JPS59152360A - Production of alkoxymethylene cyanoacetic acid ester - Google Patents

Abstract

PURPOSE:To prepare the titled compound, useful as a synthetic raw material of pharmaceuticals and heterocyclic compounds, in high yield, at a low cost, by reacting 3,3-dialkoxypropionitrile with a carbonic acid diester in the presence of an alkali metal compound, and neutralizing the reaction product. CONSTITUTION:The objective compound of formula can be prepared by reacting (A) 3,3-dialkoxypropionitrile of formula (R<1>O)2CHCH2CN (R<1> is 1-6C alkyl) with (B) a carbonic acid diester of formula (R<2>O)2CO (R<2> is 1-6C alkyl) in the presence of an alkali metal compound selected from alkali metal alkoxide, alkali metal hydride, alkali metal amide, and alkali metal alkyl amide, at -20- +150 deg.C, and neutralizing the reaction product with an acid such as hydrochloric acid, sulfuric acid, etc. The amount of the component (B) is 1-100mol per 1mol of the component (A).

Description

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

Alkoxymethylene cyanoacetate is a compound useful as a raw material for the synthesis of pharmaceuticals such as allopurinol (described in Japanese Patent Publication No. 53-10078) and other heterocyclic compounds, and can be represented by the following general formula [I]. can.

RI 0CH=C(CN)COOR2[Ico[However,
R1 and R2 are generally each an alkyl group having 1 to 6 carbon atoms, and R1 and R2 may be the same or different from each other] Conventionally, as a method for producing alkoxymethylene cyanoacetate, cyanacetate A method is known in which acetic acid ester and orthoformate are reacted in the presence of acetic anhydride [Journal of AIIlerican Ch.
Mical 5ociety: 74.4889
(11152) ], however, both cyanoacetate and orthoformate, which are the starting materials for this method, are expensive compounds, and it is necessary to use a large amount of acetic anhydride, and furthermore, the reaction yield is low. Since this is not good, it cannot be said to be a fully satisfactory method industrially.

Also, methods for carrying out the above reaction without using acetic anhydride have been disclosed (e.g., U.S. Pat. No. 2,824,1
However, since this method requires the use of a special solvent such as dimethylformamide, it cannot be said to be a fully industrially satisfactory method.

Therefore, the present invention provides a method for producing alkoxymethylene dianoacetic acid ester that can use cheaper starting materials and has an excellent reaction yield compared to the conventional methods as described above.

In the present invention, after reacting 3,3-dialkoxypropionitrile and carbonic acid diester in the presence of an alkali metal compound selected from alkali metal alkoxides, alkali metal hydrides, alkali metal amides, and alkali metal alkylamides, This method consists of a method for producing alkoxymethylene cyanacetic acid ester, which is characterized by neutralization.

Next, the present invention will be explained in detail.

The manufacturing method of the present invention consists of two steps, the first step of which is
3. This is a step in which 3-dialkoxypropionitrile and diester carbonate are reacted in the presence of an alkali metal compound such as an alkali metal alkoxide.

One of the starting materials in the present invention is 3,3-dialkoxypropionitrile, and this compound has the general formula [■]
: (R10) 2CHCH2CN [■] [However, R1 is an alkyl group having 1 to 6 carbon atoms].

Examples of the alkyl group for R1 in general formula [II] are methyl, ethyl, n-propyl, isopropyl, n-butyl,
Examples include isobutyl, pentyl, hexyl, and the like. Further, specific examples of 3,3-dialkoxypropionitrile include 3゜3-dimethoxypropionitrile, 3,3-jethoxypropionitrile, 3,3-di-
Examples include n-propoxypropionitrile, 3.3-diisopropoxypropionitrile, and 3.3-di-n-butoxypropionitrile.

The 3,3-dialkoxypropionitrile of the above general formula [Il, ] is a known compound, and can be easily produced, for example, by reacting acrylonitrile and a nitrite in the presence of a palladium catalyst. Can be done.

Another starting material in the present invention is carbonic acid diester, and this compound has the general formula [■]; (R2o)2CO
[Iul [However, R2 is an alkyl group having 1 to 6 carbon atoms]].

Examples of the alkyl group for R2 in the -Vt formula [1[] include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, and the like. Specific examples of diester carbonates include dimethyl carbonate, diethyl carbonate, di-n-propyl carbonate, diisopropyl carbonate, and di-n-butyl carbonate.

