JP3306312B2 - Process for producing O-alkyl-N-cyanoimidate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a process for producing O-alkyl-N-cyanoimidate useful as an intermediate for pharmaceuticals and agricultural chemicals, and more particularly, to a process for producing a compound having a nitrile group and an alcohol in the presence of hydrochloric acid. The present invention relates to a method for producing O-alkyl-N-cyanoimidate, comprising reacting in a lower nonpolar solvent, then adding aminonitrile to the resulting reaction solution and heating.

[0002]

2. Description of the Related Art Several methods for producing O-alkyl-N-cyanoimidates are known in the art. For example, Czechoslovak Patent No. 273050 discloses an O-alkyl-N-cyanoimidate.
A method for producing O-methyl-N-cyanoacetimidate (hereinafter sometimes abbreviated as CAIM) by reacting -methylacetimide hydrochloride with cyanamide in methanol has been proposed.

[0003]

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In this proposal, O-methylacetimide hydrochloride and cyanamide are reacted in anhydrous methanol,
After the by-product ammonium chloride crystals were separated by filtration, the filtrate was used in the next step as an O-methyl-N-cyanoacetimidate solution.

[0005] However, in the above method, ammonium chloride crystals formed as by-products are dissolved in methanol and mixed in a large amount into the filtrate, making it difficult to carry out the reaction in an industrial large-scale reaction.

When O-methyl-N-cyanoacetimidate is isolated, it must be separated by distillation from a methanol solution, and distillation in the presence of a large amount of by-product ammonium chloride causes a large loss in the distillation step. And the isolation yield of O-methyl-N-cyanoacetimidate was poor.

On the other hand, German Patent Publication DE 3815084 discloses a method for producing O-methyl-N-cyanoacetimidate without reacting ammonium chloride by reacting orthoacetate and cyanamide in a methanol solvent. It has been proposed.

[0008]

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Ortho acetic acid ester is disclosed in JP-A-52-125108.
As described in JP-A-56-59730, it is produced by alcoholysis of O-methylacetimide salt, is a low boiling flammable liquid, and reacts with moisture in the air. It is highly susceptible and requires strict care when handling on an industrial scale. In addition, a process of producing orthoacetic acid ester from an O-methylimide salt is separately required, which is a sufficient method for economically producing O-methyl-N-cyanoacetimidate on an industrial scale with a high yield. It was not something.

[0010]

An object of the present invention is to provide a method for producing O-alkyl-N-cyanoimidate in high yield from a nitrile compound and an alcohol without isolating an intermediate. That is.

[0011]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above problems, and as a result, reacted a compound having a nitrile group with an alcohol in a nonpolar solvent in the presence of hydrochloric acid, Subsequently, by adding cyanamide to the obtained reaction solution and heating, O-
The present inventors have found that alkyl-N-cyanoimidate can be produced in high yield, and have completed the present invention.

Hereinafter, the present invention will be described in detail. First, a compound having a nitrile group and an alcohol are reacted in a nonpolar solvent by acid contact. Examples of the compound having a nitrile group include aliphatic linear alkyl nitriles such as acetonitrile and lactonitrile.

[0013]

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The alcohol is not particularly limited,
Methanol, ethanol, propanol, butanol and the like are preferred, and the amount of the alcohol used is 0.7 to 5 mol, preferably 0.9 to 2 mol, per mol of the compound having a nitrile group.
Mol, particularly preferably 1 to 2 mol.

The reaction solution is prepared by dissolving the compound having a nitrile group and an alcohol in a non-polar solvent and sequentially adding an acid. The non-polar solvent is not particularly limited as long as it is a non-polar solvent that does not react with a compound having a nitrile group or an alcohol, and aromatic hydrocarbons such as benzene, toluene, and xylene, and aliphatic hydrocarbons such as hexane, octane, and dodecane. Hydrogens may be mentioned, and toluene is particularly preferable from the viewpoints of safety, recoverability, toxicity and the like, particularly in large-scale production.

The acid is preferably an inorganic acid such as hydrochloric acid or hydrobromic acid. From the viewpoint of easy handling, anhydrous hydrochloric acid gas,
Is particularly preferred, and the acid is used in an amount of 0.7 to 5 mol, preferably 0.8 to 2.5 mol, per 1 mol of the compound having a nitrile group.
It is particularly preferable to use 0.9 to 1.5 mol, and the addition of the acid is carried out at -10 ° C to 20 ° C, preferably at -5 ° C to 5 ° C or less.

Cyanamide is added to the above reaction solution, and then CAIM is manufactured. Before the reaction, the acid in the system is checked by non-aqueous titration or the like. If the acid is excessive, a base that does not form water is added to neutralize the excess acid. As a base for adjusting pH, it is preferable to use sodium methylate, sodium ethylate and the like. The amount of cyanamide added is 0.8 to 2 mol, preferably 0.1 mol, per mol of acetonitrile.
It is 9 to 1.5 mol, particularly preferably 0.9 to 1.1 mol.

The method of adding cyanamide is not particularly limited, but it is preferable to sequentially add cyanamide alcohol as a solution to control the reaction temperature. As a solvent for dissolving cyanamide, alcohols are preferable from the viewpoint of industrial easiness, and methanol or ethanol is particularly preferable from the viewpoint of easy availability on an industrial scale and ease of handling.

The reaction solution is kept at 20 ° C to 100 ° C, preferably at 30 ° C to 5 ° C.
Add the cyanamide solution while maintaining at 0 ° C. When the reaction temperature is 30 ° C. or higher, the reaction can proceed immediately after the addition, and when the reaction temperature is 50 ° C. or lower, the reaction can be carried out with almost no decomposition of cyanamide.

