JPH09278758A - Production of n-pyrazolylamidoxime compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce an N-pyrazolylamidoxime compound which is a synthetic intermediate for a compound useful as a coupler for a color photography, an intermediate for a medicine, etc., in a short process. SOLUTION: This N-pyrazolylamidoxime compound of formula I (R<1> and R<2> are each H, an alkyl, etc.; R<3> is H, an alkyl, etc.) is obtained as follows. At first, a corresponding β-keto compound, etc., is made to react with hydrazine to obtain a compound of formula II which is a starting substance. Subsequently, the compound of formula II is made to reacted with an acid chloride in the presence of a base (e.g. pyridine) followed by heating to obtain a compound of formula III. The resultant compound of formula III is treated with a halogenating agent e.g. POCl3 or PCl5 in an amount 0.5-2.5 equivalent at a reaction temperature of 0-100 deg.C to lead to a compound of formula IV (X is a halogen), and the obtained compound is converted into the objective compound of formula I by treating at a reaction temperature of 15-120 deg.C after adding an excess amount of hydroxyamine using water or an alcohol such as methanol as a solvent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 1H- which is useful as a color photographic coupler, dye intermediate or pharmaceutical intermediate.
The present invention relates to a method for producing an N-pyrazolylamide oxime compound which is a synthetic intermediate for a pyrazolo[1,5- b ][1,2,4]triazole.

[0002]

2. Description of the Related Art 1H-pyrazolo[1,5- b ][1,
The compound having a 2,4]triazole skeleton is widely used as a precursor of a silver salt color photographic coupler which forms a magenta dye having excellent color reproducibility and a precursor of a dye for sublimation heat sensitivity (Japanese Patent Publication No. 2-44051). Issue 4-5683
No. 5, JP-A-60-186567). More recently, it has been used as an important intermediate for pharmaceuticals such as antihypertensive agents (International Publication WO93/,05044).

So far, 1H-pyrazolo[1,5- b ]!
As a method for synthesizing [1,2,4]triazole, the following three methods 1 to 3 have been proposed. However, (Method 2) has _a problem that the degree of freedom of the substituent variable (selection) of R _a is extremely low, and (Method 3) has a low ring closure yield due to oxidation. ) Has _a high degree of freedom in substituent conversion of R _a , R _b and R _c , and gives good results in synthetic yield, and is therefore widely used at present (“Journal of Synthetic Organic Chemistry”, Vol. 49, 541).
P., 1991).

[0004]

[Chemical 4]

[0005]

[Chemical 5]

[0006]

[Chemical 6]

On the other hand, 1H-pyrazolo[1,5-b]
When a [1,2,4]triazole compound is used as a color photographic coupler, it is known that sterically bulky substituents for R _a and R _c in the above (Method 1) exhibit better performance. (Japanese Patent Laid-Open Nos. 61-65245 and 62-62
91948). However, by (method 1), R _c
When a sterically bulky group is introduced as a compound, its precursor, the N-pyrazolylamide oxime compound (A)
There was a problem that the yield of compound was very low (compound (A)
Can be synthesized, the subsequent dehydration ring closure reaction proceeds without problems). Therefore, 1H-pyrazolo[1,5- b ] having a sterically bulky group in R _a and R _c having excellent performance.
In order to use the [1,2,4]triazole compound as a color photographic coupler, it has been strongly desired to solve this problem.

[0008]

In the conventional synthesis method, 1
In view of the problem that it is difficult to introduce a sterically bulky group at the 2-position (R _c ) of the H-pyrazolo[1,5- b ][1,2,4]triazole compound, the present invention provides 2 Even if it has a sterically bulky group at the position, 1H-pyrazolo[1,
An object of the present invention is to develop a method capable of effectively synthesizing an N-pyrazolylamide oxime compound which is a synthetic precursor of a 5- b ][1,2,4]triazole compound.

[0009]

Means for Solving the Problems As a result of extensive studies by the present inventors, it is effective to solve the above problems by using an N-pyrazolylimidoyl halide compound, and at the same time, a general N-pyrazolylamide oxime compound is used. It was found to be a new synthetic method of. The present invention has been made based on that finding.

