JP2009530260A - Process for producing 1-bromo-3-trifluoromethoxybenzene - Google Patents

Abstract

The present invention relates to 1-bromo-3-trifluoromethoxybenzene via a synthesis process that provides excellent yields and surprising selectivity, starting from 2- or 4-trifluoromethoxyaniline or a mixture of these compounds. Relates to the manufacturing method. The process comprises bromination of 2- or 4-trifluoromethoxyaniline with a brominating agent that releases Br ⁺ ions in an acidic solvent in the presence of a weak acid, followed by a deamination reaction.

Description

  The present invention relates to 1-bromo-3-trifluoromethoxybenzene via a synthesis process that provides excellent yields and surprising selectivity, starting from 2- or 4-trifluoromethoxyaniline or a mixture of these compounds. Relates to the manufacturing method. The invention also relates to novel synthetic intermediates.

  The compound 1-bromo-3-trifluoromethoxybenzene is well known in the art. However, there are still many difficulties in its preparation. Direct bromination of trifluoromethoxybenzene fails to produce the desired compound because the trifluoromethoxy group leads to nucleophilic substitution at the ortho or para position rather than at the required meta position in the benzene ring. In this type of case, the possibility of performing a nucleophilic substitution reaction starting from a derivative with an “auxiliary substituent” that activates the non-reactive position and then is removed to provide the desired product. It is common to consider.

  For example, in the benzene ring, amine-type auxiliary substituents are commonly used and their introduction leads to nucleophilic substitution in the ortho / para position. However, the auxiliary substituent has the disadvantage of activating the substrate excessively with respect to the nucleophilic reaction, which causes nucleophilic substitution at several positions, resulting in a derivative that is also substituted at undesirable positions. Will be.

  In other words, the product of the first nucleophilic substitution is generally more reactive when an amine-type auxiliary substituent is introduced into the benzene ring to guide nucleophilic substitution at the ortho or para position. In the substitution reaction, since it competes with the raw material, multiple substitution occurs.

To remedy this drawback, auxiliary substituents with poor “activation” are often chosen to reduce the risk of nucleophilic polysubstitution, which obviously leads to loss of reaction yield. For example, if it is desired to use a primary amine group (—NH ₂ ) as an auxiliary substituent to avoid excessive activation, the amine group is converted to an amide group, eg, an acetylamine group. However, it has the disadvantage of adding an additional reaction step to the synthesis process, resulting in a loss of the overall reaction yield.

  An object of the present invention is to provide a selective synthesis of the compound 1-bromo-3-trifluoromethoxybenzene by a bromination reaction that provides excellent yields but does not produce undesirable polybrominated byproducts. is there.

  Surprisingly, the inventors do not need to deactivate the amine group in excellent yield by conducting a bromination reaction for 2- or 4-trifluoromethoxyaniline or for these compounds. Thus, it was found that the compound 1-bromo-3-trifluoromethoxybenzene was obtained.

の化合物１-ブロモ-３-トリフルオロメトキシベンゼンを製造する方法であって、
（ａ）２-トリフルオロメトキシアニリン、４-トリフルオロメトキシアニリン及びこれらの化合物の混合物から選ばれる式（II）

（式中、Ｒ₁及びＲ₂の一方は水素を表し、他方は-NH₂基を表す）を、弱酸の存在下、酸性溶媒中でBr⁺イオンを放出する臭素化剤と反応させて、式（III）

（式中、Ｒ₁及びＲ₂は上記の定義のとおりであり、Ｒ₃及びＲ₄の一方は水素を表し、他方は臭素原子を表す）の中間体を生成し、
（ｂ）式（III）の化合物を脱アミノ化して、式（I）の所望化合物を得る
ことを含んでなる１-ブロモ-３-トリフルオロメトキシベンゼンの製法に関する。 Thus, according to one of its embodiments, the present invention provides a compound of formula (I)

