JPH069631A - New production of pyrazolopyridine - Google Patents

Abstract

PURPOSE:To obtain a new method for producing a pyrazolopyridine compound useful as an intermediate for producing pyrazolopyridine derivatives useful as medicines. CONSTITUTION:A compound of formula III (R<1> is lower alkyl; R<2> is H or proper substituent group), e.g. 1-phenyl-1-butyn-3-one is made to react with a compound of formula II (R<3> is H or proper substituent group; X<-> is anion), e.g. N- aminopyridine iodide in a polar solvent such as N,N-dimethylformamide or dimethyl sulfoxide at ambient temperature to 50 deg.C to provide the objective compound of formula I, e.g. 3-acetyl-2-phenylpyrazolo[1,5-a]pyridine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing a pyrazolopyridine compound useful as an intermediate in the production of a pyrazolopyridine derivative useful as a medicine, and is useful in the field of medicine.

[0002]

OBJECT OF THE INVENTION The object of the present invention is to provide a novel method for producing a pyrazolopyridine compound which is useful as an intermediate in the production of a pyrazolopyridine derivative useful as a medicine.

[0003]

The pyrazolopyridine compound which is the object compound of the present invention is represented by the following general formula.

[Chemical 4] (In the formula, R ¹ represents a lower alkyl group, R ² represents hydrogen or a suitable substituent, R ³ represents hydrogen or a suitable substituent.) According to the present invention, the object compound (I) is produced by the following production method. can do.

Manufacturing method 1

[Chemical 5] (In the formula, R ¹ , R ² and R ³ each have the same meaning as described above, and X ⁻ represents an anion).

Suitable salts of the compound (I) include conventional non-toxic pharmaceutically acceptable salts, ie salts with various bases and acid addition salts. More specifically, alkali metal salts (eg, sodium salt, potassium salt, cesium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), salts with inorganic bases such as ammonium salt, Salts with organic bases such as organic amino salts (eg, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.), inorganic acids Addition salts (eg hydrochloride,
Hydrobromide, sulfate, phosphate, etc.), organic carboxylic acid addition salt or organic sulfonic acid addition salt (eg formate,
Acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-
Toluenesulfonate, etc.), salts with basic amino acids or acidic amino acids (eg, arginine, aspartic acid, glutamic acid, etc.) and the like.

In the above and subsequent description of the present specification, suitable examples and explanations of the definitions included in the scope of the present invention are explained in detail below. The "lower alkyl group" is, for example, a linear or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl and the like. A preferred example thereof is an alkyl group having 1 to 4 carbon atoms. Suitable "anions" include formate ion, acetate ion, trifluoroacetate ion, maleate ion, tartrate ion, methanesulfonate ion, benzenesulfonate ion, toluenesulfonate ion, chlorine ion,
Examples thereof include bromine ion, iodine ion, sulfate ion and phosphate ion. The “suitable substituent” for R ² is halogen, a lower alkoxy group, a nitro group, an amino group,
Examples thereof include lower alkylamino group, ureido group, lower alkanoylamino group, lower alkoxycarbonylamino group, lower alkanesulfonylamino group, and the like. Examples of the “suitable substituent” for the R ³ group include halogen, a lower alkyl group, a lower alkoxy group and the like. Preferable examples of the above “halogen” include fluorine, chlorine, bromine,
Examples thereof include iodine. Preferable examples of the “lower alkoxy group” include groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy. Preferable examples of the above “lower alkylamino” are substituted by the above linear or branched lower alkyl group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, pentylamino, hexylamino and the like. An amino group is mentioned. Preferable examples of the “lower alkanoylamino group” include groups such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, hexanoylamino, pivaloylamino and the like. Preferable examples of the “lower alkanesulfonylamino group” include groups such as mesylamino, ethanesulfonylamino, propanesulfonylamino, isopropanesulfonylamino, butanesulfonylamino and the like. Preferred examples of the "lower alkoxycarbonylamino group" include:
For example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, pentyloxycarbonylamino, isopentyloxycarbonylamino, neopentyloxycarbonylamino, hexyloxycarbonylamino, etc. Groups.

