JP3251713B2 - Method for producing N-thienylaminomethyleneacetic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a thieno [3,2-) useful as a drug having an antibacterial activity or an antihypertensive activity.
b] A method for producing an N-thienylaminomethylene acetic acid derivative which is a synthetic intermediate of a pyridine derivative.

[0002]

2. Description of the Related Art The following general formula (IV)

[0003]

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(In the above formula, R⁷And R⁸Are each
Independently a hydrogen atom, a halogen atom, C ₁~ C₆Archi
Represents a group such as⁹Is carboxyl group, carboxamide
Or C₁~ C₆Represents an alkoxycarbonyl group or the like,
R^TenIs C₁~ C₆Represents an alkyl group, etc.)
Eno [3,2-b] pyridine derivatives have antibacterial activity (see
57-42690) or antihypertensive activity (EP-
0269295) is known.

The N-thienylaminomethyleneacetic acid derivative represented by the following general formula (III) is a useful synthetic intermediate of the thieno [3,2-b] pyridine derivative represented by the general formula (IV). It is known that there are generally Goul
Dowthe, known as the d-Jacobs method
rm A, a method of heating at 200 to 260 ° C. in a high boiling point solvent such as diphenyl or diphenyl ether (Ric
hard L. Elliott et al. , Tet
rahedron Vol. 43, no. 14, pp3
295 to 3302, 1987) or a method of heating at 50 to 150 ° C. in polyphosphoric acid or polyphosphate ester (G Malicone et al., Eur
J Med Chem (1991) 26, 3-11, JP-A-57-116077, JP-A-57-4269.
No. 0 publication). That is, the following general formula (II
A compound having a thieno [3,2-b] pyridine skeleton (a compound in which R ¹⁰ is a hydrogen atom in the compound represented by the general formula (IV)) is converted from an N-thienylaminomethyleneacetic acid derivative represented by I). The above-mentioned general formula having an activity derived by a method generally known, for example, by reacting with an alkyl halide having an appropriate alkyl group in a solvent such as DMF in the presence of an alkali such as K ₂ CO _{3 in} a solvent such as DMF. Route for synthesizing thieno [3,2-b] pyridine derivative represented by (IV) (Richard L. Elliot)
t et al. , Tetrahedron Vol.
43, no. 14, pp3295to3302,198
7, EP-0269295) are known.

The compound represented by the following general formula (III) is obtained by hydrolyzing a compound represented by the following general formula (I) in an aqueous sodium hydroxide solution.

[0007]

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(In the above formula, R¹And R^TwoAre each
Independently a hydrogen atom, a halogen atom, C ₁~ C₆Archi
Group, phenyl group which may have a substituent or naphthyl
Group, C₁~ C₆Alkylsulfonyl group or cyano
Aminothiophene carboxylic acid derivative represented by
After isolation as the sodium salt of the product,
Compounds represented by I), for example, ethoxymethylenemalone
Toluene in the presence of acid diethyl ester and an acid such as acetic acid
Heating (80-120 ° C) with a solvent such as
(Richard
L. Elliott et al. , Tetrahedr
on Vol. 43, no. 14, p. 3295 (198
7)), the yield of this method is as low as 48%. Also the following general
The compound represented by the formula (I) is hydrolyzed with an alkali.
Thereafter, the compound is represented by the general formula (V) using an acid such as hydrochloric acid.
Isolated as aminothiophene carboxylic acid derivative
With a compound represented by the following general formula (II), for example, ethoxy
Methylene malonic acid diethyl ester, solvent-free, ether
, N, N-dimethylformamide or toluene
By heating (90-160 ° C) with the solvent
Is known to be obtained (JP-A-57-1160).
No. 77, EP-0269295), using these methods.
Has a low yield of about 50%, and has a carbohydrate on the thiophene ring.
General formula (VI) in which a xyl group remains

[0009]

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(In the above formula, R¹And R^TwoIs the general
R as defined in formula (V) ^FiveIs C₁~ C₆of
Represents an alkoxycarbonyl group or a cyano group;⁶Is
C₁~ C₆Represents an alkyl group. ) By-product
(Reacted with ethoxymethylene malonic acid diethyl ester
In this case, the compound represented by the general formula (VI)
Chi, R^FiveIs an ethoxycarbonyl group, R⁶Is an ethyl group
Compounds) are mixed.