A process for producing the compound 1-bromo-3-trifluoromethoxybenzene of
(A) Formula (II) selected from 2-trifluoromethoxyaniline, 4-trifluoromethoxyaniline and mixtures of these compounds

(Wherein _one of R ₁ and R ₂ represents hydrogen and the other represents a —NH ₂ group) is reacted with a brominating agent that releases Br ⁺ ions in an acidic solvent in the presence of a weak acid; Formula (III)

Wherein R ₁ and R ₂ are as defined above, one of R ₃ and R ₄ represents hydrogen and the other represents a bromine atom,
(B) relates to a process for preparing 1-bromo-3-trifluoromethoxybenzene comprising deaminating a compound of formula (III) to obtain the desired compound of formula (I).

The bromination reaction (a) is carried out by a brominating agent that releases electrophilic Br ⁺ in an acidic medium. Indeed, it has been observed that selectivity and yield are much lower when using reagents that release H ⁺ or HBr ions (eg, like bromine) during bromination.

Examples of brominating agents that release electrophilic Br ⁺ in acidic media include N-bromosuccinimide (NBS) and 1,3-dibromo-5,5-dimethylhydantoin (DBI) or mixtures thereof. NBS is a preferred brominating agent. The bromination reaction (a) occurs in an acidic medium, particularly in the presence of a weak acid, as described above.

  According to the invention, “weak acid” means an acid having a pKa of greater than 4, advantageously greater than 4.5, for example a pKa of 4.5 to 5.5. A weak acid advantageously used in the process of the invention is, for example, acetic acid.

  In the bromination reaction (a), a solvent such as alkane, chloroalkane or aromatic solvent inert to electrophilic reaction, such as methylene chloride, chloroform, heptane, nitrobenzene, benzotrifluoride, etc. can be used. However, it is not always necessary to use it.

  However, the weak acid used in the reaction, for example, acetic acid, also functions as a solvent, so there is no need to add a solvent.

  The reaction temperature ranges from -5 ° C to room temperature, preferably about 0 ° C. The reaction is exothermic and it is therefore advisable to provide an external cooling system.

  The starting material / solvent molar ratio is preferably about 1/6, and in the case of acetic acid, it corresponds to a weight ratio of about 1/2.

  According to one embodiment of the invention, the brominating agent is advantageously used in an excess with respect to the raw material, for example in a molar excess of 5 to 10%.

  Nevertheless, the brominating agent (preferably NBS) is used in all proportions. In fact, it can also be used in the absence of a brominating agent, for example if the raw material of formula (II) (which has not been brominated) can be easily recycled in subsequent batches, Biological production can be minimized. In this embodiment of the invention, it is necessary to deal with more raw material, but if a higher overall yield can be achieved and appropriate industrial equipment is available, an advantageous variant is constructed.

  As mentioned above, step (a) of bromination with a brominating agent (preferably NBS) provides high yields and excellent selectivity for mono-substitution.

  For comparison, the bromination reaction was performed on the same source material using other brominating agents such as chlorine in an aqueous solvent or acetic acid. The reaction did not give satisfactory results for the desired position and mono substitution.

  Tests were also conducted for bromination reactions with NBS or DBI in highly acidic media, but again, the results were unsatisfactory with respect to selectivity and resulting final yield.

  About the comparative example which reproduces the said reaction, it shows in the description part regarding the above-mentioned experiment.

  Thus, the results obtained with NBS or DBI in weakly acidic media are surprising and unpredictable.

