CS238904B1 - Process for the preparation of trans 1- [4- (2-dimethylaminoethyl) phenyl] -1,2-diphenyl-1-butone - Google Patents

Abstract

A method for producing trans isomers of 1-[Ϊ-/2- -dimethylaminoethoxy/phenyl]-1,2-diphenyl-1- -butene, where the trans isomer is the isomer with unsubstituted phenyl groups in the trans position, i.e. the substance of formula I, by heating 1-[5-/2-dimethylaminoethoxy/phenyl]-1,2-diphenyl-1-butanol of formula II at 60°C to the boiling point of acetic acid for 2 to 8 hours in an acetic acid solution. The substance is useful in the treatment of cancer.

Description

The present invention relates to a process for the manufacture of trans 1- (4- (2-dimethylaminoethoxy) phenyl) -1,2-diphenyl-1-butene useful in the treatment of cancer.

Trans l- ^ 4- / 2-dimethylamino-ethoxy / phenyl / -l, 2-diphenyl-'l-butene of formula I, _CH3-C = C / 1 / ^C 2 ^H 5 kancerotherapeutlkem effective. According to one known method, in the last step of the synthesis of the compound of formula I, the hydrogen cyanide is eliminated from the compound of formula II

(11), wherein X = CN by the action of sodium amide in dimethylformamide or by the action of potassium in liquid ammonia. In another known process, the final step in the synthesis of compound I is the elimination of water from the compound of formula II wherein X = OH.

This elimination is accomplished by the action of acid catalysts in an inert solvent or diluent at elevated temperature. By elimination of water from II, where X = OH, in addition to I, its cis isomer / trans or label is formed. cis refers to the relative position of unsubstituted phenyl groups.

The resulting mixture of isomers is separated according to the known process by fractional crystallization from methanol, acetone, petroleum ether or a mixture of these solvents. The alcohol of formula II, wherein X · OH is prepared either by reacting a Grignard reagent obtained from bromobenzene, with 4- (2-dimethylaminoethoxy) -α-ethyl-deoxybenzoin

MgBr

CH 2 ⁺ CH 3 ^{, CH 2,} 2

II or reacting the Grignard reagent prepared from 4- / 2-dimethylaminoethoxy / bromobenzene with alpha-ethyl-deoxybenzoin ^CH3 \ _CH3 N ^ / CH _2/2

+

CO —CH

^C 2 ^H 5

The process for the preparation of the compound of formula I according to the above processes has some disadvantages. The procedure based on the elimination of hydrogen cyanide from the compound of formula II, wherein X 'CN, requires work with a highly toxic material.

Elimination of water from the compound of formula (II) wherein X = OH by the action of acid catalysts in an inert solvent or diluent results in a mixture of the compound of formula (I) and its cis-isomer to be separated by fractional crystallization from highly flammable solvents.

These disadvantages are partly overcome by the process of the invention. According to him, the elimination of water from the compound of formula (II) wherein X 'OH is carried out by heating the compound in acetic acid solution.

The effect of the invention is further enhanced by heating a solution of the compound of formula II wherein X = OH in acetic acid to 60 ° C to boiling point. This method of preparation produces predominantly the compound of formula I, its cis-isomer not being produced in an amount exceeding 35%.

Fractional crystallization from flammable solvents is then not required for the isolation of the pure compound of formula (I), but ordinary crystallization from haloalkanes, for example 1,1,2-trifluoro-1,2,2-trichloroethane (Freon 113), is sufficient.

The compound of formula II, where X = OH, can be obtained according to a known procedure by preparing the Grignard reagent from 4- (2-dimethylaminoethoxy) bromobenzene and reacting with alpha-ethyl-deoxybenzoin.

However, the preparation of this Grignard reagent usually has a long initiation phase of the reaction, and it is therefore preferable to first treat the magnesium with 0.01 to 0.1 molar amount (based on 4- (2-dimethylaminoethoxy) bromobenzene) of a highly reactive neutral alkyl halide or an alkenyl halide, such as ethyl bromide or ethylenedibromide, before adding 4- (2-dimethylaminoethoxy) bromobenzene to the magnesium. In this way, the desired Grignard reagent is formed without an initiation period. The required alpha-ethyl-deoxybenzoin lz® β is advantageously prepared by alkylating deoxybenzoin in the presence of a phase transfer catalyst, which eliminates the risk associated with the commonly used alkylation method in an anhydrous environment.

According to the invention, a compound of formula II wherein X 'OH can also be prepared by reacting a Grignard reagent prepared from 1-halo-1-phenylpropane with 4- (2-dimethylaminoethoxy) benzophenone in tetrahydrofuran or ether in the presence of excess magnesium:

© A

HrC 'S ^v 2

CH.

CHMgX + ch ₃

II.

The advantage of this process for the preparation of compound II, wherein X-OH, is the easy and inexpensive preparation of both reaction components, 1-halo-1-phenylpropane can be prepared by the action of hydrogen halide on 1-phenyl-1-propanol; 4- (2-dimethylaminoethoxy) benzophenone can be obtained by reacting 2-dimethylaminoethyl halide with 4-hydroxybenzophenone, the latter being readily available from benzoic acid phenyl ester by treatment with aluminum chloride.

The invention and its effects are illustrated in more detail in the following examples.

Example 1

Trans-1- (4- (2-diraethylaminoethoxy) phenyl) -1,2-diphenyl-1-butene (1)

A solution of 13.0 g of 1- (4- (2-dimethylaminoethoxy) phenyl) -1,2-diphenyl-1-butanol (II, x = OH) in 130 ml of acetic acid was heated to boiling for 4.5 h. The colorless reaction mixture was then evaporated and 100 ml of chloroform were added to the residue.

The chloroform solution was shaken with 15% sodium hydroxide solution (until a strongly alkaline reaction of the aqueous layer), dried with magnesium sulfate and evaporated to dryness. 12.4 g, i.e. 100% of crystalline product, were obtained which, according to thin-layer chromatography on silica gel G in the system 2-propanol-conc. NH 4 OH-chloroform 5: 1: 94, iodine vapor detection or spraying with 1% cerium sulfate in 10% sulfuric acid and heating, had an R _p value of about 0.8 and did not contain II (X OH) in the trace. The mass spectrum) of the product was in accordance with the structure of formula I.

According to ¹ H-NMR spectroscopy, it was a compound of formula I and its cis-isamer (trans or resp. cis relative to the relative position of unsubstituted phenyl groups.

By integrating the triplets of the Q-CH3-CH3 group to substance I, a trans isomer with a chemical shift value of < 5.86 and its cis isomer with a chemical shift value of &gt; 4.03, it was found that I was present in 70%.

Crystallization of the product from 1,1,2-trifluoro-1,2,2-trichloroethane (freon 113) gave 6.2 g (50%) of compound I, mp 95-97 ° C, by mass and ⁴ H-NMR spectroscopy absolutely clean.

The citric acid salt prepared from compound I had a m.p. 148 DEG C. (decomposition).

EXAMPLE 2 1- [2- (2-Dimethylaminoethoxy) phenyl] -1,2-diphenyl-1-butanol (II, XOH)

In a three-necked flask equipped with a stirrer, reflux condenser and addition funnel (chloro-calcium closures) was charged 3.72 g (153 mmol) of magnesium, dried over phosphorus pentachloride and 50 ml of tetrahydrofuran.

Then, 1.36 g (12.5 mmol) of ethyl bromide was added in one portion. After a few seconds at which Grignard reagent began to form, 4- (2-dimethylaminoethoxy) bromobenzene (34.3 g, 140.5 mmol) was added dropwise in 150 ml of tetrahydrofuran and the reaction was kept under gentle heating.

After all the 4- (2-dimethylaminoethoxy) bromobenzene was added, the reaction mixture was heated to boiling until the magnesium dissolved (1 h). Then, 34.4 g (153 mmol) of alpha-ethyldeoxybenzoline in 75 ml of tetrahydrofuran was added and the reaction mixture was heated at reflux for 5 h.

After cooling, the reaction mixture was quenched with 250 mL of 10% aqueous ammonium chloride solution, 300 mL of ether was added to the mixture, and after stirring for a few minutes, the ether layer was separated by draining.

The ether layer was then extracted with 15% sulfuric acid, the aqueous extract was separated from the ether layer with 30% sodium hydroxide solution and extracted (toluene. After evaporation of toluene, 44.8 g of pure alcohol II / X = OH) was obtained. G, 2-propanol-conc. NH 4 OH-chloroform 5: 1: 94, iodine vapor detection ^

Yield 82% based on starting 4- (2-dimethylaminoethoxy) bromobenzene. After recrystallization from methanol, m.p. Mp 129-130 ° C.

