JPH0741478A - Production of pyrazolotriazole derivative - Google Patents

Abstract

PURPOSE:To obtain a pyrazolotriazole derivative which is useful as a raw material for medicine, by reacting a pyrazole compound with an ortho-acid ester to give a product which is then N-alkylated, further reacted with hydroxylamine and finally ring closed. CONSTITUTION:A compound of the formula I (where, R<1> is H, a lower alkyl) with a compound of the formula R<1>-C(OR<2>)3 (where, R<2> is a lower alkyl), are reacted to obtain an imidate of the formula II. Then, the compound of the formula II is reacted with a compound of the formula III (where, X<1>, X<2> are each a halogen (s)) to give an N-alkylated compound of the formula IV. Then, the compound of the formula IV is reacted with hydroxylamine to give a compound of the formula V, then the compound of the formula V is ring closed to give the objective compound of the formula VI. The compound of the formula VI is useful as a raw material for a pyrazolotriazole compound having angiotensin II antagonism. The compounds of the formula II, IV and V are novel synthetic intermediate compounds.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the following angiotensin.
II (hereinafter abbreviated as AII) A novel production method for producing a pyrazolotriazole derivative (VII), which is a raw material of a pyrazolotriazole compound (VIII) having an antagonistic action, and a novel intermediate used in the production method .

[0002]

[Chemical 11]

(In the formula, Rs are the same or different and each represents a hydrogen atom or a lower alkyl group.) Here, the lower alkyl group in R is a linear or branched one having 1 to 6 carbon atoms. A carbon chain, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl (amyl) group, an isopentyl group, a neopentyl group. , T
ert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group,
Isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethyl Butyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1 −
Examples thereof include an ethyl-1-methylpropyl group and a 1-ethyl-2-methylpropyl group.

[0004]

2. Description of the Related Art AII is a physiologically active peptide showing a strong pressor action and has been regarded as a causative agent of hypertension in various mammalian species. There are a few known pathways by which AII is produced in vivo, but the typical pathway is the production of angiotensin I from angiotensinogen by the action of the enzyme renin, which is then converted to angiotensin conversion. The enzyme (ACE) acts to convert it into AII.

The above-mentioned pyrazolotriazole compound (VIII)
Or, its salt acts on the AII receptor and suppresses the expression of the action of AII, and is therefore useful as a drug, especially as an AII antagonist. The present inventors previously produced the pyrazolotriazole compound (VIII) for the first time by the method represented by the following reaction formula, and applied for a patent for this compound (Japanese Patent Application No. 3-250430, Japanese Patent Application No. 3-344012).
issue).

[0006]

[Chemical 12]

(In the formula, R represents the above-mentioned meaning, R ⁵ represents an aralkyl group, and X ³ represents a halogen atom or a sulfonic acid residue.) The method is a pyrazolotriazole compound (IX) and biphenylmethyl. The objective compound (VIII) was directly produced from the halide (or sulfonate) (X). Furthermore, the present inventors found out the following separate production method of the pyrazolotriazole compound (VIII),
Filed a patent application.

[0008]

[Chemical 13]

(In the formula, R, X ¹ and X ² are as described above. R ³ is a hydrogen atom, a lithium atom, -MX _{n -1} or -B.
(OR ⁶ ) ₂ , M is a zinc atom, a magnesium atom, a copper atom, a boron atom, an aluminum atom or a cadmium atom, the ligand X is a halogen atom, and n is a valence of the metal M. . R ⁴ represents a lower alkyl group, or a lower alkylene group in combination with both, R ⁵ represents a lower alkyl group, and R ⁶ represents a hydrogen atom or a lower alkyl group. ) This production method is carried out stepwise to obtain the pyrazolotriazole compound (VIII).

[0010]

DISCLOSURE OF THE INVENTION The inventors of the present invention have earnestly studied the method for producing a pyrazolotriazole compound (VIII), and as a result, a novel production method which is completely different from the conventional production method and can be produced industrially. The present invention has been completed and the present invention has been completed.

[0011]

That is, the present invention provides a compound represented by the general formula (I)

[0012]

[Chemical 14]

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group) and a compound of the general formula (II)

[0014]

[Chemical 15] (In the formula, R ¹ has the above-mentioned meaning and R ² means a lower alkyl group), and the compound represented by the general formula (III)

[0015]

[Chemical 16]

(Wherein R ¹ is the same or different and represents a hydrogen atom or a lower alkyl group, and R ² is a lower alkyl group) (the first step), and then the compound (III) And general formula (IV)

[0017]

[Chemical 17]

(Wherein, X ¹ and X ² are the same or different and each represents a halogen atom), and the compound represented by the general formula (V) is reacted.

[0019]

[Chemical 18]

A novel compound represented by the formula (wherein R ¹ , R ² and X ¹ have the above meanings) is obtained (second step), and the obtained compound (V) is reacted with hydroxylamine. Let the general formula (VI)

[0021]

[Chemical 19]

A compound (VI) represented by the formula (wherein R ¹ and X ¹ have the above-mentioned meanings) (third step),
Compound (VI) is subjected to ring closure reaction to give general formula (VII)

[0023]

[Chemical 20]

A process for producing a pyrazolotriazole derivative, characterized in that a compound (VII) represented by the formula (wherein R ¹ and X ¹ have the above-mentioned meanings) is obtained (4th step). Further, the present invention is characterized in that it is produced using a novel intermediate. Hereinafter, each step of the production method of the present invention will be described in detail. First Step In the first step, the pyrazole compound (I) is reacted with ortho acid ester (II) in an amount corresponding to the reaction in the presence or absence of an inert solvent at room temperature to under heating (or under heating under reflux). , Step of obtaining imidate ester (III). Inert solvents include toluene, benzene, chloroform,
Tetrahydrofuran, dioxane, acetonitrile and the like can be mentioned. Second Step The second step is N-alkylation of the imidate ester (III) with halogenophenylmethyl halide (II). This N-alkylation is carried out by stirring the compound (III) and the corresponding amount of the compound (IV) in an inert solvent under ice cooling to room temperature.

Examples of the inert solvent include tetrahydrofuran, dioxane, hexane, benzene, chloroform, dichloromethane, N, N-dimethylformamide,
N, N-dimethylacetamide, acetonitrile, water, etc. are mentioned, and they can be used as a single solvent or a mixed solvent thereof. In order to accelerate this reaction, it is preferable to add a base. As the base, potassium butoxide, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,
Sodium hydroxide, sodium hydride, sodium metal, sodium methoxide, pyridine, triethylamine, diisopropylethylamine, picoline, lutidine, collidine, N, N-dimethylamine and the like are used.

Third Step In the third step, the compound (V) obtained in the second step and hydroxylamine in an amount corresponding to the reaction are stirred in an alcohol such as methanol or ethanol under ice cooling or under heating. This is a method of obtaining (VI).

Fourth Step The fourth step is a step of subjecting the compound (VI) obtained in the third step to a ring closure reaction to obtain a pyrazolotriazole derivative (VII). This ring-closing reaction is carried out by reacting compound (VI) with a corresponding amount of p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, etc. with tetrahydrofuran, dioxane, chloroform, dichloromethane, N, N-dimethylacetamide, acetonitrile, etc. After stirring in an inert solvent in the presence of a base such as triethylamine, diisopropylamine, pyridine, picoline, lutidine, and collidine under ice cooling or at room temperature, if necessary, the inert solvent or alcohol such as methanol or ethanol is selected. It is carried out by stirring in the presence of the aforementioned base in a single solvent or a mixed solvent at room temperature or under heating.

To isolate and purify the compound (VII) obtained by the above-mentioned production method, extraction from the reaction solution with an organic solvent, chromatography, crystallization and the like may be appropriately combined.

In the formula, the lower alkyl group for R ¹ or R ² means a linear or branched carbon chain having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group, Butyl group, pentyl group, hexyl group, isopropyl group, s
An ec-butyl group and the like can be mentioned. The halogen atom in X ¹ or X ² means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0030]

INDUSTRIAL APPLICABILITY The present invention provides a pyrazolotriazole compound (VIII) which is a raw material of a pyrazolotriazole compound (VIII).
It is a new production method for producing I) and is industrially useful. Further, the novel intermediates (III), (V) and (VI) used in the production method are very useful in producing the pyrazolotriazole derivative (VII).

[0031]

EXAMPLES The production method of the present invention and the novel intermediates used therein will be described in more detail below. Example 1

[0032]

[Chemical 21]

A) A mixture of 10.0 g of 3-amino-4-ethyl-1H-pyrazole, 100 ml of toluene and 18.1 ml of triethyl orthopropionate is heated to reflux overnight. The solvent is distilled off under reduced pressure and the resulting residue is subjected to silica gel column chromatography. By eluting with methanol-chloroform (1:49 v / v), 6.89 g of ethyl N- (4-ethyl-1H-pyrazol-3-yl) propionimidate was obtained as an oil.

(1) Nuclear magnetic resonance spectrum (DMSO-
_{d 6, TMS) δ (ppm} ): 0.94-1.15 (6H, m), 1.
27 (3H, t), 2.24 (4H, brq), 4.1
8 (2H, q), 7.35 (1H, brs) (2) Mass spectrum (EI) 195 (M ⁺ ).

