JP2000281600A - Production of 4-bromo-2-fluorobenzyl bromide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially safely obtain 4-bromo-2-fluorobenzyl bromide at high selectivity and high yield without a regulated solvent or an operation such as photoradiation by brominating bromo-fluorotoluene with dibromo- dimethylhydantoin in the presence of a free radical-generating agent. SOLUTION: The objective compound is obtained by brominating 1 mol 4-bromo-2-flurotoluene(BFT) with (preferably 0.4-0.6 mol) 1,3-dibromo-5,5- dimethylhydantoin(DBH) in the presence of a free radical-generating agent at preferably 40-70 deg.C in a solvent (preferably methylene chloride or 1,2- dichloroethane). The free radical-generating agent is preferably azobis(4- methoxy-2,4-dimethylvaleronitrile) or the like, each having the half-life temperature of 30-80 deg.C and is preferably used in a quantity consumed of 0.005-0.5 weight times the DBH quantity. The reaction is preferably carried out in an organic solvent of 300-800 mL based on 1 mol BFT.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 4-bromo-2-
The present invention relates to a method for producing fluorobenzyl bromide.

[0002]

2. Description of the Related Art Conventionally, 4-bromo-2-fluorobenzyl bromide is prepared by (1) converting 4-bromo-2-fluorotoluene in carbon tetrachloride in the presence of benzoyl peroxide or azobisisobutyronitrile. It is produced by reacting with N-bromosuccinimide under reflux. Generated 4
-Bromo-2-fluorobenzyl bromide has a tearing property and is usually obtained as a low-purity crude product without purification (WO9724331, WO94282896).
etc). Further, it has been reported that (2) 4-bromo-2-fluorobenzyl bromide was purified by distillation to obtain a product with a yield of 58.6% (Japanese Patent Laid-Open No. 6-228037).

As a method for producing benzyl bromides, a toluene derivative represented by the following formula 1 is reacted with bromine under light irradiation, and a benzyl bromide derivative represented by the following formula 2 is reacted with a bromine derivative represented by the following formula 3. (Where R in the formula represents a halogen atom, a nitro group, etc.), and (3) a method using benzene as a solvent (Olah. GA et. a
l. , J. et al. Org. Chem. , 22,879,195
7), (4) Method using n-hexane (JP-A-8-5)
9515) or (5) a method using ethyl acetate (JP-A-10-175883).

[0004]

Embedded image

Also, (6) a method of reacting bromine in methylene chloride in the presence of bentonite (JP-A-8-533)
7) is also known.

[0006]

However, in the method (1), it is necessary to use carbon tetrachloride which is a regulated solvent.
The method (2) has a problem in that the purity is low even after purification.
In the case of production by the methods (1) and (2), the selectivity of the reaction is low and the purification is troublesome, so that it is difficult to increase the purity and the yield is reduced. there were.
The method (3) is a method using benzene which is a regulated solvent. In the methods (3) to (6), since the HBr gas is generated, it is necessary to make the entire equipment acid-resistant. Further, there is also a problem that workability is deteriorated because the generated HBr gas is accompanied by a tearing target.

[0007] An object of the present invention is to produce 4-bromo-2-fluorobenzyl bromide with high selectivity, high yield, and industrial safety without using any special operation such as regulated solvent or light irradiation. It is inexpensive to manufacture.

[0008]

That is, the present invention provides the following:
-Bromo-2-fluorotoluene (hereinafter also referred to as BFT) in the presence of a free radical generator, 1,3-dibromo-5,
Provided is a method for producing 4-bromo-2-fluorobenzyl bromide (hereinafter, also referred to as BFBB), which is brominated with 5-dimethylhydantoin (hereinafter, also referred to as DBH).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION BFT in the present invention is a known compound and can be obtained as a commercial product. In the present invention, BFT is brominated with DBH. DBH is a less expensive brominating agent than conventional brominating agents such as N-bromosuccinimide (hereinafter referred to as NBS). DBH is BFT
It is preferable to use 0.4 to 0.6 mol per 1 mol. If the amount of DBH is more than 0.6 mol, by-products (such as 1-dibromomethyl-4-bromo-2-fluorobenzene) may be generated, and the selectivity may be reduced.

