WO2010143007A1 - Procédé de production de 2-halogéno-4-nitroimidazole - Google Patents

Procédé de production de 2-halogéno-4-nitroimidazole Download PDF

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Publication number
WO2010143007A1
WO2010143007A1 PCT/IB2009/005911 IB2009005911W WO2010143007A1 WO 2010143007 A1 WO2010143007 A1 WO 2010143007A1 IB 2009005911 W IB2009005911 W IB 2009005911W WO 2010143007 A1 WO2010143007 A1 WO 2010143007A1
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WIPO (PCT)
Prior art keywords
compound
formula
process according
iii
reacting
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Application number
PCT/IB2009/005911
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English (en)
Inventor
Guido WÜLLNER
Franz-Willi Herkenrath
Alexander JÜLICH
Original Assignee
Dynamit Nobel Gmbh Explosivstoff-Und Systemtechnik
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
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Application filed by Dynamit Nobel Gmbh Explosivstoff-Und Systemtechnik filed Critical Dynamit Nobel Gmbh Explosivstoff-Und Systemtechnik
Priority to PCT/IB2009/005911 priority Critical patent/WO2010143007A1/fr
Priority to JP2011507723A priority patent/JP5525515B2/ja
Priority to ES09788046.2T priority patent/ES2476967T3/es
Priority to EP09788046.2A priority patent/EP2323990B1/fr
Priority to PCT/JP2009/065015 priority patent/WO2010021409A1/fr
Priority to US13/059,333 priority patent/US8558005B2/en
Priority to CN200980132575.6A priority patent/CN102131787B/zh
Publication of WO2010143007A1 publication Critical patent/WO2010143007A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5

