JPH0526778B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a novel method for producing 2-hydroxyalkyl-1,4-dihydropyridine-3,5-dicarboxylic acid diester derivatives. More specifically, the present invention relates to the general formula () [In the formula, R is a lower alkyl group, R ¹ and R ² are the same or different, and are a hydrogen atom, a chlorine atom, a nitro group, or a cyano group (provided that when one of R ¹ or R ² is a hydrogen atom, the other is a chlorine atom, a nitro group or a cyano group, and when one is a nitro group or a cyano group, the other is a hydrogen atom), R ³ and R ⁴ are the same or different, and are lower alkyl, lower haloalkyl group, lower alkenyl group, lower alkynyl group, aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group, or

[Formula] (B is a linear or branched alkylene group, R ⁵ and R ⁶ are the same or different and mean a lower alkyl group or an aralkyl group), A is a linear or branched alkylene group The present invention relates to a method for producing a 2-hydroxyalkyl-1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative represented by the following formula. Prior Art When synthesizing an asymmetric 1,4-dihydropyridine derivative in which the substituents at the 2- and 6-positions of the 1,4-dihydropyridine ring have an asymmetric structure, 4-substituted acetoacetate, 4-substituted - 2
-ylideneacetoacetate or 4-substituted-
A method using 3-aminocrotonic acid ester, etc. has been described so far (Japanese Patent Application Laid-open No. 1989-1999).
5777, Japanese Patent Publication No. 53-79873). Problems to be Solved by the Invention However, according to these known methods,
When synthesizing a compound having a hydroxyalkyl group at the 2-position of a 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative, is it essential to go through the dihydropyridine derivative having a protected hydroxyalkyl group? , or a production method in which the formyl group of a separately synthesized 2-formyl-1,4-dihydropyridine derivative is reduced to form a hydroxymethyl group. That is, in the conventional manufacturing method, 2
The production of -hydroxyalkyl-1,4-dihydropyridine requires a multistep reaction, and the production yield is not sufficient. Therefore, there is a need for a method for industrially synthesizing the desired 2-hydroxyalkyl-1,4-dihydropyridine derivatives in a high yield from raw materials in a single step reaction. Means for Solving the Problems As a result of intensive research, the present inventors used a novel enamine compound represented by the general formula () and an acetylene compound represented by the general formula () as raw materials, and the hydroxyl group of the compound was 2-hydroxyalkyl-1,4 without protection
It was discovered that -dihydropyridine-3,5-dicarboxylic acid diester derivative () can be synthesized with good yield, and the present invention was completed. Below, various terms described in this specification will be explained. The lower alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, etc. and hexyl. The lower haloalkyl group refers to a haloalkyl group in which the above lower alkyl group is substituted with a halogen atom, such as β-chloroethyl, β-bromoethyl, β-chloropropyl, γ-chloropropyl,
Examples include ω-chlorobutyl and trifluoromethyl. The lower alkenyl group refers to an alkenyl group having 2 to 4 carbon atoms, such as vinyl, allyl, 3-butenyl, and isopropenyl. The lower alkynyl group refers to an alkynyl group having 2 to 4 carbon atoms, and includes, for example, propalkyl and 2-butynyl. Examples of the aralkyl group include benzyl, α-
Examples include methylbenzyl and phenethyl. Examples of the aryl group include phenyl and naphthyl. The lower alkoxyalkyl group refers to an alkoxyalkyl group in which the above-mentioned alkyl group is substituted with a linear or branched alkoxy group having 1 to 6 carbon atoms, such as β-methoxyethyl, β-
Ethoxyethyl, β-propoxyethyl, β-isopropoxyethyl, β-butoxyethyl, β-
Isobutoxyethyl, β-tertiary butoxyethyl, β-methoxypropyl, β-ethoxypropyl, β-propoxypropyl, β-isopropoxypropyl, β-butoxypropyl, γ-methoxypropyl, γ-ethoxypropyl, γ- Propoxypropyl, γ-butoxypropyl and ω-
Examples include propoxybutyl. The lower alkenyloxyalkyl group refers to an alkenyloxyalkyl group consisting of the above-mentioned alkyl group and the above-mentioned alkenyl group, such as β-vinyloxyethyl, β-allyloxyethyl, β-
Examples include (3-butenyloxy)ethyl, β-isopropenyloxyethyl, and β-allyloxypropyl. The aralkyloxyalkyl group refers to an aralkyloxyalkyl group consisting of the above-mentioned alkyl group and aralkyl group, such as benzyloxyethyl, β-phenethyloxyethyl, and β-phenethyloxyethyl group.
