JP2000026453A - 3-aminomethylthiophene derivative and production thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new 3-aminomethylthiophene derivative useful as a synthetic intermediate, etc., of a therapeutic agent of hypercholesterolemia, hyperlipidemia, arteriosclerosis, etc. SOLUTION: This new 3-aminomethylthiophene derivative is a compound of formula I [R1, R2 are each H, a halogen, hydroxy, nitro, a (halogen substituted) lower alkyl or the like; R3 is a lower alkyl; R4 to R7 are each H or a lower alkyl], e.g. N-(2-hydroxyethyl)-N-methyl-3-aminomethylthiophene. Further, the compound of formula I is obtained by reacting a thiophenecarboxyaldehyde derivative expressed by formula II with an ethanolamine derivative expressed by formula III in a solvent such as methanol in the presence of a reducing agent such as lithium aluminum hydride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 3-aminomethylthiophene derivative. The 3-aminomethylthiophene derivative according to the present invention can be
It is useful as a synthetic intermediate when producing various physiologically active substances such as pesticides.

[0002]

2. Description of the Related Art The 3-aminomethylthiophene derivative represented by the general formula [1] is a novel compound not described in any literature, and the usefulness of this compound and its production method have not been known at all.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have the following general formula [4]:

[0004]

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[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meaning as described above. R ⁸ represents a hydrogen atom or a lower alkyl group which may be substituted with a halogen atom. R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different and each represent a hydrogen atom or a halogen atom;
⁹ and R ¹¹ and / or R ¹⁰ and R ¹² together represent a single bond. R ¹³ , R ¹⁴ and R ¹⁵ represent a hydrogen atom or a lower alkyl group. Q represents an oxygen atom, a sulfur atom, or a divalent group represented by the formula: —NR ¹⁶ — (wherein R ¹⁶ represents a hydrogen atom or a lower alkyl group). ] Has been studied repeatedly for the synthesis intermediate of the benzylamine derivative represented by the formula: The benzylamine derivative represented by the general formula [4] has a strong inhibitory activity on squalene epoxidase in mammals, and as a result, has a high blood cholesterol, hyperlipidemia, arteriosclerosis, etc. It has the potential to be used as a therapeutic or preventive drug for diseases caused by excess cholesterol.

An object of the present invention is to provide a novel 3-aminomethylthiophene derivative which is extremely useful as a synthetic intermediate for producing such a useful physiologically active substance.

[0007]

The present inventors have studied various processes for producing a novel benzylamine derivative represented by the general formula [4], and have studied various methods for producing the benzylamine derivative represented by the general formula [1]. The present inventors have found that an aminomethylthiophene derivative is extremely useful as a synthetic intermediate, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula [1]:

[0009]

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[Wherein R ¹ and R ² are the same or different and are each a hydrogen atom, a halogen atom, a hydroxy group, a nitro group,
It represents a lower alkyl group, a lower alkyl group substituted with a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group, or a lower dialkylamino group. R ³ represents a lower alkyl group. R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and represent a hydrogen atom or a lower alkyl group. ]
Is a novel 3-aminomethylthiophene derivative.

The present invention provides a compound represented by the general formula [2]:

[0012]

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Wherein R ¹ and R ² have the same meaning as described above. And a thiophene carboxaldehyde derivative represented by the general formula [3]:

[0014]

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Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meaning as described above. ] The method for producing a 3-aminomethylthiophene derivative represented by the general formula [1], characterized by reacting with an ethanolamine derivative represented by the following formula: Hereinafter, the present invention will be described in detail.

First, definitions of terms used in the present specification and specific examples thereof will be described. Unless otherwise specified, the term “lower” described in the present specification refers to a straight, branched or cyclic hydrocarbon group having 1 to 6 carbon atoms in a group to which this term is assigned. Is contained.

Accordingly, examples of the lower alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl) ) Group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2
-Dimethylpropyl, hexyl, isohexyl,
1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 2,2-
Dimethylbutyl group, 1,3-dimethylbutyl group, 2,3
-Dimethylbutyl group, 3,3-dimethylbutyl group, 1-
Ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-
Examples include a 2-methylpropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, a cyclopropylethyl group, and a cyclobutylmethyl group.

The "halogen atom" is specifically a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Preferably, they are a fluorine atom, a chlorine atom and a bromine atom.

