The method of obtaining the ethyl ester of 10-(2,3,4-trimetoksi-6 - were)decanoas acid

 

(57) Abstract:

The invention relates to organic chemistry, namely the method of obtaining the ethyl ester of 10-(2,3,4-trimetoksi-6-were) decanoas acid - intermediate, suitable for the synthesis of idebenone - drug nootropic action. The method of obtaining the ethyl ester of 10-(2,3,4-trimetoksi-6-were) decanoas acid is the reaction of hydrogenation of ethyl ester 9-(2,3,4-trimetoksi-6-methylbenzoyl) nonanalog acid in the medium of organic solvent is a lower monohydroxy alcohol in the presence of a palladium catalyst, taken in sufficient quantity to conduct the process. The way technological, proceeds with high yield. 3 table.

The invention relates to organic chemistry, namely, the method of production of ethyl ester of 10-(2,3,4-trimetoksi-6-were) decanoas acid - intermediate, suitable for the synthesis of idebenone - drug nootropic action. The invention can be used in the medical industry.

There is a method of deriving arylaliphatic acid, for example, 6-(9-acetoxyphenyl)-2,3-dimethoxy-5 METHYLPHENOL (2), according to which sootvetstvuyet under hydrogen pressure of 8.5 MPa at 5% palladium on charcoal, containing 50% water, in the presence of sulfuric acid at a temperature of 30 - 40oC for 5 hours. The yield of the target product was 93.5%.

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(Patent EP N 0289223, MKI: C 07 C 50/28, 21.04.88,)

The disadvantage of this method is the length of the hydrogenation process, and the presence in the reaction medium of sulfuric acid, which entails additional manufacturing operations to neutralize it hampers the regeneration of the solvent and catalyst.

Also known is a method of obtaining another derivative arylalkylamines acid 6-(9-acetoxyphenyl)-2,3-dimethoxy-5-METHYLPHENOL (2) and 6-(10-acetoxyethyl)-2,3-dimethoxy-5-METHYLPHENOL (5) [2] recovery groups, respectively, in Arellano 6-(9-hydroxy-1-octanoyl) and 6-(10-hydroxy-1-octadecyl)-2,3-dimethoxy-5-METHYLPHENOL (3) and (4) above 5% palladium on coal in a solution of anhydrous acetic acid in the presence of 70% perchloro acid at room temperature and atmospheric pressure with a high yield within 24 hours.

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(G. Goto, Okamoto, etc. Chem. Pharm. Bull. 1985, v. 33, No. 10, p. 4422 - 4431).

The disadvantage of this method is the length of the process and the fact that in the described conditions simultaneously with the hydrogenation process is acetyl is such complexity in the process, the presence of perchloro acid creates an increased risk.

The closest in technical essence is a way to obtain 10-(2-hydroxy-3,4-dimethoxy-6-were)-decanoas acid (7) by restoring the carbonyl group at the 9-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)-nonanol acid (6) in the medium of anhydrous acetic acid over 5% palladium on coal for 6.5 hours at room temperature, and then 6.5 hours at 50 - 60oC. the Yield of the target product (7) amounted to 57.7% (K. Okamoto. M. Watanabe. etc. Chem. Pharm. Bull. 1982, v. 30, N 8, p.2797 - 2819).

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The disadvantage of this method is the length of the hydrogenation process, the low yield of the target product, using as solvent an environmentally unpromising anhydrous acetic acid.

The objective of the present invention is to develop a method of obtaining a new connection - ethyl ester 10-(2,3,4-trimetoksi-6-were)decanoas acids are biologically important intermediate using as starting compound - ethyl ester 9-(2,3,4-trimetoksi-6-methylbenzoyl) nonanalog acid.

The technical result is an increase in the yield of the final product.

Tehnicheski acid ethyl ester 9-(2,3,4-trimetoksi-6-methylbenzoyl nonanalog acid is subjected to hydrogenation in the medium of organic solvent lower monohydroxy alcohol, in the presence of a catalyst, which is used as 4% palladium catalyst on a carbon carrier Sibunit taken in an amount of 0.25 - 0.5 g 510-4mol gidrirovannogo substances and pre-treated solution, based on the rate of 1.0 l of acid per 5 ml used monohydroxy alcohol, and washed with the same solvent, and the process is carried out at a temperature of 30 - 60oC.

Used in the process of hydrogenation catalyst ICT-3-20 is a highly dispersed palladium metal, uniformly applied in the amount of 4 wt.% the carbon media Sibunit. The catalyst has high activity and selectivity in hydrogenation process of nitrobenzotrifluoride in aminobenzotrifluoride his selectivity at 99.95 - 99.99% of).

Using palladium catalyst on a carbon carrier, pre-treated with a solution of sulfuric acid, additionally, the process is carried out in the lower monohydroxy alcohols, in an atmosphere of hydrogen and a temperature of 30 - 60oC. These process conditions include the use also as a source of product - ethyl ester 9-(2,3,4-trimetoksi-6-methylbenzoyl) non what about the product 92 - 97,5%. The process of hydrogenation of from 1 to 6 hours. The amount of catalyst should be 0.25 - 0.5 g 510-4mol gidrirovannogo substances (8) (examples 10, 11; PL. 2). If the amount of the catalyst is higher or lower than this range, the yield of the target product (9) is reduced (examples 9, 12; PL. 2).

