RU2089543C1 - Method of preparing piperidone-4 (variants) derivatives and lower alkyl ester derivatives of 3-(n-lower alkyl-n- 3-2-carbolower alkoxy lower alkyl) (amino) 2,3-ene acids - Google Patents

Abstract

FIELD: chemical industry. SUBSTANCE: present invention describes methods of preparing piperidone derivatives by reductive cyclization of compounds of formula (II) followed by cyclization and treatment in acid medium. Present invention also describes novel derivatives of 3- (N-lower alkyl-N-(3-(2-carbolower alkoxy lower alkyl) amino-2,3-unsaturated carboxylic acids of general formula II:

Description

где R₁-R₇ представляют собой водород, фенил, низший алкокси, или низший алкил, возможно замещенный финилом или низшим алкокси, R₈, R₉ низший алкил.The invention relates to general organic chemistry, in particular, to methods for producing piperidone-4 (I) derivatives containing substituents in various positions [1-6] and also to new derivatives of tri- (N-alkyl-N (3- (2) alkyl esters -carboalkoxyalkyl) -2,3-unsaturated carboxylic acids (II), which can be used to synthesize piperidone-4 derivatives. piperidone-4 derivatives are widely used for the synthesis of drugs in industry [1,3,4]

where R ₁ -R ₇ are hydrogen, phenyl, lower alkoxy, or lower alkyl, optionally substituted with phenyl or lower alkoxy, R ₈ , R ₉ lower alkyl.

где R, R₁, R₂ и R₆ представляют собой H, алкил, арил и др.The following methods for the synthesis of piperidones-4 are known:
1. The condensation of aldehydes with esters of acetone dicarboxylic acid in the presence of primary amines or ammonia [2,3]

where R, R ₁ , R ₂ and R ₆ represent H, alkyl, aryl, etc.

 The disadvantage of this method is the ability to obtain only 1,2,6-substituted piperidones-4.

Недостатком этого способа является сложность синтеза исходных дивенилкетонов и их нестойкость (большое количество отходов, использование взрывоопасных производных ацетилена).2. The interaction of divinyl ketones and primary amines [1,4,5,6]

The disadvantage of this method is the complexity of the synthesis of the starting divinyl ketones and their instability (a large amount of waste, the use of explosive derivatives of acetylene).

где R, R' представляет собой H, алкил, арил и др.The closest is the method of obtaining the addition of primary amines to esters of α, β-unsaturated carboxylic acids with subsequent cyclization according to Dickman [8] according to the following scheme:

where R, R 'represents H, alkyl, aryl, etc.

 Cyclization (IIIa) is carried out under the action of an alkali metal alkonolate, subsequent hydrolysis and decarboxylation are carried out by heating (IVa) in an acidic medium.

 This method is selected as a prototype.

The disadvantage of this method is the possibility of obtaining in good yield only 1-substituted derivatives of piperidone-4, and structures with substituents in the ring are obtained with a very low yield of up to 10%
The aim of the invention is to develop a simple and technologically advanced method for producing piperidone-4 derivatives in high yield, which may contain various substituents in the ring.

где R₁-R₇ представляет собой водород, фенил, низший алкокси, или низший алкил, возможно замещенный фенилом или низшим алкокси; R₈, R₉ низший алкил.The method consists in reductive cyclization of 3- (N-alkyl-N (3- (2-carboalkoxyalkyl)) amino) -2,3-unsaturated carboxylic acid alkyl ester derivatives, followed by treatment of the resulting compound (V) in an acidic medium. The process proceeds as follows:

where R ₁ -R ₇ represents hydrogen, phenyl, lower alkoxy, or lower alkyl, possibly substituted by phenyl or lower alkoxy; R ₈ , R ₉ lower alkyl.

 The reductive cyclization process is carried out by treating the compounds of formula (II) with an alkali metal in a solvent which is a donor of the proton of the reaction, for example, a lower alcohol or a mixture thereof with an inert solvent in this reaction. The yield at this stage is 80-90%. Hydrolysis and decarboxylation are carried out by heating in an acidic medium (yield 90-95%). The general synthesis procedure (I) for reductive cyclization variants is given in Example 1.

где R₁-R₇ представляют собой водород, фенил, низший алкокси, или низший алкил, возможно замещенный фенилом или низшим алкокси; R₈, R₉ низший алкил.The compounds of formula (I) in accordance with the invention can be obtained in a two-stage way by hydrogenation of compounds of formula (II), cyclization of the obtained hydrogenated derivatives III, followed by treatment of the obtained compounds (IV) in an acidic medium according to the following scheme:

where R ₁ -R ₇ represent hydrogen, phenyl, lower alkoxy, or lower alkyl, possibly substituted by phenyl or lower alkoxy; R ₈ , R ₉ lower alkyl.

 The hydrogenation process is carried out by catalytic hydrogenation, for example, with hydrogen in the presence of a palladium catalyst. Other hydrogenation catalysts may be used.

 The general synthesis procedure (I) for the stepwise recovery and cyclization option is shown in Example 2.

 The starting compounds of the general formula (II) for the preparation of piperidone derivatives according to the method described above are novel compounds and can easily be prepared by known methods.

 Example 1. (+) - 1,2,5-trimethylpiperidin-4-one.

To a mixture of 122 g (0.5 mol) of 3- (N-methyl-N (3- (2-carbomethoxypropyl)) amino) crotonic acid ethyl ester and 400 ml of ethyl alcohol, 25.3 g (1.1 mol) are added with stirring ) of sodium metal, the alcohol is distilled off, after which 450 ml of a 20% hydrochloric acid solution are added to the reaction mixture and boiled until a negative reaction to the ketoester (IV) with ferric chloride is obtained. The reaction mixture is cooled, neutralized with an alkali solution and extracted repeatedly with ether. After distillation, 110 g of (+) - 1,2,5-trimethylpiperidin-4-one with T _bales are obtained _. = 80-83 ^o C at 11 mm Hg Yield 86%
IR spectrum (CHCl ₃ , ν, cm ^-1 ); 1720 (C = 0), 2800 (CH ₃ -N).

PMR spectrum (HMDS, d, ppm): 2.93 kV (1H, C ₂ -C ₁ H3, J 6 Hz), 2.46 kV (1H-C ₅ -CH3, J 6 Hz), 2616 C (3H, CH ₃ -N), 2.06 m (4H, CH ₂ ), 1.00 d (3H, -C ₂ H = J 6 Hz), 0.80 d (3H, -C ₅ H = J 6 Hz).

Found, C, 68.65; H 10.02; N, 9.97. C ₈ H ₁₅ NO.

 Calculated, C 68.09; H 10.83; N, 9.93.

n $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{D}}$ 1.4590. d $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{4}}$ 0.9437. GLC: 1 '30''(Inerton 5% E301, T = 220 ^o C, l = 2 m, d = 2 mm, 25 ml / min, helium).

 Example 2. (+) - 1,2,5-trimethylpiperidin-4-one.

To a mixture of 122 g (0.5 mol) of 3- (N-methyl-N (3- (2-carbomethoxypropyl)) amino) crotonic acid ethyl ester and 400 ml of ethyl alcohol was added 30 g of palladium on activated carbon obtained from 25 g palladium chloride. Next, hydrogen is bubbled through the reaction mass for several hours with vigorous stirring. 12.68 g (0.55 mol) of sodium metal are added to the filter. Further, the reaction mass is treated analogously to Example 1. 103.5 g of (+) - 1,2,5-trimethylpiperidin-4-one are obtained. Yield 81% n $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{D}}$ 1.4593.

Found C, 68.50; H 10.10; N, 9.87. C ₈ H ₁₅ NO.

 Calculated, C 68.09; H 10.63; N, 9.93.

 GLC: 1 '30' '(for chromatographic conditions, see Example 1). A joint injection of the products obtained in examples 1 and 2, showed their identity.

 Similarly to examples 1 and 2, the compounds obtained are given in table. one.

 The purity and structure of the substances given in table. 1, confirmed by data of elemental analysis, GLC, PMR spectroscopy and mass spectrometry.

 Example 12. 3- (N-methyl-N (3- (2-carbomethoxypropyl)) amino) crotonic acid ethyl ester.

A mixture of 35.2 g (0.2 mol) of ethyl 3,3-dimethoxybutanoic acid and 28.8 g (0.2 mol) of ethyl 3- (N-methyl) -2-methylpropanoic acid, 5 ml of boron trifluoride etherate and 200 ml of absolute methanol is boiled for 10 hours. Methyl alcohol is distilled off and distilled at 1 mm Hg. collecting a fraction of 90-95 ^o C.

Yield 47.47 g (92.0% of theory), n $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{<figure-callout id="1" label="D" filenames="00000015.png" state="{{state}}">D</figure-callout>}}$ 1,4372, d $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{4}}$ 0.8763. T _melt. 57-58 ^o C.

IR spectrum (CHCT ₃ , ν, cm ^-1 ): 1720, 1730 (C = 0): 1570B 2900B 3445 (CH ₃ N); 1670, 3010 (C = C).

1 H-NMR spectrum (HMDS, d, ppm): 4.30 s (1H, CH-), 3.82 d (2H, CH ₂ -, J 7 Hz), 3.71 s (3H, CH ₃ -C =). 3.30 kV (2H. -CH ₂ -CH ₃ ), 2.73 s (3H, CH ₃ O), 2.31 s (3H, CH ₃ -N), 1.10 d (3H, CH ₃ -CH ₂ -, J 6 Hz), 1.10 kV (3H, CH ₃ -CH, J 7 Hz).

Found, C, 55.70; H 8.70; N, 6.39; C ₁₂ H ₂ NO ₄ .

 Calculated, C 55.50; H 8.72; N, 6.42.

GLC: 6 '15''(Inerton 5% E301, E 220 ^o C, l = 2 m, d = 2 mm, 25 ml / min, helium).

 Similarly obtained compounds are shown in table. 2.

 The purity and structure of the substances given in table. 1 and 2, confirmed by elemental analysis, GLC and PMR spectroscopy.

 Example 21. Obtaining methyl ester of 3 (-N-methyl-N- (3- (2-ethoxycarbonyl-1-methylethyl)) amino-2-methylpropionic acid.

A solution of 24.30 g (0.1 mol) of 3- (N-methyl-N (3- (2-carbomethoxypropyl)) amino) crotonic acid ethyl ester in 100 ml of methyl alcohol is hydrogenated with hydrogen at 50 atm and room temperature for 4 hours. The solution is filtered, the liquid phase is separated, methanol is distilled off and distilled at 1 mm Hg. collecting a fraction of 110-125 ^o C. Re-distillation gives a product with T _bales. = 115-117 ^o C / 1 mm RT.article in the amount of 22.81 g. Yield 93.1%
1 H-NMR spectrum (HMDS, d, ppm): 3.98 kV (2H, -OCH ₂ -, 15 Hz), 3.53 s (3H, CH ₃ N), 3.00 m (1H, -CH-), 2.2 m ( 5H, N-CH '-, -CH' - C), 2.10 s (3H, CH ₃ O-), 1.0 m (9H, -CH ₃ -C).

Found C, 58.92; H 9.15; N, 5.85; C ₁₂ H ₂₃ NO ₄ .

 Calculated, C 58.78; H 9.32; N, 5.7.

n $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{D}}$ 1.4435 d $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{4}}$ 1.0831. GLC: 4'45 '' (Inerton 5% E301, T = 220 ^o C, l = 2 m, d = 2 mm, 25 ml / min, helium).

Sources of information
1. M.V. Rubtsov, A.G. Beichikov "Synthetic chemical and therapeutic drugs", M. Medicine, 1971, S. 195-198.

 2. Robinson r. Soc. v. 1111/112, p. 762 (1917).

 3. Hall H.K. J. Am. Chem. v. 79, No. 20, p. 5444 (1957).

 4. I.N. Nazarov, N.S. Prostakov, N.I. Shvetsov OX, t.26, N 10, p. 2798 (1956).

 5. I.N. Nazarov, V.A. Rudenko, Izv. USSR Academy of Sciences, 1948, N 6, p. 610.

 6. I.N. Nazarov et al. Izv. USSR Academy of Sciences, 1949, N 2, p. 493.

 7. Ziering A. Berger L. J. Org. Chem. v. 12, p. 895 (1947).

 8. Mc Elvain S.M. Roring K. J. Am. Chem. Soc. v. 70, Nj 5, p. 1820 (1948).

Claims (3)

1. The method of obtaining derivatives of piperidone-4 of General formula I

where R ₁ R ₇ each independently represents hydrogen, phenyl, lower alkoxy or lower alkyl, possibly substituted by phenyl or lower alkoxy,
comprising cyclization of derivatives of aminocarboxylic acid esters in the presence of alkali metal alkoxides followed by treatment of cyclization products by heating in an acidic medium, characterized in that derivatives of lower alkyl ethers 3- [N-lower alkyl-N- [3- ( 2 carbonized alkoxy lower alkyl)] amino] -2,3-enoic acids of the general formula II

where R ₁ R ₇ each independently represents hydrogen, phenyl, lower alkoxy or lower alkyl, possibly substituted by phenyl or lower alkoxy;
R ₈ and R ₉ are lower alkyl.  2. The method according to claim 1, characterized in that the process is carried out in the presence of an inert solvent. 3. A method of obtaining derivatives of piperidone-4 of General formula I

where R ₁ R ₇ each independently represents hydrogen, phenyl, lower alkoxy or lower alkyl, possibly substituted by phenyl or lower alkoxy,
comprising cyclization of derivatives of esters of monocarboxylic acids in the presence of alkali metal alkoxides followed by treatment of cyclization products by heating in an acidic medium, characterized in that derivatives of lower alkyl esters 3- [N-lower alkyl-N- [3- ( 2 carbonized alkoxy lower alkyl)] amino] carboxylic acids of the general formula III

where R ₁ R ₇ each independently represents hydrogen, phenyl, lower alkoxy or lower alkyl, possibly substituted by phenyl or lower alkoxy;
R ₈ and R ₉ are lower alkyl obtained by hydrogenation of derivatives of lower alkyl esters of 3- [N-lower alkyl-N- [3- (2-carbonized alkoxysilane alkyl)] amino] -2, 3-enoic acids of the general formula II

4. Derivatives of lower alkyl esters of 3- [N-lower alkyl-N-3- (2 carboxy lower alkoxysilane alkyl)] amino] -2,3-enoic acids of General formula II

where R ₁ R ₇ each independently represents hydrogen, phenyl, lower alkoxy or lower alkyl, possibly substituted by phenyl or lower alkoxy;
R ₈ and R ₉ are lower alkyl.

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