 °C to ⁇ 15 °C to obtain an organic layer and an acidic layer;
  • step (B) separating the organic layer and the acidic layer of step (B);
  • step (C) washing the organic layer of step (C) with an aqueous solution of an inorganic base at a temperature in the range of ⁇ 10 °C to ⁇ 15 °C;
  • step (E) concentrating the organic layer of step (D) to obtain a crude product
  • step (F) mixing the crude product of step (E) with at least one organic solvent and water and heating to a temperature in the range of ⁇ 60 °C to ⁇ 70 °C to obtain a crude mixture;
  • the present invention relates to a process for the preparation of 2- chloro-4-fluoro-5-nitrobenzotrichloride comprising A) reacting 2-chloro-4-fluorobenzotrichloride with sulfonitric mixture at a temperature in the range of ⁇ 5 °C to ⁇ 10 °C to obtain a reaction mixture;
  • step (A) adding a halogenated organic solvent to the reaction mixture of step (A) at a temperature in the range of ⁇ 10 °C to ⁇ 15 °C to obtain an organic layer and an acidic layer;
  • step (B) separating the organic layer and the acidic layer of step (B);
  • step (C) washing the organic layer of step (C) with an aqueous solution of an inorganic base at a temperature in the range of ⁇ 10 °C to ⁇ 15 °C;
  • step (E) concentrating the organic layer of step (D) to obtain a crude product
  • step (F) mixing the crude product of step (E) with at least one organic solvent and water and heat- ing to a temperature in the range of ⁇ 60 °C to ⁇ 70 °C to obtain a crude mixture;
  • the starting material 2-chloro-4-fluorobenzotrichloride
  • 2-chloro-4-fluorobenzotrichloride can be synthesized by the photochlo- rination of the corresponding toluenic derivative as described in the patent US 4,71 1 ,905.
  • the 'sulfonitric mixture is composed of concentrated nitric acid and concentrated sulfuric acid.
  • the concentrated nitric acid is preferably 90% red fuming nitric acid and the concentrated sulfuric acid is 98 %.
  • the sulfonitric mixture comprises concentrated nitric acid and concentrated sulfuric acid preferably in a weight ratio of 1 :3 to 1 :7, more preferably in a weight ratio of 1 :3 to 1 :6, even more preferably in a weight ratio of 1 :3.5 to 1 :5
  • the sulfonitric mixture comprises concentrated nitric acid and concentrated sulfuric acid in a weight ratio of 1 :4 to 1 :5.
  • the weight ration of the sulfonitric mixture to 2-chloro-4-fluorobenzotrichloride is preferably in the range of 1 :1 to 3:1 , more preferably in the range of 1 :1 to 2.8:1 or 1 .2:1 to 2.8:1 , even more preferably in the range of 1 .4:1 to 2.5:1 , most preferably in the range of 1 .4:1 to 2.2:1 or 1 .4:1 to 2:1 .
  • the weight ratio of the sulfonitric mixture and 2-chloro-4- fluorobenzotrichloride is in the range of 1.5:1 to 2:1.
  • the sulfonitric mixture is preferably prepared by adding red, fuming nitric acid to concentrated sulfuric acid at a temperature of less than 10 °C.
  • the temperature of the nitration reaction (A) is preferably in the range of ⁇ 5 °C to ⁇ 10 °C. It is observed that if the reaction temperature is below 5 °C, the reaction times are increased. On the other hand, if the reaction is carried out at a temperature above 10 °C, the acid impurity formation is more, to the effect of even 10 %.
  • the nitration step (A) is carried out without solvent. It is observed that if a solvent, such as halogenated organic solvent is used as a reaction solvent, the nitration reaction does not proceed to completion.
  • a solvent such as halogenated organic solvent
  • Halogenated organic solvent used in the extraction step (B) is preferably selected from the group consisting of dichloromethane, chloroform, monochlorobenzene, ethylenedichloride more preferably dichloromethane and ethylenedichloride are used as halogenated organic solvent.
  • Halogenated organic solvent used in the extraction step (B) is preferably selected from the group consisting of dichloromethane, chloroform, monochlorobenzene, more preferably di- chloromethane is used as halogenated organic solvent.
  • the weight ratio of halogenated organic solvent to 2-chloro-4-fluorobenzotrichloride is preferably in the range of 1 :1 to 10:1 , more preferably in the range of 2:1 to 8:1 , even more preferably in the range of 2:1 to 6:1 , most preferably in the range of 3:1 to 6:1 and in particular in the range of 3:1 to 5:1 .
  • the weight ratio of the halogenated organic solvent to 2-chloro-4- fluorobenzotrichloride is preferably in the range of 3.5:1 to 5:1 .
  • Step (B) is preferably carried out at a temperature in the range of ⁇ 10 °C to ⁇ 15 °C.
  • the extraction step (B) is preferably done only once and thus it obviates the need to use additional solvent.
  • the organic layer is separated from the acidic layer in Step (C).
  • the acidic layer removed in step (C) contains a mixture of sulfuric acid and nitric acid and can preferably be reused, thereby reducing the waste generation and waste disposal issues. This is advantageous over the prior art in which the product is isolated by quenching the reaction in water which results in substantial aqueous waste generation.
