JP2001089477A - Production of 7-azaindole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a 7-azaindole derivative, capable of producing an azaindole under a mild condition in a high yield and producing a compound which is difficult to produce by a conventional method. SOLUTION: This method for producing a compound of general formula III (X, Y and Z are each a nitrogen atom or a carbon atom; R1, R2 and R3 are each a hydrogen atom, an alkyl group or an aryl group) comprises a process for reacting a compound of general formula I with a compound of general formula II (A and B are each independently an alkoxy group or show a carbonyl group together with a carbon atom bonded to A and B). The compound of formula I or the compound of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing azaindoles useful as antibacterial compounds or intermediates for producing the same.

[0002]

2. Description of the Related Art Azaindoles are journals of
Chemical Society (JCS), 1959, 320
As shown on page 2, it is useful as an intermediate for the production of fluorescent dyes, as well as Journal of Heterocyclic Chemistry, 22, 1429 (1985).
Are also important as antibacterial compounds or intermediates for the production thereof.

As a method for producing azaindoles, for example, a method described in the above-mentioned Journal of Heterocyclic Chemistry, Vol. 22, p. 1429 (1985) is known. Is long,
There is a problem that the operation is often complicated. One of the causes is that the application of Fischer indole synthesis (a method of heating hydrazone derived from phenylhydrazine under heating under acidic conditions) that can be used for the synthesis of indole and indolenine is limited in the synthesis of azaindole. Yes, in many cases, it is necessary to carry out the reaction at a very high temperature, so that favorable results cannot be obtained. Under such circumstances, there has been a demand for a method for efficiently producing azaindoles from a compound having a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or the like under mild conditions.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for efficiently producing azaindoles under mild conditions. The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, by using the compounds represented by the following general formulas (I) and (II), azaindole was obtained in good yield under mild conditions. It has been found that a kind can be produced. The present invention has been completed based on the above findings.

That is, the present invention provides the following general formula (II)
I):

Embedded image (Wherein, X, Y, and Z each independently represent a nitrogen atom or a substituted or unsubstituted carbon atom; R ¹ , R ² , and R ³ each independently represent a hydrogen atom, an alkyl group, or an aryl group. The method for producing a compound represented by
The following general formula (I):

Embedded image (Wherein X, Y and Z are as defined above) and the following general formula (II):

Embedded image (Wherein R ¹ , R ² , and R ³ have the same meanings as described above, and A and B each independently represent an alkoxy group or a carbonyl group together with the carbon atom to which they are attached) It is intended to provide a method comprising the step of reacting with a compound.

From another viewpoint, according to the present invention, there is provided a compound represented by the above general formula (I) or the above general formula (II), which is an intermediate for producing the compound represented by the above general formula (III). Provided. Further, use of the compound represented by the general formula (I) or (II) as an intermediate for producing the compound represented by the general formula (III) is also provided.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION X, Y and Z each represent a nitrogen atom or a substituted or unsubstituted carbon atom (an unsubstituted carbon atom is represented by CH). The type of the substituent on the carbon atom is not particularly limited as long as it is a monovalent substituent. For example, a halogen atom (a halogen atom in the present specification is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom) ), An alkyl group (linear, branched, cyclic, or a combination thereof)
The number of carbon atoms is 1 to 10, preferably 1 to 8, more preferably 1 to 6, and particularly preferably 1 to 4. The same applies to the alkyl moiety of other substituents having an alkyl moiety referred to in the present specification, and an aryl group (for example, 6 to
Examples thereof include a 10-membered aryl group, more specifically, a phenyl group and a nartyl group. The same applies to the aryl moiety of other substituents having an aryl moiety referred to herein), a carboxamide group, a sulfonamide group,
Examples include an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a carbamoyl group, a cyano group, a halogenated alkyl group (such as a trifluoromethyl group), and a sulfamoyl group.