Definitions

  • the invention relates to a method for the production of 2-haIogeno-4-nitroimidazole.
  • 2-halogeno-4-nitroimidazole is a compound useful as an intermediate notably for the synthesis of various medicines or pesticides. In particular, it is useful as intermediate for the production of an antituberculous agent. There is a need to develop efficient and economic methods for the production of these compounds.
  • US-B-5,387,297 discloses a process for the production of 2,4-dinitroimidazole.
  • 1,4-dinitroimidazole is produced, by the reaction of 4-nitroimidazole in glacial acetic acid with nitric acid, in the presence of acetic anhydride. The compound is then precipitated and filtered.
  • 2,4-dinitroimidazole is produced by heating 1,4-dinitroimidazole in chlorobenzene. The obtained yield can be calculated and is rather low (63%).
  • EP-B-I 720 838 discloses a method for the production of 2-chIoro-4-nitroimidazoIe or 2- bromo-4-nitroimidazole comprising the iodination of 4-nitroimidazole and then the reduction of the obtained compound.
  • WO-A-2006035960 discloses a method for the production of 2-chloro-4-nitroimidazole comprising the reaction of l-alkoxyalkyl-2-bromo-4-nitroimidazole with hydrogen chloride.
  • the object of the present invention is to provide a more efficient method than the existing methods.
  • the process further comprises after step (i) the extraction of 1,4-dinitroimidazole, preferably with dichloromethane.
  • the process further comprises after step (i) the quenching, preferably with an ionic aqueous solution.
  • quenching and extracting are performed simultaneously.
  • the thermal rearrangement reaction temperature is between 100 and 150 0 C, preferably between 120 and 130 0 C, more preferably 125°C.
  • the thermal rearrangement is performed in chlorobenzene under reflux.
  • the chlorinating agent is hydrochloric acid.
  • the bromating agent is hydrobromic acid.
  • step (i) is followed by successive washings of the reaction mixture.
  • step (iii) is performed at a temperature between 60 and 150 0 C, preferably 100 and 1 10 0 C.
  • Another object of the invention is a process for the production of an antitubercular agent which comprises the steps of:
  • the present invention relates to a process for the production of a compound of formula (I)
  • This process comprises the step (i) of nitrating a compound of formula (II)
  • Nitric acid can be added in a molar ratio of 4-nitroimidazole over nitric acid from 1 : 1 to 1 :4, preferably from 1 : 1 to 1 :2, more preferably in a ratio of about 1 : 1,5.
  • the nitration is performed in a mixture of suitable solvents, acetic acid and acetic anhydride.
  • the molar ratio acetic acid anhydride/acetic acid is comprised between 3: 1 and 1 : 10, preferably between 1: 1 and 1:5, more preferably between 1 :2 and 1 :3.
  • the reaction is performed at a pressure comprised between 0,01 bar and 20 bar, preferably between 0,1 and 5 bar, more preferably between 0,5 and 2 bar, even more preferably under atmospheric pressure.
  • the temperature of the reaction is comprised between 5 and 30 0 C, preferably between 20 and 25°C.
  • the reaction mixture can be quenched, for example with the addition of water or of an aqueous solution of NaCl.
  • the mixture is quenched with an ionic aqueous solution as a quenching solution.
  • salts with high solubility in water are used.
  • Salts that can be used are for example KCI, CaCl 2 , or NaBr.
  • the resulting compound of formula (HI) can be extracted or precipitated from the reaction mixture.
  • the resulting compound is extracted.
  • the extraction can be done with the aid of any suitable solvent or mixture of solvents.
  • the solvent is not miscible with water.
  • the solvent is chlorobenzene.
  • the extraction solvent is xylene in combination with butyl acetate. More preferably, the solvent is xylene in combination with 10% (%volume) Butyl acetate.
  • the solvent is dichloromethane.
  • the reaction mixture is quenched then extracted, or quenched and extracted simultaneously, i.e. in a same step of the process.
  • the salts of the quenching solution force the compounds of formula (III) to go into the extraction solvent.
  • the extracted mixture can be washed with the aid of one or more suitable solutions.
  • the extracted mixture solution can be washed with an aqueous solution, for example an aqueous solution of sodium chloride.
  • the extracted mixture is washed with an aqueous solution of sodium hydrogen carbonate.
  • the extracted mixture is washed with water.
  • the extracted mixture is neutralized.
  • the mixture is neutralized by the addition of a suitable base.
  • the base can be an organic or inorganic base.
  • sodium hydroxide or potassium hydroxide can be used.
  • the pH at the end of the neutralization is comprised between 6 and 9, more preferably between 7 and 8.
  • the temperature of the neutralization reaction does not exceed about 30°C so as to avoid self-degradation of the product.
  • the neutralization is exothermic thus the temperature of the mixture is preferably controlled and regulated. Any suitable regulation devices can be used.
  • a cooler can be used. After the neutralization, the organic and aqueous phases are separated.
  • the extracted mixture is washed once or by successive washings, with the same or different solutions.
  • the mixture can be washed with an aqueous solution, then neutralized and at last washed with another aqueous solution.
  • the extracted mixture can be neutralized, then washed with an aqueous solution, then washed with water.
  • the extracted solution is neutralized with a solution of NaOH, washed with an aqueous solution OfNaHCO 3 , then washed with water.
  • the extraction solvent can be removed prior to the step immediately following. In another embodiment it can be only partly removed, for example 20 to 90%, preferably 30 to 70% by volume, and the solvent of the next step is added and then the mixture of the two solvents is distilled to remove the extraction solvent.
  • the process also comprises the step of thermally rearranging the compound of formula (III) into a compound of formula (IV)
  • the solvent resulting from the extraction process is partly removed.
  • the solvent can be partly removed by any suitable method of separation.
  • the solvent is distilled.
  • the extraction solvent is dichloromethane
  • the solvent can be distilled at 40°C at atmospheric pressure.
  • the water content of the solution is controlled. Preferably, it does not exceed
  • water can be removed by any suitable methods, preferably water is removed during the distillation of the extraction solvent if there is any.
  • the rearrangement reaction can be performed in any suitable solvent.
  • the solvent is chlorobenzene, toluene or xylene.
  • the solvent is chlorobenzene.
  • the temperature of the reaction is comprised between 45 and 130 0 C.
  • the temperature is comprised between 100 and 130 0 C, more preferably the temperature is about 125°C.
  • the reaction is performed at a pressure comprised between 0,01 bar and 20 bar, preferably between 0,1 and 5 bar, more preferably between 0,5 and 2 bar, even more preferably under atmospheric pressure.