  • the inorganic base in step (D) is preferably selected from alkali metal salts, more preferably the inorganic base is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates and bicarbonates, even more preferably the inorganic base is selected from the group consisting of sodium carbonate and sodium bicarbonate and most preferably the inorganic base is sodium carbonate.
  • Strong inorganic bases such as alkali metal hydroxides, though can be used, but when employed result in higher acidic impurity formation.
  • Step (D) is preferably carried out at a temperature in the range of ⁇ 10 °C to ⁇ 15°C.
  • the inorganic base is used in form of a saturated aqueous solution.
  • saturated aqueous solution it is meant that the inorganic base is added to water until the inorganic base no longer dissolves in water.
  • Preparation techniques of saturated aque- ous solution is well known to a person skilled in the art.
  • the aqueous solution of an inorganic base comprises inorganic base in an amount preferably in the range of 10 % to 20%, by weight.
  • the weight ratio of aqueous solution of inorganic base to 2-chloro-4-fluorobenzotrichloride is preferably in the range of 1 :1 to 4:1 , more preferably in the range of 1 .5:1 to 3.5:1 , even more preferably in the range of 1.5:1 to 3:1 and most preferably in the range of 1 .5:1 to 2.5:1 .
  • the weight ratio of aqueous solution of inorganic base to 2-chloro-4-fluorobenzotrichloride is in the range of 1 .7:1 to 2.5:1 .
  • the organic layer containing 2-chloro-4-fluorobenzotrichloride is concentrated in step E).
  • the organic solvent is removed in step (E) by preferably using conventional techniques, such as distillation or distillation under vacuum, to remove the halogenated organic solvent and obtain 2-chloro-4-fluorobenzotrichloride as a crude product.
  • a halogenated organic sol- vent such as dichloromethane
  • the organic solvent can be removed by simple distillation at a comparatively low temperature such as 40°C without applying any vacuum.
  • the crude product obtained after step (E) has a purity of ⁇ 90 % and contains ⁇ 5 % isomeric impurities and ⁇ 5 % acid impurities.
  • the crude product is subjected to further purification by crystallizing the crude product from an organic solvent mixture comprising at least one organic solvent and water.
  • the organic solvent used for crystallization in step (F) preferably is a polar protic solvent, more preferably an alkanol, even more preferably an alkanol selected from the group consisting of methanol, ethanol and isopropanol, most preferably methanol.
  • the weight ratio of the organic solvent to 2-chloro-4-fluorobenzotrichloride is preferably in the range of 0.5:1 to 3:1 , more pref- erably in the range of 1 :1 to 3:1 , even more preferably in the range of 1 :1 to 2.5:1 and most preferably in the range of 1 :1 to 2:1 .
  • the weight ratio of the organic solvent to 2-chloro-4- fluorobenzotrichloride is in the range of 1 :1 to 1.5:1
  • the weight ratio of water to 2-chloro-4-fluorobenzotrichloride is preferably in the range of 0.04:1 to 0.1 :1 , more preferably in the range of 0.04:1 to 0.09:1 , even more preferably in the range of 0.04:1 to 0.08:1 , and most preferably in the range of 0.04:1 to 0.075:1.
  • the weight ratio of water and 2-chloro-4- fluorobenzotrichloride is in the range of 0.04:1 to 0.07:1.
  • Step (F) is carried out by dissolving the crude product in the at least one organic solvent, pref- erably at a temperature in the range of ⁇ 60°C to ⁇ 70°C, preferably followed by addition of water.
  • the crude mixture is optionally seeded with 2-chloro-4-fluoro-5- nitrobenzotrichloride.
  • the crude mixture is preferably stored at a temperature in the range of ⁇ 0 °C to ⁇ 5 °C.
  • the crude mixture can be stored for any time period that is long enough to ensure sufficient and proper crystallization of 2-chloro-4-fluoro-5-nitrobenzotrichloride.
  • the crude mixture is stored for a period of 30 minutes to 8 hours, more preferably for a period of 30 minutes to 4 hours, even more preferably for a period of 30 minutes to 2 hours, most preferably for a period of 30 minutes to 90 minutes.
  • the pure product 2-chloro-4-fluoro-5-nitrobenzotrichloride
  • step (H) 2-chloro-4-fluoro-5-nitrobenzotrichloride
  • the process of the present invention leads to higher yield and higher selectivity, making it a cost-effective process.
  • the process is applicable for manufacturing at large scale.
  • HPLC analysis data is as follows:
  • Ethylenedichloride 400 g was added to the reaction mass between 10 °C to 15 °C and the contents were stirred for 15 minutes. The two layers were allowed to settle and the top organic layer (517 g) was separated from the bottom, aqueous, acidic layer (165 g).
  • the organic phase was washed with 15% aqueous solution of Na2CC"3 (200 g) between 10 °C to 15 °C and evaporated to dryness at 40 °C, to give the crude product (1 17.3 g). More specifically, organic layer (517 g) was charged back to flask. 15 % Na2C03 aqueous solution (200 g) was charged slowly to organic layer. Stirring was done for 15 min. Stirring was stopped and settling of layers was allowed. The bottom organic layer (512 g) was separated. Aqueous layer (205 g) was discarded. Organic layer was concentrated to residue. Residue (crude product) (1 14.3g) obtained was used for recrystallization.

