EP1165466A1

EP1165466A1 - Halogenation of protected phenols in meta position

Info

Publication number: EP1165466A1
Application number: EP00915292A
Authority: EP
Inventors: Jean-Roger La Jonquière Desmurs; Geneviève Padilla; Jean-Francis Spindler
Original assignee: Rhodia Chimie SAS
Current assignee: Rhodia Chimie SAS
Priority date: 1999-04-08
Filing date: 2000-04-05
Publication date: 2002-01-02
Also published as: US6576782B1; JP2004500323A; FR2791977A1; CA2369395A1; WO2000061523A1; AU3665600A; CN1348433A; FR2791977B1; CN1205151C

Abstract

The invention concerns a halogenation in position meta of a phenol function. Said halogenation comprises a step which consists in halogenating an aromatic derivative of a medium or advantageously strong acid, the aromatic radical being a phenyl substituted in ortho and in para by functions attracting electrons by inductive effect. The invention is applicable to organic synthesis.

Description

HALOGENATION IN META POSITION OF PROTECTED PHENOLS

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. In the field of aromatic organic synthesis, 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.

This problem is all the more acute as functionalization occurs at an advanced stage of synthesis. The more expensive the starting product of this functionalization step, the more important it is to obtain selective and high-yield reactions.

This is particularly the case for trifunctionalized benzene rings which should be functionalized a fourth time (that is to say that it already has 3 substituents).

The problem is often complicated by the directing effect of certain functions, especially when these functions have a very marked directing effect, as is the case with the phenol functions and their derivatives, and the aniline functions and their derivatives. Thus, in Japanese patent JPA 4356438 which relates to a general synthesis comprising a halogenation step of products similar to those which have just been mentioned above, halogenation is carried out on the methyl ether of the phenol and the one obtains a most mediocre yield since one obtains an isolated yield of less than 30%, which implies a selectivity (RT) undoubtedly very low.

In addition, among the most difficult functionalizations, it is worth mentioning 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.

This is why 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.

These aims, and others which will appear subsequently, are achieved by means of an organic synthesis process comprising at least the step of halogenation of the aromatic derivative of a medium or advantageously strong acid in which the aromatic residue is a phenyl substituted in ortho position and para position by electroattractive functions by inductive effect. Thus, according to the present invention, it has been shown that protection, by means of a strong acid and by means of a phenol or an aniline, plays a role of induction in meta and especially in position 5 of the derivatives. of the previous type. This regioselectivitis is especially marked in the case of phenyl esters.

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.

The most advantageous effects are obtained for the case where said electron-withdrawing functions, in any case at least one, preferably both, are halogen atoms.

In order to avoid side reactions, it is preferable that 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. Thus, 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.

Mention may in particular be made of the compounds which have chlorine in the ortho position and a fluorine in the para position.

With regard to said strong or medium acids, it is preferable that said strong or medium acid is chosen from oxygenated acids.

It is also desirable for said strong or medium acid to have a pKa of less than or equal to 4, advantageously less than or equal to 2, preferably less than or equal to 0.

The easiest acids to use are those which can be chosen from the list below: 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. Thus, it is possible to use either the aryisulfonic acids whose paradigms are benzenesulfonic and paratoluenesulfonic acids; alkyl sulfonic acids can also be used, the paradigm of which is methane sulfonic acid, more often called mesylic acid. The latter acid has a non-negligible hydrophilicity, which can sometimes be an advantage, sometimes a disadvantage. When more lipophilic acids are desired, it is advisable to apply to acids either containing more than 5 carbon atoms, or fluorinated acids as will be seen below. If more hydrophilic acids are desired, 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).

Particular mention must be made of 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. In the latter case, a particularly interesting reagent is the compound of formula BrCI which can be introduced directly into the medium or be synthesized in situ.

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).

To ensure the cationic nature of the halogenation, it is preferable to operate in the presence of a cationic dissociation catalyst for the halogenating agents, more particularly Lewis acid. These 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;

→ where 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.

Thus, 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.

Although they give good results and are easy to synthesize, the intermediate compounds which are both carbonated and low carbonated, while being non-fluorinated, are the least interesting.

It is thus preferable to use, as intermediate compounds, either those which do not have a carbon atom, or those which have at least 3, preferably at least 5 carbons, or finally those which are halogen, preferably fluorinated. .

The following nonlimiting examples illustrate the invention.

EXAMPLE 1 Protection of phenol = Synthesis of 2-chloro-4-fluorophenyl methane sulfonate

Load into a 150 ml reactor: 34.32 g of 2-chloro-4-fluorophenol (0.20 mol), 80 g of dichloromethane, 41, 46 g of potassium carbonate (0.300 mol) and 25.19 g of chloride of mesyl (0.218 mol). The reaction mixture is left under stirring for 3 hours. The organic phase is recovered after filtration of the salts. The dichloromethane solution is then washed successively with 100 ml of potassium carbonate solution at pH = 8, 100 ml of potassium hydrogen carbonate solution at 20% (weight / weight), then 100 ml of water. After elimination of the dichloromethane, 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%.

° Synthesis of 2-chloro-4-flurophenyl acetate Charger in a 150 ml reactor: 34.32 g of 2-chloro-4-fluorophenol

(0.100 mol), 80 g of dichloromethane, 41.46 g of potassium carbonate (0.300 mol) and 17.78 g of acetyl chloride (0.218 mol). The reaction mixture is left under stirring for 3 hours. The organic phase is recovered after filtration of the salts. The dichloromethane solution is then washed successively with 100 ml of potassium carbonate solution at pH = 8, 100 ml of 20% potassium hydrogen carbonate solution (weight / weight), then 100 ml of water.