Examples include (α-methylbenzyloxy)ethyl. The aryloxyalkyl group refers to an aryloxyalkyl group consisting of the above-mentioned alkyl group and aryl group, such as β-phenoxyethyl,
Examples include β-phenoxypropyl and ω-phenoxybutyl. Also

Examples of the group represented by the formula include β-dimethylaminoethyl, β-diethylaminoethyl, β-methylethylaminoethyl, β-dimethylaminopropyl, γ-dimethylaminopropyl, ω-dimethylaminobutyl, β-N- Examples include methylbenzylaminoethyl, β-N-methylbenzylaminopropyl, β-N-methylbenzylaminobutyl, γ-N-methylbenzylaminopropyl, and ω-N-methylbenzylaminobutyl. The alkylene group of A refers to a linear or branched alkylene group consisting of 1 to 6 carbon atoms,
For example, methylene, methylmethylene, ethylmethylene, phenylmethylene, dimethylmethylene, methylethylmethylene, methylisobutylmethylene,
Examples include phenylmethylmethylene, ethylene, methylethylene, ethylethylene, trimethylene and tetramethylene. The aromatic ring contained in the aralkyl group, aryl group, aralkyloxyalkyl group, and aryloxyalkyl group of R ³ and R ⁴ may be substituted with 1 to 3 substituents, and the substituents include a halogen atom; a cyano group ; nitro groups; hydroxyl groups; disubstituted amino groups such as dimethylamino, diethylamino and diisopropylamino; lower alkoxy groups such as methoxy, ethoxy, propoxy and butoxy; lower alkyl groups such as methyl, ethyl, propyl and butyl; and trifluoromethyl Examples include groups. Halogen atoms include fluorine, chlorine, bromine, and iodine. Hereinafter, the manufacturing method of the present invention will be explained in detail. The present invention provides: (a) General formula () [In the formula, R ⁴ is a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkynyl group, an aralkyl group, an aryl group, a lower alkoxyalkyl group, a lower alkenyloxyalkyl group, an aralkyloxyalkyl group, an aryloxyalkyl group, or

[Formula] (B is a linear or branched alkylene group, R ⁵ and
R ⁶ are the same or different and mean a lower alkyl group or an aralkyl group]
Compounds and general formulas shown by () [In the formula, R is a lower alkyl group, R ¹ and R ²
are the same or different, and are a hydrogen atom, a chlorine atom, a nitro group, or a cyano group (however, when one of R ¹ or R ² is a hydrogen atom, the other is a chlorine atom, a nitro group, or a cyano group, and one is a nitro group) or cyano group, the other means a hydrogen atom), R ³ is a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkynyl group, an aralkyl group, an aryl group, a lower alkoxyalkyl group, a lower alkenyloxyalkyl group. group, aralkyloxyalkyl group, aryloxyalkyl group or

[Formula] (B is a linear or branched alkylene group, R ⁵ and
R ⁶ are the same or different and mean a lower alkyl group or an aralkyl group]
(b) General formula () [In the formula, R ⁴ and A have the above meanings]
Compounds and general formulas shown by () [In the formula, R ¹ and R ² have the above meanings]
A compound represented by the general formula () RCOCH ₂ COOR ³ () [wherein R and R ³ have the above meanings]
(c) General formula () HO-A-C≡CCOOR ⁴ () [In the formula, R ⁴ and A have the above-mentioned meanings]
Compounds and general formulas shown by () [In the formula, R, R ¹ , R ² and R ³ have the above-mentioned meanings] is reacted with ammonia or a salt thereof, or (d) general formula () HO-A-C≡ CCOOR ⁴ () [wherein R ⁴ and A have the above meanings]
Compounds and general formulas shown by () [In the formula, R ¹ and R ² have the above meanings]
A compound represented by the general formula () RCOCH ₂ COOR ³ () [wherein R and R ³ have the above meanings]
The compound represented by the general formula () is produced by reacting the compound represented by the formula with ammonia or a salt thereof. Methods (a) and (b) relate to a method for producing compound () by reacting an enamine compound () with a benzylidene compound () or an aldehyde compound () and a β-ketoester compound (). The reaction conditions for producing compound () in methods (a) and (b) are appropriately selected depending on the type of raw material used, but generally, the benzylidene compound () is used per mole of the enamine compound ().
