JPS5919109B2 - Synthesis method of azacycloalkanone - Google Patents

Description

[Detailed Description of the Invention] Conventionally, this type of azacycloalkanone has been synthesized by reacting 2-pyridine acetic acid ethyl ester with acrylonitrile in the presence of a base, and reacting the resulting nitrile compound in the presence of a metal catalyst such as Raney nickel. A method in which hydrogenation is carried out under pressurized conditions and the resulting α(3-aminopropyl)-2-pyridine acetic acid ethyl ester is subjected to a dealcoholization reaction under heating [Journal of the American Chemical Society, Vol. Volume 81 (1959), page 737]
, and a method in which a reaction similar to the above method is carried out using α-aryl-2 pyridine acetate instead of 2-pyridine ethyl acetate (Japanese Patent No. 22
No. 1488), and a method in which a reaction similar to the above method is carried out using α-alkyl (or aryl) phenylacetic acid methyl ester instead of 2-pyridine ethyl acetate (US Pat. No. 2,524,643).
, benzeneacetonitrile or a compound in which the hydrogen at the α position is substituted with ethyl, propyl, butyl, phenyl, benzyl, phenethyl, etc. is reacted with N(3-bromopropyl)phthalimide in the presence of sodium amide, and the resulting compound is A method of hydrolyzing an amino acid with hydrobromic acid to convert the resulting hydrbromide into a free amino acid and then heating to close the ring [Chemical Abstracts, Vol. 59 (1963), column 1747g], benzene Acetonitrile or its α-position hydrogen is ethyl, phenyl,
N-(3-bromopropyl) in the presence of sodium amide to a compound substituted with benzyl or phenethyl, etc.
Reacting succinimide, hydrolyzing the resulting compound with hydrobromic acid (or hydratine hydrate), neutralizing it with sodium hydroxide, ring-closing the resulting amino acid with acetic anhydride, and converting the resulting N-acetylazacyclohexanone into Method for removing acetyl groups by hydrolysis with sodium hydroxide [Vinyltan de la Société Simique de France, p. 1547 (1963) or p. 217 of the same
5 (1963)], 3-phenyl-3-ethyl 2.
A method in which 6-piperidinedione is reacted with phosphorus pentasulfide in pyridine, and the resulting compound is reduced using Raney nickel under heating under reflux in absolute ethanol [Helvetica Himica Acta, Vol. 37 (1954), No. 185 pages],
3-phenyl-2,6-piperidinedione or 3-phenyl-2,6-piperidinedione
A method in which a compound in which the hydrogen at position is substituted with ethyl or phenyl is reduced with lithium aluminum hydride, and the resulting 6-hydroquine compound is dehydrated and then hydrogenated in the presence of platinum oxide [Helvetica Himica Acta, Vol. 37 ( 1954), page 185, and Vinyltan de la Société Simique de France, page 76 (1953)] are 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 inventors of the present invention have overcome these drawbacks of the conventional method by using two new intermediates, and have completed the present invention.

This invention relates to an acetic acid derivative represented by the general formula (wherein R1 means a pyridyl group or a thiazolyl group, R2 means hydrogen, an alkyl group, a phenyl group or a phenyl-substituted alkyl group, and R3 means an esterified carboxy group). is reacted with an amino alkylating agent represented by the general formula (in the formula, R4 means an amino group protected by two acyl groups, and X means an acid residue) in the presence of a metalating agent to obtain a general Formula (where Rl.
R2, R3, and R4 have the same meanings as before), which is reacted with an amine under anhydrous conditions and heated under neutral or alkaline conditions to form an amino acid ester of the general formula (wherein R1 and R2 are The present invention relates to a method for synthesizing an azacycloalkanone, which comprises obtaining an azacycloalkanone having the same meaning as before).

The reaction of this invention is carried out by first reacting the acetic acid derivative (1) with an aminoalkylating agent () in the presence of a metallating agent.

Here, the acetic acid derivative is represented by the above general formula (1), and more specifically, an iridyl group or a thiazolyl group is represented by R1
and has as R2 an alkyl group such as hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, a phenyl group, or a phenyl-substituted alkyl group such as benzyl, phenethyl, phenylpropyl, and an esterified carboxy group. means a compound having as R3. In addition, as an esterified carboxy group, the ester part is saturated or unsaturated such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, cyclohexyl, cycloheptyl, vinyl, 1-propenyl, 2-propenyl, 3-putenyl, etc. Alkyl, phenyl, xylyl, tolyl, aryl such as naphthyl, aralkyl such as benzyl, phenethyl, and methoxy in which the carbon atom of the alkyl part of the saturated or unsaturated alkyl and aralkyl is replaced with a sulfur atom, an oxygen atom, or carbonyl, etc. Methyl, ethoxymethyl, methylthioethyl, methylthiomethyl, phenylthiomethyl, methylsulfenylmethyl, phenylsulfenylmethyl, benzoylmethyl, triolmethyl, etc. Furthermore, these groups may be substituted with suitable substituents, such as nitro, Chloromethyl, bromomethyl, trichloroethyl, p-nitrophenyl, 2.
4,5-trichlorophenyl, 2,4,6-trichlorophenyl, pentachlorophenyl, p-methanesulfonylphenyl, 4-(phenylazo)phenyl, 2,4-
Dinitrophenyl, p-chlorobenzyl, O-nitrobenzyl, p-methoxybenzyl, p-nitrobenzyl,
3,4,5-trimethoxybenzyl, bis(p-methoxyphenyl)methyl, pentachlorobenzyl, trichlorobenzyl, 3,5-ditertiary butyl-4-hydroxybenzyl, p-nitrophenylthiomethyl, p-chlorophenylthiomethyl, p-nitrobenzoylmethyl, p
-Esterified carboxy groups such as chlorobenzoylmethyl and the like. The aminoalkylating agent is represented by the general formula (), and more specifically, includes acetyl, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl,
O-bromobenzyloxycarbonyl, O-nitrophenylsulfenyl, chloroacetyl, trifluoroacetyl, formyl, tertiary butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo) ) Benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, pyridine-1oxide-2-methoxycarbonyl, 2-pyridylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1- Two acyl groups such as dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl,
or putalol with two acyl groups in its molecule, an amino group protected by succinyl, etc. as R4, hydrochloric acid, hydrobromic acid, benzenesulfonic acid, alkyl sulfuric acid, p-toluenesulfonic acid , refers to a compound having as X a residue of an organic or inorganic acid such as dialkylcarbamic acid. The metallating agent used in this reaction includes alkali metals such as sodium, lithium, and potassium, alkaline earth metals such as calcium and magnesium, or amides, hydrides, alcoholades, hydrogen carbonates, and n-butyllithium. ,
Examples of these organic compounds include phenyllithium, phenylpotassium, tertiary butylpotassium, tertiary amylpotassium, and the like.

The reaction is generally carried out in a solvent, and examples of the solvent used include benzene, toluene, 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. The amino acid ester () thus obtained is subjected to the next reaction with or without isolation and purification. The reaction of this invention is then carried out using the amino acid ester () obtained as described above.
is carried out by reacting with an amine under anhydrous conditions followed by heating in neutral or alkaline conditions.

The amines used in the reaction of amino acid esters () and amines under anhydrous conditions include primary amines, secondary amines, tertiary amines, and others such as hydratine, phenylhydratine, methylhydratine, and hydroxyethylhydratine. Examples include hydratin derivatives such as. The reaction is generally carried out in a solvent, and the solvents used include methanol, ethanol, benzene, xylene, chloroform,
Examples include dimethylformamide, but any other solvent that does not participate in this reaction can be used.
Although the reaction temperature is not particularly limited, the reaction is often carried out by heating near the boiling point of the commonly used solvent. Next, the present invention will be explained with reference to examples.

Example 1 (a) 5.3y of 50% oily sodium hydride was suspended in 100cc of dry benzene, and these α-phenyl-2-
A solution of 24.1y of pyridine acetic acid ethyl ester dissolved in 50cc of dry benzene is added dropwise at 7-10°C.

This was stirred at 50°C for 4 hours, and then 29.5V of N-(3-promopropyl)phthalimide was added to 80% of dry benzene.
A solution dissolved in CC is added dropwise to this at a temperature below 20°C.
This is stirred at room temperature for 30 minutes and then at 50° C. for 6 hours, and 15 CC of methanol is added thereto. This 2
Extract with 0% hydrochloric acid, neutralize the aqueous layer with potassium carbonate, and extract again with ethyl acetate. After washing the ethyl acetate layer with water and drying, the solvent was distilled off, ether was added to the residue, and the precipitate was collected. This is recrystallized from a mixed solution of benzene-diisopropyl ether to obtain 15.23 vol of crystals of α-phenyl-α-(3-phthalmidopropyl)-2-pyridine acetic acid ethyl ester having a Mpl of 32-133.5°C. (5
) 50% sodium hydride 2.40t anhydrous benzene 8
4-thiazole acetic acid ethyl ester 6.84f7 was suspended in 0 CC of anhydrous benzene in a nitrogen stream.
was added dropwise at room temperature and stirred at room temperature for 1.5 hours.

Add 12. N-(3-bromopropyl)phthalimide to this.
A solution of 86y dissolved in 40 cc of anhydrous benzene was added dropwise, and the mixture was stirred at room temperature for 5.5 hours. The reaction solution is washed with water, the benzene layer is dried, and then the benzene is distilled off. The residue was subjected to silica gel column chromatography and eluted with a mixed solvent of n-hexane ether (1:3) as a developing solvent. The solvent was distilled off from the eluate, and the residue was recrystallized from 99% ethanol to obtain α-(3-
5.67y of crystals of ethyl phthalimidopropyl-4-thiazole acetate are obtained. c) 4.227 ml of 50% sodium hydride was suspended in 120 cc of anhydrous benzene in a nitrogen stream, and a solution of 13.6 y of α-methyl-2-pyridine acetic acid ethyl ester dissolved in 30 cc of anhydrous benzene was added to this while stirring under water cooling. , and stirred at 50° C. for 3.5 hours.

Add 23. N-(3-bromopropyl)phthalimide to this.
A solution of 67 dissolved in anhydrous benzene 64CC was added dropwise under water cooling, and the mixture was stirred at 50°C for 19 hours. Add 10 cc of methanol to this reaction solution, and extract with RO% hydrochloric acid.
The aqueous layer is neutralized with potassium carbonate and extracted with chloroform. After drying the chloroform layer, the solvent was distilled off, and the residue was subjected to silica gel chromatography using ether as a developing solvent. When the solvent of the first portion of the eluate was distilled off, Mp
Crystals 7.2y of α-methyl-α-(3-phthalimidopropyl)-2-pyridine acetic acid ethyl ester are obtained at 58.5-59.5°C. α at Mpl2l-122°C by essentially the same method as in Example 1-(c) using α-benzyl-2-pyridine acetic acid ethyl ester instead of α-methyl-2-pyridine acetate ethyl ester. -Benzyl-α-(3-phthalimidopropyl)-2
- Obtain crystals of pyridine acetic acid ethyl ester.

(e) To 300 CC of anhydrous benzene is added 7.2 Y of finely granulated metallic sodium, and to this is gradually added 45.3 V of 2-pyridine acetic acid methyl ester while stirring.

After stirring this at 60°C for 6 hours, 80.4V of N-(3-bromopropyl)phthalimide was added to 150% of anhydrous benzene.
The solution in CC is added dropwise under cooling and then stirred at 70° C. for 17.5 hours. After cooling, 200 cc of water is added, and 10% hydrochloric acid is added to the aqueous layer to adjust the pH to 7-8, followed by extraction with benzene. This benzene extract is combined with the previous benzene layer, washed with water, and then extracted with 10% hydrochloric acid.

The aqueous layer is washed with benzene, adjusted to pH 8-9 with potassium carbonate, and extracted with benzene. After drying the benzene layer, the solvent is distilled off, the residue is subjected to silica gel column chromatography, developed with a mixed solvent of benzene:ethyl acetate (2:1), and the solvent is distilled off from the eluate. The residue was washed with ether to obtain 28.7y of crystals of α-(3-phthalimidopropyl)-2-pyridine acetic acid methyl ester having an Mp of 85-87.5°C. (f) 2-pyridine acetic acid ethyl ester instead of 2-pyridine acetic acid methyl ester 4
Crystals 49.3y of α-(3-phthalimidopropyl)-2-pyridine acetic acid ethyl ester having a Mp of 63-635°C are obtained by essentially the same method as in Example 1-(e) using 9.5y. .

(g) α-(
A colorless candy-like substance 76y of 3-phthalimidopropyl)-3-pyridine acetic acid ethyl ester is obtained.

Infrared absorption spectrum (liquid film method) 1705, 1725,
1765c7rL-1 Example 2 (a) α-Methyl-α-(3-phthalimidopropyl)-2-pyridine acetic acid ethyl ester 9.2
Dissolve V in 120 CC of 99% ethanol, add 1.67 y of hydratine hydrate, and incubate at 80-85°C for 1
Heat to reflux for 0 hours.

After cooling, it is filtered, the P solution is concentrated under reduced pressure, and the residue is dissolved in chloroform. After removing the insoluble matter with F, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain MplO4-
3-Methyl-3-(2-pyridyl)- at 105°C
1.9 g of 2-piperidone crystals are obtained. (b) α-methyl-α-(3-phthalimidopropyl)-2
-Example 2 using α-benzyl-α-(3-phthalimidopropyl)-2-pyridine acetic acid ethyl ester 12.9V instead of pyridine acetic acid ethyl ester
- Mpl35-1 by substantially the same method as in (a)
3-benzyl-3-(2-pyridyl) at 37°C
- Obtain crystal 4V of 2-piperidone.

(c) α-phenyl-α-(3-phthalimidopropyl) instead of α-methyl-α-(3-phthalimidopropyl)-2-pyridine acetic acid ethyl ester
= Mpl7 by substantially the same method as Example 2-(a) using 2-pyridine acetic acid ethyl ester 15
Crystals 6.3y of 3-phenyl-3-(2-pyridyl)-2-piperidone are obtained at 5-176°C.

(d) Example 2-(a) using α-(3-phthalimidopropyl)-4-thiazole acetic acid ethyl ester instead of α-methyl-α-(3-phthalimidopropyl)-2-pyridine acetic acid ethyl ester Crystals of 3-(4-thiazolyl)-2-piperidone 1.52V having a Mpl of 32.5-134°C are obtained by substantially the same method as above.

(e) α-(3-phthalimidopropyl)-2
-Dissolve 5V of pyridine acetic acid ethyl ester and 0.923V of hydratine hydrate in absolute ethanol.3.
Heat to reflux for 5 hours.

The reaction solution is cooled with ice water, the precipitate is removed, and the solution is concentrated to dryness under reduced pressure. Chloroform was added to the residue to remove insoluble matter, and the slurry was concentrated to dryness under reduced pressure. Remaining. When the residue was recrystallized from ethyl acetate, Mpl47-148℃3
-(2-pyridyl)-2-piperidone crystal 1
．． Get 8y. (f) α-(3-phthalimidopropyl) instead of α-methyl-α-(3-phthalimidopropyl)-2-pyridine acetic acid ethyl ester
- Mp by substantially the same method as in Example 2-(a) using 3-pyridine acetic acid ethyl ester 6.4V
3-(3-pyridyl) of l52-154 = 2
- Obtain crystal 2.2V of piperidone.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 is a pyridyl group or a thiazolyl group, R_
2 means hydrogen, an alkyl group, a phenyl group or a phenyl-substituted alkyl group, and R_3 means an esterified carboxy group, respectively) in the presence of a metalating agent to form a compound with the general formula
4 (In the formula, R_4 means an amino group protected by two acyl groups, and X means an acid residue.) By reacting an aminoalkylating agent represented by the formula ▲ mathematical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, R_3 and R_4 have the same meanings as before) is induced into an amino acid ester, which is reacted with an amine under anhydrous conditions and then heated in neutral or alkaline conditions to form the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A method for synthesizing an azacycloalkanone, which is characterized by obtaining an azacycloalkanone represented by (in the formula, R_1 and R_2 have the same meanings as before).