JPH072836A - Method for producing n-thienylaminomethyleneacetic acid derivative - Google Patents

Abstract

PURPOSE:To produce the subject compound useful as an intermediate for synthesizing a thieno[3,2-b]pyridine derivative used as a medicine having antibacterial activity, antihypertensive activity, etc., in high purity and high yield. CONSTITUTION:A method for producing the N-thienylaminomethyleneacetic acid derivative of formula III comprises hydrolyzing an aminothiophenecarboxylic acid ester derivative of formula I (R<1>, R<2> are H, halogen, 1-6C alkyl, substitutable phenyl, substitutable naphthyl, 1-6C alkylsulfonyl, CN; R<3> is 1-6C alkyl), subjecting the produced carboxylic acid derivative of formula V to decarboxylation in an alcohol as a solvent in the acidic reaction solution containing a mineral or organic acid preferably at 10-30 deg.C for 1-4hr without isolating the compound of formula V, and subsequently reacting the produced dealkoxycarbonyl compound of formula VII with an alkoxymethyleneacetic acid derivative of formula II (R<4>, R<6> are 1-6C alkyl; R<5> is 1-6C alkoxycarbonyl, CN).

Description

Detailed Description of the Invention

[0001]

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

[0002]

PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION The following general formula (IV)

[0003]

[Chemical 4]

(In the above formula, R⁷And R⁸Are each
Independently hydrogen atom, halogen atom, C ₁~ C₆The archi
R group, etc., R⁹Is a carboxyl group, carboxamide
Or C₁~ C₆Represents an alkoxycarbonyl group of
R^TenIs C₁~ C₆Represents an alkyl group of
Eno [3,2-b] pyridine derivatives have antibacterial activity
57-42690) or antihypertensive activity (EP-
0269295).

The N-thienylaminomethylene acetic 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 above general formula (IV). Known to exist, and 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.D. Elliott et al. , Tet
rahedron Vol. 43, No. 14, pp3
295to3302, 1987) or a method of heating at 50 to 150 ° C. in polyphosphoric acid or polyphosphoric acid ester (G Malicorne et al., Eur.
J Med Chem (1991) 26, 3-11, JP-A-57-116077, JP-A-57-4269.
No. 0). That is, the following general formula (II
From the N-thienylaminomethylene acetic acid derivative represented by I) to a compound having a thieno [3,2-b] pyridine skeleton (in the compound represented by the general formula (IV), R ¹⁰ is a hydrogen atom) The above-mentioned general formula having activity by a derivatized and generally known method, for example, a method of reacting with an alkyl halide having an appropriate alkyl group in the presence of an alkali such as K ₂ CO _{3 in} a solvent such as DMF. A route for synthesizing a 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) is known.

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

[0007]

[Chemical 5]

(In the above formula, R¹And R²Are each
Independently hydrogen atom, halogen atom, C ₁~ C₆The archi
Group, phenyl group which may have a substituent or naphthyl group
Lu group, C₁~ C₆Alkylsulfonyl group or cyano
Aminothiophenecarboxylic acid derivative represented by
After isolation as the sodium salt of the body, the following general formula (I
Compounds represented by I), eg ethoxymethylene malon
In the presence of acid diethyl ester and an acid such as acetic acid, toluene
By heating (80-120 ° C) with a solvent such as
It is known that it can be obtained (Richard
L. Elliottet al. , Tetrahedr
on Vol. 43, No. 14, p3295 (198
7)) has a low yield of 48% in this method. Also the following general
The compound of formula (I) was hydrolyzed with alkali.
After that, by using an acid such as hydrochloric acid, the compound is represented by the general formula (V).
Isolated as an aminothiophenecarboxylic acid derivative,
Is a compound represented by the following general formula (II), for example, ethoxy
Methylene malonic acid diethyl ester, solvent-free, ether
L, N, N-dimethylformamide, toluene, etc.
By heating (90-160 ° C) with the solvent of
It is known that it can be obtained (JP-A-57-1160).
77, EP-0269295), these methods
Has a low yield of about 50%, and the thiophene ring has a
The following general formula (VI) in which a xyl group remains

[0009]

[Chemical 6]

(In the above formula, R¹And R²Is the general
As defined in formula (V), R ^FiveIs C₁~ C₆of
Represents an alkoxycarbonyl group or a cyano group, R⁶Is
C₁~ C₆Represents an alkyl group. ) By-product represented by
(Reacted with ethoxymethylene malonic acid diethyl ester
When added, the compound represented by the general formula (VI) above
Chi, R^FiveIs an ethoxycarbonyl group, R⁶Is an ethyl group
Compound)) is mixed in.

