JP3332171B2 - Method for producing thieno [3,2-b] pyridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a thieno [3,2-) useful as a pharmaceutical having antibacterial activity or antihypertensive activity.
b] A method for producing a pyridinecarboxylic acid derivative or an intermediate thereof, a thieno [3,2-b] pyridine derivative.

[0002]

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

[0003]

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(In the above formula, R ⁶ and R ⁷ each independently represent a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, etc., R ⁸ represents a hydroxyl group, a C ₁ -C ₆ alkoxy group. Or a thieno [3,2-b] pyridinecarboxylic acid derivative represented by an amino group or the like, and R ⁹ represents a C ₁ -C ₆ alkyl group or the like;
No. 0) or antihypertensive activity (European Patent No. 02692)
No. 95).

The thieno [3,2-b] pyridinecarboxylic acid derivative represented by the general formula (III) is generally known as a thieno [3,2-b] pyridine derivative represented by the following general formula (II). For example, a method of deriving a corresponding carboxylic acid by hydrolyzing a C ₁ -C ₆ alkoxycarbonyl group or a cyano group in the presence of an acid or an alkali, and adding an amine such as ammonia to the carboxylic acid. Reaction to induce carboxamide or R
^{When 3} is a hydrogen atom, a method for synthesizing an N-alkylated pyridine ring by reacting with an alkyl halide having an appropriate alkyl group in a solvent such as DMF in the presence of a base such as K ₂ CO ₃ And the like have been synthesized alone or in combination (Richard
d L. Elliott et al. , Tetrah
edron Vol. 43, no. 14, pp3295
to 3302, 1987, EP 026929.
5, JP-A-57-42690, JP-A-57-1
No. 16077, JP-A-57-142985).

That is, the compound of the following general formula (II) is a compound of the above general formula (III) useful as a pharmaceutical or a synthetic intermediate useful for synthesizing the compound of the above general formula (III). Thieno [3, represented by the following general formula (II)
2-b] pyridine derivative is an N-thienylaminomethylene acetic acid derivative represented by the following general formula (I);
a method known as the Old-Jacobs method, for example, a method of heating at 200 to 260 ° C. in a high boiling point solvent such as Dowtherm A, diphenyl or diphenyl ether (Richard L. Elliott et al.)
al. , Tetrahedron Vol. 43, N
o. 14, pp3295 to 3302, 1987)
Is known to be synthesized by this method.
Since a high temperature of 0 to 260 ° C. is required, there is a problem that industrial use is greatly restricted.

A thieno [3,2-b] pyridine derivative represented by the following general formula (II) is obtained by converting an N-thienylaminomethylene acetic acid derivative represented by the following general formula (I) to phosphorus oxychloride, 80 to 14 halogen-containing acidic substances such as phosphorus bromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, phosphorus tribromide, thionyl chloride and thionyl bromide.
It is known that the compound is synthesized by a method of acting at 0 ° C. (JP-A-57-42690). Among the compounds represented by the following general formula (I), R ¹ is a bromine atom,
There are no examples other than compounds in which ² and R ³ are limited to hydrogen atoms, and the obtained ring-closed product is one in which the 7-position is halogenated and the halogen atom of the halogen-containing acidic substance used is partially substituted with a bromine atom. Since it is a mixture with, its application range is naturally limited.

Further, as a method for synthesizing a thieno [3,2-b] pyridine derivative represented by the following general formula (II), an N-thienylaminomethylene acetic acid derivative represented by the following general formula (I) is synthesized by using polyphosphoric acid. Or 5 in polyphosphate ester
A method of heating at 0 to 150 ° C. (usually around 120 ° C.) (G Malicone et al., Eur J
Med Chem (1991) 26, 3-11, JP-A-57-116077) is known, but polyphosphoric acid and polyphosphate are viscous substances and are restricted in industrial production.

Further, the following compound (IV) is added to acetic anhydride, and then concentrated sulfuric acid is added to cause ring closure at a temperature of room temperature to 70 ° C. (especially 55 to 70 ° C.) while eliminating nitro groups. A method for deriving the following compound (V) is also known (Takayoshi Ishizaki et al., The Chemical Society of Japan, 1985, (1)
0), p. 2054-2056),

[0010]

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A thieno [3,2-b] pyridine derivative represented by the following general formula (II) is converted from an N-thienylaminomethyleneacetic acid derivative represented by the following general formula (I) under a mild condition of less than 50 ° C. So far, how to obtain it was not known at all.

