CS242010B1 - Method of trans 1-/4-(2-dimethylaminoethoxy)phenyl/-1,2-diphenyl-1-butene production - Google Patents

Abstract

The present invention relates to a process for the production of trans 1- - [4- (2-dimethylaminoethoxy) phenyl] -1,2- -diphenyl-1-butene, in which 4- {2-dimethylaminoethoxy] phenylmagnesium bromide shall indicate in reaction with α-ethyldeoxybenzoin v tetrahydrofuran, then the product the addition reaction is quenched with an aqueous solution ammonium chloride or acid hydrochloric acid and after addition of hydrochloric acid the ballast is removed by extraction into ether and after further addition of acid hydrochloric acid to the aqueous phase is reacted the mixture is stirred for 5 to 180 min, the excreted substance is separated, for example by filtration or centrifugation, and after alkalization to a minimum of pH 10 aqueous alkali hydroxide solution metal and after extraction into organic water-immiscible solvent, e.g. 1,1,2-trichlorotrifluoroethane; \ tor. \ T chloroform or ethyl acetate, with the product it is isolated and optionally purified by crystallization. Trans 1- (4- (2-dimethylaminoethoxy) phenyl) -1,2-diphenyl-1-butene is non-hormonal antiestrogen. It is used to treat cancer mammary glands.

Description

The present invention relates to a process for the preparation of trans 1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butene of formula I

A h ₃ c n-ch-ch _3- o / 2.

ro] rol

C

CH 2 CH 2 (I)

Trans 1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butene is a non-hormonal anti-estrogen and is used to treat breast cancer.

According to known procedures, trans 1- (4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butene is prepared from a compound of formula II

wherein X is CN or OH, by eliminating hydrogen cyanide or by eliminating water. The elimination of hydrogen cyanide is described as a catalytic reaction with strong bases such as an amide anion. Water is eliminated in an acidic environment. Both methods give a mixture of the trans- and cis-isomer of 1- (4- (2-dimethylaminoethoxy) phenyl) -1,2-diphenyl-1-butene in an isomer ratio, which is optimally 65% trans- and 35- Removal of the undesired cis-isomer requires at least four-fold crystallization, which eliminates a large amount of the difficult-to-treat mixture in which the cis-isomer predominates, which is comparable in weight to the produced trans-isomer. In order to obtain a compound of formula II having the desired purity, the crude materials after the reaction of 4- (2-dimethylaminoethoxyphenylmagnesium bromide with n-ethyldeoxybenzoin) require a number of technological operations, such as multiple extraction, distillation of flammable organic compounds. solvents to dryness, which on an industrial scale can be insurmountable obstacles, and horses These crystallization of flammable solvents. Crystallization leads to a decrease in yield as yet been found an effective method of obtaining the compound of formula II from the mother liquor after crystallization. A disadvantage is also the high toxicity of the substances occurring during the production and processing of the compound of formula II, wherein X is CN.

The above-mentioned disadvantages are largely eliminated by the process according to the invention for producing trans 1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butene, characterized in that 4- (2-dimethylaminoethoxy) The phenylmagnesium bromide is reacted with α-ethyldeoxybenzoin in tetrahydrofuran, then the product of the addition reaction is quenched with aqueous ammonium chloride solution or hydrochloric acid and after addition of hydrochloric acid the ballasts are removed by extraction into ether and after further addition of hydrochloric acid to the aqueous phase. the mixture is stirred for 5 to 180 minutes, the precipitate is separated, for example by filtration or centrifugation and after alkalization to pH 10 with at least 10 aqueous alkali metal hydroxide solution and after extraction into a non-water-miscible organic solvent such as 1,1,2-trichlorotrifluoroethane or chloroform or ethyl acetate, the product is isolated and optionally purified by crystallization.

Upon completion of the reaction of the Grignard reagent with α-ethyldeoxybenzoin, tetrahydrofuran is partially distilled off from the reaction medium. The crude reaction product is purified by crystallization from halogenated aliphatic hydrocarbons, for example 1,1,2-trichlorotrifluoroethane or carbon tetrachloride.

An advantage of the novel process for the production of trans 1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butene is that it does not require a complex techndlogical process for isolating the compound of formula II, furthermore substantially shortening the entire manufacturing process of the compound of formula I not only by the above advantage, but also because the compound of formula I is formed simply by modifying the reaction conditions directly in the reaction mixture after condensation of the Grignard reagent with α-ethyldeoixybenzoin. Another advantage of the novel process for producing trans 1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butene is that the crude product is a mixture of isomers with an average composition of 5% cis- and 95% trans This favorable composition of the crude product allows one to two crystallizations to be sufficient to obtain a trans-isomer that contains less than 1 percent of the cis-isomer. to the advantages of the novel process for producing this compound.

Example 1

A 20 L glass kettle equipped with a stirrer, a reflux condenser with a chlorine-calcium cap, a thermometer and a dropping funnel was charged with 138 g of Grignard magnesium and 0.3 g of iodine. Heat the contents of the kettle to 80 ° C for 0.5 h without stirring. After cooling to 40 ° C, 1.5 L of anhydrous tetrahydrofuran and 55 g of ethyl bromide are added. To this mixture was slowly added dropwise a solution of 1134 g of 4- (2-dimethylaminoethoxy) bromobenzene in 4.2 L of anhydrous tetrahydrofuran. The reaction mixture is stirred at 80-90 ° C for 1.5 h. A solution of 1126 g of α-ethyldeoxybenzoin in 2.1 L of anhydrous tetrahydrofuran is then added at 50 ° C and the mixture is stirred at 50 ° C for 1.5 h. It distilled off 6.3 l of tetrahydrofuran and a solution of 900 g of ammonium chloride in 9 l of water was added with vigorous stirring. The solution was cooled to 25 ° C and extracted with a total of 18 L of ether. The ether extract was extracted with a total of 16 L of 1: 1 dilute hydrochloric acid. To the aqueous acid extract was added 4 L of conc. The solution was stirred at room temperature for 2 h. The precipitate was filtered off with suction and washed with 4 L of cold water. The filter cake is transferred to a 50 L lower glass kettle, 6.5 L of water is added and a solution of 180 g of sodium hydroxide in 2.25 L of water is allowed to stir with stirring. 17 L of 1,1,2-trichlorotrifluoroethane is then added and the mixture is stirred at room temperature until all solids have dissolved. 0.016 kg of activated carbon is added to the ice extract. After filtering off the carboraffin, 14.2 L of 1,1,2-trichlorotrifluoroethane is distilled off. The distillation residue was cooled to -10 to -15 ° C. The precipitated product is filtered off with suction and recrystallized from 3 l of 1,1,2-trichlorotrifluoroethane. The yield of trans 1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butene is 500 grams with a cis-form content of less than 1%. Melting point 97-98 ° C.

Example 2

The procedure for the preparation of the compound of formula I is identical to that of Example 1 until the end of the decomposition of the addition product with aqueous ammonium chloride solution. The resulting solution was cooled to room temperature and 16 L of 1: 1 dilute hydrochloric acid was added. The acidic aqueous solution was extracted with a total of 6 L of ether. The ballast-containing ether extract is disposed of by incineration. The aqueous phase after ether extraction was treated as in Example 1.

The yield of trans 1- [4- (2-dimethylamimoethoxy) phenyl] -1,2-diphenyl-1-butene is 470 g with a cis isomer content below 1%. Mp 97-98 ° C.

Example 3

The procedure for the preparation of the compound of formula (I) is identical to Example 1 until the completion of the Grignard reaction. After 6.3 L of tetrahydrofuran was distilled off, 5 L of diluted 1: 5 hydrochloric acid was added to the reaction mixture.

The resulting mixture can be further processed according to Example 1 or Example 2.

The yield of trans 1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butene is 490 g with a cis isomer content below 1%. Mp 97-98 ° C.

Example 4

The procedure for preparing the compound of formula I is identical to Examples 1, 2 and 3 until a solution of 180 g of sodium hydroxide in 2.25 l of water is added to the reaction mixture. Then 8 L of chloroform was added and the mixture was stirred vigorously until the solid dissolved. The chloroform extract is purified by adding 0.016 kg of activated carbon. The chloroform is distilled off to dryness. The solid distillation residue was dissolved in 15 L of 1,1,2-trichlorotrifluoroethane. After distilling off 11.2 L of solvent, the distillation residue was cooled to -10 to -15 ° C. The precipitated product is filtered off with suction and recrystallized from 3 l of 1,1,2-trichlorotrifluoroethane. The crystalline mass obtained is again crystallized from 2.5 l of 1,1,2-trichlorotrifluoroethane.

The yield of trans 1- [4- (2-dimethylaminoethoxyphenyl) -1,2-diphenyl-1-butene is 400 g, with a cis isomer content below 1%.

Melting point 97-98 ° C.

Example 5

The procedure for preparing the compound of formula I is identical to Examples 1 or 2 or 3 until a solution of 180 g of sodium hydroxide in 2.25 l of water is added to the reaction mixture. Then 10 L of ethyl acetate was added. The mixture was stirred until the solid was dissolved. The ethyl acetate extract is purified by adding 0.016 kg of activated carbon. Ethyl acetate was distilled to dryness. The solid distillation residue was dissolved in 16 L of carbon tetrachloride and purified by adding 0.016 kg of activated carbon.

After distilling off 12 L of carbon tetrachloride, the distillation residue was cooled to -15 ° C. After isolation, the precipitated mass was crystallized from 4 L of carbon tetrachloride. Further crystallization from 3 liters of chloromethane gave 410 g of trans 1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butene with a cis isomer content below 1%.

Melting point 97-98 ° C.

Claims (3)

I will invent the object 1. A process for the preparation of trans 1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butene of the formula I O (I) characterized in that 4- (2-dimethylaminoethoxy) phenylmagnesium bromide of formula III ch ₅ CHt H-CH 2 CH 2 O (ni) is reacted with α-ethyldeoxybenzoin of formula IV (IV) in tetrahydrofuran, then the product of the addition reaction is quenched with aqueous ammonium chloride solution or hydrochloric acid and after addition of hydrochloric acid the ballasts are removed by extraction into ether by further adding hydrochloric acid to the aqueous phase, the reaction mixture is stirred for 5 to 180 minutes, the precipitated substance is separated, for example by filtration or centrifugation, and after alkalization to pH 10 with at least 10 aqueous alkali metal hydroxide solution and after extraction into a non-water miscible organic solvent For example, 1,1,2-trichlorotrifluoroethane or chloroform or ethyl acetate, the product is isolated and optionally purified by crystallization. 2. Process according to claim 1, characterized in that, after the reaction of the Grignard reagent with n-ethyldeoxybenzoin is complete, tetrahydrofuran is partially distilled off from the reaction medium. 3. The process according to claim 1, wherein the crude reaction product is purified by crystallization from halogenated aliphatic hydrocarbons, for example 1,1,2-trichlorotrifluoroethane or carbon tetrachloride. Severografla, n. P., Plant 7, Most