After reducing the nitro group of commercially available 3-nitrothiophene with tin and hydrochloric acid, the compound of the following general formula (II) is mixed with a compound of the following general formula (II) in a pyridine solvent:
A method of reacting at 24 ° C. for 24 hours is known (Misb
ahul Ani Khanet al. , J. et al. Het
erocyclic Chem. , 14, 807 (19
77)), but this method does not cause a problem of by-product of the compound represented by the general formula (VI), but the yield is 50 to 69.
%, And synthesis on a thiophene ring having substituents at the R ¹ and R ² positions is not known.

[0012]

Means for Solving the Problems As a result of repeated studies in view of the above-mentioned problems, the present inventors have found that aminothiophenecarboxylic acid ester derivatives represented by the following general formula (I) can be prepared under mild reaction conditions. The compound is efficiently converted to a dealkoxycarbonyl compound and then reacted with an alkoxymethylene acetic acid derivative represented by the following general formula (II) to give N-thienylamino represented by the following general formula (III) in high yield and high purity. The inventors have found that a methylene acetic acid derivative can be obtained, and have completed the present invention.

That is, the gist of the present invention is the following general formula (I):

[0014]

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(In the above formula, R¹And R^TwoAre each
Independently a hydrogen atom, a halogen atom, C ₁~ C₆Archi
Group, phenyl group which may have a substituent or naphthyl
Group, C₁~ C₆Alkylsulfonyl group or cyano
R represents a group^ThreeIs C₁~ C₆Represents an alkyl group. )so
The aminothiophene carboxylic acid ester derivative represented
Hydrolysis and decarboxylation to give the dealkoxycarbonyl form
The dealkoxycarbonyl derivative is then obtained by the following general formula
(II)

[0016]

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(In the above formula, R^FourAnd R⁶Are each
Independently C₁~ C₆An alkyl group of R ^FiveIs C₁~ C₆of
Represents an alkoxycarbonyl group or a cyano group. )
With the alkoxymethylene acetic acid derivative to be used
Having the following general formula (III)

[0018]

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(Where R ¹ , R ² , R ⁵ and R
⁶ is as defined in the above general formulas (I) and (II). )) In the production method of the N-thienylaminomethyleneacetic acid derivative. Hereinafter, the present invention will be described in detail.

The general formulas (I), (III), (V) and (V
In the compound represented by I), examples of the halogen atom defined by R ¹ and R ² include a chlorine atom, a bromine atom, and an iodine atom. As the C _{1 to} C ₆ alkyl group,
Methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like, Examples of the phenyl group which may have a substituent include a phenyl group, a para-chlorophenyl group,
Examples of a naphthyl group which may have a substituent include a 1-naphthyl group, a 2-naphthyl group, a 5-chloro-1-naphthyl group and a 6-methyl-2-naphthyl group. Examples of the C ₁ -C ₆ alkylsulfonyl group include a methylsulfonyl group, an n-propylsulfonyl group, and an iso-propylsulfonyl group.

In the compound represented by the general formula (I), the C ₁ -C ₆ alkyl group defined by R ³ includes:
Examples include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and an n-hexyl group. In the compound represented by the general formula (II), the C ₁ -C ₆ alkyl group defined by R ⁴ may be a methyl group, an ethyl group, an n-propyl group, an is
o-propyl group, n-butyl group, iso-butyl group, s
Examples include an ec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, and the like.

In the compounds represented by formulas (II), (III) and (VI), the C ₁ -C ₆ alkoxycarbonyl group defined by R ⁵ includes methoxycarbonyl, ethoxycarbonyl, n -Propoxycarbonyl group, iso-propoxycarbonyl group, n-butoxycarbonyl group, iso-butoxycarbonyl group, sec-
Butoxycarbonyl group, tert-butoxycarbonyl group and the like.

In the compounds represented by the general formulas (II), (III) and (VI), the C ₁ -C ₆ alkyl group defined by R ⁶ may be a methyl group, an ethyl group, an n-propyl group. , Iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-
Examples include a pentyl group and an n-hexyl group. The manufacturing process of the present invention will be described below.

[0024]

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(Where R ¹ , R ² , R ³ , R ⁴ , R
⁵ and R ⁶ are as defined above. First, the aminothiophene carboxylic acid ester derivative (I) is hydrolyzed (step A). This step is a usual hydrolysis step of a lower ester of a carboxylic acid, and is carried out at 0 to 150 ° C. in water or a hydrated solvent such as hydrated THF, hydrated alcohol or hydrated DMF under alkaline conditions, preferably at 20 to 120 ° C. Done.