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.

EXAMPLE 2 Bromination of the Protected Phenol

=> Synthesis of 5-bromo-2-chloro-4-fluorophenyl methane sulfonate

Load into a 150 ml reactor: 100 ml of 96% sulfuric acid, 0.1 g of iron powder (0.0018 mol), 2.04 g of 2-choro-4-fluorophenyl methane sulfonate (0 0.0091 mol), 3.14 g bromine (0.019 mol).

The reaction mixture is then heated to 50 ° C. and chlorine (1.35 g -

0.019 mol) is added over a period of one hour.

At the end of the reaction, 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.

=> Synthesis of tris (5-bromo-2-chloro-4-fluorophenyl) phosphate

Load into a 150 ml reactor: 100 ml of 96% sulfuric acid, 0.1 g of iron powder (0.0018 mol), 2.0 g of tris (2-chloro-4-fluorophenyl) phosphate ( 0.00373 mol), 3.14 g of bromine (0.019 mol).

The reaction mixture is then heated to 50 ° C and chlorine (1.35 g - 0.019 mol) is added over a period of one hour.

At the end of the reaction, 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.

EXAMPLE 3 Chlorination of Protected Phenol

≈t> Synthesis of 2.5-dichloro-4-fluorophenyl methane sulfonate

Load into a 150 ml reactor: 100 ml of 96% sulfuric acid, 0.1 g and 2.04 g of 2-chloro-4-fluorophenyl methane sulfonate (0.0091 mol).

The reaction mixture is then heated to 30 ° C and chlorine (1.35 g - 0.019 mol) is added over a period of one hour.

At the end of the reaction, 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.

= Synthesis of (2.5-dichloro-4-fluorophenyl) acetate

Load into a 150 ml reactor: 100 ml of acetic acid and 2.0 g of

(2-chloro-4-fluorophenyl) acetate (0.0106 mol).

The reaction mixture is then heated to 50 ° ^C. and chlorine (1.35 g - 0.019 mol) is added over a period of one hour.

At the end of the reaction, 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 isolated yield is 85% and the purity of the crude is 89% by weight. EXAMPLE 4 Deprotection of Phenol After Halogenation

=> Synthesis of 5-bromo-2-chloro-4-fluorophenol

Load into a 150 ml reactor: 2 g of 5-bromo-2-chloro-4-fluorophenyl methane sulfonate (0.0066 mol), 32 ml of ethanol and 8 g of 10% by weight aqueous potassium hydroxide (0, 0145 mol).

The reaction mixture is then left under stirring at room temperature for 3 hours.

At the end of the reaction, the reaction medium is acidified to pH = 1 with hydrochloric acid 1. 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.

Claims

. Process for organic synthesis, characterized in that it comprises a step of halogenation of an aromatic derivative of a medium or advantageously strong acid, in that the aromatic residue is a phenyl substituted in ortho and in para by electron-withdrawing functions by inductive effect.

2. Method according to claim 1, characterized in that the said derivative is chosen from anilides or preferably from phenyl esters.

3. Method according to one of claims 1 and 2, characterized in that at least one, preferably the two electron-withdrawing functions are preferably electron-donating by mesomeric effect.

4. Method according to one of claims 1 to 3, characterized in that at least one, preferably the two electroattractive functions are chosen from halogens.

5. Method according to claims 1 to 4, characterized in that at least one, preferably the two electroattractive functions are chosen from light halogens (chlorine and fluorine).

6. Method according to claims 1 to 5, characterized in that said electroattractive functions are respectively chlorine and fluorine.

7. Method according to claims 1 to 6, characterized in that said electroattractive functions are chlorine in ortho and fluorine in para.

8. Method according to claims 1 to 7, characterized in that said acids are oxygenated acids.

9. Method according to claims 1 to 8, characterized in that said acid has a pKa less than or equal to about 4, advantageously less than or equal to about 2, preferably less than or equal to about 0.

10. Method according to claims 1 to 9, characterized in that said acid is chosen from phosphoric, phosphonic, sulfonic, carboxylic, alpha-polyhalogenated acid and esters (twice, or even three times in the case of the acid acetic).

11. Method according to claims 1 to 10, characterized in that said acid is a sulfonic acid, including alkyl sulfonic, aryl sulfonic, perfluoroalkyl sulfonic.

12. Method according to claims 1 to 11, characterized in that the said halogenation is carried out in position 5.

13. Method according to claims 1 to 12, characterized in that said halogenation is a chlorination or preferably a bromination.

14. Method according to claims 1 to 13, characterized in that the reagent used by said halogenation is of the cationic type.

15. Method according to claims 1 to 14, characterized in that said halogenation is a bromination and in that the brominating agent is

BrCI (introduced directly or made in situ).

16. Compound of formula 1:

→ where Ac is chosen so that AcOH is an oxygenated acid with pKa less than or equal to about 4; → where X and X ', similar or different, represent a halogen advantageously chlorine and / or fluorine; - → where Y represents hydrogen, chlorine, bromine or iodine; → where Z represents NR; -0 -0; with R representing either an aryl or an alkyl radical (lato sensu); an acyl which can, if necessary, be linked with said acid to form a cyclic imide; hydrogen, preferably when said acid does not have a radical capable of being halogenated according to a radical mechanism.

17. Compounds of formula 1, characterized in that AcOH is chosen from either acids having no carbon atom, or acids comprising at least 3, preferably at least 5 carbon atoms, or acids with both halogen and carbon.

18 Use of a medium or strong acid to protect a phenol substituted in the ortho and para position before halogenation of the cationic type.