JP2951765B2 - Enaminoesters and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 4- (4-cyanoanilino) -6,7-dihydro-5H-cyclopenta [d] pyrimidines useful as antidepressants and cerebral disorders improving agents (JP-A-62-70). And Japanese Patent Application Laid-Open No. 63-183532) and a process for producing the same.

[0002]

2. Description of the Related Art 4- (4-cyanoanilino) -6,7-
As a method for producing 6,7-dihydro-3H, 5H-cyclopenta [d] pyrimidin-4-one, which is an important synthetic intermediate for producing dihydro-5H-cyclopenta [d] pyrimidines, there has been a conventional method. Reaction of 2-oxocyclopentanecarboxylic acid esters with thiourea followed by desulfurization with Raney nickel (Japanese Patent Laid-Open No. 62-7 / 1987)
0, JP-A-63-183532). However, this method has the disadvantage of using Raney nickel which is industrially expensive and difficult to handle.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have proposed 6,7-
As a result of intensive studies on the synthesis method of dihydro-3H, 5H-cyclopenta [d] pyrimidin-4-ones, a novel compound, 3-alkoxy-2-amino-1-cyclopentenecarboxylic acid ester, is a useful intermediate. The present inventors have found that, and further established an industrial production method thereof, thereby completing the present invention.

[0004]

The compound of the present invention has the general formula

[0005]

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3-alkoxy-2-amino-
1-cyclopentenecarboxylic acid esters and general formula

[0007]

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Wherein a 3-alkoxy-2-oxocyclopentanecarboxylic acid ester represented by the general formula (1) is reacted with ammonia in the presence of a catalyst.

[0009]

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3-alkoxy-2-amino-
It is intended to provide a method for producing 1-cyclopentenecarboxylic acid esters.

In the above general formulas (I) and (II), R ¹
And R ² each independently represent an alkyl group having 1 to 4 carbon atoms.

In the above general formulas (I) and (II), R ¹
And an alkyl group having 1 to 4 carbon atoms represented by R ² is a linear or branched alkyl group, for example, methyl,
Examples include an ethyl, propyl, isopropyl, butyl and isobutyl group, preferably a methyl and ethyl group.

Representative compounds of the present invention include, for example, methyl 2-amino-3-methoxy-1-cyclopentenecarboxylate, 2-amino-3-ethoxy-
1-cyclopentenecarboxylic acid methyl ester, 2-amino-3-propoxy-1-cyclopentenecarboxylic acid methyl ester, 2-amino-3-butoxy-1-cyclopentenecarboxylic acid methyl ester, 2-amino-3
-Isopropoxy-1-cyclopentenecarboxylic acid methyl ester, 2-amino-3-isobutoxy-1-cyclopentenecarboxylic acid methyl ester, 2-amino-3
-Methoxy-1-cyclopentenecarboxylic acid ethyl ester, 2-amino-3-ethoxy-1-cyclopentenecarboxylic acid ethyl ester, 2-amino-3-propoxy-1-cyclopentenecarboxylic acid ethyl ester, 2
-Amino-3-butoxy-1-cyclopentenecarboxylic acid ethyl ester, 2-amino-3-isopropoxy-
1-cyclopentenecarboxylic acid ethyl ester, 2-amino-3-isobutoxy-1-cyclopentenecarboxylic acid ethyl ester, 2-amino-3-methoxy-1-cyclopentenecarboxylic acid propyl ester, 2-amino-3-ethoxy-1- Cyclopentenecarboxylic acid propyl ester, 2-amino-3-propoxy-1-cyclopentenecarboxylic acid propyl ester, 2-amino-3
-Butoxy-1-cyclopentenecarboxylic acid propyl ester, 2-amino-3-isopropoxy-1-cyclopentenecarboxylic acid propyl ester, 2-amino-3
-Isobutoxy-1-cyclopentenecarboxylic acid propyl ester, 2-amino-3-methoxy-1-cyclopentenecarboxylic acid butyl ester, 2-amino-3-ethoxy-1-cyclopentenecarboxylic acid butyl ester, 4-amino-3-propoxy -1-cyclopentenecarboxylic acid butyl ester, 2-amino-3-butoxy-1-cyclopentenecarboxylic acid butyl ester, 2-
Amino-3-isopropoxy-1-cyclopentenecarboxylic acid butyl ester, 2-amino-3-isobutoxy-1-cyclopentenecarboxylic acid butyl ester, 2-
Amino-3-methoxy-1-cyclopentenecarboxylic acid isopropyl ester, 2-amino-3-ethoxy-1
-Cyclopentenecarboxylic acid isopropyl ester, 2
Isopropyl 2-amino-3-propoxy-1-cyclopentenecarboxylate, isopropyl 2-amino-3-butoxy-1-cyclopentenecarboxylate, isopropyl 2-amino-3-isopropoxy-1-cyclopentenecarboxylate, 2- Amino-3
-Isobutoxy-1-cyclopentenecarboxylic acid isopropyl ester, 2-amino-3-methoxy-1-cyclopentenecarboxylic acid isobutyl ester, 2-amino-3-ethoxy-1-cyclopentenecarboxylic acid isobutyl ester, 2-amino-3-propoxy -1-cyclopentenecarboxylic acid isobutyl ester, 2-amino-3-butoxy-1-cyclopentenecarboxylic acid isobutyl ester, 2-amino-3-isopropoxy-1-
Cyclopentenecarboxylic acid isobutyl ester and 2
-Amino-3-isobutoxy-1-cyclopentenecarboxylic acid isobutyl ester and the like.
-Amino-3-methoxy-1-cyclopentenecarboxylic acid methyl ester, 2-amino-3-ethoxy-1-cyclopentenecarboxylic acid methyl ester, 2-amino-
3-methoxy-1-cyclopentenecarboxylic acid ethyl ester and 2-amino-3-ethoxy-1-cyclopentenecarboxylic acid ethyl ester.