[0012]

Means for Solving the Problems As a result of repeated studies in view of the above problems, the present inventors have found that an N-thienylaminomethylene acetic acid derivative represented by the following general formula (I) can be converted into an inorganic compound such as concentrated sulfuric acid. In the presence of an acid, in an acid anhydride of an organic acid such as acetic anhydride,
The present inventors have found that a thieno [3,2-b] pyridine derivative represented by the following general formula (II) can be obtained under mild conditions of reacting at a relatively low temperature, 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, C₁~ C₆Archi
Group, phenyl group which may have a substituent or naphthyl
Group, C₁~ C₆Alkylsulfonyl group or cyano
R represents a group^ThreeIs a hydrogen atom or C₁~ C₆The alkyl of
R represents a group^FourIs C₁~ C₆Represents an alkyl group of ^Five
Is C₁~ C₆An alkoxycarbonyl group or a cyano group
Represents N-thienylaminomethylene acetic acid represented by
The derivative is reacted in the anhydride of an organic acid in the presence of an inorganic acid.
The following general formula (II):

[0016]

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(In the above formula, R ¹ , R ² , R ³ and R
⁵ is as defined in the above general formula (I). The present invention relates to a method for producing a thieno [3,2-b] pyridine derivative represented by the following formula: Hereinafter, the present invention will be described in detail. In the compounds represented by the general formulas (I) and (II),
Examples of the halogen atom defined by R ¹ and R ² include a chlorine atom, a bromine atom and an iodine atom, and C ₁ -C ₆
Examples of the alkyl group of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-
Pentyl group, n-hexyl group and the like, and the phenyl group which may have a substituent include a phenyl group, a para-chlorophenyl group, a para-methylphenyl group, and the like;
The naphthyl group which may have a substituent 1-naphthyl, 2-naphthyl, 5-chloro-1-naphthyl group, 6-methyl-2-naphthyl group and the like, C ₁ ~
Alkylsulfonyl As the group methylsulfonyl group of C _6, n-propylsulfonyl group, etc. iso- propylsulfonyl group.

The compounds represented by the above general formulas (I) and (II)
In compounds, R^ThreeC defined by ₁~ C₆The alkyl of
As the group, a methyl group, an ethyl group, an n-propyl group, is
o-propyl group, n-butyl group, iso-butyl group, s
ec-butyl group, tert-butyl group, n-pentyl
Group, n-hexyl group and the like. Formula (I)
In the compound represented by^FourC defined by₁~ C₆
Examples of the alkyl group include methyl, ethyl, n-propyl
Group, iso-propyl group, n-butyl group, iso-butyl
Tyl group, sec-butyl group, tert-butyl group, n-
Examples include a pentyl group and an n-hexyl group.

Represented by the above general formulas (I) and (II)
In compounds, R^FiveC defined by ₁~ C₆Alcoqui
Examples of the carbonyl group include a methoxycarbonyl group and an ethoxy group.
Sicarbonyl group, n-propoxycarbonyl group, iso
-Propoxycarbonyl group, n-butoxycarbonyl
Group, iso-butoxycarbonyl group, sec-butoxy
Carbonyl group, tert-butoxycarbonyl group and the like.
I can do it.

The manufacturing process of the present invention will be described below.

[0021]

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(In the above formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above.) First, an inorganic acid such as concentrated sulfuric acid or perchloric acid, preferably concentrated sulfuric acid is converted to acetic acid, An acid anhydride of an organic acid such as propionic acid, preferably acetic anhydride, is added at -20 to 40 ° C, preferably 0 to 30 ° C.
C. (Step A). The compound of the general formula (I) is added thereto, and the temperature is lower than 50 ° C, preferably 20 to 40 ° C.
And the reaction time is from 1 hour to 72 hours, preferably from 2 hours to
By reacting for 24 hours (step B), the compound represented by the general formula (II) can be obtained. In this step, if necessary, the analysis of the step can be performed by using an ordinary analysis method such as TLC or HPLC. The compound represented by the general formula (I) can be purchased and used as a reagent,
Tetrahedron, 43 (14), 3295 (1
987), JP-A-57-116077, EP 0269295, and J. Heterocyclic
c Chem. , 14 , 807 (1977);
It can also be appropriately synthesized according to the method described in JP-A-145067.

The general formula (I) obtained as described above
The thieno [3,2-b] pyridine derivative represented by I) can be arbitrarily prepared by appropriately using known separation and purification means such as filtration, concentration, extraction, chromatography, reprecipitation, and recrystallization. Can be isolated.
Thus, thieno [3,2-b] pyridinecarboxylic acid derivatives useful as pharmaceuticals such as antibacterial agents or antihypertensive agents or thieno [3,2- useful as synthetic intermediates thereof]
b) A pyridine derivative can be obtained under mild reaction conditions.

[0024]

According to the method of the present invention, a thieno [3,2-b] pyridinecarboxylic acid useful as a medicament such as an antibacterial agent or an antihypertensive agent can be produced from an N-thienylaminomethyleneacetic acid derivative under mild reaction conditions. An thieno [3,2-b] pyridine derivative which is an acid derivative or a synthetic intermediate thereof can be obtained.

[0025]

EXAMPLES The present invention will be described below with reference to examples.
The present invention is not limited by these examples. Synthesis Example 1 3- (2,2-diethoxycarbonylethenyl) aminothiophene (in the above general formula (I), R ¹ , R ² and R
³ is a hydrogen atom, R ⁵ is an ethoxycarbonyl group and R ⁴ is an ethyl group) Synthesis 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 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.
(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 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 1 7-Hydroxythieno [3,2-b] pyridine-6-carboxylic acid ethyl ester (in the above formula (II),
Synthesis of R ¹ , R ² and R ³ are a hydrogen atom and R ⁵ is a compound represented by an ethoxycarbonyl group) 687 mg (7.0 mmol) of concentrated sulfuric acid was added to acetic anhydride 9.2.
Add dropwise at 0-30 ° C to the ml. At 20 ° C
1.0 g (3.7 mmol) of (2,2-diethoxycarbonylethenyl) aminothiophene was added and
Stir for 5 hours. The reaction solution was poured into 120 g of ice, 14.7 g of potassium carbonate was added little by little with stirring, and extracted three times with chloroform. Combine the chloroform layers,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. 10 ml of diethyl ether was added to the obtained residue, and the mixture was stirred. The precipitated crystals were collected by filtration, and the target compound, 7-
316 mg (yield 38.3%) of hydroxythieno [3,2-b] pyridine-6-carboxylic acid ethyl ester was obtained.

M. p. : 205-208 ° C IR (KBr) cm ^-1 : 3061, 1697, 164
0, 1606, 1281 NMR (CDCl ₃ ) δ: 1.28 (3H, t);
22 (2H, q), 7.31 (1H, d), 8.05
(1H, d), 8.50 (1H, s), 12.80 (1
H, broad s)

Example 2 7-Hydroxythieno [3,2-b] pyridine-6-carboxylic acid ethyl ester (in the above formula (II),
Synthesis of R ¹ , R ² and R ³ are a hydrogen atom and R ⁵ is a compound represented by an ethoxycarbonyl group) 29.1 g (296.5 mmol) of concentrated sulfuric acid was added to acetic anhydride 1
Add dropwise to 20.0 ml at 0-30 ° C. To this was added 20.0 g (74.0 mmol) of 3- (2,2-diethoxycarbonylethenyl) aminothiophene at 10 ° C.
Stirred at 0 ° C. for 2.5 hours. The reaction solution was poured into 2000 ml of water and stirred for 2 hours. The precipitated crystals were collected by filtration, and the filtrate was extracted twice with chloroform. After the extracted chloroform layers were combined and dried over magnesium sulfate, the solvent was distilled off under reduced pressure. 60 ml of ethanol was added to the obtained residue and the mixture was stirred, and the precipitated crystals were collected by filtration.
8.70 g (yield 52.7%) of 7-hydroxythieno [3,2-b] pyridine-6-carboxylic acid ethyl ester, which is the target compound, was obtained by combining the crystals.

──────────────────────────────────────────────────続 き Continuation of front page (56) References JP-A-57-116077 (JP, A) JP-A-57-42690 (JP, A) JP-A-59-219288 (JP, A) JP-A-63-1988 141984 (JP, A) Tetrahedron, 1987, Vol. 43, No. 14, p. 3295-3302 J.P. Chem. Research (M), 1982, p. 1726-1746 J.P. Chem. Research (M), 1978, p. 4701-4712 Eur. J. Med. Chem. , 1991, Vol. 26, No. 1, P. 3-11 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 495/04 105 CA (STN) REGISTRY (STN)

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, C₁~ C₆Alkyl group and substituent
A phenyl or naphthyl group optionally having₁~
C₆Represents an alkylsulfonyl group or a cyano group of
^ThreeIs a hydrogen atom or C₁~ C₆Represents an alkyl group of
^FourIs C₁~ C₆Represents an alkyl group of ^FiveIs C₁~ C₆
Represents an alkoxycarbonyl group or a cyano group. )so
An N-thienylaminomethyleneacetic acid derivative represented by an inorganic
The reaction is performed in the presence of an acid in an acid anhydride of an organic acid.
The following general formula (II):(In the above formula, R¹, R^Two, R^ThreeAnd R^FiveIs the above general
As defined in formula (I). ) Represented by)
[3,2-b] A method for producing a pyridine derivative.