  • the thermal rearrangement is performed in any suitable solvent or mixture of solvents.
  • the solvent is chlorobenzene.
  • the thermal rearrangement is performed under reflux.
  • the resulting compound can then be separated from the reaction mixture.
  • Any suitable method for separating the compound can be used.
  • the compound can be precipitated or extracted by a suitable solvent.
  • the compound is precipitated by cooling the solution to a temperature at which the compound of formula (IV) precipitates, preferably at a temperature between 0 and 5°C. Then the solution is filtered.
  • the process also comprises the step of reacting the compound of formula (IV) with a chlorinating or bromating agent.
  • the chlorination agent can be any suitable chlorinating agent.
  • hydrochloric acid or phosphoryl chloride can be used.
  • hydrochloric acid is used.
  • the bromating agent can be any suitable bromating agent.
  • hydrobromic acid, bromine, or N-bromosuccinimide can be used.
  • hydrobromic acid is used.
  • the reaction temperature is comprised between 40 and 160°C.
  • the temperature is comprises between 80 and 120 0 C. More preferably, the temperature is comprised between 100 and 1 10 0 C.
  • the reaction is performed at a pressure comprised between 0,01 bar and 20 bar, preferably between 0,1 and 5 bar, more preferably between 0,5 and 2 bar, even more preferably under atmospheric pressure.
  • the resulting compound of formula (I) can be separated from the reaction mixture. It can be extracted or filtered off.
  • the process can be a continuous process or a batch process.
  • the process is a continuous process.
  • the reactants are fed in a continuous stream.
  • the resultant products are withdrawn in a continuous way.
  • the reactant may be fed as intermittent or pulsed streams and/or the products may be withdrawn as intermittent or pulsed streams.
  • a continuous process is simpler to carry out and more efficient than a batch process.
  • the compound of formula (I) can be used to manufacture an antimicrobial agent.
  • the manufacture of an antimicrobial agent starting from the compound of formula (I) is described in European Patent Application EP-A- 1555267.
  • the antimicrobial agent can be any compound described in EP-A- 1555267 and in particular compounds subject of any one of claims 1 to 43.
  • the antimicrobial agent is a compound of formula (VIII)
  • AU equivalents are molar equivalents and calculated relative to the starting material 4- nitroimidazole.
  • Step 1 In a first vessel 1,00 eq. of 4-Nitroimidazole (solid) is mixed with 2,01 eq. acetic acid anhydride and 5,83 eq. acetic acid. The mixture is cooled down to 15°C. Into this suspension 1,5 eq. nitric acid is dosed. The reaction is weakly exothermic and it has to be ensured that the temperature of the reaction mixture is not exceeding 15°C. After the addition of the nitric acid the reaction mixture is warmed up to 23-25°C and is stirred for 3 hours. After the addition of nitric acid the reaction mixture is warmed up to 23-25°C and is stirred for 3 hours. After stirring of about 2 hours a yellow-orange solution appears.
  • the reaction mixture of the first vessel is dosed into the stirred vessel (second vessel).
  • the quench is weakly exothermic and it has to be ensured not to exceed 20°C.
  • the content of the second vessel is stirred for 30 minutes, afterwards the phases were separated.
  • the upper aqueous phase is waste whereas the lower organic phase contains the product 1,4- dinitroimidazole and remains in the second vessel.
  • the content of the second vessel is stirred for 30 minutes, afterwards the phases were separated.
  • the upper aqueous phase is waste whereas the lower organic phase contains 1,4-dinitroimidazole and remains in the second vessel.
  • the phase separation is good.
  • the upper aqueous phase is of dark red to yellow brown color.
  • the intermediate phase has disappeared.
  • the water content in the residue is limited to 500 ppm. If necessary a water/dichloromethane hetero-azeotrope has to be removed until the water content in the residue is below 500 ppm.
  • the water content is controlled by Karl Fisher method.
  • the distillate is light brown, and nitrous gases are formed.
  • the mixture in the second vessel is stirred 7 hours at 125°C under reflux to perform the rearrangement reaction. After 6 hours a first in-process control can be taken, >99,0% conversion to 2,4-dinitroimidazole should be achieved.
  • the reaction mixture is cooled down to 0-2 0 C and is stirred at this temperature for 1 hour.
  • the precipitated 2,4-dinitroimidazole is filtered.
  • the mother liquor color is orange.
  • the filter cake is washed with 1,29 eq. chlorobenzene. It has to be taken care that the filter cake is not dried at this step because the solid 2,4-dinitroimidazole is shock and friction sensitive.
  • An amount of 10-15 % (w/w) residual chlorobenzene is sufficient for phlegmatizing.
  • step 2 The product of step 2 is wet 2,4-dinitroimidazole with 96% (w/w) content (Yield : 67%).
  • Step 3 To produce 2-chloro-4-nitroimidazole
  • the distillation begins at a temperature of 70-80 0 C. Water, chlorobenzene and hydrochloric acid are distilled during heating up the reaction mixture to 105 0 C. When the temperature of 105 0 C is reached, the mixture is stirred at 105 0 C for 7 hours. The conversion should be >98%. The heating to 105 0 C has to be performed carefully because the mixture tends to foam.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un procédé de production d'un composé de formule (I) dans laquelle X est Cl ou Br, comprenant les étapes de : (i) nitration d'un composé de formule (II) en vue d'obtenir un composé de formule (III) à l'aide d'acide nitrique dans un mélange d'acide acétique et d'anhydride acétique (ii) réorganisation thermique du composé de formule (III) en un composé de formule (IV) (iii) réaction du composé de formule (IV) avec un agent de chloration ou de bromation. L'invention décrit un procédé plus efficace que les procédés existants.
PCT/IB2009/005911 2008-08-21 2009-06-10 Procédé de production de 2-halogéno-4-nitroimidazole WO2010143007A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
PCT/IB2009/005911 WO2010143007A1 (fr) 2009-06-10 2009-06-10 Procédé de production de 2-halogéno-4-nitroimidazole
JP2011507723A JP5525515B2 (ja) 2008-08-21 2009-08-21 ２−ハロ−４−ニトロイミダゾール及びその中間体の製造方法
ES09788046.2T ES2476967T3 (es) 2008-08-21 2009-08-21 Métodos para la producción de 2-halo-4-nitroimidazol e intermedios del mismo
EP09788046.2A EP2323990B1 (fr) 2008-08-21 2009-08-21 Procédés pour la fabrication de 2-halo-4-nitroimidazole et leurs intermédiaires
PCT/JP2009/065015 WO2010021409A1 (fr) 2008-08-21 2009-08-21 Procédés pour la fabrication de 2-halo-4-nitroimidazole et leurs intermédiaires
US13/059,333 US8558005B2 (en) 2008-08-21 2009-08-21 Methods for the production of 2-halo-4-nitroimidazole and intermediates thereof
CN200980132575.6A CN102131787B (zh) 2008-08-21 2009-08-21 制备2-卤代-4-硝基咪唑及其中间体的方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2009/005911 WO2010143007A1 (fr) 2009-06-10 2009-06-10 Procédé de production de 2-halogéno-4-nitroimidazole