The novel compound of the present invention, 3-alkoxy-2-amino-1-cyclopentenecarboxylic acid ester, can be produced according to the following production method.

That is, in an inert solvent, the general formula

[0016]

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A 3-alkoxy-2-oxocyclopentanecarboxylic acid ester represented by the following formula is reacted with ammonia in the presence of a catalyst;

[0018]

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3-alkoxy-2-amino-
This is a method for producing 1-cyclopentenecarboxylic acid esters.

The starting material used in the production method of the present invention, that is, the 3-alkoxy-2-oxocyclopentanecarboxylic acid ester represented by the general formula (II), is subjected to a Dijkmann condensation of the corresponding adipic acid ester (Japanese Patent Application Laid-Open (JP-A) no. Showa 6
3-183532) or can be easily prepared from 2-alkoxycyclopentanone and carbonate [G.
Traverso, D .; Pirillo and E.C.
Damonti, Farmaco Ed. Sci. , 3
3,559 (1978)].

The solvent used in the production method of the present invention is not particularly limited as long as it does not participate in the reaction. For example, methanol, ethanol, propanol,
Lower alcohols such as isopropanol and butanol,
Halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform; hydrocarbons such as benzene and toluene; and ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. But are preferably lower alcohols.

The solvent used may be a single solvent or a mixture of any two or more of the above-mentioned solvents. The amount of the solvent used is based on the 3-alkoxy-2-oxocyclopentacarboxylic acid ester used. It is implemented with a volume of 1 to 30 times.

The amount of ammonia used in the production method of the present invention must be at least one mole of 3-alkoxy-2-oxocyclopentanecarboxylic acid ester.
The more the amount is used, the quicker the reaction becomes. However, in consideration of economy, it is preferably 1 to 10 moles.

Examples of the catalyst used in the production method of the present invention include heteropolyacids such as phosphomolybdic acid and phosphotungstic acid, isopolyacid salts such as ammonium molybdate and ammonium tungstate, sodium molybdate and sodium tungstate. And the like.

The amount of the catalyst used is preferably 0.01 to 5% by weight based on the 3-alkoxy-2-oxocyclopentanecarboxylic acid ester used.

The reaction temperature in the production method of the present invention is from 0 ° C to 110 ° C, preferably from 20 ° C to 70 ° C.