That is, the present invention is characterized in that (1) the N-pyrazolylamide oxime compound represented by the general formula [I] is produced via the compound represented by the general formula [II]. A method for producing a pyrazolylamide oxime compound,

[0011]

[Chemical 7]

(In the formula, R ¹ and R ² each represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an aryloxy group, an arylthio group, a disubstituted amino group, an alkoxycarbonyl group or a cyano group,
R ³ represents a hydrogen atom, an alkyl group, an aryl group or an aromatic heterocyclic group. )

[0013]

[Chemical 8]

(In the formula, R ¹ , R ² and R ³ have the same meanings as in the general formula [I], and X represents a halogen atom.) (2) Compound represented by the general formula [II] Is the general formula [II
[I]], which is synthesized via a compound represented by the formula [1], wherein the N-pyrazolylamide oxime compound is produced.

[0015]

[Chemical 9]

(Wherein R ¹ , R ² and R ³ have the same meanings as in the case of the general formula [I]).

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The general formulas [I] to
Substituents R ¹ , R ² and R ^{3 of the} compound represented by [III]
Will be described in detail.

R ¹ and R ² represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an aryloxy group, an arylthio group, a disubstituted amino group, an alkoxycarbonyl group or a cyano group. The groups other than the hydrogen atom and the cyano group are described in detail. Specifically, a halogen atom of fluorine, chlorine, bromine or iodine; methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclopentyl, cyclooctyl, 1,1. -Dimethyl-2-phthalimidoylethyl, 1-methyl-2-
A linear, branched or cyclic alkyl group such as phthalimidoylethyl; phenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, 3-nitro-2,4.
6-trimethylphenyl, 2-methylphenyl, 2,
4,6-triisopropylphenyl, 2-t-butylphenyl, 2,6-di-t-butyl-4-methylphenyl, 3-cyanophenyl, 4-ethoxycarbonylphenyl, 3-nitro-4-methylphenyl, Aryl group such as 3-methoxyphenyl, 4-biphenylyl, 1-naphthyl, 2-naphthyl, 9-anthracenyl; methoxy,
Alkoxy groups such as ethoxy, isopropoxy, t-butoxy, 2-phenoxyethoxy, 2-methoxyethoxy; phenoxy, 2-methoxyphenoxy, 2,6-dimethoxyphenoxy, 2,6-dimethylphenoxy,
2,6-di-t-butyl-4-methylphenoxy, 1-
Aryloxy groups such as naphthoxy, 2-naphthoxy, 9-anthryloxy, phenylthio, 4-nitrophenylthio, 3-nitrophenylthio, 4-t-butylphenylthio, 1-naphthylthio, 2-naphthylthio, 9-
Arylthio groups such as anthrylthio; dimethylamino,
Diethylamino, octylmethylamino, diphenylamino, methylphenylamino, N-methylacetylamino, N-phenylacetylamino, N-ethylbenzoylamino, 1-phthalimidoyl, 1-naphthylphenylamino or bis(1-naphthyl)amino, etc. Or a alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

R ³ represents a hydrogen atom, an alkyl group, an aryl group or an aromatic heterocyclic group. Explaining in detail the groups other than hydrogen atom, the alkyl group and the aryl group represent the groups exemplified in the description of R ¹ and R ² , and the aromatic heterocyclic group represents 2-, 3- or 4
-Pyridyl, 2-quinolyl, 2-pyrazyl, 2-pyrimidyl, 2-imidazolyl, 2-thiazolyl, 3-pyrazolyl, 2-quinazolyl and the like groups can be mentioned.

The group capable of having a substituent in the groups of R ¹ , R ² and R ³ may further have a substituent, and the substituent may be a halogen atom, an alkyl group, an aryl group or a hetero group. Cyclic group, cyano group, nitro group, sulfo group, alkoxy group, aryloxy group, sulfamoylamino group, alkylthio group, arylthio group, alkoxycarbonylamino group, sulfonamide group, carbamoyl group,
Ureido group, sulfamoyl group, sulfonyl group, alkoxycarbonyl group, heterocyclic oxy group, dialkylamino group, diarylamino group, N-alkyl-N-arylamino group, azo group, acyloxy group, carbamoyloxy group, silyloxy group, aryl Oxycarbonylamino group, imide group, heterocyclic thio group, sulfinyl group,
Examples thereof include a phosphoryl group, an aryloxycarbonyl group, an acyl group, a silyl group and an azolyl group.