Alternatively, the aldehyde compound () and the β-ketoester compound () are preferably used in approximately equimolar amounts each. The molar ratio can be varied over a wide range without adversely affecting the results. The reaction temperature is usually carried out under cooling, room temperature, or heating. As the reaction solvent, water, an inert organic solvent, or a mixed solvent of water and an inert organic solvent can be used. Inert organic solvents include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, diethyl ether, dioxane, tetrahydrofuran,
Acetonitrile, acetone, dimethylformamide, ethyl acetate, benzene or chloroform are used. The reaction can be promoted using a catalyst such as an acid such as acetic acid, a base such as piperidine, or a salt of an acid and a base. Methods (c) and (d) involve the reaction of an acetylene compound () and a benzylidene compound () with ammonia or its salt, or an aldehyde compound () and a β-ketoester compound () and ammonia or its salt. Regarding manufacturing methods. The reaction conditions for producing compound () in methods (c) and (d) are appropriately selected depending on the type of raw materials used, but generally the acetylene compound (), benzylidene compound (),
The aldehyde compound () and the β-ketoester compound () are each used in approximately equimolar amounts, and ammonia or its salt is used in an excess amount. The molar ratio can be varied over a wide range without adversely affecting the results. As ammonia or a salt thereof, ammonia or an ammonium salt of an organic acid such as acetic acid, formic acid, tartaric acid, benzoic acid or phenylacetic acid, or an ammonium salt of an inorganic acid such as carbonic acid, bicarbonate or boric acid, etc. are used. The reaction temperature is usually carried out under cooling, room temperature, or heating. As the reaction solvent, water, an inert organic solvent, or a mixed solvent of water and an inert organic solvent can be used. As the inert organic solvent, alcohols such as methanol, ethanol, propanol, isopropanol or butanol, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, acetone, dimethylformamide, ethyl acetate, benzene or chloroform are used. The reaction can be promoted using a catalyst such as an acid, a base, or a salt of an acid and a base. The compound () synthesized by the method of the present invention can be purified and collected by conventional operations such as extraction using an organic solvent, separation and purification by chromatography using a carrier such as silica gel or alumina, or crystallization. can. Further, when the compound of general formula () has a salt-forming ability, it can be an addition salt of an inorganic acid such as hydrochloric acid or an organic acid such as citric acid. The enamine compound represented by the general formula () used in the present invention is a new substance that has not been described in any literature, and is produced by the method shown below. Raw materials () used in methods (a) and (b) are (A)
As shown in reaction formula (B), the protected oxyalkyl β-ketoester () or the protected oxyalkylpropiolic acid ester () is reacted with ammonia or its salt, and then, if desired, deprotection is performed. can be manufactured. The present raw material compound () is described in detail in Japanese Patent Application Laid-Open No. 59-231049, written by the present inventors. The compound represented by the general formula () provided by the present invention has a vasodilatory effect and a blood pressure lowering effect, and has a particularly strong coronary vasodilatory effect and extremely low toxicity, so it can be used to treat hypertension, cardiac dysfunction, angina pectoris, etc. This drug is expected to be useful in the treatment of cardiovascular diseases such as myocardial infarction and cerebrovascular disorders. Pharmacology Pharmacology tests and toxicity tests were conducted on the compound () of the present invention. 1 Test Method a Coronary Vasodilatory Effect The coronary artery dilator effect was examined by the Langendorff method* using isolated rabbit hearts. The strength of the coronary vasodilatory effect was evaluated by the sample dose that increased the coronary blood flow by 50%, ie, ICD ₅₀ (g/ml). *；O. Langendorff: PflU¨gers arch.ges.
phisiol., 61 , 291-332 (1895) b. Antihypertensive effect Male hypertensive rats, 15-16 weeks old and weighing around 300 g.
SHR) was used. Blood pressure was measured by prewarming the SHR at 45 to 50°C for 10 to 20 minutes, and then non-invasively measuring the systolic blood pressure in the tail artery by the tail plethysmograph method using an automatic blood pressure recorder. Five animals were used in each group. The drug was dissolved in polyethylene glycol C-300 and administered orally in an amount equivalent to 10 to 100 mg/Kg. The antihypertensive effect was expressed as the decrease in blood pressure at each hour after oral administration of each drug as a percentage of blood pressure reduction relative to the blood pressure before drug administration. The calculation is as follows. % reduction in blood pressure = (blood pressure before administration) - (blood pressure at each hour after administration)
/ (pre-administration blood pressure) × 100 c Acute toxicity test Using CM male mice (18-22 g), intravenous administration was performed according to the up-and-down method.