After reducing the nitro group of commercially available 3-nitrothiophene with tin and hydrochloric acid, the compound of the following general formula (II) is added to 40 to 45 in a pyridine solvent.
A method of reacting at ℃ for 24 hours is known (Misb
ahul Ani Khanet al. J. Het
erocyclic Chem. , 14,807 (19
77)), this method does not cause the by-product problem of the compound represented by the general formula (VI), but the yield is 50 to 69.
%, And synthesis with 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 made an aminothiophenecarboxylic acid derivative ester represented by the following general formula (I) under mild reaction conditions. The N-thienylamino compound represented by the following general formula (III) can be produced in high yield and high purity by efficiently reacting with a dealkoxycarbonyl compound and then reacting with an alkoxymethylene acetic acid derivative represented by the following general formula (II). It has been found that a methylene acetic acid derivative can be obtained, and the present invention has been completed.

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

[0014]

[Chemical 7]

(In the above formula, R¹And R²Are each
Independently hydrogen atom, halogen atom, C ₁~ C₆The archi
Group, phenyl group which may have a substituent or naphthyl group
Lu group, C₁~ C₆Alkylsulfonyl group or cyano
Represents a group, R³Is C₁~ C₆Represents an alkyl group. )so
Aminothiophenecarboxylic acid ester derivative represented
Hydrolyze and decarboxylate to give dealkoxycarbonyl compounds
Then, the dealkoxycarbonyl compound was prepared by the following general formula
(II)

[0016]

[Chemical 8]

(In the above formula, R^FourAnd R⁶Are each
Independently C₁~ C₆Alkyl group of R ^FiveIs C₁~ C₆of
Represents an alkoxycarbonyl group or a cyano group. )
Reaction with alkoxymethylene acetic acid derivatives
The following general formula (III) characterized by

[0018]

[Chemical 9]

(In the above formula, R ¹ , R ² , R ⁵ and R
⁶ is as defined in the above general formulas (I) and (II). ) In N-thienyl amino methylene acetic acid derivative manufacturing method. Hereinafter, the present invention will be described in detail.

The above general formulas (I), (III), (V) and (V
In the compound represented by I), the halogen atom defined by R ¹ and R ² includes a chlorine atom, a bromine atom, an iodine atom and the like, and the C ₁ -C ₆ alkyl group includes:
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, The phenyl group which may have a substituent is a phenyl group, a para-chlorophenyl group, a para-
Examples thereof include a methylphenyl group, and the naphthyl group which may have a substituent includes a 1-naphthyl group, a 2-naphthyl group, a 5-chloro-1-naphthyl group, a 6-methyl-2-naphthyl group and the like. 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 is
Examples thereof 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. Examples of the C _{1 to} C ₆ alkyl group defined by R ⁴ in the compound represented by the general formula (II) include a methyl group, an ethyl group, an n-propyl group, is
o-propyl group, n-butyl group, iso-butyl group, s
Examples thereof include an ec-butyl group, a tert-butyl group, an n-pentyl group and an n-hexyl group.

In the compounds represented by the general formulas (II), (III) and (VI), the C ₁ -C ₆ alkoxycarbonyl group defined by R ⁵ is a methoxycarbonyl group, an ethoxycarbonyl group or n. -Propoxycarbonyl group, iso-propoxycarbonyl group, n-butoxycarbonyl group, iso-butoxycarbonyl group, sec-
Examples thereof include a butoxycarbonyl group and a tert-butoxycarbonyl group.

In the compounds represented by the general formulas (II), (III) and (VI), the C ₁ -C ₆ alkyl group defined by R ⁶ is a methyl group, an ethyl group or 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 n-hexyl group. The manufacturing process of the present invention is shown below.

[0024]

[Chemical 10]

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

Alcohols as solvents without isolation of the carboxylic acid derivative (V) produced in (Step A),
After preferably adding ethanol, an organic acid such as mineral acid or acetic acid, preferably acetic acid is added to acidify the reaction solution,
-40 ° C, preferably 10-30 ° C, 30 minutes-24
By reacting for a time, preferably 1 to 4 hours,
The decarboxylation reaction can be allowed to proceed slowly to lead to the dealkoxycarbonyl compound represented by the general formula (VII).
If necessary, this (step B) can be analyzed by using an ordinary analysis method such as TLC or HPLC to trace the reaction. In the method of the present invention, the intermediate (V) is not isolated but is decarboxylated and subjected to the following steps.

When (step B) is completed, the alkoxymethylene acetic acid derivative represented by the general formula (II) is added to the reaction solution and reacted at 0 to 40 ° C., preferably 10 to 30 ° C. , N- represented by the general formula (III)
A thienylaminomethylene acetic acid derivative is obtained. In addition, in (Step B), it is desirable to analyze the reaction process by a method such as TLC and HPLC, and the dealkoxycarbonyl derivative (VI) of the aminothiophenecarboxylic acid derivative (V) is analyzed.
Analyze conversion to I). As a result, 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 with the N-thienylaminomethylene acetic acid derivative (III), can be significantly reduced. it can.

The N-thienylaminomethylene acetic acid derivative of the above-mentioned general formula (III) obtained as described above can be isolated and purified by known means such as filtration, concentration, extraction, chromatography, reprecipitation and recrystallization. It can be isolated in any purity by using 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 drug such as an antibacterial agent or an antihypertensive agent can be obtained in high yield and high purity.

[0029]

INDUSTRIAL APPLICABILITY According to the method of the present invention, an aminothiophenecarboxylic acid ester derivative is introduced into a dealkoxycarbonyl derivative, and then reacted with an alkoxymethylene acetic acid derivative to be useful as a drug such as an antibacterial agent or an antihypertensive agent. An N-thienylaminomethylene acetic acid derivative, which is a synthetic intermediate of a thieno [3,2-b] pyridine derivative, can be obtained in high yield and high purity.

[0030]

The present invention will be described below with reference to examples.
The present invention is not limited to these examples. Example 1 3- (2,2-diethoxycarbonylethenyl) aminothiophene (in the general formula (III), R ¹ and R ² represent a hydrogen atom, R ⁵ represents an ethoxycarbonyl group, and R ⁶ represents an ethyl group. Compound) 11.2 g (282.7 mmol) of sodium hydroxide
Was dissolved in 340 ml of water, and 40.4 g (257 of 3-aminothiophene-2-carboxylic acid methyl ester) was dissolved in this.
(Mmol) and heated to reflux for 30 minutes. The reaction solution
After cooling to room temperature, 400 ml of ethanol was added, and 17.7 ml (308.4 mmol) of acetic acid was added dropwise over 1 hour. After 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 give a dealkoxycarbonyl derivative (3 -Aminothiophene) was confirmed, and 61 g (28 g) of ethoxymethylene malonic acid diethyl ester was confirmed.
(2.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (600 ml) was added to the reaction solution, the mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration to give the target compound 3- (2,2-diethoxycarbonylethenyl) aminothiophene 61.3 g.
(Yield 89.0%) was obtained.

M. p. : 80-82 ° C IR (KBr) cm ^-1 : 3443,1684,163
6,1603,1267,1238 NMR (CDCl ₃ ) δ: 1.26 to 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 general formula (III), R ¹ is hydrogen atom, R ² is bromine atom, and R ⁵ is ethoxy. Carbonyl group, compound in which R ⁶ is represented by ethyl group) 2.71 g (67.8 mmol) of sodium hydroxide,
It was dissolved in 68 ml of water, and 8.0 g (3-amino-4-bromothiophene-2-carboxylic acid methyl ester was added thereto.
3.9 mmol) was added and the mixture was heated under reflux for 1 hour. 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 added dropwise over 1 hour. After completion of the dropping, the mixture was stirred for an additional 1 hour and then subjected to HPLC analysis in the same manner as in Example 1 to give the dealkoxycarbonyl compound (3
-Bromo-4-aminothiophene) was confirmed and ethoxymethylene malonic acid diethyl ester 8.0
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, the precipitated crystals were collected by filtration, and 11.7 g of the target product, 3-bromo-4- (2,2-diethoxycarbonylethenyl) aminothiophene.
(Yield 98.7%) was obtained.

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 (In the general formula (III), R ¹ and R ² are hydrogen atoms, R ⁵ is an ethoxycarbonyl group, and R ⁶ is an ethyl group. The compound of the formula (1) 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 dissolved therein.
(159.0 mmol) was added, and the mixture was heated under reflux for 30 minutes. Cool it to room temperature and add concentrated hydrochloric acid at room temperature to adjust the pH.
<5.0, and precipitated crystals (3-aminothiophene-
2-carboxylic acid) was collected by filtration. Tetrahydrofuran (25 ml) and ethoxymethylenemalonic acid diethyl ester (41.3 g, 190.8 mmol) were added thereto, and the mixture was stirred at 85 to 90 ° C. for 2 hours while distilling off tetrahydrofuran and produced ethanol. After cooling, water and chloroform were added, the mixture was extracted with chloroform, the organic layers were combined and dried over magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (eluent, chloroform / n-hexane = 2/1), and recrystallized from isopropyl ether / n-hexane to give the target compound 3- ( 2,2-diethoxycarbonylethenyl) aminothiophene 20.4 g (yield 4
7.7%).

Claims (1)

[Claims] 1. The following general formula (I):(In the above formula, R¹And R²Are each independently hydrogen
Atom, halogen atom, C ₁~ C₆Alkyl groups and substituents
A phenyl group or a naphthyl group which may have C,₁~
C₆Represents an alkylsulfonyl group or a cyano group of
³Is C₁~ C₆Represents an alkyl group. ) Ami
Hydrolysis and hydrolysis of nothiophenecarboxylic acid ester derivatives
And decarboxylation to obtain a dealkoxycarbonyl derivative, and then
The dealkoxycarbonyl compound is represented by the following general formula (II):(In the above formula, R^FourAnd R⁶Are each independently C₁
~ C₆Alkyl group of R ^FiveIs C₁~ C₆Alkoxyka
Represents a carbonyl group or a cyano group. ) Arco
Characterized by reacting with a xymethylene acetic acid derivative
The following general formula (III):(In the above formula, R¹, R², R^FiveAnd R⁶Is the above general
As defined in formulas (I) and (II). )
For producing N-thienylaminomethylene acetic acid derivative
Law.