Without isolating the carboxylic acid derivative (V) produced in (Step A), alcohols,
Preferably, after adding ethanol, the reaction solution is acidified by adding an organic acid such as mineral acid or acetic acid, preferably acetic acid,
４０40 ° C., preferably 10-30 ° C. for 30 minutes to 24
Time, preferably 1 to 4 hours,
The decarboxylation reaction proceeds slowly, and can lead to a dealkoxycarbonyl compound represented by the general formula (VII).
This (Step B) can be analyzed using a conventional analytical method such as TLC or HPLC if necessary, and the reaction can be followed. In the method of the present invention, the above intermediate (V) is decarboxylated without isolation, and is subjected to the following steps.

At the stage when (Step B) is completed, the alkoxymethylene acetic acid derivative represented by the general formula (II) is added to the reaction solution, and the mixture is reacted at 0 to 40 ° C., preferably 10 to 30 ° C. , N- represented by the general formula (III)
A thienylaminomethyleneacetic acid derivative is obtained. In (Step B), it is desirable to analyze the reaction process by a method such as TLC, HPLC, etc., and it is preferable to use a dealkoxycarbonyl derivative (VI) of the aminothiophenecarboxylic acid derivative (V).
Analyze the conversion to I). Thereby, in the next step C,
When reacted with the alkoxymethylene acetic acid derivative (II), the formation of the compound of the general formula (VI), which is mixed as a by-product into the N-thienylaminomethylene acetic acid derivative (III), can be significantly reduced. it can.

The N-thienylaminomethylene acetic acid derivative of the general formula (III) obtained as described above can be obtained by a known separation and purification means such as filtration, concentration, extraction, chromatography, reprecipitation and recrystallization. It can be isolated at any purity by using the appropriate means. Thus, an N-thienylaminomethylene acetic acid derivative useful as a synthetic intermediate of a thieno [3,2-b] pyridine derivative useful as a pharmaceutical such as an antibacterial agent or an antihypertensive agent can be obtained in high yield and high purity.

[0029]

According to the method of the present invention, an aminothiophene carboxylate derivative is converted into a dealkoxycarbonyl derivative and then reacted with an alkoxymethylene acetic acid derivative, thereby being useful as a drug such as an antibacterial agent or an antihypertensive agent. An N-thienylaminomethyleneacetic acid derivative, which is a synthetic intermediate of a thieno [3,2-b] pyridine derivative, can be obtained with high yield and high purity.

[0030]

EXAMPLES The present invention will be described below with reference to examples.
The present invention is not limited by these examples. Example 1 3- (2,2-diethoxycarbonylethenyl) aminothiophene (in the above general formula (III), R ¹ and R ² are hydrogen atoms, R ⁵ is an ethoxycarbonyl group, and R ⁶ is an ethyl group. Of sodium hydroxide 11.2 g (282.7 mmol)
Was dissolved in 340 ml of water, and 40.4 g of methyl 3-aminothiophene-2-carboxylate (257 g) was added thereto.
Mmol), and the mixture was heated under reflux for 30 minutes. The reaction solution is
After cooling to room temperature, 400 ml of ethanol was added, and 17.7 ml (308.4 mmol) of acetic acid was further added dropwise over 1 hour. After the completion of the dropwise addition, the mixture was further stirred for 1 hour and subjected to HPLC analysis (column: Novapak ODS, mobile phase: water / methanol / triethylamine = 20/80 / 0.4, flow rate: 0.8 ml / min) to remove the dealkoxycarbonyl compound (3). -Aminothiophene) was confirmed, and 61 g of ethoxymethylenemalonic acid diethyl ester (28 g
(2.7 mmol) and stirred at room temperature for 1 hour. After adding 600 ml of water to the reaction solution and stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration, and 61.3 g of the target compound 3- (2,2-diethoxycarbonylethenyl) aminothiophene was obtained.
(89.0% yield).

