JPS59152359A - Production of alkoxymethylene malononitrile - Google Patents

Abstract

PURPOSE:To prepare the titled compound, useful as a synthetic intermediate of a heterocyclic compound, especially vitamin B1 and analogous compound, by the ring-opening and alkylation reaction of 4-isoxazole carbonitrile. CONSTITUTION:4-Isoxazole carbonitrile is subjected to ring-opening reaction at 0-100 deg.C in the presence of a base (e.g. ammonia, sodium hydroxide, sodium methylate, etc.) in a solvent such as methanol, acetone, etc. The resultant product is alkylated with dialkyl sulfate at 0-150 deg.C to obtain the objective compound of formula (R is aliphatic hydrocarbon residue). The amounts of the base and the dialkyl sulfate are 1-50mol and 1-10mol per 1mol of the 4-isoxazole carbonitrile, respectively.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing alkoxymethylene malononitrile.

Alkoxymethylene malononitrile is an important compound as a synthetic intermediate for useful heterocyclic compounds, especially vitamin B1 and its analogues, and can be represented by the following general formula [I].

N/RO-CH2O\N In the general formula [I], R means an aliphatic hydrocarbon group, particularly an aliphatic hydrocarbon group having 1 to 5 carbon atoms.

Conventionally, as a method for producing alkoxymethylenemalononitrile, a method in which malononitrile and orthoformate are reacted has been generally used. According to this production method, alkoxymethylenemalononitrile can generally be obtained in a high yield, but the above-mentioned raw material compounds are all expensive, and it cannot be said that it is an industrially advantageous production method.

Therefore, as a result of intensive research to establish a new method for producing alkoxymethylene malononitrile, the present inventors found that
This has led to the present invention.

The present invention relates to a method for producing alkoxymethylenemalononitrile (hereinafter referred to as (also called the first manufacturing method).

Next, the first manufacturing method will be explained in detail.

The above ring-opening reaction and alkylation reaction can be expressed as follows.

R2SO4CN/RO-CH=C\N 4-Inoxazolecarbonitrile used as a raw material in the first production method of the present invention is a known compound, and therefore can be easily obtained by a known production method.

In the present invention, the ring-opening reaction of 4-ynoxazole carbonitrile is carried out in the presence of a base as described above. Examples of bases used for this purpose include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, butylamine, dibutylamine, tributylamine, piperidine, morpholine, Organic amines such as pyridine and picoline; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alcoholades such as sodium methylate, sodium ethylate, potassium methylate, and potassium ethylate; and methyltriethylammonium, methyltributylammonium,
Examples include hydroxides of quaternary ammonium such as tetrabutylammonium, triethylbenzylammonium, and trioctylmethylammonium.

These bases are used in a stoichiometric or higher amount, usually about 1 to 5 to 1 mole of 4-ynoxazolecarbonitrile.
It is used in a proportion of 0 mol. In addition, when a gaseous amine is used as a base, it may be introduced into the reaction system in a gaseous state under normal pressure, or may be used in a liquid state under pressure.

Generally, the above ring-opening reaction is carried out in a solvent inert to the reaction. Examples of such solvents include methanol,
Alcohol solvents such as ethanol, propacyl, butanol, and ethylene glycol; Alcohol solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexane; Ester solvents such as methyl acetate, ethyl acetate, butyl acetate, and methyl propionate ; Ether solvents such as diethyl ether, dimethoxyethane, dioxane, and tetrahydrofuran; Hydrocarbon solvents such as benzene, toluene, xylene, hexane, heftane, and cyclohexane; methylene chloride, chloroform, carbon tetrachloride,
Examples include halogenated hydrocarbon solvents such as dichloroethane; and acetonitrile, dimethyl sulfoxide, and dimethylformamide. Note that the solvent used in this ring-opening reaction is preferably selected appropriately depending on the type of base used.

The reaction temperature of the above ring-opening reaction is preferably selected from the range of 0 to 100°C, and the reaction time is preferably selected from the range of 0°C to 5 hours.

The product obtained by the above ring-opening reaction is then alkylated using dialkyl sulfuric acid to obtain alkoxymethylene malononitrile.

The reaction solution that has undergone the ring-opening reaction may be used as is for alkylation, or the reaction solution may be used as a solvent,
Alkylation may be performed after removing a portion of the base and the like.

Examples of dialkyl sulfates used in alkylation include:
Mention may be made of dimethyl sulfate, diethyl sulfate, dipropyl sulfate, and dibutyl sulfate. The amount of dialkyl sulfuric acid used is 1 1 of the starting material 4-inoxazole carbonitrile.
It is desirable to use about 1 to 10 moles per mole.

