JPH0616667A - New production of pyrazolo(1,5-a)pyridine derivative - Google Patents

Abstract

PURPOSE:To obtain a pyrazolo[1,5-a]pyridine useful as a raw material for a medicine and its raw material under a mild condition in high yield by reacting a pyridine derivative with a specific compound. CONSTITUTION:The compound of formula I [R<1> is H, (substituted) amino, carboxyl or 2-5C alkoxycarbonyl; R<2> is H, 1-4C alkyl or 1-4C alkoxy] is reacted with a compound of the formula H2NO-R<3> [R<3> is sulfonic acid residue; (substituted) phenylsulfonyl, lower alkylsulfonyl, (substituted) phenylcarbonyl or lower alkanoyl] preferably at -5 to +10 deg.C to give the objective compound of formula II.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing a pyrazolo [1,5-a] pyridine derivative useful as a drug or a raw material for a drug.

[0002]

2. Description of the Related Art Many compounds having a pyrazolo [1,5-a] pyridine skeleton exhibit pharmacological activity. For example, Japanese Patent Publication No. 52-29318 and Japanese Patent Publication No. 4-2091.
No. 6 and Japanese Patent Publication No. 4-20917.

Conventionally, as a method for constructing a pyrazolo [1,5-a] pyridine skeleton, an acyl halide derivative is allowed to act on a 1-aminopyridinium salt derivative (J.O.
rg. Chem. , 33 , 3766 (1968)), 1
-Aminopyridinium salt derivative reacted with an acid anhydride in the presence of a deoxidizing agent (Japanese Patent Publication No. 52-29318)
However, this reaction is a reaction under heating, and coloring and the like occur, and the yield is not satisfactory.

From the viewpoint of pharmaceutical synthesis, a more convenient and more efficient method for synthesizing a pyrazolo [1,5-a] pyridine derivative under milder conditions is desired.

[0005]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention An object of the present invention is to efficiently prepare a pyrazolo [1,5-a] pyridine derivative from a pyridine derivative represented by the general formula (1) under milder conditions. It is to provide a manufacturing method.

[0006]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors to solve the above problems, the general formula (1)

[0007]

[Chemical 4]

(Wherein R ¹ is ^{1 to 2} of a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a hydroxy group, a lower alkoxy group having 1 to 6 carbon atoms, and a lower alkyl group having 1 to 4 carbon atoms.
An amino group which may be substituted by number, a carboxyl group or a lower alkoxycarbonyl group having 2 to 5 carbon atoms, R ²
Represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkoxy group having 1 to 4 carbon atoms) to a general formula (3)

[0009]

[Chemical 5]

In the production of the pyrazolo [1,5-a] pyridine derivative represented by the formula (wherein R ¹ and R ² are as described above), the general formula (2)

[0011]

[Chemical 6]

(In the formula, R ³ represents a sulfonic acid residue, a phenylsulfonyl group which may have a substituent, a lower alkylsulfonyl group, a phenylcarbonyl group which may have a substituent or a lower alkanoyl group. The present invention has been completed by finding that a pyrazolo [1,5-a] pyridine derivative can be efficiently produced under mild conditions by reacting a compound represented by the formula (1).

That is, the general formula (1)

[0014]

[Chemical 7]

(Wherein R ¹ and R ² are as described above) and the general formula (2)

[0016]

[Chemical 8]

(Wherein R ³ is as described above) and a compound not involved in the reaction such as ether, 1,2-dichloroethane, benzene, toluene and dichloromethane, at -15 ° C to room temperature, The corresponding general formula (3) is preferably obtained by reacting at −5 to 10 ° C.

[0018]

[Chemical 9]

The pyrazolo [1,5-a] pyridine derivative represented by the formula (wherein R ¹ and R ² are as described above) can be obtained in high yield.

The pyridine derivative represented by the general formula (1) can be prepared by, for example, the method of Wolfe et al. (J. Org.
Chem. , 43 , 2286 (1978)) or in accordance therewith.

R ³ of the compound represented by the general formula (2) is
A phenylsulfonyl group which may have a substituent or a lower alkylsulfonyl group is preferable, and a phenylsulfonyl group which may be substituted with 1 to 3 lower alkyl groups having 1 to 3 carbon atoms is particularly preferable.

