HU201292B - Process for producing 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalenone - Google Patents

Abstract

The present invention relates to a novel process for the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone in which 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid is used. 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone with benzene, as solvent in the excess reagent or under the reaction conditions in an intert organic solvent in the presence of a protic acid or Lewis acid catalyst, -20 and 180 ' The reaction mixture is then reacted at a temperature of C, followed by ring closure to form the cyclic ketone. Scope of the description: 5 pages without figure EN 201 292 B -1-

Description

The present invention relates to a novel process for the preparation of the known 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone.

More particularly, the present invention relates to a process for the preparation of 4- (3,4-dichlorophenyl) -4-hydro-butanoic acid or 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone directly from said 4- (3,4) -dichlorophenyl) -3,4-dihydro (1 (2H) -naphthalenone) which is a known cis (1S) (4S) -N-methyl-4- (3,4-dichlorophenyl) -1 with antidepressant effect Is a key intermediate for the preparation of 2,3,4-tetrahydro-1-naphthalamine (sertraline).

The cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalene-amine derivatives, particularly cis (1S) (4S) -N-methyl-4- (3,4-dichlorophenyl), having the antidepressant effect described The known 4,4-diphenylbutanoic acid derivatives can be used as intermediates for the preparation of -1,2,3,4-tetrahydronaphthalenamine (sertraline). In the known process, the desired 4,4-diphenylbutanoic acid intermediate is synthesized starting from the corresponding benzophenone by a multistep process. For example, the appropriately substituted benzophenone is first reacted with base-catalyzed Stobbe condensation with diethyl succinate, then hydrolyzed and decarboxylated with 48% w / w aqueous hydrobromic acid to give the corresponding 4,4-diphenylbut-3-enic acid, which is catalytically hydrogenated or hydrogenated. and iodide and red phosphorus to give the 4,4-diphenylbutanoic acid intermediate.

Thereafter, 4- (3,4-dichlorophenyl) -4-phenylbutanoic acid is first converted to 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone, followed by racemic cis- Through the N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine, the desired cis (1S) (4S) -N-methyl-4 (3 , 4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine according to the known multi-step procedure (U.S. Patent 4,536,518 to WM Wlech et al., Journal of Medicial Chemistry). , 27, 11, 11508 (1984)).

However, it has been discovered that a specific one-step process may be carried out directly on 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid or 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone directly.

Converted into 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalene, from which sertraline is obtained as described above.

The present invention therefore relates to a process for the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone, which process comprises 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid. or 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone with benzene, as a solvent in excess reagent or in an inert organic solvent under reaction conditions, in the presence of protic acid or Lewis acid catalyst, -20 and 180 The reaction is carried out at a temperature between about 1 ° C and then cyclized to form the cyclic ketone.

According to this method, 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid or 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone is reacted with benzene as a solvent in excess of the reagent or reaction in an inert organic solvent in the presence of a protic or Lewis acid catalyst at -20 to 180 ° C until alkylation of the benzene with said hydroxy salt or the corresponding dihydro-2 (3H) -furanone, and the desired cyclic ketone, i.e. The ring closure required to form 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalone is substantially complete. Suitable organic solvents for the reaction include carbon disulphide, nitrobenzene, various lower nitroalkanes such as nitromethane and nitroethane, and halogenated benzenes such as o-dichlorobenzene and bromobenzene, various lower halogenated hydrocarbons such as methylene chloride, dichloride, chloroform, trichlorethylene, tetrachloroethane and carbon tetrachloride, in particular methylene chloride and o-dichlorobenzene. Preferred protic or Lewis acid catalysts are sulfuric acid, trifluoromethanesulfonic acid, hydrogen fluoride, methanesulfonic acid, polyphosphoric acid, phosphorus pentoxide, aluminum chloride, phosphorus pentachloride, titanium tetrachloride and various acid ion exchange resins, four members are preferred. In a preferred embodiment of the process, the molar ratio of hydroxy acid or dihydro-2 (3H) -furanone starting material to benzene reagent is 1.0: 1, ΟΙ, 0: 20.0, and the starting material to acid catalyst is generally 1.0 : 0.1-1.0: 90.0, preferably 1.0: 5.0: 0.1-1.0: 10.0: 90.0 dihydro-2 (3H) furanone / benzene / acid catalyst molar ratio. The reaction temperature is generally 15-145 ° C, preferably 15-100 ° C. When the acid catalyst used is a protic acid such as sulfuric acid, trifluoromethanesulfonic acid or methanesulfonic acid, the preferred temperature is generally 15-100 ° C, especially 20100 ° C. When hydrogen fluoride is used as the protic acid, the preferred reaction temperature is generally 15-100 ° C, in particular 15-30 ° C. After completion of the reaction, the desired 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalene can be readily isolated from the reaction mixture by conventional means. This is usually done by pouring the reaction mixture on ice containing mineral acid such as concentrated hydrochloric acid, then separating the phases and isolating the final product from the organic phase, preferably by evaporation and crystallization of the residue, in a new one-step process. Starting with (3,4-dichlorophenyl) dihydro-2 (3H) -furanone or 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid, 4- (3,4-dichlorophenyl) -3,4- dihydro-1 (2H) -naphthaloneone was obtained and was complete.

The starting materials used in the process can be prepared, for example, as described in Hungarian Patent No. 198,670. In doing so, the known 4- (3,4-dichlorophenyl) -4-ketobutanoic acid is reacted with a reducing agent which selectively reacts with the carbonyl group in a polar protic or aprotic solvent at about 0-100 ° C until substantially complete conversion to the desired 4- (3,4- dichlorophenyl) -4-hydroxybutanoic acid and, if desired, converting the resulting hydroxy acid to 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone.

In the process, the reduction of 4- (3,4-dichlorophenyl) -4-ketobutanoic acid to 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid is carried out using a reducing agent which is selectively reactive with the carbonyl group, which is a carboxylic acid or in the presence of its salt. Suitable reducing agents include alkali metal borohydrides and related reagents such as amide-boranes and lithium aluminum hydride and dialkyl aluminum hydride. The reduction step is generally carried out in a polar protic or aprotic solvent at a temperature in the range of about 0 ° C to about 100 ° C until substantially the reduction reaction to the desired 4-hydroxy compound is complete. Preferred polar protic solvents are water and lower (C 1 -C 4) alkanol such as ethanol, methanol and isopropanol. Suitable aprotic solvents include actonitrile, dimethylformamide, diethylformamide, dimethylacetamide, di-xane, tetrahydrofuran, benzene and the like. An aprotic solvent is used primarily when a reagent other than an alkali metal borohydride is used as the reagent. The reduction is preferably carried out with an alkali metal borohydride such as sodium borohydride and the like in a polar protic solvent such as water at a temperature of about 50-70 ° C. When using these solvents, the pH of the reaction mixture is generally from 6 to 12. The starting keto acid is dissolved in water containing the necessary amount of alkali metal hydroxide to maintain the pH. After completion of the reaction, the resulting 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid can be isolated from the reaction mixture in a conventional manner or used directly (or in situ) in the next reaction step. When the reaction is carried out in the above-mentioned (pH = 6) aqueous medium, the hydroxy acid is generally formed as an alkali metal salt.

The resulting hydroxy acid is optionally converted to dihydro-2 (3H) -furanone. To do this, the hydroxy acid is first isolated from the reaction mixture and then heated in an aromatic hydrocarbon solvent at a temperature ranging from about 5 ° C to about 150 ° C until substantially complete conversion. Suitable aromatic hydrocarbon solvents include C 6 -C 8 hydrocarbons such as benzene, toluene, xylene and the like.

The conversion of the hydroxy acid can also be accomplished by heating in situ in an aqueous acidic solvent at about 20-100 ° C until substantially complete conversion. The aqueous-acidic solvent is preferably prepared by acidifying the aqueous-alkaline medium used in the first step. This medium also contains the hydroxy acid formed in situ. The medium also contains the hydroxy acid formed in situ. Hydrochloric acid or sulfuric acid is preferably used to acidify the medium. During the conversion, the heating is preferably carried out at 55-80 ° C until substantially complete lactonization. After completion of the reaction, the resulting reaction mixture was slowly cooled to ambient temperature and then crystallized in the usual manner. The desired 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone is readily isolated from the resulting mixture, for example, by vacuum filtration or the like, or can be extracted with a suitable solvent, such as methylene chloride.

The starting material 4- (3,4-dichlorophenyl) -4-keto-butanoic acid is a known compound which can be synthesized by known methods. EA is preferred for the preparation of the starting material. Steck et al., Journal of the American Chemical Society, 75, 1117 (1953).

The process of the present invention provides 4- (3,4-dichlorophenyl) -3,4-dihydrol (2H) -naphthalone in pure form and in high yield, time and cost.

Example L In a round-bottomed flask equipped with a reflux condenser, 8.0 g (0.093 mol) of methanesulfonic acid was charged. After heating to 95 ° C, a solution of 1.0 g (0.004 mol) of 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone in 2 ml (0.022 mol) of benzene is added dropwise over 20 minutes. After the addition was complete, the reaction mixture was stirred at 95 ° C for 7 hours, then cooled and poured onto 60 g of ice. The reaction mixture was allowed to warm to room temperature (about 20 ° C) and extracted three times with 30 ml of diethyl ether. The combined ethereal phases were washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give crude 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2K) naphthalenone as an oil. This was chromatographed on 20 g of 0.2-0.65 mm silica gel eluting with 25% ethyl acetate / hexane. yield (62%) of pure 4- (3,4-dichlorophenyl) -3 _4-dihydro-s (2H) -naphthalenone 724 mg is obtained which is identical with the product obtained Patent No. 4,536,518 U.S. specification Ie) Example. Melting point: 102-103 ° C.

Elemental analysis based on CtöHnCbO:

H, 4.15; C, 65.83; H, 3.89.

Example 2 In a 1 ml flask fitted with a reflux condenser, 1.0 g (0.004 mol) of 5- (3,4-dichlorophenyl) dihydro-2 (3H) -pyranone, 4 ml (0.045 mol) of benzene and 5 ml (0.074 mol) 96% sulfuric acid was charged at ambient temperature (about 20 ° C). The resulting reaction mixture was heated at 95 ° C for 1 hour and then 140 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and poured onto 40 g of ice. The resulting aqueous mixture was stirred at room temperature for 18 hours, then the resulting green solid was filtered off with suction and air-dried to constant weight. There was thus obtained 740 mg (63%) of high quality 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalazine, which was trace by 4- (3-D) analysis by TLC and NMR. , 4-dichlorophenyl) -4-phenylbutanoic acid, mp 102-103 ° C.

Example 3

In a 250 ml round-bottomed flask equipped with a reflux condenser, 10 g (0.04 mol) of 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone, 20 ml (0.22 mol) of benzene and 80 g (0.830 mol) of methanesulfonic acid were charged at ambient temperature (about 20 ° C). The reaction mixture was heated at 100 ° C for 20 hours, cooled to ambient temperature and poured into 200 g of ice. After mixing with 50 ml of methylene chloride, the aqueous phase is adjusted to pH 11.3 with 167 ml of 20% w / w aqueous sodium hydroxide. A further 50 mL of methylene chloride was added

-3λ; ^r ->

*. · 1 ί $: ·.

. , ν · * ·. HU; · / '-ί; 5 L 'of the alkaline-aqueous mixture, then the aqueous phase is extracted. The separated aqueous phase was extracted with another 50 ml of methylene chloride and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and distilled under atmospheric pressure. During the distillation, the leaving methylene chloride was replaced with 50 ml of hexane and 75 ml of diisopropyl ether. After cooling the remaining volume of distillate to room temperature with constant stirring. After stirring at this temperature (about 20'C) for 18 hours, the yellow solid precipitate was collected by vacuum filtration and air-dried to constant weight. so

7.24 g (62%) of high quality 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone are obtained, m.p. 102-103 ° C. .

Example 4

The j. The procedure described in Example 1B is followed except that polyphosphoric acid is used as the acid catalyst instead of methanesulfonic acid in the same molar ratio. There was also obtained pure 4- (3,4-dichlorophenyl) 3,4-dihydro-1 (2H) -naphthalenone. The same result is obtained when the phosphorus pentoxide, aluminum and clprid are replaced in a molar ratio instead of methanesulfonic acid. or titanium tetrachloride, m.p. 102-103 ° C.

Example 5

A 25 mL portion of a basic aqueous solution of 5.0 g (0.018 mol) of 4- (3,4-dichloro-phenyl) -4-hydroxybutanoic acid was treated with 25 mL of methylene chloride and 1.5 mL of 96% v / v sulfuric acid, the aqueous phase is adjusted to pH 1.0. The two layers were separated and the resulting organic extract was transferred to a 100 mL round bottom flask, connected to aq. Distillation apparatus. Benzene (25 mL, 0.28 mol) was added and the methylene chloride was removed by atmospheric distillation. An additional 25 mL (0.48 mole) of 96 wt% sulfur sulfite and 5 h0 (0.056 mole) of benzene were added to the residue, followed by? to the flask a; after removal of the distillation apparatus, a reflux condenser is connected.

The reaction mixture was heated at 95 ° C for 1 hour and then at 135 ° C for 3 hours. The resulting mixture was then cooled to ambient temperature (about 20 ° C) and poured onto 200 g of ice. The resulting aqueous phase was extracted with methylene chloride (50 mL, then 10 mL), and the combined organic layers were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. 2.89 g of a residue are obtained in the form of a yellow foam. Based on TLC and NMR spectra, the main component of the foam

4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone, m.p. 102-103 ° C.

Example 6

To a 125 mL polypropylene reaction vessel was added 3.0 g (0.012 mol) of 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone and 6 mL (0.067 mol) of benzene. The reaction vessel was connected to a polypropylene tube and 20 mL (1.0 mole) of anhydrous hydrogen fluoride was distilled to a solution at -78 ° C. The reaction mixture was allowed to warm to room temperature (about 20 ° C) and stirred at this temperature for 18 hours. Then the hydrogen-flu4?

The excess hydride and benzene were removed by vacuum distillation, and the hydrogen fluoride removed was bound with calcium oxide. The apparatus was purged with nitrogen and the vessel was removed from the hydrogen fluoride line. Methylene chloride (30 ml) and water (5 ml) were added and the mixture was cooled to 0 ° C. After adjusting to pH 12.0 with 13 ml of 1.0 N aqueous sodium hydroxide solution, the resulting organic phase is removed and the aqueous phase is extracted with 30 ml of methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate and filtered, then transferred to a 125 mL round bottom flask and evaporated with atmospheric distillation. The mixture was then concentrated to a volume of about 30 mL, diluted with hexane (40 mL), and distilled at 67 ° C. The heating was then interrupted and a white crystalline precipitate was obtained within 5 minutes. The white suspension was stirred for 16 hours and then filtered and dried under vacuum to constant weight to give 3.43 g (97%) of high quality 4- (3,4-dichlorophenyl) 3,4-dihydro-1 (2H) -naphthalone mp 102-103 ° C. The pure product was characterized by TLC and NMR.

Example 7 Into a round-bottomed flask fitted with a reflux condenser was added 3.0 g (0.012 mol) of 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone and 6 ml (0.067 mol) of benzene. . Trifluoromethanesulfonic acid (534 mL, 0.060 mol) was added to the solution with stirring at room temperature (about 20 ° C) and stirred for an additional 5 minutes. The reaction mixture was heated at 75 ° C for 13 hours and then cooled to room temperature. It is then poured onto 20 g of ice and treated with 30 ml of methylene chloride. The reaction mixture was adjusted to pH 9.0 with 15 ml of 4N aqueous sodium hydroxide solution. The two layers were separated and the aqueous layer was extracted with 30 mL of methylene chloride. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and placed in a 125 mL distillation flask. The methylene chloride solvent was evaporated at atmospheric pressure and the residue was mixed with 40 ml of hexane to a volume of about 40 ml and distilled at 67 ° C. The heating was then interrupted and a white precipitate was obtained within 5 minutes. The white slurry was stirred overnight, then filtered and dried under vacuum to a constant temperature. This gives 3.22 g (91%) of good quality 544 (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone, m.p. 103-104 ° C. The pure product was obtained by thin layer chromatography and NMR. spectrum.

Claims (5)

PATENT CLAIMS A process for the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydrol (2H) -naphthalenone, characterized in that 4- (3,4-dichlorophenyl) -4-hydroxy-butanoic acid or 5- (3,4-dichlorophenyl) -dthMro-2 (3H-Curanone with benzene, as solvent in excess reagent or in organic solvent under reaction conditions, protic acid or Lewis acid calalization) The reaction is carried out in the presence of torque at a temperature of -20 to 180 ° C, followed by ring closure to form the cyclic ketone. 2. A process according to claim 1 wherein the protic acid is sulfuric acid, trifluoromethanesulfonic acid, hydrofluoric acid or methanesulfonic acid. The process according to claim 1, wherein the hydroxy acid or dihydro-2 (3H) -furanone and benzene are 1.0: 1.0 to 1.0: 20.0, the hydroxy acid or the dihydro- 2 (3H) -furanone and the acid catalyst were used in a molar ratio of 1.0: 0.1 to 1.0: 90.0. Process according to claim 1, characterized in that the reaction is carried out at a temperature of 15 to 145 ° C. 5. The process of claim 1 wherein the solvent is an excess of benzene.