The lower alkyl group substituted with a halogen atom includes, for example, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group, 2,2-difluoroethyl group, 1,2,2-trifluoroethyl group, 2,
2,2-trifluoroethyl group, 1-fluoropropyl group, 2-fluoropropyl group, 3-fluoropropyl group, 2,2-difluoropropyl group, chloromethyl group,
Dichloromethyl group, trichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 1,1-dichloroethyl group, 1,2-dichloroethyl group, 2,2-dichloroethyl group, 1,2,2-trichloroethyl Group, 2,2,2-
Trichloroethyl group, 1-chloropropyl group, 2-chloropropyl group, 3-chloropropyl group, 2,2-dichloropropyl group, bromomethyl group, dibromomethyl group, tribromomethyl group, 1-bromoethyl group, 2-bromoethyl Group, 1,1-dibromoethyl group, 1,2-dibromoethyl group, 2,2-dibromoethyl group, 1,2,2-tribromoethyl group, 2,2,2-tribromoethyl group,
Examples thereof include a 1-bromopropyl group, a 2-bromopropyl group, a 3-bromopropyl group, and a 2,2-dibromopropyl group.

Examples of the lower alkyl group which may be substituted with a halogen atom include the above-mentioned lower alkyl group and the above-mentioned lower alkyl group substituted with a halogen atom.

The lower alkoxy group includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, 1-methylbutyloxy Group, 2-methylbutyloxy group, 3-
Methylbutyloxy group, 1,2-dimethylpropyloxy group, 1,1-dimethylpropyloxy group, hexyloxy group, 1-methylpentyloxy group, 1-ethylpropyloxy group, 2-methylpentyloxy group, 3- Methylpentyloxy group, 4-methylpentyloxy group,
1,2-dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2,3-dimethylbutyloxy group,
Examples thereof include a 1-dimethylbutyloxy group, a 2,2-dimethylbutyloxy group, and a 3,3-dimethylbutyloxy group.

Examples of the lower alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group,
Butoxycarbonyl group, isobutoxycarbonyl group, s
An ec-butoxycarbonyl group, a tert-butoxycarbonyl group and the like can be mentioned.

The lower dialkylamino group includes, for example, dimethylamino, methylethylamino, methylpropylamino, methylbutylamino, diethylamino, ethylpropylamino, ethylbutylamino,
Examples thereof include an ethylpentylamino group, a dipropylamino group, and a propylbutylamino group.

In order to more specifically disclose the compound of the present invention represented by the above general formula [1], preferred examples of the various symbols or partial structures used in the formula [1] will be given below. This will be described in detail.

[1] where:

[0026]

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The thienyl group represented by the above formula is more preferably, for example, a 3-thienyl group, a 2-methyl-3-thienyl group, a 4-methyl-3-thienyl group, a 5-methyl-3-
Thienyl group, 2,5-dimethyl-3-thienyl group, 2-
Hydroxy-3-thienyl group, 5-hydroxy-3-thienyl group, 2,3-dihydro-4-thienyl group, 2,5
-Dihydro-3-thienyl group, 2-nitro-3-thienyl group, 5-nitro-3-thienyl group, 2,5-dinitro-3-thienyl group, 5-ethyl-3-thienyl group, 5-
n-propyl-3-thienyl group, 5-isopropyl-3
-Thienyl group, 2-methyl-5-ethyl-3-thienyl group, 2-methyl-5-isopropyl-3-thienyl group,
Examples thereof include a 2,5-diethyl-3-thienyl group and a 2,5-diisopropyl-3-thienyl group.

Further, 2-chloro-3-thienyl group, 5-chloro-3-thienyl group, 2,5-dichloro-3-thienyl group, 2-fluoro-3-thienyl group, 4-fluoro-thienyl group
3-thienyl group, 5-fluoro-3-thienyl group, 2,
5-difluoro-3-thienyl group, 2-bromo-3-thienyl group, 4-bromo-3-thienyl group, 5-bromo-
3-thienyl group, 2,5-dibromo-3-thienyl group,
5-methoxy-3-thienyl group, 5-ethoxy-3-thienyl group, 5-methoxycarbonyl-3-thienyl group,
5-ethoxycarbonyl-3-thienyl group, 5-fluoromethyl-3-thienyl group, 5-difluoromethyl-3
-Thienyl group, 5-trifluoromethyl-3-thienyl group, 5- (2-fluoroethyl) -3-thienyl group and the like.

