JPH0753476A - Production of 2,6-difluorobenzylamine - Google Patents

Abstract

PURPOSE:To provide an industrially effective process for the production of 2,6-difluorobenzylamine useful as a synthetic intermediate for various derivatives used in the field of agrochemicals and pharmaceuticals. CONSTITUTION:This process for the production of 2,6-difluorobenzylamine comprises the reduction of 2,6-difluorobenzonitrile with sodium borohydride and dimethyl sulfate in tetrahydrofuran.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 2,6-difluorobenzylamine by reducing 2,6-benzonitrile, which is used as a synthetic intermediate for many derivatives used in agricultural chemicals and pharmaceuticals. It is useful.

[0002]

2. Description of the Related Art Conventionally, a method for producing a benzylamine derivative by reducing a benzonitrile derivative has already been synthesized with various reducing agents. For example, (1) Journal of the American Chemical Society., V
The method described in ol. 70, 3738 (1948) is a method of reducing o-tolunitrile with lithium aluminum hydride. (2) The method described in Collect Czeck Commun., Vol.34, 1033 (1969) is a method in which benzonitrile is hydrogenated with bis (2
-Methoxyethoxy) aluminum sodium reduction method. (3) Journal of the American Chemical Society., V
The method described in ol.78,2582 (1956) is a method of reducing benzonitrile with sodium borohydride and aluminum chloride. (4) Journal of the American Chemical Society., V
The method described in ol. 82, 681 (1960) is a method of reducing m-nitrobenzonitrile with sodium borohydride and boron trifluoride. (5) Journal of Industrial Chemistry, Vol. 55, 476 (1952) describes a method of electrolytically reducing benzyl cyanide.

[0003]

In the methods (1) and (2) among the above-mentioned production methods, the side reactions mainly proceed and the intended product cannot be obtained. Also, the use of lithium aluminum hydride is industrially dangerous in handling and poses a serious problem. In the method (3), a small amount of the target product is obtained, but the amount of by-products is significantly increased. Further, industrially using the boron trifluoride of the method (4) is dangerous in handling. Furthermore, the method (5) is difficult to industrialize in terms of equipment. As described above, none of the methods can obtain the target product in a high yield, and there are various problems in industrial production, which is a useful production method of 2,6-difluorobenzylamine. It's hard. An object of the present invention is to provide a method for producing 2,6-difluorobenzylamine which can be produced safely in a high yield by a simple operation method.

[0004]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that 2,6-difluorobenzonitrile is reduced with sodium borohydride and dimethylsulfate in tetrahydrofuran to give 2 We have found a method to obtain 6,6-difluorobenzylamine in high yield.
The present invention will be described in more detail below. The reaction of the present invention comprises a reduction reagent preparation reaction and a main reduction reaction. The reaction for preparing the reducing agent is carried out in a tetrahydrofuran solvent,
Sodium borohydride was added in an amount of 2.0 to 7.0 moles, preferably 3.0 to 4.0 moles to 1.0 mole of 2,6-difluorobenzonitrile, and dimethylsulfate (1. 0-3.5 mol, preferably 1.5-2.
0 mol is gradually added dropwise to completely react dimethylsulfate. If unreacted dimethylsulfate remains, a by-product due to N-methylation is produced in the next main reaction. Therefore,
The ratio of sodium borohydride and dimethyl sulfate used is
The theoretical amount is sufficient, but the former is 1.8 to 3.0 times the molar amount of the latter. When the amount is 1.8 times or less, the side reaction product of N-methylation increases, and when the amount used is large, the cost becomes high. The amount of the tetrahydrofuran solvent is 2 to 8 times by weight, preferably 4 to 5 times the amount of 2,6-difluorobenzonitrile. The preparation reaction temperature is 15 to 30 ° C., preferably 2
It is about room temperature of 0 to 25 ° C. The reduction main reaction is carried out by appropriately adding 2,6-difluorobenzonitrile to the reduction reagent preparation liquid. The reaction temperature is in the range of 10 to 60 ° C, preferably 30 to 40 ° C.
2,6-Difluorobenzonitrile is gradually added dropwise over 0.5 to 3.0 hours so as to maintain the temperature at 30 to 50 ° C. per 1.0 mol. Further, after the dropping, stirring is performed in the range of 45 to 60 ° C. for 1.0 to 5.0 hours. The post-treatment method can be carried out by combining appropriate treatment methods such as extraction, washing, dehydration, liquid separation, concentration and distillation.

