HU227156B1 - Process for producing 1-(4-fluor-phenyl)-1,2-diphenyl-1-butene - Google Patents

Abstract

The product is prepared by reacting ~a-ethyl-des-oxy-benzoin and p-fluorine-bromine-benzol in the presence of a Grignard reagent.

Description

The present invention relates to the preparation of 1- (4-fluorophenyl) -1,2-diphenyl-1-butene of formula (I).

The compound of formula (I) is a valuable pharmaceutical intermediate useful in the manufacture of a pharmaceutical active ingredient of tamoxifen, an international non-proprietary anti-estrogenic agent for breast cancer. Tamoxifen is 1- (p-beta-dimethylaminoethoxyphenyl) -trans-1,2-diphenylbut-1-ene (II).

1- (4-Fluorophenyl) -1,2-diphenyl-1-butene of formula (I) is a mixture of the E and Z isomers. The compound of formula (I) may be prepared from deoxybenzoin of formula (III) [T. E. Zalleskaja, 0. A. Netskaja: Zs. Org. Khim. 5, 1076 (1969); 151,747 Is. Hungarian Patent Specification]. The compound of formula (I) is prepared in three steps. In the first step, the deoxybenzene of formula (III) is alkylated in the usual manner with ethyl iodide, the resulting a-ethyldioxybenzene of formula (IV) is reacted with Grignard reagent of p-bromofluorobenzene, and the resulting 1,2-diphenyl-1- -fluorophenyl) -1-butanol is dihydrated.

The above synthesis is based on generally known reactions. In the first step of the synthesis, the acidic hydrogen atom of the deoxybenzoin of formula (III) is ethylated via the corresponding α-anion. The resulting product also contains the deoxybenzoin derivatives used as the starting material, thus forming a crude product containing a-ethyl deoxybenzoin of formula IV and deoxybenzene of formula III.

In the second step of the synthesis, the resulting oxo compound is reacted with Grignard reagent. This operation is one of the basic reactions of organic chemistry [Gábor Fodor: Organic Chemistry II. Vol. Budapest, (1960); Gyula Deák: Named Reactions in Organic Chemistry Budapest (1967). The reaction is carried out on any carbonyl-containing compound. Therefore, the chemical literature recognizes the intrinsic property of carbonyl compounds.

Due to the activity of the Grignard reagent, each carbonyl compound reacts to form a complex crystal of triphenylalkene derivatives.

In order to avoid known, expected side reactions, alkyldioxybenzoin derivatives are carefully purified prior to reaction with Grignard reagent. No. 151,747, No. According to Example 5 of the Hungarian Patent, the alkyl deoxybenzoin derivative is purified by extraction and distillation before the Grignard reaction. No. 171,269. According to the Hungarian patent, the alkyl deoxybenzoin derivative is filtered, dried and vacuum distilled after preparation in water.

The distillation and extraction purification procedures used in the known processes have significant disadvantages. These are energy-intensive procedures that use environmentally polluting, costly equipment and cause significant losses. A further disadvantage is that extraction purification requires the use and movement of significant amounts of solvent. Losses in the purification process reduce yield.

It is an object of the present invention to eliminate the purification operations used in the prior art processes discussed above, thereby avoiding environmental damage, extraction operations using high solvent volumes, and the use of expensive equipment.

This object is achieved by the present invention and by the process of the present invention the preparation of the highly pure 1- (4-fluorophenyl) 1,2-diphenylbutene of formula (I) without purification.

The present invention relates to a process for the preparation of 1- (4-fluorophenyl) -1,2-diphenyl-1-butene of formula (I) by the use of a Grignard reagent of α-ethyl deoxybenzoin of formula (IV) and p-fluorobromobenzene. by reacting a mixture of α-ethyl deoxybenzoin of formula (IV) and deoxybenzene of formula (III).

The present invention is based on the discovery that 1- (4-fluorophenyl) -1,2-diphenyl-1-formula (I) is of sufficient purity even when α-ethyl-deoxybenzoin (IV) is contaminated with deoxybenzoin (III). butene t is obtained.

It has been found that 1- (4-fluorophenyl) -1,2-diphenylethene (V) formed from the deoxybenzoin (III) in the above reaction mixture is present in the final product (I) at a concentration of two orders of magnitude less than the ratio represented in the starting mixture. This recognition was confirmed by analytical measurements. According to the present invention, the crude α-ethyl-deoxybenzoin containing the deoxybenzoin of formula (III) can be successfully used to obtain a compound of the formula (I) of sufficient purity. This recognition makes it possible to eliminate the purification of α-ethyl-deoxybenzoin of formula (IV) and is very advantageous in terms of reducing the amount of solvent and eliminating purification operations which cause environmental damage.

The discovery underlying the present invention is all the more surprising since the desired compound of formula (I) and the unwanted contaminant of formula (V) can all be produced in good yield under the same conditions.

