RU2796102C1 - Method for obtaining 1-(2-bromoethoxy)-2-methoxybenzene - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: new method for the preparation of an intermediate compound for the preparation of the drug Carvedilol, known as an alpha- and beta-blocker, namely, a method for the preparation of 1-(2-bromoethoxy)-2-methoxybenzene. Guaiacol is introduced into interaction with 1,2-dibromoethane in the presence of 3-13 wt.% aqueous sodium hydroxide solution at a temperature of 70-90°C. The ratio of guaiacol, 1,2-dibromoethane and an aqueous solution of sodium hydroxide is 1:2.5-16:1.0-1.4 molar equivalents.

EFFECT: reduction of the process time.

2 cl, 4 tbl, 34 ex

Description

The invention relates to a new method for producing 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 producing 1-(2-bromomethoxy) -2-methoxybenzene.

A known method for producing 1-(2-bromoethoxy)-2-methoxybenzene, including the reaction of 2-methoxyphenol (0.08 mol) with 1,2-dibromoethane (0.02 mol) in an acetone solution (70 ml) in the presence of potassium carbonate (0.04 mol) and potassium iodide (0.3 mmol) as a catalyst by heating the reaction mixture for 72 hours at 60°C. After filtering off inorganic residues, distilling off the solvent, and passing the reaction mixture through a silica gel chromatographic column, 1-(2-bromoethoxy)-2-methoxybenzene was obtained in 62% yield as a yellow oil. [Canale, Vittorio; Kurczab, Rafa; Partyka, Anna; Sataa, Grzegorz; Ledna, Tomasz; Jastrzebska-Wiesek, Magdalena; Wesoowska, Anna; Bojarski, Andrzej J.; Zajdel, Pavel; European Journal of Medicinal Chemistry; vol. 108; (2016); p. 334 - 346].

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

A known method for producing 1-(2-bromoethoxy)-2-methoxybenzene, including the sequential addition to an aqueous solution of 2-methoxyphenol (1 eq) an aqueous solution of potassium hydroxide (2.0 eq) and tetrabutylammonium bromide (0.2 eq) and then 1,2-dibromoethane (5 equiv.), boiling the reaction solution for 19 h, cooling, extracting the aqueous reaction medium with methylene chloride. After distilling off the solvent and passing the reaction mixture through a silica gel column chromatography, 1-(2-bromoethoxy)-2-methoxybenzene was obtained in 38% yield as a white solid. [Moritz, Amy E.; Free, R. Benjamin; Weiner, Warren S.; Akano, Emmanuel O.; Gandhi, Disha; Abramyan, Ara; Keck, Thomas M.; Ferrer, Marc; Hu, Xin; Southall, Noel; Steiner, Joseph; Aubé, Jeffrey; Shi, Lei; Frankowski, Kevin J.; Sibley, David R.; Journal of Medicinal Chemistry; vol. 63; nb. 10; (2020); p. 5526 - 5567].

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

A known method for the synthesis of 1-(2-bromoethoxy)-2-methoxybenzene based on the reaction of an aqueous solution (25 ml) of 2-methoxyphenol (4.0 ml, 36.38 mmol, 1 eq.) and NaOH (4.37 g, 109 ,13 mmol, 3 eq.) by slowly adding it to 1,2-dibromoethane (25.08 ml, 291.03 mmol, 8 eq.) and then boiling the reaction mass at 130°C for 3 hours. Flash column chromatography of the reaction mixture gave a yellow oil which crystallized at room temperature to give 1-(2-bromoethoxy)-2-methoxybenzene as a yellow solid in 22% yield. [O'Reilly, Molly; Kirkwood, Nerissa K.; Kenyon, Emma J.; Huckvale, Rosemary; Cantillon, Daire M.; Waddell, Simon J.; Ward, Simon E.; Richardson, Guy P.; Kros, Corné J.; Derudas, Marco; Journal of Medicinal Chemistry; vol. 62; nb. eleven; (2019); p. 5312 - 5329].

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

A known method for producing 1-(2-bromoethoxy)-2-methoxybenzene, including the interaction of 2-methoxyphenol (0.5 ml, 4.46 mmol, 1 eq) with 1,2-dibromoethane (1.25 g, 6.69 mmol , 1.5 eq) in aqueous sodium hydroxide solution (0.78 g, 4.46 mmol, 1 eq) at 130°C for 16 hours. After extracting the reaction mixture with ethyl acetate, distilling off the solvent, and passing the residue through a chromatographic column with silica gel, 1 g of 1-(2-bromoethoxy)-2-methoxybenzene was obtained with a yield of 34.8%. (WO2016100940A1, US patent No. 10633336, IPC C07D 211/48).

The disadvantage of this method is the low yield of the target product and the duration of the process.

The closest in execution and the achieved result is a method for obtaining 1-(2-bromoethoxy)-2-methoxybenzene, including the interaction (bromination) of guaiacol (2-methoxyphenol) with 2 equivalent excess of 1,2-dibromoethane in the presence of 1.2 molar equivalents of 20 % alkali by heating for 48 hours at a temperature of 80°C. After extracting the reaction mixture with methylene chloride, distilling off the solvent, and passing the residue through a chromatographic column with silica gel, 1-(2-bromoethoxy)-2-methoxybenzene was obtained with a yield of 75%. (European Journal of Medicinal Chemistry 44 (2009) 809e817 // Synthesis and adrenolytic activity of 1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy) ethyl]amino}propan-2-ol and its enantiomers, Part 1 Grazyna Groszek, Marek Bednarski, Ma1gorzata Dyba1, Barbara Filipek, Example 6.3.1).

The disadvantage of this method is the duration of the process, as well as insufficiently high yields of 1-(2-bromoethoxy)-2-methoxybenzene (30-40%) with the reproducibility of the method (example 1).

The technical result of the proposed method is to reduce the process time.

The technical result is achieved by the fact that guaiacol 1 is introduced into interaction with 1,2-dibromoethane (DBE) 2 in the presence of a 3-13% aqueous solution of sodium hydroxide at a ratio of 1: 2.5-16: 1.0-1.4 molar equivalents at a temperature of 70-90°C (scheme 1).

To increase the yield of the product 3 can be carried out during the process periodic, for example hourly, isolation of the resulting 1-(2-bromoethoxy)-2-methoxybenzene 3 .

Isolation of 1-(2-bromoethoxy)-2-methoxybenzene can be carried out by separating the organic layer of the reaction mass (RM) containing 1-(2-bromoethoxy)-2-methoxybenzene and DBE from the aqueous layer containing the starting products (unreacted guaiacol and alkali), and subsequent separation from the target product DBE, which can be returned to the aqueous layer of the RM or fresh reagent 2 can be added there.

An excess of 1,2-dibromoethane (DBE) is necessary to reduce the degree of formation of a by-product of double substitution - 1,2-bis(2-methoxyphenoxy)ethane 4 (Scheme 2),

as well as to increase the degree of conversion of guaiacol (taking into account the shift in chemical equilibrium), and at the same time the yield of the product.A series of experiments showed that the yield of the product, although weakly, grows with an increase in the amount of DBE used, but only up to a certain limit, and then begins to fall. In this case, the amount of by-product formed4 falls all the time.

Experiments have shown that the conversion of guaiacol increases with the amount of added alkali, however, the product yield increases slightly, along with this, the formation of a second by-product was found5, the amount of which grows in proportion to the amount of added alkali, since under these conditions the following reaction is possible (Scheme 3):

At 1.0-1.4 molar equivalent of alkali, the yield of product 3 is quite high, and the formation of the second by-product 5 is minimal.

An increase in the concentration of alkali solutions increases the formation of by-products, and when using less concentrated solutions, the conversion of guaiacol decreases. Concentrations of 3-13% NaOH are optimal.

The difference between the proposed method and the prototype is the increase in the excess of 1,2-dibromoethane2 (from 2 mol equiv. to 2.5-16 mol equiv.) and a decrease in the concentration of alkali (from 20% to 3-13%), which leads to a reduction in process time.

Below are examples of the invention.

Example 1 Obtaining 1-(2-bromoethoxy)-2-methoxybenzene according to the prototype method: European Journal of Medicinal Chemistry 44 (2009) 809e817 // Synthesis and adrenolytic activity of 1-(1H-indol-4-yloxy)-3-{ [2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol and its enantiomers. Part 1 Grazyna Groszek, Marek Bednarski, Malgorzata Dyba, Barbara Filipek example 6.3.1

Guaiacol 1 (44.25 ml; 0.4 mol), water (145 ml), 1,2-dibromoethane 2 (69 ml; 0.8 mol) and NaOH aqueous solution (20%, 70 ml; 0.48 mol ) were heated together for 48 hours at 80°C. The organic phase was separated; the aqueous phase was shaken with methylene chloride (2×150 ml). The combined organic phase was washed with 10% NaOH aqueous solution and water, and then the solvent was evaporated. The oily residue was chromatographed on a silica gel column using hexane/ethyl acetate as eluent. Product 3 was obtained as colorless crystals in 35% yield (32.57 g), m.p. 38-40°C.

Example 2 Obtaining 1-(2-bromoethoxy)-2-methoxybenzene 3 by the proposed method

Example 2.1 Guaiacol 1 (10.0 g, 80.6 mmol, 1 mol. equiv.) and 1,2-dibromoethane 2 (60.5 g, 4 mol. equiv.) were placed in a flask. The flask was heated in an oil bath to a reaction mass temperature (RM) of 80°C, after which an aqueous solution of sodium hydroxide (42.0 g, 8.7% wt., 1.2 mol. eq.) was added dropwise over 20 minutes, and then RM was boiled for 1 hour. PM was separated on a separating funnel, the lower organic layer was separated, washed with 5 ml of 9.2% NaOH, then with 5 ml of water, combined with an aqueous layer of PM and returned to the flask, 1,2-dibromoethane (60.5 g, 4 mol . equiv.) and continued to boil. The process was repeated every hour. In total, RM was boiled for 4 hours. Distillation of the organic layer yielded 194.8 g of dibromoethane (~13 mol. equiv. of recovered DBE, which can be reused) and a residue of 13.66 g of technical product 3 , which was subjected to fractional distillation. Collected colorless transparent fraction (110 - 115°C, 1 Torr), which crystallizes within an hour. Received 10.68 g of the target product 3 that corresponds to a yield of 57%.

By heating PM for 4 hours continuously without separating the organic layer, the yield of product 3 was 51%.

In both cases, colorless crystals were obtained, m.p. 39-40°C.

^1H NMR spectra were recorded on a Varian 400 MHz spectrometer. NMR ¹ H (CDCl ₃ , 400 MHz): 7.00-6.88 (m, 4H), 4.34 (t, J = 6.7, O-CH ₂ ), 3.88 (s, -CH ₃ ), 3.65 (t, J = 6.7 , Br-CH ₂ ).

Similarly, product 3 is obtained at a temperature of heating a mixture of guaiacol and DBE at a temperature of 70° and 90°C.

Table 1 shows data on the change in the yield of product 3 with a change in the process time, where GLC is gas-liquid chromatography on a GC - 2010 chromatograph with a flame ionization detector (Shimadzu, Japan).

Table 1 No. exp. Loading of guaiacol, g Time, h Substance peak area on GLC, % Unreacted guaiacol Product 3 By-Product 4 1 1.0 0 100.0 0.0 0.0 2 1.0 0.5 82.5 17.3 0.2 3 1.0 1 53.9 44.8 0.9 4 1.0 2 43.2 53.9 1.3 5 1.0 3 31.9 64.8 1.7 6 1.0 4 22.3 73.1 3.0 7 1.0 5 23.2 72.2 3.0 8 1.0 6 23.5 71.5 3.1 9 1.0 7 23.9 72.0 3.1 10 1.0 8 24.1 71.7 3.2 eleven 1.0 16 25.2 67.0 6.0 12 1.0 24 22.1 66.3 9.7 13 1.0 48 20.1 65.1 12.8

As can be seen, with a 4 equivalent excess of 1,2-dibromoethane (DBE) in the presence of a 1.2 molar equivalent of 8.7% NaOH, 4-8 hours are sufficient for the maximum yield of the target product.

Example 2.2

Analogously to example 2.1, the target product was obtained with different amounts of DBE.

Table 2 shows data on the change in the product yield with a change in the amount of DBE.

table 2 No. exp. Loading of guaiacol, g Number of eq. DBE Substance peak area on GLC, % Unreacted guaiacol Product 3 By-Product 4 14 1.0 2 21.2 73.3 3.5 15 1.0 2.5 21.9 73.8 2.1 16 1.0 3 22.6 74.6 1.8 17 1.0 3.5 23.3 74.4 1.5 18 1.0 4 23.1 75.0 1.3 19 1.0 6 24.1 74.3 0.7 20 1.0 8 25.7 73.1 0.4 21 1.0 10 29.3 70.3 0.3 22 1.0 15 32.4 66.7 0.1 23 1.0 20 35.5 62.6 0.0

As can be seen, 4 hours of the process to obtain a sufficient amount of the target product in the presence of 1.2-molar equivalent of 8.7% NaOH is sufficient when using 2.5-16 equivalent excess of 1,2-dibromoethane (DBE).

Example 2.3

Analogously to example 2.1 received the target product with different amounts of NaOH.

Table 3 shows data on the change in the yield of the product with a change in the amount of NaOH.

Table 3 No. exp. Guaiacol loading, g Number of eq. NaOH Substance peak area on GLC, % Unreacted guaiacol Product 3 By-Product 4 By-Product 5 24 1.0 1 26.9 70.0 1.6 1.0 25 1.0 1.2 22.2 75.1 1.7 0.9 26 1.0 1.4 20.0 74.7 1.6 2.8 27 1.0 1.6 18.5 75.1 1.7 3.7 28 1.0 1.8 17.0 74.1 1.6 6.5 29 1.0 2 14.2 75.4 1.6 8.4

As can be seen, 4 hours of the process to obtain a sufficient amount of the target product using 4 equivalent excess of 1,2-dibromoethane (DBE) in the presence of 8.7% NaOH is sufficient when using 1.0-1.4 molar equivalent of NaOH. More alkali leads to an increase in the yield of by-product 5 .

Example 2.4

Analogously to example 2.1 received the target product at various concentrations of alkali.

Table 4 shows data on the change in the yield of the product with a change in the concentration of alkali.

Table 4 No. exp. Guaiacol loading, g Alkali concentration, % wt. Substance peak area on GLC, % Unreacted guaiacol Product 3 By-Product 4 thirty 1.0 25.0 16.1 57.4 14.8 31 1.0 12.9 22.6 74.1 3.1 32 1.0 8.7 23.1 74.9 1.5 33 1.0 5.3 25.6 72.3 1.3 34 1.0 2.9 31.2 67.1 1.2

As can be seen, 4 hours of carrying out the process to obtain a sufficient amount of the target product using 4 molar equivalents of 1,2-dibromoethane (DBE) and 1.2 molar equivalents of NaOH is sufficient in the presence of 3-13% NaOH.

Thus, the proposed method makes it possible to obtain 1-(2-bromoethoxy)-2-methoxybenzene within about 4 hours using 2.5-16 molar equivalents of 1,2-dibromoethane (DBE) in the presence of 1.0-1.4 molar equivalent of 3-13% alkali.

Claims (3)

1. A method for producing 1-(2-bromoethoxy)-2-methoxybenzene, characterized in that guaiacol is introduced into interaction with 1,2-dibromoethane in the presence of 3-13 wt.% aqueous sodium hydroxide solution at a ratio of 1:2.5 -16:1.0-1.4 molar equivalents at 70-90°C. 2. The method according to p. 1, characterized in that during the process periodic separation of the formed 1-(2-bromoethoxy)-2-methoxybenzene from the reaction mass is carried out. 3. The method according to p. 2, characterized in that the isolation of 1-(2-bromoethoxy)-2-methoxybenzene is carried out by separating the organic layer of the reaction mass from the aqueous layer, followed by its isolation from the organic layer.