The process of hydrogenation at a temperature below 30oC and above 60oC also leads to a decrease of the yield of the target product (9) (PL. 1).

The invention is illustrated by the following examples.

Example 1.

0.5 g of the catalyst is palladium on a carbon carrier with the content of the active phase of 4% Pd by weight) is treated with sulfuric acid solution (1 l of H2SO4in 5 ml of isopropyl alcohol). After settling, the upper layer is decanted, and the catalyst was washed with the same solvent. The hydrogenation is carried out in an autoclave, which is made of 0.2 g ethyl ester 9-(2,3,4-trimetoksi-6-methylbenzoyl) nonanalog acid in 20 ml of isopropyl alcohol at 50oC and atmospheric pressure. The hydrogenation process is over 190 minutes, the Catalyst was separated by filtration. The residue is evaporated and chromatographic on a column of silica gel askg. The system hexane: ether 4:1. The yield of the target product is UB>6D6, , M. D.: 0,9 - to 1.70 (m, 17H, 7 CH2CH3), of 2.15 (t, J8 Hz, 2H, CH2COO), of 2.21 (s, 3H, CH3arene.), 2,72 (so J10 Hz, 2H, CH2when arene. ), 3,44 (s, 3H, CH3O), 3,82, of 3.84 (s, 6H, CH3O) 4,00 (K. J8 Hz, 2H, OCH2CH3).

Mass spectrum, m/z: 380 (M+), 335, 195.

The infrared spectrum, CCl4cm-1: 1735 (COO-), 1600, 1575.

Example 2.

In the conditions of example 1 restore 0.2 g ethyl ester 9-(2,3,4-trimetoksi-6-methylbenzoyl)-nonanol acid in ethanol at 50oC. the Yield of the target product (9) of 96.5% (0,1861 g).

Example 3.

0.5 g of the catalyst is palladium on a carbon carrier with the content of the active phase of 4% Pd by weight) is treated with sulfuric acid solution (1 l of H2SO4in 5 ml of isopropyl alcohol). After settling, the upper layer is decanted, and the catalyst was washed with the same solvent. The hydrogenation is carried out in an autoclave, which is made of 0.6 g of ethyl ester of 9-(2,3,4-trimetoksi-6-methylbenzoyl)-nonanol acid in 20 ml of isopropyl alcohol at 50oC and atmospheric pressure for 350 minutes Yield (9) - 97,3% (0,5630 g).

Examples 4, 5, 6, 7, 8.

The hydrogenation is carried out in the conditions of example 1 at various temperatures. The results of predstawila ester 9-(2,3,4-trimetoksi-6-methylbenzoyl)-nonanol acid with different amounts of catalyst. The results are presented in table 2.

Examples 13, 14, 15.

In the conditions of example 3 changing the partial pressure of hydrogen. The results are presented in table 3.

Example 16.

Synthesis of ethyl ester 9-(2,3,4-trimetoksi-6-methylbenzoyl)-nonanol acid.

To a suspension of 33.3 g of AlCl3in 35 ml of methylene chloride, cooled to 0oC, was added in small portions to 40.8 g w-canbetkasinoonline.html in 15 ml of methylene chloride. The mixture was cooled to -5oC and was added for 1 hour in a stream of N230 g of 3,4,5-trimethoxyphenol in 35 ml of methylene chloride. Stirred the reaction mass at a current of N23.5 hours at 0oC. was Poured into 100 ml ice water, was extracted with 50 ml of hexane. Shared layers. The organic layer was washed with water (100 ml x 4) and the aqueous layer was extracted with 25 ml ethyl acetate. The organic extracts were combined, dried Na2SO4was filtered , evaporated. The remainder (69 g) was chromatographically on a column of silica gel Asch (400 g) in the solvent system hexane : acetone (50:1). Return 10 g of 3,5-trimethoxysilane. Received 25 g (yield of 38.5%, 58%, taking into account the conversion) ethyl ester 9-(2,3,4-trimetoksi-6-methylbenzoyl) nonanalog acid.

Ethyl ester 9-(2,3,4-t3), of 2.15 (t, J7 Hz, 2H, CH2COO), 2,22 (s, 3H, CH3ring), 2,78 (t, Hz, 2H, CH2C) of 3.32 (s, 3H, CH3O), 3,70 - and 3.72 (s, 6H, 2CH3O) 4,00 (K, J7 Hz, 2H, OCH2CH3), to 6.22 (s, 1H, H-arene.).

Mass spectrum, m/z : 394 (M+), 379, 349, 209, 182, 195.

The infrared spectrum, CCl4cm-1: 1735 (COO-), 1700 (CO), 1600, 1575.8

The method of obtaining the ethyl ester of 10-(2,3,4-trimetoksi-6-were) decanoas acid, which consists in the fact that the ethyl ester of 9-(2,3,4-trimetoksi-6-methylbenzoyl)nonanalog acid is subjected to hydrogenation in the environment organic solvent is a lower monohydroxy alcohol in the presence of a catalyst, which is used as 4% palladium catalyst on a carbon carrier Sibunit taken in an amount of 0.25 - 0.5 g 510-4mol gidrirovannogo substances and pre-treated with a solution of sulfuric acid, based on 1 l of acid per 5 ml used monohydroxy alcohol, and washed with the same solvent, and the process is carried out at a temperature of 30 - 60oC.

 

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