SK16482000A3 - Process for the preparation of sertraline and its 1,r-stereoisomer - Google Patents

Abstract

The invention relates to a process for the preparation of cis-(1R, 1S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalene-1-amine of formula (I) and pharmaceutically acceptable acid addition salts thereof by reducing (+/-)-4-(S,R)-[(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1-ylidene]-methylamine of formula (II) in the presence of a palladium catalyst and if desired converting the base of formula (I) obtained into a pharmaceutically acceptable acid addition salt thereof which comprises using a palladium catalyst applied on a carrier, containing 5-30 % by weight of palladium and pre-treated with an alkali halide. The compound of formula (I) is a useful pharmaceutical active ingredient.

Description

A process for the preparation of sertraline and its 1, R-stereoisomer

Technical field

The invention relates to a new and improved process for the preparation of a pharmaceutical active ingredient. In particular, the invention relates to a process for the preparation of cis- (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalen-1-amine and its pharmaceutically acceptable addition salts with acids.

BACKGROUND OF THE INVENTION

Cis- (1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalene-1-amine hydrochloride of formula

is a drug suitable for the treatment of mental depression and its 1NN name is sertraline The chemical name of sertraline is cis- (1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4 tetrahydro-1-naphthalene amine.

Hitherto known compounds of the formula I are possible

(I) prepared by reducing (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalene-1- ylidenemethylamine of formula II

The compound of formula I contains two asymmetric centers and can exist in 4 stereoisomeric forms. Said forms correspond to formulas 1a-1d.

(1a) db) (1c) cis-1S cis-1R trans-1S

trans-1 R

To date, the reduction of the compound of formula II can be carried out in toluene as the reaction medium using sodium borohydride [Welch, W.M.Tsai, J.Med.Chem. 27, 1508 (1984)]. Said reduction with borohydride affords a 1: 1 diastereomeric mixture of cis 1S, 1R (1a and Ib) and trans 1S, 1R (Ic and Id) diastereomers, which can be separated by chromatographic methods.

According to EP 30081, sertraline is prepared from a mixture of cis- (1R) and cis- (1S) enantiomers. The enantiomeric mixture forms salts with R-mandelic acid, whereby the cis (1S) -enantiomer salt with R-mandelic acid precipitates while the salt of the cis- (1R) -enantiomer with R-mandelic acid remains in solution. A base is formed from the cis- (1S) -enantiomeric salt of the mandelic acid in isolated pure form by addition of an alkaline agent and by addition of hydrochloric acid, the cis- (1S) -stereoisomer (sertraline) hydrochloride.

According to U.S. Pat. No. 4,536,518 the compound of formula II is reduced with molecular hydrogen in the presence of 10% palladium on activated carbon catalyst, wherein the reaction is carried out at atmospheric pressure and in tetrahydrofuran environment. The sertraline end product is cis-isomer, it is desirable to achieve a final cis / trans isomer ratio as high as possible. Sertraline is isolated by separation of the obtained cis-racemate. In reproducing the process of U.S. Pat. No. 4,536,518, the present inventors have found that in the above reaction, in addition to the stereoisomers of formulas Ia-Id, monochlorinated compounds of formulas III and IV are also formed.

in an amount of about 8% and a dechlorinated compound of formula V

in an amount of about 3%. The separation of these by-products is minor on the one hand, but on the other hand their formation reduces the yield of the desired compound.

SUMMARY OF THE INVENTION

It is an object of the invention to eliminate the drawbacks of the known methods and to provide a higher cis / trans stereoisomer ratio than can be achieved by the known methods, and also to suppress the formation of by-products.

The above objects are solved by the method according to the invention.

The invention provides a process for the preparation of cis- (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalen-1-amine of formula (I) (1a and 1b) and pharmaceutically acceptable acid addition salts thereof, by reduction of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] methylamine of the formula II in the presence of palladium catalyst and, if desired, converting the obtained base of formula I (Ia and 1b) to pharmaceutically acceptable acid salts, said process comprising using a supported palladium catalyst wherein the palladium content is 5-30% by weight and the catalyst is treated with an alkali halide prior to use metal.

The present invention is based on the finding that the diastereoselectivity of the reaction can be significantly increased by carrying out catalytic hydrogenation of the compound of formula II in the presence of a palladium catalyst pretreated with the process of the invention. The method according to the invention achieves a cis / trans ratio of 85-95 / 15-5 (in%).