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WO2010143007A1 true WO2010143007A1 (fr) 2010-12-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019146113A1 (fr) * 2018-01-29 2019-08-01 Otsuka Pharmaceutical Co., Ltd. Procédé de production de dérivés de 2-chloro-4-nitroimidazole

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1555267A1 (fr) * 2002-10-11 2005-07-20 Otsuka Pharmaceutical Co., Ltd. 2,3-dihydro-6-nitroimidazo 2,1-b]oxazoles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1555267A1 (fr) * 2002-10-11 2005-07-20 Otsuka Pharmaceutical Co., Ltd. 2,3-dihydro-6-nitroimidazo 2,1-b]oxazoles

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
NAGARAJAN K ET AL: "NITROIMIDAZOLES: PART XX-REACTIONS OF 2,4-DINITROIMIDAZOLE WITH 2-HALOETHANOLS, 3-CHLOROPROPIONITRILE & PROPYLENE OXIDE", INDIAN JOURNAL OF CHEMISTRY, JODHPUR, IN, vol. 23B, 1 April 1984 (1984-04-01), pages 363 - 368, XP009044352 *
SUWINSKI J ET AL: "NITROIMIDAZOLES . PART V. CHLORONITROIMIDAZOLES FROM DINITROIMIDAZOLES, A REINVESTIGATION", POLISH JOURNAL OF CHEMISTRY, POLISH CHEMICAL SOCIETY, XX, vol. 56, no. 10 - 12, 1 January 1982 (1982-01-01), pages 1261 - 1272, XP009048285 *
V. SUDARSANAM ET AL.: "Nitroimidazoles: Part XI- Some Halonitro- and Dinitroimidazoles", INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY, vol. 21B, no. 11, November 1982 (1982-11-01), pages 1022 - 1026, XP009125221 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019146113A1 (fr) * 2018-01-29 2019-08-01 Otsuka Pharmaceutical Co., Ltd. Procédé de production de dérivés de 2-chloro-4-nitroimidazole
US11104650B2 (en) 2018-01-29 2021-08-31 Otsuka Pharmaceutical Co., Ltd. Process for production of 2-chloro-4-nitroimidazole derivatives

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