Abstract

La présente invention concerne un procédé amélioré pour la préparation de 2-chloro-4-fluoro-5-nitrobenzotrichlorure. La présente invention concerne en outre un procédé de purification de 2-chloro-4-fluoro-5-nitrobenzotrichlorure, qui réduit les impuretés isomères et les sous-produits acides.
PCT/EP2018/051928 2017-02-06 2018-01-26 Procédé de préparation de 2-chloro-4-fluoro-5-nitrobenzotrichlorure WO2018141642A1 (fr)

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EP17154825.8 2017-02-06
EP17154825 2017-02-06

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109232258A (zh) * 2018-11-20 2019-01-18 宿州学院 一种2-氯-4-氟-5-硝基三氯甲苯合成后处理方法
CN109265349A (zh) * 2018-11-20 2019-01-25 宿州学院 一种高效合成2-氯-4-氟-5-硝基三氯甲苯的方法
US11261145B2 (en) 2017-03-20 2022-03-01 Basf Se Process for preparing bromotrichloromethane
US11358922B2 (en) 2017-11-02 2022-06-14 Basf Se Process for preparing 4-chlorobenzyl propargyl ether

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4711905A (en) 1982-05-11 1987-12-08 Bayer Aktiengesellschaft 2,4-dihalogenobenzoyl-(thio)urea insecticides
WO2005075425A2 (fr) * 2004-01-30 2005-08-18 Merck Patent Gmbh Derives de bisaryluree
WO2006090210A1 (fr) 2005-02-22 2006-08-31 Miteni S.P.A. Procede et methodes de preparation de gabapentine et de produits intermediaires du gabapentine
CN106083595A (zh) * 2016-06-08 2016-11-09 常州安迪沃克医药科技有限公司 抗癌药物色瑞替尼中间体2‑氯(溴)‑4‑氟‑5‑硝基甲苯的合成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4711905A (en) 1982-05-11 1987-12-08 Bayer Aktiengesellschaft 2,4-dihalogenobenzoyl-(thio)urea insecticides
WO2005075425A2 (fr) * 2004-01-30 2005-08-18 Merck Patent Gmbh Derives de bisaryluree
WO2006090210A1 (fr) 2005-02-22 2006-08-31 Miteni S.P.A. Procede et methodes de preparation de gabapentine et de produits intermediaires du gabapentine
CN106083595A (zh) * 2016-06-08 2016-11-09 常州安迪沃克医药科技有限公司 抗癌药物色瑞替尼中间体2‑氯(溴)‑4‑氟‑5‑硝基甲苯的合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI 9 November 2016 Derwent World Patents Index; AN 2017-085223, XP002768017 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11261145B2 (en) 2017-03-20 2022-03-01 Basf Se Process for preparing bromotrichloromethane
US11358922B2 (en) 2017-11-02 2022-06-14 Basf Se Process for preparing 4-chlorobenzyl propargyl ether
CN109232258A (zh) * 2018-11-20 2019-01-18 宿州学院 一种2-氯-4-氟-5-硝基三氯甲苯合成后处理方法
CN109265349A (zh) * 2018-11-20 2019-01-25 宿州学院 一种高效合成2-氯-4-氟-5-硝基三氯甲苯的方法

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