The reaction is carried out using the amount of DBH in 0.2 to 0.4 mol per mol of BFT, and the unreacted BF is reacted.
A method of recycling T and reacting DBH again may be employed. The method has the advantage that the selectivity is high and the final yield is high.

In the present invention, DBH is used as a brominating agent.
The absolute amount of the brominating agent can be made smaller than the amount of a conventional brominating agent such as NBS. Therefore,
The amount of water and the number of times of water washing at the time of washing after the reaction can be reduced, which is advantageous in that post-treatment is easy and workability is improved. There is also an advantage that waste liquid is reduced.

The reaction between BFT and DBH is carried out in the presence of a free radical generator. As a free radical generator, the half-life temperature is 3
It is preferable to use a known free radical generator having a temperature of 0 to 80 ° C., particularly, azobis (4-methoxy-2,4-dimethylvaleronitrile) (10-hour half-life temperature: 30)
° C), azobis (2,4-dimethylvaleronitrile)
(10-hour half-life temperature: 51 ° C), azobisisobutyronitrile (10-hour half-life temperature: 65 ° C), diisopropylperoxydicarbonate (10-hour half-life temperature: 4)
1 ° C.), isobutyl peroxide (10-hour half-life temperature: 33 ° C.), cumyl peroxyneodecanoate (10-hour half-life temperature: 37 ° C.), and the like. When the half-life temperature of the free radical generator is higher than 80 ° C., the reaction temperature becomes high, so that by-products are generated, and when the reaction is carried out at a low temperature, the free radical generator remains.

The free radical generator is used in an amount of 0.0
It is preferable to use from 0.5 to 0.05 times the weight. The free radical generator may be added in its entirety from the beginning of the reaction, or may be gradually added as the reaction proceeds.

The reaction of the present invention is preferably carried out in the presence of an organic solvent. As the organic solvent, methylene chloride,
1,2-dichloroethane, n-hexane, cyclohexane, monochlorobenzene and the like are preferable, and methylene chloride or 1,2-dichloroethane is particularly preferable.
The amount of organic solvent is BFT1 due to cost, safety, workability, etc.
It is preferably 300 to 800 mL per mol.

The reaction temperature in the production method of the present invention can be appropriately changed depending on the types of the free radical generator and the solvent.
From the viewpoint of safety and reaction rate, 40 to 70 ° C is preferable. The reaction time can be appropriately selected depending on the solvent, the reaction temperature, and the like.
It is preferable to carry out in 2 to 9 hours from the viewpoint of safety and workability.

The crude reaction product obtained by the reaction of the present invention is obtained by removing unreacted raw materials and reaction by-products (5,5-dimethylhydantoin and the like) by washing with water or the like, followed by distillation to obtain a high crude product. It is preferably obtained as BFBB of purity. BFBB is a compound useful as a pharmaceutical intermediate or the like.

[0017]

EXAMPLES The present invention will be described below with reference to specific examples, but the present invention is not limited to these examples. Examples 1 to 1 below
At 0, the components contained in the obtained organic layer were analyzed by gas chromatography (hereinafter referred to as GC). The amounts of products other than the solvent were determined as GC area%, and are shown in Table 1. Further, BFBB ₂ represents a 1-dibromomethyl-4-bromo-2-fluorobenzene. The selectivity in Table 1 is a value calculated by the following equation. Selectivity (%) = ΔBFBB peak area (%) / (10
0-BFT peak area (%)) x 100.

Example 1 BFT18.9 was placed in a 200 mL four-necked flask equipped with a stirrer, a thermometer, and a condenser.
g (100 mmol), 1,2-dichloroethane (ED
C) 65.5 mL, 0.62 g (2.5 mmol) of azobis (2,4-dimethylvaleronitrile) (V-65)
And 15.0 g (52.5 mmol) of DBH were added,
The reaction was performed at a reaction temperature (internal temperature) of 50 to 60 ° C. for 9 hours. After cooling, 100 mL of water was added, and the mixture was separated.
The organic layer was washed with water to remove 5,5-dimethylhydantoin. Further, the organic layer was washed with 25 mL of saturated saline.
, And dried over magnesium sulfate to obtain an organic layer.
Table 1 shows the analysis results of the organic layer.