By comparative experiment, it was proved that the amount of impurity V from the deoxybenzoin III obtained in the product of formula I was two orders of magnitude lower than the content of the deoxybenzoin III in the starting compound IV (a). One skilled in the art would have expected that the amount of impurity (V) in the final product would be the amount of the starting compound (IV) deoxybenzoin (III). Surprisingly, it has been found that the desired product contains orders of magnitude less impurity than the starting material. The results are summarized in Table I after the examples.

Surprisingly, it has also been found that the content of the a-ethyl deoxybenzoin (IV) used as starting material has a favorable effect on the yield of the Grignard reaction with respect to the α-ethyl-deoxybenzoin. The compound of formula (III)

The by-product of formula (V) formed from Β1 deoxybenzoin therefore has an unforeseen "salting" effect. The above recognition is supported by the data in the last column of Table I.

The process of the present invention is preferably carried out as follows.

A carbanion is formed on the α-carbon of the deoxybenzoin of formula (III) using a base and then the carbanion is ethylated. The reaction is carried out in a known manner. The base is preferably an alkali metal alcoholate, particularly preferably sodium methylate. Ethyl iodide is preferably used as the alkylating agent. The reaction is carried out under heating for several hours. Advantageously, the reaction mixture can be worked under reflux. After completion of the reaction, the reaction mixture is filtered and then sprayed onto water, preferably by means of a pump. The excellent α-ethyl-deoxybenzene of formula (IV) is isolated and further processed without purification.

The resulting α-ethyl-deoxybenzoin of formula (IV) contains up to 20% of deoxybenzine of formula (III). The reaction with the Grignard compound is carried out using a mixture of a-ethyldioxybenzoin of formula IV and deoxybenzoin of formula III. This mixture preferably contains from 2.5 to 20.0% by weight of deoxybenzene of formula (III).

In the next step of the synthesis, a-ethyl deoxybenzene of formula (IV) containing deoxybenzene (III) is reacted with Grignard reagent made from p-fluorobromobenzene. The reagent is prepared by reacting p-fluorobromobenzene with magnesium in a conventional solvent for Grignard reactions. The solvent is preferably tetrahydrofuran, diethyl ether, dioxane or a mixture of tetrahydrofuran and diethylene glycol dibutyl ether (butyl diglyme). The Grignard compound is preferably prepared in a tetrahydrofuran medium. The Grignard compound is preferably prepared in the presence of a catalyst (e.g., methyl iodide). The Grignard reagent is prepared in a manner known per se.

The Grignard reagent thus prepared is added to a solution of a mixture of α-ethyl deoxybenzoin of formula IV and deoxybenzoin of formula III in an inert organic solvent. The initial deoxybenzene mixture is preferably dissolved in tetrahydrofuran, diethylene glycol dibutyl ether (butyl diglyme), a mixture of tetrahydrofuran and an aromatic hydrocarbon (preferably toluene) or a mixture of tetrahydrofuran and diethylene glycol dibutyl ether (butyl diglyme). Advantageously, the same solvent is used to prepare the Grignard reagent and to dissolve the mixture of compounds of formulas IV and III. In a particularly preferred embodiment of the invention, the reaction medium is tetrahydrofuran or a mixture of tetrahydrofuran and diethylene glycol dibutyl ether (butyl diglyme). The reaction may be carried out under heating, preferably while refluxing the reaction mixture. The reaction is completed in a short time (1-3 hours). The resulting complex is then decomposed, preferably by treatment with ammonium chloride.

The 1- (4-fluorophenyl) 1,2-diphenylbutanol obtained after the complex is decomposed is then dehydrated. The reaction is carried out in an acidic medium, preferably in hydrochloric acid ethanol. From the hydrochloric acid reaction mixture, the desired product is obtained after evaporation, clarification and cooling.

According to the present invention, 1- (4-fluorophenyl) -1,2-phenyl-1-butene of formula (I) is formed from 1- (4-fluorophenyl) -1,2-diphenyl (V) formed from deoxybenzoin of formula (III). ethylene.

This process gives high purity (about 99% GC) of 1- (4-fluorophenyl) 1,2-diphenyl-1-butene of high yield (GC).

The process of the present invention eliminates the purification of α-ethyl deoxybenzoin of formula (IV). Our procedure has the following advantages over known methods:

- reducing solvent requirements for synthesis, leading to significant solvent processing and storage savings, and solving solvent disposal problems;

- environmental damage is reduced;

- non-purification operations improve yields by reducing losses;

- the number of operational steps is reduced;

Reducing the number of operations and improving the yield reduces the labor cost required to produce one unit of product, improves the capacity of the apparatus and thus makes synthesis more economical.

The following examples further illustrate the invention without limiting the invention to the examples.