The _LD50 value was determined. 2. Test results The coronary vasodilator effect on rabbits and the acute toxicity on mice according to the Langendorff method were as shown in Table 1 below.

[Table] As is clear from Table 1, the compounds of the present invention act on coronary blood vessels and exhibit a strong coronary artery dilating effect. Also, acute toxicity is clearly reduced compared to nifedipine. Next, the antihypertensive effect on hypertensive rats (SHR) was as shown in Table 2.

[Table] As is clear from Table 2, the compound of the present invention exhibits a strong antihypertensive effect when administered orally to hypertensive rats (SHR). Furthermore, the compound of the present invention exhibited antihypertensive action even 6 hours after administration, suggesting that the action was sustained. From the results of the pharmacological and toxicity tests shown above, the compound () of the present invention has strong vasodilatory and antihypertensive effects and weak toxicity, so it can be used to treat hypertension, cardiac dysfunction, angina pectoris, myocardial infarction. It has become clear that it is expected to be a therapeutic agent for cardiovascular diseases such as cerebrovascular disorders. The administration form of the compound of the present invention () generally includes parenteral administration such as intravenous, subcutaneous or intramuscular injection or rectal administration, or oral administration such as tablets, powders, granules, capsules, sublingual tablets or syrups. can be mentioned. The dosage varies depending on the patient's symptoms, age, weight, and mode of administration, but is usually 1 to 500 mg per day for adults. Each of the above formulations can be manufactured by a well-known method. Next, the manufacturing method of the present invention will be explained in detail with reference to Examples, but the present invention is not particularly limited thereto. Example 1 Methyl 3-amino-4-hydroxycrotonate
1.31 g (10 mmol) and 2.73 g (10 mmol) of methyl 2-(2,3-dichlorobenzylidene)acetoacetate
mmol) in 50 ml of ethanol and heated to 70-80℃.
Stir for 24 hours to react. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from benzene to give needle-like crystals of 4-(2,3-dichlorophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarvone. 3.6 g (yield 93.2%) of acid dimethyl ester are obtained. mp: 167-168℃ UV: λ ^MeOH _nax. 236, 362nm IR (KBr, cm ^-1 ): 3370, 1670, 1475, 1440,
1220, 1120, 1020, 800, 785 ¹ H−NMR (90MHz, DMSO−d ₆ ), δ in
ppm: 2.34 (s, 3H), 3.53 (s, 6H), 4.58 (d,
2H, J=3Hz), 5.41 (s, 1H), 5.57 (t,
1H, J=3Hz), 7.18-7.55 (m, 3H),
8.53 (s, 1H) Examples 2 to 25 According to the method described in Example 1, the compounds listed in Table 3 are obtained.

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[Table] Example 26 Methyl 3-amino-4-hydroxycrotonate
1.31 g (10 mmol), 1.75 g (10 mmol) of 2,3-dichlorobenzaldehyde and 1.16 g (10 mmol) of methyl acetoacetate in 50 ml of ethanol.
and react by stirring at 70-80°C for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from benzene to give needle-like crystals of 4-(2,3-dichlorophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarvone. 2.6 g (yield 67.5%) of acid dimethyl ester are obtained. mp; 167-168°C The UV, IR and NMR instrumental analysis data of this product showed good agreement with that of the product of Example 1. Example 27 Methyl 4-hydroxytetrolate 1.14 g (10
2.73 g (10 mmol) of methyl 2-(2,3-dichlorobenzylidene)acetoacetate and 1.93 g (25 mmol) of ammonium acetate are dissolved in 50 ml of ethanol and reacted by stirring at 60-70°C for 16 hours. . The reaction mixture was concentrated under reduced pressure, and the oily residue was extracted with ethyl acetate (100 ml). The ethyl acetate extract is dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was collected using a preparative liquid chromatograph (Waters, System 500A).