、式（IIIb）

又は式（IIIc）

で表される４-ブロモ-２-トリフルオロメトキシアニリン、２-ブロモ-６-トリフルオロメトキシアニリン又は２-ブロモ-４-トリフルオロメトキシアニリンである）を、溶媒の蒸発、任意の中和及び蒸留によって単離できる。２-トリフルオロメトキシアニリンを原料とする場合、式（IIIa）又は（IIIb）の化合物の混合物からなる臭素化生成物が得られる。４-トリフルオロメトキシアニリンを原料とする場合には、化合物（IIIc）のみが得られる。原料物質（II）として、２-トリフルオロメトキシアニリン及び４-トリフルオロメトキシアニリンの混合物を使用する場合には、式（III）の３種の全ての成分の混合物が得られることは明らかである。 Brominated products of formula (III) (respectively of formula (IIIa)

, Formula (IIIb)

Or formula (IIIc)

4-bromo-2-trifluoromethoxyaniline, 2-bromo-6-trifluoromethoxyaniline or 2-bromo-4-trifluoromethoxyaniline represented by the following formula: Can be isolated by distillation. When 2-trifluoromethoxyaniline is used as a raw material, a brominated product comprising a mixture of compounds of formula (IIIa) or (IIIb) is obtained. When 4-trifluoromethoxyaniline is used as a raw material, only compound (IIIc) is obtained. When a mixture of 2-trifluoromethoxyaniline and 4-trifluoromethoxyaniline is used as raw material (II), it is clear that a mixture of all three components of formula (III) is obtained. .

  2-Bromo-5-trifluoromethoxyaniline (IIIb) is a novel compound and constitutes another object of the present invention.

  In any case, the compound of the formula (III) (compound (IIIa), (IIIb), (IIIc) or a mixture thereof) is unambiguously subjected to the deamination reaction (b). Of the compound.

  The deamination reaction (b) is performed according to a known method.

  According to one preferred embodiment, the deamination comprises diazotization followed by dediazotization (in the presence of an acid and a reducing agent, optionally in the presence of a solvent, intermediate (III) and an inorganic or organic nitrite. According to the reaction of

  When inorganic nitrite is used, water can be used as a solvent, and as a reducing agent, other reagents such as hypophosphorous acid, alcohol (for example, 2-propanol), or a water-soluble reagent such as DMF can be used. It can be used advantageously.

  An inorganic nitrite which can advantageously be used is sodium nitrite used in excess, for example a 30% molar excess, with respect to compound (III).

  The reducing agent used advantageously is 2-propanol and is generally used in excess, for example 10 molar times, for compound (III).

  On the other hand, when organic nitrite is used, an alcohol solvent or a hydro-alcohol solution that simultaneously functions as an alcohol solvent and a reducing agent can be used (Tetrahedron Letters (42) (2001) 5367-5369).

  According to the present invention, both types of nitrites described above can be used, but economically, organic nitrites are more expensive (and also have more significant recovery and environmental challenges) It is preferred to use inorganic nitrites.

  An advantageous acid for the diazotization reaction and the subsequent dediazotization reaction is sulfuric acid, preferably concentrated sulfuric acid. This acid is advantageously used in a molar ratio of about 1/1 with respect to the compound of formula (III).

  The temperature of reaction (b) is about 30-60 ° C, preferably about 35-45 ° C.

  The reaction is generally complete in a few hours. The progress of the reaction is followed by those skilled in the art using conventional techniques.

  The final product of formula (I) is isolated according to known methods, for example by dilution of the reaction mixture with water, phase separation, followed by washing with water and isolation of the final product.

  The compound of formula (I) isolated in this way can be further purified by distillation to obtain a product with a final titration of 99.5% or more, preferably 99.9%.

  Examples of the process according to the invention and examples of comparative reactions are illustrated in the description part of the experiment below.

  The compounds of formula (I) are versatile intermediates that are very useful in the preparation of agrochemical-pharmaceutically active ingredients and used in other chemical transformations.

  The following description of the experiment is illustrative of the invention, but the invention is not limited thereto.