Generally, the above alkylation reaction is carried out in a solvent inert to the reaction. Examples of such solvents can be similarly selected from those listed as solvents used in the ring-opening reaction. The solvent used in the alkylation reaction may be the same as the solvent used in the ring-opening reaction, or may be different.

The reaction temperature of the alkylation reaction is preferably selected from the range of 0 to 150°C, and the reaction time is preferably selected from the range of 0°C to 10 hours.

The alkoxymethylenemalononitrile produced by the above method can be produced by known methods such as filtration, concentration, distillation, and recrystallization, depending on the nature of the solvent used in the alkylation reaction, the nature of the reaction product, the desired purity, etc. It can be isolated by using physical separation means, purification means, etc.

Alkoxymethylene malononitrile, which is the target substance of the present invention, can also be produced via the same route starting from an alkali metal salt of 2-hydroxymethylene-3゜3-dialkoxypropanenitrile and a mineral acid salt of hydroxylamine. can.

That is, the present invention allows an alkali metal salt of 2-hydroxymethylene-3,3-dialkoxypropanenitrile to react with a mineral acid salt of hydroxylamine, and the resulting reaction product is reacted without isolating it from the reaction solution. The present invention also provides a method for producing alkoxymethylene malononitrile (hereinafter also referred to as a second production method), which is characterized by reacting with a base and then alkylating using dialkyl sulfuric acid.

The present inventor has already discovered that 2-hydroxymethylene-3,3-
4, which is the starting material for the above production method, by reacting (cyclization reaction) an alkali metal salt of dialkoxypropanenitrile and a mineral acid salt of hydroxylamine in an inert solvent.
It has been discovered that -isoxazole carbonitrile can be easily obtained, and a patent application has already been filed for this production method (Japanese Patent Application No. 57-227467).

The present inventor unexpectedly achieved cyclization by reacting the reaction product obtained in the above reaction with a base without isolating it from the reaction solution (cyclization reaction solution), and further alkylating it using dialkyl sulfuric acid. It has been found that alkoxymethylenemalononitrile is produced in an amount greater than that expected to be produced by ring-opening and alkylating 4-yneoxazolecarbonitrile present in the reaction solution. This is because a part of the 4-ynoxazole carbonitrile produced during the cyclization reaction is ring-opened through successive reactions to become hydroxymethylenemalononitrile, which is present in the cyclization reaction solution, and this hydroxymethylenemalononitrile is This is thought to be because it is converted into alkoxymethylenemalononitrile in the same manner by the chemical reaction.

Therefore, 4-ynoxazolecarbonitrile is obtained by a cyclization reaction between an alkali metal salt of 2-hydroxymethylene-3,3-dialkoxypropanenitrile and a mineral acid salt of hydroxylamine, and this 4-ynoxazolecarbonitrile is When producing alkoxymethylenemalononitrile by carrying out the ring-opening reaction and alkylation reaction described above, rather, the 4-ynoxazolecarbonitrile is not isolated from the cyclization reaction solution. It is advantageous to use the second production method described above, in which the reaction solution is subjected to the next ring-opening reaction.

Next, the second manufacturing method will be explained in detail.

2-Hydroxymethylene-3,3-dialkoxy.

The alkali metal salt of cypropanenitrile has the following general formula [I
I].

R1 and R2 in the general formula [nl can be arbitrarily selected from aliphatic hydrocarbon groups having 1 to 5 carbon atoms, and R1 and R
2 may be the same or different. M is selected from alkali metals such as sodium and potassium.

Examples of mineral acid salts of hydroxylamine include hydrochloride, sulfate, and phosphate. These mineral acid salts of hydroxylamine are desirably used in a proportion of about 0.7 to 1.5 mol per 1 mol of the compound represented by the general formula [nl.

The reaction (cyclization reaction) between the compound represented by the general formula [II] and the mineral acid salt of hydroxylamine is generally carried out in an inert solvent. The inert solvent used in this cyclization reaction is preferably an alcoholic solvent such as methanol, ethanol, propatool, butanol, or ethylene glycol. However, these alcohol solvents and other inert solvents, such as ester solvents such as methyl acetate, ethyl acetate, butyl acetate, and methyl propionate; ether solvents such as diethyl ether, dimethoxyethane, dioxane, and tetrahydrofuran; benzene ,toluene,
Use a mixed solvent with hydrocarbon solvents such as xylene, hexane, heptane, and cyclohexane; halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; and solvents such as acetonitrile, dimethylsulfoxide, and dimethylformamide. You can also.