The method for producing the object compound (I) will be described in detail below. Production Method 1 Compound (I) is prepared by converting Compound (II) into Compound (III)
It can be produced by reacting with. The reaction is preferably carried out in a polar solvent such as N, N-dimethylformamide, dimethylsulfoxide, etc., more preferably in dimethylsulfoxide, but any other solvent may be used as long as it does not adversely affect the reaction. The reaction can be carried out. The reaction can also be carried out in a two-layer solvent. Examples of such a two-layer system solvent include a two-layer system solvent of water and an organic solvent which is immiscible with water, and a preferable example thereof is water and methylene chloride, toluene or benzene. A layer system solvent can be mentioned, and a more preferable example is a two layer system solvent of water and methylene chloride. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling, room temperature, and heating or heating, preferably at room temperature or heating, and more preferably at room temperature to 50 ° C. When a two-layer solvent is used as the solvent, the reaction temperature is not particularly limited, but is usually 0 to under heating, preferably 0 to 50 ° C. In this reaction, the compound (I
It is preferable to use I) in a slightly excessive amount with respect to the compound (III), and it is more preferable to use the compound (II) and the compound (III) in a ratio of 1: 1 to 3: 1. preferable.

The present invention will be described below with reference to examples and reference examples. Example 1 1-Phenyl-1-butyn-3-one (5.00 g),
N-aminopyridine iodide (11.55 g) and dimethyl sulfoxide (50 ml) are added together, and the mixture is stirred at room temperature to dissolve. While stirring, potassium carbonate (4.79 g) crushed at an internal temperature of 20 ° C. was added all at once, and then the internal temperature was adjusted to 3
React at 3 to 37 ° C for 1 hour. After completion of the reaction, the reaction solution is dropped into water (300 ml) having an internal temperature of 20 ° C. for 20 minutes. After cooling the inner temperature to 0 to 5 ° C., the precipitated crystals are collected by filtration and washed with 50 ml of cooled 70% water-containing methanol (water: methanol = 30: 70). The crystals are dried under vacuum overnight to obtain 3-acetyl-2-phenylpyrazolo [1,5-a] pyridine (6.66 g). mp: 84-85 ° C. MASS: 236 IR (Nugeol): 1640, 1500
cm ^-1 NMR (CDCl ₃ , δ): 2.15 (3H,
s), 7.03 (1H, d-t, J = 1.4Hz, J
= 6.9 Hz), 7.45-7.62 (6H, m),
8.45 (1H, d, J = 8.9 Hz), 8.53
(1H, d, J = 6.9Hz)

Example 2 Water (740 ml) and 85% potassium hydroxide (70.7)
g) are combined and dissolved by stirring at room temperature. Then add methylene chloride (740 ml) and cool. Under stirring, internal temperature 5 ℃
At 1-phenyl-1-butyn-3-one (74.0
g) was added, and then N-aminopyridine iodide (11
3.2 g) is added. Thereafter, the reaction is carried out at an internal temperature of 15 to 25 ° C for 1 hour. After completion of the reaction, the layers are separated and the methylene chloride layer is separated. The aqueous layer is extracted with methylene chloride (370 ml). The methylene chloride layer is laminated, washed with water (740 ml), and concentrated under reduced pressure. Isopropyl alcohol (5
90 ml) is added. Further, water (1258 ml) is added to precipitate crystals. After cooling the inner temperature to 0 to 5 ° C., the crystals are collected by filtration and washed with 30% hydrous isopropyl alcohol (water: isopropyl alcohol = 70: 30) (370 ml). The crystals were dried under vacuum overnight, and 3-acetyl-2-phenylpyrazolo [1,5-a] pyridine (11
3.2 g) are obtained. mp: 84-85 ° C. MASS: 236 (molecular ion peak) IR (Nujol): 1640, 1500
cm ^-1 NMR (CDCl ₃ , δ): 2.15 (3H,
s), 7.03 (1H, d-t, J = 1.4Hz, J
= 6.9 Hz), 7.45-7.62 (6H, m),
8.45 (1H, d, J = 8.9 Hz), 8.53
(1H, d, J = 6.9Hz)