Particularly preferred are a 3-thienyl group, a 5-methyl-3-thienyl group, a 2,5-dimethyl-3-thienyl group, a 5-hydroxy-3-thienyl group and a 2,3-dihydro-4-thienyl group. 2,5-dihydro-3-thienyl group, 5-nitro-3-thienyl group, 5-ethyl-3-thienyl group, 5-n-propyl-3-thienyl group, 5-isopropyl-3-thienyl group, A 2-fluoro-3-thienyl group, a 4-fluoro-3-thienyl group, a 5-fluoro-3-thienyl group, a 2,5-difluoro-3-thienyl group, and a 5-fluoromethyl-3-thienyl group.

The lower alkyl group represented by R ³ is preferably, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. And a cyclopropyl group, a cyclopropylmethyl group, etc., and particularly preferably a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.

The groups represented by R ^{4 to} R ⁷ are preferably the same or different and include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, and more preferably a hydrogen atom. Atom, methyl group or ethyl group.

Next, a general method for producing the compound of the present invention will be described.

The compound of the present invention represented by the general formula [1]
For example, as shown in the following reaction formula [I], it can be produced by a reductive amination reaction between a 3-thiophenecarboxaldehyde derivative (formula [2]) and an ethanolamine derivative represented by general formula [3]. .

Reaction formula [I]

[0035]

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[Wherein, R ^{1 to} R ⁷ have the same meaning as described above. In this reaction, for example, a compound represented by the general formula [2] and a compound represented by the general formula [3] are mixed in a solvent at room temperature,
After stirring for 1 minute to 3 hours, a reducing agent is added to the mixture, and the mixture is further reacted at room temperature to 150 ° C. for 30 minutes to 72 hours. The compound represented by the general formula [2] and the compound represented by the general formula [3] are preferably reacted with each other in an equimolar amount or by using an excess mol of the compound represented by the general formula [3]. As the reducing agent used in the reaction, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride,
Sodium triacetoxyborohydride is preferably used. The amount of these reducing agents to be added is 1 to 2 equivalents, preferably 1.3 to 1.6 equivalents, relative to the compound represented by the general formula [2].

As a reaction solvent, an alcoholic solvent such as methanol, ethanol, isopropyl alcohol and the like,
Aromatic hydrocarbon solvents such as benzene, toluene, and xylene; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; and chlorine solvents such as methylene chloride, chloroform, and 1,2-dichloroethane can be used. .

In this reaction, an acid may be added, if necessary, for the purpose of accelerating the reaction. Such acids include hydrochloric acid or acetic acid. Similarly, for the purpose of accelerating the reaction, a molecular sieve (molecular sieves) may be added as a dehydrating agent. This reaction can also be carried out in an inert gas for the purpose of preventing an undesired double reaction such as an oxidation reaction. Examples of such an inert gas include nitrogen and argon. In addition to the reduction treatment using the above-mentioned various metal hydrogen complex compounds, a reduction treatment with borane or a reduction treatment by catalytic hydrogenation using various metal catalysts such as platinum oxide, palladium carbon or Raney nickel can also be performed.

Of the starting compounds used in the above reaction,
The compound represented by the general formula [2] may be purchased as a commercial product or may be obtained by a method described in a literature [eg, Journal of
Organic Chemistry (J. Org. Che)
m. (1987), 52 (1), 104; Tetrahedron (1976), 32
(12), 1403, Heterocycles
cycles) (1984), 22 (5), 1175,
Chemica Script
a) (1971), 1 (1), 33, Bulletin de.
La Societe Simique de France (Bull. S
oc. Chim. Fr. ) (1967), (11), 4
115, same (1967), (11), 4121, same (1
970), 1,302, tetrahedron letters (Te
trahedron Lett. 1987), 28.
(26), 3021 etc.] or a method based on them.

Compound [3] can be purchased as a commercial product or can be produced by a synthetic reaction represented by the following reaction formula [II].

Reaction formula [II]

[0042]

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Wherein Y is a leaving group, and R ^{3 to} R ⁷ have the same meaning as described above. The above reaction is a generally well-known alkylation reaction of an amine, for example, in the presence or absence of a basic substance,
It can be produced by reacting at -80 ° C to 100 ° C for several minutes to 24 hours in a solvent-free or solvent. [5] In the formula, Y is a leaving group, and specific examples include a halogen atom such as chlorine, bromine and iodine, and a sulfonyloxy group such as a methanesulfonyloxy group and a p-toluenesulfonyloxy group.

