FI91391C - Process for the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone - Google Patents

Description

i 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 an article by WM Welch, Jr et al. in Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 15 (1984) discloses a method for certain 4- (substituted phenyl) -4- (optionally substituted phenyl) for the preparation of butanoic acids in which the possible substituent is always other than alkoxy. Certain of these 4,4-diphenylbutanoic acid derivatives are shown to be useful as vS-20 l-products which result in 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 previous method described in the publication involves the multi-step synthesis of the desired 4,4-diphenylbutanoic acid substitutes starting from the corresponding Bent-phenophenone compound. For example, an 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 substitute product.

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 to give the excess of said reagent. or in a reaction-inert organic solvent with 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 like gamma-butyrolactone compound and subsequent cyclization to substantially complete the desired ring-terminated.

The compound of the invention is a valuable selected product in the preparation of the antidepressant centralin, 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 the 4- (3,4-dichlorophenyl) -4-ketobutanedioic acid using a carbonyl reducing agent capable of reducing the carboxylic acid of its ketone or with the presence of salt. 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 nearly complete. Preferred polar protic solvents for use in this connection 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 sufficient 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 substitute product 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 no further treatment required. After the reaction is carried out in an aqueous solvent as described above (pH 6), the hydroxy acid end product is normally lasal as an alkali metal salt.

The formed hydroxy acid substitute product 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 to an aromatic hydrocarbon solvent at about -1 ° C to about 55 ° C. . Preferred aromatic hydrocarbon solvents for these purposes are 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 contains the hydroxy acid formed in situ by myOs. The preferred acid for making the acid-10 base in this context is either hydrochloric acid or sulfuric acid, and the heating step is preferably performed at about 55 ° C to about 80 ° C until lactonization is almost complete. Thereafter, the final reaction mixture is slowly cooled to ambient temperature and granulated in a conventional manner, and the desired 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone compound or optionally isolated from the mixture is preferably isolated from the mixture by such a method. by extraction with a solvent such as methylene chloride, which is also suitable for the next step.

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 solvent or in a reaction-inert organic solvent with a protic or Lewis acid catalyst at a temperature of about -20 to 180 ° C until alkylation of benzene with either said hydroxy acid or the corresponding halonututene solvent 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 any 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 first-exchange resins, the most preferred being ion exchange resins. In a preferred embodiment of this reaction, the molar ratio of hydroxy acid tax gamma-butyrolactone supercharger 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 the most preferred gamma-butyrolactone / benzene / acid catalyst ratios being approximately valium 1.0: 5.0: 0.1 to 1.0: 10.0: 90: 0. In use, the reaction is preferably carried out at a temperature ranging from about 15 ° C to 145 ° C, with the most preferred lamp range being from about 15 ° C to about 100 ° C, in the case where the acid catalyst used is a protic acid such as sulfuric acid, trifluoromethanesulfonic acid or methanesulfonic acid. , the preferred range of conditions 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 scavenger is a known compound which can be readily prepared by those skilled in the art from the general chemicals of the bays and using conventional methods of organic synthesis. For example, this compound 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, p. 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 slurried in 5,772 ml of water in a reaction flask and heated to 70-80 ° C while slowly adding 70 ml of 15N aqueous sodium hydroxide (1.05 moles) over a half hour pi tåen system at a pH of 10.7 - 11.9. The resulting dark brown solution had a pH of 11.7 (at 75 ° C), to which was added a solution of 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. Upon completion of this step, the resulting reaction mixture was stirred at the same temperature for an additional 45 minutes. Thin layer chromatography of the sample taken at this stage 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 on 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 at all times): throughout 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. Removal of the drying agent 011 by filtration and evaporation of the solvent under reduced pressure gave 10 g of 4- (3,4-dichlorophenyl) -4-hydroxybutanoic acid as a brown-orange 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-hydroxy. sibutanoic acid (as dicyclohexylamine salt), melting point 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 with 130 ml portions of 15N aqueous sodium hydroxide and 47 , 5 ml of 1.5N aqueous sodium hydroxide. The time taken for 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 pond 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 for 44 minutes.

The reaction mixture resulting from this step was stirred at this same temperature for about two hours.

Thin layer chromatography of the sample taken six minutes after the additional 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 without the need to isolate 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 time-na 35 due to foaming. The resulting mixture of Gljy and acidic water after this step was stirred vigorously and warmed to 65-70 ° C for four hours before being allowed to cool to room temperature (about 20 ° C). Thin layer chromatography of samples taken at 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 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 over a core (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, at which time 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 was then treated dropwise with hexane and allowed to cool to room temperature to give a light brown solid. This material was granulated in a room bath 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. in the foregoing prior art by describing the method with an prepared authentic sample.

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-ring round bottom reaction flask under nitrogen at 18 ° C was slowly added. a dropwise solution of 149.6 g (0.648 moles) of 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone (product of Example 3) dissolved in 800 ml of benzene. The addition step was performed for 50 minutes, keeping the lamp state of the reaction mixture at approximately 15-20 ° C by means of a fractional bath. The reaction mixture of the fraction from this step was stirred at room temperature (about 20 ° C) for two hours to give a dark brown solution. The stirred mixture was poured into 648 mlraan-ice / water containing 129.6 ml of concentrated hydrochloric acid is 1 to 30 ° C and the resulting acidic aqueous 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 precipitated and extracted twice with 100 ml of benzene. The combined benzene layers 35 were filtered and vacuum filtered to remove benzene. The off-white to 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 pyOrea-based flask and granulated for approximately 16 hours. After filtration and washing with 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 an off-white 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 (1.49 moles) of benzene (146.3 mL) and 86.4 g (0.640 moles) of aluminum chloride in 186 mL of o-dichlorobenzene in a 2 L four-necked python-based reaction flask under nitrogen. in an 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 slowly was added dropwise. To 600 ml of o-dichlorobenzene An additional step was performed over 2.5 hours, maintaining the temperature of the reaction mixture in the range of approximately 7 to 9 ° C with a fraction bath, and the reaction mixture of this fraction 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 lamp state of the resulting aqueous acidic mixture below 28 ° C throughout the quenching step.The coolest mixture 30 (now a white slurry) was stirred for ten minutes and was allowed to stand out in two n floor. the contaminated organic phase was washed twice with warm water and a 550 ml portion of this washed layer was transferred to a 3 liter three neck necked flask and 500 ml of water and 60 ml of 50% aqueous sodium 91391 11 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 then 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 jåljelle jååvå thick liquid was seeded with authentic 4- hyppysellisellå (3.4 to 10 dichlorophenyl) -4-phenylbutanoic acid (prepared as in the Example 4), mi TAA followed by stirring for about half an hour, there was a very thick crystalline slurry which is then li-såttiin 400 ml of heptane. The resulting mixture was stirred for about 16 hours (i.e. over yOn), 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 relatively identical to Example 4, were finally obtained. with the product.

Example 7

To a 25 mL reflux condenser 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 moles) of 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone was added dropwise over 20 minutes (Example 3) dissolved in 2 ml of benzene. The reaction mixture of this step jS1-30 was stirred at 95 ° C for seven hours and then cooled and quenched into 60 mL of partition. 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 oil 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 was finally obtained, which was identical in all respects to the example of U.S. Patent No. 4,536,518. 1 (E) with the product.

Example 8

To a 20 mL pyro-based 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 of which were added at ambient lamp 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. The reaction mixture of the fraction from this step was cooled to ambient lamp temperature and quenched into 40 grams of fraction. 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

To a reflux condensed 250 mL pyramid-based reaction flask was charged 10 g (0.04 moles) of 5- (3,4-dichlorophenyl) -dihydro-2 (3H) -furanone (product of Example 35 3), 20 mL (0.22 moles). ) benzene and 80 g (0.830 91391 13 moles) of methanesulfonic acid at room 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 pellets. In TSssS step 5, 50 ml of methylene chloride were 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 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 amount of residual distillate 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., 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 the benign 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 the case of TSssS, the corresponding end product was also pure 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone. Similar results were obtained myds 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 pH of the aqueous phase 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 reaction flask equipped with a pyridine-based distillation apparatus. At this point, 25 mL (0.28 moles) of benzene was added and the methylene chloride solvent was removed by atmospheric distillation. Subsequently, an additional 25 mL of 96% sulfuric acid 10 (0.48 moles) and 5 mL (0.056 moles) of benzene were 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 from step 15 to 15 was cooled to ambient temperature (about 20 ° C) and then quenched with 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 sulphate 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 a vessel containing the above-mentioned Bentene solution at -78 ° C was distilled with 20 ml (1.0 mol) of anhydrous hydrofluoric acid (hydrogen fluoride). The reaction mixture was allowed to warm to ambient temperature (about 20 ° C) and stirred at that point for 18 hours. After this 91391 step, the excess hydrogen fluoric acid and benzene were removed from the mixture by vacuum distillation, and the recovered hydrogen fluoric 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 the added base was needed). 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 temperature of the distillate was 67 ° C. At this point, the heating mantle was removed and a white precipitate began to form within five to 20 minutes. 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 that point for 5 minutes. The resulting reaction mixture was heated at 75 ° C for 1.5 hours and allowed to cool to ambient temperature. The final mixture of the fraction from this step was quenched into 20 grams of fraction and treated with 30 mL of methylene chloride. The quenched reaction mixture was basified with 15 mL of 4N aqueous sodium hydroxide solution to bring 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 pyrose-based distillation 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 temperature of the distillate 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. As such, 3.22 g (91%) of good quality 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalenone, m.p. 103-104 ° C, were finally obtained. The pure product was determined by thin layer chromatography and high field taproton and carbon nuclear magnetic resonance results.

Claims (5)

A process for preparing 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 an 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 then cyclization to form the desired ring ketone end product is substantially complete. 2. A process according to claim 1, wherein the protic acid used as a catalyst, sulfuric acid, trifluoromethanesulfonic acid, fluoroacetic acid or methanesulfonic acid can be used. 3. A process according to claim 1, characterized in that the molar ratio of the hydroxy acid or gamma-butyrolactone starting substance to the benzene reagent and the acid catalyst is about 1.0: 1.0 - 1.0: 20.0 and approx. 1.0: 0.1 - 1.0: 90.0. 4. A process according to claim 1, characterized in that the reaction is carried out at a temperature of about 15-145 ° C. 5. A process according to claim 1, characterized in that the reaction is carried out using a benzene excess as solvent.