CS238934B1 - Process for the preparation of alpha-ethyldeoxybenzoin - Google Patents

Abstract

A method for producing alpha-ethyldeoxybenzoin is the reaction of benzoin with ethyl bromide in the presence of an aqueous solution of an alkali metal hydroxide and a phase transfer catalyst, in which the pH of the reaction mixture is adjusted to 7 to 0 by adding a mineral acid after the completion of the first phase of the reaction at a temperature of 20 to 100 °C, after which the mixture, after possible partial removal of water, is treated with ethyl bromide in the presence of a 50% solution of an alkali metal hydroxide in at least a 4 molar excess and a phase transfer catalyst, and the reaction mixture is maintained at a temperature of 20 to 100 °C for 30 to 180 minutes, and then the product is isolated by extraction into a water-immiscible solvent, the extract is dried, and then the product is isolated by distilling off the solvent. Alpha-ethyldeoxybenzoin is used to produce tamoxifen, which is used to treat, in particular, advanced breast tumors.

Description

The invention relates to a process for the preparation of alpha-ethyldeoxybenzoin of the formula

O / O \ -C- CH- <O \

CHj -CMj

Alpha-ethyldeoxybenzoin is used to make tamoxifen, which acts as a non-hormonal antlestrogen and is used to treat some cancers, particularly advanced breast cancer.

According to the known process, alpha-ethyldeoxybenzoin is prepared by reacting benzoline with ethyl bromide in the presence of an aqueous sodium hydroxide solution and in the presence of a phase transfer catalyst such as benzyltriethylammonium bromide.

Upon completion of the reaction, the addition of ice-water precipitated the product which was collected by filtration and the wet crystallized from methanol. This preparation method has several disadvantages. The first disadvantage is that only ethyldeoxybenzolone containing up to 20% ballast can be prepared according to the described process.

A second disadvantage is the method of product isolation. Its melting point around 50 ° C makes the drying process very difficult. The presence of a protic solvent in the product is undesirable due to its use in reaction with the Grignard reagent. Also, crystallization from methanol does not give a purifying effect, but reduces the yield by up to 20%.

The above disadvantages are overcome by the process for producing alpha-ethyldeoxybenzoin by reacting deoxybenzoin with ethyl bromide in the presence of an aqueous solution of an alkali metal hydroxide and a phase transfer catalyst such as benzyltriethylammonium bromide according to the invention. the reaction phase is 7 to 0 at a temperature of 20 to 100 ° C, after which the mixture is optionally treated with ethyl bromide in the presence of a 50% alkali hydroxide solution in at least 4 molar excess and a phase transfer catalyst, after possibly partially de-watering; held at 20 to 100 ° C for 30 to 180 minutes, and then the product was isolated by extraction. If the solvent is mixed with water, preferably 1,1,2-trifluoro-1,2,2-trichloroethane (ice 113), the extract is dried and then the product is isolated by distilling off the solvent.

The advantage of the new process for the preparation of alpha-ethyldeoxybenzoin is higher yields of up to 20% and an increase in product quality of at least 15% so that the produced alpha-ethyldeoxybenzoin contains at most 3% ballast and its yield is at least 97% of theory.

The process according to the invention is illustrated by the following examples:

Example 1

To a duplicated glass kettle with a lower outlet was added 1.6 L of water and 1.6 kg of sodium hydroxide. To this solution was added 1.963 kg of deoxybenzoin, 1.2 kg of ethyl bromide and 0.010 kg of benzyltriethylammonium bromide.

The mixture was stirred at 60-65 ° C for 1 hour. A mixture of 3.35 L conc. hydrochloric acid and 2 L of water at 70-80 ° C. Stirring at 70-80 ° C was continued for 15 minutes.

Water was then added and the lower aqueous layer was drained. To the organic oil phase was added a solution of 0.5 kg of sodium hydroxide in 0.5 L of water, 0.24 kg of ethyl bromide and 0.01 kg of benzyltriethylammonium bromide.

The mixture was stirred at 60-65 ° C for 1.5 hours. After this time, the reaction mixture was cooled to 20 ° C and 7.5 L of ice 113 was added. The ice-cold extract was dried by adding 0.2 kg of calcium chloride and stripped of color by adding 0.2 kg of activated carbon.

Total distillation of ice 113 yields 2.175 kg of ethyldeoxybenzoin (97%) containing a maximum of 3% impurities and a maximum of 0.1% water. 52-53 ° C.

He attaches

Following the procedure of Example 1. After adding a solution of 0.5 kg of sodium hydroxide in 0.6 L of water, 0.24 kg of ethyl bromide and 0.01 kg of benzyltriethylammonium bromide to the organic oil phase, the resulting mixture was stirred at 20 ° C for 180 minutes.

The procedure of Example 1 is followed again. The yield and quality of the product are the same as those of Example 1.

Example 3

Following the procedure of Example 1. After adding a solution of 0.5 kg of sodium hydroxide in 0.6 l of water, 0.24 kg of ethyl bromide and 0.01 kg of benzyltriethylammonium bromide to the organic oil phase, the resulting mixture was stirred at 100 ° C for 30 minutes.

The procedure is repeated as in Example 1. Yield: 2.175 kg (97%) of ethyldeoxybenzoin containing not more than 10% impurities and not more than 0.1% water. Mp 50-53 ° C.

Claims (1)

Object of the invention A process for producing alpha ethyldeoxybenzolnu the formula CH ₂ CH ₃ by reaction of benzoin with ethyl bromide in the presence of aqueous alkali metal hydroxide and a phase transfer catalyst, characterized in that the addition of a mineral acid, adjusting the pH of the reaction mixture after completion of the first reaction stage to a value of 7 to ON when The mixture is treated with ethyl bromide in the presence of a 50Ϊ solution of alkali metal hydroxide in at least 4 molar excess and a phase transfer catalyst, and the reaction mixture is maintained at a temperature of 20 to 100 ° C for a period of 20 to 100 ° C. 30 to 180 minutes and then the product is isolated by extraction into a water-immiscible solvent, the extract is dried and then the product is isolated by distilling off the solvent.