The reaction temperature of the above cyclization reaction is preferably selected from the range of 0 to 100°C, and the reaction time is preferably selected from the range of 0°C to 10 hours.

Next, the reaction product from the above cyclization reaction, i.e., 4
- inoxazole carbonitrile and other products (
For example, hydroxymethylene malononitrile) is reacted with a base without being isolated from the reaction solution. Through this reaction, 4-ynoxazolecarbonitrile in the reaction solution is ring-opened according to the reaction formula described above.

Examples of the base used in the above reaction include the same bases used in the ring-opening reaction of 4-ynoxazolecarbonitrile described in the explanation of the first production method. The base is preferably used in an amount of about 1 to 50 moles per mole of the alkali metal salt of 2-hydroxymethylene-3,3-dialkoxypropanenitrile as a raw material.

The above reaction using a base is preferably carried out in an inert solvent, and examples of the inert solvent are the same as those that can be used in the cyclization reaction using a base in the first production method described above. .

Note that the above base can be used as is or after partially removing or increasing the amount of the solvent used in the reaction of the alkali metal salt of 2-hydroxymethylene-3,3-dialkoxypropanenitrile with the mineral salt of hydroxylamine. May be used for reactions.

The reaction temperature for the reaction using the above base is preferably selected from the range of 0 to 100°C, and the reaction time is preferably selected from the range of 0.1 to 5.
It is preferable to choose from a time range.

Alkoxymethylenemalononitrile can be obtained by alkylating the compound present in the reaction solution obtained by the above reaction using dialkyl sulfuric acid.

The reaction solution that has undergone the ring-opening reaction may be used as is for alkylation, or alkylation may be carried out after removing a portion of the solvent or base from the reaction solution.

Examples and usage amounts of dialkyl sulfates used in alkylation,
The solvent, reaction temperature, reaction time, etc. preferably used in the reaction can be selected in the same manner as in the alkylation step in the first production method.

The alkoxymethylenemalononitrile produced by the above method can be isolated by using known product separation means, purification means, etc., as in the case of the first production method.

Next, examples of the present invention will be shown.

[Example 1] 0.94 g (10 mmol) of 4-inoxazole carbonitrile and 10 g of methanol were placed in a 100 mJl round bottom flask, and while stirring these, ammonia φ was added.
10 g of a methanol mixture (2:8, weight ratio) was added. After the flask was sealed with a silica gel tube to block moisture, the contents were stirred at room temperature for 30 minutes.

Next, the contents of the flask were placed under reduced pressure to distill off excess ammonia, and then 3.78 g (30 mmol) of dimethyl sulfate was added. Then, after attaching a silica gel tube material reflux condenser to this flask, the above mixture was poured for 30 minutes.
Stir under reflux for a minute.

After the reaction mixture was cooled, it was subjected to gas chromatography, and the reaction product was analyzed using an internal standard method. As a result, it was confirmed that methoxymethylenemalononitrile was produced in a yield of 61%.

[Example 2] In a second flask of 100m capacity equipped with a reflux condenser, 0.9% of 4-inoxazole carbonitrile was added to the silica gel tube.
4 g (10 mmol) and 20 g of acetone were added, and while stirring these, 1.52 g (1.5 mmol) of triethylamine was added.
5 mmol) was added. The mixture was then stirred at room temperature for 30 minutes.

Next, add 3.0 ml of dimethyl sulfate to the above mixture. ．． 78'g (30
mmol) was added and the mixture was stirred under reflux for 1 hour.

The reaction mixture was analyzed in the same manner as in Example 1, and it was confirmed that methoxymethylenemalononitrile was produced in a yield of 89%.

[Example 3] The reaction was carried out in the same manner as in Example 2 except that the same amount of benzene was used instead of acetone and the stirring time under reflux after addition of dimethyl sulfuric acid was changed to 3 hours.

The reaction mixture was analyzed in the same manner as in Example 1, and it was confirmed that methoxymethylenemalononitrile was produced in a yield of 90%.

[Example 4] In a 100 mM round bottom flask, 0.94 g (10 mmol) of 4-inoxazole carbonitrile and 1 methanol were added.
0 g was added thereto, and while stirring these, 10 g of an ammonia/methanol mixed solution (2:8, weight ratio) was added. After the flask was sealed with a silica gel tube to block moisture, the contents were stirred at room temperature for 30 minutes.

