RU2792273C1 - Method for obtaining 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a new method for obtaining an intermediate compound for the preparation of Carvedilol, known as an alpha- and beta-blocker, which, among other things, produces a pronounced vasodilating effect that reduces afterload on the heart, namely, to a method for obtaining 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione. The method consists in introducing 1-(2-bromoethoxy)-2-methoxybenzene into interaction with potassium phthalimide in a solution of dimethylformamide at 70-100°C, followed by separation of the target product by adding water. EFFECT: technical result of the proposed method is reduction of the process time in the absence of a catalyst and isolation and purification of the target product without using organic solvents to obtain the target product in the shape of small crystals.

3 cl, 1 tbl, 6 ex

Description

The invention relates to a new method for obtaining an intermediate compound for the preparation of the drug Carvedilol, known as an alpha- and beta-blocker, which, among other things, has a pronounced vasodilating effect that reduces afterload on the heart, namely, to a method for obtaining 2-[2-(2 -methoxyphenoxy)-ethyl]-isoindole-1,3-dione.

A known method of obtaining 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione, which consists in the interaction of phthalimidoalcohol with guaiacol under the action of triphenylphosphine and diethyl ester of azodicarboxylic acid (DEAD) in tetrahydrofuran at room temperature (Mitsunobu reaction) . The output of 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione does not exceed 40% [Carocci A. and other. Bioorganic and Medicinal Chemistry; vol. 18; nb. 17; (2010); p. 6498].

The disadvantage of this method is the low yield of the product.

A known method for producing 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione, based on the Mitsunobu reaction, which consists in the interaction of guaiacol with N- (2-hydroxyethyl)phthalimide and triphenylphosphine. The reaction mixture was stirred at room temperature overnight. Yield not reported [Wu Zhaoyang and other. ACS Medicinal Chemistry Letters; vol. 7; nb. 12; (2016); p. 1131].

The disadvantage of this method is the duration of the process.

Other methods for producing 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione are known based on the Mitsunobu reaction [Li Linhu and other. ACS Medicinal Chemistry Letters; vol. 9; nb. 7; (2018); p. 742]. [Chen, Min; and others. New Journal of Chemistry; vol. 45; nb. 12; (2021); p. 5623]. Product yields are not indicated.

The disadvantage of the methods is the duration of the process.

A known method for producing 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione consisting in the interaction of 31 g of 1-(2-chloroethoxy)-2-methoxybenzene, 27.6 g of potassium phthalimide in 100 g dimethylformamide (DMF) at 170° C. for 3 hours. At the end of the reaction, 50 ml of DMF was distilled off under reduced pressure, and 100 g of methanol was added to disperse. Cooled and filtered off the precipitate. Recrystallized from 95% ethanol to give 2-[2-(2-methoxyphenoxy)-ethyl]isoindole-1,3-dione 41.2 g (86.4% yield). [CN patent No. 109206328; 2019; (A)].

The disadvantage of this method is the high temperature of the process and the lengthy procedure for isolating the target product.

A known method for producing 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione, including the interaction of potassium hydroxide with the phthalimide derivative of 1-(2-chloroethoxy)-2-methoxybenzene at 130°C and stirring for about 13 hours, followed by extraction with dichloromethane and further purification [international application WO 2009128088, C07C 209/62, 2009].

The disadvantage of this method is the high temperature of the process and the lengthy procedure for isolating the target product.

A known method for producing 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione, including the reaction of 1-(2-bromoethoxy)-2-methoxybenzene (0.2 mol) in 200 ml of dimethylformamide with 0.2 mol of phthalimide potassium at 50°C for 30 minutes. 300 ml of chloroform was added to the reaction mixture and poured into 500 ml of water. The aqueous phase was separated and extracted with two portions of 100 ml of chloroform. The combined chloroform extract was washed with 200 ml of 0.2N NaOH. NaOH (to remove unreacted phthalimide) and 200 ml of water. After drying (MgSO ₄ ), the chloroform was distilled off. The crystalline residue was triturated with 40 ml of ether and the precipitate was filtered off. 2-[2-(2-Methoxyphenoxy)-ethyl]-isoindole-1,3-dione was obtained. Exit not specified [Liang, Jhy-Chong and other. Bioorganic and Medicinal Chemistry; vol. 10; nb. 3; (2002); p. 726].

The disadvantage of this method is the lengthy procedure for isolating and purifying the target product.

A known method for producing 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione, including the reaction of 1-(2-bromoethoxy)-2-methoxybenzene with potassium phthalimide in the presence of potassium iodide. The reaction was carried out in DMF at 50°С for 5 h; then water was added and the resulting precipitate was stirred at room temperature for 12 hours. 2-[2-(2-Methoxyphenoxy)-ethyl]-isoindole-1,3-dione was obtained as a creamy precipitate. Product yield not specified [Drabczyk Anna K. and other. European Journal of Medicinal Chemistry; vol. 227; (2022); Art.No: 113931].

The disadvantage of this method is the duration of the process.

A known method for producing 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione, including the reaction of 1-(2-bromoethoxy)-2-methoxybenzene (0.700 g, 3.03 mmol), potassium phthalimide (0.597 g, 3.23 mmol) and 18-crown-6 ether (0.024 g, 0.09 mmol) in dry DMF (3 ml) for 3 hours at 50°C. The reaction mixture was diluted with water (poured into 25 ml of water) and stirred for one hour. Get 2-(2-(2-methoxyphenoxy)ethyl)isoindoline-1,3-dione in the form of a white solid with a yield of 67% [Sniecikowska Joanna and other. Journal of Medicinal Chemistry; vol. 63; No. 19; (2020); p. 10949; Supporting Information, p. 30, 34].

The disadvantage of this method is the duration of the process and the use of an expensive catalyst.

The closest in execution and the achieved result is a method for obtaining 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione, including the reaction of 1-(2-bromoethoxy)-2-methoxybenzene (5 g; 0 .0216 mol) with potassium phthalimide (4.26 g; 0.023 mol) in the presence of 18-crown-6 ether catalyst (0.15 g; 6.25×10 ^-4 mol) in DMF (20 ml) for 5 h at a temperature of 50°C, followed by the addition of the reaction mass (RM) to 170 ml of water (9-fold excess of water). The mixture was stirred for 2 h, the precipitate was filtered off, washed with water, and dried in air. N-[2-(2-methoxyphenoxy)ethyl]phthalimide is obtained in 88% yield (5.69 g). So pl. 102-108°C [Groszek Grazyna and others. European Journal of Medicinal Chemistry; vol. 44; nb. 2; (2009); p. 815].

The disadvantage of this method is the duration of the process and the use of an expensive catalyst.

The technical result of the proposed method is to reduce the process time in the absence of a catalyst and to isolate and purify the target product without the use of organic solvents to obtain the target product in the form of small crystals.

The technical result is achieved by the fact that 1-(2-bromoethoxy)-2-methoxybenzene 1 is introduced into interaction with potassium phthalimide 2 in a solution of dimethylformamide (DMF) at 70-100°C, followed by separation of the target product by adding water (scheme 1).

Scheme 1

Starting products 1 and 2 are introduced into interaction preferably in the ratio: 1 molar equivalent of 1-(2-bromoethoxy)-2-methoxybenzene with 1.0-1.2 molar equivalent of potassium phthalimide.

The addition of water is preferably carried out in a 7-12-fold excess by volume with respect to DMF.

The addition of water is preferably carried out by its gradual introduction into the reaction mixture to obtain smaller crystals.

The difference between the proposed method and the prototype is carrying out the reaction at a higher temperature (70-100°C instead of 50°C) and adding water to the reaction mass (RM) in the process of isolating the target product instead of adding RM to water.

At a given temperature, the product is formed in high yield. With an increase in temperature, by-products are formed, leading to a decrease in the conversion of the initial product and the yield of the target product. Under the proposed isolation conditions, the product crystallizes out in the form of friable (not clumping), small crystals, in contrast to the products of the closest analogues.

The isolation process is simpler compared to the isolation processes by the methods of some of the closest analogues and consists in water treatment and drying.

Below are examples of the invention.

Example 1. Obtaining 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione 3 according to the method of the prototype [Groszek, Grazyna; Bednarski, Marek; Dybala, Malgorzata; Filipek, Barbara // European Journal of Medicinal Chemistry; vol. 44; nb. 2; (2009); p. 815]

A mixture of bromide 2 (5 g; 0.0216 mol), potassium phthalimide (4.26 g; 0.023 mol), 18-crown-6 ether (0.15 g; 6.25×10-4 mol) in DMF (20 cm ³ ) was heated for 5 h at a temperature of 50°C. The reaction mixture was poured into 170 ml of water, stirred for 2 h, the precipitate was filtered off, washed with water, and dried in air. Received 5.69 g of N-[2-(2-methoxyphenoxy)ethyl]phthalimide large solid agglomerates of particles with a yield of 88%, so pl. 102-108°C.

Example 2. Obtaining 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione 3 by the proposed method

A solution of commercially available (https://www.molbase.com/name/1-(2-Bromoethoxy)-2-methoxybenzene.html China) 1-(2-bromoethoxy)-2-methoxybenzene (10.0 g, 43, 3 mmol, 1 mol. equiv.), potassium phthalimide (8.50 g, 1.06 mol. equiv.) in 40 ml of DMF was heated with stirring to 80°C and held for 45 minutes. After that, 400 ml of distilled water was added to the flask. Stirred for 1 hour. The precipitate was filtered off, washed with 2x50 ml of distilled water and dried in a stream of air for 0.5 h, then on a rotary-film evaporator (RFI) at 6°C for 0.5 h. white precipitate (crystals do not crumple, are easily poured and tared), yield 91.6%, purity 99.6% by GLC, mp. 107-10°C.

Similarly, the product is obtained using 1-(2-bromoethoxy)-2-methoxybenzene and potassium phthalimide in a ratio of 1:1 and 1:1.2.

Similarly, the product (with slightly smaller crystals) is obtained by gradually adding water to the reaction mixture.

Similarly, the product is obtained by adding water in an amount of 7 (280 ml) and 12 (480 ml) volume excess relative to DMF.

^1H NMR spectra were recorded on a Varian 400 MHz spectrometer. ^1H NMR (CDCl ₃ , 400 MHz): 7.86-7.69 (m, 4H), 6.96-6.83 (m, 4H), 4.29 (t, J = 6.1 Hz, 2H, O-CH2), 4.11 (t, J = 6.1 Hz, 2H, N-CH2), 3.74 (s, -CH ₃ ).

Table 1 shows the data on the conversion of 1-(2-bromoethoxy)-2-methoxybenzene 1 with temperature changes over time, where GLC is gas-liquid chromatography on a GC - 2010 chromatograph with a flame ionization detector (Shimadzu, Japan).

Table 1 No. exp. Loading 1 , g Temperature, °C Time Conversion 1 by GLC % 1 1.0 50 5 h 99+ 2 1.0 60 2.5 h 99+ 3 1.0 70 1.5 h 99+ 4 1.0 80 45 min 99+ 5 1.0 90 30 min 98 6 1.0 100 25 min 96

As can be seen, at a reactant interaction temperature of 70-100°C and when water is added to the PM, the reaction time with a sufficient yield of the target product (conversion of the starting product) is reduced compared to the prototype and is about an hour instead of 5 hours. The crystals are small, do not crumple and easily poured in contrast to large solid agglomerates of particles obtained by the method of the prototype.

Thus, the proposed method allows you to get 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione for about 0.45-1.5 (and not 5 hours as in the prototype) using 1 -(2-bromoethoxy)-2-methoxybenzene and potassium phthalimide in the absence of catalysts and carrying out the isolation and purification of the target product without the use of organic solvents to obtain the target product in the form of small crystals (in contrast to the prototype method and closest analogues).

Claims (4)

1. A method for producing 2-[2-(2-methoxyphenoxy)-ethyl]-isoindole-1,3-dione, characterized in that 1-(2-bromoethoxy)-2-methoxybenzene is reacted with potassium phthalimide in a solution of dimethylformamide at 70-100°C, followed by separation of the target product by adding water. 2. The method according to claim 1, characterized in that the starting products are introduced into interaction in the ratio: 1 molar equivalent of 1-(2-bromoethoxy)-2-methoxybenzene with 1.0-1.2 molar equivalent of potassium phthalimide. 3. The method according to p. 1, characterized in that the addition of water is carried out in a 7-12-fold volume excess with respect to dimethylformamide. 4. The method according to p. 1, characterized in that the addition of water is carried out by its gradual introduction into the reaction mixture.