Examples of the alkoxy groups represented by A and B include, for example, methoxy, ethoxy, propoxy,
Butoxy group and the like. A and B may form a carbonyl group (C = O) together with the carbon atom to which they are attached. Preferred examples of the alkyl group represented by R ¹ , R ² and R ³ include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, and tert group -Butyl group and the like. The aryl group represented by R ¹ , R ² and R ³ is preferably a phenyl group, and one or more substituents may be present on the ring of the phenyl group. Examples of such a substituent include a halogen atom, an alkyl group, an aryl group, a carboamide group, a sulfonamide group, an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, a carboxyl group, an alkoxycarbonyl group, and an aryloxycarbonyl group. Carbamoyl group, cyano group, halogenated alkyl group, sulfamoyl group and the like.

[0009] The N-substituted hydroxylamine represented by the general formula (I) is generally an aromatic compound obtained by hydroxylamine and a heterocyclic compound in which the corresponding nitrogen is substituted with a highly releasable group such as halogen. It can be synthesized by a nuclear substitution reaction. At this time, as a solvent, dimethylformamide, dimethylacetamide, dimethylsulfoxide,
Polar solvents such as sulfolane, methanol, ethanol, water and isopropyl alcohol are preferably used. If the reaction is slow, a method of dissociating hydroxylamine by adding a strong base such as sodium hydride or metal alkoxide can also be used. With respect to the ketone represented by the general formula (II) or the acetal thereof, a general synthesis method is known. Regarding this method, it is possible to refer to books such as experimental chemistry courses.

In the synthesis method of the present invention, a compound represented by the general formula (I) and a compound represented by the general formula (II) are mixed,
Generally, by heating in a solvent or without a solvent, an azaindole represented by the general formula (III) can be obtained. A and B in the compound represented by the general formula (II)
Is an alkoxy group, it is preferable to use an acid catalyst. Also, when A and B are not alkoxy groups, the reaction rate may be increased by using an acid catalyst. Examples of the acid catalyst include protic acids such as paratoluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, pyridinium salt of paratoluenesulfonic acid, and acetic acid, and aluminum chloride, zinc chloride, boron trifluoride, and boron trifluoride etherate. , Iron chloride, tin chloride and other Lewis acids can be used.

When the reaction is carried out in a solvent, the type of the solvent is not particularly limited as long as it is inert in the reaction. However, when A and B in the compound represented by the general formula (II) are alkoxy groups, Is an aprotic solvent, for example,
Dimethylformamide, toluene, benzene, xylene, p-cymene, anisole, chlorobenzene, dichlorobenzene, sulfolane and the like can be preferably used. The molar ratio of the compound represented by the general formula (I) to the compound represented by the general formula (II) is, for example, 1:10 to 10: 1.
About 1: 3 to 3: 1, preferably 1: 1 to 1:
2 is more preferred. The reaction temperature is from room temperature to the reflux temperature of the solvent when a solvent is used, or from room temperature to 1 when no solvent is used.
It can be performed in a range up to about 50 ° C. In the method of the present invention, a salt of the compound represented by the general formula (I) or (II) may be used. In addition, the compound represented by the general formula (III) can be isolated as a salt according to a method well known to those skilled in the art.

Specific examples of the compound represented by formula (I) or (II) which can be suitably used in the method of the present invention are shown below. However, the method of the present invention is limited to the case where these compounds are used. Never.

[0013]

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[0014]

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[0015]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. The compound numbers in the examples correspond to the compound numbers exemplified as the preferred compounds above.

Example 1: Synthesis of 2-isopropyl-5-trifluoromethyl-1H-pyrrolo [2,3-b] pyridine.

Embedded image 2-chloro-5-trifluoromethylpyridine (200
Grams), hydroxylamine hydrochloride (153 grams),
Sodium bicarbonate (185 grams) and dimethyl sulfoxide (500 milliliters) were mixed and heated to 100 ° C. After reacting for 12 hours, the reaction mixture was poured into 10 liters of water, and the precipitated crystals were collected by filtration and dried to obtain 128 g of 2-hydroxyamino-5-trifluoromethylpyridine (Compound I-3). Yield 65.2%.