The invention is also based on the further finding that by hydrogenating a compound of formula II in the presence of a palladium catalyst pretreated by the process of the invention, the formation of by-products of formulas III, IV and V is suppressed. When carrying out the catalytic hydrogenation according to the invention, the total amount of said by-products impurities in the reaction mixture is below 0.5%.

The catalyst used in the process of the invention is a supported palladium catalyst containing preferably 5-30% by weight of palladium relative to the carrier calculated on the dried carrier. Activated carbon or barium sulphate is used as the palladium carrier, preferably activated carbon.

The palladium / activated carbon catalyst is preferably treated with potassium halide or sodium halide prior to use. Preferably, potassium chloride, potassium bromide, potassium fluoride, potassium iodide or sodium iodide may be used. Said alkali metal halide is used in an amount of 0.005-5 g, preferably 0.05-0.5 g per 1 g of palladium.

The alkali metal halide is preferably used in the form of a solution prepared with a lower alkanol, water or a mixture of said components. As the lower alkanol, straight-chain or branched lower alkanols having 1 to 4 carbon atoms (e.g. methanol, ethanol, propanol, isopropanol or butanol) can be used. In a particularly preferred embodiment of the invention, an alkali metal halide is used in the form of a solution in water or in a mixture of water and methanol or water and ethanol.

In a preferred embodiment of the invention, the catalyst is pretreated in the presence of a starting reaction component, i. (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-l (2H) -naphthalene-l-ylidene] -methyl-amine. This embodiment can advantageously be carried out in such a way that the solution of the starting component, i.e. the (±) -4- (S, R) - [(3,4-Dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] methylamine is first added with an aqueous-alkanolic alkali metal halide solution and then the catalyst . In an alternative embodiment of the process, the palladium catalyst is first treated with an alkali metal halide solution and then added to the reaction mixture.

As the solvent of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) naphthalen-1-ylidene] methylamine, and polar protic or aprotic solvents. Ethers (e.g. tetrahydrofuran, dioxane, diethyl ether), lower alkyl esters (e.g. ethyl acetate), chlorinated hydrocarbons (e.g. dichloromethane, chloroform) or lower alkanols (e.g. methanol, ethanol, etc.) can be used as the reaction medium. Particularly preferred for use in the reaction medium are tetrahydrofuran, ethanol, dichloromethane or ethyl acetate.

The reaction is preferably carried out at a temperature of 0 - 150 ° C, preferably at a temperature of 10 - 100 ° C.

The hydrogenation can be carried out at a pressure of 1 - 25 atm (1-25 x ^{10 5} Pa), preferably at a pressure of 1 - 10 atm (1 - 10 x 10 ⁵ Pa).

In a preferred embodiment of the invention, the process is carried out in the following manner: starting component of the reaction, (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] -methylamine is dissolved in ethanol, tetrahydrofuran, dichloromethane or ethyl acetate, then an alkali metal halide solution prepared in a mixture of water and methanol or a mixture of water and ethanol is added, followed by the addition of palladium catalyst on activated carbon. The hydrogenation is carried out with stirring at room temperature and atmospheric pressure.

The reaction time is determined in preliminary experiments depending on stirring.

The reaction mixture can then be worked up in various ways. Preferably, the catalyst is removed by filtration or centrifugation, and then a pharmaceutically acceptable salt is precipitated from the base-containing filtrate of the compounds of formulas Ia-Id by addition of the corresponding acid, and the precipitated salt is isolated by filtration or centrifugation.

In a preferred embodiment of the invention, the hydrochloride salt is precipitated by treatment with hydrochloric acid. However, other pharmaceutically acceptable salts (e.g., sulfate, nitrate, phosphate, acetate, tartrate, maleate, fumarate, succinate) may be prepared.

The preparation of the salts is carried out by methods generally known.

The method according to the invention has the following advantages:

the obtained cis / trans ratio in the prepared compound of formula I is highly preferred; the desired cis isomers are produced in a higher ratio than is possible with the known processes;

the amount of monochlorinated and dechlorinated derivatives is reduced; the formation of undesirable by-products is inhibited;

cis (±) racemate having high purity is prepared;

From the cis (±) racemate prepared, sertraline of high purity can be prepared very easily as the final product.