Examples

Example 1 Preparation of α-Ethyl Deoxybenzoin of Formula IV To a solution of sodium methylate (g, 0.59 mol) in ethanol (350 ml) was added deoxybenzene (80 g, 0.41 mol). To the resulting solution was added 95 g (0.6 mol) of ethyl iodide. The reaction mixture was refluxed for 3.5 hours, cooled to 10-12 ° C, filtered and sprayed with 800 ml of water at 0 ° C. The resulting suspension is stirred for half an hour, the precipitated crystals are filtered off and carefully dried. 90.6 g (98.9%) of alpha-ethyl deoxybenzene of formula IV are obtained, m.p. 52-58 ° C.

The quality of the product is analyzed by gas chromatography. The product obtained according to the following method contains 4-7 GC% of unreacted deoxybenzine. Sample preparation: Dissolve 0.1 g of the substance to be examined in 1.5 ml of chloroform

Measurement: 1 μΙ

Measuring conditions:

HP 5890 gas chromatograph

Column length: 10 m

Column Fill: HP 5 (5% Phenylmethylsilicone)

Column Diameter: 530 μίτι

Column temperature: 160 ° C

Injector temperature: 190 ° C

Detector temperature: 300 ° C

HU 227 156 Β1

Carrier gas: High purity nitrogen: Total: 100 ml / min Column: 23 ml / min Purge: 5.5 ml / min

Hydrogen: 30 ml / min

Air: 300 ml / min

Rank: 6

Integrator: HP 3390 A

Retention times: deoxybenzoin: 5.1 min. A-ethyl deoxybenzoin: 6.75 min.

Example 2 Preparation of 1- (4-fluorophenyl) -1,2-diphenyl-1-butene of formula (I)

A) A solution of Grignard's reagent in tetrahydrofuran was prepared using 12.75 g of magnesium turnings, 0.5 g of methyl iodide and g (0.525 mol) of p-fluorobromobenzene.

The resulting Grignard reagent was added to a solution of a-ethyl deoxybenzoin (80 g) prepared in Example 1 in 200 ml of tetrahydrofuran under gentle reflux. The reaction mixture was refluxed for one hour and then added to 700 g of 14% aqueous ammonium chloride solution at such a rate as to maintain the temperature below 20 ° C.

The decomposed complex is extracted with benzene. The organic phase is evaporated in vacuo (internal temperature up to 80 ° C), the resulting carbinol solution is cooled to 25-30 ° C and a mixture of ethanol (200 ml) and concentrated hydrochloric acid (112.5 ml) is added.

Dehydration is accomplished by refluxing. The hydrochloric acid ethanol was distilled off in vacuo, the residue was taken up in water and extracted with benzene. The organic phase is evaporated and the residue is taken up in 275 ml of ethanol, clarified, filtered and crystallized by cooling. The product was filtered and dried. 95.6 g (93%) of 1- (4-fluorophenyl) 1,2-diphenyl-1-butene (4-fluorostilbene) are obtained.

The quality of the product is analyzed by gas chromatography.

Instrument:

HP 5890 gas chromatograph

Column Fill: HP-1

Column length: 10 m

Column Diameter: 530 μίτι

Film thickness: 2.65 μίτι

Injector temperature: 200 ° C

Detector temperature: 300 ° C

Rank: 6

ATTN: 5

Programmed temp .: 180 ° C -------> 230 ° C min. 10 ° C / min. 5 min

Sample preparation: Dissolve 0.2 g of 4-fluorostilbene (I) in 5 ml of chloroform.

Surprisingly, the compound of formula (I) obtained in the above reaction contains only a negligible amount (0.082 GC%) of the desethyl fluorostilbene (V), despite the use of the compound of formula (IV) ethyl deoxybenzoin contained 4.6 GC% of deoxybenzine of formula (III).

B) Follow the procedure of Example 2A), except that the Grignard reagent solution is added dropwise to a solution of α-ethyl deoxybenzoin in 100 ml of tetrahydrofuran and 100 ml of toluene, and the reaction is refluxed for 2.5 hours. over boiling. 91.0 g of 1- (4-fluorophenyl) -1,2-diphenyl-1-butene of formula I are obtained. Yield: 88.5%.

C) Grignard prepared using 3.2 g of magnesium turnings, 0.13 g of methyl iodide, 25 ml of tetrahydrofuran, 50 ml of diethylene glycol dibutyl ether (butyl diglyme) and 23 g (0.131 mol) of p-fluorobromobenzene. Reagent solution is added to a solution of 20 g of a-ethyl deoxybenzoin prepared in Example 1 in 50 ml of diethylene glycol dibutyl ether (butyl diglyme). After 2.5 hours, the reaction mixture is added to a cooled solution of 25 g of ammonium chloride and 150 ml of water, the phases are separated and the organic phase is washed with 50 ml of water.