3-methyl-2-ethanol in 3 liters
Butanone (820 grams)) was mixed and 0.5 grams of paratoluenesulfonic acid monohydrate was added and heated to reflux. The progress of the reaction was monitored by nmr, and after confirming the disappearance of the raw materials, the reaction mixture was cooled and an aqueous solution of sodium hydroxide in the same mole as the added paratoluenesulfonic acid was added. Next, ethanol was distilled off, and the remaining liquid was distilled under reduced pressure. Reduce the pressure with an aspirator, 110-120
The fraction at C was collected to give 2,2 diethoxy-3-methylbutane (Compound II-5). Yield 1010 grams, 66.2% yield.

2-hydroxyamino-5-trifluoromethylpyridine (10 grams), 2,2-diethoxy-
3-Methylbutane (18 grams) and 120 ml of toluene were mixed and stirred. PPT was added to this reaction mixture.
0.1 g of S (pyridinium p-toluenesulfonate) was added and the mixture was heated to reflux. The reaction was monitored by thin layer chromatography, and after the disappearance of the raw materials, the mixture was further heated under reflux for 3 hours. After cooling the reaction solution, toluene was distilled off, and the residue was purified by silica gel column chromatography. The nmr spectrum of each fraction of the chromatography was examined. Fractions containing the target compound were collected, the solvent was distilled off, and the residue was recrystallized from hexane. Yield 4.1 grams, 32.0% yield. ¹ H-NMR (CDCl ₃ ) δ (ppm) 11.9
(B, 1H), 8.51 (d, 1H), 8.12 (d,
1H), 6.33 (s, 1H), 3.23 (m, 1
H), 1.45 (d, 6H)

In the reactions of the above Examples, it is noted that sigmatropic rearrangement occurs on the less substituted side of the compound represented by the general formula (II). In general, Fischer's indole synthesis via a hydrazone intermediate (RJS
uberg, "The Chemistry of
Indoles "(Academic Press, N
ew York) in 1970. This means that a product reacted at a reaction site opposite to that of the product of (1) is obtained. According to the method of the present invention, a product that is difficult to obtain by Fischer's indole synthesis can be obtained.

For comparison, 2-hydrazino-5-trifluoromethylpyridine was reacted with 3-methyl-2-butanone to form a hydrazone and then heated to 220 ° C., but the desired reaction did not proceed. When the reaction temperature was raised to 250 ° C., some products were obtained by decomposition of the raw material compounds, but the desired ring-closure was not obtained at all. In this reaction, the same result was obtained even when an acid catalyst such as pyridinium paratoluenesulfonate was added.

[0021]

According to the method of the present invention, azaindoles can be produced from the compounds represented by the general formulas (I) and (II) under mild conditions with good yield, and the production is difficult with the conventional method. Compound can be produced.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 49/11 C07C 49/11 C07D 213/76 C07D 213/76 213/82 213/82 213/85 213 / 85 237/20 237/20 239/42 239/42 Z 239/47 239/47 Z 241/20 241/20 487/04 140 487/04 140 F term (reference) 4C050 AA01 BB04 CC07 CC08 EE03 EE04 EE05 FF02 FF05 GG01 HH01 4C055 AA01 BA02 BA03 BA39 BA52 BB15 CA01 CA02 CA13 CA58 CA59 DA01 4C065 AA04 BB04 DD02 EE02 HH03 JJ01 KK02 LL01 PP01 QQ02 4H006 AA01 AB81 AB84 GP01

Claims (3)

[Claims] 1. The following general formula (III): (Wherein, X, Y, and Z each independently represent a nitrogen atom or a substituted or unsubstituted carbon atom; R ¹ , R ² , and R ³ each independently represent a hydrogen atom, an alkyl group, or an aryl group. The method for producing a compound represented by
The following general formula (I): (Wherein X, Y and Z are as defined above) and the following general formula (II): (Wherein R ¹ , R ² , and R ³ have the same meanings as described above, and A and B each independently represent an alkoxy group or a carbonyl group together with the carbon atom to which they are attached) A method comprising the step of reacting with a compound. 2. The compound represented by the general formula (I) according to claim 1, which is an intermediate for producing the compound represented by the general formula (III) according to claim 1. 3. The compound represented by the general formula (II) according to claim 1, which is an intermediate for producing the compound represented by the general formula (III) according to claim 1.