JPH11228500A - Production of methine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a methine derivative useful as an intermediate for a medicine, an agrochemical or the like in a short reaction time while reducing the amount of byproducts with good filterability by reacting a specific alkyl halide compound with an active methylene compound under a specified condition. SOLUTION: An alkyl halide compound of formula I [R<1> and R<2> are each independently H, a 1-4C alkyl, hydroxyl, nitro or a halogen; A is a linear or branched 1-6C alkyl; X is a halogen; (n) is 0 or 1] is reacted with an active methylene compound of the formula Y-CH2 -Z (Y and Z are each independently CO2 R<3> or CN; R<3> is H or a 1-4C alkyl) in the presence of an alkali metal carbonate or an alkali metal hydrogen carbonate to provide a methine derivative of formula II in the method for producing the methine derivative. The active methylene compound can be used as a reaction solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an improved method for producing a methine derivative, which is useful as an intermediate for pharmaceuticals, agricultural chemicals and the like.

The methine derivative represented by the above general formula (3) of the present invention can be used as an active ingredient of an antiarrhythmic agent described in, for example, JP-A-3-112948.
Of pyrimidinedione derivatives such as -dimethyl-6- [2- {N- (2-hydroxyethyl) -3- (4-nitrophenyl) propylamino} ethylamino] -2,4 (1H, 3H) -pyrimidinedione It is useful as an intermediate of N- (2-hydroxyethyl) -3- (4-nitrophenyl) propylamine, which is useful as a production intermediate.

[0003]

2. Description of the Related Art Conventionally, methine derivatives represented by the above general formula (2) have been used, for example, in MERCK & CO., I.
NC. Published Organic Name Reactions, page ONR
-57 (1983), Malonic Ester Synthesis, reaction of malonic acid diethyl ester with sodium ethoxide to obtain malonic acid diethyl ester monosodium salt, which is obtained by reacting with an alkyl halide.

[0004]

However, this method requires a secondary material called sodium ethoxide, and also needs to remove ethanol separated during the reaction. In this method, the use of sodium ethoxide, which is a strong base, results in poor selectivity of the target product and a low yield.
There is no description that a product is obtained in a very short reaction time. The same is also explained in more detail in JOHN WILE
Y & SONS, INC. Published by Synthetic Organic
Chemistry, pages 426-429, Method 264, but also requires the removal of a secondary material, sodium ethoxide, and ethanol that separates during the reaction. This method does not disclose that a product is obtained in a very short reaction time and in a high yield in the same manner as described above.

It is also known to react malonic acid diethyl ester with a halogen compound in the presence of an inorganic alkali compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like. . However, these methods generally require a reaction time of 10 hours or more, and the amount of by-product dimer (bis-isomer) is large, and the filterability is poor.

An object of the present invention is to provide a method for producing a methine derivative which has a very short reaction time, a small amount of a dimer (bis-form) by-produced, and a good filterability. Another object of the present invention is to provide a method for producing a methine derivative in which an active methylene compound as a reaction material can be used as a solvent and a separate ordinary solvent does not need to be used.

[0007]

According to the present invention, there is provided an aromatic metal compound represented by the general formula (1) and an active methylene compound represented by the general formula (2). The present invention relates to a method for producing a methine derivative, which comprises reacting in the presence of a fine powder of a salt to obtain a methine derivative represented by the general formula (3).

[0008]

Embedded image (Wherein, R ¹ and R ² are a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a nitro group or a halogen, A is a linear or branched alkyl group having 1 to 6 carbon atoms, and X is a halogen. , N represents 0 or 1.) Y—CH ₂ —Z (2) (wherein, Y and Z each represent COOR ³ or CN, and R ³ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms). )

[0009]

Embedded image (In the formula, R ¹ , R ² , A, Y, Z, and n are the same as described above.)

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the aromatic ring-substituted alkyl halide compound represented by the general formula (1) of the present invention, the alkyl group having 1 to 4 carbon atoms in R ¹ and R ² includes methyl, ethyl and
Propyl, butyl, etc., as halogen, chlorine, bromine,
Iodine and the like, as a linear or branched C 1-6 alkyl group of A, in addition to the above, pentyl, hexyl and the like,
As the halogen for X, the same as those described above can be mentioned. Specific examples include benzyl chloride, benzyl bromide, nitrobenzyl chloride, nitrobenzyl bromide, naphthylmethyl chloride, naphthylmethyl bromide, naphthylethyl bromide and the like.

As the alkyl group having 1 to 4 carbon atoms in R ³ of the active methylene compound represented by the general formula (2), those similar to the above can be exemplified. Specific compounds (2) include malonic acid, malonic acid dimethyl ester, malonic acid dibutyl ester, malonic acid dinitrile,
Examples thereof include cyanoacetic acid, cyanoacetic acid ethyl ester, and cyanoacetic acid propyl ester. In the present invention, examples of the alkali metal carbonate or alkali metal hydrogencarbonate (hereinafter, sometimes simply referred to as carbonate) include, for example, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like.

In the present invention, the active methylene compound (2)
Is usually about 0.5 to 20 mol, preferably 5 to 15 mol, per 1 mol of the aromatic ring-substituted alkyl halide compound (1).
Used on a molar basis. Carbonate fine powder is 9
Preferably, 0 to 100% by weight has a particle size of 250 μm or less, more preferably 70 to 100% by weight has a particle size of 100 μm or less, especially 50 to 100% by weight.
It is preferred that the weight percent has a particle size of 45 μm or less. The amount of the carbonate to be used is generally 0.1 with respect to 1 mol of the compound (1).
About 5 mol, preferably about 0.5 to 3 mol. The reaction temperature is usually about -10C to 100C, preferably about 20-80C. The reaction time is drastically shortened by using the above fine carbonate, and is usually 20 to 30.
Minutes, and 20 to 60 minutes is sufficient. The short reaction time of the present invention is due to the use of the special carbonate as described above. In the present invention, the filterability of the bis-form which is an inorganic salt or a by-product is also improved.

In the present invention, since the active methylene compound (2) used serves as a solvent, it is not necessary to use a solvent, but a solvent can be used. Examples of the solvent include acetone, methyl ethyl ketone, ethyl acetate, benzene, toluene, xylene, ethylbenzene, chloroform, dichloroethane, dimethylformamide and the like, but are not particularly limited. Specific examples of the methine derivative (3) obtained by the reaction of the present invention include dimethyl benzylmalonate, diethyl 4-hydroxybenzylmalonate, dimethyl 4-nitrobenzylmalonate, and the like. In the present invention, the methine derivative obtained above can be separated by ordinary isolation and purification methods, and examples thereof include filtration, extraction, concentration, cooling crystallization, crystallization by addition of a poorly soluble solvent, and chromatography. Can be.

[0014]

The present invention will be described below with reference to examples and comparative examples. Example 1 In a 200 ml flask, 30 ml of acetone, 50.0 g (370.9 mmol) of dimethyl malonate (98%), 10.0 g (46.2 mmol) of 4-nitrobenzyl bromide, fine potassium carbonate powder (particle size: 44 μm or less) Is 63.9
%, Particle size 100 μm or less 90.9%) 12.9 g (92.
9 mmol) and an exothermic reaction from 22 ° C. to 48 ° C.
At which point 4-nitrobenzyl bromide had disappeared. The mixture was cooled to 25 ° C, filtered with a Nutsche filter, washed with 30 ml of acetone, then concentrated and dried to obtain 4-nitrobenzylmalonic acid dimethyl ester (yield 85%, HPLC purity 96.0%).

Mp. 82.8-84.0 ° C. 300 MHz, ¹ H-NMR (δ ppm) (CDCl ₃ ) 8.15 (d, j = 8 Hz, 2H) 7.39 (d, j =
8 Hz, 2H) 3.68 to 3.77 (m, 1H) 3.72 (s, 6H) 3.33 (d, j = 8 Hz, 2H)

Example 2 Dimethyl malonate (98%) was placed in a 1000 ml flask.
308.9 g (2291.2 mmol), 4-nitrobenzyl bromide 50.0 g (229.1 mmol), 63.7 g (458.6 mm) of the fine potassium carbonate powder used in Example 1
ol), the exothermic reaction causes the temperature to rise from 18 ° C to 58 ° C.
It rose in 5 minutes, at which point 4-nitrobenzyl bromide had disappeared. The mixture was cooled to 25 ° C, filtered with a Nutsche filter, washed with 300 ml of acetone, then concentrated and dried to obtain dimethyl 4-nitrobenzylmalonate (yield 9).
2.2%, HPLC purity 95.63%).

Example 3 Diethyl 4-nitrobenzylmalonate was obtained in the same manner as in Example 1 except that diethyl malonate was used in place of dimethyl malonate (yield: 85%, HPLC purity: 96.0%). ).

M.p. 58.5-59.2 ° C. 300 MHz, ¹ H-NMR (δ ppm) (CDCl ₃ ) 8.15 (d, j = 8 Hz, 2H) 7.39 (d, j =
8Hz, 2H) 4.28 (q, 4H) 3.70 (t, 1H) 3.33
(D, 2H) 1.42 (t, 6H)

Comparative Example 1 In a 200 ml flask, 30 ml of acetone, 50.0 g (370.9 mmol) of dimethyl malonate (98%), 10.0 g (46.2 mmol) of 4-nitrobenzyl bromide, potassium carbonate (particle size: 150 μm) The following is 2.1%) 12.9 g
(92.9 mmol) was added and reacted at room temperature. Three hours later, since 4-nitrobenzyl bromide had not disappeared, the mixture was further heated to reflux temperature and reacted for 10 hours.
However, at this point, 4-nitrobenzyl bromide did not completely disappear, and 20% remained.

[0020]

According to the present invention, the target methine derivative can be produced efficiently with a very short reaction time, a small amount of by-product dimer (bis-form) and good filterability. In the present invention, an active methylene compound as a reaction material can be used as a solvent, and a methine derivative can be produced without using a separate ordinary solvent.

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Claims (3)

[Claims] 1. An aromatic ring-substituted alkyl halide compound represented by the general formula (1) and an active methylene compound represented by the general formula (2) in the presence of a fine powder of an alkali metal carbonate or an alkali metal hydrogencarbonate. Reacting to obtain a methine derivative represented by the general formula (3). Embedded image (Wherein, R ¹ and R ² are a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a nitro group or a halogen, A is a linear or branched alkyl group having 1 to 6 carbon atoms, and X is a halogen. , N represents 0 or 1.) Y—CH ₂ —Z (2) (wherein, Y and Z each represent COOR ³ or CN, and R ³ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms). ) (In the formula, R ¹ , R ² , A, Y, Z, and n are the same as described above.) 2. The method according to claim 1, wherein the aromatic ring-substituted alkyl halide compound is nitrobenzyl halide. 3. 90 to 100% by weight of the fine powder of the alkali metal carbonate or alkali metal bicarbonate is 2%.
The production method according to claim 1, wherein the particle diameter is 50 µm or less.