[0035]

[Chemical formula 22]

B) 4.00 g of ethyl N- (4-ethyl-1H-pyrazol-3-yl) propionimidate is dissolved in 120 ml of N, N-dimethylformamide.
2.42 g of potassium t-butoxide was added, and the mixture was stirred at room temperature for 15 minutes. After cooling with ice, p-iodobenzyl bromide 6.
After adding 70 g and stirring for 1 hour, the mixture is returned to room temperature and stirred overnight. After evaporating the solvent under reduced pressure, ethyl acetate is added to the residue and the mixture is washed twice with water.

The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and eluted with ethyl acetate-n-hexane (1: 4 v / v). Ethyl N- [4-ethyl-1- (4-iodo) benzyl-1H-pyrazol-3-yl] propionimidate (Compound A) and N- [4-ethyl-2- (4-iodo) benzyl-2H.
A mixture of ethyl-pyrazol-3-yl] propionimidate (Compound B) (Compound A: Compound B = about 3:
1) 5.64 g was obtained as an oil. (1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS, proton of 5th position of pyrazole ring of compound B is 1H) δ (ppm): 0.87 (3H, t), 1.06-1.
15 (21H, m), 1.30-1.35 (12H,
m), 1.95 (2H, q), 2.17 (2H, q),
2.24-2.30 (12H, m), 4.22-4.2
8 (8H, m), 5.00 (2H, s), 5.08 (6
H, s), 6.90-6.94 (8H, m), 7.06
(3H, s), 7.31 (1H, s), 7.59-7.
64 (8H, m) (2) Mass spectrum (EI) 411 (M ⁺ )

[0038]

[Chemical formula 23]

C) 1.02 g of hydroxylamine hydrochloride
Is dissolved in 10 ml of methanol by heating. 28% after cooling
1. A methanol solution containing sodium methoxide.
Add 84 g and stir at room temperature for 30 minutes, then cool with ice. On the other hand, N
-[4-Ethyl-1- (4-iodo) benzyl-1H-
A mixture of ethyl pyrazol-3-yl] propionimidate (Compound A) and ethyl N- [4-ethyl-2- (4-iodo) benzyl-2H-pyrazol-3-yl] propionimidate (Compound B) ( Compound A: Compound B =
About 3: 1) 4.00 g was dissolved in 13 ml of methanol,
Add to the above hydroxylamine in methanol solution.

After stirring for 1 hour under ice cooling, the temperature is returned to room temperature and stirring is continued overnight. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with methanol-chloroform (1.5: 98.5 v / v) to give N- [4-ethyl-1- (4- Iodo) benzyl-
3.67 g of 1H-pyrazol-3-yl] propionamide oxime was obtained as a starch syrup.

(1) Nuclear magnetic resonance spectrum (CDCl
₃ , TMS) δ (ppm): 1.00 (3H, t), 1.15 (3
H, t), 2.34-2.42 (4H, m), 5.10.
(2H, s), 6.94 (2H, d), 7.09 (1
H, s), 7.66 (2H, d) (2) Mass spectrum (EI) 398 (M ⁺ ).

[0042]

[Chemical formula 24]

D) 3.07 g of N- [4-ethyl-1- (4-iodo) benzyl-1H-pyrazol-3-yl] propionamide oxime are dissolved in 15 ml of N, N-dimethylacetamide. Pyridine 1.24 under ice cooling
ml and p-toluenesulfonyl chloride 1.45 g
Is added and the mixture is stirred for 15 minutes, then returned to room temperature and further stirred for 3 hours. The reaction mixture is poured into diluted aqueous sodium hydrogen carbonate solution and extracted with chloroform.

Chloroform in the organic layer was distilled off under reduced pressure, the resulting residue was dissolved in 50 ml of methanol, 1.24 ml of pyridine was added, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography and eluted with methanol-chloroform (1.5: 98.5 v / v) to give:
2,7-diethyl-5- (4-iodo) benzyl-5H
-2.09 g of pyrazolo [1,5-b] [1,2,4] triazole was obtained as a pale yellow oil.

(1) Nuclear magnetic resonance spectrum (CDCl
₃ , TMS) δ (ppm): 1.26 (3H, t), 1.37 (3
H, t), 2.61 (2H, q), 2.83 (2H,
q), 5.15 (2H, s), 6.90 (1H, s),
7.01 (2H, d), 7.67 (2H, d) (2) Mass Spec (FAB) 381 (MH ⁺ ) Example 2

[0046]

[Chemical 25]

A) 2.65 g of ethyl N- (4-ethyl-1H-pyrazol-3-yl) propionimidate and 3.74 g of p-bromobenzyl bromide were used in the same manner as in Example 1b) to give N- [4 -Ethyl-1- (4-bromo) benzyl-1H-pyrazol-3-yl] propionimidate (Compound C) and N- [4-ethyl-
2- (4-bromo) benzyl-2H-pyrazole-3-
3.67 g of a mixture of ethyl] propionimidate (Compound D) (Compound C: Compound D = about 3: 1) was obtained as an oil.

(1) Nuclear magnetic resonance spectrum (CDCl
₃ , TMS, the proton at the 5-position of the pyrazole ring of compound D is 1H) δ (ppm): 0.87 (3H, t), 1.06-1.
15 (21H, m), 1.30-1.35 (12H,
m), 1.95 (2H, q), 2.18 (2H, q),
2.22-2.31 (12H, m), 4.22-4.2
9 (8H, m), 5.01 (2H, s), 5.09 (6
H, s), 7.03-7.07 (11H, m), 7.3.
2 (1H, s), 7.39-7.44 (8H, m) (2) Mass spectrum (FAB) 364, 366 (eac)
h MH ⁺ )

[0049]

[Chemical formula 26]

B) Ethyl N- [4-ethyl-1- (4-bromo) benzyl-1H-pyrazol-3-yl] propionimidate (Compound C) and N- [4-Ethyl-2].
In the same manner as in Example 1C, 3.54 g of a mixture of (ethyl 4- (4-bromo) benzyl-2H-pyrazol-3-yl] propionimidate (Compound D) (Compound C: Compound D = about 3: 1) was used. 2.60 g of N- [4-ethyl-1- (4-bromo) benzyl-1H-pyrazol-3-yl] propionamide oxime was obtained as a starch syrup.

(1) Nuclear magnetic resonance spectrum (CDCl
₃ , TMS) δ (ppm): 1.00 (3H, t), 1.15 (3
H, t), 2.34-2.42 (4H, m), 5.11.
(2H, s), 7.06-7.09 (3H, d), 7.
46 (2H, d) (2) Mass spectrum (EI) 350,352 (each)
M ⁺ )

[0052]

[Chemical 27]

C) N- [4-Ethyl-1- (4-bromo) benzyl-1H-pyrazol-3-yl] propionamido oxime from 2.49 g was treated in the same manner as in Example 1d to give 2,7-diethyl- 5- (4-bromo) benzyl-
1.04 g of 5H-pyrazolo [1,5-b] [1,2,4] triazole was obtained as a pale yellow oil.

(1) Nuclear magnetic resonance spectrum (CDCl
₃ , TMS) δ (ppm): 1.26 (3H, t), 1.37 (3
H, t), 2.61 (2H, q), 2.83 (2H,
q), 5.16 (2H, s), 6.89 (1H, s),
7.15 (2H, d), 7.47 (2H, d) (2) Mass Spec (EI) 332, 334 (each)
M ⁺ )

Claims (4)

[Claims] 1. A compound represented by the general formula (I): (Wherein R ¹ represents a hydrogen atom or a lower alkyl group) and a compound of the general formula (II) (In the formula, R ¹ has the above-mentioned meaning and R ² means a lower alkyl group), and the compound represented by the general formula (III) (Wherein R ¹ is the same or different and represents a hydrogen atom or a lower alkyl group, and R ² is a lower alkyl group) (step 1), and then the compound (III) and the general formula (IV) [Chemical 4] (In the formula, X ¹ and X ² are the same or different and each represents a halogen atom), and the compound represented by the general formula (V) (Wherein R ¹ , R ² and X ¹ have the above-mentioned meanings) (second step), and the obtained compound (V)
Reacting with hydroxylamine to give a compound of general formula (VI) (Wherein R ¹ and X ¹ have the above-mentioned meanings), the compound (VI) is subjected to a ring closure reaction (4th step), and the compound of the general formula (VII) [Chemical 7] (In the formula, R ¹ and X ¹ have the above-mentioned meanings.) A method for producing a pyrazolotriazole derivative, which comprises obtaining a compound (VII) represented by the above. 2. A compound represented by the general formula (III): (In the formula, R ¹ is the same or different and represents a hydrogen atom or a lower alkyl group, and R ² is a lower alkyl group.) A pyrazole derivative represented by the formula. 3. A compound represented by the general formula (V): (Wherein R ¹ is the same or different and is a hydrogen atom or a lower alkyl group, R ² is a lower alkyl group, and X ¹ is a halogen atom). 4. A compound represented by the general formula (VI): (In the formula, R ¹ is the same or different and represents a hydrogen atom or a lower alkyl group, and X ¹ represents a halogen atom.) A pyrazole derivative.