Reference Example 1 A mixture of 3-acetyl-2-phenylpyrazolo [1,5-a] pyridine (40.00 g) and glyoxalic acid monohydrate (20.27 g) was added at 100 ° C. to 2.5. Heat and stir for hours. The reaction mixture was ethyl acetate (220 ml)
And dissolved in a mixture of sodium hydroxide aqueous solution (12%, 220 ml). The aqueous layer is chloroform (100 ml)
Wash with and then acidify with 10% hydrochloric acid. It is extracted twice with chloroform (150 ml). Combine the extracts and wash with saturated aqueous sodium chloride. The solvent was distilled off, and the residue (39.8 g) was added to an aqueous ammonia solution (120 m).
l) and dissolved in hydrazine monohydrate (42
g) is added. The mixture is refluxed for 2 hours. The precipitate was collected by filtration to give 3- (3-oxo-2,3-dihydropyridazin-6-yl) -2-phenylpyrazolo [1,5-a].
Pyridine (14.45 g) is obtained. mp: 212-214 ° C. IR (Nugeol): 1660, 1625,
1580, 1510 cm ^-1 NMR (CDCl ₃ , δ): 6.87 (1H, d,
J = 11Hz), 7.00 (1H, td, J = 7Hz
And 1 Hz), 7.08 (1H, d, J = 11
Hz), 7.23-7.73 (6H, m), 7.8
3 (1H, d, J = 8Hz), 7.77 (1H, d,
J = 7 Hz) Elemental analysis: As C ₁₇ H ₁₂ N ₄ O, calculated value: C 70.82, H 4.20, N
19.43 Found: C 70.75, H 4.83, N
19.24

Reference Example 2 3- (3-oxo-2,3-dihydropyridazine-6-
Iyl) -2-phenylpyrazolo [1,5-a] pyridine (0.43 g), methyl acrylate (1.29 g), 4
A mixture of 0% methanolic trimethylbenzylammonium hydroxide (0.4 ml) and methanol (2 ml) in chloroform (8 ml) is refluxed for 40 minutes and then the solvent is evaporated under reduced pressure. Methylene chloride (30 m
1) and water (30 ml) are added, the organic layer is separated and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure.
The crystalline residue was recrystallized from a mixture of ethyl acetate and diethyl ether to give 3- [2- (2-methoxycarbonylethyl) -3-oxo-2,3-dihydropyridazine-
6-yl] -2-phenylpyrazolo [1,5-a] pyridine (0.37 g) is obtained. mp: 133-133.5 ° C. IR (Nugeol): 1730, 1660,
1585 cm ^-1 NMR (CDCl ₃ , δ): 2.09 (1H, d,
J = 6 Hz), 3.67 (3H, s), 4.57
(2H, t, J = 6Hz), 6.70 (1H, d, J
= 9 Hz), 6.87 (1H, t, J = 7 Hz),
7.00 (1H, d, J = 9 Hz), 7.17-7.
73 (6H, m), 8.00 (1H, d, J = 9H
z), 8.50 (1 H, d, J = 7 Hz) Elemental analysis: as C ₂₁ H ₁₈ N ₄ O ₂ , calculated value: C 67.37, H 4.85, N
14.96 Found: C 67.31, H 5.35, N
14.94

Reference Example 3 3- [2- (2-methoxycarbonylethyl) -3-oxo-2,3-dihydropyridazin-6-yl] -2-
Phenylpyrazolo [1,5-a] pyridine (1.94
A mixture of g) and 24% aqueous sodium hydroxide solution (2 ml) in methanol (8 ml) is refluxed for 30 minutes and then the solvent is distilled off under reduced pressure. The residue was dissolved in water (30 ml), the aqueous solution was acidified with hydrochloric acid and chloroform (25 m
Extract with l). The extract is dried over magnesium sulfate,
The solvent is distilled off under reduced pressure. The residue was recrystallized from a mixture of ethanol and n-hexane to give 3- [2- (2-carboxyethyl) -3-oxo-2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [ 1,5-
a] Pyridine (1.24 g) is obtained. mp: 155.5-156 ° C. IR (Nugeol): 1835, 1640,
1570, 1520, 1490 cm ^-1 NMR (CDCl ₃ , δ): 2.97 (2H, d,
J = 7Hz), 4.60 (2H, t, J = 7Hz),
6.15-7.00 (1H, broad d),
6.75-7.70 (9H, m), 8.00 (1H,
d, J = 9Hz), 8.53 (1H, d, J = 7Hz) Elemental analysis: as _{C 20 H 16 N 4 O 3} , Calcd: C 66.66, H 4.47, N
15.55 Found: C 66.61, H 4.61 N
15.50

Claims (1)

[Claims] 1. A general formula: (Wherein R ¹ represents a lower alkyl group, R ² represents hydrogen or a suitable substituent), and a compound represented by the general formula: (Wherein R ³ represents hydrogen or an appropriate substituent, X ⁻ represents an anion), and the compound represented by the general formula: (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) A method for producing a pyrazolopyridine compound, which comprises: