JPS5833228B2 - Azacycloalkanone - Google Patents

Description

Detailed Description of the Invention Conventionally, this type of azacycloalkanone has been synthesized by reacting α-aryl-2-pyridine acetate with acrylonitrile in the presence of a base, and the resulting nitrile is treated with a metal such as Raney nickel. A method in which hydrogenation is carried out under pressure conditions in the presence of a catalyst, and the resulting α-aryl-α-(3-aminopropyl)-2-pyridine acetic acid ethyl ester is subjected to a dealcoholization reaction under heating (Japanese Patent No. 2214)
No. 88), and in the above method, α-alkyl (or aryl) is substituted for 2-pyridine acetic acid ethyl ester.
A method in which a reaction similar to the above method is carried out using phenylacetic acid methyl ester (US Pat. No. 2,524,643), a compound in which the α-position of benzeneacetonitrile is substituted with hydrogen canyl, propyl, butyl, phenyl, benzyl, phenethyl, etc. In the presence of amide, N-(
A method in which 3-bromopropyl) phthalimide is reacted, the resulting compound is hydrolyzed with hydrobromic acid, the resulting amino acid hydrbromide is converted into a free amino acid, and then the ring is closed by heating [Chemical Abstracts, Volume 59 (19
1747g column], a compound in which the hydrogen at the α-position of benzeneacetonitrile is substituted with ethyl, phenyl, benzyl, phenethyl, etc. is reacted with N(3-promopropyl succinimide) in the presence of sodium amide. The compound is hydrolyzed with hydrobromic acid (or hydratine hittride), neutralized with sodium hydroxide, the resulting amino acid is ring-closed with acetic anhydride, and the resulting N-acetylazacyclohexanone is hydrated with sodium hydroxide. Method of decomposing and removing acetyl group [Purtemp de U.
Société Simique de France, page 1547 (196
3) or p. 2175 (1963)],]3
-Phenyl-3-2-pyridyl)-2,5-pyrrolidinedione or 3-phenyl-3-ethyl-2,6-piperidinedione is reacted with phosphorus pentasulfide in pyridine, and the resulting compound is A method of reduction using Raney nickel in anhydrous ethanol or in dioxane under heating under reflux [Helvetica Himica,
Acta, Vol. 37 (1954), p. 185], obtained by reducing a compound in which hydrogen at the 3-position of 3-phenyl-2,6-piperidinedione is replaced with ethyl or phenyl with lithium aluminum hydride. A method of hydrogenating the 6-hydroxy compound in the presence of platinum oxide after dehydration [Helvetica Himica Acta, Vol. 37 (1954), p. 76 pages (1953)] is known.

However, these methods require multiple steps to obtain the desired product, require special equipment such as an autoclave, or a precious metal catalyst (such as platinum oxide), and are not suitable for production on an industrial scale.

The method of the present invention overcomes all of these drawbacks of the conventional methods through a novel reaction.

This invention relates to a 3-monosubstituted compound represented by the general formula: Azacycloalkanone is reacted with a compound represented by the general formula (in the formula, R3 means an alkyl group, an aryl group, or an aralkyl group, and X means a halogen) in the presence of a metalating agent. , R1, R2, R3 and n have the same meanings as before).

The reaction of this invention is a 3-monosubstituted azacycloalkanone (
This is carried out by reacting compound (■) with I) in the presence of a metallating agent.

Here, the 3-monosubstituted azacycloalkanone is represented by the above general formula (I), and more specifically includes alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isophthyl, and aryl groups such as phenyl, tolyl, and xylyl. or pyridyl group as R1, hydrogen, an aryl group or alkyl group as described above, or an aralkyl group such as benzyl, phenethyl, xylylmethyl, tolylmethyl, α-methylbenzyl, phenylpropyl, etc. as R2, and n is 2 or 3.

Further, the compound (II) has an alkyl group, aryl group or aralkyl group as R3 as described above, chlorine,
It means a compound having a halogen such as bromine or iodine as X.

In addition, the metalating agent used in the reaction of the present invention includes alkali metals such as sodium, lithium, and potassium, alkaline earth metals such as calcium and magnesium, or amides, hydrides, alcolades, etc. of these metals.
Hydrocarbons, or organic compounds thereof such as han-7''chillithium, phenyllithium, phenylpotassium, tertiary butylpotassium, tertiary amylpotassium, and the like can be mentioned.

The reaction is generally carried out in a solvent, and examples of the solvent used include benzene, toluene, ethanol, dimethylformamide, and tetrahydrofuran, but any other solvent that does not participate in the reaction can be used.

Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under mild conditions such as cooling or heating.

Moreover, metallization can be carried out more effectively by carrying out the reaction in the presence of an inert gas such as nitrogen or argon.

Next, the present invention will be explained with reference to examples.

Example 1 In a nitrogen stream, a solution of 1.91 1-methyl-3-(2-pyridyl)-2-piperidone dissolved in 6 cc of anhydrous tetrahydrofuran was added to a solution of 1.68 f of potassium butoxide dissolved in 20 cc of anhydrous tetrahydrofuran. Add dropwise over 10 minutes while cooling with ice water.

The reaction solution was gradually warmed to room temperature and stirred for 2 hours, and 2.84 f? of methyl iodite was added to the reaction solution. A solution prepared by dissolving .

After adding 10 cc of water to this mixture, the tetrahydrofuran was distilled off, and the residue was extracted with ☆☆ dichloroform.

After drying the chloroform layer, the solvent is distilled off.

Fractional distillation of the residue under reduced pressure yields bp130-132℃1
1,61 of an oil of 1,3-dimethyl-3-(2-pyridyl)-2-piperidone of 0.55 Hg is obtained.

Example 2 50% sodium hydride in a nitrogen stream 0.96 f? was suspended in 60 cc of dry benzene, 3.52 f of 3-(2-pyridyl)-2-piperidone was added, and then heated at 50°C.
Stir on a hot water bath for 4 hours.

To this was added 2.0% of α-chlorotoluene. Ill' was added dropwise under cooling, and the mixture was stirred at room temperature for 2 hours and then on a 50°C water bath for 3.5 hours.

3 Qcc of water is added to this, the organic layer is separated, the aqueous layer is extracted with chloroform, the chloroform layer is combined with the organic layers, and the solvent is distilled off.

Petroleum ether was added to the residue to remove Nujol, and the residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform:acetone (4:1).

Collect the eluate in 1 fraction of 20CC and
The solvent of the fraction is distilled off.

The residue is again subjected to silica gel column chromatography, eluted with ethyl acetate, and the first 200 CCs are collected and the solvent is distilled off.

When the residue is recrystallized from ether, mp 136-137
．． 1.21 of crystals of 3-(2-pyridyl)-3-benzyl-2-piperidone are obtained at 5°C.

Example 3 The following compound is obtained in essentially the same manner as in the above example.

Claims (1)

[Claims] 1 General formula (wherein R1 is an alkyl group, an aryl group, or a pyridyl group, R2 is hydrogen, an alkyl group, an aryl group, or an aralkyl group, and n means 2 or 3, respectively) A 3-monosubstituted azacycloalkanone is reacted with a compound represented by the general formula (in the formula, R3 means an alkyl group, an aryl group, or an aralkyl group, and X means a halogen) in the presence of a metalating agent to form a general compound. A method for synthesizing an azacycloalkanone, which is characterized by obtaining a 3,3-disubstituted azacycloalkanone represented by the formula (wherein R1, R2, R3 and n have the same meanings as before).