Method of producing 2-(adamantyl-1)-4-bromophenol

FIELD: chemistry.

SUBSTANCE: invention relates to chemistry of adamantane derivatives and specifically to a method of producing 2-(adamantyl-1)-4-bromophenol, which is an intermediate product in the synthesis of adapalene - 6-[3-(adamantyl-1)-4-methoxyphenyl]-2- naphthoic acid, which is widely used in dermatology as an effective anti-acne agent. The method of producing 2-(adamantyl-1)-4-bromophenol involves reacting 4-bromophenol with 1-adamantanol and 1-bromoadamantane in molar ratio of 2:1:0.1, respectively, in the presence of 0.01 ml water or without water at temperature of 110-130°C for 2 hours.

EFFECT: simple, ecologically clean method of producing 2-(adamantyl-1)-4-bromophenol without using a catalyst and a solvent.

6 ex

 

The invention relates to the chemistry of adamantane derivatives, and in particular to a method for producing 2-(substituted-1)-4-bromophenol, which is an intermediate product in the synthesis of adapalene - 6-[3-(substituted-1)-4-methoxyphenyl]-2-naphthoic acid, which is widely used in dermatology as an effective remedy against acne.

2-(Substituted-1) 4 - bromophenol has the following formula:

In patents receiving adapalene are several methods of synthesis of 2-(substituted-1)-4-bromophenol from 1-adamantanol and 4-bromophenol, the difference in the use of acid catalyst from concentrated sulfuric to methanesulfonic acid.

A method of obtaining 2-(substituted-1)-4-bromophenol described in patent US 4717720, publ. 05.01.1988. 1-Adamantanol subjected to interaction with 4-Bromphenol when the molar ratio of reactants is 1:1 in the environment of methylene chloride at ambient temperature for 8 h in the presence of a catalyst of sulfuric acid, taken in equimolar number. The yield of 2-(substituted-1)-4-bromophenol - 86%.

The disadvantage of this method is the use of a large number of acid and corrosive catalyst (sulfuric acid).

There is a method of adamantylamine 4-Bromphenol 1-adamantanol in the presence of another acid catalyst - methansulfonate in Rast is oricle (CH 2Cl2) or without (yield 87.3%, or 97%) (WO 2007125542, publ. 11.08.2007). Also in this patent is used as a catalyst for sulfuric acid in acetic acid solution, (yield 90%). The disadvantage of this method is the use of acid and corrosion of the catalyst.

The closest to the technological nature and purpose of the present invention is a method of obtaining 2-(substituted-1)-4-bromophenol (CN 101955417, 2011-01-26), which also use 1-adamantanol and 4-bromophenol when a molar ratio of 1:1, and as a catalyst using an acidic ion-exchange resin in glacial acetic acid. The reaction is carried out at a temperature of 100°C for 3-5 hours. The yield of 2-(substituted-1)-4-bromophenol - 92-99%.

This method is the most environmentally friendly in comparison with the previous one. It allows you to recaliberate acetic acid, adding after the reaction of acetic anhydride to bind water (a by-product of the reaction). However, the preparation of the catalyst (acidic ion-exchange resin) long and time-consuming.

The technical result of the invention is to develop a simple, environmentally friendly method of obtaining 2-(substituted-1)-4-bromophenol without the use of catalyst and solvent.

The technical result is achieved in that the method of obtaining 2-(substituted-1)-4-bromophenol, which consists in the interaction of 4-bromo is the enol 1-adamantanol when heated, according to the invention, the reaction mixture was further added 1-bromodomain at a molar ratio of reagents 4-Bromphenol:1-adamantanol:1-bromodomain equal to 2:1:0.1, respectively, and the reaction is carried out at a temperature of 110-130°C for 2 hours in the presence of 0.01 ml of water or without water.

The advantage of this method is the possibility of carrying out the reaction without solvent and catalyst, easy selection of the reaction product. Adding a small amount of water allows to obtain a by-product O-alkylation (adamantinoma ether 4-bromophenol). Decreasing the reaction temperature output is reduced. Further increase in the reaction temperature during the addition of water leads to another byproduct of 2,6-di(1-substituted-)-4-bromophenol.

Way of the following examples:

Example 1. Getting 2-(substituted-1)-4-bromophenol

4-Bromophenol in the number 0,346 g (0,002 mol) is mixed with 0.152 g (about 0.001 mole) of 1-adamantanol, of 0.022 g (of 0.0001 mole) of 1-bromoguanine (the molar ratio of reagent 2:1:0,1) and 0.01 ml of water in a vial and heated in a sealed ampoule at a temperature of 120°C for 2 hours. After cooling, the reaction mass is treated with 2% NaOH solution to remove excess 4-bromophenol. The residue is dried and recrystallized from isooctane. The yield of the target product - 0,280 g (1%); TPL 148-149°C. PMR Spectrum (CDCl3, δ, ppm): 1.80 (c, 6H); 2.11 (c, 9H); 4.87 (1H, OH); 6.56 (D., 1H, H6; J=8.4 Hz); 7.18 (Shostakovich, 1H, H5; J=8.4, 2.4 Hz); 7.32 (D., 1H, H3; J=2.4 Hz). Found, %: C, 62.61; H 6.18. C16H19BrO. Calculated, %: C, 62.54; H, 6.19.

Example 2.

Analogously to example 1. Only the reaction temperature of 115°C. the Yield of the target product 0,273 g (89%).

Example 3.

Analogously to example 1. Only the reaction temperature of 125°C. the Yield of the target product 0.267 g (87%).

Example 4.

4-Bromophenol in the number of 0.346 g (0.002 mole) is mixed with 0.152 g (0.001 mole) of 1-adamantanol and 0.022 g (0.0001 mole) of 1-bromoguanine (the molar ratio of reagent 2:1:0.1) in the ampoule and heated at a temperature of 120°C for 2 hours. Allocate analogously to example 1. The yield of 2-(substituted-1)-4-bromophenol 0.230 g (75%). Range PMR (CDCl3, δ, ppm): 1.80 (c, 6H); 2.11 (c, 9H); 4.87 (1H, OH); 6.56 (D., 1H, H6; J=8.4 Hz); 7.18 (Shostakovich, 1H, H5; J=8.4, 2.4 Hz); 7.32 (D., 1H, H3; J=2.4 Hz).

Example 5.

4-Bromophenol in the number of 0.346 g (0.002 mole) is mixed with 0.152 g (0.001 mole) of 1-adamantanol and 0.022 g (0.0001 mole) of 1-bromoguanine (the molar ratio of reagent 2:1:0.1) in the ampoule and heated at 110°C for 2 hours. Allocate analogously to example 1. The yield of 2-(substituted-1)-4-bromophenol 0.166 g (54%). Range PMR (CDCl3, δ, ppm): 1.80 (c, 6H); 2.11 (c, 9H); 4.87 (1H, OH); 6.56 (D., 1H, H6; J=8.4 Hz); 7.18 (Shostakovich, 1H, H5; J=8.4, 2.4); 7.32 (D., 1H, H3; J=2.4 Hz).

Example 6.

4-Bromophenol in the number 0346 g (0.002 mole) is mixed with 0.152 g (0.001 mole) of 1-adamantanol and 0.022 g (0.0001 mole) of 1-bromoguanine (the molar ratio of reagent 2:1:0.1) in an autoclave and heated at a temperature of 130°C for 2 hours. Allocate analogously to example 1. The yield of 2-(1-substituted)-4-bromophenol 0.236 g (77%). Range PMR (CDCl3, δ, ppm): 1.80 (s, 6H); 2.11 (s, 9H); 4.87 (1H, OH); 6.56 (D., 1H, H6; J=8.4 Hz), 7.18 (Shostakovich, 1H, H5; J=8.4, 2.4 Hz), 7.32 (D., 1H, H3; J=2.4 Hz).

Thus, a simple, eco-friendly method of obtaining 2-(substituted-1)-4-bromophenol without catalyst and solvent.

The method of obtaining 2-(substituted-1)-4-bromophenol formula

which consists in the interaction of 4-bromophenol 1-adamantanol when heated, characterized in that the reaction mixture was further added 1-bromodomain at a molar ratio of reagents 4-Bromphenol: 1-adamantanol: 1-bromodomain equal to 2:1: 0.1, respectively, and the reaction is carried out at a temperature of 110-130°C for 2 h in the presence of 0.01 ml of water or without water.



 

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