EP1165466A1 - Halogenation en position meta de phenols proteges - Google Patents

Halogenation en position meta de phenols proteges

Info

Publication number
EP1165466A1
EP1165466A1 EP00915292A EP00915292A EP1165466A1 EP 1165466 A1 EP1165466 A1 EP 1165466A1 EP 00915292 A EP00915292 A EP 00915292A EP 00915292 A EP00915292 A EP 00915292A EP 1165466 A1 EP1165466 A1 EP 1165466A1
Authority
EP
European Patent Office
Prior art keywords
acid
halogenation
acids
functions
chosen
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00915292A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jean-Roger La Jonquière Desmurs
Geneviève Padilla
Jean-Francis Spindler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rhodia Chimie SAS
Original Assignee
Rhodia Chimie SAS
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 Rhodia Chimie SAS filed Critical Rhodia Chimie SAS
Publication of EP1165466A1 publication Critical patent/EP1165466A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds

Definitions

  • Synthesis process comprising a halogenation in meta position of an aromatic acid derivative, intermediate compounds and use of these.
  • the present invention relates to a technique for protecting phenols in order to make functionalization of the latter or at least of their skeleton selective. It more particularly relates to the protection of phenols substituted in ortho and para so as to functionalize in meta position, advantageously in position 5 of the phenyl skeleton.
  • one of the most acute problems lies in the selectivity of the functionalization of an aromatic nucleus and more precisely the regioselectivity of the functionalization of aromatic nuclei.
  • halogenations which can be non-selective to several titles, on the one hand, at the level of regioselectivity and, on the other hand, at the level of the number of halogenations that the nucleus must undergo.
  • one of the aims of the present invention is to provide a process for the selective halogenation in the meta position of an aromatic derivative having an aniline function or a phenol function.
  • Another object of the present invention is to provide a process of the above type in which the aromatic nucleus has in the ortho position (in position 2) and in the para position (in position 4) electro-pulling functions (these electro-pulling functions being advantageously by inductive effect; it is preferable that said electron-withdrawing functions be electron-withdrawing by inductive effect and advantageously electrodosing by mesomeric effect), whether the latter are similar or different.
  • Another object of the present invention is to provide a protection system which promotes the selectivity of the above halogenations. Another object of the present invention is to provide a use of a molecule thus protected with a view to selective halogenation.
  • Another object of the present invention is to provide a process for halogenating the molecule thus protected with a view to selective halogenation in position 5 when the latter is distinct from position 3.
  • Another object of the present invention is to provide a process of the previous type which has selectivity (RT, that is to say transformation yield, namely the ratio between the quantity obtained of desired product and the quantity disappeared from the initial substrate, all expressed in moles) to less equal to 80%, advantageously 85%, preferably 90%.
  • Another object of the present invention is to provide a process of the preceding types which makes it possible to obtain a reaction yield (RR, that is to say the ratio between the quantity obtained of product and the quantity introduced of initial substrate) at least equal to 60%, advantageously to 70%, preferably to 80%.
  • Another object of the present invention is to provide intermediate synthesis compounds.
  • At least one in particular that in ortho of the protected phenol function, advantageously the two electron-withdrawing functions, has (have) an electrodosing property by mesomeric effect.
  • At least one, if not the two electron-withdrawing functions are light halogens, that is to say chlorine or fluorine atoms.
  • Selectivity is all the more interesting as the starting materials are difficult to obtain.
  • the starting materials or the electron-withdrawing functions are respectively chlorine and fluorine, are particularly well suited to the process according to the present invention.
  • said strong or medium acid is chosen from oxygenated acids.
  • said strong or medium acid prefferably has a pKa of less than or equal to 4, advantageously less than or equal to 2, preferably less than or equal to 0.
  • acids or acid esters of phosphoric acids (ortho-, pyro- or poly-) or phosphonic, or even phosphinic, sulfonic and alpha polyhalo-carboxylic acids Particular mention should be made of the sulfonic acids which are particularly well suited to the present invention.
  • sulfonic acids which are particularly well suited to the present invention.
  • the latter acid has a non-negligible hydrophilicity, which can sometimes be an advantage, sometimes a disadvantage.
  • hydrophilic acids it is advisable to apply to acids either containing more than 5 carbon atoms, or fluorinated acids as will be seen below.
  • polyacids such as phosphoric or phosphonic acids can be used; polyhalocarboxylic acids are to be classified among compounds with a lipophilic tendency (this lipophilicity means good solubility in the organic phases).
  • fluorinated sulfonic acids on the alpha position and, if necessary, on the beta position. Mention may thus be made of trifluoromethyl sulfonic acid or triflic acid. It should however be emphasized that perfluorosulfonic acids are particularly liposoluble, which allows good solubility in organic phases immiscible with water.
  • This solubility in the organic phases can constitute an advantage or a disadvantage, depending on the case, and depending on whether or not it is desired to separate the final product by recovering it in an organic phase.
  • the halogenation is advantageously carried out in a known manner using the techniques which use the halogens which are qualified as cationic.
  • This halogenation can be chlorination or bromination.
  • a particularly interesting reagent is the compound of formula BrCI which can be introduced directly into the medium or be synthesized in situ.
  • reaction medium As regards the solvents and the other components of the reaction medium, it should be indicated that it is preferable that there are in the reaction medium at least as many acid functions as phenol functions esterified in the substrate.
