SK34199A3 - Process for the preparation of a pharmaceutical intermediate - Google Patents

Abstract

The invention relates to a process for the preparation of highly pure 4-(3,4-dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of formula (I), by reacting <u>o</u>-dichloro-benzene and alpha -naphthol in a solvent as medium in the presence of a Friedel-Crafts catalyst which comprises crystallizing the crude reaction product of formula (I) at least once from a polar solvent and at least once from an apolar solvent, whereby said crystallization steps can be carried out in optional order of succession, and whereby the amount of the by-product 4-(2,3-dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of formula (II) is decreased below 1 %. The compound of formula (I) is a useful pharmaceutical intermediate. The advantage of the process is that the described compound is obtained in highly pure form.

Description

A process for the preparation of a pharmaceutical intermediate

Technical field

The invention relates to a process for the preparation of a pharmaceutical intermediate.

More particularly, the present invention relates to the preparation of 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) naphthalen-1-one according to Formula I:

(D

BACKGROUND OF THE INVENTION

The compound of formula (I) is a valuable intermediate that can be used in the pharmaceutical industry to prepare pharmaceutically active substances. The compound of formula (I) is useful in the preparation of sertraline, a known therapeutic agent used to treat mental depression. The chemical name of sertraline is cis- (1S, 4S) -N-methyl-N- (3,3-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalenamine.

Several methods are known for the preparation of a compound of formula (I). The method described in U.S. Pat. No. 4,536,518, shown in Reaction Scheme 1. In the first reaction step, σ-dichlorobenzene and benzoyl chloride are reacted to give the corresponding substituted benzophenone derivative. In the next step, this benzophenone derivative is subjected to a base-catalyzed Stobe condensation to react with diethyl succinant. The next step in the reaction

Hydrolysis and decarboxylation, e.g. in the presence of hydrogen bromide. The mixture of E- and Z-4,4-diaryl-butanoic acids thus obtained is reduced with hydrogen in the presence of a catalyst. Acid chlorides are obtained from 4,4-diaryl-butanoic acid derivatives which are formed with thionyl chloride and then converted to 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (H) -naphthalene-1. cyclization in the presence of aluminum chloride. A disadvantage of this process is that it consists of many reaction steps and according to said patent the total yield is only 8%.

According to the method of Williams / Chem. And Ind. 316 (1990)], a yield increase of 33% can be achieved.

U.S. Pat. No. 4,777,288 discloses an improved process for the preparation of appropriately substituted 4,4-diphenyl-butanoic acids. The reaction is shown in Reaction Scheme 2. In the first step, o-chlorobenzene is reacted with succinic anhydride in the presence of a catalyst. There was thus obtained 4- (3,4-dichloro-phenyl) -4-keto-butanoic acid, which was reduced with sodium borohydride, after which the butirolactone derivative formed in situ was subjected to Friedel-Crafls reaction with benzene without coming into its isolation. Benzene also acts as a solvent. The diarylbutanoic acid derivative thus obtained is further converted to the compound of formula I as described in U.S. Pat. 4,536,518. The downside of this process is that it is made up of a large number of reaction steps, according to said US patenting a total yield of 60%.

The method described in U.S. Pat. No. 4,839,104 is shown in Reaction Scheme 3. The butirolactone derivative is converted to the desired naphthalen-1-one of Formula I in the presence of a strong acid in one reaction step without isolating the diarylbutyric acid derivative formed as an intermediate. As a strong acid, 98% sitic acid, trifluoromethylsulfonic acid or hydrogen fluoride can be used. According to the aforementioned US patent, the highest yield (overall yield of the three reaction steps is 82%) can be achieved using hydrogen fluoride. However, the use of hydrogen fluoride requires an apparatus made of poly- (trifluoro-monochloro-ethylene) -uiflon. A disadvantage of this process is that the Daiflon apparatus Another disadvantage of this process is that hydrogen fluoride is a very corrosive substance that can only be used on an industrial scale if very strict requirements and demands for expensive safety measures are observed. The use of trifluosulfonic acid can also give a very good yield. However, also

This reagent is too expensive, so this process is uneconomical in industrial scale production. When the reaction is carried out in the presence of sulfuric acid, the yield is only 53%. This is a value that does not exceed that disclosed in U.S. Pat. Ns 4,777,288.

