RU2755123C1 - (6r,8r,10s,12r,13ar)-5-methyl-3,6,7,8,9,10,11,12,13,13а-decahydro-1н-2,6: 6а,10:8,12-trimethanocyclonone[c]-azocine production method - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to a method for producing (6R,8R,10S,12R,13аR)-5-methyl-3,6,7,8,9,10,11,12,13,13а-decahydro-1H-2,6:6а,10:8,12-trimethanocyclonone[c]-azocine, which can be considered as a starting substrate in the synthesis of functionally substituted derivatives with biological activity, and can be used in the pharmaceutical industry and fine organic synthesis.

EFFECT: development of new method for the preparation of (6R,8R,10S,12R,13аR)-5-methyl-3,6,7,8,9,10,11,12,13,13а-decahydro-1H-2,6:6а,10:8,12-trimethanocyclonone[c]-azocine by reacting 1[2-(adamant-1-yl)-2-hydroxyethyl-1]-4-methyl-1,2,3,6-tetrahydropyridine with concentrated sulfuric acid with good yield.

1 cl, 6 ex

Description

The invention relates to a method for producing (6R, 8R, 10S, 12R, 13aR) -5-methyl-3,6,7,8,9,10,11,12,13,13а-decahydro-1H-2,6: 6а , 10: 8,12-trimethanocyclonone [c] -azocine, a pentacyclic alkene of the framework structure. Due to the presence of a double bond in the structure, this compound can be considered as a starting substrate in the synthesis of functionally substituted derivatives with biological activity, and can be used in the pharmaceutical industry and fine organic synthesis. In addition, the invention is a one-step conversion of synthetically available starting compounds into products of increased molecular complexity in good yield. Applications - pharmaceutical industry and fine organic synthesis.

This invention solves the problem of obtaining a pentacyclic alkene of the framework structure - (6R, 8R, 10S, 12R, 13aR) -5-methyl-3,6,7,8,9,10,11,12,13,13а-decahydro-1Н- 2.6: 6a, 10: 8,12-trimethanocyclonone [c] -azocine:

Known laboratory method for obtaining pentacyclic alkene framework structure, which consists in the interaction of 1- [2- (adamant-1-yl) -2-hydroxyethyl-1] -4-methyl-1,2,3,6-tetrahydropyridine with trifluoromethanesulfonic acid [Chem ... Heterocyclic Compd. 2020. 56. 898-908]. The product yield is 65%. The disadvantage of this method is the use of a 30-fold excess of an expensive and toxic reagent - trifluoromethanesulfonic acid, which, due to its hygroscopicity, requires the use of absolute solvents, the reaction in an inert atmosphere and a large consumption of alkali to isolate the product.

The objective of the present invention is to develop a method for producing (6R, 8R, 10S, 12R, 13aR) -5-methyl-3,6,7,8,9,10,11,12,13,13а-decahydro-1H-2,6 : 6а, 10: 8,12-trimethanocyclonone [c] -azocine - a pentacyclic alkene of a framework structure.

The technical result of the invention is a technologically simpler, cost-effective and environmentally less hazardous method of obtaining (6R, 8R, 10S, 12R, 13aR) -5-methyl-3,6,7,8,9,10,11,12, 13,13a-decahydro-1H-2,6: 6a, 10: 8,12-trimethanocyclonone [c] -azocine.

The technical result is achieved by the fact that the synthesis of (6R, 8R, 10S, 12R, 13aR) -5-methyl-3,6,7,8,9,10,11,12,13,13а-decahydro-1H-2,6 : 6а, 10: 8,12-trimethanocyclonone [c] -azocine was carried out by the reaction of 1- [2- (adamant-1-yl) -2-hydroxyethyl-1] -4-methyl-1,2,3,6-tetrahydropyridine with concentrated sulfuric acid in a molar ratio of 1: 10-40 based on the original substrate in methylene chloride at a temperature of 0-40 ° C for 1-10 hours.

Isolation of the target product was carried out by adding 30% sodium hydroxide to the reaction mixture, separating the aqueous-organic phase, evaporating the organic phase, additionally extracting the product from the aqueous medium with methylene chloride and then distilling off the solvent. The resulting product was purified by column chromatography CH ₂ Cl ₂ -i-PrOH (1: 1).