The reaction time of the production method of the present invention depends on the amount of ammonia, the amount of catalyst, the temperature and the like, but is usually 0.5 to 1
It is 2 hours, preferably 0.5 to 5 hours.

In the production method of the present invention, the order of addition of the reactants is not particularly limited, but it is preferable to add 3-alkoxy-2-oxocyclopentanecarboxylic acid esters to an ammonia solution of a solvent.

As a method for isolating the 3-alkoxy-2-amino-1-cyclopentenecarboxylic acid ester obtained by the production method of the present invention from the reaction mixture, for example, the solvent obtained is concentrated under reduced pressure and the residue obtained is concentrated. Can be employed by ordinary methods such as distillation, recrystallization and column chromatography.

The compounds represented by the general formulas (I) and (II) have optical isomers, and the formulas (I) and (II) represent one or a mixture of the isomers.

[0031]

EFFECT OF THE INVENTION By utilizing 3-alkoxy-2-amino-1-cyclopentenecarboxylic acid esters, which are novel compounds of the present invention, as intermediates, compounds useful as antidepressants, cardiotonic agents and cerebral disorder improving agents 4- (4
-Cyanoanilino) -6,7-dihydro-5H-cyclopenta [d] pyrimidines can be produced at lower cost and more efficiently than before.

That is, for example, the compound of the present invention, 2-amino-1-cyclopentenecarboxylic acid ester, is reacted with formamide in an alcohol in the presence of a base,
6,7-dihydro-3H, 5H-cyclopenta [d] pyrimidin-4-ones (IV) are produced, and further, antidepressants and cardiotonic agents according to the reaction formula shown in the following process table (JP-A-2-295980). In addition, 4- (4-cyanoanilino) -6,7-dihydro-5H-cyclopenta [d] pyrimidine, which is a compound useful as a brain disorder improving agent, can be produced at lower cost and more efficiently than before.

In the process for producing 3-alkoxy-2-amino-1-cyclopentenecarboxylic acid esters,
The desired product can be produced at low cost, and the operation is simple in a short time, and the yield is low and there are few by-products.

[0034]

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[0035]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 2-amino-3-methoxy-1-cyclopentenecarbo
4 g of ammonia was blown into 50 ml of methanolic acid methanol while cooling with ice, and then 17.2 g of methyl 2-oxo-3-methoxycyclopentanecarboxylate and 0.1 g of ammonium molybdate were dissolved in 50 ml of methanol. The solution is added dropwise in 10 minutes, and the reaction is further performed at 50 ° C. for 1 hour. When the reaction solution was quantified by a gas chromatography internal standard method, 16.3 g of methyl 2-amino-3-methoxy-1-cyclopentenecarboxylate was produced. The reaction mixture was concentrated and distilled under reduced pressure to give 2-amino-3-methoxy-1.
-Cyclopentene carboxylic acid methyl ester at 14.5
g was obtained. The distillate crystallizes. Boiling point 95-96 ° C /
1.2 mmHg Melting point 51.5-52.5 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.65 (1 H, m, CH ₂ ) 2.21 (1 H, m, CH ₂ ) 2.32 ( 1H, m, CH ₂ ) 2.54 (1H, m, CH ₂ ) 3.36 (3H, s, OCH ₃ ) 3.69 (3H, s, COOCH ₃ ) 4.38 (1H, t, J = 7.2 Hz, CH) 5.65 (2H, bs, NH ₂ ) Elemental analysis C: 56.25% (calculated: 56.11%) H: 7.75% (〃7.67%) N: 8. Example 2 2-amino-3-methoxy-1-cyclopentenecarbo 12% ( メ ト キ シ 8.18%)
Ammonium tungstate in phosphate methyl esters of methanol 50 ml 0.0
After adding and absorbing 2.5 g of ammonia while cooling with ice and absorbing 2.5 g of ammonia, a solution in which 17.2 g of methyl 2-oxo-3methoxycyclopentanecarboxylate was dissolved in 50 ml of toluene was added dropwise over 10 minutes, and further added at 50 ° C. And react for 3 hours. The reaction solution was quantified by gas chromatography internal standard method to give 16.6 g of 2-amino-3-methoxy-1-cyclopentenecarboxylic acid methyl ester.