According to EP-A 346,226, 4-allyl-substituted-1-tetralone derivatives are prepared by reacting alpha-naphthol with the corresponding disubstituted benzene in the presence of one of the aluminum halide catalysts. According to this EP-A, 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one of formula I is prepared as follows (shown in Reaction Scheme 4).

A mixture of 1 mole of alpha-naphthol, 1.3 mole of aluminum chloride was stirred at 65 ^° C for three hours. The reaction mixture was then poured onto ice and the aqueous layer was extracted with o-chlorobenzene. The organic layer was dried, evaporated, the residue dissolved in methyl ethyl ketone and purified with activated carbon. After filtration, methanol is added, the solution is cooled to 0 ° C to 4 ° C while stirring and the precipitated crystals are filtered off. According to EP-A 346,226, the precipitated compound of the formula I is obtained in a yield of 61% and a GC purity of 98 to 99%.

In reproducing the Example in EP-A 346,226 and subjecting a product having a GC purity of 98-99% to careful analysis, it was found that the product was not homogeneous but formed by a mixture consisting of 4- (3,4-dichlorophenyl) - 3,4-dihydro-1 (2H) -naphthalen-1-one according to formula I and 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one according to general formula I formula II:

in a 95: 5 ratio.

The contaminating isomer of formula (II) is a novel compound not previously described in the art. The presence of this by-product is undesirable since the amount of the 2,3-isomer of the compound of formula II exceeds 1%,

The corresponding contaminating 2,3-isomer also appears in the sertraline end product; in analogous reactions, the isomer cannot be removed to the desired extent.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a highly pure compound of formula I which contains a contaminating 2,3-isomer of formula II in an amount of less than 1%.

According to the present invention, the above object of the invention is achieved by subjecting the crude reaction product of formula 1 to crystallization as described below, reducing the amount of the isomer of formula Π to below the desired tolerated limit.

According to the present invention there is also provided a process for preparing high purity 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one according to Formula I:

reacting o-chloro-benzene and alpha-naphthol in a solvent environment in the presence of a Friedel-Crafts catalyst, further crystallizing the crude reaction product of formula I in at least one of polar solvents and at least one of the troublesome solvents, wherein said crystallization step may optionally and wherein the amount of 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one by-product of Formula II:

(Η) is less than 1%.

The present invention is based on the discovery that the novel 2,3-isomer of Formula U, which is not described in the art, has not been isolated, identified by spectroscopic methods, and a suitable method for eliminating such contamination has been devised. A detailed capillary GC and HPLC method has been developed for the qualitative determination of side-by-side substances for isomers of formula I and Π. This method allows control of the purity of the isomer and serves as a basis for the detailed elaboration of the purification process of the resulting high purity compound of Formula I.

In the process of the present invention, it is preferred to use a C 1-6 alkane (methanol, ethanol, n-propanol or isopropanol) as the polar solvent. It is preferred to use methanol for crystallization.

In the process of this invention, a C 1-10 alkane (e.g., n-hexane, n-heptane, g-octane) may be used as the polar solvent, or an ether (e.g., dioxane, diethyl ether, methyl tert-butyl ether and the like) may be used. In this process, it is preferred to use n-hexane or methyl tert-butyl ether as the nonpolar solvent.

It is also possible to use a mixture of solvents which contain a non-polar solvent (for example a mixture of n-hexane and ethyl acetate or n-hexane and isopropanol) in the process according to the invention.

In the process of the present invention, it is desirable to use a certain order of successive individual steps, particularly with respect to crystallization. It is possible to crystallize the crude product first from a polar solvent and then from a non-polar solvent or

-6the verse. In a preferred embodiment of the process, it is preferable to use the crystallization of the crude product first from a polar solvent and then from a non-polar solvent or, thereafter, from a non-polar solvent or from a solvent mixture containing a non-polar solvent.