The diester carbonate is used in an amount of about 1 to 100 moles per mole of 3,3-dialkoxypropionitrile, and it is usually preferable to use an excess amount of diethyl carbonate.

As mentioned above, the alkali metal compound is selected from alkali metal alkoxides, alkali metal hydrides, alkali metal amides, and alkali metal alkylamides, but alkali metal alkoxides are preferred.

Alkali metal alkoxides generally include alkali metals with a carbon number of 1, such as lithium, potassium, and lithium.
~6 alkoxides are used. Examples of alkali metal alkoxides include sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium 5ec-butoxide, sodium tert-butoxide, potassium methoxide, potassium Ethoxide, potassium n-propoxide, potassium isopropoxide, potassium n-butoxide, potassium 5ec-butoxide,
Potassium tert-butoxide may be mentioned.

Among these alkali metal alkoxides, potassium secondary and tertiary alkoxides are preferred and give particularly good results.

Other alkali metal compounds include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal amides such as sodium amide and potassium amide; and alkali metal alkylamides such as lithium diisopropylamide.

The alkali metal compound such as alkali metal alkoxide is used in an amount of about 1 to 5 mol (preferably about 2 to 5 mol) per 1 mol of 3,3-dialkoxypropionitrile.

3. When carrying out the reaction between a 3-dialkoxypropionitrile and a carbonic acid diester in the presence of an alkali metal compound such as an alkali metal alkoxide, the reactant carbonic acid diester may be utilized as a solvent; A suitable solvent may also be present. Examples of such solvents include aromatic hydrocarbons such as benzene and toluene, and ether compounds such as dioxane, tetrahydrofuran, diethyl ether and dibutyl ether. When an alkali metal alkoxide is used as the alkali metal compound, an alcohol corresponding to the alkali metal alkoxide may be used. In addition, since the yield of this reaction decreases if water is present in the reaction solution, it is desirable to sufficiently remove water in the solvent and reactants before the reaction.

The reaction temperature of the first step in -1- is -20 to 15
You can choose from the range 0'0, but generally it is 0~
It is preferable to select from a range of 100°C.

Further, the reaction is usually carried out for 0.5 to 10 hours.

In addition, the unreacted portion of the carbonate diester used in this first step (if the carbonate diester is also used as a solvent,
) may be removed by means such as distillation before carrying out the next second step.

The second step in the production method of the present invention is a step of neutralizing the product of the first step.

This neutralization step can be carried out by adding an acid to the product of the first step. Examples of the alcohol used include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as formic acid, acetic acid and zlopionic acid. These acids can be used diluted with a solvent such as water,
Particularly when using an inorganic acid, it is desirable to add it to the reaction product of the first step as a diluted acid diluted with water.

After the neutralization in the second step is completed, the product can be extracted by distillation, etc., but usually by using a solvent extraction method using an organic solvent that is immiscible with water and further distilling, etc. The desired alkoxymethylene cyanoacetate can be obtained.

In addition, the solvent used in the first step (including diester carbonate)
If a large amount of remains after the completion of the second step, the product of the second step can be taken out in the same manner thereafter by using the above solvent instead of the extraction solvent without adding any extraction solvent.

Next, examples of the present invention will be shown.

[Example 1] After purging the inside of a three-bottle flask equipped with a reflux condenser and a three-way stopcock with alcon gas, 5.62 g (48.9 mmol) of 3,3-dimethoxypropionitrile was added to the flask, and enough 60 m of dimethyl carbonate (0,67
mole) was added. While stirring this mixture thoroughly under water cooling, 12.0 g of potassium tert-butoxide (
107 mmol) was added in 5-6 portions over the course of 1 hour.

After the addition was complete, the ice bath was removed, the temperature of the reaction mixture was allowed to return to room temperature, and the reaction mixture was then reacted at 50° C. for 2 hours. Thereafter, the reaction mixture was ice-cooled again, and 5 mL of acetic acid was added thereto, followed by stirring for 5 minutes. Then 100 ml of water were added and the separated organic phase was extracted with 4-methyl-2-pentanone.

The solvent was distilled off from the above extract under reduced pressure, and then by vacuum distillation, the boiling point was 132-135°C/lmmH.
g of a solid (melting point: 89-900C) was obtained. This solid had an IR spectrum, NMR spectrum, and mass spectrum that all matched with methyl methoxymethylene cyanoacetate produced by a conventional method.