Further details will be apparent from the following examples, but the invention is not limited to the examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) naphthalen-1-ylidene] -methylamine in 120 ml of tetrahydrofuran is added 7 5 ml of a 1: 1 mixture of water and methanol containing 60 mg of potassium chloride. 1 g of palladium catalyst (palladium content 8%; carbon content 28%; water content 64%) is then added. Then the reaction mixture is purged with nitrogen stirring and then hydrogenated at atmospheric pressure at room temperature. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product is filtered off. 10.3 g of cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalene-1-amine hydrochloride are obtained. Yield 91%, mp: 280-283 ° C.

Example 2

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] -methylamine in 200 mL of ethanol is added 20 mL of of a mixture of water and ethanol in a ratio of Γ. 1 containing 60 mg of potassium chloride. Then 0.85 g of palladium catalyst (palladium content 8%; carbon content 28%; water content 64%) is added. Then the reaction mixture is purged with nitrogen stirring and then hydrogenated at atmospheric pressure at room temperature. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product was filtered off and recrystallized from methanol-water. There was thus obtained cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalene-1-amine hydrochloride (8.25 g). Yield 74%, mp: 282-285 ° C.

Example 3

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-l (2H) _b b naphthalen-1-ylidene-methylamine in 150 ml of ethyl acetate was added 15 ml of a 1: 1 mixture of water and methanol containing 60 mg of potassium chloride. Then 1 g of palladium catalyst (palladium content 8%; carbon content 28%; water content 64%) is added. Then the reaction mixture is purged with nitrogen stirring and then hydrogenated at atmospheric pressure at room temperature. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product is filtered off and recrystallized from a mixture of methanol and water. There was thus obtained 7.58 g of cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalen-1-amine hydrochloride. Yield 68%, mp: 282-285 ° C.

Example 4

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] -methylamine in 150 ml of tetrahydrofuran is added 9 g. ml of a 1: 1 mixture of water and methanol containing 23 mg of potassium chloride. 1 g of palladium catalyst (palladium content 8%; carbon content 28%; water content 64%) is then added. Then the reaction mixture is purged with nitrogen stirring and then hydrogenated at atmospheric pressure at room temperature. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product is filtered off and recrystallized from methanol-water. There was thus obtained 8.83 g of cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-naphthalen-1-amine hydrochloride. Yield 79%, mp: 282-285 ° C.

Example 5

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) naphthalen-1-ylidene] -methylamine in 150 mL of tetrahydrofuran was added 10 ml of a 1: 1 mixture of water and methanol containing 50 mg of potassium fluoride and 1.0 g of palladium catalyst on activated carbon (palladium content 8%; carbon content 28%; water content 64%). Then the reaction mixture is purged with nitrogen stirring and then hydrogenated at atmospheric pressure at room temperature. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product is filtered off and recrystallized from methanol-water. There was thus obtained cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalen-1-amine hydrochloride (7.38 g). Yield 66%, mp: 282-285 ° C.

Example 6

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] -methylamine in 150 ml of tetrahydrofuran is added 1. 5 ml of a 1: 1 mixture of water and methanol containing 24 mg of sodium iodide and 1.0 g of palladium catalyst on activated carbon (palladium content 8%; carbon content 28%; water content 64%) Then the reaction mixture is purged with nitrogen and then hydrogenated at atmospheric pressure at room temperature. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product is filtered off. There was thus obtained cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalen-1-amine hydrochloride (9.28 g). Yield 83%, mp: 280-283 ° C.

Example 7

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] -methylamine in 150 ml of ethanol is added 1. 5 ml of a 1: 1 mixture of water and methanol containing 27 mg of potassium iodide and 1.0 g of palladium catalyst on activated carbon (palladium content 8%; carbon content 28%; water content 64%). Then the reaction mixture is purged with nitrogen stirring and then hydrogenated at atmospheric pressure at room temperature. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product is filtered off and recrystallized from methanol-water. There was thus obtained 8.04 g of cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalene-1-amine hydrochloride. Yield 72.1%, mp: 282-285 ° C.

Example 8

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] -methylamine in 175 ml of tetrahydrofuran is added 0 5 ml of a mixture of water and methanol v1 containing 9 mg of potassium iodide and 1,0 g of palladium catalyst on activated carbon (palladium content 8%; carbon content 28%; water content 64%). Then the reaction mixture is purged with nitrogen stirring and then hydrogenated under 3 bar pressure at room temperature. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product is filtered off. 10.3 g of cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalene-1-amine hydrochloride are obtained. Yield 91%, mp: 280-283 ° C.

Example 9

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] -methylamine in 150 ml of ethyl acetate was added 1 5 ml of a 1: 1 mixture of water and methanol containing 27 mg of potassium iodide and 1.0 g of palladium catalyst on activated carbon (palladium content 8%; carbon content 28%; water content 64%). Then the reaction mixture is purged with nitrogen stirring and then hydrogenated at atmospheric pressure at room temperature. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product is filtered off and recrystallized from methanol-water. 6.91 g of cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalene-1-amine hydrochloride are obtained. Yield 62%, mp: 282-285 ° C.

Example 10

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] -methylamine in 150 mL of tetrahydrofuran was added 1.5 ml of a 1: 1 mixture of water and methanol containing 27 mg of potassium iodide, 1.5 ml of a 1: 1 mixture of water and methanol containing 12 mg of potassium chloride and 1.0 g of palladium catalyst on activated carbon (palladium content) 8%; 28% carbon14; 64% water). Then the reaction mixture is purged with nitrogen stirring and then hydrogenated at atmospheric pressure at room temperature. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product is filtered off and recrystallized from a mixture of methanol and water. 10.3 g of cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalen-1-amine hydrochloride are obtained. Yield 91%, mp: 282-285 ° C.

Example 11

To a solution of 10 g of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) naphthalen-1-ylidene] -methylamine in 175 ml of tetrahydrofuran is added 0 5 ml of a 1: 1 mixture of water and methanol containing 10 mg of potassium iodide and 1.0 g of palladium catalyst on activated carbon (palladium content 8%; carbon content 28%; water content 64%). Then the reaction mixture is purged with nitrogen stirring and then hydrogenated at 80 ° C at 8 bar. The hydrogenation is allowed to proceed until the starting imine is consumed in the reaction mixture.

After completion of the hydrogenation, the catalyst was filtered off and the filtrate was acidified at room temperature with concentrated aqueous hydrochloric acid. The precipitated product is filtered off. 10.3 g of cis (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalene-1-amine hydrochloride are obtained. Yield 91%, mp: 280-283 ° C.

Claims (7)

PATENT CLAIMS A process for the preparation of cis- (1R, 1S) -N-methyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-1-naphthalen-1-amine of formula I and its pharmaceutically acceptable addition salts with acids, reducing (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] methylamine of formula II in the presence of a palladium catalyst, and if desired, converting the prepared base of formula (1) into a pharmaceutically acceptable acid addition salt thereof, said process comprising using a palladium catalyst on a support containing 5 to 30% by weight palladium pretreated with an alkali metal halide. Process according to claim 1, characterized in that it comprises the use of a palladium catalyst pretreated with potassium chloride, potassium fluoride, potassium iodide or sodium iodide or a mixture thereof, preferably with potassium chloride or potassium iodide or a mixture thereof. A process according to any one of claims 1 and 2, characterized in that it comprises pretreating the palladium catalyst in a solution prepared with a lower alkanol, water or a mixture thereof. Process according to any one of claims 1 to 3, characterized in that it comprises pretreating the palladium catalyst with an alkali metal halide in the presence of (±) -4- (S, R) - [(3,4-dichlorophenyl) -3,4 -dihydrol (2H) -naphthalen-1-ylidene] -methylamine of formula II. Process according to any one of claims 1 to 4, characterized in that the catalytic hydrogenation is carried out in a polar protic or aprotic solvent. The process according to claim 5, characterized in that an ether, preferably tetrahydrofuran; a lower alkyl ester (wherein the alkyl contains 1 to 4 carbon atoms), preferably ethyl acetate or a lower alkanol (containing 1 to 4 carbon atoms), preferably ethanol. Process according to any one of claims 1 to 6, characterized in that the hydrogenation is carried out at a temperature of 0 to 150 ° C, preferably at 10 to 100 ° C. Process according to any one of claims 1 to 7, characterized in that the hydrogenation is carried out at a pressure of 1 to 25 atm (1 to 25.10 ⁵ Pa), preferably at a pressure of 1 to 10 atm (1 to 10.10 ⁵ Pa).