In the process according to the invention, it is possible to obtain the 3,4-isomer of the formula I contaminated with less than 1% - preferably less than 0.5% - of the 2,3-isomer of the formula Π.

The crude product of formula I, which is used as the starting material, can be prepared by reacting ε-dichlorobenzene and α-naphthol in a solvent medium and in the presence of a Friedel-Crafts catalyst.

Preference is given to an excess of o-dichlorobenzene reagent which acts as a solvent. Preferably, the reaction may be carried out in the absence of an additional solvent, in excess of the Q-dichlorobenzene used as reagent. However, it is also possible to carry out the reaction in an inert solvent environment. Nitrobenzene, dichloroethane, trichloroethane or carbon disulfide can be used for this purpose.

The reaction is carried out in the presence of a Friedel-Crafts catalyst. The use of aluminum chloride, aluminum bromide, tin (II) chloride or antimony fluoride is preferred, with aluminum chloride being preferred.

The reaction can be advantageously carried out using the components alpha-naphthol: FriedelCrafts catalyst: beta-dichlorobenzene in a ratio of 1: 2: 3 to 1: 10: 100. The molar ratio of these components is particularly preferred 1: 3: 10.

The reaction may be carried out at a temperature between 30 ^° C and 200 ° C, preferably at 90 ° C. The reaction takes place for several hours; the reaction time is usually three hours to six hours.

The reaction mixture may be worked up according to known methods. One preferred method is pouring the mixture into ice-cooled water, extracting with an organic solvent (eg, halogenated alkanes such as dichloromethane, chloroform or other water-immiscible solvents such as ethyl acetate), and washing, filtering and evaporating the organic layer.

An advantage of the process according to the invention is its economic advantage and also its simplicity on an industrial scale, whereby a highly pure compound of the formula I is obtained which contains less than 1% of the contaminating isomer of the formula II.

The following examples are provided to illustrate the invention in further detail without restricting the scope or scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

First, the properties of the substances involved will be listed and then illustrative of the examples.

Physical properties of the desired 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one according to the general formula I

Melting point: 101-102 ° C

Elemental analysis: C 1 H ₂ Cl ₂ O ₂

C H Cl calculated (%) 66.00 4.15 24.35 found (%) 65.77 4.05 25.15

IR (KBr) cm ^-1 : 2952, 1675, 1594, 1471, 1450, 1400, 1346, 1331, 1287, 1252, 1204, 1153, 1028,882,771,726,670, 555,447, 1 H-NMR (CDCl ₃ ): δ ppm (numbering) Fig. 4): / 8.12 dd (8Hz, 2Hz) (1H), (H-8) /, 7.3-7.5m (3H) (H-5, H-6, H-7) ) /; (7.24 d (1H) (H-2 ')); (6.95 m (2H), (H-5 ') (H-6')) = 4-8 dd (J = 8Hz, J = 4.5Hz) (1H), (H-4)], 2.68 m (1H) (H-3); 2.3 m (lH) (H-3) Z.

C-NMR (CDCl 3): δ ppm (numbering Fig. 4): (197.2 C-1); (144.9 C-4,); (133.8 C-6); (132.8 C-3); (132.7 C-4 '); (130.99 C-1 '); (130.57 C-2); (130.49 C-5 &apos;); (129.2 C-6 *); (127.9 C-5); (127.5 C-7); (127.36 C-8); (44.47 C-4); (36.4 C-2); (31.6 C-3).

CLAM-C1291.

-8Physical properties of the contaminating 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one according to the general formula II

Melting point: 66-70 ° C

Elemental analysis: C 18 H 17 Cl 2 O 2

Calcd (%) 66.00 4.15 24.35 found (%) 65.67 4.01 24.10

IR (KBr) cm ^-1 : 2951, 1680, 1598, 1450, 1419, 1330, 1287, 1232, 1172, 1116, 1043, 922, 839,772,739,711,558.