A portion of the above extract was subjected to gas chromatography and analyzed using the internal standard method. As a result, the extract contained 6.21 g (
The presence of methyl methoxymethylenecyanoacetate (44.0 mmol) was confirmed. Yield: 90%. Note that the products other than methyl methoxymethylene cyanoacetate were [Examples 2 to 7 Example 1 except that 107 mizamol of another alkali metal alkoxide was used instead of copotassium tert-butoxide.
I performed a similar operation.

The alkali metal alkoxides used were sodium tert-butoxide [Example 2], sodium ethoxide [Example 3], sodium n-butoxide [Example 4], potassium n-butoxide [Example 5], and potassium impropoxide. [Example 6] and sodium isopropoxide [Example 7].

The results are shown in Table 1.

Table 1 Reaction rate Production amount Yield Selectivity example (%) (mmol) (%) (%)2
47 20 41 783 92
4.0 8.0 8. =, 74 46
8.9 15 395 32 12
24 766 73 28
57 797 4
5 17 34 76 Note) Reaction rate: Reaction rate of 3,3-dimethoxypropionitrile Production amount: Production amount of methyl methoxymethylene cyanoacetate Yield: Yield of methyl methoxymethylene cyanoacetate Selectivity = [Methoxymethylene cyanoacetic acid Yield of methyl]÷[reaction rate of 3,3-dimethoxypropionitrile] [Example 8] 3.3-instead of 3.3-dimethoxypropionitrile
The same procedure as in Example 1 was carried out except that the same mole of di-n-butoxypropionitrile was used and the same mole of di-n-butyl carbonate was used instead of dimethyl carbonate. Acetate ester was obtained. However, the heating temperature after adding potassium tert-butoxide is 8
The temperature was 0°C.

The details and results of this reaction are shown in Table 2.

[Examples 9 to 11] The same operation as in Example 8 was performed except that 107 mmol of another metal alkoxide was used instead of potassium tart-butoxide.

The metal alkoxides used were sodium n-butoxide [Example 9], potassium isopropoxide [Example 10], and potassium n-butoxide [Example 11], respectively.
It is Ko. The results are shown in Table 2.

Table 2 Reaction rate Production amount Yield Selectivity example (%) (mmol) (%) (%) 8
100 32 66 669 82
18 36 4410 91 3
0 61 6711 85 23
47 55th edition) Reaction rate = Reaction rate of 3,3-di-n-butoxypropionitrile Amount of production: Amount of production of methyl n-butoxymethylenecyanoacetate Yield: Yield of methyl n-butoxymethylenecyanoacetate Selectivity = [Yield of methyl n-butoxymethylenecyanoacetate] ÷ [Reaction rate of 3,3-di-n-butoxypropionitrile co[Examples 12 to 14] The acetic acid used in the neutralization operation was The same operation as in Example 1 was performed except that acid was used. The acids used and the results are shown in Table 3.

Table 3 Example Acid Amount Yield (mmol) (%) 12 5N Hydrochloric acid 42 8513 5N Sulfuric acid 41 8314 5N Phosphoric acid 44
Note 90) Amount of production: Amount of methyl methoxymethylene cyanoacetate produced Yield: Yield of methyl methoxymethylene cyanoacetate Patent applicant: Ube Industries, Ltd. Agent Patent attorney: Yasuo Yanagawa

Claims (1)

[Claims] 1゜3,3-dialkoxypropionitrile represented by the general formula: %formula% [wherein R1 is an alkyl group having 1 to 6 carbon atoms] and the general formula: %formula% ) [However, R2 is an alkyl group having 1 to 6 carbon atoms, and a carbonic acid diester represented by 2 is treated in the presence of an alkali metal compound selected from an alkali metal alkoxide, an alkali metal hydride, an alkali metal amide, and an alkali metal alkyl amide. A method for producing an alkoxymethylene cyanacetic ester represented by the following general formula: % formula % [However, R1 and R2 are the same as above]. 2. The method for producing an alkoxymethylene dianoit [ester] according to claim 1, wherein the alkali metal compound is an alkali metal alkoxide. 3. The method for producing an alkoxymethylene cyanacetic acid ester according to claim 2, wherein the 3° alkali metal alkoxide is a secondary or tertiary alkoxide of potassium.