The contents of the flask were then evaporated to dryness under reduced pressure to remove excess ammonia and methanol, followed by 20 g of acetone and 3.78 g of dimethyl sulfate (3.78 g of dimethyl sulfate).
0 mmol) was added. Then, a silica gel tube reflux condenser was attached to this flask, and the above mixture was stirred under reflux for 1 hour.

The reaction mixture was analyzed in the same manner as in Example 1, and it was confirmed that methoxymethylene malononitrile was produced in a yield of 97%.

[Example 5] 0.94 g (10 mmol) of 4-inoxazole carbonitrile and 10 g of tetrahydrofuran were placed in a 100 m fl round bottom flask, and while stirring these, a methylamine/tetrahydrofuran mixture (1:9, weight) was added. ratio) 10g was added. After the flask was sealed with a silica gel tube to block moisture, the contents were stirred at room temperature for 30 minutes.

Next, the contents of the flask were placed under reduced pressure to distill off excess methylamine, and then 3.78 g (30
mmol) was added. Then, after attaching a silica gel tube material reflux condenser to this flask, 1% of the above mixture was added.
Stir under reflux for an hour.

The reaction mixture was analyzed in the same manner as in Example 1, and it was confirmed that methoxymethylene malononitrile was produced in %.

[Example 6] 4-Inoxazole carbonitrile 0.9 in a second 100 mM flask equipped with silica gel tubing reflux condenser
Add 4 g (10 mmol) and 20 g of ethanol, and while stirring, add 0.82 g of sodium ethylate.
g (12 mmol) was added. The mixture was then stirred at room temperature for 10 minutes.

Next, 3.08 g (20 mmol) of diethyl sulfuric acid was added to the above mixture, and the mixture was stirred under reflux for 1 hour.

After the reaction mixture was cooled, it was subjected to gas chromatography, and the reaction product was analyzed using an internal standard method. As a result, it was confirmed that ethoxymethylene malononitrile was produced in a yield of 54%.

[Example 7] 0.94 g (10 mmol) of 4-isoxazole carbonitrile and 15 g of benzene were placed in a 100 mJlj round bottom flask, and while stirring these, an ethanol solution of sodium hydroxide (0.48 g of sodium hydroxide) was added.
12 mmol)/5 g of ethanol) was added. The flask was sealed with a silica gel tube to keep out moisture, and the contents were stirred at room temperature for 30 minutes.

Next, the contents of the flask were placed under reduced pressure to distill off the solvent, and then 20 g of ethyl acetate and 3.0 g of diethyl sulfate were added.
8 g (20 mmol) was added. After a reflux condenser with a silica gel tube was attached to the flask, the above mixture was stirred under reflux for 1 hour.

The reaction mixture was analyzed in the same manner as in Example 6, and it was confirmed that ethoxymethylene malononitrile was produced in %.

[Example 8] In a 100 ml round bottom flask, 2.62 g of sodium salt of 2-hydroxymethylene-3,3-ditoxypropanenitrile (purity 91.6%, 14.5 mmol) and 15 g of methanol were added. and 1.01 g (14.5 mmol) of hydroxylamine hydrochloride was added thereto while stirring. After the flask was sealed with a silica gel tube to block moisture, the contents were stirred at room temperature for 30 minutes.

Next, 3.36 g of a methanol solution of sodium methylate (28% by weight of sodium methylate) was added to the above flask.
, 17.4 mmol) and stirred at room temperature for 10 minutes. Thereafter, 25 g of benzene was added to the reaction mixture, and the mixture was evaporated to dryness under reduced pressure, which was repeated twice to obtain a pale yellow dry product.

Add 40g of acetone and dimethyl sulfur #5 to the above dry matter,
50 g (43, 6 mmol) were added. Then, a silica gel tube reflux condenser was attached to this flask, and the above mixture was stirred under reflux for 1 hour.

The reaction mixture was analyzed in the same manner as in Example 1, and it was confirmed that methoxymethylenemalononitrile was produced in a yield of 83%.

Separately, sodium salt of 2-hydroxymethylene-3,3-dimethoxypropanenitrile and hydroxylamine hydrochloride were used in the same amounts as above and reacted under the same conditions.
-Inoxazole carbonitrile was produced, the reaction solution was subjected to gas chromatography, and the yield of 4-inoxazole carbonitrile was determined to be 79% by internal standard method. This means that in the above-mentioned method for producing methoxymethylene malononitrile, the 4-isoxazole power generated during the production process is +1J
When this is subjected to ring-opening and alkylation reactions, the yield A of methoxymethylenemalononitrile (Jul 2
-Hydroxymethylene-3,3-dimethoxypropanenitrile from the sodium salt) does not exceed 79%.