[Example 2] An organic layer was obtained in the same manner as in Example 1, except that the reaction temperature was changed to 60 to 62 ° C and the reaction time was changed to 6.5 hours. Table 1 shows the analysis results of the organic layer.

[Example 3] An organic layer was obtained in the same manner as in Example 1, except that the reaction temperature was changed to 60 to 70 ° C and the reaction time was changed to 3.5 hours. Table 1 shows the analysis results of the organic layer.

Example 4 14.3 g of DBH (50.0 m
mol) and the reaction time was changed to 6.5 hours to obtain an organic layer in the same manner as in Example 1. Table 1 shows the analysis results of the organic layer.

Example 5 13.6 g of DBH (47.5 m
mol) and the reaction time was changed to 6.5 hours to obtain an organic layer in the same manner as in Example 1. Table 1 shows the analysis results of the organic layer.

Example 6 13.6 g (47.5 m) of DBH
mol), 65.5 mL of EDC was added to 65.5 mL of methylene chloride.
An organic layer was obtained in the same manner as in Example 1, except that the reaction temperature was changed to 44 to 45 ° C, and the reaction time was changed to 5.0 hours. Table 1 shows the analysis results of the organic layer.

Example 7 12.1 g of DBH (42.5 m
mol) and the reaction time was changed to 4.5 hours to obtain an organic layer in the same manner as in Example 1. Table 1 shows the analysis results of the organic layer.

Example 8 (Comparative Example) Using the apparatus of Example 1,
BFT 18.9 g (100 mmol), NBS 17.8
g (100 mmol), 113 mL of carbon tetrachloride, and 0.28 g of benzoyl peroxide under reflux (80 to 82
C.) for 2 hours and post-treated in the same manner as in Example 1 to obtain an organic layer. Table 1 shows the analysis results of the organic layer.

Example 9 (Comparative Example) Using the apparatus of Example 1,
18.9 g (100 mmol) of BFT, carbon tetrachloride 11
16.0 g (100 mmol) of bromine was added to a mixture of 3 mL and 0.28 g of benzoyl peroxide at an internal temperature of 75 to 76 ° C.
After that, the mixture was refluxed for 2 hours. Post-treatment was carried out in the same manner as in Example 1 to obtain an organic layer. Table 1 shows the analysis results of the organic layer.

Example 10 (Comparative Example) Using the apparatus of Example 1, 9.60 g (60 mmol) of bromine in a mixture of 18.9 g (100 mmol) of BFT and 113 mL of carbon tetrachloride under UV irradiation at an internal temperature of 70 ° C. Was added dropwise over 2 hours, and then refluxed for 30 minutes. Post-treatment was carried out in the same manner as in Example 1 to obtain an organic layer. Table 1 shows the analysis results of the organic layer.

[0028]

[Table 1]

Example 11 107.8 g of DBH was placed in a 1 L four-necked flask equipped with a stirrer, a thermometer and a condenser.
(0.377 mol), 150 g of BFT (0.794 m
ol) and 524 mL of EDC, and the mixture was stirred while being heated to 60 ° C., and 1.0 g of V-65 was added.
The reaction was carried out at 2 ° C for 3 hours, and 0.83 g of V-65 was further added, followed by a reaction at an internal temperature of 60 to 62 ° C for 3.5 hours. After cooling, add 500 mL of water and separate, and further 500 mL
The organic layer was washed with water to remove 5,5-dimethylhydantoin. Further, the organic layer was washed with 200 mL of a saturated saline solution and dried over magnesium sulfate.