Example 3 2-amino-3-ethoxy-1-cyclopentenecarbo
3 g of ammonia was blown into 70 ml of ethanol ethyl acetate while cooling with ice, and 20.0 g of ethyl 3-ethoxy-2-oxocyclopentanecarboxylate and 0.04 g of phosphomolybdic acid were dissolved in 50 ml of ethanol. The solution is added dropwise in 10 minutes and reacted at 50 ° C. for 2 hours. When the reaction solution was quantified by gas chromatography internal standard method, 2-
18.7 g of amino-3-ethoxy-1-cyclopentenecarboxylic acid ethyl ester was produced. The reaction solution was concentrated and distilled under reduced pressure to obtain 16.0 g of ethyl 2-amino-3-ethoxy-1-cyclopentenecarboxylate. Boiling point 100 to 100.5 ° C./0.6 mmHg ¹ H-NMR (CDCl ₃ ) δ (ppm) 1.22 (3H, m, OCH ₂ CH ₃ ) 1.28 (3H, t, J = 6.8 Hz) , CO ₂ CH ₂ C
_{H 3) 1.64 (1H, m} , CH 2) 2.21 (1H, m, CH 2) 2.32 (1H, m, CH 2) 2.53 (1H, m, CH 2) 3.46 _{(1H, m, OC H 2} CH 3) 3.60 (1H, m, OC H 2 CH 3) 4.18 (2H, q, J = 6.8Hz, CO 2 C H 2 C
_{H 3) 4.43 (1H, t} , J = 7.3Hz, CH) 5.55 (2H, bs, NH 2) Elemental analysis C: 60.09% (calc 60.26%) H: 8. 55% (〃8.62%) N: 7.16% ( 〃7.03 %) (Reference Example) 7-methoxy-6,7-dihydro-3H, 5H-cyclo
Penta [d] pyrimidin-4-one 28% sodium methylate 77.2 g and butanol 6
After heating 5 ml of the mixed solution, the solvent was distilled off until the internal temperature reached 100 ° C. A solution of 17.1 g of methyl 2-amino-3-methoxy-1-cyclopentenecarboxylate in 15.8 g of formamide in 30 ml of butanol was added dropwise over 2 hours, and further reacted at 100 to 110 ° C. for 2 hours. The reaction solution was cooled, neutralized with sulfuric acid, filtered, and the filtrate was quantified by liquid chromatography internal standard method.
15.5 g of methoxy-6,7-dihydro-3H, 5H-cyclopenta [d] pyrimidin-4-one was produced.
The filtrate was concentrated under reduced pressure and recrystallized with isopropanol to give 1
2.9 g of 7-methoxy-6,7-dihydro-3H, 5
H-cyclopenta [d] pyrimidin-4-one was obtained.

Mp 182.5-183.5 ° C.

¹ H-NMR (CDCl ₃ ) δ (ppm) 2.04 (1 H, m, CH ₂ ) 2.45 (1 H, m, CH ₂ ) 2.72 (1 H, m, CH ₂ ) _{93 (1H, m, CH 2} ) 3.56 (3H, s, CH 3) 4.73 (1H, t, CH) 8.21 (1H, s, CH) 13.20 (1H, bs, NH)

────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Fuse Kensaku 5 Ube, Ube City, Yamaguchi Prefecture, 1978 Kobe, 5 Ube Industries, Ltd. Ube Research Laboratories (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 229/48 C07C 227/08 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (Wherein, R ¹ and R ² each independently represent an alkyl group having 1 to 4 carbon atoms.) 3-alkoxy-2-amino-1-cyclopentenecarboxylic acid esters represented by the formula: 2. A compound of the general formula (Wherein R ¹ and R ² each independently represent an alkyl group having 1 to 4 carbon atoms) in the presence of a catalyst in the presence of a 3-alkoxy-2-oxocyclopentanecarboxylic acid ester represented by the following formula: A compound of the general formula: (Wherein R ¹ and R ² have the same meanings as described above.) A process for producing 3-alkoxy-2-amino-1-cyclopentenecarboxylic acid esters represented by the formula: