JP3127505B2 - Method for producing pyrazolopyridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to pyrazolo [1,5-
a] A method for producing a pyridine derivative. The compounds of the present invention are useful as synthetic intermediates for diuretic / hypertensive agents.

[0002]

2. Description of the Related Art (2)
R) -1- [3- (2-Phenylpyrazolo [1,5-
a] pyridin-3-yl) acryloyl] -2- (2-
Hydroxyethyl) piperidine is useful as a diuretic / hypertensive agent and the like. However, 3- (2-phenylpyrazolo [1,5-a] pyridin-3-yl) acrylate, which is a key compound for the synthesis, needs to be synthesized through several steps using an N-aminopyridine compound as a raw material. was there. The present invention has been found as a result of intensive studies on a method for synthesizing the above-mentioned key compound from an N-aminopyridine compound in a short step and with high yield.

[0003]

SUMMARY OF THE INVENTION The present invention provides a method for producing a pyrazolopyridine derivative from an N-aminopyridine compound in a single step and at a high yield. Thus, according to the present invention, formula ^{(III): R 2 -C≡C-} A-R 3 ( wherein, R ² is an optionally substituted aryl group, R ³ is a protected carboxyl group, and A represents a lower alkenylene group) and a compound represented by the formula (II):

[0004]

Embedded image (Wherein, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, and X ⁻ represents an anion) in the presence of a base. To a protected carboxyl group according to formula (I):

[0005]

Embedded image (Wherein R ¹ , R ² and A have the same meaning as described above, and R ^{3 ′} represents a carboxyl group or a protected carboxyl group) or a salt thereof. preparation of pyrazolopyridine derivatives, and formula (IV) R ² -C≡C-CHO aldehyde compound represented by (wherein, R ² denotes an aryl group which may be substituted) and formula (V)

[0006]

Embedded image (Wherein R ³ represents a protected carboxy group, A ¹ represents a lower alkylene group, and R ⁴ represents a lower alkyl group) in the presence of a base; A compound represented by R ² -C≡C-A-R ³ (wherein each symbol has the same meaning as described above) is produced, and without isolating the compound, the compound represented by the formula (II)

[0007]

Embedded image (Wherein, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, and X ⁻ represents an anion) in the presence of a base. To a carboxyl group protected according to the formula (I)

[0008]

Embedded image (Wherein R ¹ , R ² and A have the same meaning as described above, and R ^{3 ′} represents a carboxyl group or a protected carboxyl group) or a salt thereof. A method for producing a pyrazolopyridine derivative is provided.

In the above formula, the lower alkyl group represented by R ¹ and R ⁴ is C ^1-5 alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-alkyl.
Butyl, t-butyl, n-pentyl, i-pentyl, s
-Pentyl and the like, among others, methyl, ethyl,
N-propyl and the like are preferred. As the lower alkoxy group represented by R ¹ , C ^1-3 alkoxy, for example, methoxy,
Ethoxy, n-propoxy, i-propoxy and the like can be mentioned, and methoxy, ethoxy and the like are particularly preferable. The halogen atom represented by R ^1, fluorine, chlorine, bromine,
Iodine.

R^TwoThe “optionally substituted
As the aryl group in the "reel group", for example,
Nil, naphthyl, indenyl, anthryl and the like.
And phenyl is particularly preferred. These aryl groups
Suitable substituents in are, for example, fluorine, chlorine,
Halogen atoms such as bromine and iodine; for example methoxy,
C such as ethoxy and propoxy_1-3Alkoxy group, nitro
Group, amino group, mono- or di-C_1-3Alkylamino
Group, ureido group, C_1-3Alkanoylamino group, C _1-3A
Lucoxycarbonylamino group, C_1-3Alkansulfoni
And an amino group. The number of substituents is preferably 1 to 3.
Good. Specific examples of the optionally substituted aryl group
Phenyl, chlorophenyl, methoxyphenyl,
Nitrophenyl, aminophenyl, acetylaminophen
Nil, methoxycarbonylaminophenyl, methanesul
Honylaminophenyl, methylaminophenyl and dimethyl
Tylaminophenyl and the like.

The protected carboxyl group represented by R ³ includes a C _1-6 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl. And the like.

The lower alkenylene group represented by A includes a C _2-6 alkenylene group, preferably a C _2-4 alkenylene group, and more preferably a vinylene group.

The alkylene group represented by A ¹ is C _2-6
An alkylene group, preferably a C _2-4 alkylene group, for example, a methylene, ethylene, propylene group and the like can be mentioned.

[0014] X ^- include anions represented by the halogen ion, hydroxyl ion, and nitrate ions.
Salts of the compound of formula (I) of the present invention include, for example,
Metal salts such as alkali metal salts such as sodium salt and potassium salt and alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine Salts, organic base salts such as N, N'-dibenzylethylenediamine salt, for example, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, bezelsulfonate, formate , Organic acid salts such as toluenesulfonate, for example, hydrochloride, hydrobromide, hydroiodide, sulfate,
Inorganic acid salts such as phosphates, for example, salts with amino acids such as arginine, aspartic acid, glutamic acid and the like can be mentioned.

The reaction between the compound of the formula (III) and the N-aminopyridine compound of the formula (II) is usually carried out in an inert organic solvent in the presence of a base. Examples of the base include alkali metal hydroxides (eg, potassium hydroxide and sodium hydroxide), alkali metal alcoholates (eg, sodium methylate, sodium ethylate, and the like). The amount of the base used is preferably at least 1 molar equivalent to the N-aminopyridine compound of the formula (II).

Examples of the organic solvent inert to the reaction include dimethyl sulfoxide, dimethylformamide, dimethylacetamide and the like. However, it is not particularly limited to these.

The amount of the N-aminopyridine compound of the formula (II) to be used is at least 1 molar equivalent, preferably 1.1 to 2.0 molar equivalents, relative to the compound of the formula (III). The reaction is
Usually, it is performed in a low temperature region, for example, about room temperature for one to several hours.
The generated pyrazolopyridine compound of the formula (I) is subjected to a deprotection reaction if necessary. The deprotection reaction is represented by the formula (I)
According to the type of the carboxyl-protecting group in the compound of the above, the method can be appropriately selected and used from known means. In the case of an esterified carboxyl group, such as an ethoxycarbonyl group, alkali hydrolysis in a suitable solvent can be mentioned.

The isolation and purification of the pyrazolopyridine compound of the formula (I) from the reaction solution can be carried out by a means known per se, for example, concentration, phase transfer, solvent extraction, distillation, recrystallization and the like. it can.

The compound of the formula (III) used in the present invention is a compound not described in any literature. Compounds of formula (III)
It is obtained by reacting an aldehyde compound of the formula (IV) with a phosphorus compound of the formula (V) in the presence of a base. The base used here is the compound of the above formula (III) and the compound of the formula (II)
The same bases as those used in the condensation reaction with the compound (a) can be used. The base is mainly used to trap phosphoric acid by-produced by the reaction as a salt. Therefore, the amount used is preferably at least equimolar to the phosphorus compound of the formula (V). On the other hand, this reaction is usually carried out by the formula (III)
And the compound of formula (II) in the same solvent as used in the condensation reaction. The reaction temperature is in a low temperature range, for example, about room temperature. The reaction time is one to several hours.

The resulting compound of the formula (III) is usually preferably used without isolation for the condensation reaction with the N-aminopyridine compound of the formula (II). Therefore, according to the present invention, a desired compound of the formula (I) can be derived from the aldehyde compound of the formula (IV) in a single reaction vessel in a so-called one-stage method.

The N-aminopyridine compound of the formula (II) is
It is at least 1 molar equivalent, preferably 1.1 to 2.0 molar equivalents, based on the aldehyde compound of the formula (IV). The pyrazolopyridine compound of the present invention wherein R ^{3 ′ in} formula (I) is a carboxyl group can be prepared, for example, according to a known method.
By reacting (2-hydroxyethyl) piperidine, a compound having a diuretic / hypertensive effect or the like can be obtained.

[0022]

The present invention will be described in more detail with reference to the following examples.

Example 1 Phenylpropargyl aldehyde [compound of formula (IV)]
10.0 g (0.077 mol) of dimethyl sulfoxide 1
Dissolved in 00 ml. At room temperature, 20.6 g of ethyl diethylphosphonoacetate [compound of formula (V)] (0.1
60 mol), and 4.7 g (0.120 mol) of potassium hydroxide was added while maintaining the temperature at 20 ± 5 ° C., and stirring was continued for 2 hours. Then, the 5-phenyl-2- obtained above.
To the reaction mixture containing pentene-4-ethyl formate, 1-
Aminopyridinium iodo salt [compound of formula (II)] 2
5.6 g (0.120 mol) and 6.5 g of potassium hydroxide
(0.120 mol) and stirred at 20 ± 5 ° C. for 2 hours. The reaction solution was previously cooled to 10 to 15 ° C. with 200 m of water.
and 100 ml of methylene chloride, and adjusted to pH 6 to 7 with hydrochloric acid. The separated methylene chloride layer was washed with water 1
After washing with 00 ml, the separated methylene chloride layer was concentrated under reduced pressure. 20 ml of ethyl acetate was added to the concentrated residue, and the mixture was stirred, cooled to -10 ° C, stirred for 30 minutes, and the precipitated crystals were collected by filtration and dried to give 3- (2-phenylpyrazolo [1,5-a]. ] Pyridin-3-yl) acrylate [compound of formula (I), 11.0 g, 51.0%] was obtained. mp 122 DEG-123 DEG C. MS 292 (M @ ⁺ ) IR (nujol, cm @ -1) 2850, 1690, 16
20,698 NMR δ (ppm, DMSO-d ₆ ) 8.9 (1H, d, J = 7 Hz), 8.2 (1H, d, J)
= 9 Hz), 7.8 (1H, d, J = 13 Hz), 7.4
７7.7 (6H, m), 7.2 (1H, dd, J = 1H)
z, 6 Hz), 6.4 (1H, d, J = 16 Hz), 4.
2 (2H, dd, J = 7 Hz), 1.2 to 1.3 (3H,
t, J = 7Hz)

[0024]

According to the method of the present invention, an intermediate for synthesizing a pyrazolo [1,5-a] pyridine derivative exhibiting an excellent diuretic hypotensive action and the like can be produced in a high yield by a one-step method.
In addition, it is possible to obtain a high-purity target product without requiring special purification, and it is industrially highly useful.

────────────────────────────────────────────────── (5) References JP-A-1-45385 (JP, A) JP-A-57-53486 (JP, A) JP-A-57-123181 (JP, A) (58) Investigation Field (Int.Cl. ⁷ , DB name) C07D 471/04 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] [Claim 1] Formula ^{(III): R 2 -C≡C-} A-R 3 ( wherein, R ² is an optionally substituted aryl group, R ³ is a protected carboxyl group, and A is a lower An alkenylene group) and a compound of formula (II): (Wherein, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, and X ⁻ represents an anion) in the presence of a base, If necessary, the protected carboxyl group may be subjected to a deprotection reaction to obtain a compound of the formula (I): (Wherein R ¹ , R ² and A have the same meaning as described above, and R ^{3 ′} represents a carboxyl group or a protected carboxyl group) or a salt thereof. A method for producing a pyrazolopyridine derivative. Wherein formula (IV) R ² -C≡C-CHO aldehyde compound represented by (wherein, R ² meaning a optionally substituted aryl group) and formula (V) ## STR3 ## (Wherein, R ³ is protected carboxy group, A1 is lower alkylene group, and R4 represents a lower alkyl group) and a phosphorus compound represented by in the presence of a base, formula (III) R ² -C≡C-A-R ³ (where A is a lower alkenylene group, and R ² and R ³ have the same meanings as described above), and without isolation, the compound represented by the formula ( II) (Wherein, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, and X ⁻ represents an anion) in the presence of a base. To a carboxyl group protected according to the formula (I) (Wherein R ¹ , R ² and A have the same meaning as described above, and R ^{3 ′} represents a carboxyl group or a protected carboxyl group) or a salt thereof. A method for producing a pyrazolopyridine derivative.