1 H-NMR (CDCl ₃ ): δ ppm (numbering Fig. 4): (8.13 dd (8Hz, 2Hz) (1H), (H-8)); (7.71-7.48 m (3H) (H-5, H-6, H-7)); (7.09 t (8Hz) (1H) (H-5 ')); / 6.95 dd (8Hz, 2Hz) (1H), (H-6) // 6.70 dd (8Hz, 2Hz) (1H) (H-4 ') (/ 4.90 dd (J = 6, ₇ Hz, J (4.7 Hz) (1H), (H-4) (2.66 m (2H) (H-2)), 2.39 m (2H) (H-3).

¹³ C-NMR (CDCl ₃ ): δ ppm (numbering Fig. 4): (197.7 Cl); (144.8 C-4); (144.3 C-8); (133.98 C-2 '); (133.15 C-1 '); (132.49 C-6); (129.38 C-6); (129.04 C-4 '); (128.33 C-5 '); (127.53 C-7); (127.34 C-8); (127.27 C-5); (42.46 C-4); (36.12 C-2); (29.01 C-3).

MSAP ⁺ C1291.

The following GC and HPLC conditions were used to separate the two isomers.

GC:

GC Shimadzu GC9A Column: SUPELCO SPB5 (15mx0.2mmlD-FD: 0.2 µπι) Temperature: 50 to 250 ^° C, Grades: 10 ”/ min Carrier gas: N2 (19.8 cm / sec) Inj .: at 250 ° C 0.25 μΐ solution (MeOH) detector: FID temperature 270 ° C

-9 Retention Time 2,3-Isomer: 11.08 min. retention time of 3,4-isomer: 11.83 min.

HPLC:

The HPLC method was used to control the Standards.

Column: Cyclobond 1 (b-cyclodextrin) S mm, 25 cm x 4 mm (ASTEC)

Elution: acetonitrile - 1% TEAA buffer (25: 75)

TEAA buffer: 10 ml triethylamine, 10 ml glacial acetic acid, 1000 ml water

Flow rate: 1.0 mL / minute

Detection: UV 254 nm

Socket volume: 20 ml (4-5 mg / dissolved in 10 ml acetonitrile, diluted with eluent)

Calibration: 1.716 mg / ml

Retention time of the 2,3-isomer: 5.57 minutes

Retention time of 3,4-isomer: 6.88 minutes

Example 1

4- (3,4-dichloro-phenyl) -3,4-dihydro-l (2H) -naphthalene-l-one

To a mixture of 5.19 g (36 millimoles) of alpha-naphthol and 30 g of 1,2-dichlorobenzene was added 15 g (112 millimoles) of anhydrous aluminum chloride. The reaction mixture was heated to an internal temperature of 90 ^° C with stirring. The reaction mixture is kept at this temperature for three hours, then poured onto 170 g of crushed ice and extracted four times, each time with 45 ml of ethyl acetate. The organic phase is dried, purified with charcoal and evaporated at 40 to 60 ° C at 0.5 mm Hg.

The material thus obtained was dissolved in 84 ml of methanol with stirring and heating under reflux. The solution is then filtered and the mother liquor is slowly cooled with stirring. During cooling, crystals slowly precipitate - fall out. Order to make crystallization complete, the mixture was cooled to 0 ⁰ C. The precipitated crystals are filtered and washed twice with 8 ml of methanol each time.

The crystals thus obtained are dried under an infrared lamp for 24 hours. The anhydrous crystals were heated to reflux in 188 ml of n-hexane until the entire product had dissolved. The solution is then filtered and the mother liquor is slowly cooled with stirring. Crystals slowly precipitate during cooling. Order to make crystallization complete, the mixture was cooled to 0 ⁰ C. The precipitated crystals are filtered and washed twice with 8 ml of icecold n-hexane.

Thus, 8.2 g of the title compound are obtained in a yield of 60%. The purity of the product is 99.5%, the amount of 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one formed as a by-product is less than 0, 5%.

Example 2

4- (3,4-Dichloro-phenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one

To a mixture of 5.19 g (36 millimoles) of alpha-naphthol and 30 g of 1,2-dichlorobenzene was added 15 g (112 millimoles) of anhydrous aluminum chloride. The reaction mixture is heated to an internal temperature of 90 ^° C with slow stirring. The reaction mixture is kept at this temperature for three hours, then poured onto 170 g of crushed ice and extracted four times, each time with 45 ml of ethyl acetate. The organic phase is dried, purified with activated carbon and evaporated at a temperature of 40 to 60 ^° C at 1 mm Hg.

The material thus obtained was dissolved in 84 ml of methanol with stirring and heating to reflux. The solution is then filtered and the mother liquor is slowly cooled with stirring. Crystals slowly precipitate during cooling. Order to make crystallization complete, the mixture was cooled to 0 ⁰ C. The precipitated crystals are filtered and washed twice with 8 ml of methanol each time.

The crystals thus obtained are dried under an infrared lamp for 24 hours. The anhydrous crystals were stirred in 55 ml of n-hexane / ethyl acetate 9; 1 under reflux until the entire product has dissolved. The solution is then filtered and the mother liquor is slowly cooled with stirring. Order to make crystallization complete, the mixture was cooled to 0 ⁰ C. The precipitated crystals are filtered and washed twice with 8 ml of icecold n-hexane.

Thus 7.0 g of the title compound are obtained in a yield of 68%. The purity of the obtained substance 99.5%, the amount of 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one, which is formed as a by-product in the reaction, is less than 0.5%.

- 11 Example 3

4- (3,4-Dichloro-phenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one

To a mixture of 5.19 g (36 millimoles) of alpha-naphthol and 30 g of 1,2-dichlorobenzene was added 15 g (112 millimoles) of anhydrous aluminum chloride. The reaction mixture is heated to an internal temperature of 90 ^° C with slow stirring. The reaction mixture is kept at this temperature for three hours, then poured onto 170 g of crushed ice and extracted four times, each time with 45 ml of ethyl acetate. The organic phase is dried, purified with activated carbon and evaporated at a temperature of 40 to 60 ° C at a pressure of 53 Pa.

To the residue (9.8 g) was added 30 ml of methanol at 0 ° C. The precipitated crystals are filtered off and washed twice with 5 ml of ice-cold methanol each time.

The product thus obtained is stirred in 210 ml of rthexane under heating to reflux until all the product has dissolved. Then the solution is filtered and the mother liquor is slowly cooled while stirring. Crystals slowly precipitate during cooling. Order to make crystallization complete, the mixture was cooled to 0 ⁰ C. The precipitated crystals are filtered and washed twice with, in each case 8 ml of ice-cold methanol.

The crystals thus obtained are dried under an infrared lamp for 24 hours. The anhydrous crystals are heated in 50 ml of a 3: 4 mixture of n-hexane and isopropanol under reflux until the whole product is dissolved. The solution is filtered and the mother liquor is slowly cooled while stirring. Crystals slowly precipitate during cooling. To complete the crystallization, the mixture is cooled to 0 ^° C. The precipitated crystals are filtered off and washed twice with 8 ml of n-hexane each time.

Thus 7.0 g of the title compound are obtained in a yield of 67%. The purity of the product is 99.5%, the amount of 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one, a byproduct formed in the reaction, is less than 0 , 5%.

Example 4

4- (3,4-Dichloro-phenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one

To a mixture of 5.19 g (36 millimoles) of alpha-naphthol and 30 g of 1,2-dichlorobenzene was added 15 g (112 millimoles) of anhydrous aluminum chloride. The reaction mixture is warmed to internal temperature

- 1290 ^° C with slow stirring. The reaction mixture is kept at this temperature for three hours, then poured onto 170 g of crushed ice and extracted four times, each time with 45 ml of ethyl acetate. The organic phase is dried, purified with activated carbon and evaporated at a temperature of 40 to 60 ° C at a pressure of 53 Pa.

The material thus obtained was dissolved in 84 ml of methanol with stirring and heating to reflux. The solution is then filtered and the mother liquor is slowly cooled with stirring. Crystals slowly precipitate during cooling. Order to make crystallization complete, the mixture was cooled to 0 ⁰ C. The precipitated crystals are filtered and washed twice with 8 ml of methanol each time.

The crystals thus obtained are dried under an infrared lamp for three hours. The anhydrous crystals are stirred in 40 ml of methyl tert-butyl ether while heating under reflux until the entire product has gone into solution. Then the solution is filtered and the mother liquor is slowly cooled while stirring. Crystals precipitate during cooling. To complete the crystallization, the mixture is cooled to 0 ^° C. The precipitated crystals are filtered off and washed twice with 8 ml of ice-cold n-hexane each time.

There was thus obtained 6.1 g of the title compound in a yield of 58%. The purity of the product is 99.5%, the amount of 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one formed as a byproduct in the reaction is less than 0 , 5%.

Example 5

4- (3,4-dichloro-phenyl) -3,4-dihydro-l (2H) -naphthalene-l-one

To a mixture of 5.19 g (36 millimoles) of alpha-naphthol and 30 g of 1,2-dichlorobenzene was added 15 g (112 millimoles) of anhydrous aluminum chloride. The reaction mixture is heated to an internal temperature of 90 ^° C with slow stirring. The reaction mixture is kept at this temperature for three hours, then poured onto 170 g of crushed ice and extracted four times, each time with 45 ml of ethyl acetate. The organic phase is dried, purified with charcoal and evaporated at 40 to 60 ° C at 0.5 mm Hg.

125 ml of n-hexane are added to the evaporation residue at room temperature. A solution is formed; crystals will precipitate within an hour. The mixture was stirred at room temperature for 12 hours and cooled to a temperature between -5 ° C and -10 ° C. The crystals were filtered, washed with 10 ml

- ice-cold methanol and dried under an infrared lamp for 24 hours.

The material thus obtained was dissolved in 84 ml of methanol with stirring and heating to reflux. The solution is then filtered and the mother liquor is slowly cooled with stirring. Crystals slowly precipitate during cooling. To complete the crystallization, the mixture is cooled to 0 ° C. The precipitated crystals are filtered off and washed twice with 8 ml of methanol each time.

Thus, 6.6 g of the title compound are obtained. Yield 63%. The purity of the product is 99.5%, the amount of 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one formed as a byproduct in the reaction is less than 0 , 5%.

Industrial usability

The method of the present invention relates to a compound which is a pharmaceutical intermediate in the preparation of sertraline, a known drug formulation used to treat mental depression; it is therefore important for the pharmaceutical industry.

Claims (7)

PATENT CLAIMS A process for the preparation of high purity 4- (3,4-dichlorophenyl) -3,4-dihydro-1 ( 2H) -naphthalen-1-one according to general formula I: by reacting o-dichlorobenzene and alpha-naphthol in a solvent environment in the presence of a FrededCrafts catalyst, characterized in that it comprises crystallizing the crude reaction product of formula I in at least one of polar solvents and at least one of the worst solvents, the crystallization step may be carried out, if appropriate, in a certain preferred order and wherein the amount of 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one by-product according to the general formula Π: is less than 1%. -152. A process for the preparation of a highly pure 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one according to the general formula I according to claim 1, characterized in that the solvent will use a Cu alkanol. A process for the preparation of high purity 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one according to the general formula I according to claim 1, characterized in that methanol is used as the polar solvent. A process for the preparation of high purity 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one according to the general formula I according to claim 1, characterized in that it is not broken the solvent will use a C 10 alkane or ether or a mixture of solvents containing such a solvent. A process for the preparation of a highly pure 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one according to the general formula I according to claim 4, characterized in that n-hexane or methyl tert-butyl ether is used as the nonpolar solvent. A process for the preparation of high purity 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one according to the general formula I according to any one of claims 1 to 5, characterized in that The method according to claim 1, characterized in that it comprises crystallization of the crude product of the general formula I, first from a polar solvent and then from a non-polar solvent or from a mixture of solvents containing a non-polar solvent. A process for the preparation of high purity 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one according to the general formula I according to any one of claims 1 to 6, characterized in that The amount of by-product of formula II is less than 0.5%.