  • These acids are preferably protic or Bnansted acids, and in particular medium or strong acids, that is to say the acids whose pKa is at least equal to that of the carboxylic acids (i.e. about 4). It is preferred to have used strong acids such as sulfuric acid or any other acid of similar acidity (pK a less than or equal to 2, preferably 0).
  • a cationic dissociation catalyst for the halogenating agents more particularly Lewis acid.
  • Lewis acids are advantageously present at a level of 1/1000 to 10%, preferably from 1 to 5 mol% relative to the substrate to be halogenated.
  • the preferred Lewis acids are the metals whose salts are well dissociated in a sulfuric medium and more particularly the trivalent metals. Mention may in particular be made of aluminum (Al +++ ) and especially ferric iron.
  • the presence of acids as solvents or simply present in the medium in an amount at least equal to 1 time the number of phenol functions, advantageously 1, 5 times (in general and preferably there is only one phenol function and therefore the quantity of acids present and serving as solvents is therefore at least equal to 1 times the molar quantity of substrates, or even at least equal to 1.5 times the quantity of substrates) tends to reduce the reactivity of the substrates for halogenation reagents. It is therefore desirable to heat the reaction medium to a temperature at least equal to 30 ° C. In general, it is not necessary to heat above 100 ° C.
  • the preferred substrates are the compounds of formula 1 below in which Y is hydrogen, the halogenation then being carried out in position 5.
  • Another object of the present invention is to provide, as intermediate compounds, compounds of formula 1:
  • Formula 1 ⁇ where Ac represents a residue such that AcOH is an oxygenated acid of pK_ less than or equal to 2, advantageously less than or equal to 1, preferably less than or equal to 0; ⁇ where X and X ′, which are similar and / or different, advantageously represent a halogen, chlorine and / or fluorine; ⁇ where Y represents a hydrogen atom, a chlorine, bromine or iodine atom; ⁇ where Z represents either a group - NR - or a chalcogen, preferably oxygen or sulfur, more preferably oxygen;
  • R represents a lato sensu acyl group, that is to say the remainder of an oxygenated acid after elimination of an OH group; R can also be a hydrogen atom. It should be noted that R can be linked to the Ac group, so as to form a cyclic imide group with the nitrogen atom. This group may contain residues of carboxylic acid function to form cyclic imides, or mixed carboxylic or sulfonic imides, or any pair consisting of two elements. similar or different likely to form an imide or an imide equivalent per cycle.
  • the present invention relates to the use of mono or polyacids to protect an amino function, or more preferably a phenol function, so as to promote a halogenation which can be chlorination, bromination or iodination in the meta position, advantageously in position 5, with respect to said aniline or phenol function.
  • the crude product is purified by recrystallization from a MeOH-water mixture (70.30 w / w).
  • the isolated product has a titer greater than 98% and the yield of 2-chloro-4-fluorophenyl methane sulfonate is equal to 65%.
  • the 2-chloro-4-fluorophenyl acetate is recovered crude after removal of the dichloromethane and excess acetyl chloride.
  • the isolated yield of 2-chloro-4-fluorophenyl acetate is 84% and the titer is 95% by weight.
  • reaction mixture is then heated to 50 ° C. and chlorine (1.35 g -
  • the sulfuric solution is raised to nitrogen, then it is poured into 250 ml of ice water.
  • the crude 5-bromo-2-chloro-4-fluorophenyl methane sulfonate is extracted from the sulfuric solution with dichloromethane (3 ⁇ 50 ml).
  • the dichloromethane solution is then washed with water to a pH equal to 5.
  • the crude 5-bromo-2-chloro-4-fluorophenyl methane sulfonate is collected after distillation of the dichloromethane and drying.
  • the isolated yield is 90% and the purity of the crude is 92% by weight.
  • reaction mixture is then heated to 50 ° C and chlorine (1.35 g - 0.019 mol) is added over a period of one hour.
  • the sulfuric solution is stripped with nitrogen, then it is poured into 250 ml of ice water.
  • the crude methane tris (5-bromo-2-chloro-4-fluorophenyl) phosphate is extracted from the sulfuric solution with dichloromethane (4 x 50 ml).
  • the dichloromethane solution is then washed with water to a pH equal to 5.
  • the crude tris (5-bromo-2-chloro-4-fluorophenyl) phosphate is collected after distillation of the dichloromethane and drying. The isolated yield is 83% and the purity of the crude is 94% by weight.
  • reaction mixture is then heated to 30 ° C and chlorine (1.35 g - 0.019 mol) is added over a period of one hour.
  • the sulfuric solution is stripped with nitrogen, then it is poured into 250 ml of ice water.
  • the crude 2,5-dichloro-4-fluorophenyl methane sulfonate is extracted from the sulfuric solution with dichloromethane (3 ⁇ 50 ml).
  • the dichloromethane solution is then washed with water to a pH equal to 5.
  • the crude 2,5-dichloro-4-fluorophenyl methane sulfonate is collected after distillation of the dichloromethane and drying.
  • the isolated yield is 93% and the purity of the crude is 91% by weight.
  • reaction mixture is then heated to 50 ° C. and chlorine (1.35 g - 0.019 mol) is added over a period of one hour.
  • the acetic solution is stripped with nitrogen, then it is poured into 250 ml of ice water.
  • the crude (2,5-dichloro-4-fluorophenyl) acetate is extracted from the aqueous solution with dichloromethane (4 x 50 ml).
  • the dichloromethane solution is then washed with water to a pH equal to 5.
  • the crude (2,5-dichloro-4-fluorophenyl) acetate is collected after distillation of dichloromethane and acetic acid.
  • the reaction mixture is then left under stirring at room temperature for 3 hours.
  • the crude 5-bromo-2-chloro-4-fluorophenol is extracted from the aqueous solution with dichloromethane (3 x 5 ml).
  • the dichloromethane solution is then washed with water to a pH equal to 3.
  • the crude product is collected after distillation of dichloromethane and ethanol.
  • the isolated yield is 89% and the purity of the crude is 95% by weight.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP00915292A 1999-04-08 2000-04-05 Halogenation en position meta de phenols proteges Withdrawn EP1165466A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9904399A FR2791977B1 (fr) 1999-04-08 1999-04-08 Halogenation en position meta d'un aromatique presentant une fonction phenol protegee par condensation avec un acide
FR9904399 1999-04-08
PCT/FR2000/000851 WO2000061523A1 (fr) 1999-04-08 2000-04-05 Halogenation en position meta de phenols proteges