The main distinguishing features of the proposed method can be formulated as follows.

1. The use of concentrated sulfuric acid as a catalyst, which reduces the cost of the method.

2. Carrying out the synthesis at room temperature, the absence of the need to use absolute solvents and to carry out the reaction in an inert atmosphere simplifies the instrumental scheme of the process and, therefore, makes this method more attractive from an economic point of view.

3. Small amount of waste water, low environmental impact.

4. The possibility of obtaining (6R, 8R, 10S, 12R, 13aR) -5-methyl-3,6,7,8,9,10,11,12,13,13а-decahydro-1H-2,6: 6а, 10: 8,12-trimethanocyclonone [c] -azocine under mild conditions.

Execution of the method

The structure of the synthesized compounds was confirmed by the data of NMR spectroscopy. ¹ H NMR spectra and ¹³ C are recorded on a Jeol JNM ECX 400 instrument (400 MHz) in DMSO-d6. Elemental analysis was performed on an automatic CHNS analyzer "EuroVectorEA-3000".

The invention is illustrated by the following examples. The examples describe the production by the claimed method of a new pentacyclic alkene of a framework structure.

Example 1

To a solution of 5 g (0.018 mol) of 1- [2- (adamant-1-yl) -2-hydroxyethyl-1] -4-methyl-1,2,3,6-tetrahydropyridine in 10 ml of methylene chloride is added portionwise 30 ml (54.6 g, 0.545 mol) concentrated sulfuric acid for an hour while cooling with an ice bath. Then the reaction mixture was stirred at room temperature for 5 h, poured into ice, basified with 20% NaOH solution to pH 10-11 and extracted with methylene chloride (3 × 25 ml). The combined organic extracts were dried with anhydrous Na ₂ SO ₄ , evaporated under reduced pressure, the residue was separated by column chromatography CH ₂ Cl ₂ -i-PrOH (1: 1). Yield 3.40 g (74%). ¹ H NMR spectrum, δ, ppm: 0.72-0.80 (1H, m); 1.16-1.47 (7H, m); 1.57-1.64 (1H, m); 1.70-1.94 (10H, m); 2.02 (1H, d, J 14.0 Hz); 2.43 (1H, dt, J 12.6 Hz, J 2.0 Hz); 2.52 (1H, ddd, J = 14.0 Hz, J = 4.5 Hz, J = 1.1 Hz); 2.68 (1H, dd, J = 13.5 Hz, J = 11.9 Hz); 2.96 (1H, dt, J = 11.6 Hz, J = 2.0 Hz); 3.08 (1H, dd, J = 12.6Hz, J = 1.3Hz); 3.52 (1H, d, J = 18.5 Hz); 5.41 (1H, d, J = 1.1 Hz, 4-CH). ¹³ С NMR spectrum, δ, ppm: 26.7 (СН ₃ ); 27.5 (CH); 27.8 (CH); 31.2 (CH); 35.9 (CH ₂ ); 36.0 (CH); 36.1 (CH ₂ ); 37.3 (CH ₂ ); 38.4 (C); 39.6 (CH ₂ ); 40.4 (CH ₂ ); 47.1 (CH ₂ ); 48.9 (CH); 49.1 (CH ₂ ); 53.0 (CH ₂ ); 59.6 (CH ₂ ); 123.3 (CH); 137.1 (C). Mass spectrum, m / z (I,%): 257 [М] + (4), 109 (39), 91 (22), 81 (33), 79 (60), 67 (31), 55 (40 ), 42 (79), 41 (100). Found,%: C 84.02; H 10.54; N 5.50. C ₁₈ H ₂₇ N. Calculated,%: C 83.99; H 10.57; N 5.44.

Example 2

To a solution of 5 g (0.018 mol) of 1- [2- (adamant-1-yl) -2-hydroxyethyl-1] -4-methyl-1,2,3,6-tetrahydropyridine in 10 ml of methylene chloride is added portionwise 20 ml (36.4 g, 0.363 mol) concentrated sulfuric acid for an hour while cooling with an ice bath. Then the reaction mixture is stirred at a temperature of 40 ° C for 5 h, poured into ice, made alkaline with 20% NaOH solution to pH 10-11 and extracted with methylene chloride (3 × 25 ml). The combined organic extracts were dried with anhydrous Na ₂ SO ₄ , evaporated under reduced pressure, the residue was separated by column chromatography CH ₂ Cl ₂ -i-PrOH (1: 1). Yield 2.77 g (60%).

Example 3

To a solution of 5 g (0.018 mol) of 1- [2- (adamant-1-yl) -2-hydroxyethyl-1] -4-methyl-1,2,3,6-tetrahydropyridine in 10 ml of methylene chloride is added portionwise 20 ml (36.4 g, 0.363 mol) concentrated sulfuric acid for an hour while cooling with an ice bath. Then the reaction mixture was stirred at 40 ° C for 10 h, poured into ice, made alkaline with 20% NaOH solution to pH 10-11 and extracted with methylene chloride (3 × 25 ml). The combined organic extracts were dried with anhydrous Na ₂ SO ₄ , evaporated under reduced pressure, the residue was separated by column chromatography CH ₂ Cl ₂ -i-PrOH (1: 1). Yield 2.86 g (62%).

Example 4

To a solution of 5 g (0.018 mol) of 1- [2- (adamant-1-yl) -2-hydroxyethyl-1] -4-methyl-1,2,3,6-tetrahydropyridine in 10 ml of methylene chloride is added portionwise 40 ml (72.8 g, 0.726 mol) concentrated sulfuric acid over one hour while cooling with an ice bath. Then the reaction mixture was stirred at room temperature for 5 h, poured into ice, basified with 20% NaOH solution to pH 10-11 and extracted with methylene chloride (3 × 25 ml). The combined organic extracts were dried with anhydrous Na ₂ SO ₄ , evaporated under reduced pressure, the residue was separated by column chromatography CH ₂ Cl ₂ -i-PrOH (1: 1). Yield 3.23 g (70%).

Example 5

To a solution of 5 g (0.018 mol) of 1- [2- (adamant-1-yl) -2-hydroxyethyl-1] -4-methyl-1,2,3,6-tetrahydropyridine in 10 ml of methylene chloride is added portionwise 10 ml (18.2 g, 0.181 mol) concentrated sulfuric acid over 1 hour while cooling with an ice bath. Then the reaction mixture was stirred at 40 ° C for 10 h, poured into ice, made alkaline with 20% NaOH solution to pH 10-11 and extracted with methylene chloride (3 × 25 ml). The combined organic extracts were dried with anhydrous Na ₂ SO ₄ , evaporated under reduced pressure, the residue was separated by column chromatography CH ₂ Cl ₂ -i-PrOH (1: 1). Yield 1.25 g (27%).

Example 6

To a solution of 5 g (0.018 mol) of 1- [2- (adamant-1-yl) -2-hydroxyethyl-1] -4-methyl-1,2,3,6-tetrahydropyridine in 10 ml of methylene chloride is added portionwise 30 ml (54.6 g, 0.545 mol) concentrated sulfuric acid for an hour while cooling with an ice bath. Then the reaction mixture was stirred at 40 ° C for 10 h, poured into ice, made alkaline with 20% NaOH solution to pH 10-11 and extracted with methylene chloride (3 × 25 ml). The combined organic extracts were dried with anhydrous Na ₂ SO ₄ , evaporated under reduced pressure, the residue was separated by column chromatography CH ₂ Cl ₂ -i-PrOH (1: 1). Yield 3.40 g (74%).

Claims (1)

Method of obtaining (6R, 8R, 10S, 12R, 13aR) -5-Methyl-3,6,7,8,9,10,11,12,13,13а-decahydro-1H-2,6: 6а, 10: 8,12-trimethanocyclonone [c] -azocine by reacting 1- [2- (adamant-1-yl) -2-hydroxyethyl-1] -4-methyl-1,2,3,6-tetrahydropyridine with concentrated sulfuric acid in molar ratio 1: 10-40 based on the original substrate in methylene chloride at a temperature of 0-40 ° C for 1-10 hours.