Preparation of 1-bromo-3-trifluoromethoxybenzene (formula (I))
1a. Preparation of 4-bromo-2-trifluoromethoxyaniline (formula (IIIa)) 4 thermometer with thermostat with bottom outlet, brine cryostat, equipped with mechanical stirrer, bubble cooler and thermometer A lined glass reactor (10 L) is charged with 3462 g of acetic acid and 1700 g of 2-trifluoromethoxyaniline, followed by 1894.26 g of NBS while cooling the mixture to 0-5 ° C. and maintaining the temperature at 0-5 ° C. Was added. At the end of the reaction, the mixture was allowed to return to room temperature and acetic acid was removed by distillation. The residue was washed with water, the phases were separated, the organic phase was neutralized with NaHCO ₃ , the phases were separated again, the inorganic phase was washed with water and the title product was isolated.
Boiling point: 115 ° C / 30mmHg
1b. Preparation of 1-bromo-3-trifluoromethoxyaniline Into a 4-necked lined glass reactor (10 L) with a bottom discharge port was placed 2579.53 g of 2-propanol and 1100 g of the product from 1a above, and prepared water in advance. A solution containing 382.52 g NaNO _{2 in} 766.18 g was added. Next, 459.6 g of concentrated sulfuric acid was slowly weighed in. The acid was diluted and the upper organic phase was separated from the lower aqueous phase. The organic phase was washed and the first organic phase and the upper aqueous phase were separated. The latter was further diluted with water until the second organic phase was released. This organic phase is added to the first organic phase and the mixture is washed again, whereby the aqueous phase and the organic phase are separated, this organic phase is dehydrated with CaCl ₂ and then subjected to distillation. Product was obtained (final yield: 84%).
Boiling point: 156-158 ° C / 760 mmHg

Preparation of 1-bromo-3-trifluoromethoxybenzene (formula (I))
2a. Preparation of 4-bromo-2-trifluoromethoxyaniline (formula (IIIa)) and 2-bromo-6-trifluoromethoxyaniline (formula (IIIb)) The procedure was carried out as described in Example 1a, provided that The reaction was carried out at room temperature instead of 0-5 ° C. to give 4-bromo-2-trifluoromethoxyaniline (formula (IIIa)) / 2-bromo-6-trifluoromethoxyaniline (formula (IIIb)) A mixture of the title compounds with a ratio of 93/7 was obtained.
2-Bromo-6-trifluoromethoxyaniline (formula (IIIb)), RTX-5MS column 30 m × 0.25 mm, film 0.25 μm, 5% phenyl-95% methylpolysiloxane, programmed temperature 50 ° C. × 2 min, Identified by GC-MS analysis using 10 min at 5 ° C / min to 240 ° C. Peaks are rt = 13.45 min, relative MS: m / z = 225 (M ⁺ ), 257 (M2 ⁺ ), 237 (M ⁺ ), 215 (M ⁺ ), 155 (M ⁺ ), 158 (M ⁺ ) have.
2b. Preparation of 1-bromo-3-trifluoromethoxyaniline The procedure is as described in Example 1 1b except that instead of the product of 1a, a mixture of the two compounds obtained from 2a above is used. The title compound was obtained.
(Comparative Example 1)

Preparation of 1-bromo-3-trifluoromethoxybenzene by DBI in concentrated sulfuric acid 30.1 g of concentrated sulfuric acid (95-98%) was placed in a reactor (100 ml) and one drop of 10.1 g of 2-trifluoromethoxyaniline. Added in increments. During this operation, the temperature was maintained at about 40 ° C. for about 30 minutes. After obtaining a homogeneous solution, it was cooled to 0-5 ° C. using a cryostat and BDI was weighed in small portions. During the addition of the brominating agent (which takes about 1 hour), the mixture turned brown. After completion of the reaction (30 minutes), gas chromatographic analysis was performed:
2-Trifluoromethoxyaniline: 13.6%
The title monobromo derivative: 34.0%
Dibromo and tribromo derivatives:> 40%
(Comparative Example 2)

Preparation of 1-bromo-3-trifluoromethoxybenzene by NBS in concentrated sulfuric acid 30.3 g of concentrated sulfuric acid (95-98%) was placed in a reactor (100 ml) and, as described in Example 3 above, about At 40-45 ° C., 10 g of 2-trifluoromethoxyaniline was added dropwise. After a homogeneous solution was obtained, it was cooled to 0-5 ° C. using a cryostat. NBS 10.1 g was weighed in portions over 1 hour and then left for another 30 minutes to complete the reaction. The mixture gradually turned yellow and then turned brown. After the reaction was completed, gas chromatographic analysis was performed:
2-trifluoromethoxyaniline: 15.3%
The title monobromo derivative: 66.6%
Dibromo and tribromo derivatives: 11.1%
(Comparative Example 3)