Examples of the basic substance used in the above reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and sodium hydride. , An alkali metal hydride such as lithium hydride, an alkaline earth metal hydride such as calcium hydride, n
-Butyllithium, sec-butyllithium, tert
Organic lithium compounds such as -butyl lithium, lithium diisopropylamide, or pyridine, collidine, lutidine, triethylamine, trimethylenediamine, 1,
Organic bases such as 8-diaza-bicyclo [5.4.0] -7-undecene (DBU) can be mentioned.

Examples of the solvent used in this reaction include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, alcohol solvents such as methanol, ethanol, n-propyl alcohol and isopropyl alcohol, benzene, toluene and o-solvent.
Aromatic hydrocarbon solvents such as xylene and p-xylene,
An aprotic polar solvent such as dimethylacetamide, dimethylformamide, dimethylsulfoxide and the like can be used.

The target compound or starting compound of the present invention obtained in each of the above steps can be isolated and purified by a conventional method such as solvent extraction, distillation, recrystallization, or column chromatography.

[0047]

Industrial Applicability The 3-aminomethylthiophene derivative of the present invention is a specific benzylamine derivative which can be used as a therapeutic or preventive drug for diseases caused by excessive blood cholesterol such as hypercholesterolemia, hyperlipidemia, and arteriosclerosis. In addition to being a useful synthetic intermediate for obtaining the compound, it is expected to be effective as a synthetic intermediate for various physiologically active substances such as medicines and agricultural chemicals.

[0048]

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

Example Synthesis of N- (2-hydroxyethyl) -N-methyl-3-aminomethylthiophene A solution consisting of 2.0 g of 3-thiophenecarboxaldehyde and 15 ml of ethanol was mixed with N-methyl under ice cooling. A solution composed of 13.5 g of ethanolamine and 15 ml of ethanol was added dropwise, and the mixture was further stirred at room temperature for 40 minutes. After ethanol was distilled off from the obtained reaction solution under reduced pressure, 50 ml of water and 100 ml of saturated saline were added. The solution was extracted with ether, and the organic layer was washed with saturated saline, and then the solvent was distilled off under reduced pressure to obtain 3.3 g of a red-brown oil. This reddish-brown oil is treated with 50 m of ethanol.
, and 2.0 g of sodium borohydride was added to the solution under ice-cooling.
Stirred for hours. After the reaction was stopped by adding 100 ml of water dropwise to the obtained solution, the solvent was distilled off under reduced pressure. 100 ml of saturated saline was added, and the resulting solution was extracted with ether. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 6: 1) to obtain the desired N- (2-hydroxyethyl) -N-methyl −
1.9 g of 3-aminomethylthiophene were obtained.

¹ H-NMR (500 MHz, CDCl ₃ ,
δ ppm) 2.24 (s, 3H), 2.58 (t, J =
5.5 Hz, 2H), 3.48-3.63 (m, 4
H), 7.03 (d, J = 4.5 Hz, 1H), 7.1
1 (s, 1H), 7.27-7.30 (m, 1H) IR (neat, cm ^-1 ) 3370, 2940, 27
801450,1030,765 pale orange oil.

[0051]

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Yasuaki Hanasaki 4-40-9-203 Shonandai, Fujisawa-shi, Kanagawa (72) Inventor Kimio Katsuura 2-23-3 Nishi-Ochiai, Shinjuku-ku, Tokyo F-term (reference) 4C023 CA01 HA04

Claims (2)

[Claims] 1. A compound of the general formula [1] [Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom,
It represents a halogen atom, a hydroxy group, a nitro group, a lower alkyl group, a lower alkyl group substituted with a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group, or a lower dialkylamino group. R ³ represents a lower alkyl group. R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and represent a hydrogen atom or a lower alkyl group. A novel 3-aminomethylthiophene derivative represented by the formula: 2. A compound of the general formula [2] Wherein R ¹ and R ² have the same meaning as described above. And a thiophene carboxaldehyde derivative represented by the general formula [3]: [Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meaning as described above. ] The method for producing a 3-aminomethylthiophene derivative represented by the general formula [1], characterized by reacting with a ethanolamine derivative represented by the following formula: