JPH1171359A - Production of aminothiazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily obtain in a high yield the subject compound having enterokinesis-improving effect by reaction of an amide derivative with an alkyldiamine. SOLUTION: This aminothiazole derivative of formula III is obtained by reaction of an amide derivative of formula I (R1 is a lower alkyl; R2 to R4 are each H, OH, a lower alkyl, lower alkoxy or the like; R5 is H, a lower alkyl or the like; A is a lower alkoxy or OH) with an alkyldiamine of formula II ((m) is 1-4; R6 and R7 are each H or a lower alkyl) in a polar solvent (pref. sulfoxide-based one such as dimethyl sulfoxide, or amide-based one such as N,N-dimethylformamide or N,N-dimethylacetamide). The above production method needs no process for protected hydroxyl deprotection reaction, enabling side reactions to be suppressed, therefore being excellent in operability and economy and effective from an industrial point of view.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel method for producing an aminothiazole derivative having a gastrointestinal motility improving effect.

[0002]

2. Description of the Related Art 2- [N- (4,5-dimethoxy-2-)
[Hydroxybenzoyl) amino] -4-[(2-diisopropylaminoethyl) aminocarbonyl] -1,3-
Aminothiazole derivatives represented by thiazole have excellent gastrointestinal motility-improving activity and are useful compounds for prevention and treatment of various gastrointestinal motility disorders. The production of these aminothiazole derivatives is described in International Patent Publication WO 96/3661.
It can be produced according to the method described in JP-A No. 9-No. According to this method, an aminothiazole derivative having a hydroxyl group at the 2-position on the benzene ring of the benzoyl group, for example, 2-
[N- (4,5-dimethoxy-2-hydroxybenzoyl) amino] -4-[(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole is 4,4
5-dimethoxy-2-hydroxybenzoic acid or an activated form thereof and 2-amino-4-alkoxycarbonyl-1,
It is produced by an amide-forming reaction with 3-thiazole (Step 1) and an amide-forming reaction between the compound obtained by this amide forming reaction and N, N-diisopropylethylenediamine (Step 2).

[0003]

However, step 1
In order to achieve the amide formation reaction in
When the carboxy group of dimethoxy-2-hydroxybenzoic acid is activated by a condensing agent or a halogenating agent, a reaction such as polymerization occurs, and it is difficult to obtain a target product in a high yield. For this reason, a reaction for protecting the 2-position hydroxy group of 4,5-dimethoxy-2-hydroxybenzoic acid with a known protecting group is performed followed by an amide formation reaction, or 4,5-dimethoxy-2-hydroxybenzoic acid. It is preferable to carry out the amide formation reaction using a raw material in which the hydroxyl group at the 2-position on the benzene ring has been converted to an alkoxy group, such as 2,4,5-trimethoxybenzoic acid. And the step of selectively converting the 2-position alkoxy group on the benzene ring to a hydroxyl group by a known dealkylation reaction is indispensable. In terms of the selectivity to the alkoxy group at the position and the yield, it is not always satisfactory when an aminothiazole derivative is produced industrially.

[0004]

As a result of further studies, the present inventors have found that benzoic acid in which the hydroxyl group at the 2-position on the benzene ring has been converted to an alkoxy group and 2-amino-4.
Under specific reaction conditions for the compound obtained by reaction with -alkoxycarbonyl-1,3-thiazole,
The present inventors have found that by performing a reaction with N, N-diisopropylethylenediamine, the 2-position alkoxy group on the benzene ring is converted to a hydroxyl group together with the amidation reaction, and completed the present invention.

That is, the present invention provides a compound represented by the general formula (I)

[0006]

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Wherein R ₁ represents a lower alkyl group;
R ₂ , R ₃ , and R ₄ are the same or different and are each a hydrogen atom, a hydroxyl group,
R ₅ represents a hydrogen atom, a lower alkyl group, a nitro group or a cyano group, and A represents a lower alkoxy group or a hydroxyl group. ) And an amide derivative represented by the general formula (II)

[0008]

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(Wherein m represents an integer of 1 to 4, R ₆ ,
R ₇ is the same or different and represents a hydrogen atom or a lower alkyl group. Wherein the alkyl diamine represented by the general formula (III) is reacted in the presence of a polar solvent.

[0010]

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Wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ ,
m has the same meaning as described above. )).

In the present invention, "lower" means having 1 to 1 carbon atoms.
Means 6 straight, branched or cyclic carbon chains. Therefore, as the "lower alkyl group", a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group , Sec-butyl group, tert-
Butyl, cyclobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-
Pentyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, cyclopentyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1-ethylbutyl Group, 2-ethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3 -Dimethylbutyl group, 1-methyl-
1-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,2,2
-A trimethylpropyl group, a cyclohexyl group and the like. Among these, a more preferred lower alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms.

The "lower alkoxy group" includes a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, cyclopropoxy, isopropoxy, butoxy. Group, isobutoxy group, sec-butoxy group, tert-butoxy group, cyclobutoxy group, pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, isopentyloxy group, te
rt-pentyloxy group, 1,2-dimethylpropoxy group, neopentyloxy group, 1-ethylpropoxy group,
Cyclopentyloxy group, hexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3
-Methylpentyloxy group, isohexyloxy group, 1
-Ethylbutoxy group, 2-ethylbutoxy group, 1,1-
Dimethylbutoxy group, 1,2-dimethylbutoxy group,
1,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3-dimethylbutoxy group, 1-methyl-1-ethylpropoxy group,
-Ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group, cyclohexyloxy group and the like. Among these, a more preferred lower alkoxy group is a linear or branched alkoxy group having 1 to 4 carbon atoms.

In the present invention, “halogen atom”
It means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

As the polar solvent used in the present invention, known solvents can be appropriately selected. Among them, sulfoxide solvents such as dimethyl sulfoxide and N, N-dimethylformamide, N, N-dimethylacetamide and the like can be used. Amide solvents are preferred. Further, these polar solvents can be arbitrarily mixed and used.

[0016]

DETAILED DESCRIPTION OF THE INVENTION The present invention is achieved by reacting an amide derivative (I) with an alkyl diamine (II) in the presence of a polar solvent. As the polar solvent, a known solvent can be appropriately selected. Among them, a sulfoxide solvent such as dimethyl sulfoxide and an amide solvent such as N, N-dimethylformamide and N, N-dimethylacetamide are preferable. Further, these polar solvents can be arbitrarily mixed and used. The reaction temperature is not particularly limited, and the reaction can be performed under cooling, at room temperature, under heating or under heating. After the reaction, it is isolated and purified by appropriately performing ordinary chemical operations such as filtration, washing, crystallization, recrystallization, and extraction.If desired, an acid addition salt of an organic acid or an inorganic acid or a solvate is obtained. It can lead to the desired aminothiazole derivative (III).

The production method of the present invention does not require a dealkylation step as compared with the production method described in the above-mentioned International Patent Publication or a combination of known reactions. Since no reaction occurs, there is an advantage that the yield and purity are high.

[0018]

EXAMPLES The production method of the present invention will be described in detail below with reference to examples, but the present invention is not limited thereto.

Example 2 Preparation of 2- [N- (4,5-dimethoxy-2-hydroxybenzoyl) amino] -4-[(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole hydrochloride

Step 1 Preparation of 2- [N- (2,4,5-trimethoxybenzoyl) amino] -4-methoxycarbonyl-1,3-thiazole

2,4,5-trimethoxybenzoic acid 500
g, suspended in 2 L of dry toluene, at room temperature, 206 ml of thionyl chloride and 1.0 ml of N, N-dimethylformamide.
Was added and stirred at 80 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, n-hexane was added to the residue, and the mixture was azeotropically distilled.
2,4,5-Trimethoxybenzoic acid chloride was obtained. To this, 372.7 g of 2-amino-4-methoxycarbonyl-1,3-thiazole and 1,2-dichloroethane4.
5 L was added and the mixture was heated under reflux for 6 hours. After the reaction, the mixture was cooled, and the precipitated crystals were collected by filtration, washed with 1,2-dichloroethane, and then air-dried. The crystals were suspended in 8 L of water, 2 kg of ice was added, and 94 g of sodium hydroxide was added with cooling to 850 ml of water.
After adding an aqueous solution dissolved in to adjust the pH to about 7.5,
Stir at room temperature for 3 hours. The precipitated crystals were collected by filtration, washed with water, and air-dried to give 702.7 g of the title compound.
I got Melting point: 251-252 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 3.77 (3H, s), 3.82 (3H, s), 3.
91 (3H, s), 4.03 (3H, s), 6.84 (1H, s), 7.44 (1H, s), 8.04 (1H,
s), 11.44 (1H, s) IR (KBr) cm- ¹ : 3304, 3123, 3019, 1736, 1668, 1610 MS (FAB) m / e: 353 (MH ⁺ )

Step 2 Preparation of 2- [N- (4,5-dimethoxy-2-hydroxybenzoyl) amino] -4-[(2-diisopropylaminoethyl) aminocarbonyl] -1,3-thiazole hydrochloride

Under an argon atmosphere, 2- [N- (2,4,
5-trimethoxybenzoyl) amino] -4-methoxycarbonyl-1,3-thiazole 500 g and N, N-
617 ml of diisopropylethylenediamine was suspended in 617 ml of N, N-dimethylacetamide and stirred at 135 ° C. for 6 hours. The reaction solution was allowed to cool, 5 L of 1-butanol was added, and the mixture was washed sequentially with a 0.5N aqueous sodium hydroxide solution and saturated saline, and then 2 L of 2-propanol was added. Hydrochloric acid gas was blown into the solution under ice cooling until the solution became acidic,
The precipitated crystals were collected by filtration and air-dried. The crystals are mixed with a mixed solvent of 2-propanol and water (2-propanol: water = 4: 1).
To give 468.3 g of the title compound. Melting point: 160 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 1.32 (6H, d), 1.35 (6H, d),
3.17 (2H, brs), 3.55-3.70 (4H, m), 3.77 (3H, s), 3.82 (3H,
s), 6.87 (1H, s), 7.49 (1H, s), 7.89 (1H, s), 8.23 (1H, t), 9.6
5 (1H, brs), 11.79 (1H, s), 12.07 (1H, brs) IR (KBr) cm ^-1 : 3493,3300,3096,1649 MS (FAB) m / e: 451 (MH ⁺ )

[0024]

The production method of the present invention does not require a step of deprotection reaction of a protected hydroxy group, suppresses side reactions, is simple, and provides a high yield in comparison with the conventional production method. Aminothiazole derivative can be obtained,
It is excellent in operability and economy, and is industrially useful.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Katsuyuki Ishii, Inventor 2512-1, Nishigami, Ojiri, Konan-cho, Osato-gun, Saitama 1 Inside Zeria Shinyaku Kogyo Co., Ltd. 2512-1 Numagami 1 Zeria Shinyaku Kogyo Co., Ltd. Central Research Laboratory

Claims (2)

[Claims] 1. A compound of the general formula (I) (Wherein, R ₁ represents a lower alkyl group, and R ₂ , R ₃ , and R ₄ may be the same or different and represent a hydrogen atom, a hydroxyl group, a lower alkyl group,
A lower alkoxy group, a nitro group or a cyano group, R ₅
Represents a hydrogen atom, a lower alkyl group, a nitro group or a cyano group, and A represents a lower alkoxy group or a hydroxyl group. ) And an amide derivative represented by the general formula (II): (Wherein m represents an integer of 1 to 4, and R ₆ and R ₇ are the same or different and each represent a hydrogen atom or a lower alkyl group) in the presence of a polar solvent in the presence of a polar solvent. Having the general formula (III): (Wherein, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and m have the same meanings as described above). 2. The method for producing an aminothiazole derivative according to claim 1, wherein the polar solvent is a sulfoxide solvent, an amide solvent or a mixed solvent thereof.