JP2727243B2 - Method for producing 2-acylaminocinnamic acid derivatives - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing a 2-acylaminocinnamic acid derivative.

2. Description of the Related Art Cinnamic acid derivatives are useful intermediates for the production of medical and agricultural chemicals, and especially useful for the production of indazole acetic acids and indole acetic acids. As a method for synthesizing a cinnamic acid derivative having an amino group, the following cinnamic acid derivative is known.

However, this method is industrially problematic in that the reaction time is as long as 80 hours and a large amount of expensive catalyst is used. It is considered that the reason why the reaction time is long is that the amino group at the 2-position coordinates to the catalyst, thereby reducing its activity.

Problems to be Solved by the Invention There is a demand for a cinnamic acid derivative useful for the synthesis of intermediates for medical and agricultural chemicals, especially 5-halogen-substituted indazole acetic acids and 5-halogen-substituted indole acetic acids, and development thereof.

Means for Solving the Problems The present inventors have made intensive studies to solve the above-described problems, and have completed the present invention. That is, the present invention relates to general formula (I) (In the formula (I), Ac represents lower acyl, X ₁ represents fluorine or chlorine, and X ₂ represents bromine or iodine.) General formula (II) CH ₂ CHCHCOOR (II) (In the formula (II) , R represents hydrogen or lower alkyl) wherein a compound represented by the formula (III) is reacted with an acrylic acid or an ester thereof in the presence of a palladium catalyst, triphenylphosphine and an acid binder. (In the formula (III), Ac, R and X ₁ have the same meanings as described above.) A process for producing a 2-acylaminocinnamic acid derivative represented by the formula: Particularly useful compounds among the cinnamic acid derivatives represented by the formula (III) are 2-acetylamino-5-chlorocinnamic acid, 2-acetylamino-5-fluorocinnamic acid, and 2-acetylamino-5-chlorocinnamic acid. Methyl, ethyl 2-acetylamino-5-chlorocinnamate, methyl 2-propionylamino-5-fluorocinnamate and the like.

Examples of aryl substitution on iodobenzenes or bromobenzenes substituted with an acylamino group at the 2-position have not been reported before, and there are concerns about steric hindrance and hydrolysis of the acylamino group, and the yield cannot be expected much. As expected, they did not have any problems contrary to expectations according to the method of the present invention. The compound of the formula (III) is obtained by partially reducing a vinylene group (-CH = CH-) and then N-nitronizing and then ring-closing, or hydrolyzing an ester group and an acylamino group to obtain a 5-halogen-substituted 2-. The aminocinnamic acid can be easily converted into 5-
Halogen-substituted indazole-3-acetic acids can be derived.

 The present invention will be described in detail.

The compound represented by the general formula (I) as a raw material is obtained by brominating or iodinating a 4-halogen-substituted aniline, and then anhydrides of lower fatty acids such as acetic anhydride, lacnic anhydride, acetyl chloride, and propionic chloride. It can be easily obtained by acylation using an acid chloride or the like. In the general formula (I), X ₁ is chloro or fluorine. Ac represents a lower acyl such as formyl, acetyl, propionyl, butyl, valeryl, etc., and preferred is acetyl.

Further, as the compound represented by the formula (II), acrylic acid,
Methyl acrylate, ethyl acrylate, butyl acrylate, octyl acrylate and the like can be used. The amount of the compound used is usually 1.0 to the compound represented by the general formula (I).
The molar ratio is 0 to 3.0. Examples of the palladium catalyst that can be used in the production method of the present invention include palladium chloride, palladium acetate, palladium salts such as palladium sulfate,
Examples include palladium black, palladium adsorbed on an adsorbent such as activated carbon or diatomaceous earth. The use amount thereof is suitably 1/10 to 1/5000 mol ratio, more preferably 1/100 to 1/1000 mol ratio, relative to the compound represented by formula (I).

Another catalyst, triphenylphosphines,
It is preferable to use 1 to 4 mole ratio, particularly 2 mole ratio, to the palladium catalyst. Examples of triphenylphosphines that can be used include triphenylphosphine, tri (p-tolyl) phosphine, tri (2,4-dimethylphenyl) phosphine, tri (2,4,6-trimethylphenyl) phosphine, Compounds having a substituent on the phenyl group, such as tri (p-chlorophenyl) phosphine, may be mentioned.

As the acid binding agent, both inorganic bases and organic bases can be used. Particularly, potassium acetate, sodium acetate, ammonium acetate, calcium acetate, potassium bicarbonate, sodium bicarbonate, ammonium bicarbonate, potassium carbonate,
Relatively weak inorganic bases such as sodium carbonate, ammonium carbonate, calcium hydroxide, or trimethylamine, triethylamine, tributylamine, pyridine,
Organic bases such as piperidine, N-methylpiperidine, 4-diazabicyclo [2,2,2] octane are suitable.
The amount used is 1 to the compound represented by the general formula (I).
A molar ratio of .about.3 is suitable.

As the reaction solvent, amide solvents and alcohol solvents are generally used, and amide solvents are particularly preferable. For example, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylimidazolidinone (DMI), dimethylsulfoxide, hexamethylphosphoramide, dioxane, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether , Methyl isobutyl ketone is used. An inert solvent such as benzene, toluene, xylene and chlorobenzene may be used in combination. The amount of the solvent used is usually 2 to 10 times (weight ratio) based on the total weight of the raw materials. The reaction temperature is preferably 50 to 250 ° C, more preferably 100 to 15 ° C.
0 ° C. After completion of the reaction, the reaction solution can be poured into water to separate crystals, or the solvent used in the reaction can be distilled off to extract crystals.

The compound of the formula (III) obtained in the present invention is useful for synthesizing 5-halogen-substituted indazole acetic acids and 5-halogen-substituted indole acetic acids which are useful as medicines and agricultural chemicals, especially as plant growth regulators.

Examples The present invention will be described more specifically by way of examples, but these examples do not limit the scope of the present invention in any way.

Example 1. A 200 ml reaction flask was charged with 40 ml of N, N-dimethylformamide (hereinafter abbreviated as DMF), into which 20 g (0.0677 mol) of 2-acetylamino-5-chloroiodobenzene and 5.94 g of methyl acrylate (0.069 mol) were added. Mol), anhydrous sodium acetate 6.94 g (0.0846 mol), palladium chloride 10m
g and triphenylphosphine 30 mg were sequentially charged. After stirring the mixture at 130 to 135 ° C. for 3 hours, 200 ml
When poured into water, a large amount of crystals were precipitated. The crystals were separated, washed thoroughly with water, and dried in vacuo to obtain 14.1 g of methyl 2-acetylamino-5-chlorocinnamate. The yield was 82.2% of theory. Melting point 172-1
74 ° C. Nuclear Magnetic Resonance spectrum of the ⁽¹ H-NMR),
The infrared absorption spectrum (IR) was as follows. ^{1 H-NMR (δ, DMSO} -d 6); 2.04 (s, -COC H 3), 7.69
(D, -C H = CHCOO- 16Hz), 3.68 (s, -OC H 3), 9.78
(Bs, -NH), 6.48 ( d, -CH = C H -COO-16Hz) IR (KBr ^{method); 3250cm -1 (νNH),} 1720cm -1 (νC = O, ester), 1660cm ^-1 (νC = O, amide), 1635cm ^-1 (νC
Example 2 A 200-ml reaction flask was charged with 40 ml of DMF, and 20 g (0.0677 mol) of 2-acetylamino-5-chloroiodobenzene, 5.85 g (0.0812 mol) of acrylic acid, and 7.77 g of anhydrous sodium acetate were added thereto. 0.0947 mol), 10 mg of palladium chloride,
30 mg of triphenylphosphine was charged. This mixture
After stirring at 115 ° C. for 5 hours, the mixture is poured into 200 ml of water. Although a large amount of crystals precipitate, if the pH of the aqueous solution is adjusted to 9.0 with sodium hydroxide under stirring as it is, the crystals dissolve and become a homogeneous solution. 2 g of activated carbon was added to this solution, and the mixture was stirred at room temperature for 15 minutes. After separating the insoluble matter, the pH was adjusted to 1.5 with concentrated hydrochloric acid, whereby white crystals were precipitated. After that, the crystals were dried under vacuum to give 2-acetylamino-5-chlorocinnamic acid (13.9).
g was obtained. The yield was 85.2% of theory. (Melting point: 243 to 245 ° C.) The ¹ H-NMR and IR of this product were as follows. ^{1 H-NMR (ppm);} 2.07 (s, -COC H 3), 9.83 (bs, -N H
-), 6.51 (d, -CH = C H COO-16Hz), 7.68 (d, -C H
= CHCOO-16Hz) IR (KBr method); 3250 cm ^-1 (νNH), 1665 cm ^-1 (νC = O amide), 1625 cm ^-1 (νC = C), 1700 cm ^-1 (νC = O carboxylic acid) In Example 1, triphenylphosphine was replaced with tri-o
14.5 g of methyl 2-acetylamino-5-chlorocinnamate was obtained by carrying out the same reaction as in Example 1 except that 30 mg of -tolylphosphine was used. The yield was 84.2% of theory.