Dehydration was accomplished by adding 83 ml of 17% hydrochloric acid ethanol to the carbinol solution. The hydrochloric acid ethanol is then distilled off in vacuo and the butyl diglyme is removed at 140-150 ° C / 1300 Pa. The residue was recrystallized from ethanol to give 1- (4-fluorophenyl) -1,2-diphenyl-1-butene (23.3 g). Yield: 86.5%. The product was found to be 99.65% pure by gas chromatography.

Comparative examples

A) Preparation of purified α-ethyl deoxybenzoin of formula IV

No. 151,747, No. reproduction of Example 5 of the Hungarian patent.

To a solution of sodium methylate (32.0 g, 0.59 mol) in ethanol (350 ml) was added deoxybenzene (III) (80 g, 0.44 mol). To the resulting solution was added diethyl iodide (95 g, 0.6 mol) dropwise. The reaction mixture was refluxed for 3.5 hours, cooled to 20 ° C, poured into a mixture of water (240 mL) and ice (200 g) and extracted three times with ether. The separated organic layers were combined, dried over magnesium sulfate and the ether removed. The residue was purified by fractional vacuum distillation. Yield: 70.0 g (76.5%) of α-ethyl-deoxybenzene of formula (IV), b.p. 175-178 C / 1500 Pa.

The product contained 0.65% of unreacted deoxybenzine of the formula (III) as determined by gas chromatography as described in Example 1. The product thus obtained is described in Ref. used in a comparative experiment.

B) Preparation of 1- (4-fluorophenyl) -1,2-diphenyl ethene of formula (V)

The procedure of Example 2 was performed except that 70.0 g (0.35 mol) of deoxybenzine was used as starting material.

During the dehydration and processing described above, 83.5 g (85.5%) of 1- (4-fluorophenyl) -1,2-diphenyl ethene

156 Β1 is obtained, which is used as the standard for gas chromatography. 51.8-55.7 ° C.

The compound of formula (V) prepared according to the above reaction may be separated from the desired compound of formula (I) by gas chromatography as described in Example 2.

Retention times:

1- (4-Fluorophenyl) -1,2-diphenyl-1-butene 7.05 min 1- (4-Fluorophenyl) -1,2-diphenyl ethene 7.35 min

C) Preparation of 1- (4-fluorophenyl) -1,2-diphenyl-1-butene of formula (I) from various grades of a-ethyl deoxybenzoin of formula (IV)

The procedure described in Example 2 was followed, however, starting from a-ethyl deoxybenzine contaminated with varying degrees of deoxybenzoline of formula (III).

The results obtained are summarized in Table I below.

/. spreadsheet

Example number Composition of starting material Composition of final product mining, (IV) (III),% (IV)% (l)% (V)% 2 / 4.6 95.4 99.41 0.082 95.6 g 93,0% B 100 - - 99.27 83.5 g 85.5% C / 1 0.65 99.35 99.42 0.03 92.8 g 86.8% C / 2 3.5 96.5 99.39 0,054 96.5 g 92.9% C / 3 13.5 86.5 99.33 0.073 86.7 g 93.2% C / 4 19.5 80.5 99.27 0.069 80.3 g 92.7%

From the data in the table, it appears that the content of 25-α-ethyl deoxybenzoin of formula (IV) surprisingly advantageously influences the yield of the Grignard reaction to α-ethyl-deoxybenzoin. The by-product of formula (V) thus exhibits an unpredictable "salting" effect. 30

The table also shows that the amount of impurity V from the deoxybenzoin III in the desired product of formula I is two orders of magnitude lower than the content of the deoxybenzoin 35 in the compound of formula IV used as a sample starting material. .

Claims (5)

PATENT CLAIMS A process for the preparation of 1- (4-fluorophenyl) -1,2-diphenyl-1-butene of formula (I) by reaction of a-ethyl deoxybenzoin of formula (IV) with Grignard reagent of p-fluorobromobenzene , characterized in that a mixture of α-ethyl deoxybenzoin of formula IV and deoxybenzoin of formula III is used for the reaction. Process according to Claim 1, characterized in that the starting material used is a mixture of a-ethyl deoxybenzoin of formula (IV) and a mixture of deoxybenzoin of formula (IV) without purification. The process according to claim 1 or 2, wherein the alpha-ethyl deoxybenzene containing up to 20% by weight of the deoxybenzine of formula (III) is used. 4. A process according to claim 3, wherein the alpha-ethyl deoxybenzene of the formula (III) is from 2.5 to 20% by weight. The process of claim 1, wherein the 1- (4-fluorophenyl) -1,2-diphenyl-1-butene of formula (I) is the 1- (4-fluorophenyl) of formula (V) ) From a reaction mixture containing -1,2-diphenyl ethene.