After completion of the reaction, the by-product salt is separated. The separation means is not particularly limited, but in the present solvent composition, since the dispersibility of the by-product salt in the solution is good, even on an industrial scale,
By-product salts can be easily separated. Since the by-product salt has extremely low solubility in the non-polar solvent, the amount of the by-product salt dissolved in the filtrate is small, and the rectification yield of CAIM can be increased.

Next, toluene is recovered by atmospheric distillation. The distillation is carried out at a temperature not exceeding 100 ° C., preferably at 60 ° C. If the temperature in the tank does not exceed 100 ° C., almost no decomposition of CAIM generated in the tank is observed.

When the distillation stops, the recovery of toluene is stopped and the CAIM is separated by rectification. The rectification conditions vary depending on the structure of the rectification apparatus, but it is desirable to carry out the rectification at a temperature not exceeding 100 ° C. in order to prevent the decomposition of CAIM during rectification. It is particularly preferable to carry out under a reduced pressure condition.

In this manner, O-alkyl-N-cyanoimidate can be produced in high yield without isolating the reaction intermediate.

Hereinafter, the present invention will be further described with reference to examples. Example 1 In a 200 CC four-necked flask equipped with a stirrer and a cooling device, 43.0 g of toluene, 11.6 g (0.34 mol) of methanol,
12.4 g (0.3 mol) of acetonitrile is added, 11.6 g (0.32 mol) of dry hydrochloric acid is added at 10 ° C. or less, and the mixture is reacted at 5 ° C. for 6 hours. Then, a 50% methanol solution of cyanamide 2
6.2 g (0.30 mol) are added and reacted at 40 ° C. for 6 hours.
Thereafter, the reaction solution was cooled to 5 ° C., ammonium chloride as a by-product was filtered, washed with a small amount of toluene, and the CAIM reaction solution was washed.
80.6 g (CAIM content: 32.3%; conversion: 88.3%) were obtained. The obtained CAIM reaction solution was rectified under reduced pressure from normal pressure to 10 mmHg
24.1 g of CAIM (purity 99.8%, isolated yield 81.7%) was obtained as a fraction at a temperature of 75/78 ° C. The amount of by-product ammonium chloride separated by filtration was 15.3 g (95.0% of the theoretical value) after drying.

Example 2 In the same apparatus as in Example 1, 43.5 g of toluene, 12.4 g (0.3 mol) of acetonitrile, 10.7 g (0.34 mol) of methanol
Then, 16.5 g (0.45 mol) of dry hydrochloric acid is added at 10 ° C. or lower, and the mixture is reacted at 5 ° C. for 4 hours. Next, 27.4 g (0.15 mol) of 28% sodium methylate was added to neutralize excess hydrochloric acid, and a cyanation reaction was carried out in the same manner as in Example 2. A CAIM reaction solution (101.6 g (CAIM content: 26.5%: reaction rate)) 9
1.5%). The resulting CAIM reaction solution was rectified from normal pressure to reduced pressure, and 25.2 g of CAIM was obtained as a fraction of 10 mmHg / 75 to 78 ° C.
(Purity 99.5%: Isolation yield 85.2%) was obtained. The by-product ammonium chloride separated by filtration was 15.2 g after drying (theoretical value).
95.0%).

Example 3 346 g of toluene, 106 g (3.31 mol) of methanol, and 126.1 g (3.07 mol) of acetonitrile were charged into a 3 L four-necked flask equipped with a stirrer and a cooling device, and 112.0 g of dry hydrochloric acid at 10 ° C. or lower. (3.07 mol) and react at 5 ° C for 6 hours. Next, a 50% methanol solution of cyanamide 260.6
g (3.07 mol) and react at 40 ° C. for 6 hours. Thereafter, the reaction solution was cooled to 5 ° C., and the by-product ammonium chloride was filtered to obtain 909.9 g of a CAIM solution (CAIM content: 30.1%: reaction rate: 91.0%). The resulting CAIM solution was rectified from normal pressure to reduced pressure to obtain a CAIM259.2 fraction of 10 mmHg / 75-78 ° C.
g (purity 99.2%, isolated yield 86.1%). The amount of by-product ammonium chloride separated by filtration was 154.4 g (94% of the theoretical value) after drying.

Comparative Example 1 15.3 g (0.14 mol) of O-methylacetimide hydrochloride was prepared according to the method described in Czechoslovak Patent No. 273050.
Was reacted with 5.9 g (0.14 mol) of cyanamide in 20.3 ml of anhydrous methanol and washed with a small amount of methanol to produce 35.6 g of a CAIM methanol solution (CAIM content: 32.3%; conversion: 83.7%). The by-product ammonium chloride was filtered, rectified under normal pressure to reduced pressure, and distilled at 10 mmHg / 75-78 ° C as CAIM.
9.8 g (purity 99.0%: isolation yield from acetimide hydrochloride)
70.6%). The amount of by-product ammonium chloride separated by filtration was 5.4 g (86.1% of the theoretical value) after drying.

Claims (2)

(57) [Claims] 1. A method comprising reacting a compound having a nitrile group with an alcohol in a nonpolar solvent in the presence of an acid, and then adding cyanamide to the reaction solution without isolating the resulting intermediate , followed by heating. To produce O-alkyl-N-cyanoimidate. 2. Acetonitrile and methanol are reacted in a nonpolar solvent in the presence of an acid, and the resulting intermediate is isolated.
The method for producing O-methyl-N-cyanoacetimidate according to claim 1, wherein cyanamide is added to the reaction solution without heating.