Example 4. 12.8 g of methyl 2-acetylamino-5-chlorocinnamate was prepared in the same manner as in Example 1 except that 4.5 g of sodium carbonate was used instead of anhydrous sodium acetate. Obtained. The yield was 75.0% of theory.

Example 5 2-acetylamino-5 was prepared in the same manner as in Example 1, except that methyl acrylate was changed to 7.45 g (0.0745 mol) of ethyl acrylate.
16.3 g of ethyl chlorocinnamate were obtained. The yield is the theoretical value of 90.
It was 0%. 157-159 ° C. ¹ H-NMR, IR of this
Was as follows. ^{1 H-NMR (ppm);} 2.09 (s, -COC H 3), 1.26 (t, -CH 2 C
_{H 3, 7Hz), 4.18 (} q, -C H 2 CH 3, 8Hz), 9.87 (bs, -N H
-), 6.62 (d, -CH = C H COO-, 16Hz), 7.78 (d, -C H
= CHCOO-, 16 Hz) IR (KBr method); 3260 cm ^-1 (νNH), 1660 cm ^-1 (νC = O amide), 1640 cm ^-1 (νC = C), 1720 cm ^-1 (νC = O ester) . In 100 ml of ethylene glycol monoethyl ether,
10 g of 2-acetylamino-5-chloroiodobenzene,
3.96 g of anhydrous potassium acetate, 2.84 g of methyl acrylate, 5.8 mg of palladium acetate and 17.4 mg of triphenylphosphine were charged and reacted at 130 ° C. for 8 hours in a nitrogen stream. After cooling to 50 ° C., the solution was poured into 300 ml of water to precipitate a large amount of white crystals. This was separated, washed with water and dried in vacuo to give methyl 2-acetylamino-5-chlorocinnamate 6.
2 g were obtained. The yield was 72.5%.

Example 7. A 200-ml reaction flask was charged with 40 ml of DMF, and 20 g of 2-acetylamino-5-fluoroiodobenzene (0.0717) was added thereto.
Mol), 5.85 g (0.0812 mol) of acrylic acid, 7.77 g (0.0947 mol) of anhydrous sodium acetate, 10 m of palladium chloride
g and 30 mg of triphenylphosphine were charged. The mixture is stirred at 125-130 ° C. for 3 hours and then poured into 200 ml of water. Although a large amount of crystals precipitate, if the pH of the aqueous solution is adjusted to 9.0 with sodium hydroxide under stirring as it is, the crystals dissolve and become a uniform solution. 2 g of activated carbon was added to this solution, and the mixture was stirred at room temperature for 15 minutes.
When the pH was adjusted to 4.0, white crystals precipitated. After this, the crystals were dried in vacuo to give 2-acetylamino-5-
12.6 g of fluorocinnamic acid were obtained. The yield is 78.
5%. (Melting point 232-3 ° C) ¹ H-NMR, IR
Was as follows. ^{1 H-NMR (ppm);} 2.05 (s, -COC H 3), 9.77 (bs, -N H
-), 6.36 (d, -CH = C H COO-, 16Hz), 6.62 (d, -C H
= CHCOO-, 16 Hz) IR (KBr method); 3280 cm ^-1 (νNH), 1700 cm ^-1 (νC = O carboxylic acid), 1660 cm ^-1 (νC = O amide), 1630 cm ^-1 (ν
C = C) Example 8 Example 1 was repeated except that 2-acetylamino-5-chloroiodobenzene was changed to 16.8 g (0.0677 mol) of 2-acetylamino-5-chlorobromobenzene.
By performing the same reaction as described above, 2-acetylamino-
14.7 g of methyl 5-chlorocinnamate were obtained. The yield was 85.4% of theory.

Effects of the Invention 2-Acylamino-5-halogen-substituted cinnamic acids useful as intermediates for the production of medicines and agricultural chemicals have been found. Also, its advantageous production method has been established.

Claims (1)

(57) [Claims] 1. A compound of the general formula (I) (In the formula (I), Ac represents lower acyl, X ₁ represents fluorine or chlorine, and X ₂ represents bromine or iodine.) General formula (II) CH ₂ CHCHCOOR (II) (In the formula (II) , R represents hydrogen or lower alkyl) wherein a compound represented by the formula (III) is reacted with an acrylic acid or an ester thereof in the presence of a palladium catalyst, triphenylphosphine and an acid binder. (In the formula (III), Ac, R and X ₁ have the same meanings as described above.) A method for producing a 2-acylaminocinnamic acid derivative represented by the formula: