FI91391B - Method for production of 4-(3,4-dichlorophenyl)-3,4- dihydro-1(2H)-naphthalenone - Google Patents

Description

91391

Process for the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone

By division separated from application 882779.

5

The invention relates to a new process for the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone. This compound is a key intermediate in the preparation of the antidepressant cis- (1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-10 tetrahydro-1-naphthalenamine (sertraline).

U.S. Patent No. 4,536,518 to W. M. Welch, Jr. et al. and W. M. Welch, Jr. et al., Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 15 (1984) discloses a process for the preparation of certain 4- (substituted phenyl) -4- (optionally substituted phenyl) butanoic acids in which the possible substituent is always other than alkoxy. These certain 4,4-diphenylbutanoic acid derivatives have been shown to be useful as intermediates to give cis- (1S) (4S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4- various antidepressant derivatives of tetrahydro-1-naphthalenamine, including cis- (IS) (4S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydronaphthalenamine (sertraline), which is a particularly preferred embodiment of this series 25. In W. M. Welch Jr. et al. the prior art described in the publication involves the multi-step synthesis of the desired 4,4-diphenylbutanoic acid intermediates starting from the corresponding Bent-phenophenone compound. For example, the appropriately substituted benzophenone starting material is first subjected to base-catalyzed Stobbe condensation with diethyl succinate, followed by hydrolysis and decarboxylation with 48% aqueous hydrobromic acid to give the corresponding 4,4-diphenyl-nitric acid, then by hydrogenation or using hydrodioic acid and red 2 phosphorus to ultimately produce the desired 4,4-diphenylbutanoic acid intermediate.

The present invention relates to a process for the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone. The process is characterized in that 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid or 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone is reacted with benzene in excess of said reagent as solvent or in a reaction-inert organic solvent) in the presence of a protic or Lewis acid catalyst at a temperature of about -20 to 180 ° C until alkylation of benzene with said hydroxy acid or the corresponding gamma-butyrolactone compound and subsequent cyclization to form the desired ring chelate final product is substantially complete.

The compound of the invention is a valuable intermediate in the preparation of the antidepressant centraline, which is cis- (IS) (4S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1 -naphthalenamine 20 [see U.S. Patent No. 4,536,518 and Journal of Medicinal Chemistry, Vol. 27, no. 11, pp. 1508 (1984)].

The 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid used as a starting material in the process of the invention is obtained by reducing 4- (3,4-dichlorophenyl) -4-ketobutanoic acid using a carbonyl reducing agent capable of reducing a ketone in the presence of a carboxylic acid or a salt thereof. . This category includes alkali metal borohydrides and the like, amine boranes and reagents derived from lithium aluminum hydride, and dialkylaluminum hydride reagents. Generally, the reduction step is performed in a polar protic solvent or aprotic solvent at a temperature of about 0 to 100 ° C until the reduction reaction to form the desired 4-hydroxy compound is almost complete. Preferred polar protic solvents for use herein include e.g. water and 91391 3 lower alkanols (C 1-4), such as methanol, ethanol and isopropanol, etc., propanol, etc., while aprotic solvents include e.g. acetonitrile, dimethylformamide, diethylformamide, dimethylacetamide, dioxane, tetrahydrofuran-5, benzene and the like. Solvents of the latter type are particularly preferred when using reagents other than alkali metal borohydrides. A preferred embodiment involves the use of 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 to 75 ° C. The pH of the reaction in this type of solvent is generally in the range of about pH 6 to pH 12. The starting keto acid is dissolved in water containing a sufficient amount of alkali metal hydroxide to maintain the pH above the desired range. Upon completion of the reaction, the desired 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid intermediate is readily recovered from the reaction mixture by a conventional method or used as such (i.e., in situ) in the next reaction step, with more treatment being unnecessary. After the reaction is carried out in an aqueous solvent as described above (pH 6), the hydroxy acid final product is normally present as an alkali metal salt.

The formed hydroxy acid intermediate is then converted to the corresponding gamma-butyrolactone compound by first separating the hydroxy acid from the reaction mixture as described above and then heating said acid in an aromatic hydrocarbon solvent at a temperature in the range of about 55 to 150 ° C until the above lactone is almost complete. Preferred aromatic hydrocarbon solvents for these purposes include e.g. those having from six to eight carbon atoms such as benzene, toluene, xylene and the like. Benzene is particularly preferred in this context because the reaction mixture can be used directly in the next step.

4

Alternatively, 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid can be converted to the gamma-butyrolactone compound by heating the hydroxy acid in situ in an aqueous acid solvent at about 20-100 ° C until conversion to the lactone compound is almost complete. The aqueous acid solvent is preferably obtained by acidifying the warm aqueous basic solvent obtained in the previous step; the latter substance also contains hydroxy acid formed in situ. The preferred acid for making the hap-10 base in this context is either hydrochloric acid or sulfuric acid and the heating step is preferably performed at a temperature of about 55 to 80 ° C until lactonization is almost complete. The final reaction mixture is then slowly cooled to ambient temperature and granulated in a conventional manner, and the desired 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone compound is preferably isolated from the mixture by a method such as suction filtration or the like, or optionally extracted with a solvent such as methylene chloride. , which is also suitable for the next step-20.

According to the invention, a hydroxy acid intermediate, i.e. 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid, or a gamma-butyrolactone compound, i.e. 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone, is reacted with benzene 25 excess of said reagent as a solvent or in a reaction-inert organic solvent in the presence of a protic or Lewis acid catalyst at about -20 to 180 ° C until alkylation of benzene with either said hydroxy acid or the corresponding gamma-butyrolactone compound and subsequent cyclization To form 3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone is almost complete. Preferred reaction-inert organic solvents are methylene chloride and o-dichlorobenzene. Preferred protic or Lewis acid catalysts for this reaction include e.g.

91391 (but not limited to) sulfuric acid, trifluoromethanesulfonic acid, hydrofluoric acid, methanesulfonic acid, polyphosphoric acid, phosphorus pentoxide, aluminum chloride, phosphorus pentachloride, titanium tetrachloride, and various acidic acid exchange resins are the first four of which are most preferred. In a preferred embodiment of this reaction, the molar ratio of hydroxy acid or gamma-butyrolactone starting material to benzene reagent and acid catalyst is in the range of about 1.0: 1.0 to 1.0: 20.0 and 1.0: 0.1 to 1.0: 90.0, with more preferred gamma-butyrolactone / with benzene / acid catalyst ratios of approximately 1.0: 5.0: 0.1 to 1.0: 10.0: 90: 0. In practice, the reaction is preferably carried out at a temperature ranging from about 15 to 145 ° C, with the most preferred temperature range being about 15 to 100 ° C, in which case the acid catalyst used is a protic acid such as sulfuric acid, trifluoromethanesulfonic acid or methanesulfonic acid, preferred the temperature range is generally about 15 to 100 ° C and most preferably about 20 to 100 ° C. In the case where the protic acid used is hydrofluoric acid, the preferred temperature range is generally about 15 to 100 ° C, and most preferably about 15 to 30 ° C. The desired 4- (3,4-dichloro-phenyl) -3,4-dihydro-1 (2H) -naphthalenone is readily recovered from the reaction mixture in the usual manner.

The required 4- (3,4-dichlorophenyl) -4-ketobutanoic acid starting material is a known compound which can be readily prepared by those skilled in the art from general chemicals and using conventional methods of organic synthesis. For example, it is this compound that can be readily prepared using the method of E. A. Steck et al. the method described in the Journal of the American Chemical Society, Vol. 75, pp. 1117 (1953).

The following examples illustrate the invention.

6

Example 1 A sample of 193 g (0.781 mol) of 4- (3,4-dichlorophenyl) -4-ketobutanoic acid [E. A. Steck Journal of the American Chemical Society, vol. 75, p 1117 (1953)] was suspended in 5 772 ml of water in a reaction flask and heated to 70-80 ° C. While adding slowly 70 mL of 15 N aqueous sodium hydroxide (1.05 mol) over a half hour while keeping the pH of the system at 10; 7 - 11.9. The resulting dark brown solution had a pH of 11.7 (at 75 ° C), to which was added a solution containing 10.35 g (0.272 moles) of sodium borohydroxide dissolved in 52.2 ml of water and 0, 53 ml of 15 N aqueous sodium hydroxide (0.008 mole) over a half an hour. After completion of this step, the resulting reaction mixture was stirred at the same temperature for another 45 minutes. Thin layer chromatography of the sample taken at this point showed complete absence of keto acid starting material. This solution now contained 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid as the sodium salt.

A 50 ml portion of the basic solution described above (5% by volume) was removed from the reaction flask and cooled with ice to 0-10 ° C and the pH was adjusted to 1.0 by the addition of 5N hydrochloric acid (keeping the temperature below 10 ° C throughout). during this addition phase). The resulting solution was extracted with methylene chloride, and the organic extracts were combined, washed with water and dried over anhydrous sodium sulfate. After removal of desiccant 011 by filtration and evaporation of the solvent under reduced pressure, 10 g of 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid were obtained as a brown-orange residual oil. This material was then dissolved in 40 mL of diethyl ether. The resulting crystalline slurry was stirred and cooled to 10 ° C for one hour. In this way, the corresponding crystalline cyclohexylamine salt was easily obtained, which was then removed by suction filtration, washed with diethyl ether 35 and dried in vacuo to constant weight to give 9.691 g of pure 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid ( as the dicyclohexylamine salt), m.p. 152-154 ° C. Recrystallization of this material (9.4 g) from ethyl acetate (300 mL) did not increase the melting point.

5 Example 2

A mixture of 370.62 g (1.5 moles) of 4- (3,4-dichlorophenyl) -4-ketobutanoic acid [E. A. Steck Journal of the American Chemical Society, vol. 75, p. 1117 (1953)] and 1.505 liters of demineralized water, were stirred and heated to 70-80 ° C while gradually adding 130 ml of 15N aqueous sodium hydroxide and 47.5 ml of 1.5N aqueous sodium hydroxide in portions. The time to complete dissolution is approximately one hour and the pH of the resulting dark brown solution was 10.73 (at 78 ° C). The solution was transferred to a 5 liter flask and the temperature was maintained at approximately 65 ° C (+ 3 ° C) while a solution of 19.86 g (0.525 moles) of sodium borohydride dissolved in 100.3 ml of demineralized water and 1 .03 ml of 15N aqueous sodium hydroxide over 44 minutes.

The reaction mixture formed after this step was stirred at this same temperature for about two hours.

Thin layer chromatography of a sample taken six minutes after the addition step showed complete absence of keto acid starting material. This solution now contained 4- (3,4-25 dichlorophenyl) -4-hydroxybutanoic acid as the sodium salt.

It was used as such (i.e. in situ) in the next step of the process with no isolation of the product.

Example 3 The warm basic solution of 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid described in Example 2 was stirred and heated at 57-62 ° C with the slow dropwise addition of 5.8N hydrochloric acid (436 ml) over 65 minutes. with particular care in the first half-hour to 35-na due to foaming. The resulting mixture of oil and acidic water after this step was stirred vigorously and heated to 65-70 ° C for four hours before being allowed to cool to room temperature (about 20 ° C). Thin layer chromatography of the samples taken 1, 2, 2.5 and 3.5 hours after the start of the final heating step showed that the conversion of hydroxy acid to lactone was complete after 3.5 hours. The final mixture was allowed to gradually cool and granulate overnight over about 16 hours and the white solid precipitate thus obtained was collected by suction filtration and then washed with two 80 ml portions of deminarized water. After first air-drying in a filter funnel and then drying in vacuo in a 46 ° C vacuum oven overnight (about 16 hours), 320 g (92%) of pure 5- (3,4-di-15-chlorophenyl) -dihydro- 2 (3H) -furanone, melting point 64-65 ° C.

Example 4 (not according to the invention)

To a well-stirred slurry of 19.5 g (0.25 moles) of benzene and 13.5 g (0.10 moles) of aluminum-20 dichloride in 22.5 mL of methylene chloride was added dropwise a solution of 23, 1 g (0.10 mol) of 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone (product of Example 3) dissolved in 22.5 ml of methylene chloride. The addition step was performed over 15 minutes as the temperature of the reaction mixture rose from 23 ° C to 35 ° C. After this step, the reaction mixture was stirred at room temperature (about 20 ° C) for 2 hours to give a dark brown solution. Thin layer chromatography of the sample taken at 1.5 hours showed that no starting material was present at this stage. The stirred mixture was then poured into 100 grams of ice containing 20 ml of concentrated hydrochloric acid, and the resulting aqueous acidic mixture was stirred for 15 minutes. The organic phase of the resulting biphasic system was separated and washed well with water and distilled in the atmosphere to remove methylene chloride.

91391 9

The liquid residue was then treated dropwise with hexane and allowed to cool to room temperature to give a light brown solid. This material was granulated at room temperature for one hour and finally recovered from the mixture by suction filtration and washed with a small portion of fresh hexane. After drying in vacuo to constant weight, 28.0 g (91%) of 4- (3,4-dichlorophenyl) -4-phenylbutanoic acid, m.p. 121-122 ° C [m.p. 118-120 ° C in the literature] were finally obtained. WM Welch , 10 Jr et al. either in U.S. Patent No. 4,536,418 or Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 (1984). The nuclear magnetic seasonality spectrum of the material was found to be identical to that of W. M. Welch, Jr. et al. with an authentic sample prepared by the method described in the previous methods mentioned above.

Example 5 (not according to the invention)

To a well-stirred slurry of 126.4 g (1.49 moles) of benzene and 86.4 g (0.640 moles) of aluminum chloride in a 2-liter four-bottomed round bottom reaction flask under a nitrogen atmosphere at 18 ° C was slowly added dropwise the solution. with 149.6 g (0.648 mol) of 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone (product of Example 3) dissolved in 800 ml of benzene. The addition step was performed over 50 minutes while maintaining the temperature of the reaction mixture at approximately 15-20 ° C with an ice bath. After this step, the reaction mixture was stirred at room temperature (about 20 ° C) for 2 hours to give a dark brown solution. The stirred mixture was poured into 648 ml of ice / water containing 129.6 ml of concentrated hydrochloric acid in 30 1 ° C, and the resulting aqueous acidic mixture was stirred for half an hour. The organic phase of the resulting biphasic system was separated from the aqueous phase, and the latter was saved and extracted twice with 100 ml of benzene. The combined benzene layers 35 were filtered and vacuum filtered to remove benzene. The remaining heavy tan solid was granulated with 500 mL of hexanes for 45 minutes, filtered and then washed with three 100 mL portions of fresh hexanes. The solid product and hexane washes were then transferred to a 2,000 mL three-necked round bottom flask and granulated for approximately 16 hours. After filtration and washing with a further three 100 ml portions of fresh hexanes followed by vacuum drying at about 50 ° C, 154.7 g (77%) of pure 4- (3,4-10 dichlorophenyl) -4-phenylbutanoic acid were finally obtained. as a heavy solid powder. This product was identical in all respects to the product of Example 4.

Example 6 (not according to the invention)

To a well-stirred slurry of 126.22 g of 15 (1.49 moles) benzene (146.3 mL) and 86.4 g (0.640 moles) of aluminum chloride in 186 mL of o-dichlorobenzene in a 2-liter four-necked round bottom reaction flask under a nitrogen atmosphere At 7 ° C, a solution of 149.6 g (0.648 moles) of 5- (3,4-dichloro-20-phenyl) -dihydro-2- (3H9-furanone (product of Example 3)) dissolved in 600 was slowly added dropwise. The addition step was carried out over 2.5 hours, maintaining the temperature of the reaction mixture at approximately 7 to 9 ° C with an ice bath, after which the reaction mixture was stirred at room temperature (about 20 ° C) for 35 minutes and then quenched into a mixture of 650 ml of water and 130 ml of concentrated hydrochloric acid at -4 ° C, keeping the temperature of the resulting aqueous acid mixture below 28 ° C throughout the quenching step.The latter mixture 30 (now a white slurry) was stirred for ten minutes and allowed to separate into two layers. The saved organic phase was washed twice with the same amount of warm water and a 550 ml portion of this washed layer was transferred to a 3-liter three-necked round bottom flask and 500 ml of water and 60 ml of 50% aqueous sodium hydroxide solution were added and stirred for ten minutes. The resulting organic layer was separated from the aqueous lye layer and extracted once more with 500 ml of 50% aqueous sodium hydroxide. The combined aqueous lye layers were next extracted with 300 mL of methylene chloride and the latter organic layer was separated, saved and vacuum distilled to remove almost all of the methylene chloride. When the residual thick liquid was seeded with a pinch of authentic 4- (3.4-10-dichlorophenyl) -4-phenylbutanoic acid (prepared as in Example 4), followed by stirring for about half an hour, there was a very thick crystalline slurry which was then added 400 mL of heptane . The resulting mixture was stirred for about 16 hours (i.e. overnight), filtered and the crystalline product was collected by suction filtration and washed with a fresh portion of heptane to give a white solid. After rewetting this product with heptane and filtering and drying in a vacuum oven to constant weight, 82.0 g (41%) of pure 4- (3,4-20 dichlorophenyl) -4-phenylbutanoic acid, which was identical to the product of Example 4, was finally obtained. with.

Example 7

To a 25 mL round bottom reaction flask equipped with a reflux condenser was charged 8.0 g (0.083 mol-25) of methanesulfonic acid. This material was heated to 95 ° C and a solution of 1.0 g (0.004 mol) of 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone was added dropwise over 20 minutes (Example 3: product) dissolved in 2 ml of benzene. After this step, the reaction mixture was stirred at 95 ° C for seven hours and then cooled and quenched into 60 ml of ice. After warming to ambient temperature (about 20 ° C), the quenched reaction mixture was extracted with three 30 mL portions of diethyl ether. The separated ether layers were combined and washed with aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration and evaporation of the solvent under reduced pressure, an oily residue was finally obtained, which turned out to be crude 4- (3,4-dichlorophenyl) -5,4-dihydro-1 (2H) -naphthalenone. This material was chromatographed on 20 g of 70-230 mesh silica gel eluting with 25% ethyl acetate / hexane. In this way, 724 mg (62%) of pure 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone were finally obtained, which was identical in all respects to Example 1 of U.S. Patent No. 4,536,518 ( E) with the product.

Example 8

To a 20 mL round bottom reaction flask equipped with a reflux condenser was charged 1.0 g (0.004 mol) of 5- (3,4-dichlorophenyl) dihydro-2 (3H) -furanone (product of Example 3), 4 mL (0.045 mol). benzene and 5 ml of 95% sulfuric acid (0.094 mol), all added at ambient temperature (about 20 ° C). The resulting reaction mixture was heated at 95 ° C for one hour and then at 140 ° C for 1.5 hours. After this step, the reaction mixture was cooled to ambient temperature and quenched into 40 grams of ice. After the resulting aqueous mixture was stirred at ambient temperature for 18 hours, the light green solid product was collected by suction filtration and air dried to constant weight. In this way, 740 mg (63%) of good quality 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone was finally obtained, containing only a small amount of 4- (3,4-dichlorophenyl) -4- phenylbutanoic acid as evidenced by thin layer chromatography and high field proton and carbon-30 nuclear magnetic resonance results.

Example 9

Reflux A 10 ml (0.04 mol) of 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone (product of Example 35 3), 20 ml (0.22 mol) was placed in a 250 ml round bottom reaction flask equipped with a cooling condenser. moles) of benzene and 80 g (0.830 91391 13 moles) of methanesulfonic acid at a temperature (about 20 ° C). The reaction mixture was heated at 100 ° C for 20 hours. After this step, the reaction mixture was cooled to ambient temperature and quenched into 200 grams of ice. In this step, 50 ml of methylene chloride was added and the pH of the aqueous phase was adjusted to 11.3 with 167 ml of 20% aqueous sodium hydroxide. An additional 50 mL portion of methylene chloride was added to the basic aqueous mixture and the aqueous phase was extracted. The separated aqueous layer was re-extracted with 50 ml of methylene chloride, and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and distilled in an atmosphere to remove the solvent. In the distillation step, methylene chloride was replaced with 50 ml of hexanes and 75 ml of isopropyl ether. After the remaining amount of distillate-15 was reduced to about 90 ml, the reaction mixture was allowed to cool to ambient temperature with constant stirring. After stirring at this point (i.e., at about 20 ° C) for 18 hours, the yellow solid product was collected by suction filtration and air dried to constant weight. In this way, 7.24 g (62%) of good quality 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone were finally obtained.

Example 10

The procedure described in Example 7 was repeated, except that polyphosphoric acid was used as a catalyst instead of methanesulfonic acid, using the same molar ratios as before. In this case, the corresponding end product was also pure 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone. Similar results were obtained when phosphorus pentoxide, aluminum chloride and titanium tetrachloride were used individually instead of methanesulfonic acid, again using the same molar ratios as before.

Example 11 A 25 ml portion of an aqueous basic solution containing 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid 14 (5.0 g, 0.018 mol) prepared according to Example 2 was treated with 25 ml of methylene chloride and the aqueous phase The pH was adjusted to 1.0 with 96% sulfuric acid (1.5 mL). The two layers were separated and the resulting organic extract was transferred to a 100 mL round bottom reaction flask equipped with a distillation apparatus. At this point, 25 ml (0.28 moles) of benzene was added and the methylene chloride solvent was removed by atmospheric distillation. An additional 25 mL of 96% sulfuric acid 10 (0.48 moles) and 5 mL (0.056 moles) of benzene were then added to the distillate, and a reflux condenser was placed in the reaction flask after the distillation apparatus was first removed. The reaction mixture in the flask was then heated to 95 ° C for one hour and then to 135 ° C for three hours. The resulting mixture after this step was cooled to ambient temperature (about 20 ° C) and then quenched into 200 grams of ice. The resulting aqueous phase was extracted twice with methylene chloride (50 ml / 10 ml) and the combined organic extracts were dried over anhydrous magnesium sulfate and filtered. After removal of the drying agent by filtration and evaporation of the solvent under reduced pressure, a residue of 2.89 g was finally obtained as a yellow foam. Thin layer chromatography and high field proton nuclear magnetic resonance results showed that the main component of the foam was 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone.

Example 12 A 125 ml polypropylene reaction vessel was charged with 3.0 g (0.012 mol) of 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone (product of Example 3) dissolved in 6 ml (0.067 30 moles) of benzene. The reaction vessel was connected to a polypropylene nanofold, and 20 ml (1.0 mol) of anhydrous hydrofluoric acid (hydrogen fluoride) was distilled into a vessel containing the above-mentioned Bentene solution at -78 ° C. The reaction mixture was allowed to warm to ambient temperature (about 20 ° C) and stirred at that point for 18 hours. After this 91391 15 step, the excess hydrofluoric acid and benzene were removed from the mixture by vacuum distillation and the recovered hydrofluoric acid was purified with calcium oxide. The system was purged with nitrogen and the reaction vessel was removed from the hydrofluoro-5 silicic acid manifold. At this point, 30 ml of methylene chloride and 5 ml of water were added to the polypropylene reaction vessel, and its contents were cooled to 0 ° C. Aqueous sodium hydroxide (1.0 N) was added to the reaction system until the pH of the aqueous solution was 12.0 (13 ml of 10 bases were required). The resulting organic layer was separated from the biphasic system and the aqueous layer was re-extracted with 30 mL of methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the resulting organic filtrate was transferred to a 125 mL round bottom flask before being concentrated by atmospheric distillation. After the volume was first reduced to about 30 ml, hexane (40 ml) was added and distillation was continued until the distillate temperature was 67 ° C. At this point, the heating mantle was removed and within five to 20 minutes a white precipitate began to form. After stirring the resulting white suspension for 16 hours, the completely precipitated white solid product was collected by filtration and then dried in a vacuum oven to constant weight. In this way, 3.43 g (97%) of good quality 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone, m.p. 102-103 ° C, were finally obtained.

The pure product was further determined by thin layer chromatography and high field proton and carbon core magnetic resonance results.

30 Example 13

To a 25 mL round bottom reaction flask equipped with a reflux condenser was charged 3.0 g (0.012 moles) of 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone (product of Example 3) dissolved in 6 mL (0.067 moles). 35 benzene. To the stirred benzene solution was then added 5.34 mL (0.060 moles) of trifluoromethanesulfonic acid at ambient temperature (about 20 ° C) and stirring was continued at this point for five minutes. The resulting reaction mixture was heated at 75 ° C for 1.5 hours and allowed to cool to ambient temperature. After this step, the final mixture was quenched into 20 grams of ice and treated with 30 mL of methylene chloride. The quenched reaction mixture was basified with 15 mL of 4N aqueous sodium hydroxide solution to adjust the pH of the aqueous material to 9.0. At this point, the two layers were separated and the aqueous layer was re-extracted with methylene chloride.

The organic layers were combined and dried over anhydrous magnesium sulfate and filtered, and the filtrate was transferred to a 125 ml round bottom flask. The methylene chloride solvent was removed by atmospheric distillation until the volume of the substance to be distilled in the flask was reduced to about 40 ml, at which point 40 ml of hexane was added and the distillation was continued until the distillate temperature was 67 ° C. At this point, the heating mantle was removed and within 5 minutes a white precipitate began to form. After stirring the resulting white suspension for 16 hours, the completely precipitated white solid product was collected by filtration and then dried in a vacuum oven to constant weight. In this way, 3.22 g (91%) of good quality 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone, melting point 103-104 ° C, were finally obtained. The pure product was further determined by thin layer chromatography and high field proton and carbon nuclear magnetic resonance results.

Claims (5)

A process for the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone, characterized in that 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid or 5- (3,4-Dichlorophenyl) dihydro-2 (3H) -furanone is reacted with benzene in excess of said reagent as a solvent or in an inert organic solvent in the presence of a protic or Lewis -10 acid catalyst at a temperature of about -20 - 180 ° C until the alkylation of benzene with said hydroxy acid or the corresponding gamma-butyrolactone compound and subsequent cyclization to form the desired ring ketone end product is substantially complete. 15 2. A process according to claim 1, characterized in that the protic acid used as a catalyst, sulfuric acid, trifluoromethanesulfonic acid, hydrofluoric acid or methanesulfonic acid. Process according to claim 1, characterized in that the molar ratio of the hydroxy acid or gamma butyrolactone starting material to the benzene reagent and the acid catalyst is about 1.0: 1.0 - 1.0: 20.0 and about 1.0: 0.1 - 1.0: 90.0. Process according to claim 1, characterized in that the reaction is carried out at a temperature of about 15-145 ° C. Process according to claim 1, characterized in that the reaction is carried out using a benzene excess as a solvent.