X represents a halogen atom, and more specifically,
It is a chlorine atom, a bromine atom or an iodine atom.

R ¹ is preferably a hydrogen atom, an alkyl group, an aryl group, an alkoxy group or an aryloxy group, and R ² is a hydrogen atom, a halogen atom, an alkyl group, an aryloxy group, an arylthio group, an alkoxycarbonyl group or It is a cyano group, R ³ is an alkyl group or an aryl group, and X is a chlorine atom or a bromine atom.

More preferably, R ¹ is an alkyl group, an alkoxy group or an aryloxy group, R ² is a hydrogen atom, a halogen atom, an alkyl group or an aryloxy group, and R ³ is a branched alkyl group or an ortho position ( 2nd or 6th
Is a phenyl group having at least one substituent at the position) and X is a chlorine atom. Particularly preferably, R ¹ is an alkyl group, R ² is a hydrogen atom or a chlorine atom, and
³ is a tertiary alkyl group or a phenyl group having at least one substituent at the ortho position.

The following are formulas [I], [II] and [II]
Specific examples of the compound represented by I] are shown below, but the present invention is not limited thereto.

[0025]

[Chemical 10]

[0026]

[Chemical 11]

[0027]

[Chemical formula 12]

[0028]

[Chemical 13]

[0029]

[Chemical 14]

[0030]

[Chemical 15]

[0031]

[Chemical 16]

[0032]

[Chemical 17]

[0033]

[Chemical 18]

[0034]

[Chemical 19]

[0035]

[Chemical 20]

[0036]

[Chemical 21]

[0037]

[Chemical formula 22]

Next, the manufacturing method will be described in detail. The production method of the present invention is represented by the following <Scheme 1>.

[0039]

[Chemical formula 23]

(R ¹ , R ² , R ³ and X in the general formulas [I], [II] and [III] are the same as defined above)

Although some of the starting materials 1 are commercially available, they can be generally synthesized by reacting the corresponding β-keto or iminonitrile or a similar compound thereof with todazine. The compound represented by the general formula [III] can be easily obtained by reacting the starting material 1 with an acid chloride in the presence of a base (pyridine, triethylamine, etc.) and heating.

Examples of the halogenating agent used for converting the general formula [III] into the general formula [II] include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus pentabromide, phosgene and oxy. Examples thereof include zalyl chloride and a phosphorus-based halogenating agent represented by the following general formula [IV].

[0043]

[Chemical formula 24]

(In the formula [IV], Z represents a substituted or unsubstituted phenyl or phenoxy group, and Y represents CC.
represents a _{l 4, Cl 2, Br 2} , I 2 or imide halogenating agent. )

The phosphorus halogenating agent represented by the general formula [IV] will be described in detail. Examples of the substituent of the substituted phenyl or phenoxy group include an alkyl group (methyl,
Ethyl, isopropyl, t-butyl, etc.) or alkoxy groups (methoxy, ethoxy, isopropoxy, etc.) are preferred, with the preferred substituents being alkyl groups. Preferred Z is an unsubstituted phenyl or phenoxy group, particularly preferably an unsubstituted phenyl group.

More specifically, the imide halogenating agent for Y is N-chloro, bromo, or iodosuccinimide, 5,5-dimethyl-1,3-dichloro, dibromo or diiodohydantoin, or trichloro, tribromo or triiodo. Isocyanuric acid, etc.
Preferred Y is CCl ₄ , Cl ₂ , Br ₂ , 5,5-dimethyl-1,3-dichlorohydantoin or trichloroisocyanuric acid. Particularly preferred Y is CCl ₄ or C
It is l ₂ .