Here, among the compounds represented by the general formula (2), the compound in which R ³ is a phenylsulfonyl group which may have a substituent is represented by the general formula (4)

[0023]

[Chemical 10]

(In the formula, R ⁴ represents a lower alkyl group having 1 to ⁴ carbon atoms, R ⁵ represents a lower alkoxy group having 1 to 4 carbon atoms, and R ⁶ represents phenyl which may have a substituent. It can be produced by reacting a compound represented by sulfonyl group) with an aqueous solution of perchloric acid or the like in a solvent such as dioxane or methanol that does not participate in the reaction. It can be used for the reaction with the compound represented by the general formula (1) without separation.

The compound represented by the general formula (4) can be obtained by, for example, the method of Tamura et al. (J. Org. Chem.,
38 , 1239 (1973)) or in accordance therewith.

The obtained pyrazolo [1,5-a] pyridine derivative represented by the general formula (3) is reacted with, for example, an acid anhydride and, if necessary, further treated to obtain a desired compound.
No. 2-29318, Japanese Patent Publication No. 4-20916, Japanese Patent Publication No. 4
The compound described in JP-A-20917 can be used as a compound useful as a drug or a raw material for a drug.

[0027]

EXAMPLES The usefulness of the method of the present invention is shown below, but the present invention is not limited to the examples.

Example 1 Preparation of 2-isopropylpyrazolo [1,5-a] pyridine

[0029]

[Chemical 11]

3-Methyl-1- (2-pyridyl) -2-butanone (179.5 m) in methylene chloride (1.8 ml).
g, 1.10 mM) and dissolved under stirring at 0 ° C.
A solution of toluenesulfonylhydroxylamine in methylene chloride (6 ml) (corresponding to 1.20 mM) was slowly added dropwise. After stirring for 30 minutes at the same temperature, saturated sodium bicarbonate water, water,
The reaction solution was washed successively with saturated saline. After the reaction solution was dried over anhydrous sodium sulfate, methylene chloride was distilled off under reduced pressure to obtain a crude product. The crude product was subjected to silica gel thin layer chromatography (developing solvent; n-hexane: ethyl acetate =
3: 1) and the desired product (143.2 mg, yield 8)
1.3%) was obtained.

NMR (CCl ₄ , TMS standard) δPP
M: 8.30 (1H, d, J = 7Hz), 7.31 (1H,
d, J = 7 Hz), 6.90 (1H, t, J = 7H)
z), 6.49 (1 H, t, J = 7 Hz), 6.17
(1H, s), 3.12 (1H, m, J = 7Hz),
1.33 (6H, d, J = 7Hz) Example 2 Preparation of 2 -methylpyrazolo [1,5-a] pyridine

[0032]

[Chemical 12]

1- (2- in methylene chloride (1.0 ml)
Pyridyl) -2-propanone (135.2 mg, 1.0
mM), and the solution of O-p-toluenesulfonylhydroxylamine in methylene chloride (3 m) was stirred at 0 ° C.
1) (corresponding to 1.0 mM) was slowly added dropwise. After stirring at the same temperature for 30 minutes, the reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. After the reaction solution was dried over anhydrous sodium sulfate, methylene chloride was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica gel thin layer chromatography (developing solvent; n-hexane: ethyl acetate = 3: 1) to obtain the desired product (105.9 mg, yield 80.1%).

NMR (CCl ₄ , TMS standard) δPP
M: 8.30 (1H, d, J = 7Hz), 7.32 (1H,
d, J = 7 Hz), 6.93 (1H, t, J = 7H)
z), 6.51 (1H, t, J = 7Hz), 6.12
(1H, s) 2.41 (3H, s)

[0035]

As described above, according to the method of the present invention, a pyrazolo [1,5-a] pyridine derivative can be produced from a pyridine derivative in a high yield under mild conditions.

Claims (1)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ is a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, a hydroxy group, a lower alkoxy group having 1 to 6 carbon atoms,
An amino group which may be substituted with 1 to 2 lower alkyl groups having 1 to 4 carbon atoms, a carboxyl group or 2 to 2 carbon atoms
5 is a lower alkoxycarbonyl group, R ² is a hydrogen atom,
A pyridine derivative represented by a lower alkyl group having 1 to 4 carbon atoms or a lower alkoxy group having 1 to 4 carbon atoms is represented by the general formula (2): (In the formula, R ³ represents a sulfonic acid residue, an optionally substituted phenylsulfonyl group, a lower alkylsulfonyl group, an optionally substituted phenylcarbonyl group or a lower alkanoyl group) A compound represented by the general formula (3): (In the formula, R ¹ and R ² are as described above) A method for producing a pyrazolo [1,5-a] pyridine derivative.