Publications (1)

Publication Number Publication Date
EP1165466A1 true EP1165466A1 (fr) 2002-01-02

Family

ID=9544173

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00915292A Withdrawn EP1165466A1 (fr) 1999-04-08 2000-04-05 Halogenation en position meta de phenols proteges

Country Status (8)

Country Link
US (1) US6576782B1 (zh)
EP (1) EP1165466A1 (zh)
JP (1) JP2004500323A (zh)
CN (1) CN1205151C (zh)
AU (1) AU3665600A (zh)
CA (1) CA2369395A1 (zh)
FR (1) FR2791977B1 (zh)
WO (1) WO2000061523A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1314869C (zh) * 2004-02-25 2007-05-09 华南理工大学 钢管混凝土柱与楼盖梁连接处的节点结构及其施工方法
CN102958913B (zh) * 2010-05-19 2015-11-25 罗地亚（中国）投资有限公司 制备邻位取代的5-卤代酚及其合成中间体的方法
CN105272828B (zh) * 2014-08-21 2018-03-09 连云港致诚化工有限公司 一种制备2,5‑二氯苯酚的方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2457805A (en) * 1946-11-02 1949-01-04 Burton T Bush Inc Aliphatic esters of 2,4,5-trichlorophenol
US2508334A (en) 1948-03-20 1950-05-16 Dow Chemical Co 2, 4, 5-trichlorophenol esters
US3416911A (en) 1965-12-09 1968-12-17 Chemagro Corp Method of defoliating and desiccating plants with substituted triphenyl phosphates and phosphites
DE1593846A1 (de) 1967-01-28 1971-02-25 Hoechst Ag Verfahren zur Herstellung von Sulfamidsaeure-arylestern
JP3268459B2 (ja) * 1991-05-31 2002-03-25 日本農薬株式会社 アセトフェノン類の製造法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0061523A1 *

Also Published As

Publication number Publication date
FR2791977A1 (fr) 2000-10-13
JP2004500323A (ja) 2004-01-08
FR2791977B1 (fr) 2003-04-11
AU3665600A (en) 2000-11-14
CN1205151C (zh) 2005-06-08
US6576782B1 (en) 2003-06-10
WO2000061523A1 (fr) 2000-10-19
CA2369395A1 (fr) 2000-10-19
CN1348433A (zh) 2002-05-08

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