[0005]

EXAMPLES The present invention will now be described more specifically with reference to examples. [Example 1] The glass reactor was completely replaced with argon gas in advance, and tetrahydrofuran (200 ml) was used.
And 12.11 g (0.32 mol) of sodium borohydride were charged, and 20.2 g of dimethylsulfate was added to this at room temperature.
(0.16 mol) was gradually added dropwise. At this time, 5-10
An exotherm of ℃ occurs. Then, before the fever is completed 2,6
-Difluorobenzonitrile 13.9 g (0.1 mol)
Was gradually added dropwise to maintain the temperature at 30 to 40 ° C. The mixture was stirred at room temperature until the exotherm was completed, and further at 54 to 57 ° C. for 3 hours. After completion of the reaction, 25% -sodium hydroxide aqueous solution was added to the reaction solution for washing, and after dehydration / separation with 48% -sodium hydroxide aqueous solution, the tetrahydrofuran layer was separated and concentrated under reduced pressure. Crude 2,6-difluorobenzylamine obtained after the post-treatment was distilled under reduced pressure (69 ° C / 16 mmHg).
To give 2,6-difluorobenzylamine 1
0.8g (purity 99.2%) and yield 83.5% were obtained.
The analysis results of IR, ¹ H-NMR and ¹³ C-NMR all agreed with the desired standard substance.

[Comparative Example 1] The reaction was carried out in the same manner as in [Example 1] except that the reducing aid dimethylsulfate was removed, but 2,6-difluorobenzylamine was not obtained. [Comparative Example 2] 7.57 g of sodium borohydride (0.
2 mol), dimethylsulfate 25.23 g (0.2 mol),
1,6-Difluorobenzonitrile 13.9 g (0.1
The reaction was carried out in the same manner as in [Example 1] except that the addition amount of (mol) was changed, and as a result, the composition of the reaction product by GC analysis was 2,6-difluorobenzylamine 71.9%.
The amount of 2,6-difluorobenzonitrile was 0.7%, and the amount of by-products was 17.3%. Since the amount of by-products was large, the subsequent post-treatment was not performed.

[0007]

According to the conventional method, obtaining 2,6-difluorobenzylamine from reduction of 2,6-difluorobenzonitrile has various problems such as decomposition, increase of by-products and handling problems. Although the use of a suitable reducing agent was not good, a simple, safe and high-yield production of 2,6-difluorobenzylamine was achieved by combining the reducing agent with sodium borohydride and dimethylsulfate in the present invention. be able to.

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[Procedure amendment]

[Submission date] June 29, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0001

[Correction method] Change

[Correction content]

[0001]

BACKGROUND OF THE invention are 2,6 by reduction of difluoro <br/> benzonitrile, 2,6-difluoro benzylamine relates to a method for producing a number of used in agrochemical and pharmaceutical It is useful as a synthetic intermediate for derivatives.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0004

[Correction method] Change

[Correction content]

[0004]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that 2,6-difluorobenzonitrile is reduced with sodium borohydride and dimethylsulfate in tetrahydrofuran to give 2 We have found a method to obtain 6,6-difluorobenzylamine in high yield.
The present invention will be described in more detail below. The reaction of the present invention comprises a reduction reagent preparation reaction and a main reduction reaction. The reaction for preparing the reducing agent is carried out in a tetrahydrofuran solvent,
Sodium borohydride was added in an amount of 2.0 to 7.0 moles, preferably 3.0 to 4.0 moles to 1.0 mole of 2,6-difluorobenzonitrile, and dimethylsulfate (1. 0-3.5 mol, preferably 1.5-2.
0 mol is gradually added dropwise to completely react dimethylsulfate. If unreacted dimethylsulfate remains, a by-product due to N - methylation is produced in the next main reaction. Therefore, the use ratio of sodium borohydride and dimethylsulfate may be theoretical, but the former is 1.8 to 3.0.
It is twice the mole. If the amount is 1.8 times or less, the side reaction product of N - methylation will increase, and if the amount used is large, the cost will increase. The amount of the tetrahydrofuran solvent is 2 to 8 times by weight, preferably 4 to 5 times the amount of 2,6-difluorobenzonitrile. The preparation reaction temperature is 15 to 30 ° C.,
It is preferably at about room temperature of 20 to 25 ° C. The reduction main reaction is carried out by appropriately adding 2,6-difluorobenzonitrile to the reduction reagent preparation liquid. Reaction temperature is 1
The temperature is in the range of 0 to 60 ° C, preferably 30 to 40 ° C. 2,6-difluorobenzonitrile is 1.
Gradually 0.5 ~ to maintain 30 ~ 50 ℃ per 0 mol
Add dropwise over 3.0 hours. Furthermore, 45-60 after dropping
It is performed by stirring in the range of ° C for 1.0 to 5.0 hours. The post-treatment method can be carried out by combining appropriate treatment methods such as extraction, washing, dehydration, liquid separation, concentration and distillation.

Claims (2)

[Claims] 1. A method for producing 2,6-difluorobenzylamine by reduction of 2,6-difluorobenzonitrile, which comprises reacting sodium borohydride and dimethylsulfate as a reducing agent in the presence of a tetrahydrofuran solvent. A method for producing 2,6-difluorobenzylamine, which comprises: 2. A reducing agent is used in an amount of 2.0 to 7.0 mol of sodium borohydride and 1.0 to 3.5 mol of dimethylsulfate per mol of 2,6-difluorobenzonitrile.
The method according to claim 1, which is a molar ratio.