Separation and purification is carried out by developing ethyl acetate-hexane (3:2) on a Prep PAK-500/SILICA column. The effective fractions were collected and concentrated under reduced pressure, and the residue was crystallized from benzene to form needle-like crystals of 4-(2,3-dichlorophenyl)-2-hydroxymethyl-6-
Methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester 2.1g (yield 54.4%)
get. mp: 167-168°C The UV, IR and NMR instrumental analysis data of this product showed good agreement with that of the product of Example 1. Example 28 Methyl 4-hydroxytetrolate 1.14 g (10
mmol), 2,3-dichlorobenzaldehyde
1.75g (10mmol), methyl acetoacetate 2.73g
(10 mmol) and ammonium acetate 1.93 g
(25 mmol) dissolved in 50 ml of ethanol, 60 ~
The reaction is stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The ethyl acetate extract is dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is separated and purified on a Prep PAK-500/SILICA column using a preparative liquid chromatograph (Waters Corporation, System 500A) by developing ethyl acetate-hexane (3:2). The effective fractions were collected and concentrated under reduced pressure, and the residue was crystallized from benzene to form needle-shaped crystals.
-(2,3-dichlorophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester 1.8g
(yield 46.6%). mp: 167-168°C The UV, IR and NMR instrumental analysis data of this product showed good agreement with that of the product of Example 1. Reference example Methyl 3-amino-4-hydroxycrotonate Methyl 4-acetoxyacetoacetate 17.4g (0.1
mol) in 100 ml of dimethylformamide,
Add 10 g (0.13 mol) of ammonium acetate to this and stir at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was extracted with 50 ml of ethyl acetate, the extract was washed with water and dehydrated, and then concentrated under reduced pressure to obtain 14.7 g of methyl 4-acetoxy-3-aminocrotonate in the form of needle-like crystals. mp73-74℃ Subsequently, 4-acetoxy-3- obtained above
14.7 g (0.085 mol) of methyl aminocrotonate is dissolved in 100 ml of methanol, 0.25 ml of 4.54N sodium methoxide-methanol solution is added thereto, and the mixture is stirred at room temperature for 1 hour. The reaction solution was neutralized with glacial acetic acid and then concentrated under reduced pressure. The residue is extracted with 100 ml of ethyl acetate, and the extract is washed with water, dehydrated, and then concentrated under reduced pressure to obtain 10 g of methyl 3-amino-4-hydroxycrotonate (yield: 76.3%) in the form of needle-like crystals. mp: 93~94℃ UV: λ ^MeOH _nax. 273nm (ε19500) IR (KBr, cm ^-1 ): 3500, 3430, 3340, 1660,
1640, 1550, 1280, 1160, 1010, ^7901H -NMR (90MHz, DMSO- _d6 ), δin ppm:
3.53 (s, 3H), 4.01 (s, 2H), 4.52 (s,
1H), 5.33 (broad s, 1H), 6.3-7.9
(broad 2H) Effects of the invention 2-hydroxyalkyl- represented by the general formula (), which is expected to be useful for the treatment of cardiovascular diseases such as hypertension, cardiac dysfunction, angina pectoris, and myocardial infarction. It has become possible to industrially and efficiently produce 1,4-dihydropyridine derivatives.

Claims (1)

[Claims] 1 General formula () [In the formula, R is a lower alkyl group, R ¹ and R ² are the same or different, and are a hydrogen atom, a chlorine atom, a nitro group, or a cyano group (provided that when one of R ¹ or R ² is a hydrogen atom, the other is a chlorine atom, a nitro group or a cyano group, and when one is a nitro group or a cyano group, the other is a hydrogen atom), R ³ and R ⁴ are the same or different, and are lower alkyl, lower haloalkyl group, lower alkenyl group, lower alkynyl group, aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched 2-hydroxyalkyl represented by an alkylene group, R ⁵ and R ⁶ are the same or different and mean a lower alkyl group or an aralkyl group), A means a linear or branched alkylene group] In producing the 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative, (a) General formula () [In the formula, R ⁴ and A have the above meanings]
Compounds and general formulas shown by () [In the formula, R, R ¹ , R ² and R ³ have the above-mentioned meanings] or (b) General formula () [In the formula, R ⁴ and A have the above meanings]
Compounds and general formulas shown by () [In the formula, R ¹ and R ² have the above meanings]
A compound represented by the general formula () RCOCH ₂ COOR ³ () [wherein R and R ³ have the above meanings]
(c) General formula () HO-A-C≡CCOOR ⁴ () [In the formula, R ⁴ and A have the above-mentioned meanings]
Compounds and general formulas shown by () [In the formula, R, R ¹ , R ² and R ³ have the above-mentioned meanings] is reacted with ammonia or a salt thereof, or (d) general formula () HO-A-C≡ CCOOR ⁴ () [wherein R ⁴ and A have the above meanings]
Compounds and general formulas shown by () [In the formula, R ¹ and R ² have the above meanings]