A preferred halogenating agent used for the conversion of the general formula [III] into the general formula [II] is phosphorus oxychloride,
Phosphorus pentachloride is a phosphorus-based halogenating agent of the general formula [IV], and particularly preferably a phosphorus-based halogenating agent of the general formula [IV]. The amount of the halogenating agent used is represented by the general formula [III]
It is 0.8 to 2.5 equivalents, preferably 0.9 to 1.5 equivalents, relative to the compound represented by.

Solvents that can be used are halogenated hydrocarbon type, aromatic hydrocarbon type, ester type, nitrile type,
Examples include ether solvents. For more information, dichloromethane,
Halogenated hydrocarbon system such as chloroform or dichloroethane; aromatic hydrocarbon system such as benzene, toluene or xylene; ester system such as ethyl acetate or methyl acetate; nitrile system such as acetonitrile or propionitrile; or diethyl ether, diether Examples include ether solvents such as ethoxymethane, tetratedrofuran, and dioxane. Preferred solvents are halogenated hydrocarbon-based, aromatic hydrocarbon-based or nitrile-based solvents, and particularly preferred are nitrile-based solvents.

The reaction temperature is generally 0°C to 100°C, preferably 10°C to 70°C.

The conversion of the general formula [II] to the general formula [I] is achieved by the addition of hydroxylamine. More specifically, the use of hydroxyamine is carried out by using a commercially available aqueous solution of hydroxylamine or a commercially available hydroxylamine salt. Dissolving an aqueous solution prepared by neutralization in water or a commercially available hydroxylamine hydrochloride in methanol, adding a metal alcoholate such as sodium methoxide, and adding a methanol solution prepared by filtering inorganic salts Performed by. Hydroxyamine is used in an excess amount with respect to the compound represented by the general formula [II], preferably 1.1 to 10 equivalents, more preferably 1.5.
~6 equivalents.

The solvent used in the reaction is a solvent which is sufficiently mixed with water or methanol, and more specifically, an ether solvent such as tetrahydrofuran or dioxane; an alcohol solvent such as methanol, ethanol or isopropanol; methyl acetate or ethyl acetate. Is an ester solvent. Preferred are ether solvents or alcohol solvents. The reaction temperature is generally 15°C to
The temperature is 120°C, preferably 25°C to 80°C.

The compounds represented by the general formula [I] and the general formula [III] can be obtained in high purity by using an ordinary isolation and purification method such as extraction method, recrystallization method or column chromatography. .. When the compound represented by the general formula [II] is a crystalline compound, it can be isolated and purified by the recrystallization method, but it is generally unstable and decomposes especially when it is contacted with moisture for a long time. It is preferably used in the next step.

[0053]

[Synthesis of Exemplified Compounds (III-1), (II-1) and (I-1)]

(1) Synthesis of Exemplified Compound (III-1) 5-Amino-3-t-butyl-1H-pyrazole 18.
7 g (0.134 mol) of acetonitrile solution (10
10.9 ml (0.134 mo) of pyridine in 0 ml)
l) and 16.2 g (0.134 mo) of pivaloyl chloride
1) was added, and the mixture was heated under reflux for about 4 hours. After returning to room temperature, adjust the pH to 10 with an aqueous solution of sodium hydroxide to about 30.
After stirring for a minute and then adjusting the pH to 6 with concentrated hydrochloric acid, crystals were precipitated. The reaction solution was poured into about 400 ml of water, and the precipitated crystals were filtered, washed with acetonitrile and dried to give 21.7 g (72.5%) of Exemplified compound (III-1).
%), as colorless crystals.

(2) Exemplified compounds (II-1) and (I-
Synthesis of 1) 2.3 g (10.3 mmol) of Exemplified Compound (III-1) was stirred in 50 ml of acetonitrile, 4.0 ml (41.2 mmol) of carbon tetrachloride was added, and then triphenylphosphine 5 was added. 0.4 g (20.6 mmol) was added in two portions. The reaction solution became transparent, and a white precipitate gradually precipitated. The product is the exemplified compound (II-1),
It was confirmed that it existed in a sufficiently stable state during the time of development on thin layer chromatography (TLC), but since it gradually decomposed, it proceeded to the next step without isolation. After standing overnight, a solution of hydroxyamine in methanol {hydroxylamine 3.6 g (51.5 mmol) was dissolved in 50 ml of methanol, and 10 ml of 28% sodium methoxide methanol solution was added thereto, and the precipitated sodium chloride was filtered. Preparation} was added, the mixture was stirred at room temperature for about 45 minutes, and then heated under reflux for about 2 hours. After returning to room temperature, it was poured into water to filter the insoluble matter, and the filtrate was extracted with ethyl acetate and washed with water.
After drying and concentration, the residue was purified by silica gel chromatography (eluent; chloroform, then chloroform/acetonitrile=1/1) to give the exemplified compound (I
It was possible to obtain 0.4 g (16.3%) of -1). Melting point 195-197°C (decomposition).

Example 2 [Exemplified Compounds (III-7), (II-4) and (I-7)]
Synthesis of (1) Synthesis of Exemplified Compound (III-7) 5-Amino-3-t-butyl-1H-pyrazole 20 g
(0.144 mol) was dissolved in 200 ml of acetonitrile, and 11.6 ml (0.144 m) of pyridine was dissolved therein.
ol) and then 4-nitrobenzoyl chloride 2
At room temperature, 6.7 g (0.144 mol) was added in several divided portions. The reaction was exothermic and yellow crystals precipitated. After about 30 minutes, the temperature was raised, and the mixture was heated under reflux for about 5 hours to return to room temperature, the precipitated crystals were filtered, washed with acetonitrile, and dried to give 26.9 g (64) of the exemplary compound (III-7) as yellow crystals. .8%) could be obtained.

(2) Exemplified compounds (II-4) and (I-
Synthesis of 7) 2.9 g (10 mmol) of the exemplified compound (III-7) was put in 100 ml of acetonitrile and stirred, and 3.9 ml of carbon tetrachloride (40 mmol) was added thereto. First, 3.2 g of 6.6 g (25 mmol) of triphenylphosphine was added and stirred, but the reaction solution remained cloudy (I
II-7) did not seem to be completely melted. Then, 50 ml of tetrahydrofuran was added to dissolve almost (III-7), and the remaining triphenylphosphine was added in three divided portions. After standing overnight, TLC showed that (III-7) almost disappeared, and spots of the exemplified compound (II-4) were observed. Methanol solution of hydroxylamine {hydroxylamine hydrochloride, 2.8 g (40 mm
Ol) was dissolved in 50 ml of methanol, 28% sodium methoxide methanol solution was added, and the extracted sodium chloride was filtered to prepare}, which was added at room temperature and stirred for about 5 hours. 2.0 g (yield 65%) was obtained by pouring into water, extracting with ethyl acetate, washing with water, drying, and concentrating under reduced pressure.
The exemplified compound (I-7) of was obtained as a crystal.

Example 3 [Exemplified compounds (III-2), (II-2) and (I-2)]
Synthesis of (1) Synthesis of Exemplified Compound (III-2) Except that 5-amino-3-t-butyl-4-chloro-1H-pyrazole and pivaloyl chloride were used, (1) of Example 1 Similarly, the exemplified compound (III-2) was obtained in a yield of 75
Earned in %.

(2) Exemplified compounds (II-2) and (I-
2) Synthesis 17.4 g (0.1 mol) of Exemplified Compound (III-2) was dissolved in 200 ml of chloroform, and phosphorus pentachloride 2
0.8 g (0.1 mol) was added and the mixture was heated under reflux. Chloroform and phosphorus oxychloride were removed by vacuum distillation to obtain a crude product of Exemplified compound (II-2). This crude product was dissolved in methanol, and a hydroxyamine methanol solution {hydroxylamine hydrochloride 27.8 g was dissolved therein.
(Prepared from (0.4 mol) and an equimolar amount of sodium methoxide in the same manner as in Example 1)}, heated under reflux for 2 hours, returned to room temperature, poured into water, filtered to remove insoluble matter, and extracted with ethyl acetate. -After washing with water and drying, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 2.4 g of the exemplary compound (I-2) (yield 10
%)Obtained.