M. p. : 80-82 ° C IR (KBr) cm ^-1 : 3443, 1684, 163
_{6,1603,1267,1238 NMR (CDCl 3) δ:} 1.26~1.41 (6H,
m), 4.18 to 4.35 (4H, m), 6.86 (1
H, d), 6.99 (1H, d), 7.33 (1H, d
d), 8.39 (1H, d), 11.03 (1H, d)

Example 2 3-Bromo-4- (2,2-diethoxycarbonylethenyl) aminothiophene (In the above formula (III), R ¹ is a hydrogen atom, R ² is a bromine atom, and R ⁵ is ethoxy. Synthesis of carbonyl group, compound in which R ⁶ is an ethyl group) 2.71 g (67.8 mmol) of sodium hydroxide was
This was dissolved in 68 ml of water, and 8.0 g of 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (3 g) was added thereto.
3.9 mmol) and heated to reflux for 1 hour. After the reaction solution was cooled to room temperature, 80 ml of ethanol was added, and 4.23 ml (74.6 mmol) of acetic acid was further added dropwise over 1 hour. After completion of the dropwise addition, the mixture was further stirred for 1 hour, and subjected to HPLC analysis in the same manner as in Example 1 to remove the dealkoxycarbonyl compound (3
-Bromo-4-aminothiophene) was confirmed, and ethoxymethylenemalonic acid diethyl ester 8.0 was added thereto.
6 g (37.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 120 ml of water was added to the reaction solution, and the precipitated crystals were collected by filtration, and 11.7 g of the desired product, 3-bromo-4- (2,2-diethoxycarbonylethenyl) aminothiophene, was obtained.
(98.7% yield).

M. p. : 90-93 ° C IR (KBr) cm ^-1 : 3430, 1684, 164
7,1595,1260 NMR (CDCl ₃ ) δ: 1.30 to 1.41 (6H,
m), 4.21 to 4.38 (4H, m), 6.91 (1
H, d), 7.32 (1H, d), 8.35 (1H,
d), 11.00 (1H, d)

Reference Example 3- (2,2-diethoxycarbonylethenyl) aminothiophene (wherein R ¹ and R ² are hydrogen atoms, R ⁵ is an ethoxycarbonyl group, and R ⁶ is an ethyl group in the general formula (III)) The title compound was synthesized according to the method described in JP-A-57-116077.

7.0 g (174.9 mmol) of sodium hydroxide was dissolved in 180 ml of water, and 25.0 g of 3-aminothiophene-2-carboxylic acid methyl ester was added thereto.
(159.0 mmol) was added and the mixture was refluxed for 30 minutes. This was cooled to room temperature, and concentrated hydrochloric acid was added at room temperature to adjust the pH.
<5.0, and the precipitated crystals (3-aminothiophene-
2-carboxylic acid) was collected by filtration. To this, 25 ml of tetrahydrofuran and 41.3 g (190.8 mmol) of diethyl ethoxymethylenemalonic acid were added, and the mixture was stirred at 85 to 90 ° C. for 2 hours while distilling off tetrahydrofuran and generated ethanol. After cooling, water and chloroform were added, extracted with chloroform, and the organic layers were combined and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (eluent, chloroform / n-hexane = 2/1), and further recrystallized from isopropyl ether / n-hexane to obtain the desired compound 3- ( 20.4 g of 2,2-diethoxycarbonylethenyl) aminothiophene (yield 4
7.7%).

────────────────────────────────────────────────── ─── Continuation of the front page (56) References Special Table 2-503317 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 333/36

Claims (1)

(57) [Claims] 1. A compound represented by the following general formula (I)(In the above formula, R¹And R^TwoAre each independently hydrogen
Atom, halogen atom, C ₁~ C₆Alkyl group and substituent
A phenyl or naphthyl group optionally having₁~
C₆Represents an alkylsulfonyl group or a cyano group of
^ThreeIs C₁~ C₆Represents an alkyl group. Ami represented by)
Hydrolysis of notthiophenecarboxylic acid ester derivatives
And decarboxylation to obtain a dealkoxycarbonyl compound.
The dealkoxycarbonyl compound is converted to the following general formula (II):(In the above formula, R^FourAnd R⁶Are each independently C₁
~ C₆An alkyl group of R ^FiveIs C₁~ C₆Alkoxyka
Represents a rubonyl group or a cyano group. Arco represented by)
Characterized by reacting with a ximethylene acetate derivative
The following general formula (III)(In the above formula, R¹, R^Two, R^FiveAnd R⁶Is the above general
As defined in formulas (I) and (II). )
For producing N-thienylaminomethyleneacetic acid derivatives
Law.