A compound represented by the general formula () RCOCH ₂ COOR ³ () [wherein R and R ³ have the above meanings]
A method for producing a 2-hydroxyalkyl-1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative represented by the general formula (), which comprises reacting the compound represented by the formula with ammonia or a salt thereof. 2 General formula () [In the formula, R ⁴ is a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkynyl group,
Aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched alkylene group, R ⁵ and R ⁶ are the same or different, meaning a lower alkyl group or an aralkyl group), A means a linear or branched alkylene group] and the compound represented by the general formula () [In the formula, R is a lower alkyl group, R ¹ and R ² are the same or different, and are a hydrogen atom, a chlorine atom, a nitro group, or a cyano group (provided that when one of R ¹ or R ² is a hydrogen atom, the other is a chlorine atom, a nitro group or a cyano group, and when one is a nitro group or a cyano group, the other is a hydrogen atom), ^R3 is a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkynyl group, Aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched alkylene group, R ⁵ and R ⁶ are the same or different;
lower alkyl group or aralkyl group)
The manufacturing method according to claim 1, characterized in that the method comprises reacting with a compound represented by: 3 General formula () [In the formula, R ⁴ is a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkynyl group,
Aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched alkylene group, R ⁵ and R ⁶ are the same or different, meaning a lower alkyl group or an aralkyl group), A means a linear or branched alkylene group] and the compound represented by the general formula () [In the formula, R ¹ and R ² are the same or different,
Hydrogen atom, chlorine atom, nitro group or cyano group (however, when one of R ¹ or R ² is a hydrogen atom, the other is a chlorine atom, nitro group or cyano group, and when one is a nitro group or cyano group, the other means a hydrogen atom] and the compound represented by the general formula () RCOCH ₂ COOR ³ () [wherein R is a lower alkyl group, R ³ is a lower alkyl group, a lower haloalkyl group, a lower alkenyl group] , lower alkynyl group, aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched alkylene group, R ⁵ and R ⁶ are the same or different,
lower alkyl group or aralkyl group)
The manufacturing method according to claim 1, characterized in that the method comprises reacting with a compound represented by: 4 General formula () HO-A-C≡CCOOR ⁴ () [In the formula, R ⁴ is a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkynyl group,
Aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched alkylene group, R ⁵ and R ⁶ are the same or different, meaning a lower alkyl group or an aralkyl group), A means a linear or branched alkylene group] and the compound represented by the general formula () [In the formula, R is a lower alkyl group, R ¹ and R ² are the same or different, and are a hydrogen atom, a chlorine atom, a nitro group, or a cyano group (provided that when one of R ¹ or R ² is a hydrogen atom, The other is a chlorine atom, a nitro group or a cyano group, and when one is a nitro or cyano group, the other is a hydrogen atom), ^R3 is a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkynyl group, Aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched alkylene group, R ⁵ and R ⁶ are the same or different;
lower alkyl group or aralkyl group)
The method according to claim 1, characterized in that the compound represented by the following formula is reacted with ammonia or a salt thereof. 5 General formula () HO-A-C≡CCOOR ⁴ () [In the formula, R ⁴ is a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkynyl group,
Aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched alkylene group, R ⁵ and R ⁶ are the same or different, meaning a lower alkyl group or an aralkyl group), A means a linear or branched alkylene group] and the compound represented by the general formula () [In the formula, R ¹ and R ² are the same or different,
Hydrogen atom, chlorine atom, nitro group or cyano group (however, when one of R ¹ or R ² is a hydrogen atom, the other is a chlorine atom, nitro group or cyano group, and when one is a nitro group or cyano group, the other means a hydrogen atom] and the compound represented by the general formula () RCOCH ₂ COOR ³ () [wherein R is a lower alkyl group, R ³ is a lower alkyl group, a lower haloalkyl group, a lower alkenyl group] , lower alkynyl group, aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched alkylene group, R ⁵ and R ⁶ are the same or different,
lower alkyl group or aralkyl group)
The method according to claim 1, characterized in that the compound represented by the following formula is reacted with ammonia or a salt thereof.