After the EDC in the organic layer was distilled off, the residue was distilled under reduced pressure to recover 26.4 g of BFT to obtain 151 g of BFBB (74.8% based on DBH). Obtained B
FBB has a GC purity of 98.8%, b. p. Actual measured value of 12
It was 4-125 ° C / 15 mmHg, and solidified upon standing (mp 33-35 ° C). The isolation yield based on BFT consumed was 86.2%.

Example 12 107.8 g of DBH was placed in a 1 L four-necked flask equipped with a stirrer, a thermometer and a cooler.
(0.377 mol), 150 g of BFT (0.794 m
ol), 524 mL of methylene chloride, 1.6 g of V-65
The mixture was charged and reacted at 44 to 46 ° C. for 3 hours while gently refluxing. Further, 2 mL of a methylene chloride solution in which 0.8 g of V-65 was dissolved was added dropwise and reacted for 2 hours. After cooling, post-treatment and distillation were carried out in the same manner as in Example 11, and BFT22.
5 g was recovered to obtain 157 g of BFBB (77.7% yield based on DBH). The obtained BFBB had a GC purity of 98.0%, b. p. 127-129 ° C / 1
It was 8 mmHg, and the isolated yield based on BFT consumed was 86.9%.

Example 13 Instead of V-65 of Example 11, 3 g of azobis (4-methoxy-2,4-dimethylvaleronitrile) was dissolved in 7 mL of methylene chloride to obtain a methylene chloride solution. While refluxing, 3 mL of methylene chloride solution
And reacted for 2 hours.
mL was added dropwise and reacted for 4 hours, and further 2 mL of methylene chloride solution was added dropwise and reacted for 1 hour. After cooling, Example 11
The mixture was treated and distilled in the same manner as described above, and 23.0 g of BFT was recovered.
159 g of FBB were obtained (yield based on DBH 78.
7%). The isolated yield based on the consumed BFT is 88.3.
%Met.

Example 14 (Comparative Example) NBS14 was placed in a 2 L four-necked flask equipped with a stirrer, a thermometer and a condenser.
1 g (0.794 mol), BFT 150 g (0.79 mol)
4 mol), 900 mL of carbon tetrachloride and 2.25 g of benzoyl peroxide were charged and reacted under reflux for 2 hours. After cooling, the mixture was treated and distilled in the same manner as in Example 11, and 12.8 g of BFT was recovered to obtain 129 g of BFBB (60.6% based on NBS). The isolation yield based on the consumed BFT was 66.3%.

[0034]

According to the production method of the present invention, high purity B
FBB can be obtained with high selectivity and high yield. Also,
Since DBH used as a brominating agent is inexpensive and can be reacted in a small amount, removal of impurities is facilitated and workability is improved. Further, since no HBr gas is generated during the reaction, the equipment can be simplified as compared with the method using bromine, the workability and safety are improved, and this is an industrially advantageous production method.

Continued on the front page (72) Inventor Hiroaki Maruta 3-2-1-10 Chigasaki, Chigasaki-shi, Kanagawa Prefecture Inside Seimi Chemical Co., Ltd. (72) Masao Ohashi 3-2-1-10 Chigasaki, Chigasaki-shi, Kanagawa Prefecture Inside Seimi Chemical Co., Ltd. F term (reference) 4H006 AA02 AC30 BA93 BB11 BB12 BC10 BC31 BC35 BD33 BD52 BE90 BM10 BM30 BM71 BM73 FE71 FE73 FE74 FE76

Claims (5)

[Claims] (1) brominating 4-bromo-2-fluorotoluene with 1,3-dibromo-5,5-dimethylhydantoin in the presence of a free radical generator; Method for producing benzyl bromide. 2. 1 m of 4-bromo-2-fluorotoluene
The production method according to claim 1, wherein 1,3-dibromo-5,5-dimethylhydantoin is used in an amount of 0.4 to 0.6 mol based on ol. 3. The method according to claim 1, wherein the bromination reaction temperature is 40 to 70 ° C. 4. The process according to claim 1, wherein the bromination reaction is carried out in the presence of a solvent. 5. The method according to claim 4, wherein the solvent is methylene chloride or 1,2-dichloroethane.