Example 3 1- (7- (2-Dimethylaminoethoxy) phenyl) -1,2-diphenyl-1-butanol (II, X OH)

In the same apparatus as described in Example 2, a Grignard reagent was prepared from 4.86 g (200 mmol) of dry magnesium, 25.9 g (130 mmol) of 1-bromo-1-phenylpropane and 300 ml of ether.

The halogenated derivative was added to the reaction mixture very slowly (over 5 hours) so that there was no substantial amount of unreacted halogenated derivative in the reaction mixture. then 26.9 g (100 mmol) of 4- (2-dimethylaminoethoxy) benzophenone were added with stirring and the reaction mixture was heated to boiling under stirring for 4 h.

After cooling, 250 mL of 10% aqueous ammonium chloride solution was added, and after stirring for a few minutes, the ether layer was separated from aqueous. The ether layer was extracted with 15% hydrochloric acid, the acidic extract basified with 30% sodium hydroxide solution and then shaken with 100 ml of toluene.

Drying of the toluene with magnesium sulfate and evaporation of toluene gave 25.3 g of chromatographically pure product (see Example 2), corresponding to a 65% yield based on 4- (2-dimethylamino-ethoxy) -benzophenone.

Example 4

Alpha-ethyldeoxybenzoin

To a 250 ml flask equipped with an efficient stirrer and reflux condenser was weighed 50 g deoxybenzoin, 70 ml 50% sodium hydroxide solution, 0.3 g triethylbenzylammonium chloride and 30 g ethyl bromide in 70 ml toluene were added.

The reaction mixture was heated with vigorous stirring. 3.5 h at 55 ° C. Then, the organic layer was separated, washed with water and dried over magnesium sulfate. After evaporation of toluene, 50 g of crystalline product were obtained by recrystallization from methanol 42 g (74% based on deoxybenzoin), m.p. 53-54 ° C, by chromatography on silica gel G in 3: 1 benzene-petroleum ether system, detection of iodine parahydroxy, pure product.

Example 5

4- (2-Dimethylaminoethoxy) benzophenone

To a 500 mL flask equipped with a stirrer and a descending condenser was weighed 39.6 g (200 mmol) of 4-hydroxybenzophenone, 200 mL of toluene and 63 mL of 3.2 M sodium methoxide in methanol (201 mmol) were added.

The reaction mixture was heated to boiling with stirring when the azeotropic toluene-water methanol distilled off, 34.5 g (240 mmol) of 2-dimethylaminoethyl chloride hydrochloride, 75 ml of 3.2 M sodium methoxide in methanol (240 mmol) were added to the reaction mixture. and 200 ml of toluene.

The reaction mixture was again heated to boiling with stirring if it distilled the methanol-toluene azeotrope. The descending condenser was then replaced with a reflux condenser and the reaction mixture was heated to reflux for 6 hours with stirring.

Thereafter, 200 ml of water was added to the reaction mixture, the toluene layer was separated from aqueous, and after concentrating the toluene solution to half its volume, 1 N p-toluenesulfonic acid was added to the pH of the toluene concentrate containing the basic reaction product.

Crystals of solif-toluenesulfonic acid with 4- (2-dimethylaminoethoxy) benzophenone of m.p. 118-120 ° C and a weight of 80 g (181 mmol, i.e. 90% based on 4-hydroxybenzophenone).

The salt was recrystallized from acetone-ether to give an m.p. increased to 120 to 121 ° C. The free base, i.e. 4- (2-dimethylaminoethoxy) benzophenone, was obtained from this salt by treatment with 30% sodium hydroxide solution and extraction of the base into toluene.

Claims (2)

Ρ 8 E D MEASURE OF THE INVENTION X. A process for producing trans 1- (7- (2-dimethylaminoethoxy) phenyl) -1,2-diphenyl-1-butene of formula (I) wherein the trans isomer is an isomer with unsubstituted phenyl groups in the trans position, characterized in that 1- [beta] - (2-dimethylamino-ethoxy) -phenyl] -1,2-diphenyl-1-butanol of formula (H) (11) is heated in a solution of acetic acid at 60 DEG C. to boiling point of acetic acid for 2 to 8 hours and recovering the reaction product. 2. The process according to claim 1, wherein the isolation is carried out by crystallization from haloalkanes, e.g. freons.