SK284671B6 - Process for the preparation of highly pure 4-(3,4-dichlorophenyl)-3,4,dihydro-1(2H)-naphtalene-1-one - Google Patents

Abstract

Process for the preparation of highly pure 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphtalene-1-one of formula (I) by reacting o-dichlorobenzene and alpha-naphtol in a solvent as medium in the presence of a Friedel-Crafts catalyst which comprises crystallising the crude reaction product of formula (I) at least once from a polar solvent and at least once from an apolar solvent, whereby said crystallisation steps can be carried out in optional order of succession. The compound of formula (I) is obtained in highly pure form with the content of the by-product 4-(2,3-dichlorophenyl)-3,4-dihydro-1(2H)- naphtalene-1-one of formula (II) decreased below 1 % by weight. The compound of formula (I) is used as a pharmaceutical intermediate.

Description

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 of formula (I):

BACKGROUND OF THE INVENTION

The compound of formula (I) is a valuable intermediate which 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 drug that is used to treat mental depression. The chemical name of sertraline is cis- (1S, 4S) -A-methyl-N- (3,3-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthaleamine.

Several methods are known for preparing the compound of formula (I). The method described in U.S. Pat. No. 4,536,518, is shown in Reaction Scheme 1. In the first step, o-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 Stobbe condensation by reaction with dictyl succinate. In the next step of the reaction sequence, hydrolysis and decarboxylation, e.g. in the presence of hydrogen bromide. The mixture of E- and Z-4,4-diarylbutanoic acids thus obtained is reduced with hydrogen in the presence of a catalyst. Acid chlorides are obtained from 4,4-diarylbutanoic acid derivatives which are formed with thionyl chloride and then converted to the thionyl chloride.

4- (3,4-dichlorophenyl) -3,4-dihydro-1 (1H-naphthalen-1-one by cyclization in the presence of aluminum chloride. %.

According to the method of Williams [Chem. and Ind. 316 (1990)], an increase in yield to 33% can be achieved.

U.S. Pat. No. 4,777,288 describes an improved process for the preparation of suitably substituted 4,4-diphenylbutanoic 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-dichlorophenyl) -4-ketobutanoic acid, which was reduced with sodium borohydride, after which the butirolactone derivative formed in situ was subjected to Friccl-Crafts reaction with benzene without 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. The drawback 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 butyrolactone 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 strong acid, 98% sulfuric 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 polytrifluoro monochlorethylene - Daiflon. The disadvantage of this is that the Daiflon apparatus is very expensive. A further disadvantage of this is that hydrogen fluoride is a very corrosive substance that can only be used on an industrial scale on the basis of very strict requirements and demands for expensive precautions. The use of trifluosulfonic acid can also give a very good yield. However, this reagent is too expensive, so the process is uneconomical in industrial scale production. When the reaction is carried out in the presence of sulfuric acid, the yield is only 53%, a value which does not exceed that disclosed in U.S. Pat. 4,777,288.

According to EP-A 346 226, 4-aryl-substituted-1-tetralone derivatives are prepared by reacting an-n-nole with the corresponding disubstituted benzene in the presence of one of the aluminum halide catalysts.

A mixture of 1 mol of α-naphthol, 1.3 mol of o-dichlorobenzene and 2.1 mol 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 formula (I) is obtained in a yield of 61% and a GC purity of 98 to 99%.

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 of formula (I) and 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one of formula (II) )

O o Λ / Ci r

Cl (Π) 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 because if the amount of the 2,3-isomer of the compound of formula (II) exceeds 1%, then 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% by weight.

According to the invention, the object of the invention is achieved by subjecting the crude reaction product of formula (I) to crystallization as described below, while reducing the amount of the isomer of formula (II) below an acceptable level.

According to the present invention there is also provided a process for the preparation of highly pure 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one of formula (I):

by reacting o-chlorobenzene and α-naphthol in a solvent environment 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 a non-polar solvent, these crystallization steps being carried out in any order.

4- (2,3-Dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one by-product amount of formula (II)

falls below 1% by weight.

The present invention is based on the discovery that a novel 2,3-isomer of formula (II), which has not been described in the art, was isolated and identified by spectroscopic methods and a suitable method for eliminating this contamination was developed. A detailed procedure of capillary gas chromatography and high performance liquid chromatography for the qualitative determination of side-by-side substances has been developed for the isomers of formulas (I) and (II). This method makes it possible to check the purity of the isomer and serves as the basis for the detailed elaboration of the purification process of the resulting highly pure compound of formula (I).

In the process of the present invention, it is preferred to use a C _1-3 alkane (methanol, ethanol, n-propanol or isopropanol) as the polar solvent.

In the method of the invention may be used as polar solvents _{C6., 0} alkane directly (for example n-hexane, n-heptane, / 1-octane) or an ether (e.g., dioxane, diethyl ether, methyl zerc-butyl ether, etc.). . In this manner, 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 t-hexane and ethyl acetate or n-hexane and isopropanol) in the process according to the invention.

In the process according to the invention, the order of the individual crystallization steps is arbitrary. It is possible to crystallize the crude product first from a polar solvent and then from a non-polar solvent or vice versa. In a preferred embodiment of the process, the crude product is preferably crystallized first from a polar solvent and then 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 formula (I) contaminated with less than 1% by weight, preferably less than 0.5% by weight of the 2,3-isomer of formula (II).

The crude product of formula (1), which is used as the starting material, can be prepared by reacting o-dichlorobenzene and α-naphthol in a solvent medium and in the presence of a Friedel-Crafts catalyst.

An excess of o-dichlorobenzene reagent, which has the role of solvent, is preferred. Preferably, the reaction may be carried out in the absence of an additional solvent, in excess of the o-dichlorobenzene used as reagent. It is also possible to carry out the reaction in an inert solvent. For example, nitrobenzene, dichloroethane, trichloroethane or carbon disulphide may be used for this purpose.

The reaction is carried out in the presence of a Fricdcl-Crafts catalyst. Preference is given to using aluminum chloride, aluminum bromide, stannous chloride or antimony fluoride, aluminum chloride being preferred.

The reaction can be advantageously carried out using the components α-naphthol: Friedel-Crafts catalyst: o-dichlorobenzene in a ratio of 1: 2: 3 to 1: 10: 100. A particularly preferred molar ratio of these components is 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 several hours; the reaction time is usually three 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 (for example, 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 in carrying out on an industrial scale, whereby a highly pure compound of formula (I) is obtained which contains less than 1% by weight of the contaminating isomer of formula (II).

The following are examples of embodiments of the present invention which are intended to illustrate the invention in more detail, but do not limit the scope or scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Physical properties of the desired 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one of formula (I): M.p .: 101-102 ° C

H

4.15

4.05

Cl

24.35

25.15

Elemental analysis: C ₁₆ H 12 Cl ₂ O

C calculated (%) 66.00 found (%) 65.77

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 in Figure 4): [8.12 dd (8Hz, 2Hz) (1H), (H-8)]; [7.3-7.5 m (3H) (H-5, H-6, H-7)]; [7.24 d (1H) (H-2 ')]; [6.95 m (2H), (H-5 ') (H-6 ')]; [4.28 d (J _M 8Hz, J 4.5 Hz _eq) (H), (H-4) J; [2.68 m (1H) (H-3); 2.3m (1H) (H-3)].

¹³ C-NMR (CDCl ₃ ): δ ppm (numbering in Figure 4): (197.2 Cl); (144.9 _C-4a); (133.8 C-6); (132.8 C-3 '); (132.7 C-4 '); (130.99 C-1 '); (130.57 C-2 '); (130.49 C-5 '); (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).

MS AP Cl 291.

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

Melting point: 66 - 70 ° C Elemental analysis: C ₁₆ H ₁₂ Cl ₂ O

CH calc. (%) 66.004.15 found (%) 65.674.01

Cl

24.35

24,10

JR (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 in Figure 4): [8.13 dd (8Hz, 2Hz) (1H), (H-8)]; [7.37-7.48 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 < 6 & gt _; Hz, J _eq 4.7Hz) (1H), (H-4)]; [2.66 m (2H) (H-2)]; [2.39 m (2H) (H-3)].

¹³ C-NMR (CDCl ₃ ): δ ppm (numbering of Figure 4): (197.7 Cl); (144.8 _C-4a); (144.3 C-8J; (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).

MS AP ⁺ Cl 291.

The following gas chromatography (GC) and high performance chromatography (HPLC) conditions were used to separate the two isomers.

GC:

GC Shimadzu GC9A Column: SUPELCO SPB5 (15m x 0.2mm! D-FD: 0.2µm) Temperature: 50 to 250 ° C, Grades: 10 ° min.

carrier gas: N ₂ (19.8 cm / s) injection: at 250 ° C 0.25 µl solution (MeOH) detector: FID temperature 270 ° C retention time of 2,3-isomer; 11.08 min. retention time of 3,4-isomer: 11.83 min.

HPLC:

The HPLC method was used to check the standards.

Column: Cyclobond 1 (b-cyclodextrin) 5mm, 25cm x 4mm (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 Injection volume: 20 ml (4-5 mg / dissolved in 10 ml acetonitrile, diluted with eluent) Calibration: 1.716 mg / ml

Retention time of 2,3-isomer: 5.57 minutes Retention time of 3,4-isomer: 6.88 minutes

Example 1

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

To a mixture of 5.19 g (36 mmol) of alpha-naphthol and 30 g of 1,2-dichlorobenzene was added 15 g (112 mmol) of anhydrous aluminum chloride. The reaction mixture is 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 to reflux. The solution is then filtered and the mother liquor is slowly cooled with stirring. During cooling, crystals slowly precipitate - fall out. Cool the mixture to 0 ° C to complete crystallization. The precipitated crystals are filtered off 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. Cool the mixture to 0 ° C to complete crystallization. The precipitated crystals are filtered off and washed twice with 8 ml of n-hexane each time.

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% weight.

Example 2 4- (3,4-Dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one

To a mixture of 5.19 g (36 millimoles) of α-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.

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. Cool the mixture to 0 ° C to complete crystallization. The precipitated crystals are filtered off 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 a 9: 1 mixture of n-hexane and ethyl acetate under reflux until the whole product had dissolved. Roz4

The flow is then filtered and the mother liquor is slowly cooled with constant stirring. Cool the mixture to 0 ° C to complete crystallization. The precipitated crystals are filtered off and washed twice with 8 ml of n-hexane each.

Thus 7.0 g of the title compound are obtained in a yield of 68%. The purity of the substance obtained is 99.5%, the amount of 4- (2,3-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one formed as a by-product in the reaction is less than 0, 5% by weight.

Example 3 4- (3,4-Dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one

To a mixture of 5.19 g (36 millimoles) of α-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.

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 n-hexane while heating under a reflux condenser until all the product has gone into solution. Then the solution is filtered and the mother liquor is slowly cooled while stirring. Crystals slowly precipitate during cooling. Cool the mixture to 0 ° C to complete crystallization. The precipitated crystals were filtered off and washed twice with 8 ml of ice-cold methanol each time.

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. Cool the mixture to 0 ° C to complete crystallization. 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 % By weight.

Example 4

4- (3,4-Dichlorophenyl) -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 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 to reflux. The solution is then filtered and the mother liquor is slowly cooled with stirring. Crystals slowly precipitate during cooling. Cool the mixture to warm 0 ° C to complete crystallization. The precipitated crystals are filtered off 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. Cool the mixture to 0 ° C to complete crystallization. The precipitated crystals were 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 % by weight.

Example 5 4- (3,4-Dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one

To a mixture of 5.19 g (36 millimoles) of α-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 are filtered, washed with 10 ml of 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. Cool the mixture to 0 ° C to complete crystallization. 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 % By weight.

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 that is used to treat mental depression; it is therefore important for the pharmaceutical industry.

Claims (6)

PATENT CLAIMS A process for the preparation of high purity 4- (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-one of formula (I): by reacting o-dichlorobenzene and α-naphthol in a solvent environment in the presence of a Friedel-Crafts catalyst, characterized in that the crude reaction product of formula (I) is crystallized at least once from a polar solvent and at least once from a semi-solvent. in any order. 2. The process of claim 1 wherein the polar solvent is alkanol. 3. A process according to claim 2 wherein the polar solvent is methanol. 4. The method of claim 1, characterized in characterized in that as non-polar solvent is .io _C6 alkane or an ether. 5. The process of claim 4 wherein the non-polar solvent is n-hexane or methyl tert-butyl ether. Process according to any one of claims 1 to 5, characterized in that the crude product of formula (I) is crystallized first from a polar solvent and then from a non-polar solvent.