Comparative Example [Exemplified compound (I based on Japanese Patent Publication No. 5-66386)
-1) Synthetic Attempts] 5-Amino-3-t-butyl-1
H-pyrazole, methyl pivalimidate hydrochloride (prepared by Pinner method from pivalonitrile) in a solution of 13.9 g (0.1 mol) in methanol (100 ml) 1
When 5.2 g (0.1 mol) was added and stirred, N-(3-
A mixture of methyl t-butyl-5-pyrazolyl)pivalimidate and N-(3-t-butyl-5-pyrazolyl)pivalamidine hydrochloride (the former is the main product) was obtained. Hydroxyamine methanol solution therein (hydroxyamine hydrochloride 27.8 g (0.4 mol) in the same manner as in Example 1)
Was prepared by adding an equimolar amount of sodium methoxide} and refluxed under heating (2 to 10 hours).
Almost no generation of -1) was confirmed.

Reference Example [Exemplified Compound (I-1) to 2,6-di-t-butyl-
Synthesis of 1H-pyrazolo[1,5-b][1,2,4]triazole] Exemplified compound (I-1) 4 g (16.8 mm)
ol) was dissolved in 50 ml of tetrahydrofuran, and 3.2 g (16.
8 mmol) and then 1.4 ml of pyridine (16.
8 mmol) was added and the mixture was stirred at room temperature for 1 hour. After standing overnight, 1.4 ml (16.8 mmol) of pyridine and 150 ml of methanol were added, and the mixture was heated under reflux for about 2 hours. The reaction solution was concentrated under reduced pressure, and water and ethyl acetate were added to the residue to precipitate crystals. When the crystals were filtered, 1.0 g of crystals were obtained. This is the target 2,6-
Di-t-butyl-1H-pyrazolo[1.5-b][1,
It was found to be 2,4]triazole. Next, the filtrate was extracted 3 times with ethyl acetate, washed with water, dried and concentrated under reduced pressure.
When acetonitrile was added to the obtained residue, crystals were precipitated. After filtration and drying, 1.5 g of crystals were obtained, which was also the target 2,6-di-t-butyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
A total of 2.5 g (yield 67.5%). Melting point 250° C. or higher (recrystallized from acetonitrile/MeOH) Mass spectrum m/e=220 (Mt), 205
(Bp) NMR spectrum δ(CDCl ₃ ), 1.37 (9
H, s), 1.43 (9H, s), 5.57 (1H,
s), 8.50 (~1H, br)

[0061]

INDUSTRIAL APPLICABILITY According to the present invention, 1H-pyrazolo[1,5-
b ] [1,2,4]triazole synthetic intermediate N
-Pyrazolylamide oxime compounds could be synthesized in short steps. Particularly, it is useful because it can be synthesized even when the substituent at the 2-position has a large steric hindrance, which is difficult to synthesize by the conventional method. With the present invention, various 1H ever more
It has become possible to synthesize pyrazolo[1,5- b ][1,2,4]triazole, and its usefulness as an intermediate for photographic couplers and dyes or as a pharmaceutical intermediate is expanded.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07D 403/12 209 C07D 403/12 209

Claims (2)

[Claims] 1. A method for producing an N-pyrazolylamide oxime compound, characterized in that the N-pyrazolylamide oxime compound represented by the general formula [I] is synthesized via the compound represented by the general formula [II]. .. [Chemical 1] (In the formula, R ¹ and R ² each represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an aryloxy group, an arylthio group, a disubstituted amino group, an alkoxycarbonyl group or a cyano group, and R ³ represents Represents a hydrogen atom, an alkyl group, an aryl group or an aromatic heterocyclic group.) (In the formula, R ¹ , R ² and R ³ have the same meaning as in the case of formula [I], and X represents a halogen atom.) 2. The production of the N-pyrazolylamide oxime compound according to claim 1, wherein the compound represented by the general formula [II] is synthesized via the compound represented by the general formula [III]. Method. [Chemical 3] (In the formula, R ¹ , R ² and R ³ have the same meanings as in the general formula [I].)