[Example 9] 2-Hydroxymethylene was added to a 100 m round bottom flask.
Sodium salt of 3,3-dimethoxypropanenitrile 1
．． 90 g (purity 91.6%, 10.5 mmol) and 40 g of methanol were added, and while stirring these, 0.89 g (5.4 mmol) of hydroxylamine sulfate was added. The flask was sealed with a silica gel tube to block moisture, and the contents were stirred at room temperature for 6 hours.

Next, 2.45 g of a methanol solution of sodium methylate (28% by weight of sodium methylate) was added to the above flask.
, 12.7 mmol) and stirred at room temperature for 10 minutes. Thereafter, 25 g of toluene was added to the reaction mixture, and the mixture was evaporated to dryness under reduced pressure, which was repeated twice to obtain a pale yellow dry product.

Add 20 g of dioxane and 6.0 g of diethyl sulfate to the above dried product.
40 g (41.5 mmol) was added.

Then, a silica gel tube reflux condenser was attached to this flask, and the above mixture was stirred under reflux for 1 hour.

The reaction mixture was analyzed in the same manner as in Example 6, and it was confirmed that ethoxymethylenemalononitrile was produced in a yield of 63%.

Separately, the same amounts of 2-hydroxymethylene-3,3-dimethoxypropanenitrile salt and hydroxylamine sulfate were used and reacted under the same conditions to produce 4-isoxazolecarbonitrile. When the reaction solution was subjected to gas chromatography and quantitatively determined using an internal standard method, the yield of 4-inoxazolecarbonitrile was 42%. This means that in the above-mentioned method for producing methoxymethylene malononitrile, if the 4-ynoxazole carbonitrile produced during the process is isolated and subjected to ring-opening and alkylation reactions,
This means that the yield of nodoxymethylenemalononitrile (from the sodium salt of 2-hydroxymethylene-3,3-dimethoxypropanenitrile as a raw material) does not exceed 42%.

[Example 10] 2-Hydroxymethylene- in a 100mM round bottom flask
Sodium salt of 3,3-di-n-butoxypropanecotrile2. ．． 50g (90.5% purity, 9.1 mmol)
and 25 g of methanol were added thereto, and while stirring these, 0.63 g (9.1 mmol) of hydroxylamine hydrochloride was further added. The flask was sealed with a silica gel tube to block moisture, and the contents were stirred at room temperature for 1 hour.

Next, add 1°42 g of triethylamine (
14 mmol) and stirred at room temperature for 30 minutes. Thereafter, 25 g of toluene was added to the reaction mixture, and the mixture was evaporated to dryness under reduced pressure, which was repeated twice to obtain a pale yellow dry product.

Add 30 g of methyl acetate and 3.0 g of dimethyl sulfate to the above dry product.
78 g (30 mmol) was added. Then, a silica gel tube reflux condenser was attached to this flask, and the above mixture was stirred under reflux for 3 hours.

The reaction mixture was analyzed in the same manner as in Example 1, and it was confirmed that methoxymethylene malononitrile was produced in a yield of 80%.

In addition, separately 2-hydroxymethylene-3,3-di-n-
The sodium salt of butoxypropanenitrile and hydroxylamine hydrochloride are used in the same amounts as above and reacted under the same conditions to produce 4-ynoxazole carbonitrile,
When the reaction solution was subjected to gas chromatography and quantitatively determined by an internal standard method, the yield of 4-ynoxazole carbonitrile was 75%. This means that in the above-mentioned method for producing methoxymethylene malononitrile, if the 4-isoxazole carbonitrile produced during the process is isolated and subjected to ring-opening and alkylation reactions, the methoxymethylene malononitrile I. Yield of rill (raw material 2
- The yield of hydroxymethylene-3,3-di-n-butoxypropanenitrile from sodium chloride does not exceed 75%. Applicant: Yasuo Yanagawa, Patent Attorney, Ube Industries Co., Ltd. Agent: Yasuo Yanagawa 41

Claims (2)

[Claims] 1. A method for producing alkoxymethylenemalononitrile cnl, which comprises ring-opening 4-inoxazole carbonitrile in the presence of a base, and then alkylating the obtained product with dialkyl sulfuric acid. 2. Reacting the alkali metal salt of 2-hydroxymethylene-3,3-dialkoxypropanenitrile with the mineral acid salt of hydroxylamine, and reacting the obtained reaction product with a base without isolating it from the reaction solution. , followed by alkylation using dialkyl sulfuric acid.