Preparation of 1-bromo-3-trifluoromethoxybenzene with Br ₂ in acetic acid A flask (100 cc) was charged with 60 g of acetic acid and then 30 g of 4-trifluoromethoxyaniline was slowly added. The mixture was brought to 0-5 ° C. and 27 g of bromine was slowly weighed in. After the reaction was completed, gas chromatographic analysis was performed:
4-trifluoromethoxyaniline: 20%
The title monobromo derivative: 37%
Dibromo derivative:> 41%
(Comparative Example 4)

Preparation of 1-bromo-3-trifluoromethoxybenzene with Br ₂ in water At room temperature, 17.7 g of 4-trifluoromethoxyaniline and 53 g of water are placed in a flask (100 cc), the mixture is brought to 35 ° C., and 32 g of bromine Weighed in slowly over 2 hours. After 0.8 equivalent, gas chromatographic analysis was performed:
4-trifluoromethoxyaniline: 10%
The title monobromo derivative: 34%
Dibromo derivative: 54%

Claims (17)

Formula (I)

A process for producing the compound 1-bromo-3-trifluoromethoxybenzene of
(A) Formula (II) selected from 2-trifluoromethoxyaniline, 4-trifluoromethoxyaniline and mixtures of these compounds

(Wherein _one of R ₁ and R ₂ represents hydrogen and the other represents a —NH ₂ group) is reacted with a brominating agent that releases Br ⁺ ions in an acidic medium in the presence of a weak acid; Formula (III)

Wherein R ₁ and R ₂ are as defined above, one of R ₃ and R ₄ represents hydrogen and the other represents a bromine atom,
(B) A process for producing 1-bromo-3-trifluoromethoxybenzene comprising deaminating the compound of formula (III) to obtain the desired compound of formula (I).   The process according to claim 1, wherein the weak acid is acetic acid.   The process according to claim 1 or 2, wherein the brominating agent is selected from N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBI) and mixtures thereof.   The process according to claim 3, wherein the brominating agent is N-bromosuccinimide (NBS).   The process according to any one of claims 1 to 4, wherein the temperature of the reaction (a) is -5 ° C to room temperature.   The process according to claim 5, wherein the temperature of the reaction (a) is -5 to 0 ° C.   The process according to any one of claims 1 to 6, wherein the molar ratio of the compound of formula (II) / weak acid is about 1/6.   The deamination (b) is carried out by diazotization by reacting intermediate (III) with an inorganic nitrite in the presence of an acid, a solvent and a reducing agent, followed by dediazotization. The manufacturing method.   The process according to claim 8, wherein the inorganic nitrite is sodium nitrite.   10. The process according to claim 8 or 9, wherein the inorganic nitrite is used in equimolar ratio or molar excess with respect to the compound of formula (III).   The process according to any one of claims 8 to 10, wherein the solvent is water and the reducing agent is water-soluble.   The process according to any one of claims 8 to 11, wherein the reducing agent is 2-propanol.   The deamination (b) is carried out by diazotization by reacting intermediate (III) with an organic nitrite in the presence of an acid and in the presence of a solvent and a reducing agent or reducing solvent, followed by dediazotization. The manufacturing method in any one of 1-7.   The process according to claim 13, wherein the reducing solvent is selected from alcohols and hydro-alcohol solutions.   The process according to any one of claims 8 to 14, wherein the acid is sulfuric acid.   The process according to claim 15, wherein sulfuric acid is used in an approximately equimolar ratio with respect to the compound of formula (III). Formula (IIIb)

2-Bromo-6-trifluoromethoxyaniline represented by